Genetic Disorders Among Arab Populations

Genetic Disorders Among Arab Populations . Ahmad S. Teebi Editor Genetic Disorders Among Arab Populations Second E...

Author: Ahmad S. Teebi

1840 downloads 8555 Views 8MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form

DOWNLOAD PDF

Genetic Disorders Among Arab Populations

.

Ahmad S. Teebi Editor

Genetic Disorders Among Arab Populations Second Edition

Editor Ahmad S. Teebi Weill Cornell Medical College in Qatar Qatar Foundation Doha Education City Qatar [email protected]

First edition published by Oxford University Press, 1997. ISBN 978-3-642-05079-4 e-ISBN 978-3-642-05080-0 DOI 10.1007/978-3-642-05080-0 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2010932676 # Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Cover design: WMXDesign GmbH, Heidelberg, Germany Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

To my parents, brothers and sisters, and my children Saeed, Basel, Asil and Asma and the whole Arab Family.

.

Acknowledgements

The editor is grateful to the authors of the individual chapters who welcomed the initiative and were keen to provide their contributions on time. Special thanks to Professor Charles R. Scriver, who made the effort to write the foreword to this book. I am thankful to my wife Mrs. Amal Teebi for her encouragement and support and to Saeed Teebi for his assistance in some parts of the manuscript. The assistance of Mrs. Mariette D’ Souza, Gemma Fabricante and Martin Marion from Weill Cornell Medical College in Qatar, in preparation of some chapters and maps, is greatly appreciated. I express my gratitude also to Springer press and in particular to Andrea Pillman and Ursula Gramm for their help in the publication of this book.

vii

.

Foreword

Genetic Disorders among Arab Populations by Ahmad S. Teebi and co-authors appears here in its second edition. The first edition (in 1997) shows how one could tap into a rich load of information on human and medical genetics, a source probably too little mined until now. One can be pleased that the first edition was warmly welcomed by Prof. Victor McKusick, the author of the Foreword to that edition. The authors of this edition have taken pains to remind us again that persons and patients, and the corresponding families and communities, represent a stream of human history and a region of the world that embraces ethnic, cultural and religious attributes more diverse than we might have imagined, yet with a commonality that gives “coherence to an account of it and a usefulness [when it is considered] as a unit” (VA McKusick, Foreword to first edition). Arab populations have their repertoire of genetic disorders, both universal and particular. Genetic diversity within these source populations, along with the fact that rates of inbreeding are often high and family sizes are often large, constitutes conditions that facilitate the emergence and detection of phenotypes explained notably by autosomal recessive inheritance, in which case, the use of homozygosity gene mapping will facilitate discovery of the corresponding genes. Meanwhile, the interval between the publication of the first and second editions of genetic disorders has witnessed emergence of the Middle East Genetic Association of America and the creation of ethnic (Arabic)-related, locus-specific mutation databases to serve as nodes in the network of related interests. Driven by relevant research interests, initiatives are emerging in the Arabic world to address issues such as taxonomy and fine-grained descriptions of variant disease phenotypes, their origins, distributions and frequencies in populations, their molecular infrastructure, and with a better knowledge of their pathogenetic processes, better opportunities to address counseling, prevention and treatment. The authors of the second edition have again chosen not to provide an exhaustive list of relevant genetic disorders; that can be done eventually when there is a curated online database. Rather, the authors again highlight various issues and perspectives that can be seen through the windows offered by a number of prevalent genetic disorders in the Arabic world. Accordingly, the attitudes and responses generated ix

x

Foreword

by these problems, as they are influenced by Islamic perspectives, wisely constitute the recurrent underlying theme in the book, because the cultures and faith of the Arabic communities yield quite different responses and perspectives from the corresponding encounters in the non-Islamic world. It is a particular form of a larger issue attracting notice (viz. Suther and Kiros, Genet Med 11:655–662, 2009; Krotoski et al. Genet Med 11:663–668, 2009). The authors use prevalent, pan-Arabic disorders (Table 1.1), along with a selection of rarer “founder” disorders (Table 1.2), to delve into the biological explanations for their occurrence and impact. These disorders set the scene to explain important demographic issues, the related population dynamics, indicators of individual collective health, and the impacts of endogamy and consanguinity on the frequencies and distribution of the disorders. Familial Mediterranean Fever, for example, illustrates these perspectives well and is highlighted accordingly. The authors examine 15 different countries and regions harbouring Arabic populations, to discern issues with more specific aspects. One might say that in this diversity, there is a unity and vice versa. Consolidations of the expanding information on genetic disorders in Arabic populations improves our knowledge of them. Whether that leads to better wisdom, in how we help the individuals, families and communities harboring them, is, I am convinced, a sincere motivation to pursue the course undertaken by Professor Teebi and his co-authors. It has indeed yielded this enhanced second edition of Genetic Disorders among Arab Populations. Charles R. Scriver MDCM FRS Alva Professor Emeritus of Human Genetics Professor of Pediatrics and Biology McGill University Montreal, Canada

Contents

Part I 1

Introduction

Introduction: Genetic Diversity Among Arabs . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Ahmad S. Teebi

Part II

Demography, Economy, and Genetic Services in Arab Countries

2

Arab Demography and Health Provision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Sulayman S. Al-Qudsi

3

Influences of Systems’ Resources and Health Risk Factors on Genetic Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Amal A. Saadallah and Ahmad S. Teebi

4

Endogamy and Consanguineous Marriage in Arab Populations . . . . . . 85 Alan H. Bittles and Hanan A. Hamamy

Part III

Selected Disease Entities Prevalent Among the Arabs

5

Familial Mediterranean Fever and Other Autoinflammatory Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 Hatem El-Shanti and Hasan Abdel Majeed

6

Muscular Dystrophies and Myopathies in Arab Populations . . . . . . . . . 145 Mustafa A.M. Salih

7

New Syndromes First Reported Among Arabs . . . . . . . . . . . . . . . . . . . . . . . . 181 Ahmad S. Teebi

xi

xii

Contents

Part IV

Genetic disorders in Arab Countries Geographic Regions

8

Genetic Disorders in Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Samia A. Temtamy, Mona S. Aglan, and Nagwa A. Meguid

9

Genetic Disorders in Ancient Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Chahira Kozma

10

Genetic Diseases in Iraq . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Hanan Ali Hamamy

11

Genetic Disorders in Jordan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 Majed Dasouki and Hatem El-Shanti

12

Genetic Disorders in Kuwait . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 Nawal Makhseed

13

Genetic Disorders in Lebanon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377 Vazken M. Der Kaloustian

14

Genetic Disorders in Libya . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443 Tawfeg Ben-Omran

15

Genetic Disorders in Morocco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455 Abdelaziz Sefiani

16

Genetic Disorders in Oman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 Anna Rajab

17

Genetic Disorders Among the Palestinians . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 Bassam Abu-Libdeh and Ahmad Said Teebi

18

Genetic Disorders in Qatar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 Ahmad S. Teebi and Tawfeg Ben-Omran

19

Genetic Disorders in Saudi Arabia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531 Zuhair N. Al-Hassnan and Nadia Sakati

20

Genetic Disorders in Sudan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575 Mustafa A.M. Salih

21

Genetic Disorders in Tunisia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 Elham Hassen and Lotfi Chouchane

Contents

xiii

22

Genetic Disorders in the United Arab Emirates . . . . . . . . . . . . . . . . . . . . . 639 Lihadh Al-Gazali and Bassam R. Ali

23

Genetic Disorders Among Jews from Arab Countries . . . . . . . . . . . . . . . 677 Efrat Dagan and Ruth Gershoni-Baruch

Part V

Cultural and Religious Attitudes Towards Genetic Issues

24

Prevention and Care of Genetic Disorders: An Islamic Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705 Aida I. Al Aqeel

25

Genetic Counseling in the Middle East . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725 Shelley J. Kennedy and Muna Al-Saffar

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741

.

Contributors

Hasan Abdel Majeed Professor Emeritus of Pediatrics, University of Jordan, Amman, Jordan Bassam Abu-Libdeh Makassed Hospital & Al-Quds University, Jerusalem, [email protected] Mona S. Aglan Professor of Clinical Genetics, Clinical Genetics Department, Human Genetics and Genome research division, National Research Centre, Cairo, Egypt, [email protected] Aida I. Al Aqeel Pediatrics, Medical Genetics and Endocrinology, Department of Pediatrics, Riyadh Military Hospital, P. O. Box 7897, Riyadh 11159, Kingdom of Saudi Arabia, [email protected], [email protected] Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh 11211, Kingdom of Saudi Arabia Lihadh Al-Gazali Department of Paediatrics, Faculty of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates, [email protected] Zuhair N. Al-Hassnan Associate Prof. of Genetics, College of Medicine, Alfaisal University Consultant, Department of Medical Genetics, MBC-75, King Faisal Specialist Hospital & Research Center, P.O. BOX 3354, Riyadh 11211, Saudi Arabia, [email protected] Bassam R. Ali Faculty of Medicine and Health Sciences, Department of Pathology, UAE University, Al-Ain, United Arab Emirates Sulayman S. Al-Qudsi Chief Economist and Head of Research Department-Arab Bank, PLC. Amman-Jordan.Shaker bin Zeid Street, Shmeisani Area, 950545, Amman, Jordan, [email protected]; [email protected] Muna Al-Saffar Certified Genetic Counsellor, Children’s Hospital Boston, MA, USA

xv

xvi

Contributors

Project Manager, Dubai Harvard Foundation for Medical Research (DHFMR), Dubai Health Care City, Dubai, United Arab Emirates Tawfeg Ben-Omran Section of Clinical and Metabolic Genetics, Qatar Medical Genetics Center, Hamad Medical Corporation, Doha, Qatar, [email protected] Alan H. Bittles Centre for Comparative Genomics, Murdoch University, South Street, Perth, WA 6150, Australia, [email protected] Lotfi Chouchane Professor of Genetic Medicine and Immunology, Genetic Medicine Department, Weill Cornell Medical College, Qatar, loc2008@qatar-med. cornell.edu Efrat Dagan Institute of Human Genetics, RAMBAM Health Care Campus and Department of Nursing, University of Haifa, Haifa, Israel Majed Dasouki Professor of Pediatrics & Internal Medicine University of Kansas, Kansas City, Kanasa, USA Vazken M. Der Kaloustian Emeritus Professor of Pediatrics and Human Genetics, Mchill University, Montreal, Quebec, Canada, [email protected] Hatem El-Shanti Director, Shafallah Medical Genetics Center, Doha, Qatar; Adjunct Associate Professor of Pediatrics, University of Iowa, Iowa City, Iowa, USA, [email protected] Ruth Gershoni-Baruch Institute of Human Genetics, RAMBAM Health Care Campus and the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Institute of Technology, Haifa, Israel, [email protected] Hanan A. Hamamy Department of Genetic Medicine and Development, Geneva University Hospital, Geneva, Switzerland (formely Al-Mustansiriyah Medical College, Baghdad, Iraq), [email protected] Elham Hassen Molecular Immuno-Oncology Laboratory, Faculty of Medicine, Monastir, Tunisia, [email protected] Shelley J. Kennedy Certified Genetic Counsellor, Ontario Newborn Screening Program & Regional Genetics Program, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada, [email protected] Chahira Kozma Department of Pediatrics, Georgetown University Hospital, 3800 Reservoir Rd N.W., Washington DC, USA, [email protected]; cck2@ gunet.georgetown.edu Nawal Makhseed Department of Pediatrics, Jahra Hospital, Ministry of Health, Kuwait, [email protected] Samia A. Temtamy Professor of Human Genetics, Clinical Genetics Department, Human Genetics and Genome, research division, National Research Centre, Cairo, Egypt, [email protected]

Contributors

xvii

Anna Rajab Consultant Clinical Geneticist, Genetic Unit, Ministry of Health, Sultanate of Oman, [email protected] Amal A. Saadallah Medical College, Ain Shams University, Cairo, Egypt, [email protected] Nadia Sakati Consultant, Department of Pediatrics, MBC-58, King Faisal Specialist Hospital & Research Center, P.O. BOX 3354, Riyadh 11211, Saudi Arabia Mustafa A.M. Salih Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia, mustafa_salih05 @yahoo.com; [email protected] Abdelaziz Sefiani Department of Medical Genetics, National Institute of Heath/ University Mohammed V Souissi, Rabat 27, Avenue Ibn Batouta, BP 769, 11400, Rabat, Morocco, [email protected] Ahmad S. Teebi Weill Cornell Medical College, Qatar Foundation, Doha, Qatar, [email protected] Samia A. Temtamy Professor of Human Genetics, Clinical Genetics Department, Human Genetics and Genome research division, National Research Centre, Cairo, Egypt, [email protected] Nagwa A. Meguid Profssor of Human Genetics, National Research Centre, Tahrir street Dokki, Giza, Egypt, [email protected]

.

Part I Introduction

Chapter 1

Introduction: Genetic Diversity Among Arabs Ahmad S. Teebi

There is perhaps no region with a richer history or a more diverse ethnic, cultural and religious makeup than the Arab world. It is the cradle of civilization and birthplace of the world’s three major monotheistic religions. Despite their heterogeneity, the Arab countries are united by their common language and location in the largest arid zone of the world: the Sahara and African deserts and their contiguous semi-arid lands. The geographical area of the Arab world covers about 14 million km2 and spans two continents, covering a distance of 6,375 km from Rabat on the Atlantic to Muscat on the Arabian (Persian) Gulf (Bolbol and Fatheldin 2005) (Fig. 1.1). Consequently, the Arab populations, currently exceeding 300 million, representing 5% of the world populations, are mainly concentrated in the relatively fertile regions, particularly along the Nile River, in the valleys of the Euphrates and the Tigris, and along the coastal area of North Africa, Syria, Lebanon and Palestine/ Israel. These four regions account for 84% of the Arab populations and only 54% of their income. The GCC countries (Gulf Co-operation Council), comprising Saudi Arabia, Kuwait, United Arab Emirates, Qatar, Bahrain and Oman, have about 45% of the income but only 10% of the Arab populations (Grissa 1994). With two thirds of the Arab countries producing oil, there is little doubt that it is the single most important factor in the region’s economic development (Raffer 2007).

Past and Present The history of the Arabs extends back more than 5,000 years. Around 3500 BC, Semitic-speaking people of Arabian origin migrated into the valley of the Tigris and Euphrates rivers in Mesopotamia, eventually becoming the Assyro-Babylonians.

A.S. Teebi Weill Cornell Medical College, Qatar Foundation, Doha, Qatar e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_1, # Springer-Verlag Berlin Heidelberg 2010

3

4

A.S. Teebi

Fig. 1.1 Map of the Arab world

Another group of Semites left the Arabian Peninsula about 2500 BC and settled along the eastern shore of the Mediterranean; some of these migrants became the Amorites and Canaanites of later times (Bram and Dickey 1993). Beginning from the seventh century, Arabs, proclaiming the new religion of Islam, ventured from the Arabian Peninsula and conquered the wide area from the Arabian/Persian Gulf to the Atlantic ocean. The Arab civilization soon became the world’s most prominent, and Arab and Islamic science and medicine flourished. Islamic medicine was based on Greek medicine and also on Quranic teachings and the model set by the prophet Mohammad in the Hadith. Islamic medical scholars and centers flourished and several authors, including Al-Ruhawi and Al-Tabari, wrote on Islamic medicine and medical ethics (Rispler-Chaim 1993). During the past few decades, good but inconsistent economic progress has been made by the Arab countries of the Middle East and North Africa. In the same period, most Arab countries have maintained high total fertility rates. Only recently have these rates declined, and only in a few Arab countries, notably Bahrain, Egypt, Tunisia and Lebanon (Faour 1989). Infant mortality has fallen by more than half and life expectancy has increased from 48 to 67 years. High inbreeding continues to prevail in most Arab countries. Education levels have improved: primary school enrollment is nearly 100%, secondary school enrollment has tripled and female enrolment has increased fivefold (World Bank 1994). Language is what unites the Arabs. Formal Arabic is the official language in all the 22 countries of the Arab League. The overwhelming majority of Arabs (over 90%) are Muslim, and predominantly Sunni. In some countries such as Iraq,

1 Introduction: Genetic Diversity Among Arabs

5

Lebanon and Bahrain, Shi’ite Muslims exist in proportions similar to or slightly higher than Sunnis. A number of Arab countries contain sizeable Christian communities; in Lebanon, for example, 43% of the population is Christian (Husseini 1994). On the health front, the region, while undergoing tremendous transformations (reduced mortality rates, the eradication of several epidemics and the improved overall health conditions) still suffers from an increased incidence of nutritional problems, malaria and tuberculosis, in addition to the rise in importance of health problems that are related to modern lifestyles – smoking, stress, heart disease, diabetes mellitus and genetic disorders. Furthermore, the interplay of culture, economics, natural endowments and man-made pollution activities results in health problems, some of which are genetically related.

Ethnic Diversity Despite its linguistic, religious and cultural cohesion, the Arab world is also rich in diversity. In addition to Muslim and Christian Arabs, the area is home to Kurds, Druze, Berber, Armenians, Circassians, Jews and other minorities. The Arabs themselves, in most parts of the Arab world, are the result of admixture with other populations in the area, through migration to or from other parts of the world, or across the borders (such as Persians, Turks, South-East Asians, Europeans and Africans). Wars throughout history, particularly the Crusades, have contributed to this unique mosaicism. Other than this mosaic of genetically heterogeneous populations, relatively homogeneous populations or isolates exist. These include some Bedouin tribes, Nubians and Druze among others.

The Arab/Muslim Family Among Arabs, descent is reckoned through males rather than females. Married men and their wives live with their father in one large household (or at least very close to him) whenever possible, and marriages with relatives are favored. Although polygamy is allowed in Islam, it is practiced only on a narrow scale and mainly with the aim of producing more children. In some societies, such as in Tunisia, polygamy is strictly controlled. Broadly speaking, the Arab man or woman values being related to a large tribe or extended kindred. He or she can often trace back his or her origin through several generations. Many tribes, in GCC countries for instance, keep family trees that contain information going back ten or more generations. The number of children per family is large, averaging more than four. The average family size that includes the parents (from 1987 to 1993) varied between five in Egypt and eight in Kuwait.

6

A.S. Teebi

Religion, Culture and Genetic Issues The Arab family, Muslim or Christian, typically has strong faith in God. Muslims believe the occurrence of disease to be God’s will, as explained in the Quran (Surah 57, pp. 22–23), “No misfortune can happen on earth or in your souls but it is recorded in a decree before We bring it into existence” (Ali 1991). Such belief helps parents to alleviate feelings of guilt by relating the reason for the child’s problem to God’s purposeful, non-questionable action, rather than to a “blind probabilistic event” (Panter-Brick 1992). In Arab countries, prenatal diagnosis is acceptable for purposes of reassurance or therapy. Termination of pregnancy, however, at any stage is absolutely forbidden (Haram), unless the mother’s life is endangered (Hathout 1972). Under Islamic law, according to some interpretations, termination of pregnancy is considered a crime (Shaltout 1959). However, couples may avoid pregnancy if they are at an unacceptably high risk of having a child with a certain genetic defect. On the other hand, while artificial insemination using the husband’s sperm (AIH) and in vitro fertilization using the husband’s sperm are acceptable (Mubah), using donor sperm is absolutely forbidden. In general, assisted reproduction using the husband’s and wife’s gametes is acceptable. Adoption has been practised since the early ages of Islam. However, “legal adoption” is not permitted (For details see Al-Aqeel 2007).

Consanguineous Marriage and Endogamy Consanguineous marriage is common in most Arab populations and is not necessarily limited to geographic or religious isolates or ethnic minorities. Unlike its largely taboo status in Western countries, the practice is deeply rooted in the Arab culture and has been over many generations. The rates are generally high. They range between 25% in Beirut (Khlat and Khudr 1984) up to 60% in Saudi Arabia and 90% in some Bedouin communities in Kuwait and Saudi Arabia (Al-Roshoud and Farid 1991; Panter-Brick 1992). An average figure of about 40% appears to be true in most Arab countries. The most common form of intermarriage is between first cousins, particularly paternal first cousins and includes double first-cousin marriage. Uncle/niece, aunt/nephew marriages are forbidden by Quran and are in fact non-existent (Teebi and Marafie 1988). Consanguineous marriage is more common among Muslims than among Christians, though it is strictly a cultural feature and not a religious prescription. In fact, and according to some religious scholars, Islam discourages consanguineous marriages, though it does not forbid it. Inbreeding is more common in rural areas than in urban regions, although it does not seem to correlate with the economic status. However, in some rich families and tribes, consanguineous marriages prevail because of the attachment of people to their families or villages and to keep the property within the family or tribe. One of the reasons favoring cousin marriage can be extrapolated from the common Arabic saying “a spouse that you know is better


7

than the one you don’t know, and a cousin takes better care of you” (Panter-Brick 1992). Another contributing factor is the popular belief that consanguineous marriage offers a major advantage in terms of compatibility of the bride and her husband’s family, particularly her mother-in-law (Jaber et al. 1994). Some studies have reported a secular decline in consanguineous marriage, for example, in Kuwait (Radovanovic et al. 1999), Saudi Arabia (Al-Abdulkareem and Ballal 1998), Jordan (Hamamy et al. 2005), and Israeli Arab and Palestinians (Jaber et al. 2000; Zlotogora et al. 2002; Sharkia et al. 2008; Assaf and Khawaja 2009). By comparison, in the UAE (Al-Gazali et al. 1997), Yemen (Jurdi and Saxena 2003) and Qatar (Bener and Alali 2006), the overall levels of consanguineous marriage, including first-cousin unions, have actually increased. This suggests that future trends may depend on the local political, economic and social factors. Similar to most Arab populations, the consanguinity rate among the semi-isolated Druze community in Israel is 49% (Freundlich and Hino 1984). On the other hand, as an exception, marriages within the clan are forbidden among the Nubian people (Bayoumi and Saha 1987), and consanguinity studies among four tribes living in western Sudan found no incidence of consanguineous marriages among the indigenous people living within the Nuba mountains. However, this may not be exactly the case of the Egyptian Nubian people of Kom Ombo.

Autosomal Recessive Disorders When a rare autosomal recessive mutation is present in a family, the chance that a disease will manifest in this family increases if a consanguineous marriage occurs and when the number of children is large. Such conditions are optimal in the Arab world, where previous observations demonstrated an increase in the frequencies of autosomal recessive conditions (Teebi 1994; Hamamy and Alwan 1994; Teebi and Teebi 2005; Al-Gazali et al. 2006). Autosomal recessive disorders among Arabs have a characteristic pattern that will be subsequently discussed according to their conspicuous features.

Hemoglobinopathies Hemoglobinopathies constitute a major health problem in Arab countries. The genes for sickle cell hemoglobin (HbS) and a and b thalassemias are found in all Arab countries with different frequencies in different Arab countries and even within different regions within the same country, as is the case in Saudi Arabia. The sickle cell trait frequency ranges from less than 1% along the Nile in Egypt to 20% or more in Siwa oasis in Egypt, Bahrain and some parts of Saudi Arabia. Generally, HbC is very rare except in Morocco, where it is twice as common as HbS. A number of new Hb variants have been reported also, including HbO-Arab,

8

A.S. Teebi

HbJ-Cairo, Hb-Riyadh and Hb-Khartoum among others. Hb S/O-Arab is a severe sickling hemoglobinopathy similar to homozygous sickle cell anemia; however, it is rarely found (Zimmerman et al. 1999). Molecular studies of HbS indicate that an independent mutation (Arab-Indian or Saudi-Indian haplotype) occurred in eastern Saudi Arabia and the Indian subcontinent region and spread from there to other parts of the Arab world, while in the western region of Saudi Arabia and North African countries, the gene may have been transported from Benin and Senegal in Africa (Benin and Senegal haplotypes). No specific ß thalassemia mutations are confined to Arabs and the Mediterranean and Asian mutations are encountered at variable frequencies. a thalassemias, however, generally result from a gene deletions.

FMF and Other Auto-inflammatory Disorders Familial Mediterranean fever (FMF), also known as paroxysmal polyserositis, is an important clinical and public health problem in a number of Arab countries. It is very common in Lebanon, Jordan and among Palestinians. The frequency among Palestinians and Jordanians was estimated to be at least 1 in 2,000, a figure similar to that of Armenians and Sephardic Jews (Barakat et al. 1986; Majeed and Barakat 1989). FMF is present also in Iraq, Syria, Kuwait, Egypt and Saudi Arabia. In a number of situations, the diagnosis is missed and the chronic nature of the problem taxes the medical care facilities. Patients with amyloidosis as a complication of FMF form a large proportion of the load of dialysis and kidney transplantation in a number of Arab countries. FMF is caused by mutations in MEFV gene on chromosome 16 (Pras et al. 1992). The most frequent MEFV mutations found among the Arabs from Jordan, Palestine, Syria, Iraq, and Egypt, according to their magnitude of frequency, are M694V, V726A, 694I, and M680I (Majeed et al. 2005; El-Shanti et al. 2006). The most common mutations among patients from the Maghreb are M694V and M694I (Belmahi et al. 2006). A744S mutation seems specific to Arab pouulations and R761H is frequently found in the Lebanese (Medlej-Hashem et al. 2004). There seems to be distinctive clinical picture in Arab patients with FMF (El-Shanti et al. 2006). Other auto-inflammatory disorders including Majeed syndrome are discussed elsewhere in the book.

Muscular Dystrophies and Myopathies The magnitude of disease entity is apparently large, mostly due to autosomal recessive conditions. In two surveys, one in the eastern part of Saudi Arabia (Al-Rajeh et al. 1993) and the other in Kelbia in Tunisia (Romdhane et al. 1993), the prevalence rate of anterior horn cell diseases, including Werdnig-Hoffmann


9

disease, was 133 and 177 per million respectively compared to 12 per million from the World Survey (Emery 1991). Similar high incidence was observed in the Egyptian Karaite community in Israel (Fried and Mundel 1977). In a Libyan study, the estimated overall frequency of muscular dystrophies was 132 per million (Radhakrishnan et al. 1987). On the other hand, in the Saudi study, the frequency of Duchenne muscular dystrophy and myotonic dystrophy was 44 and 88 per million compared to the same World Survey of 32 and 50 per million respectively. The figures do not appear to be remarkably different in the two surveys. A severe childhood autosomal recessive muscular dystrophy (SCARMD) resembling Duchenne muscular dystrophy was first noted in several families from Sudan and Tunisia. Subsequently, the disease was found to be prevalent in other Maghreb countries and in the Arabian Peninsula. Recent data comparing Tunisian and Algerian patients with patients from Morocco indicate genetic homogeneity of disease in the Maghreb countries (El-Kerch et al. 1994) In a study from Tunisia, the frequency of this form of muscular dystrophy was found to be equivalent to that of Duchenne muscular dystrophy (Ben Hamida and Marrakchi (1980). Meanwhile, in Kuwait the proportion of families with this autosomal recessive disease was found to constitute at least 36.3% of all ascertained Duchenne or Duchenne-like muscular dystrophies (Farag and Teebi 1990) compared to 5% in North America and United Kingdom (Emery 1987). Because this disease is characteristically highly prevalent among Arabs, it is considered, however, an example of Arab diseases (Table 1.1). Details of molecular bases of SCARMD are found elsewhere in this book. Other relatively common disorders include SCARMD-like disorders, Duchenne and Becker muscular dystrophy, congenital muscular dystrophy, congenital myopathies, mitochondrial myopathies and Schwartz-Jampel syndrome. The latter seems to be more common in the United Arab Emirates.

New Genetic Syndromes First Reported Among Arabs In the last three decades, the area of new genetic syndromes among Arabs became a hot point of research and publications. Reports describing new syndromes and variants came from countries with established genetic services such as in Israel, Lebanon, Kuwait, UAE, Oman, Egypt, Qatar and Saudi Arabia. In this book, an exhaustive list of all such syndromes has been compiled. However, it remains inclusive of very early reports, reports that do not mention the origin of the patient (s) or reports published in unindexed periodicals. The list contains 160 syndromes, compared to 113 syndromes in the first edition of this book, published in 1997. Of these, 133 syndromes are autosomal recessive, 27 are autosomal dominant and five are possible X-linked, autosomal recessive or mitochondrial disorders. Many other “newly” characterized disorders were not included in the recent review, either because they are awaiting further characterization or because of some overlap with previously known disorders requiring molecular etiologic characterization. Despite the fact that most Arab populations are still poorly studied genetically, the

10

A.S. Teebi

Table 1.1 Arab genetic diseases: autosomal recessive disorders that are characteristically highly prevalent among Arabs Disease MIM # Estimated frequency/ References livebirths Bardet-Biedl syndrome 209900 1–2/13,000 Farag and Teebi (1988a, Farag and Teebi 1989a) Congenital chloride 214700 1/5,500–13,000 Kagalwalla (1994), diarrhea (Arabian Badawi et al. (1998) Peninsula) Congenital 241410 Unknown; most Sanjad et al. (1991), hypoparathyroidism, reported patients Marsden et al. (1994), seizure, growth are from Arabian Naguib et al. (2009) failure, dysmorphic Peninsula features Meckel syndrome 249000 1/3,500 Teebi et al. (1992), Familial Mediterranean 249100 1-1500-2000 Majeed and Barakat (1989), fever Palestinians and El-Shanti et al. (2006) Jordanians Werdnig-Hoffmann 253300 1/1,000–1,500 Al-Rajeh et al. (1993), Romdhane disease et al. (1993) Severe childhood 253700 1/3,500 (approximate) Ben Hamida and Marrakchi autosomal recessive (1980), Farag and Teebi muscular (1990) dystrophy (SCARMD) Nesidioblastosis of 256450 1/2,675 (Saudi Arabia) Mathew et al. (1988), pancreas Cherian and Abduljabbar (2005), Karawagh et al. 2008) Osteopetrosis with renal 259730 Unknown; 70% of all Ohlsson et al. (1986), Fathallah tubular acidosis reported patients et al. (1994) are Arabs

number of autosomal recessive syndromes characterized so far appears relatively large for a group constituting no more than 5% of the world populations. More than half of the new autosomal recessive disorders were described among people from Jordan, Palestine and Lebanon, who collectively constitute less than 5% of the Arab populations. This may reflect the genetic diversity of the Palestinians or Jordanians and Lebanese as a result of their admixture over time with many populations, including Arabs, Turks, Kurds, Europeans and Jews, among others. The apparent clustering of new syndromes and other rare genetic disorders among the Palestinians and Lebanese may also be an indication that they have access to genetic services that are not yet available in many other parts of the Arab world. Seven major groups of syndromes are noted among the newly described syndromes among Arabs. They include Neurological/neuromuscular/muscular, Dysmorphic syndromes, Ophthalmological and Hearing disorders, Bone dysplasia and Skeletal disorders, Dermatological and Fertility syndromes and Inborn Errors of Metabolism. Many of the newly described syndromes were thought to be “private”, or limited to single families. Subsequent reports negated the concept of privacy in syndromes. One of those syndromes was the Nablus mask-like facial syndrome. An autosomal


11

Table 1.2 Examples of genetic disorders reported to have definite tribal occurrence or limited to extended kindreds or isolates Disorder MIM # Community References Arthrogryposis multiplex 208100 Palestinian Jaber et al. (1995) congenita, neurogenic type Bardet-Biedl syndrome 209900 Bedouin in Israel Kwitek-Black et al. (1993) Cerebrotendinous 213700 Druze in Israel Leitersdorf et al. (1994) xanthomatosis Cystic fibrosis 219600 Bedouin tribe in Qatar Abdul Wahab et al. (2001), Deafness, Autosomal recessive 220290 Northern Tunisia Ben Arab et al. (2004) Homocystinuria 236200 Bedouin tribe in Qatar El-Said et al. (2006) Hypophosphatemic rickets and 241530 Bedouin tribe in Israel Tieder et al. (1987) hypercalcuiria Metachromatic leucodystrophy 250100 Palestinian Zlotogora et al. (1994a), Heinisch et al. (1995) Krabbe disease 255200 Palestinian; Druze in Zlotogora et al. (1991), Israel Oehlman et al. (1993) Pseudohermaphroditism 264300 Palestinian in Rosler (2006) (male)-17-b-Ketosteroid Gaza strip dehydrogenase def. Ozand et al. (1990a, 1992) GM2 gangliosidosis, Sandhoff 268800 Bedouin in variant Saudi Arabia Glanzmann thromboasthenia 273800 Palestinian Rosenberg et al. (2005) Usher syndrome type I 276900 Samaritans in Nablus Bonne´-Tamir et al. (1994)

recessive example is the Limb/pelvis-hypoplasia/aplasia syndrome described first in a Palestinian from Kuwait (Al-Awadi et al. 1985). Subsequently, reports also came from Brazil, Saudi Arabia, Egypt, Israel, Italy and again from Kuwait in a Bedouin family. Recently the causative gene was elucidated (Woods et al. 2006). The other example was a new hypogonadism syndrome reported in a Jordanian family from Kuwait, later seen in a Lebanese family, and recently reported in two sisters of consanguineous parents from Turkey (Tatar et al. 2009). One of the newly described syndromes was initially described in five siblings of a Bedouin family in Kuwait (Teebi et al. 1988). The same syndrome was found in several sibships of the same tribe, an example of the founder effect (Teebi and Al-Awadi 1991). Several examples of autosomal recessive disorders relatively common in Qatar, but rare elsewhere, were recently documented (See Qatar Chapter in this book). They represent classical examples of founder effect. Table 1.2 provides examples of disorders with definite tribal occurrence or restricted to large kindred or isolates.

Inborn Errors of Metabolism Data on metabolic diseases among Arabs are becoming available due to the introduction of diagnostic facilities and nationwide neonatal screening in several

12

A.S. Teebi

Arab countries (Saadallah and Rashed 2007). However, such data are almost nonexistent from several other countries in the Arab world.

Classic Phenylketonuria and Other Hyperphenylalaninemia In Egypt, Phenylketonuria (PKU) patients constituted 2.3% of the mentally retarded (Temtamy et al. 1991). In Kuwait, PKU was found to have a frequency between 1.6% and 1.86% among institutionalized mentally retarded patients. Six inmates with PKU belonged to three sibships in a large Kuwaiti kindred originating in Iran. At least 20 other patients were ascertained at the genetic clinics or elsewhere (Teebi 1994). A Bedouin family was reported recently (Usha et al. 1992). The incidence of classic PKU in Kuwait was found to be 1:6,479 livebirths as estimated in the course of a neonatal screening project, versus the North American incidence of 1:11,000. The incidence of classic PKU in the United Arab Emirates was found to be 1: 20,050 (Al-Hosani et al. 2003). On the other hand, no case of PKU was detected among 70,000 newborns screened by Aramco in the eastern province in Saudi Arabia, a nearby area (Abu-Osba et al. 1992). However, at a referral center in Saudi Arabia, patients with Hyperphenylalaninemia (HPA) secondary to 6-pyruvoyltetrahydropterin synthase deficiency were frequently seen and appeared to be more common than classic PKU patients (Al-Aqeel et al. 1991; Ozand et al. 1992). Mutations and polymorphisms at the phenylalanine hydroxylase (PAH) gene were studied in 36 Palestinian families in Israel (Kleiman et al. 1994). Four mutations previously identified in Europe were found among the Palestinians, indicating that gene flow from Europe into the Palestinian gene pool could have occurred at previous periods in history. In addition, three PAH mutations unique to Palestinian Arabs (IVSnt 2, ED(197-205) and R2705) were identified, indicating high genetic diversity of this population. A study of patients from Kuwait and Egypt showed the presence of four common European haplotypes, in addition to four rare haplotypes and three unclassified ones (Bender et al. 1994). In addition, a new MspI-polymorphism was found in one Egyptian family and one individual control from Kuwait. The same polymorphism has been described in American blacks (Hoffmann et al. 1991). This may indicate that the associated mutation probably originated from Africa and spread within Africa to Arabia as well as to America. Another study on Egyptian patients showed a high degree of molecular heterogeneity at the PAH locus (Effat et al. 1999). From Paris, 26 families with at least one child affected with HPA were studied together with 100 unrelated families from North Europe and the Mediterranean region (Berthelon et al. 1991). An exclusive or preferential linkage disequilibrium between a particular haplotype and PAH mutation with clear geographic partitioning of the mutations was observed. The spectrum of mutations commonly observed in North European populations differed from that observed among patients from the Mediterranean with specificity within this group; interestingly, the majority of North African patients were homozygous cases rather than compound heterozygote states. A novel specific mutation, Glu!lys at codon 280, was identified in endogamous North African families, and it was later


13

demonstrated to be the most frequent in the whole Maghreb (Lyonnet et al. 1989). This mutation was also identified in a French family, thus raising the question of a relation with the Arab invasion of France during the seventh century AD (Lyonnet et al. 1989). In another study (Beńit et al. 1994), novel frame shift deletions were found in two Arab patients from north Africa. One of these patients had a 22 bp deletion previously described in an Arab patient from Israel (Kleiman et al. 1994).

Other Inborn Errors of Metabolism Homocystinuria is among the common aminoacidopathies observed in Saudi Arabia and Kuwait (Ozand et al. 1992; Teebi 1994; Al-Essa et al. 1998). Recently, the incidence homocystinuria in Qatar was found to be greater than 1 in 3,000, representing the highest incidence in the world (El-Said et al. 2006). Based on figures from the national neonatal screening program, the incidence of homocystinuria among the National Qatari newborns was 1 in 1,400. Other frequently diagnosed disorders include branched-chain aminoaciduria (MSUD) in classic and intermediate forms (Ozand et al. 1992), non-ketotic hyperglycinemia, cystinuria, tyrosinemia type I and tyrosinemia type II (Hashem 1982; Yadav and Reavey 1988; Teebi 1994; Charfeddine et al. 2006). Urea cycle defects, in particular the autosomal recessive types, are also common. Among these are Citrullinemia, Argininosuccinic aciduria and Carbamoyl phosphate synthase deficiency (Yadav and Reavey 1988; Issa et al. 1988b). Organic acidemias, namely Methylmalonic acidemia, 3-Hydroxyl-3-methylglutaryl coenzyme A lyase deficiency and Propionic acidemia are common (Ozand et al. 1992; Teebi 1994; Rashed et al. 1994). Methylmalonic acidemia and other organic acidopathies were found to have characteristic tribal occurrence in Saudi Arabia (Ozand et al. 1992) and other Gulf countries. Also, they were found to have high frequency among the Palestinians (Zlotogora 1996, personal communication). Lysosomal storage disorders (LSD) constitute a large sector of the diagnosable neurometabolic disorders among the Arabs in Kuwait, Saudi Arabia, Egypt and Israel. Among the commonly diagnosed conditions are the Hurler and Hurler– Scheie syndromes, Morquio syndrome, Maroteaux-Lamy syndrome, Sanfilippo syndrome – type B, GM1 gangliosidosis, GM2 gangliosidosis – Sandhoff variant, multiple sulfatase deficiency, ceroid lipofuscinosis, Niemann Pick – types A, B, and C, Canavan disease, Metachromatic leucodystrophy, Krabbe disease, Gaucher disease – neuropathic type and Neuroaminidase deficiency (Hashem 1982; Ozand et al. 1990a, b, 1992; Teebi 1994). A new variant of multiple sulfatase deficiency, which differs clinically from the classic neonatal, childhood and juvenile-onset multiple sulfatase deficiency, was described in eight Saudi patients. (Al-Aqeel et al. 1992). Some of these disorders have shown definite tribal occurrence and might even be restricted to certain Bedouin tribes or large kindred. They include GM2 gangliosidosis – Sandhoff’s variant, mucolipidosis Sanfilippo’s syndrome – type B, Canavan disease, neuroaminidase deficiency and Niemann-Pick – type C.

14

A.S. Teebi

Metachromatic leucodystrophy was found to be more frequent among Arabs living in two restricted areas in Israel (Heinisch et al. 1995). While multiple mutations are responsible for this high frequency, a single origin for the most frequent mutation was found (Zlotogora et al. 1994a). It is suggested that this mutation may have been introduced into Jerusalem at the time of the Crusades. Among the Arab Druze community in Israel, Hurler syndrome and mucolipidosis – type III are highly prevalent (Zlotogora, personal communication). Tay-Sachs disease is a common disorder among the Jews, particularly Ashkenazis and Moroccan Jews, but rarely described among Arabs (Jacoub 1938; Navon et al. 1981). In Kuwait, at least three families were found to have one or more affected members (Farag et al. 1993a; Teebi 1994; Shaabani et al. 2010), and in Egypt, six families were ascertained in one center in Cairo (Hashem 1982). Recently, an Israeli Arab with Tay-Sachs disease was found to have G786A transition in the HEX A gene (Drucker and Navon 1993). This specific mutation was originally described in a British infantile patient (Triggs-Raine et al. 1991), which raises the question of whether this mutation was introduced into Palestine during the Crusades or is a recurrent mutation. Molecular studies on Arab patients with LSD have shown wide ranges of causative mutations (Bargal et al. 2006; Brautbar et al. 2008; Kaya et al. 2008a, b) Dyggve–Melchior–Clausen disease, a condition resembling Morquio syndrome in some aspects, was suggested to have a high gene frequency in the Lebanese (Naffah 1976; Bonafede and Beighton 1978) and Lebanese from Montreal. It was also described in Moroccan Jews and Palestinians from Gaza (Schorr et al. 1977. Glycogen storage disorders, notably types I & III, are commonly diagnosed in several parts of the Arab world. Other relatively common disorders are fatty acid oxidation defects, in particular VLCAD in Saudi Arabia. MCAD incidence was found to be close to that of the Caucasians, with one mutation identified in 72% of cases (Al-Hassnan, personal communication 2009). Primary hyperoxaluria type 1 is particularly frequent in Tunisia, where it was described in 23 cases (Ben Moussa et al. 1993). On the other hand, classic congenital adrenal hyperplasia due to 21 hydroxylase defiency was found to be more frequent in Kuwait than in Europe and Canada (Lubani et al. 1990). Vitamin D-dependent rickets type I and Wilson disease are also apparently common in Kuwait (Teebi 1994).

Cystic Fibrosis and Congenital Chloride Diarrhea Although rare in blacks and Asians, Cystic fibrosis (CF) is the most common lethal genetic disease in the Caucasian populations. In this sense, the old belief that CF is rare or non-existent in Arabs, who are Caucasian by descent, is surprising. The first report on CF in Arabs came from Lebanon (Salem and Idrees 1962). This was followed by reports from other Arab countries (Al-Hassani 1977; Aluwihare et al. 1981; Kamal and Nazer 1984; Kolberg 1986; Nazer et al. 1989; Farag and


15

Teebi, 1989b; Dawson and Frossard 1994). The diagnosis was often missed because of mild manifestations or atypical presentation with metabolic alkalosis in the Arabian Peninsula’s hot and humid weather (Issa et al. 1988a; Mathew et al. 1991), or because many deceased infants were labeled as having succumbed to gastrointestinal and/or respiratory infections, the two leading causes of infant deaths in Arab children. Recent data concerning CF have shown that the estimated incidence among Arab populations ranges from 1/2,188 to 1/4,243 livebirths; these are similar to figures from Europe and North America. A study of 70 patients from 46 families from Saudi Arabia has identified eight novel mutations, with1548delG being the most prevalent (Banjar et al. 1999; Kambouris et al. 2000). In a Bedouin tribe from Qatar with approximately 40,000–50,000 people, at least 70 children were documented to have CF, accounting for an incidence higher than 1 in 1,000 Qatari-livebirths. All patients belonging to this tribe have homozygous I1234V mutation in exon 9 of CFTR gene (Abdul Wahab et al. 2001). This extremely high incidence of CF with a single mutation provides a classical example of genetic drift due to a Founder effect. Data from Israel have shown that the DF508 mutation, which accounts for approximately 70% of all CF chromosomes in a worldwide survey, was found to account for 22–25% of CF chromosomes in Palestinians and Israeli Arabs (Lerer et al. 1990; Shoshani et al. 1992). Four mutations (DF508, G542X, W1282X and N1303K) accounted for 55% of the CF alleles in Arab patients (Abeliovich et al. 1992). In a study of 38 Tunisian families, the common allele was DF508, accounting for 18.4% of CF chromosomes. In addition, several other mutations were found at lower frequencies, including a few new mutations and a strikingly high number of true homozygotes of rare alleles. In the UAE, eight unrelated patients were all observed to have the same S549R mutation (Frossard et al. 1994), a rare mutation previously observed in a Jewish family from Israel (Kerem et al. 1990). In Kuwait, a Bedouin family of three affected individuals was studied for six CF mutations (DF508, D1007, G542X, S549N, G551D and R553X). Of these mutations, none was detected in this family (Farag et al. 1994b). Wei et al. (2006) performed carrier screening on 805 Arab-Americans, testing for at least the original 25 mutations recommended by the American College of Medical College. The observed carrier frequency was 1 in 115; this could be an underestimate due to the expected rare and novel mutations, specific to the population, that were not in the panel of testing. Congenital Chloride Diarrhea (CLD) is a rare and treatable autosomal recessive disorder of chloride transport that was diagnosed in 16 Kuwaiti patients, mostly Bedouins. The incidence was estimated to be 7.6/100,000 livebirths, which is similar to that in Finland (Lubani et al. 1989; Badawi et al. 1998). In a study from Saudi Arabia (Kagalwalla 1994), a remarkably high incidence of 1/5,500 livebirths was observed. Thus far, all reports of Arab patients with CCD came from the Arabian Peninsula, suggesting that this condition is especially common there (Kagalwalla 1994). Allelic diversity of CLD was studied in high incidence populations of Poland, Finland, Saudi Arabia and Kuwait. A major founder effect was found in Arab patients (Hoglund et al. 1998).

16

A.S. Teebi

Osteopetrosis Syndromes Data from Saudi Arabia indicate that the severe autosomal recessive form of osteopetrosis is common in the Arabian Peninsula (Mahdi 1988; Abdel-Al et al. 1994). The estimated minimum prevalence appears to be higher than in other countries (Abdel-Al et al. 1994). Osteopetrosis with renal tubular acidosis and cerebral calcification due to carbonic anhydrase II deficiency has been reported frequently in the Arabian Peninsula and the Maghreb countries (Ohlsson et al. 1986; Bejaoui et al. 1991; Al-Rasheed et al. 1998), and in fact 72% of the cases reported were Arabs (Fathallah et al. 1994). Among the four mutations described, a splice junction mutation at the 50 end of intron 2 in the CA II gene was reported to underlie the molecular defects of this syndrome in six Arab kindred from various countries (Hu et al. 1992). A recent study of ten Tunisian patients revealed that they were homozygous to the same unique mutation (Fathallah et al. 1994); this mutation appears to be confined to Arabs.

Persistent Hyperinsulinemic Hypoglycemia Also called Nesidioblastosis of Pancreas (NP), it is an autosomal recessive disorder, frequently diagnosed among Bedouin and nationals of Saudi Arabia and Kuwait. Glaser et al. (1990) described seven pedigrees from Israel, including a large Bedouin family and an Arab family. In a Saudi population with high consanguinity rate, Mathew et al. (1988) established the incidence as 1/2,675 livebirths, compared to 1/50,000 in a randomly mating population (Bruining 1990). A large number of families were also reported in Saudi Arabia (Cherian et al. 1994; Bin-Abbas et al. 2003; Cherian and Abduljabbar 2005; Karawagh et al. 2008). Also, it was reported in Bedouin children from Kuwait (Ramadan et al. 1999). Thomas et al. (1995) used the homozygosity mapping strategy to localize the mutation for this disorder on 11p in five consanguineous Saudi Arabian families.

Sanjad-Sakati Syndrome The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD) or Sanjad-Sakati syndrome is a relatively common autosomal recessive disorder reported almost exclusively among the Arabs mainly from Saudi Arabia, Kuwait, Israel and Palestinian territories (Sanjad et al. 1991; Marsden et al. 1994; Parvari et al. 2002; Hershkovitz et al. 2004; Naguib et al. 2009). Data suggest that a common founder mutation of TBCE gene accounts for Arab patients (Hershkovitz et al. 2004; Naguib et al. 2009). Preimplantation diagnosis was possible as a tool for the prevention of the disease in Saudi Arabia (Hellani et al. 2004).


17

Malformation Syndromes When considered collectively, malformation syndromes are common; individually, however, they are extremely rare. Nonetheless, a few autosomal recessive malformations appear to be common in Arab countries. Bardet-Biedl syndrome (BBS), for example, is common in Kuwait, particularly among the Bedouin, Kuwaiti, Syrian and Palestinian populations (Farag and Teebi, 1988a). The estimated prevalence among the whole Bedouin community is 1/13,500, about 15 times higher than that of Switzerland. The incidence of BBS among Bedouins in a small geographic area was 1/6,900 livebirths (Farag and Teebi, 1989a). Similar findings were noted in Bedouin tribes and Palestinian Arabs (Leitersdorf et al. 1994; Zlotogora 1997). BBS also appears to be common in Egypt, Lebanon and Israel. Another very common disorder is Meckel syndrome, which has an incidence of at least 1/3,530 livebirths in Kuwait (Teebi et al. 1992). High frequencies of Meckel syndrome were reported also among Tatars (Lurie et al. 1984) and in Gujarati Indians (Young et al. 1985). Multiple pterygium syndrome is a frequently diagnosed disorder in Kuwait, Saudi Arabia, and Qatar. An estimated prevalence of 1/31,000 was found in the general population in Kuwait (Teebi and Daoud 1990). Autosomal recessive hydrocephalus of prenatal onset was found to be common among Palestinian Arabs in Kuwait and Israel (Teebi and Naguib 1988; Zlotogora et al. 1994b; Zlotogora 1997). On the other hand, autosomal recessive microcephaly with normal intelligence or associated with mental retardation and severe neurologic defects appears to be common among various Arab communities in Kuwait, Saudi Arabia and Qatar. Familial intestinal atresias, particularly the apple-peel variant, and the autosomal recessive congenital diaphragmatic hernia are not uncommon based on reports from Lebanon and Kuwait (Mishalany and Najjar 1968; Mishalany and Der Kaloustian 1971; Farag et al. 1993b, 1994a).

Xeroderma Pigmentosum Xeroderma Pigmentosum (XP) appears to be common in several Arab countries, including Kuwait, Lebanon, Syria, Iraq, Jordan, the Palestinian territories Egypt, UAE and the Maghreb countries (German et al. 1984; El-Hayek et al. 2004; Zghal et al. 2005). Molecular studies are available from some countries, some of which have confirmed potential founder effect by haplotype analysis in Tunisian patients (Matsumura et al. 1995; Falik-Zaccai et al. 2006; Ben Rekaya et al. 2009). The prevalence is unknown but the disease accounts for 9–14% of childhood malignancies in Tunisia (Miller 1977; Maalej et al. 2007). This is partly due to an environmental effect owing to the sunny climate in that region.

18

A.S. Teebi

Non-Syndromic Deafness Non-syndromic deafness is very common among Arabs. It is not unexpected that the majority of the cases belong to the autosomal recessive inheritance, a remarkably heterogeneous group. In a large Palestinian kindred originating from the West Bank, 13 cases in several sibships were reported to have uncomplicated profound deafness from early infancy (Kabarity et al. 1981). High incidence of profound deafness reaching 2% of the inhabitants of a Palestinian/Israeli village was documented (Zlotogora and Barges 2003). Most cases were due to mutations in Connexin-26 gene. A large Israeli–Arab pedigree with sensorineural deafness was determined simultaneously by two loci-one mitochondrial and one autosomal recessive (Jaber et al. 1992; Bu et al. 1993). Further studies in the same family and three unrelated families with aminoglycoside-induced deafness showed an A-to-G transition at nucleotide 1,555 in the 12 S r-RNA gene (Prezant et al. 1993). This mutation is responsible for antibiotic-induced ototoxity as well as non-syndromic deafness. Other studies among the Palestinians and Bedouin in Israel have shown high incidence of prelingual deafness with remarkable genetic heterogeneity (Fischel-Ghodsian et al. 1995; Scott et al. 1996; Shahin et al. 2002; Walsh et al. 2006). In Tunisia, sensorineural deafness became an active area of research in the last few years. Several autosomal recessive genes and many mutations have been identified. Data from Northern Tunisia have shown that the prevalence of nonsyndromic deafness ranges between 2% and 8% in the isolates there (Ben Arab et al. 2004). Evidence for genetic heterogeneity was provided, even within isolates. However, the most frequent was the 35delG mutation of GJB2 gene (Ben Arab et al. 2000, 2004). Somewhat similar circumstances related to high frequencies of nonsyndromic deafness in relation to consanguinity and isolation are also found in other Arab countries (Al-Gazali 1998; Tabchi et al. 2000; Al-Khabori and Khandekar 2004).

Osteochondrodysplasias Skeletal dysplasia are frequently diagnosed in the Arab world, though the delineation needs an expert opinion in many instances. A study from UAE has shown that 36 out of 38,046 births had some type of skeletal dysplasia (almost 1:1,000) (Al-Gazali et al. 2003). Half of them (18) were attributed to autosomal recessive genes. The most common recessive type was fibrochondrogenesis followed by chondrodysplaia punctata. An unpublished study from Qatar showed an incidence of 5:1,000 births, which is half of the UAE figure. Lethal chondrodystrophies were frequently diagnosed as well. Other relatively common skeletal/connective tissue disorders include the spondyloepiphyseal dysplasia tarda with progressive arthropathy (Teebi and Al-Awadi 1985;


19

Hurvitz et al. 1999) in Jordan and Lebanon, Stueve_Wiedemann syndrome (Langer et al. 2007) in the UAE and an arterial tortuosity syndrome with skeletal manifestations in Qatar and Saudi Arabia (Al Fadley et al. 2000; Faiyaz-UlHaque et al. 2008, 2009)

Genetic Predisposition to Non-disjunction A study from Kuwait (Alfi et al. 1980) showed that Down syndrome (DS) was four times more frequent among the children of closely related parents (p > 0.005). Another study from Kuwait (Naguib et al. 1989) suggests an association between consanguinity and occurrence of non-disjunction, though a single gene effect was not observed. The other study from Kuwait showed a DS incidence of 4.5/1,000 livebirths in an area inhabited mainly by Bedouins, whereas in an area with a mixed Arab population, the incidence was 1.7/1,000 livebirths (Farag and Teebi 1988b). A remarkably higher incidence of DS was noted in the higher inbreeding coefficient group with nearly similar maternal ages, suggesting the existence of some recessive elements predisposing to non-disjunction. Comparable high frequencies of DS were also reported from West Jerusalem and among the Negev Bedouins in Israel (Harlap 1974; Abeliovich et al. 1986). It is not uncommon to find examples of recurrent aneuploidies in the same family among the Bedouins in Kuwait or other locations (Farag and Teebi 1988b; Krishna Murthy and Farag 1995). This may provide support to the hypothesis of existence of a recessive gene or genes controlling non-disjunction. Recently, based on a case report of a child with DS and neural tube defect, it was suggested that the altered folate status plus homozygous mutation of the MYHFR gene in the mother could promote chromosomal instability and meiotic non-disjunction resulting in trisomy 21 (Al-Gazali et al. 2001).

Male Pseudohermaphroditism Familial male pseudohermaphroditism (MPH) due to defects in steroid metabolism or due to persistent mullerian duct syndrome are common among the Arabs (Rosler et al. 1992; Farag 1993; Al-Attia 1997; El-Gohary 2003). MPH due to 17-bhydroxysteroid dehydrogenase 3 deficiency is particularly common in Palestinian territories and the Gaza Strip. Eighty-five males with this disorder were identified among Palestinians and 57 studied over 25 years. The founders of this defect originated in the mountainous regions of Lebanon and Syria, but most of the families live in Jerusalem, Hebron, the Tel-Aviv area, and Gaza, where the frequency of affected males is estimated at 1 in 100 to 150 (Rosler 2006).

20

A.S. Teebi

Other Disorders Frequently Diagnosed Among Arabs Autosomal recessive epidermolysis bullosa, Cutis laxa, Wrinkly skin syndrome, Gerodermia osteodyslastica, autosomal recessive icthyosis and mal de meleda are among the relatively common genodermatosis syndromes. Clinical anophthalmia or nonsyndromic microphthalmia with CHX10 mutations is prevalent in Gaza and Qatar with clear founder effect in one Qatari tribe (Kohn et al. 1988; Bar-Yosef et al. 2004; Faiyaz-Ul-Haque et al. 2007). Cytochrome b5-reductase deficiency was found to be prevalent in Algeria, mostly in the south, with a heterozygous frequency of 3% (Reghis et al. 1981). Homozygous cases are associated with cyanotic methemoglobinemia with or without mental retardation and neurologic impairment (Vieira et al. 1995). Glanzmann thromboasthenia was described in 12 Jordanian patients in 9 families (Awidi 1983). A founder mutation was found to predominate in Palestinian patients (Rosenberg et al. 2005). It was found to be frequent among the Iraqi Jews and Arabs in Israel (Coller et al. 1987; Kannan and Saxena 2009). Brain or CNS malformations are frequently diagnosed; they have received some attention in the past few years. Several new forms have been delineated so far. Several examples of study cohorts are available. Homozygosity for the two autosomal recessive traits in the same sibship is not rare. Numerous examples were observed in the highly inbred population of Kuwait, particularly among the Bedouins. Some of these examples were recorded (Teebi 1994).

Autosomal Dominant and X-Linked Disorders Apart from the apparent rarity of Huntington disease and the increased frequencies of homozygotes for familial hypercholesterolemia, the pattern and apparent frequencies of autosomal dominant disorders in Arab countries are not remarkably different from those in Western countries. On the basis of studies in Lebanon, Khachadurian (1964) first established the existence of homozygous familial hypercholestrolemia (FHC). In Lebanon the frequency of FHC homozygotes due to low-density lipoprotein receptor gene defect is more than ten times higher than in other parts of the world (Lehrman et al. 1987). Presumably, this is the result of an increased rate of consanguinity as well as a high frequency of the trait. The allele was named the Lebanese allele and was also found in patients from Syria, as well as in five Christian Arab kindred from Israel (Oppenheim et al. 1991). Several other mutations were found among Arabs and named according to the country of origin or community from which the patients came from; they include FH Bahrain, FH Syria, FH Algeria, FH Kuwait, FH Druze, etc. (McKusick 1994). In Kuwait the frequency of homozygotes of FHC was found to be 1/23,000 in a mostly Bedouin population (Palkovic et al. 1994). Of the 502


21

screened card samples from the same population, ten neonates were detected with total cholesterol over the 98th percentile (unpublished data). An autosomal dominant example of a new syndrome originally described is the hypertelorism syndrome resembling craniofontonasal dysplasia, found in an Iraqi kindred with 16 affected individuals living in Kuwait (Teebi 1987). The same diagnosis was subsequently reported in Caucasian and black families from the USA (Stratton 1991; Toriello and Delp 1994; Tsai et al. 2002; Han et al. 2006), Japan (Tsukahara et al. 1995), Germany (Koenig 2003) and South America (Machado-Paula and Guion-Ameida 2003). Glucose-6-phosphate dehydrogenase deficiency (G6PD) is an example of an X-linked disorder that has a special importance in the Arab world. The trait has polymorphic frequencies throughout the region with wide variations ranging from 0.02 and 0.03 in Jordan, parts of Saudi Arabia and Lebanon to 0.58 among the Kurdish Jews and 0.65 in the Qatif oasis in Saudi Arabia (Kurdi-Heidar et al. 1990). The latest figures are the highest in the world (Sheba et al. 1961; El-Hazmi et al. 1986). G6PD-Mediterranean, a common variant in the Middle East, is characterized by severe enzyme deficiency underlying not only acute hemolytic crisis following the ingestion of fava beans (a popular meal in the Middle East), but also neonatal jaundice and acute hemolytic anemia triggered by drugs or infection. Studies from Oman, a country with frequency of G6PD deficiency of 0.25–0.27 in males and 0.10–0.11 in females (White et al. 1993; Daar et al. 1996; Al-Riyami and Ebrahim 2003), showed that despite such high frequencies, the oxidative hemolytic syndromes are very uncommon, supporting earlier findings reviewed and stressed by Beutler (1991). Kurdi-Heidar et al. (1990) concluded that the large majority of Middle Eastern subjects with G6PD-Mediterranean may have the same mutation found in Italy and that the mutation probably arose on a chromosome that already carried the silent mutation, an independent polymorphism in the Middle East.

Interest in the Genetic Disease Among Arabs It had been my hope that the first edition of this book would stimulate interest and research in the Arab world on this important set of diseases prevalent among the Arabs, with a view to potential preventability. Soon after its publication, interest began to foment with the formation of Middle East Genetic Association of America, which held its first scientific meetings in Tunisia in December 1997 (Fathallah et al. 1998) and in Egypt in 1999 (Teebi and Shawky 2000). This was followed by the establishment of the first curated Arab Genetic Disease Database based at the Hospital for Sick Children in Toronto. This was in response to Human Genome Organisation Initiative to establish ethnic genetic databases (Teebi et al. 2002) (This database was later discontinued due to lack of funding). In 2005, a different database was formed in Dubai (Tadmouri et al. 2006). The interest in genetic disease among the Arabs is continuing and receiving wide attention

22

A.S. Teebi

internationally, and has given rise to a better understanding of the prevalent disorders, the establishment of collaborations with many first class world-centers and an improvment in quality and quantity of publications. I hope that we are able to continue stimulating active research in the many aspects of Arab genetic disorders, including their characterization, frequencies and distribution, molecular bases, pathogenesis and origins. Genetic services and research in the field of medical genetics are still far from being adequate in many parts of the Arab world (Teebi and Teebi 2005; Al-Gazali et al. 2006). Genetic diversity among Arabs, high rates of inbreeding and large family size are optimal for the manifestation of many autosomal recessive disorders (Teebi and El-Shanti 2006). There is little doubt that genetic disease from this part of the world has the potential of becoming a major area of research, one that has the potential to benefit mankind at large.

This Edition This is the second edition of the book “Genetic Disorders Among Arab Populations”, first published by Oxford University Press in 1997. Rather than provide the reader with an exhaustive list of genetic disorders among the Arabs, our intention in this book is to highlight the prevalent conditions, genes and mutations involved, the frequencies of diseases and mutations when available, their characteristics and the global pattern of genetic disorders at large and the contributing factors. In addition, we discuss the attitudes of people toward both genetic counseling and the available options on the ground, options that are influenced by the Islamic perspective. Indeed, the attitudes are largely affected by the culture and faith of the Arabs and are remarkably different in many aspects from those of the Western world. To achieve these goals, I have designed this book with four major sections. After the introductory chapter, an overview of the monograph, the first section contains three chapters dealing with the unique demographic and economic characteristics in the Arab world. In addition to population dynamics and health indicators, endogamy and consanguinity are also discussed as prominent demographic features of great importance among Arabs. The second section contains three chapters discussing in some detail selected common entities: autoinflammatory disorders including FMF, muscular dystrophies and myopathies, and new syndromes first reported among Arabs. Fourteen Arab countries or geographic regions are represented in the 15 chapters of the third section, with the aim of discussing aspects of genetic disease in each. These entities include the Jews from Arab countries, in addition to a chapter discussing genetic disorders in ancient Egypt. For the purpose of avoiding redundancy, a separate chapter on Bedouins has been omitted from this edition, as much of the data are provided in the chapters on Saudi Arabia, Kuwait, Qatar, Oman, UAE and Palestine. Although some aspects of genetic disease in other countries such as Syria, Yemen, Mauritania and Somalia can be found in other chapters,


23

they are not included in this section owing to the extreme scarcity of genetic information from them. The fourth section includes two chapters examining issues related to the prevention and care of genetic disorders from an Islamic perspective, as well as the related issue of genetic counseling in the Middle East, including its medical, genetic and psychological implications and real, everyday practice. Genetic information generated so far from some Arab countries provides a valuable indicator of the prevailing disorders in the Arab world at large. However, such information is quite fragmentary in several other parts of the Arab world. It is often largely based on case reports and case series studies, rather than prospective epidemiological and molecular studies. Nonetheless, it is felt that such information is useful, as it well emphasizes the points of weakness and strength in the available knowledge, as well as what could be done to improve it. In comparison with the first edition, data in this book show that the research has certainly taken a remarkable step forward. The book has been mostly re-written and in some chapters, the information has been extensively revised and updated. A large part of the book was written by a new generation of experts in the field. The reader will recognize the genetic diversity among the Arabs from the varied clinical phenotypes and genotypes within the same region or country and or between individual Arab Countries. The information provided here will prove beneficial to those planning to implement health services in the Arab world, as well as to national and international bodies that provide advice to these. It will also helpf physicians and medical students in the Arab world who are confronted with the varied aspects of genetic disease. Physicians in the West who encounter Arab patients as immigrants or seeking help in specialized centers will also find this book useful.

References Abdel-Al YK, Shabani IS, Lubani MM, Al-Ghanem MA, Ibrahim MD, Al-Mohtaseb S, Duodin K (1994) Autosomal recessive osteopetrosis in Arab children. Ann Trop Paediatr 14:59–64 Abdul Wahab A, Al-Thani G, Dawod ST, Kambouris M, Al-Hamed M (2001) Heterogeneity of the cystic fibrosis phenotype in a large kindred family in Qatar with cystic fibrosis mutation (I1234V). J Trop Pediatr 47:110–112 Abeliovich D, Atia Y, Sarov B (1986) Down syndome in Negev region. Am J Med Genet 25:183 Abeliovich D, Lavon IP, Lerer I, Cohen T, Springer C, Avital A, Cuttnig GR (1992) Screening for five mutations detects 97% of Cystic Fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in The Jewish Ashkenazi population. Am J Hum Genet 51:951–956 Abu-Osba YK, Mallouh A, Salaman M, Hann R, Thalji A, Hamdan J, Sa’di AR (1992) Comprehensive newborn screening program: Aramco experience, the national need and recommendations. Ann Saudi Med 132:235–240 Al-Abdulkareem AA, Ballal SG (1998) Consanguineous marriage in an urban area of Saudi Arabia: rates and adverse side effects on the offspring. J Commuinty Health 23:75–83 Al-Aqeel AI (2007) Islamic ethical framework for research into and prevention of genetic disease. Nat Genet 39:1293–1298

24

A.S. Teebi

Al-Aqeel A, Ozand PT, Brismar J, Gascan GG, Nester M, Sakati N (1992) Saudi variant of multiple Sulfutase deficiency. J Child Neurol 7(12(Suppl)):20 Al-Aqeel A, Ozand PT, Gascon G, Nester M, Al-Nasser M, Brismar J, Blau N, Hughes H, Subramanyan SB, Reynolds CT (1991) Biopterin-dependent hyperphenylalaninemia due to deficiency of 6-pyruoyl tetrahydropterin synthase. Neurology 41:730–737 Al-Attia HM (1997) Male pseudohermaphroditism due to 5 alpha reductase-2 deficiency in an Arab kindred. Postgrad Med J 73:802–807 Al-Awadi SA, Teebi AS, Farag TI, Naguib KM, El-Khalifa MY (1985) Profound limb deficiency, thoracic dystrophy, unusual faces and normal intelligence: a new syndrome. J Med Genet 22:36–38 Al-Essa M, Rashed M, Ozand PT (1998) Saudi experience with classic homocystinuria. Ann Saudi Med 18:230–233 Al Fadley F, Al Manea W, Nykanen DG, Al Fadley A, Al Haless Z (2000) Severe tortuosity and stenosis of the systemic, pulmonary and coronary vessels in 12 patients with similar phenotypic features: a new syndrome? Cardiol Young 10:582–589 Alfi OS, Chang R, Azen S (1980) Evidence for genetic nondisjunction in man. Am J Hum Genet 32:477–483 Al-Khabori M, Khandekar R (2004) The prevalence and causes of hearing impairment in Oman: a community-based cross-sectional study. Int J Audiol 43:486–492 Al-Gazali LI (1998) A genetic survey of severe childhood deafness in the United Arab Emirates. J Trop Pediatr 44:156–160 Al-Gazali LI, Bakir M, Hamid Z, Varady E, Varghes M, Haas D, Bener A, Padmanabhan R, Abdulrrazzaq YM, Dawadu A (2003) Birth prevalence and pattern pf osteochondrodysplasias in an inbred high risk population. Birth Defects Res A Clin Mol Teratol 67:125–132 Al-Gazali LI, Bener A, Abdulrazzaq YM, Al-Khayat MR, AI GT (1997) Consanguineous marriages in the United Arab Emirates. J Biosoc Sci 29:491–497 Al-Gazali L, Hamamy H, Al-Arrayad S (2006) Genetic disorders in the Arab world. BMJ 333:831–834 Al-Gazali LI, Padmanabhan R, Melnyk S, Yi P, Pogribny IP, Pogribna M, Bakir M, Hamid ZA, Abdulrazzaq Y, Dawodu A, James SJ (2001) Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube effect. Am J Med Genet 103:128–132 Al-Hassani M (1977) Cystic fibrosis in Iraqi children. J Trop Med Hyg 23:136–137 Al-Hosani H, Salah M, Saade D, Osman H, Al-Zahid J (2003) United Arab Emirates national newborn screening programme: an evaluation 1998–2000. East Mediterr Health J 9:324–332 Ali AY (1991) English translation of the meanings of the Holy Qur’an. Amana Corporation, Brentwood, MD, p 1227 Al-Rajeh S, Bademosi O, Ismail H, Awada A, Dawodu A, Al-Freihi H, Assuhaime S, Borollosi M, Al-Shammasi S (1993) A community survey of neurological disorders in Saudi Arabia. The Thugbah Study. Neuroepidemiology 12:164–178 Al-Rasheed SA, Al-Mohrij O, Al-Jurayyan N, Al-Herbish A, Al-Mugeiren M, Al-Salloum A, Al-Hussain M, El-Desouki M (1998) Osteopetrosis in children. Int J Clin Pract 52:15–18 Al-Riyami A, Ebrahim GJ (2003) Genetic blood disorders survey in the Sultanate of Oman. J Trop Pediatr 49(1(Suppl)):11–20 Al-Roshoud R, Farid S (1991) Kuwait child health survey. Ministry of Health Publications, Kuwait Aluwihare APR, Ali SM, Ahmad MS, Mirghani GA, Mohacsy J (1981) Cystic fibrosis in Kuwait. Lancet ii:1056 Assaf S, Khawaja M (2009) Consanguinity trends and correlates in the Palestinian territories 41:107–124 Awidi AS (1983) Increased incidence of Glanzmanns thromboasthenia in Jordan compared with Scandanavia. Scand J Haematol 30:218–222


25

Badawi MH, Zaki M, Ismail EA, Majid Molla A (1998) Congenial chloride diarrhoea in Kuwait: a clinical reappraisal. J Trop Pediatr 44:296–299 Banjar H, Kambouris M, Meyer BF, Al-Mehaidib A, Mogarri I (1999) Geographic distribution of cystic fibrosistransmembrane regulator gene mutations in Saudi Arabia. Ann Trop Paediatr 19:69–73 Barakat MH, Karnik AM, Majeed HWA, El-Sobki NI, Fenech FF (1986) Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs – a study of 175 patients and review of literature. Q J Med 60:837–847 Bar-Yosef U, Abuelaish I, Harel T, Hendler N, Ofir R, Birk OS (2004) CHX10 mutations cause non-syndromic microphthalmia/anophthalmia in Arab and Jewish kindreds. Hum Genet 115:302–309 Bargal R, Zeigler M, Abu-Libdeh B, Zuri V, Mandel H, Ben Neriah Z, Stewart F, Elcioglu N, Hindi T, Le Merrer M, Bach G, Raas-Rotchschild A (2006) When Mucolipidosis III meets Mucolipidosis II: GNPTA gene mutations in 24 patients. Mol Genet Metab 88:359–363 Bayoumi RA, Saha N (1987) Some blood genetic markers of the Nuba and Hawazma tribes of Western Sudan. Am J Phys Anthropol 43:103–112 Bejaoui M, Kamoun A, Barraket M, Bourguiba H, Lakhoua R (1991) Le syndrome associant: osteopetrose, acidose tubulaire, retard mental et calcification intracraniennes par de´ficit en anhydrase carbonique II. Arch Fr Pediatr 48:711–714 Belmahi L, Sefiani A, Fouveau C, Feingold J, Delpech M, Grateau G, Dode C (2006) Prevalence and distrtibution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever. C R Biol 329(2):71–74 Ben Arab S, Hmani M, Denovelle F, Boulila-Elgaied A, Chardenoux S, Hachicha S, Petit C, Ayadi H (2000) Mutations of GJB2 in three geographic isolates from northern Tunisia: evidence for genetic heterogeneity within isolates. Clin Genet 57:439–443 Ben Arab S, Masmoudi S, Beltaief N, Hachicha S, Avadi H (2004) Consanguinity and endogamy in Northern Tunisia and its impact on non-syndromic deafness. Genet Epidemiol 27:74–79 Ben Hamida M, Marrakchi D (1980) Dystrophie musculaire progressive de type Duchenne et Tunisie: a propos de 13 familles et 31 cas d’une forme en apparence recessive autosomique. J Genet Hum 28:1–9 Ben Moussa F, Kamoun A, El-Younsi F, Lakhoua H, Ben Maiz H (1993) Primary hyperoxaluria type I – study of 23 cases. Saudi Kidney Dis Transplant Bull 4(suppl):CN 23 Ben Rekaya M, Messaoud O, Talmoudi F, Nouira S, Ouragini H, Amouri A, Boussen H, Boubaker S, Mokni M, Mokthar I, Abdelhak S, Zghal M (2009) High frequency of the V548A fs X572 XPC mutation in Tunisia: implication for molecular diagnosis. J Hum Genet 54:426–429 Bender C, B€uchler A, Schmidt-Mader B, Schlotter M, Teebi AS, Konecki DS, Trefz FK (1994) Haplotype analysis and a new MspI-polymorphism at the phenylalanine hydroxylase gene in the Arab population. Eur J Pediatr 153:392 Bener A, Alali KA (2006) Consanguineous marriage in a newly developed country: the Qatar poulation. J Biosoc Sci 38:239–246 Beńit P, Rey F, Melle D, Munnich A, Rey J (1994) Novel frame shift deletions of the phenylalanine hydroxylase gene in phenylketonuria. Hum Mol Genet 3:675–676 Berthelon M, Cailland C, Rey F, Labrune P, Melle D, Feingold J, Frezal J, Briard ML, Farriaux JP, Guibaud P, Journel H, Maurin N, Le Marrec B, Nivelon JL, Planchu H, Saudubray JM, Tron P, Rey J, Munnich A, Lyonnet S (1991) Spectrum of phenylketonuria mutations in western Europe and North Africa, and their relation to polymorphic DNA haplotypes at the phenylalanine hydroxylase locus. Hum Genet 86:355–358 Beutler E (1991) Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 324:169–174 Bin-Abbas BS, Al-Mulhim AN, Sakati NA, Al-Ashwal AA (2003) Persistent hyperinsulinemic hypoglycemia of infancy in 38 children. Saudi Med J 24:890–894 Bolbol A, Fatheldin A (2005) Intra-Arab exports and direct investment: an empirical analysis. AMF, Abu Dhabi

26

A.S. Teebi

Bonafede RP, Beighton P (1978) The Dyggve–Melchior–Clausen syndrome in adult siblings. Clin Genet 14:24–30 Bonne´-Tamir B, Korostishevsky M, Kalinsky H, Seroussi E, Becker R, Weiss S, Godel V (1994) Genetic mapping of the gene for Usher syndrome: linkage analysis in a large Samaritan kindred. Genomics 20:36–42 Bram L, Dickey NH (eds) (1993) Funk and Wagnalls new encyclopedia. Funk and Wagnalls Corporation, New York Brautbar A, Abrahamouv A, Hadas-Halpern I, Elstein D, Zimran A (2008) Gaucher disease in Arab patients at an Israel referral clinic. Isr Med Assoc J 10:600–602 Bruining GC (1990) Recent advances in hyperinsulinism and the pathogenesis of diabetes mellitus. Curr Opin Pediatr 2:758–765 Bu X, Shohat M, Jaber L, Rotter JI (1993) A form of sensorineural deafness is determined by a mitochondrial and an autosomal locus: evidence from pedigree segregation analysis. Genet Epidemiol 10:3–15 Charfeddine C, Monastiri K, Mokni M, Laadimi A, Kaabachi N, Perin O, Nilges M, Kassar S, Keirallah M, Guediche MN, Kamoun MR, Tebib N, Ben Dridi MF, Boubaker S, Ben Osman A, Abdelhak S (2006) Clinical and mutational investigations of tyrosinemia type II in Northern Tunisia: identification and structural characterization of two novel TAT mutations. Mol Genet Metab 88:184–191 Cherian MP, Abduljabbar MA (2005) Persistent hyperrinsulinemic hypoglycemia of infancy (PHHI): long-term outcome following 95% pacreatectomy. J Pediatr Endocrinol Metab 18:1441–1448 Cherian MP, Haddad MJ, Saádi AR, Mathew PM (1994) Familial nesidioblastosis: more evidence for autosomal recessive inheritance (review). Ann Trop Pediatr 14:287–291 Coller BS, Seligsohn U, Little PA (1987) Type 1 Glanzmann thromboasthenia patients from the Iraqi-Jewish and Arab populations in Israel can be differentiated by platelet glycoprotein IIIa immunoblot analysis. Blood 69:1696–1703 Daar S, Vulliamy TJ, Kaeda J, Mason PJ, Luzzatto L (1996) Molecular characterization of G6PD deficiency in Oman. Hum Hered 46:172–176 Dawson K, Frossard P (1994) Cystic fibrosis in the UAE: I. Clinical presentation. Emerg Med J 12:245–247 Drucker L, Navon R (1993) Tay-Sachs disease in an Israeli Arab family: Try26 6stop in the a subunit of hexosaminidase A. Hum Mut 2:415–417 El-Hayek M, Lestringant GG, Frossard PM (2004) Xeroderma pigmentosum in four siblings with three different types of malignancies simultaneously in one. J Pediatr Hematol Oncol 26:473–475 El-Hazmi MAF, Swailen AR, Faleh FZ, Warsy AS (1986) The frequency of glucose-6-phosphate dehydrogenase, pyruvate kinase and hexokinase deficiency in the Saudi population. Hum Hered 36:45–49 Effat L, Kuzmin A, Kasem N, Meguid NA, Kotb S, Eisensmith RC, Temtamy SA, Rushdi S, Woo S, El-Awady M (1999) Haplotypes and mtations of the PAH ocus in Egyptian families with PKU. Eur J Hum Genet 7:259–262 El-Gohary MA (2003) Laproscopic management of persistent mullerian duct syndrome. Pediatr Surg Int 19:533–536 El-Kerch F, Sefiani A, Azibi K, Boutaleb N, Yahyaoui M, Bentahila A, Vinet M-C, Leturcq F, Bachner L, Beckmann J, Campbell KP, Tome´ FMS, Fardeau M, Kaplan J-C (1994) Linkage analysis of families with severe childhood autosomal recessive muscular dystrophy in Morocco indicates genetic homogeneity of the disease in North Africa. J Med Genet 31:342–343 El-Said MF, BadiiR BMS, Shahbek N, El-Ali MG, El-Marikhie M, El-Zyoid M, Salem MS, Bener A, Hoffmann GF, Zschocke J (2006) A common mutation in the CBS gene explains a high incidenceof homocystinuria in the Qatari population. Hum Mutat 27:719–724 El-Shanti H, Majeed HA, El-Khateeb M (2006) Familial Mediterranean fever in Arabs. Lancet 367 (9515):1016–1024


27

Emery AEH (1987) Duchenne muscular dystrophy. Oxford University Press, New York Emery AEH (1991) Population frequencies of inherited neuromuscular diseases – a world survey. Neuromuscul Disord 1:19–29 Faiyaz-Ul-Haque M, Zaidi SH, Al-Mureikhi MS, Peltekova I, Tsui LC, Teebi AS (2007) Mutations in the CHX10 gene in non-syndromic microphthalmia/anophthalmia patients from Qatar. Clin Genet 72:164–166 Faiyaz-Ul-Haque M, Zaidi SH, Al-Sanna N, Alswaid A, Momenah T, Kaya N, Al-Dayel F, Bouhoaigah I, Saliem M, Tsui LC, Teebi AS (2009) A novel missence and recurrent mutation in SLC2A10 gene of patients affected with arterial tortousity syndrome. Atherosclerosis 203:466–471 Faiyz-Ul-Haque M, Zaidi SHE, Wahab AA, Altohami A, Al-Mureikhi MS, Al-Thani G, Peltekova VD, Tsui L-C, Teebi AS (2008) Identification of a p.Ser81Arg encoding mutation in SLC2A10 gene of arterial tortuosity syndrome from 10 Qatari patients. Clin Genet 74:189–193 Falik-Zaccai T, Kfir N, Laskar M, Segel R, Khyat M, Slor H (2006) Clinical biochemical and molecular characterization of rare genetic disorders, related to nucleotide excision repair (NER) system. Harefuah 145(889–894):942 Faor M (1989) Fertility policy and family planning in the Arab countries. Stud Fam Plann 20(4): 254–263 Farag TI, Al-Awadi SA, El-Badramany MH, Aref MA, Kasrawi B, Krishna-Murthy DS, El-Khalifa MLY, Yadav G, Marafie MJ, Bastaki L, Wahba RA, Mohammed FM, Abul Hassan S, Redha AA, Redha MA, Al-Aboud H, Al-Hijjis S, Al-Dighashem D, Al-Hasash N, Al-Jeryan L, Al-Khorafi H, Qurban EA, Al-Sulaiman I (1993a) Disease profile of 400 institutionalized mentally retarded patients in Kuwait. Clin Genet 44:329–334 Farag TI, Al-Awadi SA, El-Badramany MH, Usha R, El-Ghanem M (1993b) Second family with “apple peel” syndrome affecting four siblings. Autosomal recessive inheritance confirmed. Am J Med Genet 47:119–121 Farag TI, Bastaki L, Marafie M, Al-Awadi SA, Krsz J (1994a) Autosomal recessive congenital diaphragmatic defects in the Arabs. Am J Genet 50:300–301 Farag TI, Samilchuk E, AbulHasan S, Al-Awadi SA, Kandil H, Mady SA, El-Ghanem M (1994b) Cystic fibrosis in Kuwait and neighbouring populations. J Kuwait Med Assoc 26: 176–179 Farag TI, Teebi AS (1988a) Bardet-Biedl and Laurence-Moon syndromes in a mixed Arab population. Clin Genet 33:78–82 Farag TI, Teebi AS (1988b) Possible evidence for genetic predisposition to nondisjunction in man. J Med Genet 25:136–137 Farag TI, Teebi AS (1989a) High incidence of Bardet-Biedl syndrome among the Bedouin. Clin Genet 36:463–465 Farag TI, Teebi AS (1989b) Observations on cystic fibrosis (CF) in Kuwait. Am J Hum Genet 45(4(Suppl)):A238 Farag TI, Teebi AS (1990) Duchenne-like muscular dystrophy in the Arabs. Am J Med Genet 37:290 Farag TI (1993) Familial persistant M€ ullerian duct syndrome in Kuwait and neighbouring populations. Am J Med Genet 47:432–434 Fathallah DM, Bejaoui M, Sly WS, Lakhoua R, Dellagi K (1994) A unique mutation underlying carbonic anhydrase II deficiency syndrome in patients of Arab descent. Hum Genet 94:581–582 Fathallah DM, Dellagi K, Qumsiyeh MB, Teebi AS (1998) Recent advances in molecular genetics of the Maghreb and the Middle East populations: the first Middle East Association of America (MEGA) conference. Am J Med Genet 78:90–91 Fischel-Ghodsian N, Prezant TR, Fournier P, Stewart IA, Maw M (1995) Mitochondrial mutation associated with nonsyndromic deafness. Am J Otolaryngol 16:403–408 Freundlich F, Hino N (1984) Consanguineous marriage among rural Arabs in Israel. Isr J Med Sci 20:1035–1038

28

A.S. Teebi

Fried K, Mundel G (1977) High incidence of spinal muscular atrophy type I (Werdnig-Hoffmann disease) in the Karaite community in Israel. Clin Genet 12:250–251 Frossard P, John A, Dawson K (1994) Custic fibrosis in the UAE: II. Molecular genetic analysis. Em Med J 12:249–254 German J, Hashem N, El-Hefnawi M, Cleaver JE (1984) Xeroderma pigmentosum in Egypt. III. ABO blood grouping in 22 affected families. Ann Hum Genet 48(Pt1):61–64 Glaser B, Philip M, Carmi R, Lieberman E, Landau H (1990) Persistant hyperinsulinemic hypoglycemia of infancy (“nesidioblastosis”): autosomal recessive inheritance in 7 pedigrees. Am J Med Genet 37:511–515 Grissa A (1994) Arab economic integration: current reality and future prospects. Economic Research Forum. Working paper 9405 Hamamy H, Alwan A (1994) Hereditary disorders in the eastern Mediterranean region. Bull WHO 72:145–154 Hamamy H, Jamhawi L, Al-Darawsheh J, Ajlouni K (2005) Consanguineous marriages in Jordan: why is the rate changing with time? Clin Genet 67:511–516 Han XD, Cox V, Slavotinek A (2006) Atrioventricular block and wiry hair in Teebi hypertelorism syndrome. Am J Med Genet A 140:1960–1964 Harlap S (1974) Down’s syndrome in west Jerusalem. Am J Epidemiol 97:225–232 Hashem N (1982) Preventable aspects of genetic morbidity. Proceedings of the first international conference, Ain Shams University, Cairo, Egypt Hathout H (1972) Abortion and Islam. Leb Med J 25:237–239 Heinisch U, Zlotogora J, Kafert S, Gieselmann V (1995) Multiple mutations are responsible for the high frequency of metachromatic leucodystrophy in a small geographic area. Am J Hum Genet 65:51–57 Hellani A, Aqueel A, Jaroudi K, Ozand P, Coskun S (2004) Pregnancy after preimplantation genetic diagnosis for Sanjad-Sakati syndrome. Prenat Diagn 24(4):302–306 Hershkovitz E, Parvari R, Diaz GA, Gorodischer R (2004) Hypoparathyroidism–retardation–Dysmorphism (HRD) syndrome – a review. J Pediatr Endocrinol Metab 17:1583–1590 Hoglund P, Auraren M, Socha J, Popinska K, Nazer H, Rajaram U, Al Sanie A, Al-Ghanim M, Holmberg C, de la Chapelle A, Kere J (1998) Genetic background of congenital chloride diarrhea in high-incidence populations: Finland, Poland, and Saudi Arabia and Kuwait. Am J Hum Genet 63:760–768 Hoffmann KJ, Steel G, Kazazian HH, Valle D (1991) Phenylketonuria in US blacks; molecular analysis of the phenylalanine hydroxylase gene. Am J Hum Genet 48:791–798 Hu PY, Roth DE, Skaggs LA, Venta PJ, Tashian RE, Guibaud P, Sly WS (1992) A splice junction mutation in intron 2 of carbonic anhydrase II gene of osteopetrosis patients from Arabic countries. Hum Mut 1:288–292 Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Fuga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV, Ezai-Delui H, Leguis E, Le Merrer M, Al-Alami J, Bahabri SA, Warman ML (1999) Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 23:94–98 Husseini S (1994) La redistribution territoriale des Chre´tiens au Liban. Cah Orient 32–33:145–174 Issa ARA, Teebi AS, Issa MA, Shaabani IS, Ramadan D (1988a) Metabolic alkalosis in cystic fibrosis: atypical presentation in Kuwait. Ann Trop Pediatr 8:271–272 Issa ARA, Yadav G, Teebi AS (1988b) Intra-familial variability in citrullinemia. J Inherit Metab Dis 11:306–307 Jaber L, Bailey-Wilson JE, Haj-Yehia M, Hernandez J, Shohat M (1994) Consanguineous matings in an Israeli-Arab community. Arch Pediatr Adolesc Med 148:412–415 Jaber L, Halpern GJ, Shohat T (2000) Trends in the frequencies of consanguineous marriages in the Israeli Arab community. Clin Genet 58:106–110 Jaber L, Shohat M, Bu X, Fischel-Ghodsian N, Yang H-Y, Wang S-J, Rotter J (1992) Sensorineural deafness inherited as a tissue specific mitochondrial disorder. J Med Genet 29:36–39


29

Jaber L, Weitz R, Bu X, Fischel-Ghodsian N, Rotter JI, Shohat M (1995) Arthrogryposis multiplex congenita in an Arab kindred: update. Am J Med Genet 55:331–334 Jacoub B (1938) Tay-Sachs disease in Egypt. J Egypt Med Assoc 21:377 Jurdi R, Saxena PC (2003) The prevalence and correlates of consanguineous marriages in Yemen: similarities and contrasts with other Arab countries. J Biosoc Sci 35:1–13 Kabarity A, Al-Awadi SA, Farag TI, Mallalah G (1981) Autosomal recessive “uncomplicated” profound childhood deafness in an Arabic family with high consanguinity. Hum Genet 57:444–446 Kagalwalla AF (1994) Congenital chloride diarrhea: a study in Arab children. J Clin Gastrol 19:36–40 Kamal MF, Nazer H (1984) Cystic fibrosis in Jordan: a pilot study. Ann Trop Paediatr 4:243–246 Kambouris M, Banjar H, Mogarri I, Nazer H, Al-Hamed M, Meyer BF (2000) Identification of novel mutations in Arabs with cystic fibrosis and their impact on the cystic fibrosis transmembrane regulator mutation detection rate in Arab populations. Eur J Pediatr 159:303–309 Kannan M, Saxena R (2009) Glanzmann’s thrombasthenia: an overview. Clin Appl Thromb Hemost 15:152–165 Karawagh AM, Abdullah LS, Gasim AM, Abdelaziz MM (2008) Noninsulinoma pancreatogenous hypoglycemia syndrome in Saudi male. Saudi Med J 29:1654–1657 Kaya N, Al-Zahrani F, Al-Odaib A, Rahbeeni Z, Al-Hassnan Z, Al-Sharif F, Ozand P, Al-Sayed M (2008a) Identification of Gaucher disease mutations found in Saudi Arabia. Blood Cells Mol Dis 41:200–201 Kaya N, Imtiaz F, Colak D, Al-Sayed M, Al-Odaib A, Al-Zahrani F, Al-Mubarak BR, Al-Owain M, Al-Dhalaan H, Chedrawi A, Al-Hassnan Z, Coskun S, Sakati N, Ozand P, Meyer BF (2008b) Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan disease. Genet Med 10:675–684 Kerem B, Zielewski J, Markiewicz D, Bozon D, Gazit E, Yahaf J, Kennedy D, Riordan JR, Collins FS, Rommens JR, Tsui L-C (1990) Identification of mutations in regions corresponding to 2 putative nucleotide (ATP) binding folds of the cystic fibrosis gene. Proc Natl Acad Sci USA 87:8447–8451 Khachadurian AK (1964) The inheritance of essential familial hypercholesterolemia. Am J Med 37:402–407 Khlat M, Khudr A (1984) Cousin marriages in Beirut, Lebanon: is the pattern changing? J Biosoc Sci 16:369–373 Kleiman S, Avigad S, Vanagaite L, Shamuelevitz A, David M, Eisensmith RC, Brand N, Schwartz G, Rey F, Munnich A, Woo SLC, Shiloh Y (1994) Origins of hyperphenylalaninemia in Israel. Eur J Hum Genet 2:24–34 Koenig R (2003) Teebi hypertelorism syndrome. Clin Dysmorphol 12:187–189 Kohn G, el Shawwa R, el Rayyes E (1988) Isolated “clinical anophthalmia” in an extensively affected Arab kindred. Clin Genet 33:321–324 Kolberg H (1986) Cystic fibrosis in Kuwait. J Trop Paediatr 32:293–294 Langer R, Al-Gazali L, Raupp P, Varady E (2007) Radiological manifestations of the skeleton, lungs and brain in Stueve-Wiedemann syndrome. Australas Radiol 51:203–210 Krishna Murthy DS, Farag TI (1995) Recurrent regular trisomy 21 in two Bedouin families. Parental mosaicism versus genetic predisposition. Ann Genet 38:1–8 Kurdi-Heidar B, Mason PJ, Berrebi A, Ankra-Badu G, Al-Ali A, Oppenheim A, Luzzatto L (1990) Origin and spread of glucose-6-phosphate dehydrogenase variant (G6PD-Mediterranean) in the Middle East. Am J Hum Genet 47:1013–1019 Kwitek-Black AE, Carmi R, Duyk GM, Buetow KH, Elbedour K, Parvari R, Naidu Yandava C, Stone EM, Sheffield VC (1993) Linkage of Bardett-Biedl syndrome to chromosome 16q and evidence for genetic heterogeneity. Nat Genet 5:135–139 Lehrman MA, Schneider WJ, Brown MS, Davis CG, Elhammer A, Russell DW, Goldstein JL (1987) The Lebanese allele at the low density lipoprotein receptor locus: nonsense mutation

30

A.S. Teebi

produces truncated receptor that is retained in the endoplasmic retuculum. J Biol Chem 262:401–410 Leitersdorf E, Safadi R, Meiner V, Reshef A, Bjorkhem I, Friedlander Y, Morkos S, Berginer VM (1994) Cerebroteninous xanthomatosis in the Israeli Druze: molecular genetics and phenotypic characteristics. Am J Hum Genet 55:907–915 Lerer I, Cohen S, Chemke M, Sanilevish A, Rivlin J, Golan A, Yahav J, Friedman A, Abeliovich D (1990) The frequency of the DF508 mutation on cystic fibrosis chromosomes in Israeli families: correlation to CF haplotypes in Jewish communities and Arabs. Hum Genet 85:416–417 Lubani MM, Doudin KI, Sharda DC, Shaltout AA, Al-Shab TS, Abdul-Al YK, Said MA, Salhi MM, Ahmed SA (1989) Congenital chloride diarrhoea in Kuwaiti children. Eur J Pediatr 148:333–336 Lubani MM, Issa ARA, Bushnaq R, Al-Saleh QA, Dudin KI, Reavy PC, El-Khalifa MY, Manadhar DS, Abdul-Al YK, Ismail EA, Teebi AS (1990) Prevalence of congenital adrenal hyperplasia in Kuwait. Eur J Pediatr 149:391–392 Lurie IW, Prytkov AN, Meldere LY (1984) Meckel syndrome in different populations. Am J Med Genet 18:661–669 Lyonnet S, Cailland C, Rey F, Betthelon M, Frazal J, Rey J, Munnich A (1989) Molecular genetics of phenylketonuria in Mediterranean countries: a mutation associated with partial phenylalanine hydroxylase deficiency. Am J Hum Genet 44:511–517 Maalej M, Hentati D, Slimene M, Kenon S, Hechiche M, Ben Romdhane K, Ben Abdallah M (2007) Skin cancer in Tunisia: a retrospective study: 1379 cases and risk factors. Tunis Med 85:728–733 Machado-Paula L, Guion-Ameida ML (2003) Teebi hypertelorism syndrome: additional cases. Am J Med Genet A 117A:181–183 Mahdi AH (1988) Osteopetrosis in Saudi children: a report of 10 cases. Ann Trop Paediatr 8:112–115 Majeed HA, Barakat M (1989) Familial mediterranean fever (recurrent hereditary polyserositis) in children: analysis of 88 cases. Eur J Pediatr 148:636–641 Majeed HA, El-Khateeb M, El-Shanti H, Rabaiha ZA, Tayeh M, Najib D (2005) The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum 34:813–818 Marsden D, Nyhan WL, Sakati NO (1994) Syndrome of hypoparathyroidism, growth hormone deficiency and multiple minor anomalies. Am J Med Genet 52:334–338 Matsumura Y, Sato M, Nishigori C, Zghal M, Yagi T, Imamra S, Takebe H (1995) High prevalence of mutations in the p53 gene in poorly differentiated squamous cell carcinomas in xeroderma pigmentosum patients. J Invest Dermatol 105:399–401 McKusick VA (1994) Mendelian inheritance in man. A catalog of human genes and genetic disorders, 11th edn. Johns Hopkins University Press, Baltimore Mathew PM, Hamdan JA, Nazer H (1991) Cystic fibrosis presenting with recurrent vomiting and metabolic alkalosis. Eur J Pediatr 150:264–266 Mathew PM, Young JM, Abu-Osba YK, Mulhem BD, Hammoudi S, Hamdan JA, Saadi AR (1988) Persistent neonatal hyperinsulinism. Clin Pediatr 27:148–151 Medlej-Hashem M, Loiselet J, Lefranc G, Megarbane A (2004) Familial mediterranean fever (FMF): from diagnosis to treatment, Sante 14:261–266 Miller RW (1977) Ethnic differences in cancer occurrence: genetic and environmental influences with particular references to neuroblastoma. In: Mulvihill JJ, Miller RW, Fraumeni JF Jr (eds) Genetics of human cancer. Raven Press, New York, pp 1–14 Mishalany HG, Der Kaloustian VM (1971) Familial multiple level intestinal atresia: report of two siblings. J Pediatr 79:124 Mishalany HG, Najjar FB (1968) Familial jejunal atresia: three cases in one family. J Pediatr 73:753–755 Naffah J (1976) The Dyggve-Melchior-Clausen syndrome. Am J Hum Genet 28:607–614


31

Naguib KK, Al-Awadi SA, Moussa MAA, Farag TI, Teebi AS (1989) Effect of paternal age, birth order and consanguinity on nondisjunction in the population of Kuwait. J Kuwait Med Assoc 23:37–43 Naguib KK, Gouda SA, Elshafey A, Mohammed F, Bastaki L, Azab AS, Al-Awadi SA (2009) Sanjad-Sakati syndrome/Kenny-Caffey syndrome type 1: a study of 21 cases in Kuwait. East Mediterr Health J 15:345–352 Navon R, Nutman J, Kopel R, Gaber L, Gadoth N, Goldman B, Nitzan M (1981) Hereditary heat labile hexosaminidase B: its complications for recognizing Tay-Sachs genotypes. Am J Hum Genet 33:907–915 Nazer H, Riff E, Harfi H, Sakati N, Mathew R, Majeed-Saidan MA (1989) Cystic fibrosis in Saudi Arabia. Eur J Pediatr 148:330–332 Oehlman R, Zlotogora J, Wenger DA, Knowlton RG (1993) Localization of the Krabbe disease gene (GALC) on chromosome 14 by multipoint analysis. Am J Hum Genet 53:1250–1255 Ohlsson A, Cumming WA, Paul A, Sly WS (1986) Carbonic anhydrase deficiency II syndrome: recessive osteopetrosis with renal tubular acidosis and cerebral calcification. Pediatrics 77:371–381 Oppenheim A, Friedlander Y, Dann EJ, Berkman N, Schwartz SP, Leitersdorf E (1991) Hypercholesterolemia in five Israeli Christian-Arab kindreds is caused by the “Lebanese” allele at low density lipoprotein receptor gene locus and by an additional independent major factor. Hum Genet 88:75–84 Ozand PT, Devol EB, Gascon GG (1992) Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Center. J Child Neurol 7(Suppl):4–11 Ozand PT, Gascon GG, Al-Aqeel A, Roberts G, Dhalla M, Subramanyam SB (1990a) Prevalence of different types of lysosomal storage diseases in Saudi Arabia. J Inter Metab Dis 13:849–861 Ozand PT, Gascon GG, Dhalla M (1990b) Aspartocylase deficiency and Canavan disease in Saudi Arabia. Am J Med Genet 35:266–268 Palkovic M, Rajaram LU, Al-Ghanim MM, Khawam EM, Kandil HH, Al-Awadi SA, Farag TI (1994) Hyperlipoproteinemia among Bedouins: cord blood study. Ann J Hum Genet 55 (Suppl): A1662 Panter-Brick C (1992) Coping with an affected birth: genetic counseling in Saudi Arabia. J Child Neurol 7:569–575 Parvari R, Hershkovitz E, Grossman N, Gorodischer R, Loevs B, Zecic A, Mortier G, Gregory S, Sharony R, Kambouris M, Sakati N, Meyer BF, Al Aqeel AI, Al Humaidan AK, Al Zanhrani F, Al Swaid A, Al Othman J, Diaz GA, Weiner R, Khan KT, Gordon R, Gelb BD, HRD/ Autosomal Recessive Kenny-Caffey Syndrome Consortume (2002) Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome. Nat Genet 32(3):448–452 Pras E, Aksentijevich I, Gruber L, Balow JE, Prosen L, Dean M, Steinberg AD, Pras M, Kastner DL (1992) Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med 326:1509–1513 Prezant TR, Agapian JV, Bohlman MC, Bu X, Oztas S, Qui W-Q, Arnos KS, Cortopassi GA, Jaber L, Rotter JI, Shohat M, Fischel-Ghodsian N (1993) Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and nonsyndromic deafness. Nat Genet 4:289–294 Radhakrishnan K, El-Mangoush MA, Gerryo SE (1987) Descriptive epidemiology of selected neuromuscular disorders in Benghazi, Libya. Acta Neurol Scand 75:95–100 Radovanovic Z, Shah N, Behbehani J (1999) Prevalence and correlates to consanguinity in Kuwait. Ann Saudi Med 19:206–210 Raffer K (2007) Macro-economic evaluations of Arab economies: a foundation for structural reforms. OFID Pamphlet series 36, OPEC Vienna Ramadan DG, Badawi MH, Zaki M, El Mazidi Z, Ismail EA, El Anzi H (1999) Persistent hyperinsulinaemic hypoglycaemia of infancy (nesidioblastosis): a report from Kuwait. Ann Trop Paediatr 19(1):55–59

32

A.S. Teebi

Rashed M, Ozand PT, Al-Aqeel A, Gascon GG (1994) Experience of King Faisal Specialist Hospital and Research Center with Saudi organic acid disorders. Brain Dev 16 (Suppl):1–6 Reghis A, Benabadji M, Tchen P, Kaplan JC (1981) Quantitative variations of red cell cytochrome b5 reductase (NADH-methemoglobin reductase) in Algerian populations. Hum Genet 59:148–153 Rispler-Chaim V (1993) Islamic medical ethics in the twentieth century. Leiden, New York Romdhane NA, Ben Hamida M, Mrabet A, Larnaout A, Samoud S, Ben Hamda A, Ben Hamda M, Oueslati S (1993) Prevalence study of neurologic disorders in Keliba (Tunisia). Neuroepidemiology 12:285–299 Rosenberg N, Hauschner H, Peretz H, Mor-Cohen R, Landau M, Shenkman B, Kenet G, Coller BS, Awidi AA, Seligsohn U (2005) A 13-bp deltion in alpha(llb) gene is a founder mutation that predominates in Paletentian-Arab patients with Glanzmann thrombasthenia. J Thromb Haemost 3:2764–2772 Rosler A (2006) 17-beta-hydroxysteroid dehydrogenase 3 deficiency in the Mediterranean population. Pediatr Endocrinol Rev 3(3(Suppl)):455–461 Rosler A, Belanger A, Labrie F (1992) Mechanisms of androgen production in male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 75:773–778 Saadallah AA, Rashed MS (2007) Newborn screening: experiences in the Middle East and North Africa. J Inherit Metab Dis 30:482–489 Salem M, Idrees H (1962) Cystic fibrosis in the Middle East. J Med Liban 15:61–74 Sanjad SA, Sakati NA, Abu Osba YK, Kaddora R, Milner RDG (1991) A new syndrome of congenital hypoparathyroidism, seizure, growth failure and dysmorphic features. Arch Dis Child 66:193–196 Schorr S, Legum C, Ochshorn M, Hirsch M, Moses S, Lasch EE, El-Masri M (1977) The DyggveMelchior-Clausen syndrome. Am J Toentgen 128:107–113 Scott DA, Carmi R, Elbedour K, Yosefsberg S, Stone EM, Sheffield VC (1996) An autosomal recessive nonsyndromic-hearing-loss locus identified by DNA p[ooling using two inbred Bedouin kindreds. Am J Hum Genet 59:385–391 Shaabani I, Ben-Omran T, Teebi AS (2010) Tay-Sachs disease among the Arabs. Qatar Medical Journal (In press) Shahin H, Walsh T, Sobe T, Lynch E, King MC, Avraham KB, Kanaan M (2002) Genetics of congenital deafness in the Palestinian population: multiple connexin 26 alleles with shared origins in the Middle East. Hum Genet 100:284–289 Shaltout M (1959) Al-Fatwa, General culture administration at Al-Azhar, Cairo, Egypt Sharkia ZM, Athmna A, Cohen D, Azem A, Zalan A (2008) The changing pattern of consanguinity in a selected region of the Israeli Arab community. Am J Hum Biol 20:72–77 Sheba C, Szeinberg A, Adam A, Ramot B. 1961. Distribution of glucose-6-phosphate dehydrogenase deficiency (G6PD) among various communities in Israel. International Congress, Ser 32 Excerpta Medica, Amsterdam, pp 633–634 Shoshani T, Augarten A, Gazit E, Bashan N, Yahav Y, Rivlin Y, Tal A, Seret H, Yaar L, Kerem E, Kerem B (1992) Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. Am J Hum Genet 50:222–228 Stratton RF (1991) Teebi hypertelorism syndrome (Brachycephalofrontonasal dysplasia) in a U.S. family. Am J Med Genet 39:78–80 Tabchi B, Rassi B, Akl E, Fares G (2000) Epidemiology of profound neurosensory deafness in Lebanese children. J Med Liban 48:294–297 Tadmouri GO, Al Ali MT, Al-Haj Ali S, Khaja N (2006) CTGA: the database for genetic disorders in Arab populations. Nucleic Acids Res 34:D602–D606 Tatar A, Ocak Z, Tatar A, Yesilyurt A, Borekci B, Oztas S (2009) Primary hypogonadism, partial alopecia, and Mullerian hypoplasia: report of third and review. Am J Med Genet A 149A: 501–504


33

Teebi AS (1987) New autosomal dominant syndrome resembling craniofrontonasal dysplasia. Am J Med Genet 28:581–591 Teebi AS (1994) Autosomal recessive disorders among Arabs. An overview from Kuwait. J Med Genet 31:224–233 Teebi AS, Al-Awadi SA (1985) Spondyloepiphyseal dysplasia tarda with progressive arthropathy: a rare disorder frequently diagnosed among Arabs. J Med Genet 23:189–191 Teebi AS, Al-Awadi SA (1991) Kuwait type faciodigito-genital syndome. J Med Genet 28:805–808 Teebi AS, Al-Saleh QA, Odeh H (1992) Meckel syndrome and neural tube defects in Kuwait. J Med Genet 29:140–144 Teebi AS, Daoud AS (1990) Multiple pterygium syndrome: a relatively common disorder among Arabs. J Med Genet 27:791–792 Teebi AS, El-Shanti HI (2006) Consanguinity: implications for practice, research, and policy. Lancet 367(9515):970–971 Teebi AS, Marafie MJ (1988) Uncle-Niece/Aunt-Nephew marriages are not existing in Muslim Arabs. Am J Med Genet 30:981 Teebi AS, Naguib KK, Al-Awadi SA, Al-Saleh QA (1988) New autosomal recessive faciodigitogenital syndrome. J Med Genet 25:400–406 Teebi AS, Naguib KK (1988) Autosomal recessive nonsyndromal hydrocephalus. Am J Med Genet 31:467–470 Teebi AS, Shawky RM (2000) Population and molecular genetic update: the second Middle East Genetic Association of America (MEGA) conference. Am J Med Genet 92:293–294 Teebi AS, Teebi SA (2005) Genetic diversity among the Arabs. Community Genet 8:21–26 Teebi AS, Teebi SA, Porter CJ, Cuticchia AJ (2002) Arab genetic disease database (AGDDB): a population specific clinical and mutation database. Hum Mutat 19:615–621 Temtamy SA, Adbel-Salam M, Hussein FA, Meguid NA, El-Gindy E (1991) Clinical biochemical and cytogenetic studies of mental retardation in Egyptian children. J Egypt Public Health Assoc 65(Suppl):189–199 Thomas PM, Cote GJ, Hallman DM, Mathew PM (1995) Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet 56:416–421 Tieder M, Modai D, Shaked U, Samuel R, Arie R, Halabe A, Maor J, Weissgarten J, Abverbakh Z, Cohen N, Edelstein S, Liberman UA (1987) Idiopathic hypercalciuria and hereditary hyophosphatemic rickets: two phenotypical expressions of a common genetic defect. N Engl J Med 316:125–129 Toriello HV, Delp K (1994) Teebi hypertelorism syndrome: report of a third family. Clin Dysmorphol 3:335–339 Triggs-Raine BL, Akerman BR, Clarke JTR, Gravel RA (1991) Sequence of DNA flanking the exons of the Hex A gene and identification of mutations in Tay-Sachs disease. Am J Hum Genet 49:1041–1045 Tsai AC, Robertson JR, Teebi AS (2002) Teebi hypertelorism syndrome: report of a family with previously unrecognized findings. Am J Med Genet 113:302–306 Tsukahara LM, Uchida M, Shinohara T (1995) Teebi hypertelorism syndrome: further observations. Am J Med Genet 59:59–61 Usha R, Uma R, Farag TI (1992) Late diagnosis of phenylketonuria in a Bedouin mother. Am J Med Genet 44:713–715 Vieira LM, Kaplan JC, Kahn A, Leroux A (1995) Four new mutations in the NADH-Cytochrome b5 reductase gene in patients with recessive congenital methemoglobinemia type II. Blood 85:2254–2262 Walsh T, Abu Rayan A, Abu Sa’ed K, Shahin H, Shepshelovich J, Lee MK, Hirschberg K, Tekin M, Salhab W, Avraham KB, King MC, Kanaan M (2006) Genomic analysis of a heterogeneous Mendelian phenotype: multiple novel alleles for inherited hearing loss in the Palestinian population. Hum Genomics 2:203–211

34

A.S. Teebi

Wei S, Feldman GL, Monaghan K (2006) Cystic fibrosis testing among Arab-Americans. Genet Med 8:255–258 White JM, Christie BS, Nam D, Daar S, Higgs DR (1993) Frequency and clinical significance of erythrocyte genetic abnormalities in Omanis. J Med Genet 30:396–400 World Bank (1994) Forgoing a partnership for environmental action: An environment strategy toward sustainable development in the Middle East and North Africa. World Bank Yadav GC, Reavey PC (1988) Aminoacidopathies: a review of 3 years experience of investigation in a Kuwait hospital. J Inherit Metab Dis 11:277–284 Young ID, Rickett AB, Clarke M (1985) High incidence of Meckel syndrome in Gujarati Indians. J Med Genet 22:301–304 Woods CG, Stricker S, Seemann P, Stern R, Cox J, Sherridan E, Roberts E, Springell K, Scott S, Karbani G, Sharif SM, Toomes C, Bond J, Kumar D, Al-Gazali L, Mundlos S (2006) Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. Am J Hum Genet 79:402–408 Zimmerman SA, O’Branski EE, Rosse WF, Ware RE (1999) Hemoglobin S/O(Arab): thirteen new cases and review of the literature. Am J Hematol 60:279–284 Zghal M, El-Fekih N, Fazaa B, Fredj M, Zhioua R, Mokhtar I, Mrabet A, Ferjani M, Gaigi S, Kamoun MR (2005) Xeroderma pigmentosum. Cutaneous, oscular, and neurologic abnormalities in 49 Tunisian cases. Tunis Med 83:760–763 Zlotogora J (1997) Autosomal recessive diseases among Palestinian Arabs. J Med Genet 34: 765–766 Zlotogora J, Barges S (2003) High incidence of profound deafness in an isolated community. Genet Test 7(2):143–145 Zlotogora J, Furman-Shaharabani Y, Harris A, Barth ML, Von Figura K, Gieselmann V (1994a) A single origin for the most frequent mutation causing late infantile metachromatic leucodystrophy. J Med Genet 31:672–674 Zlotogora J, Habiballa H, Odatalla BS (2002) Changing family structure in a modernizing society: a study of marriage patterns in a single Muslim village in Israel. Am J Hum Biol 14:680–682 Zlotogora J, Levy-Lahad E, Legum C, Iancu TC, Zeigler M, Bach G (1991) Krabbe disease in Israel. Isr J Med Sci 31:196–198 Zlotogora J, Sagi M, Cohen T (1994b) Familial hydrocephalus of prenatal onset. Am J Med Genet 49:202–204

Part II Demography, Economy, and Genetic Services in Arab Countries

Chapter 2

Arab Demography and Health Provision Under Stressed Economics Sulayman S. Al-Qudsi

Introduction The chapter is concerned with the dynamics of health profile of Arab economies in the changing context of demographic transitions and volatile economic growth, both globally and regionally, and in the midst of rapid technological change that transforms the health sector and changes the relative importance of health priorities, in terms of investment spending and importance at the family and public policy agenda. The dynamic transformation of the health sector is closely intertwined with socio-economic and technological developments. To illustrate, the current global economic downturn of 2008 and 2009 has adversely impacted on the region and beyond economics, specifically, the global economic downturn threatens the very sustainability of health and education progress – by reducing the ability of both households and governments to invest in education and health sectors. The crisis could lead to spending cuts if governments cannot find additional financing in the event that private capital inflows and domestic fiscal revenues drop sharply. For instance, it is estimated that a 50 percent drop from the 2007 net assistance level from advanced to developing countries would reduce health support for developingcountry health programs by more than US$ 2.5 billion (USAID, 2009). Children and young people may be pressed to drop out of school to work more hours at home or take on outside jobs. In addition, the newly emerging diseases such as Swine flu coupled with pandemics of chronic diseases are likely to challenge both

Disclaimer: All the analysis and views presented here are strictly those of the author and do not in any way represent the views or judgments of the Arab Bank or its affiliates where Sulayman Al-Qudsi works as the Chief Economist. Arab Bank is not liable in any way for the accuracy, completeness, representation, or implications of the information and opinions reported or expressed here. S.S. Al-Qudsi Chief Economist and Head of Research Department-Arab Bank, PLC. Amman-Jordan.Shaker bin Zeid Street, Shmeisani Area, 950545, Amman, Jordan e-mail: [email protected]; [email protected]


37

38

S.S. Al-qudsi

the global and regional health systems. Economic volatility and stressed financial and economic conditions with fluctuations in oil prices are likely to affect the growth of the pharmaceutical industry adversely. The economic downturns may also worsen the already high out-migration of the Arab health workforce, especially doctors, nurses, and paramedical staff. While the broad objective here is to provide a basic assessment of the Arab health profile with the overall context of Arab economic transformations both overall and among constituent economies, the chapter assesses such issues as overall health sector provision, accessibility and inequities, size of employment in the health activities, mortality and morbidity issues, and the “brain drain” of health sector workers. The chapter highlights some of the policy challenges and imperatives that the dynamic interactions between volatile economic times and demography induce for the health services provision. These imperatives require immediate policy focus to safeguard the future for successive Arab generations.

Geography, History, and Ethnicity Geographically, the Arab world straddles two continents, covering a distance of 6,370 km from Rabat on the Atlantic to Muscat on the Gulf (Bolbol and Fatheldin 2005). Representing nearly 10% of the world’s geography and with a share of 3% of the world’s GDP, the Arab World has nearly 300 million inhabitants or about 5% of the world’s population. The region gained increasing importance during the period 2002–2007, which witnessed massive increases in the prices of commodities such as oil and natural gas. Being resource-rich, the region was sizzling with economic growth and trade and investment in-and-out-flows. Many oil-exporting countries of the region experienced unprecedented growth and realized huge foreign reserves accumulations. These petro-surpluses led to enhancements of sovereign wealth funds (SWFs) that were largely invested in the international financial centers of the world, notably in the USA and the EU. Despite its linguistic, religious, and cultural cohesion, the Arab region is also rich in diversity. In territorial size, some countries (Sudan and Saudi Arabia) comprise vast areas that approach one million square miles, while others (Bahrain) are small enough to fit into a major Western city. It is the home of diverse ethnic and religious groups including Muslim and Christian Arabs, Kurds, Druze, Berbers, and Armenians. It is also a fountain of political and ideological ferment and a locus of some of the most persistently explosive conflicts in the world. No country on earth can be unconcerned with the course of major developments in the region (Held 1993). The history of Arabs goes back a few 1,000 years before Christ. The origin of the word “Arab” remains obscure, although philologists have offered various explanations. One such explanation associates the term with nomads; the root “Ahbar” means to move or pass. Arabs themselves seem to have used the word at an early date to distinguish the Bedouin from the Arabic speaking town and village dwellers;

2 Arab Demography and Health Provision

39

and indeed, this use persists to some extent (Lewis 1993). The earliest known events in Arabian history are migrations from the Arabian Peninsula into neighboring areas. About 3,500 BC, Semitic-speaking peoples of Arabian origin migrated into the valley of the Tigris and Euphrates rivers in Mesopotamia, supplanted the Sumerians, and became the Assyro–Babylonians. Another group of Semites left Arabia about 2,500 BC and settled along the eastern shore of the Mediterranean Sea; some of these migrants became the Amorites and Canaanites of later times (Bram and Dickey 1992). Beginning in the seventh century (AD), Arabs, proclaiming the new religion of Islam, ventured out from the Arabian Peninsula to conquer wide regions extending from the Arabian/Persian Gulf to the Atlantic Ocean. Arabic became the language of all the peoples who lived between Baghdad and Cordoba – a significant aspect of Islamic civilization. It became both the language of daily life and the language of science and literature, completely replacing Coptic, Aramaic, Greek, and Latin. The strategic geographical position of Islamic countries enabled them to dominate international trade in the middle Ages and to attract and nurture intellectuals from all over the world (Hassan and Hill 1986). Islamic science and medicine thrived; scholars such as Abu Bakr al-Razi and Jabir B. Hayyan were world renowned; scientific institutions flourished – for example, Bayt al-Hikma (House of Wisdom). The common denominator among residents of the Arab world is their language. Formal Arabic is the official language in all countries of the Arab League. In addition to their common language, most Arabs follow the same religion. The overwhelming majorities (over 90%) are Muslims, predominantly of the Sunni persuasion, and Islam is a vital force in everyday life. However, being the home of the three revealed religions, the Arab world is home for prominent Christian minorities especially in Palestine, Egypt, Lebanon, Iraq, and Syria. In addition, Jewish Arab enclaves live in such countries as Iraq, Morocco, and Yemen. Geopolitically, the region has been the center of intellectual debates and controversy that culminated in September 11, 2001 in the aftermath of the terrorist attack on the twin towers, which brought to the center stage the issue of the clash of civilizations. The ensuing adversarial political and military standing of the G.W. Bush administration subjected the region to wars, conflict, and mass killings and deteriorated regional integrity and cohesion. Not surprisingly, the policies were vehemently opposed by some of the region’s best think tanks. Realizing apparent deficiencies in the whole concept, they posed the counterarguement that the world is interdependent and that globalization leads to a common global destiny irrespective of the diversity of cultural and ethnic backdrop. That is to say, diversity is a common feature on earth and in fact in the whole universe and does not, per se, imply or lead to conflict. For instance, the Arab scholar, Edward Said (2001) mocked the whole thesis of clash of civilization dubbing it “the clash of ignorance” and concluded that “The real question is whether in the end we want to work for civilizations that are separate, or whether we should be taking the more integrative, but perhaps more difficult path, which is to see them as making one vast whole, whose exact contours are impossible for any person to grasp, but whose certain existence we can intuit and feel and study”.

40

S.S. Al-qudsi

Perhaps it is not difficult to understand the economic and resource underpinnings of the conflict theories. The region contains more than 60% of the world’s proven oil reserves and more than 25% of the world’s natural gas reserves. With two thirds of Arab countries producing oil, crude is undoubtedly the most important factor in the region’s economic development (Raffer 2007). The economies of the Arab world exhibit great diversity in income and structure. The variety is highlighted by the fact that GDP per capita of the wealthiest country, Qatar, is 73 times higher than that of the poorest country, Mauritania. In addition, the economies are characterized by a multiplicity of structures. Some countries have accumulated significant wealth through the extraction of natural resources, while others follow more traditional trajectories of development, starting with lower-end manufacturing and slowly moving up the value chain. These differences affect the competitive performance in many ways, the most important being the availability of resources for public investment. The organization of this chapter is as follows. Section “Stylized Economic and Financial Facts” provides an overall summary of Arab volatile economic development and economic stylized facts. The re-assessment of these stylized facts and global regional and economic turmoil is taken up in Section “Reevaluation of Stylized Facts” followed in section 3 by a review of Arab population dynamics including demographic transition and rural–urban migration. Section “Health Systems and Health Expenditures” presents the health system and the Arab health expenditures including the pharmaceuticals markets and trade. The section deals also with health inequality indicators within and across Arab countries. The final section summarizes salient issues and policy implications.

Stylized Economic and Financial Facts The conventional wisdom about Arab economies is that the region’s natural resource endowments provide ample financial capital and foreign exchange for economic diversification and for the transformation of oil wealth into versatile portfolio of human capital that could ultimately generate high value-added growth path for the Arab economies. On the downside however, Arab mineral resource endowments pose challenges associated with the so-called “resources curse” and Dutch disease syndromes which affect the exchange rates and in the process, could cause de-industrialization. Perhaps more seriously, they introduce frequent and sharp economic and financial volatilities which could set limits on the growth potential of a region that already has high population momentum and rapidly rising labor supply and high unemployment and inactivity rates. Figure 2.1A–F displays growth volatility in several Arab economies that are resource-based. The figures demonstrate how economic volatility derives in part from resource price volatility; that is how oil and natural gas prices affect the trends and cyclical patterns of economic growth of these economies. Moreover, and despite impressive transformations, the region is still considered lagging in requisite quality human capital stock which adversely affects international


41

competitiveness. In addition, compared with international levels, the annual infusions of physical capital and R&D investment rates are insufficient and the region is virtually in the early stages of fostering its organizational capabilities and corporate governance. These forces tend to drag the overall productivity to levels below the region’s long-term potential. This is corroborated by recent work that indicated that the role of total factor productivity (TFP) in determining economic growth in Arab countries is insignificant and often detrimental. Most of the growth is due to the accumulation of physical capital and improvements in the quality of labor (Al-Qudsi, 2006; Al-Qudsi and Abu-Dahesh, 2004). Last but not least, Arab economic performance has been adversely influenced by protracted conflict conditions and by geopolitical and global competition to secure reliable supply of hydrocarbon energy sources. (1980–2007) 10

300000

8

250000

6

GDP (%)

8

10

6

Natural Gas US Henry Hub ‡

GDP (LCU m) 350000

8

4

6

2 4

200000

4 0

2

2 –2

150000 1990

1980

2010

2000

Real GDP(m LCU) (LHS) Natural Gas US Henry Hub

1990

2000

2010

GDP Growth Rate% Natural Gas US Henry Hub

(1980–2007)

GDP( LCU m)

GDP(%)

120000

10

25

10

100000

8

20

8

80000

6

15

6

4

10

4

2

5

60000 40000 1990

2000

2

2010

1980

Real GDP(LCU m )(LHS) Natural Gas US Henry Hub

(1980–2007)

800000

80

700000

60

600000

40 20

500000

0

400000 1990

2000

Real GDP(LCU m)(LHS) WTI( $/bbl ‡)

Fig. 2.1 Continued

2000

2010

GDP Growth Rate Natural Gas US Henry Hub

GDP(LCUm)

1980

1990

2010

GDP(%)

10

80 60

5

40 0

20 0

–5 1980

1990

2000 GDP Growth Rate WTI( $/bbl ‡)

2010

WTI($/bbl ‡)

1980

Natural Gas US Henry Hub ‡

1980

42

S.S. Al-qudsi

(1980–2007) GDP (%)

20000

80

150

80

15000

60

100

60

10000

40

50

40

5000

20

0

20

0

0 1980

1990

2000

–50

0 1980

2010

WTI($/bbl ‡)

GDP(LCUm)

2000

1990

Real GDP(LCU m)(LHS)

2010

GDP Growth Rate WTI( $/bbl ‡)

WTI( $/bbl ‡)

(1980–2007)

GDP(LCUm)

80

400000

GDP (%)

30

80

60 10

40

40 0

200000

20

WTI($/bbl ‡)

20 60 300000

20 –10

0

100000 1980

1990

2000

0

–20

2010

1980

Real GDP(LCUm)(LHS) WTI( $/bbl ‡)

1990

2000

2010

GDP Growth Rate WTI( $/bbl ‡)

(1980–2007) GDP(LCU m)

GDP (%) 80

18000

60

16000

40

10

80

60 5 40 0

20

14000

0

12000 1980

1990

2000

2010

WTI($/bbl ‡)

20000

20

0

–5 1980

1990

2000

Real GDP(LCU m)(LHS)

GDP Growth Rate

WTI( $/bbl ‡)

WTI( $/bbl ‡)

2010

Fig. 2.1 (a) Algeria’s GDP versus natural gas price. (b) Qatar’s GDP versus natural gas price. (c) KSA’s GDP versus WTI. (d) Kuwait’s GDP versus WTI. (e) UAE’s GDP versus WTI. (f) Libya’s GDP versus WTI Source: IMF and EIU


43

Reevaluation of Stylized Facts However, these stylized facts have recently become subject to reevaluation and reassessment because of several emerging trends. First, most Arab countries have recently initiated and are implementing structural reforms that enabled them to enhance their economic growth which proceeded at an estimated average rate of 5.4% over 2000–2007, Table 2.1. While individual country growth rates varied in the latest available year, 2006, the regional average economic growth reached an all time high rate of 6.6% in 2006. Due to an amalgam of forces including the rapid population and labor growth rates and the mismatch between the education system and labor markets requirements, the region suffers from high unemployment which hovers around 15% on average. Also, while inflation used to be mild, it has recently picked up momentum, Fig. 2.2. Even in the traditionally low inflation economies of the GCC, inflation is becoming an increasingly painful issue. To combat high unemployment rates as well as the region’s rising cost of living, recent reform policies have focused on sustaining Table 2.1 Real GDP growth (Annual change, in percent) Avg. 2002 2003 1998–2001 Middle East & Central Asia 3.8 4.3 6.3 Oil Exporters 3.6 4.8 7.5 Algeria 3.6 4.7 6.9 Bahrain 4.8 5.2 7.2 Iraq 8.2 7.8 41.4 Kuwait 2.5 5.1 13.4 Libya 1.7 3.3 9.1 Oman 3.6 2.6 2 Qatar 7.4 7.3 5.9 Saudi Arabia 1.5 0.1 7.7 Syria 2.4 3.7 1 UAE 4 2.6 11.9 Low-income countries 4.9 5.4 5.9 Mauritania 3.1 1.1 5.6 Sudan 5.7 6.4 4.9 Yemen 4.3 3.9 3.1 Emerging Markets 4 3.1 4.4 Egypt 5.1 3.2 3.1 Jordan 4.3 5.8 4.2 Lebanon 1.9 2.9 5 Morocco 3.6 3.2 5.5 Tunisia 4.4 1.7 5.6 CIS 6 7.8 8.7 MENA 3.7 4.1 6.3 Of which GCC 2.5 1.6 8.5 Maghreb 3.5 3.6 6.6 Source: IMF 2008

2004

2005

2006

2007

6 6.1 5.2 5.4 46.5 6.2 4.6 5.6 11.2 5.3 3.1 9.7 6.2 5.2 5.2 2.6 5.8 4.1 8.4 6 4.2 6 9 5.4

6.3 6.6 5.3 6.9 3.7 8.5 3.5 6.7 6.5 6.6 2.9 8.5 7.2 5.4 7.9 3.8 5.7 4.9 7.2 1 1.7 4.2 10.9 5.5

6.6 6.6 4.9 7.1 4 6.2 5 7.1 6.7 5.8 3.2 11.5 9.2 14.1 12.1 3.9 5.9 5.6 6 -3.2 7.3 5.8 10.8 6.1

6.2 6.2 5 6.3 14.4 4.7 4.6 5.7 4.7 6.5 3.7 5.8 8.4 10.6 11.3 2.5 5.9 5.6 5 5 3.3 6 11 5.5

6.6 5

7.1 4

7.2 5.8

6.1 4.8

44

S.S. Al-qudsi

Jordan

Kuwait

Sep08: 18.5%

20 15 10 5 0

Apr09: –1.6%

Aug08: 11.6%

12 11 10 9 8 7

2008m1 2008m4 2008m7 2008m10 2009m1 2009m4

Jan09: 6.8%

2008m1 2008m4 2008m7 2008m10 2009m1 2009m4

KSA

Oman

Jul&Oct08: 11%

12 10 8 6 4

Apr09: 5.2%

Jun08: 14%

14 12 10 8 6

Mar09: 6.9% 2008m1 2008m4 2008m7 2008m10 2009m1 2009m4

2008m1 2008m4 2008m7 2008m10 2009m1 2009m4

Morocco 6 5 4 3 2

Tunisia Apr08: 6%

May08: 5.4%

6 5

Feb&Mar09: 3.1%

4 3

Jan08: 1.8% 2008m1

2008m4

2008m7 2008m10 2009m1

2009m4

2008m1

2008m4

2008m7 2008m10 2009m1

2009m4

Fig. 2.2 Consumer price index, selected countries Source: Economic Intelligence Unit, EIU

economic growth, and curbing inflation and joblessness, the three main challenges faced by Arab economies in general. Second, the utilization of “petro-dollar” surpluses in the oil-producing Arab countries appears more prudently managed, which induced favorable internal and external balances relative to historical records. For instance, Saudi public debt has declined from 93% of GDP to the current 28%. In the non-oil-exporting countries of the Mashreq region, growth accelerated in 2006 in the context of an upturn in foreign direct investment and an overall favorable external environment. Third and equally important, however, is the fact that, in the course of time, Arab countries have gradually nurtured their nascent and banking. Infrastructures and applied policies that incrementally benefitted from the oil-induced financial surpluses on one hand and also embodied invaluable lessons gained from stressful financial episodes that occurred in other regional settings in Asia, North and Latin Americas, and Europe. The sustained growth of the region during 2002–2008 came to a halt when the global economy was hit by the financial crisis which initially started with the subprime crisis in the USA in August 2007 but was rapidly transmitted into Europe and the emerging economies including that of the MENA region. These profound developments were transmitted to the region and by now, there is little doubt that


45

Arab economies in the Middle East and North African region, MENA, have been adversely affected by the global economic downturns. The main drivers of the contraction were lower and more volatile oil prices, reduced trade and contracted investment flows, and reduced trade and investment flows and lower investor and consumer confidence in key sectors such as construction and real estate. To exacerbate the downward trend, many government and private investors and SWFs in our region have endured major investment losses. According to one estimate by a senior GCC minister and Kuwaiti Harvard graduate, Dr. Mohammed Al-Sabah, “the financial crisis has cost the Arab world US$2.5 trillion in the past 4 months alone”. He estimates that “Up to 60% of the region’s development projects had been canceled or postponed”. The crash in oil prices has hit the region just as hard.

Arab Population Dynamics According to the revised population estimates of the United Nations, the population of Arab countries rose from 171.6 million in 1980 to 300.2 million in 2002. Table 2.2 summarizes population estimates in selected Arab countries. In terms of medium variant projections, the population of the 22 countries of the Arab region is expected to reach 385.2 million in 2015 and 631.2 million in 2050. The average, Table 2.2 Population in Arab countries, figures in thousands (2001–2007) Country Populations 2001 2002 2003 2004 2005 2006

Gr. rate 4,940 5,070 5,200 5,350 5,470 5,595 5,724 2.3 3,488 3,754 4,041 4,368 4,105 4,175 5,215 1.72 654.62 672.123 689.418 707.16 724.695 742.561 760.168 1.68 9,650.6 9,748.9 9,839.8 9,932.4 10,031.1 10,130 10,238 1.08 3,083 31,281 31,738 3,236 32,786 33,278 33,810 1.6 545 557 570 583 600 616.8 618.9 3 20,957.6 21,486.72 22,022.11 22,563.89 23,118.99 23,678.8 24,242.6 2.4

Jordan UAE Bahrain Tunisia Algeria Djibouti Saudi Arabia Sudan 31,913 32,769 33,648 Syria 16,720 17,171 17,635 Somalia 9,691 9,787 9,885 Iraq 24,813 25,565 26,340 Oman 2,478 2,538 2,341 Palestine 3,381.75 3,562.001 3,844.044 Qatar 648.744 682.434 717.766 Kuwait 2,182.61 2,262.959 2,325.44 Lebanon 3,636 3,675 3,714 Libya 5,300 5,581 5,669 Egypt 65,298 66,628 67,976 Morocco 29,170 29,631 30,088 Mauritania 2,568 2,669 2,913 Yemen 18,948 19,631 20,357 Total 287,814 294,722.1 301,553.6 Source: WHO, Statistical database, 2009

34,512 17,793 9,983 27,139 2,416 3,922.06 744.029 2,390.591 3,754 5,880 69,330 30,590 2,983 21,104 279,281.1

35,397 18,138 10,082 27,954 2,452 4,106.455 789.392 2,457.257 3,794 6,097 69,997 31,101 3,054 21,868 314,122.9

35,470 18,581 10,083 28,793 2,489 4,297.07 885.359 2,525 3,835 6,263 70,473 31,620 3,186 22,649 319,366

2007

36,400 19,175 10.184 29,656 2,526 4,491.72 918.16 2,666.4 3,876 6,431 71,844 32,150 3,262 23,464 317,479

2.63 2.45 1 3 1.5 3.4 1.5 5.6 1.07 2.7 1.9 1.5 2.4 3.5 2.4

46

S.S. Al-qudsi

exponential growth rate of 2.6% per annum during the period 1980–2002 could drop to 1.9% per annum during 2002–2015, and is likely to fall after 2025 to approximately 1.3% per annum during the period 2025–2050. High population growth rates reflect high fertility. In fact the single most remarkable demographic aspect of the Arab region is the nearly universal high level of fertility – the average level of childbearing is six children per woman. While fertility levels are high in general, disparities exist within and across countries. In Algeria in 1988, for instance, women still gave birth to more than six children in the southern part of the country but less than four in the north. Lebanon, despite its small size, harbors strong regional contrasts: Beirut (2.3 children/woman) versus the north (4.3 children/woman), for instance. In Egypt, the average family numbers only 3.6 children in Port Said but 8.2 in Fayoum (Fargues 1994). Similar to other developing regions, fertility did drop markedly, however, when considered over longer time horizons. For instance, it dropped from 5.7 births per woman in Egypt during the 1970–1975 to 3.3 births per woman during 2000–2005. Similar downward trend is discerned in other countries: in Iraq the corresponding drop was from 7.2 to 4.8 live births per woman during 1975–2005. Jordan’s total fertility dropped from 7.8 to 3.5 and in Lebanon, the drop was from 4.8 to 2.3 live births per woman. In Saudi Arabia, the drop was from 7.4 to 4.1 and in Syria total fertility declined from 7.5 to 3.5 live births per woman (Sanchez-Barricarte and Veira-Ramos 2008). The region’s rapid population growth was the result of a substantial decline in mortality triggered by the increasing use of antibiotics, by vaccinations, and by the spread of disease control and sanitation programs. Most countries of the region have made considerable progress in improving health conditions for their citizens, and these conditions still fall short of aspirations. “Good health” is obviously a multidimensional, complex phenomenon; measuring it is correspondingly difficult. Life expectancy at birth and infant mortality rates are two indicators of health conditions that are widely used. Life expectancy at birth has improved substantially throughout the Arab world. In most countries, a newly born child can expect to live 20 years longer than his or her parents. While mortality in the MENA declined over time, the decline in the number of “births per woman” did not occur until the mid-1970s and beyond as discussed earlier. As a result, the second half of the twentieth century witnessed explosive population growth throughout the region as births far outnumbered deaths. The region’s growth rate reached a peak of 3% a year around 1980. Currently, the population of MENA is growing at about 2% a year, still higher than the world average. The world as a whole reached its peak of population growth of 2% a year in the mid-1960s and is currently growing at 1.2% a year. The aforementioned demographic pattern produced youthful population structure and invariably reduced the median age of the Arab countries as shown in Table 2.3. One of the results of the youthful population structure is the rapid increase in labor force and in the face of sluggish economic growth and inability to create productive jobs; unemployment rates remain high, greater than 25% for the young age cohorts.

2 Arab Demography and Health Provision Table 2.3 Demographic and socioeconomic statistics Median Under Over Annual growth rate age 15(%) 60(%) (%|) 2007 2007 2007 1987–1997 1997–2007 Egypt 23 33 7 2 1.8 Jordan 22 36 5 4.5 2.7 Kuwait 30 23 3 0.5 4.4 Lebanon 28 28 10 2.3 1.2 Libya 25 30 6 2.1 2 Morocco 25 29 8 1.7 1.2 Oman 23 32 4 3.2 1.3 Qatar 31 21 3 3 4.2 Saudi Arabia 24 34 4 2.9 2.5 (KSA) Sudan 20 40 6 2.5 2.2 Syria 21 36 5 2.8 2.6 Tunisia 28 25 9 1.8 1.1 UAE 30 20 2 5.5 4.7 Yemen 17 45 4 4.2 3 Source: WHO Statistics, 2009

47

Living in urban areas (%) 1990 2000 2007 43 42 43 72 80 78 98 98 98 83 86 87 79 83 77 48 55 56 65 72 72 92 95 96 77 80 81 27 49 60 79 21

36 50 63 77 25

43 54 66 78 30

The high population growth rates make the population histograms of many Arab countries flat-based, reduce the doubling time (the time during which the population will become double its current size if population growth rate remain at current levels), enhance the population momentum, increase the dependency ratio, and temporally put tremendous pressure on the labor markets. Such transition crops the question about the demographic consequences for longrun per capita GDP growth. Recent research has highlighted the importance of demographic transitions in explaining cross-country differences in per capita GDP growth. In short, what matters for economic growth is not the rate of population growth per se, but rather the changing age distribution of populations as countries move from conditions of high fertility and mortality to low levels in both. Thus, when a large share of the population is dependent, nonworking, and under the age of 14 or over 65, an economy carries a demographic burden that lowers labor input per capita, depresses the savings rate, and reduces the rate of GDP per capita growth. This was the case in Asia and Latin America in the 1950s and 1960s. Conversely, countries are endowed with a demographic gift when a larger share of the population is economically active (between the ages of 15 and 64), raising the labor force per capita, capital accumulation, and GDP per capita growth as was the case in Asia during the miracle years of the 1970s and 1980s, East Asia in particular. From this perspective, one is able to understand the role of demography in MENA in the past and its potential contribution in the future (Yousef 2005). Because of the dynamics of international migration that the region witnessed during the past decades, many countries of the region have a high male-to-female sex ratio. In the oil-producing countries, for instance, the selectivity of the immigration process and policies render the sex ratio predominantly male. In fact, seven Arab countries top the list of the world’s most-male countries. In the United Arab

48

S.S. Al-qudsi

Emirates, there are 206 men for every 100 women; Qatar, 168; Bahrain, 145; Kuwait, 133; Saudi Arabia, 119; Oman, 110; and Libya, 110 (The Economist 1991). Dynamic population mobility is yet another notable characteristic of the Arab Middle East, both by choice and necessity. For example, the Bedouins of the Arabian Peninsula migrate from one geographic location to another in search of hunting and grazing land. Other movements are mandated by political reasons, such as the displacement of Palestinians in 1948 following the establishment of the state of Israel. Similarly, Syrians, Egyptians, and Lebanese have all been subjected to displacement due to the Arab-Israeli wars; the Lebanese conflict has led to massive population dislocation; the Iraq–Iran war has led to a large influx of Kurds into Turkey; and the conflict between the North and the South in Sudan has led to movement of refugees to the capital and other cities, creating large squatter settlements. Other forces causing population displacement include man-induced engineering developments. For instance, the construction of the Aswan Dam in 1964 submerged agricultural land in Aswan and Merowe in Egypt and Sudan, respectively. The Nubians who inhabited the areas were forced to resettle in large numbers. During the Arab oil decade of the 1970s, over three million workers migrated from “labor surplus” Arab countries to the Gulf and Libya, making up for labor shortages and helping to sustain development efforts. Most recently, the Gulf crisis and war led to the displacement of several million “third-country nationals”, including 500,000 Palestinians, one million Yemenis, 800,000 Egyptians, and several hundred Sudanese from Kuwait, Iraq, and Saudi Arabia (Shami 1993; Al-Qudsi et al. 1993).

The Population Aging Problem Currently, nearly 21% of the population in advanced countries is 60 years of age or older, which is three times the corresponding rate in developing countries where the ratio is 8.4%. The U.N predicts that globally, the percentage of people aged 65 years or older will double between 2007 and 2050. By 2050, one-third of the population in developed countries will be 60 years or older, while in less-developed countries, one fifth (20%) will be over 60(WEF 2008). MENA countries encounter somewhat of a variant aging issue however: Specifically, the growth rate of the urban population of the elderly is found to exceed the rural growth rate. Indeed, some countries are projected to lose their rural populations in that age segment by 2015. This unexpected trend could stem from factual errors in the data. In fact, with the rapid mortality transition, the absolute number of survivors and therefore, the percentage of the old population are expected to increase. However, owing to the above-mentioned assumption of a constant age structure of the rural population, the elderly segment does not show the change in the percentage of rural population, thereby suppressing the effect of aging on the age structure of the rural population. Moreover, given that the urban population was obtained as the residual of the total projected population, the urban population could be overestimated in the 65+ group, which could account for the high urban


49

growth rate observed for that age segment of the population. However, migrations away from rural areas for the 65+ group could equally stem from a lack of rural infrastructure, particularly in the health and economic sectors. A majority of those engaged in economic activity in old age could lack adequate cover under social security schemes and therefore feel compelled to move to urban areas in search of employment (ESCWA 2007 Population Aging in Arab Countries UN, NY).

Rural-to-Urban Migration According to a study by ESCWA (2007), available evidence suggests a migration from rural to urban areas, particularly in working-age groups, to varying degrees of magnitude across the Arab region. Generally, this phenomenon is supported by the age-structural transition of the urban populations of the eight selected Arab countries and by the analysis of trends in the growth rates of rural and urban populations. A downward and sometimes negative growth rate of rural population in some countries suggests a heavy rural-to-urban shift; and the upward trend in the growth rate of urban populations is expected to continue unabated until 2015. In addition, and in tandem with the pattern in many developing countries, aging of rural populations is now well underway in Arab countries. The phenomenon of aging comprises both population aging and individual aging, which represent macro and micro concepts of aging. The former refers to aging of populations in an aggregate sense whereby the structure of a population by age and gender, which is represented by a pyramid, undergoes a shift as a result of changes in mortality, fertility, and migration flows. Individual aging, on the other hand, is solely influenced by reductions in mortality rates and has not contributed to a significant degree toward rural aging in the Arab region. Utilizing the aforementioned ESCWA study, in Table 2.4 three

Table 2.4 Indices of aging for rural and urban populations of selected Arab countries Country Rural Urban 1980 1980 2000 2015 AI YDR ODR AI YDR ODR AI YDR ODR AI YDR ODR Egypt 8.2 73.0 6.0 10.9 79.2 8.6 20.8 45.0 9.4 45.0 25.4 11.4 Iraq 5.7 98.9 5.6 6.7 92.1 6.2 7.1 69.6 4.9 10.6 46.6 5.0 Jordon 5.9 83.9 5.0 6.5 120.0 7.8 7.2 67.6 4.9 14.2 44.3 6.3 Morocco 18.5 39.9 7.4 4.7 198.0 9.3 11.4 68.5 7.8 23.9 39.8 9.5 Tunisia 15.4 66.9 10.3 4.1 88.3 3.6 22.4 37.9 8.5 46.8 19.6 9.2 Syrian Arab 9.3 42.7 4.0 3.7 88.3 10.7 6.3 37.9 7.4 10.4 19.6 7.1 Republic Somalia 3.3 90.2 3.0 14.1 286.5 10.7 4.9 117.5 7.4 11.3 67.9 7.1 Yemen 7.2 118.8 8.5 6.5 82.1 5.3 NA 54.3 NA 16.5 27.7 4.6 Source: ESCWA 2008 Note: AI, YDR and ODR refer, respectively to aging index, young dependency ratio and old dependency ratio. NA Indicate that data are not available

50

S.S. Al-qudsi

indices of aging are presented for rural and urban populations of selected Arab countries, namely, the aging index (AI), which measures the number of 65+ per 100 persons aged 15 years and under; the young dependency ratio (YDR), which measures the number of persons aged 15 years and under per 100 persons aged 15–64 years; and the old dependency ratio (ODR), which measures the number of 65+ per 100 persons aged 15–64 years. Within the context of the latter, it is important to note that labor force participation is higher among the elderly in Arab countries where more than 38% were still working as against 27% in developed countries (ESCWA 2007). The AI for rural population is highest in Morocco (18.5%), followed by Tunisia (15.4%). In the other countries, the index ranges between 3.3% in Somalia and 9.3% in the Syrian Arab Republic, thereby suggesting that the aging process is considerably slower in the rural populations of Arab countries. However, the AI is expected to rise in the wake of drops in fertility and increases in life expectancy. The rural YDR is comparatively high in all eight selected countries, particularly in Yemen, Iraq, Somalia, and Jordan. This could be attributed to prevailing high fertility in rural areas coupled with shrinking rural populations, owing to migration of economically active age groups.

Health Systems and Health Expenditures The health system of Arab countries tends to be pluralistic and segmented with many different public and private providers and financing agents. In general, financing agents are the public sector, the private sector such as private insurance companies, unions, professional organizations and NGO’s, and finally the household sector. The public sector provides health care through government hospitals and clinics, teaching, and university hospitals. The provision of health in the private sector occurs through a suite of profit and nonprofit providers including medication for service charges and fees, charity hospitals, pharmacies and clinics. Health expenditure has increased markedly over time. Table 2.5 records comparative data on the health expenditures both as shares of each country’s GDP and by private and public sector spending. Expenditure on health in Arab countries was generally in the vicinity of 4.5% of GDP versus globally this ratio was about 8.7% of GDP, with the highest level in the Mashreq (Jordan 9.9%) and the lowest in the GCC (Kuwait 2.2%). This translates to 116 USD per capita on average but varies however from low per capita levels in Syria to US$ 2,753 in Qatar. The provision of health requires the sufficient availability of good-quality staff, that is the number of health workers and their proficiency. Table 2.6 shows health workforce data in a set of Arab countries. Unequivocally, Qatar leads in terms of density (providers per 10,000 populations) in the case of physicians and dentistry providers. Two favorable factors induce these outcomes: small population size and

6.2

37.1 47.6 43.7 72.9

46.4

44.8 25.6 40.4 48.5 78.6

Source: WHO, 2009

41.9

4.2 7.2 6.5 6.8 7.6

77.3 27.5 66.4 75.4 40.7 55.6 72.5 42 78.9 46.8 70.2 35.9 84 16.4 78.1 77.2

73.3 1 67.5 67.8 40.1 37 34.2 46.6 78.1 30 60.7 31.2 83.6 20 68.8 76.4

Algeria Afghanistan Bahrain Djibouti Egypt Iran Iraq Jordan Kuwait Lebanon Libya Morocco Oman Pakistan Qatar Saudi Arabia Somalia Sudan Syria Tunisia United Arab Emirates Yemen

General government expenditure on health as percentage of total government expenditure, 2000 9 1.1 10.2 12 7.5 9.6 1.3 10.3 8.8 7.8 6.9 4.3 7.3 1.8 5 9.2

Gov. expenditure on health(%) of total exp. on health, 2000

Country

Gov. expenditure on health(%) of total exp. on health, 2006

5.6

6.3 5.9 6.5 8.7

General government expenditure on health as percentage of total government expenditure, 2006 9.5 4.4 9.5 13.4 7.3 9.2 3.4 9.5 4.9 11.3 6.5 5.5 5.4 1.3 9.7 8.7

Table 2.5 Health expenditure Indicators in the Mena Region

28

8 8 43 177 478

97 25%), Qatar (45%) , and the United Arab Emirates (>60%) and also in Japan (>45%) in comparison to the other Arab countries and developed countries included in the chart (Fig. 3.8) (World Health Organization 2007b). This probably calls for NBS and genetic services among other measures to be on the primary list of national health services for these nations. The ECOSOC of the United Nations (UN), the WHO, and development aiding banks assess progress in countries by several outcome and process indicators. One category of these indicators involves the measure of extent of access, especially of the poor, to such basic government services as health, education, infrastructure, water, and power at the local level (United Nations 2004). A simple mode for estimating the overall national competencies including the capabilities and resources of healthcare services is by the measuring of the level of access to improved drinking water sources, and improved sanitation. Two charts (Figs. 3.10 and 3.11) demonstrate the percentages of population with sustainable access of both improved drinking water and improved sanitation in the Arab nations. Both these figures demonstrate the level of inequity (if existing) of allocation of water and/or sanitation services between rural and urban areas in each Arab

Fig. 3.10 Sustainable access of improved drinking water in Arab countries

3 Influences of Systems’ Resources and Health Risk Factors on Genetic Services

77

Fig. 3.11 Sustainable access of improved sanitation in Arab countries

country. This will shed light on probable parallel trends in the existence of other basic infrastructures like electricity, waste disposal, and roads. This will also reflect presence of matching trends in the healthcare services provided. This is because a prerequisite for establishment and proper operation of any health facility is the presence of constant and intact infrastructures. Each country, Arab or otherwise, that displays major disparities between its rural and urban areas is ethically required to examine the health allocation disparities that will definitely arise if it chooses to introduce what it will term a “national” NBS and genetic testing service. This is because, to be effective these services demand the presence of not only intact national infrastructures, but also dedicated and constant financial resources; equipped facilities; modern modes of communication like telephones, faxing, and Internet; prompt and constant delivery of health services; unremitting follow-ups; and experienced workforce. An alternate route for countries facing such type of situation is to provide NBS and genetic testing services as a high-risk approach or as a supplemental testing service, and then nationalize these services as conditions improve. In conclusion, the product of the different mortality rates and profiles in each country, coupled with inadequate rural and in some cases even urban access to both improved drinking water and improved sanitation, highlights the extent of demands on basic infrastructure as well as on primary health services in each Arab country. Bearing in mind that as per the WHO, high-quality health care is defined by the criteria of effectiveness, cost, and social acceptability, assuring primary health care will probably take precedence over services like NBS and genetic testing for a few

78

A.A Saadallah and A.S Teebi

years to come in several of the Arab countries. That is, if countries with such parameters are seeking to satisfy equity, quality, and efficiency of their health services on a national level.

Projection of Health System Performance This section of the chapter will try to provide some insight into a simple mode for directly predicting overall performances of health systems on national levels. It is by examining health services coverages as monitoring (1) the percentages of antenatal care coverage, (2) the percentages of births attended by skilled health professionals, and (3) the percentages of children immunized. Even though monitoring the percentages of antenatal care coverage is a simple mode for directly predicting the overall performances of national health systems of the 22 Arab countries, Bahrain, Morocco, Oman, Saudi Arabia, and UAE did not measure and/or did not report such data to the relevant WHO regional offices. Information available on this performance measure is as follows. There are six data points for “at least one visit of antenatal care coverage”, four of which have less than 80% of their pregnant population receiving at least one antenatal care visit (66.7%). Also, there are 14 data points for “at least four visits of antenatal care coverage,” 11 of which have less than 80% of their pregnant population having at least four antenatal care visits (78.6%). The dual situation of missing data and nonoptimal antenatal care services are not encouraging as these trends could occur with delivering babies or measuring the performance indicators of national NBS programs, as short-term and long-term follow-ups of screened children. Thirteen of the 22 Arab countries are close to 90% or even above in the parameter of the percentages of the births that are attended by skilled health professionals (Fig. 3.12). On the other hand, less than 80% of the births are attended by skilled health professionals in Egypt, Iraq, Morocco, Somalia, Sudan, Yemen, Comorous, and Mauritania. A small percentage of these numbers are due to local customs of preference to home births over births in health centers or hospitals. Another important type of national health services is that of nationwide vaccination coverages. Closer examination of vaccination trends provides some insight for gauging overall performances of health systems on national levels. This is because, for a country to provide vaccination services to all its newborns and children, it needs to solicit participation of several branches of its health system on a national level. This national vaccination service activity parallels what will be needed to establish newborn and genetic testing systems on a national level. But we need to be cautious, as newborn and genetic testing systems are at a more complex and demanding levels. Data on vaccination of 1-year-olds immunized by one dose measles immunization and 1-year-olds immunized by three doses DTP3 (diphtheria, tetanus, pertussis) immunization in most Arab countries are comparable to those in developed countries. It is evident that Comoros, Djibouti, Mauritania, Somalia, Sudan, and Yemen have the lowest immunization rates


79

Fig. 3.12 Births attended by skilled health professionals

compared to the rest of the Arab countries. This is expected as these six countries are categorized as least-developed (GNI per capita less than $750, weaknesses in human resources, and economic vulnerability) as per the ECOSOC of the United Nation (UN Office of the High Representative for the Least Developed Countries 2008). The coming section displays available genetic services in the Arab world as to date.

Genetic Services in the Arab World Excluding Gulf Cooperation Council (GCC) countries, Lebanon, Egypt, and Jordan, medical genetic services in Arab countries are generally considered scant. One of the early genetic services offered to the public was in Egypt as part of university research. Late Dr Nemat Hashem of Ain Shams University in Cairo started some genetic service in the early 1960s; later on, other academic institutions in Cairo became involved. In 1966, Dr S. Temtamy earned her Ph.D from John Hopkins University on her work on limb malformations and that formed the basis of the book that was co-authored with Dr McKusick. Following this, she initiated the department of Human Genetics within the National Research Centre in Cairo. Later on, the department expanded remarkably to include a large number of

80


researchers and clinical geneticists, many of whom were students of Dr Hashem and Dr Temtamy. Later on, Alexandria University developed genetic counseling services (Dr S. Rushdy). This was followed by the development of services by departments at the Universities of Mansoura, Suez Canal, Assuit, October 6, and other universities. Most of these services remained to be selective. In early 1960s, cytogenetic services became available in Lebanon, offered by the American University of Beirut. Dr V Der Kaloustian was the leading geneticist in Lebanon since his return from USA after he finished his training in Medical genetics in late 1960s. He published his famous book on Genetics of Skin Disease while in Lebanon. After he left for Canada in the 1990s, a new generation of geneticists from different places continued to provide services in Lebanon; however, services remained scattered and not sufficient. In Kuwait, Dr O Alfi initiated a cytogenetic laboratory and a genetic clinic in late 1960s. This continued only for a few years, as he decided to immigrate to the USA. However, comprehensive genetic services started in Kuwait in 1979 led by Dr S. Al-Awadi. A group of geneticists/pediatricians including Dr T Farag, Dr K Naguib, and Dr A Teebi were instrumental in providing high standard of services and research that included neonatal screening. The invasion of Kuwait in 1990 caused delays in the development of more genetic services. They later developed but at a slower pace, in particular with regard to neonatal screening. In Saudi Arabia, King Faisal Specialist Hospital and Research Centre (KFSH & RC) represents the leading comprehensive genetic service since its establishment in late 1970s. Dr N Sakati who had pediatric genetic and endocrinology training in the USA was recruited to be the first geneticist there. The clinical care provided at KFSH & RC covers diagnostic, therapeutic, and preventive interventions with the presence of molecular, biochemical, and cytogenetics laboratories, advanced treatment modalities, and the availability of preventive interventions via prenatal diagnosis, preimplantation genetic diagnosis, and carrier screening, in addition to well established genetic counseling services. Both Dr P Ozand and Dr M Rashed left important landmarks during their service in the metabolic clinics and laboratories. Less comprehensive, genetic services are also provided in other Saudi healthcare institutions as in ministry of Health (MOH) tertiary centers, the National Guard, and Military Hospitals; however, most of the services cluster in the capital, Riyadh, with scattered services offered in other regions. In the mid-1980s, a number of genetic clinics were developed in Bahrain, Oman, and UAE and were supported by cytogenetic facilities; some were noticeably expanded to involve molecular genetics and biochemical genetics laboratories. The large number of genetic publications from UAE (Dr L Al-Gazali) and Oman (Dr Anna Rajab) reflects the richness and diversity of clinical cases as well as the scholarly activities of the physicians involved. Many of such publications are cited elsewhere in this book. In Qatar, the move was fast to include comprehensive genetic services including premarital counseling and expanded neonatal screening, within less than 20 years from the start of small cytogenetic laboratory at the main hospital in Doha in the early 1990s.


81

In Tunisia, similar to Egypt and Lebanon, some genetic services were offered as part of research at universities or research centers. The interest in neurogenetic disorders was clear since the 1970s (Dr M Ben Hamida) from the National Neurology Institute and then from Pasteur Institute. The involvement of other groups came with the work of Dr H Chaabouni in the field of pediatrics genetics and genetic counseling since the mid-1980s. Now, several centers across the country offer diagnostic as well as counseling services but are still far from being comprehensive or sufficient. The published work of Dr H Hamamy from Iraq and Dr M Salih from Sudan points to some genetic services including diagnostic facilities that were available in academic centers in their respective countries since the 1980s. However, it remained fragmented because of the political situation or the lack of funding. In Jordan and Morocco, some cytogenetic and molecular diagnostic facilities were available since early 1990s. Clinical genetic services are available in one or two locations in the country based in a university or an academic center. However, such services are far from being able to cover the need of the population. In Syria and Libya, very little diagnostic and clinical genetic services are offered by pediatricians and other nongenetic specialists. Genetic testing is sent abroad on demand basis only. In Comoros, Djibouti, Mauritania, Somalia, and Yemen, such services are virtually not available.

NBS in the Arab World In 2008, the second newborn conference of the Middle East and North Africa NBS initiative was held in Cairo with representatives from most Arab countries excluding Algeria, Comoros, Djibouti, Iraq, Mauritania, Somalia, and Sudan. Representatives were asked to identify the current status of NBS in their countries. According to their responses, the countries were put into three groups (Krotoski et al. 2009). Group 1 included countries that have not begun national NBS. The countries are Libya, Morocco, Syria, and Yemen. Morocco and Syria, however, had developed plans to start some NBS in particular for congenital hypothyroidism. Group 2 included countries that have completed pilot studies for at least one condition and anticipated expansion to national programs. Countries in this group are Jordan, Kuwait, Lebanon, and Tunisia. Group 3 countries included Bahrain, Egypt, the Palestinian Authority, Oman, Qatar, Saudi Arabia, and United Arab Emirates. All countries in this group screen for at least one condition, primarily congenital hypothyroidism, and most screen for two or more conditions. Saudi Arabia and Qatar use tandem mass spectrometry (MS/MS) for a large panel of metabolic conditions. There is growing recognition in the Arab World of the importance of NBS and its role in preventing or ameliorating mental retardation, physical disability, neurological damage, and even death in disorders amenable to NBS, particularly in those conditions in which treatment is simple and relatively inexpensive (Saadallah and Rashed 2007).

82


Common barriers for implementing NBS were the need of trained professionals and obtaining financial and political support. Other difficulties included the issue of geographic challenges due to large distances and isolated areas, as well the need for policies to mandate NBS.

Conclusion We have attempted to give a comprehensive preview on both the national and healthcare levels to evaluate some of the resources, burdens, strengths, and weaknesses that affect national health systems in their respective Arab countries. Topics discussed included healthcare systems and services, development levels, health resources including human and financial, risk factors and demands, projection of performance, and genetic services and NBS in the Arab world. This collective view will probably help to answer the questions posed at the beginning of this chapter. Can national healthcare systems of the Arab nations, most of which are developing, accommodate neonatal screening and genetic testing as a standard service? Moreover, could these services prove to become efficient and equitable as part of a national public health service? On the other hand, should these services only become a high-risk approach, or a supplemental testing? Even though the directions of responses to these and other questions could seem evident from the statistics and the charts, the final answers lie mostly in the hands of authorities of each country on the basis of its assigned health goals and priorities. At the end, it is pertinent to add that the goals for national health systems are good health, responsiveness to the expectations of the population, and fair financial contribution (World Health Organization 2000).

References Alliance for Health Policy and Systems Research, Geneva (2004) Strengthening health systems: the role and promise of policy and systems research. http://www.who.int/alliance-hpsr/ resources/Strengthening_complet.pdf Department of Child and Adolescent Health and Development of the World Health Organization (n.d.) (IMCI) Technical seminar on the sick young infant. http://www.who.int/child-adolescenthealth/New_Publications/IMCI/WHO_FCH_CAH_01.10/Young_Infant/TS-Sick_Young_ Infant.doc Goldman DP, McGlynn EA (2005) U.S. health care. Facts about cost, access, and quality. http:// www.rand.org/pubs/corporate_pubs/2005/RAND_CP484.1.pdf Krotoski D, Namaste S, Raouf RK, El Nekhely I, Hindi-Alexander M, Engelson G, Hanson JW, Howell RR, on behalf of the MENA NBS Steering Committee (2009) Conference report: second conference of the Middle East and North Africa newborn screening initiative: partnerships for sustainable newborn screening infrastructure and research opportunities. Genet Med 11(9):663–668


83

Saadallah A, Rashed M (2007) Newborn screening: experiences in the Middle East and North Africa. J Inherit Metab Dis 30:482–489 The Group of 77 at the United Nations (2006) Conclusions and recommendations of the meeting of ministers of science and technology. Meeting of the ministries of science and technology of the member states of the Group of 77. Angra dos Reis, Rio de Janeiro, Brazil. http://www.g77.org/ mmst/conclusion.html The Group of 77 at the United Nations (2008a) About the group of 77. http://www.g77.org/doc/ The Group of 77 at the United Nations (2008b) Member states of the group of 77. http://www.g77. org/doc/members.html UN Office of the High Representative for the Least Developed Countries, Landlocked Developing Countries, and Small Island Developing States (UN-OHRLLS) (2008, July 17) The criteria for identification of Least Developed Countries. LDCs. http://www.un.org/special-rep/ohrlls/ldc/ ldc%20criteria.htm United Nations (2004) Economic and Social Council. Supplement 13. Committee for Development Policy. Report on the sixth session, 29 March-2 April 2004. http://www.un.org/specialrep/ohrlls/ldc/E-2004-33.pdf World Atlas (n.d.) http://www.worldatlas.com/webimage/countrys/asia/arableag.htm World Health Organization Regional office of the Eastern Mediterranean (2005) Palestine. http:// www.emro.who.int/emrinfo/index.asp?Ctry=pal World Health Organization (2000) The world health report 2000. Health systems: improving performance. http://www.who.int/whr/2000/en/ World Health Organization (2006a) WHO statistical information system. WHOSIS. Core health indicators. http://www.who.int/whosis/database/core/core_select.cfm World Health Organization (2006b) The global shortage of health workers and its impact. Fact sheet N 302. http://www.who.int/mediacentre/factsheets/fs302/en/index.html World Health Organization (2007a) Human resources for health. http://www.who.int/whosis/ indicators/2007HumanResourcesForHealth/en/index.html World Health Organization (2007b) World health statistics 2007. http://www.who.int/whosis/dat abase/core/core_select.cfm?strISO3_select=btn&strIndicator_select=healthpersonnel&int Year_select=latest&language=english

Chapter 4

Endogamy and Consanguineous Marriage in Arab Populations Alan H. Bittles and Hanan A. Hamamy

Introduction Arabs are a Semitic people basically defined as individuals speaking Arabic as their native tongue, although with many different dialects, who self-identify as being of Arab ancestry. The Arab world extends from Iraq and the Gulf States in the east to Morocco and Mauritania on the Atlantic coast of North Africa in the west, and through time it has incorporated many populations with ancestral origins outside the Arabian Peninsula. Large Arab communities are now permanent residents in Western Europe, North and South America, and Australia, and so the global Arab population is estimated to number 300–350 million (Hamamy and Bittles 2009). All Arabs share certain core cultural values and beliefs, with the family accepted as the central structure of society. Marriage is primarily regarded as a family matter and arranged marriage is widespread within all Arab societies. The practice of arranged marriage does not entail a union contracted against the will of the partners but essentially reflects the fact that the marriage has been mutually agreed by both families on familial and traditional grounds.

Traditional and Contemporary Patterns of Endogamy in Arab Societies Although social life and identity traditionally focuses on the family, family ties extend into the structure of clans and tribes, and for this reason an individual’s sense of loyalty continues to be oriented to extended patrilineal kin relations, i.e., the hamula or clan, and more widely to the tribe. Family support is expected in all A.H. Bittles (*) Centre for Comparative Genomics, Murdoch University, South Street, Perth, WA 6150, Australia e-mail: [email protected]


85

86

A.H. Bittles and H.A. Hamamy

circumstances, and so “one turns to a member of the family for assistance in almost any area, whether it is a question of health, financial need, employment, or even admission to school” (Khlat 1997). Tribal structure and composition can change through time and for example, a detailed study of the Abbad tribe in Jordan indicated that the present-day grouping coalesced approximately 250 years ago from a number of quite diverse sub-groups, which had previously been affiliated with other older tribal communities (Nabulsi 1995). The Abbad tribe now incorporates some 120,000 individuals and is subdivided into 76 male lineages, ranging in numbers from approximately 250 to 2,000 persons. Some 90% of marriages are contracted within the tribe, and half of all marriages are between members of the same paternal descent line (Nabulsi 1995). Given this complex tribal and clan structure and the quite restricted effective population sizes of many sub-groups, a substantial level of random inbreeding is inevitable within Arab communities and internal genetic differentiation is probable on the basis of tribe and clan membership. However, the degree to which these processes apply will be dependent on the specific history of each tribe and clan, and more particularly on past and present frequencies and patterns of tribal admixture and inter-clan marriage. Marriage within tribal boundaries is largely paralleled by religious endogamy. In multi-faith countries such as Lebanon, with three main religious communities, Sunni and Shia Muslims and Maronite Christians, plus the smaller Druze, Greek Orthodox, Greek Catholic and Armenian communities, denominational endogamy has historically been the norm and is accompanied by a variable level of genetic differentiation (Klat and Khudr 1986).

Consanguineous Marriage Within Arab Societies As previously noted, Arab societies place great emphasis on the role and importance of the family. Thus, in addition to tribal and clan endogamy, consanguineous marriage is customary in most, if not all, Arab communities.

The Prevalence and Preferred Types of Consanguineous Marriage Intra-familial unions between couples related as second cousins or closer (F 0.0156) currently account for approximately 20–50% of all marriages in Arab countries (Table 4.1). Specific inter-country comparisons are often difficult because of the different study populations sampled, for example, through household surveys versus antenatal clinics or maternity wards, and researchers also vary in the level of detail collected, with some studies based on data on first-cousin and nonconsanguineous marriages only.

Table 4.1 Prevalence and types of consanguineous marriage in representative studies on Arab populations Country Study region Consanguinity (%) Marriages studied Mean coefficient of inbreeding (a) Algeria All-Algeria 22.6 1C, 2C – 0.0152 Bahrain Bahrain 31.8 1C, 11/2C, 2C 0.0101 Egypt All-Egypt 24.5 D1C, 1C, 11/2C, 2C Iraq All-Iraq 33.0 D1C, 1C 0.0219 0.0177 Israel Arab Muslim 32.1 D1C, 1C, 11/2C, 2C 0.0142 Jordan Amman 25.5 D1C, 1C, 11/2C, 2C 0.0219 Kuwait All-Kuwait 34.3 D1C, 1C, 11/2C, 2C Lebanon Beirut 25.0 1C,1C, 1C, 11/2C, 2C 0.0245 United Arab Emirates Al Ain 37.4 D1C, 1C, 11/2C, 2C 0.0244 Yemen Sana’a 44.7 D1C, 1C, 11/2C, 2C Marriages studied: D1C double first cousin, F ¼ 0.125 1C first cousin, F ¼ 0.0625 11/2C first cousin once removed, F ¼ 0.0313 2C second cousin, F ¼ 0.0156 Source: www.consang.net

Benalle`gue and Kedji (1984) Al Arrayed (1994) Hafez et al. (1983) COSIT (2005) Vardi-Saliternik et al. (2002) Hamamy et al. (2005) Al-Awadi et al. (1985) Khlat (1988) Lamdouar Bouazzaoui (1994) Rajab and Patton (2000) Assaf and Khawaja (2009) Bener and Alali (2006) El-Hazmi et al. (1995) Saha and El Sheikh (1988) Riou et al. (1989) Al-Gazali et al. (1997) Gunaid et al. (2004)

Reference

4 Endogamy and Consanguineous Marriage in Arab Populations 87

88


It is important to acknowledge that the consanguinity estimates and mean coefficients of inbreeding reproduced in Table 4.1 refer only to relationships that extend back to the grandparental generation. Given the long history and preference for consanguineous marriage in Arab societies and their tradition of tribe and clan endogamy, the cumulative levels of inbreeding and thus the percentage of homozygosity would be substantially higher than suggested by these data. Determination of ancestry in Arab societies and the construction of family pedigrees are greatly advantaged by the precise terminology that exists in Arabic to describe various family relationships. First-cousin unions are especially popular, in particular the paternal parallel subtype ‘Bint amm, i.e., between a man and his father’s brother’s daughter. ‘Bint amm unions are favoured culturally and socially and they are considered to be the usual or expected form of marriage for first cousins whether they have been reared in adjoining or separate households. As indicated in Table 4.2, parallel-cousin marriages (‘Bint amm and ‘Bint khala) predominate in Arab countries, ranging from 59.9% of first-cousin unions in Lebanon (Khlat 1985) to 73.3% in UAE (Al-Gazali et al. 1997). The prevalence of ‘Bint amm marriages varies significantly between populations, with the lowest rates in urban Lebanon (Khlat 1985) and the highest in lower income, rural and Bedouin tribal communities (Khlat et al. 1986; Radovanovic et al. 1999; Raz and Atar 2004; Joseph 2007). However, no hard and fast rule exists, and in communities or extended families with few marriageable offspring, it may be difficult to ensure that a ‘Bint amm, or indeed any other type of first-cousin marriage, is possible within the socially acceptable age differences of the groom and bride. In more traditional Arab societies it is held that a man has the common-law right (urf) to marry his first cousin, and if she marries another male he may be entitled to

Table 4.2 Preferred patterns of first cousin marriage in different Arab societies Country Type I Type II Type III Type IV All first Authors (%) (%) (%) (%) cousin ‘Bint amm ‘Bint khala ‘Bint amma ‘Bint khal unions (%) Lebanon 37.4 22.5 10.4 29.7 14.1 Khlat (1985) Jordan 62.8 9.9 7.7 11.3 32.0 Khoury and Massad (1992) UAE 64.9 8.4 12.2 14.5 26.2 Al-Gazali et al. (1997) Israel 48.2 20.3 13.5 17.7 24.3 Jaber et al. (2000) Yemen 48.9 18.1 14.2 18.8 29.4 Gunaid et al. (2004) Palestinian 47.9 17.6 20.1 14.4 14.4 Assaf and territories Khawaja (2009) Parallel-cousin marriage Type I father’s brother’s daughter, F ¼ 0.0625, Fx ¼ 0 Type II mother’s sister’s daughter, F ¼ 0.0625, Fx ¼ 0.1875 Cross-cousin marriage Type III father’s sister’s daughter, F ¼ 0.0625, Fx ¼ 0 Type IV mother’s brother’s daughter, F ¼ 0.0625, Fx ¼ 0.125

4 Endogamy and Consanguineous Marriage in Arab Populations

89

financial compensation (El-Badramany et al. 1997; Joseph 2007). In practice, the girl’s paternal uncle can agree to forego his son’s right to their marriage (Joseph 2007). If his permission is not granted, practices such as revoking the marriage of a cousin to another man have persisted in some Palestinian villages, even occurring on the marriage night (Assaf and Khawaja 2009). While all four types of first-cousin marriage have the same coefficient of inbreeding at autosomal loci (F ¼ 0.0625), an often understated factor is the difference in the equivalent coefficient of inbreeding at X-chromosome loci (Fx). As shown in Table 4.2, from a theoretical perspective, homozygosity at X-chromosome loci is zero for ‘Bint amm and ‘Bint amma progeny, but Fx ¼ 0.125 for ‘Bint khal and 0.1875 for ‘Bint khala offspring. As a result, it would be expected that the expression of X-chromosome disorders, such as glucose 6-phosphate dehydrogenase deficiency, reflects the proportional prevalence of each first-cousin sub-type in a population.

Religion and Consanguinity It is generally accepted that consanguineous marriage in the Arab world is a preIslamic tradition (Stern 1939). The practice may, however, have been encouraged by the rules of inheritance introduced by the Holy Quran, with daughters entitled to inherit half of the amount received by sons and the wife inheriting a determinate share from her husband (Sura Al-Nisa: 7,11,12). Under Islamic law, a dower (mahr) is specified as part of the marriage arrangement, with these goods transferred to the bride at marriage (Khuri 1970; Tucker 1988). Consanguineous marriage is also common within Christian Arab communities, although usually at a lower prevalence than among their Muslim compatriots (Freundlich and Hino 1984; Khlat 1988). In Arab Christian denominations affiliated with the Roman Catholic Church, and in the Greek Orthodox Church, religious dispensation requirements may apply to marriages contracted between couples related as first cousins or closer, whereas in the Coptic Orthodox Church no such regulation applies to first-cousin unions. The basic guidelines on permitted marital relationships within Islam allow marriages up to and including first-cousin unions (F ¼ 0.0625) to be contracted. Uncle–niece marriage (F ¼ 0.125) is proscribed by the Holy Quran. However, double first-cousin marriage, also F ¼ 0.125, is allowed within Islam and the current prevalence of double first-cousin unions typically ranges from 0.6% to 5.8% (Al-Gazali et al. 1997; Radovanovic et al. 1999). It has been mistakenly assumed that consanguineous marriage is favoured within Islam, when a number of the hadith (oral pronouncements of the Prophet Muhammad) actually encourages marriage between non-relatives (Hussain 1999). In addition, the second Caliph, Omer Ibn Al-Khatab, reputedly advised the Bani Assayib tribe to avoid close-cousin marriage and resultant ill-health by intermarrying with other tribes (Albar 1999). Nonetheless, Fatima, the daughter of the Prophet, married Ali,

90


the Prophet’s ward and first cousin, so in practice the advice offered on consanguinity appears not to have been intended or regarded as binding.

Demographic, Social and Economic Correlates of Consanguinity Across the Arab world, consanguineous marriage is most prevalent in rural communities following more traditional life styles (Al-Salem and Rawashdeh 1993; Al-Gazali et al. 1997; Radovanovic et al. 1999; Zaoui and Bie´mont 2002; El-Mouzan et al. 2007; Joseph 2007). In general, the highest prevalence of consanguineous marriage is contracted among families with the lowest standard of living (Saedi-Wong et al. 1989; Assaf and Khawaja 2009) and wives in consanguineous marriages mostly have a lower level of education (Al-Thakeb 1985; Khlat 1988; Jurdi and Saxena 2003). As indicated in Table 4.3, in keeping with a more traditional lifestyle, consanguinity is generally associated with younger maternal and paternal ages at marriage and so longer female reproductive spans (Khlat 1988; Assaf and Khawaja 2009). These generalisations are by no means uniform, and historical records from eighteenth and nineteenth century Palestine indicate that cousin marriage was most prevalent in upper-class Arab societies (Tucker 1988). Upper socioeconomic status males in Kuwait favour consanguineous marriage (Al-Thakeb 1985), and males with advanced educational backgrounds express a similar preference for intrafamilial marriage in the UAE (Bener et al. 1996) and Yemen (Jurdi and Saxena 2003). Representative surveys in the Palestinian Territories also showed no significant difference in the prevalence of consanguineous marriage across female educational standards (Assaf and Khawaja 2009). A small number of detailed studies have been conducted into the social outcomes of consanguineous marriage, although they have mainly involved female subjects only. An early report from Sudan indicated greater marital stability in consanguineous unions, irrespective of the type of cousin relationship, with divorce in 3.6% of first-cousin marriages as against 14.6% in other types of marriage (Hussien 1971). This pattern has also been reported in non-Arab populations, possibly because of the highly disruptive effect of marriage failure on the stability of the extended family (Bittles 2005).

Table 4.3 Demographic and social correlates of consanguinity Younger maternal and paternal age at marriage Extended maternal reproductive span Larger completed family sizes Low level of maternal education Rural residence More traditional mode of life


91

A higher degree of dissatisfaction may, however, arise when there is a large age differential between consanguineous partners (El-Islam 1976), and in Saudi Arabia there was a positive but statistically non-significant association between the degree of consanguinity and marital discord (Chaleby 1988). More recent investigations have centred on the highly sensitive issue of domestic violence, with no significant advantage or disadvantage reported for consanguineous marriage among lowincome women in Syria (Maziak and Asfar 2003) or Palestinian refugees in Lebanon (Khawaja and Tewtel-Salem 2004).

Contemporary Attitudes Toward Consanguineous Marriage As shown in Table 4.4, when questioned about consanguineous marriages, a number of reasons are commonly advanced for the popularity of intra-familial unions (Hamamy and Bittles 2009). In general, besides various social and economic explanations, women who married a close biological relative or whose family has a tradition of consanguineous unions are more favourably disposed to the practice (Khlat et al. 1986; Jaber et al. 1996). The fact that espoused partners would have met at family gatherings before betrothal is held to be especially helpful, and it is also useful in promoting and achieving harmony between a bride and her future in-laws to whom she is related (Khlat et al. 1986). Some studies have reported a secular decline in the prevalence of consanguineous marriages, for example, in Beirut, Lebanon (Khlat 1985), urban Kuwait (Radovanovic et al. 1999), Saudi Arabia (Al-Abdulkareem and Ballal 1998), Jordan (Hamamy et al. 2005), Israeli Arab communities (Jaber et al. 2000; Zlotogora et al. 2002; Sharkia et al. 2007) and the Palestinian Territories (Assaf and Khawaja 2009). By comparison, in the UAE (Al-Gazali et al. 1997), Yemen (Jurdi and Saxena 2003) and Qatar (Bener and Alali 2006), the overall levels of consanguineous marriage and the prevalence of first-cousin unions have actually increased. The latter observations may reflect the larger family sizes of recent generations and hence the greater availability of potential cousin spouses. But some caution needs to be exercised in interpreting and comparing the prevalence of consanguineous marriages across time, especially given the different study populations sampled,

Table 4.4 Perceived social and economic advantages of consanguineous marriage The assurance of marrying within the family and the strengthening of family ties Simplified premarital negotiations, usually conducted in the partners’ early or late teens Knowledge of one’s spouse prior to marriage Greater social compatibility of the bride with her husband’s family, in particular her mother-in-law Lower risk of undeclared health problems in the intended spouse Reduced requirement for dowry payments, with consequent maintenance of the family goods and monies In land-owning families, maintenance of the integrity of family land-holdings

92


the variant study protocols employed, and the major economic and educational changes which have occurred in most Arab countries during the second half of the twentieth century (Bittles 2008).

Endogamy, Consanguinity and Genetic Disease in Arab Populations Of the six World Health Organization (WHO) Regions, the highest rate of severe congenital disorders and genetic diseases that are lethal or could potentially cause lifelong impairment was reported in the Eastern Mediterranean Region, with >65 affected children per 1,000 live births as opposed to 52/1,000 live births in Europe, North America and Australia (Alwan and Modell 2003; Christianson et al. 2006). The elevated level of inherited disorders in the Eastern Mediterranean Region can mostly be attributed to higher rates of inherited blood disorders and other autosomal recessive conditions, for example, with carrier rates of 2–15% for b-thalassaemia, 2–50% for a-thalassaemia, and 0.3–30% for sickle cell disease in Arab countries. In addition, G6PD deficiency has been estimated to range from 2.5% to 27% in different Arab countries (Hamamy and Alwan 1994; Alwan and Modell 1997; Al-Gazali et al. 2006), possibly reflecting the elevated levels of homozygosity at X-chromosome loci (Table 4.2). The large sizes of many Arab families, in conjunction with clan/tribe endogamy and high consanguinity rates, facilitate the expression of autosomal recessive disorders, with rare or previously unreported syndromes and metabolic defects especially apparent (Teebi 1994; Al-Gazali et al. 2005; Hamamy et al. 2007a, b). Consanguineous marriages continue to be contracted within the Arab diaspora in Western countries, and so the reported rates of inherited disease in these communities are comparable to those in their countries of origin, including a large proportion of autosomal recessive diseases and developmental disorders (Hoodfar and Teebi 1996; Nelson et al. 1997).

Consanguinity and Reproductive Health Increased numbers of pregnancies have been recorded in a majority of global studies of consanguineous marriages and, in a meta-analysis of 30 populations, on average first cousins had 11.9% more live-born children than non-consanguineous couples (Bittles et al. 2002a). This pattern of higher fertility holds true in most Arab populations (Khlat 1988; al-Abdulkareem and Ballal 1998; Hammami et al. 2005; Kerkeni et al. 2007). The primary reasons are more probably social than biological, with younger parental ages at marriage in consanguineous unions and longer potential reproductive spans as important contributory factors (Table 4.3). In the more traditional rural Arab communities where consanguineous marriage is most prevalent, there may be a lower uptake of contraception with consequent larger family sizes.


93

Most studies worldwide have shown that consanguinity is not associated with increased abortion or miscarriage rates (Bittles et al. 2002a). With some exceptions (Mokhtar and Abdel-Fattah 2001; Assaf et al. 2009), there was also no significant association between consanguinity and prenatal losses in a majority of Arab populations (Al-Awadi et al. 1986; Khlat 1988; Saha et al. 1990; Abdulrazzaq et al. 1997; al Husain and al Bunyan 1997; Jaber et al. 1997a; al-Abdulkareem and Ballal 1998; Khoury and Massad 2000; Saad and Jauniaux 2002; Kerkeni et al. 2007), but it has to be acknowledged that data on very early pregnancy terminations are at best partial, and so an unknown proportion of these early losses may be unrecorded. Although information on stillbirths is more reliable, the reported outcomes with respect to consanguinity are varied, with some studies reporting a positive association (Khoury and Massad 2000; Mokhtar and Abdel-Fattah 2001; Assaf et al. 2009) but no significant difference in stillbirth prevalence in consanguineous pregnancies in a majority of cases (Al-Awadi et al. 1986; Khlat 1988; Saha et al. 1990; Abdulrazzaq et al. 1997; al Husain and al Bunyan 1997; Jaber et al. 1997a; Kerkeni et al. 2007). A cross-sectional study which reported an association between consanguinity and apnoea of prematurity in Lebanon awaits confirmation in other populations (Tamim et al. 2003).

Anthropometric Studies at Birth and in Childhood Investigations into the influence of consanguinity on birth measurements, including weight, recumbent length and head circumference, often produce conflicting results. Thus in different Arab populations, a positive association between consanguinity and low birth weight was both reported (Al-Eissa et al. 1991; Jaber et al. 1997a; Mumtaz et al. 2007) and refuted (Khlat 1989; Saedi-Wong and al-Frayh 1989; Wong and Anokute 1990; al-Abdulkareem and Ballal 1998). Possible reasons for these contradictory findings include the variability of the investigative protocols employed, with a common lack of discrimination between different levels of consanguinity, and limited or no control for potential confounding factors, including socioeconomic status, and maternal nutrition, health status and disease. The importance of these factors was demonstrated in a study in Jordan, in which univariate analysis initially indicated a highly significant positive association between consanguinity and low birth weight. However, this relationship disappeared in multivariate analysis when control for age, body mass index, occupation, education, smoking, gravidity, parity, medical problems during pregnancy and a family history of premature deliveries was introduced (Obeidat et al. 2008). Inbreeding depression in stature among school children was observed in Egypt (Abolfotouh et al. 1990). But, as with birth weight, studies with better control for the effect of socioeconomic variables on stature are needed, taking into consideration the rapidly changing socioeconomic and nutritional parameters which have occurred in most Arab countries.

94


Early Postnatal Mortality In keeping with studies conducted in other major populations (Bittles 2001), almost all data from Arab countries indicate higher postnatal mortality in consanguineous versus non-consanguineous couples, especially during the first year of life (Jaber et al. 1997a). For example, among Palestinian families resident in different Middle Eastern countries, infant mortality among first cousin progeny was on average 15/1,000 live births higher than in non-consanguineous offspring (Pedersen 2002). Given the higher homozygosity that would be expected in the progeny of biologically related couples, the findings are strongly suggestive of deleterious recessive gene expression, although in most published reports on Arab populations no specific causes of death were diagnosed to support this contention. Besides a larger number of pregnancies and live births and despite a higher percentage of infant and childhood deaths, consanguineous couples commonly have more surviving children. In some cases, these findings can be explained in terms of differentials between consanguineous and non-consanguineous couples with respect to factors such as socioeconomic status, religious affiliation and marriage duration (Khlat 1988). Reproductive compensation is a probable additional factor, with families replacing children who have died in infancy or early childhood, either through choice or via cessation of lactational amenorrhoea.

Consanguinity and Childhood Morbidity Studies of childhood deafness (Zakzouk et al. 1993; Al-Gazali 1998; Attias et al. 2006; Khabori and Patton 2008), blindness (Al-Idrissi et al. 1992; Elder and De Cock 1993) and dental anomalies, especially structural defects and malocclusion (Maatouk et al. 1995), all have implicated parental consanguinity in the disease aetiology. The case for a significant recessive gene contribution to deafness is strongest, with 92% and 57% respectively of non-syndromic and syndromic deafness examined in the UAE attributed to autosomal recessive inheritance (Al-Gazali 1998). As in other major populations, a significantly elevated risk of birth defects has been widely recorded in the progeny of Arab first-cousin couples. The actual rates and types of congenital defect reported vary widely between populations, with differing study protocols, highly variable sample sizes and limited control for sociodemographic variables making a detailed summary and overall assessment very difficult. In many instances, attempts to determine the genetic weighting are also hampered by affected individuals being designated only as “consanguineous”, which in Arab populations could range from F ¼ 0.0156 to 0.125, or “nonconsanguineous” (F ¼ 0). Percentage consanguinity rates are often cited for children referred with a major congenital defect and compared with the equivalent cousin marriage rate in the


95

“general population”; the implication being that there is a causal relationship between consanguinity and the expression of the defect(s) under investigation. Unfortunately, in Arab populations with restricted effective population sizes and strongly preferential clan and tribal endogamy, this type of comparison may fall far short of the minimum requirement for rigorous case-control studies. Across generations, significant inter-clan, and more especially inter-tribal, genetic differences could have arisen via founder effect and drift, and been amplified by intra-familial marriage. Several studies directly compared the prevalence of major congenital defects in first-cousin and non-consanguineous progeny with, for example, an excess of 7.5% (Jaber et al. 1992) and 6.1% at F ¼ 0.0625 (Bromiker et al. 2004). The frequency of consanguineous marriages was higher among the parents of offspring with congenital malformations compared with the figures for the general population in virtually all studies reported among Arabs, including the UAE (Al-Gazali et al. 1995; Abdulrazzaq et al. 1997; Al Hosani et al. 2005; Dawodu et al. 2005), Kuwait (Madi et al. 2005), Oman (Sawardekar 2005; Patel 2007), Iraq (Hamamy and Al-Hakkak 1989; Mahdi 1992), Jordan (Khoury and Massad 2000; Obeidat et al. 2008), Egypt (Temtamy et al. 1998), Lebanon (Khlat 1988; Bittar 1998), Tunisia (Khrouf et al. 1986) and Saudi Arabia (El Mouzan et al. 2008). Elevated rates of consanguinity have been consistently reported for congenital heart defects, in particular septal defects (Gev et al. 1986; Bassili et al. 2000; Subramanyan et al. 2000; Becker et al. 2001; Nabulsi et al. 2003; Yunis et al. 2006; Seliem et al. 2007; El Mouzan et al. 2008), but for other heart defects such as transposition of the great vessels and coarctation of the aorta, the results varied between study centres, suggesting community-specific causes. Studies of neural tube defects also showed positive associations with consanguinity (Zlotogora 1997; Rajab et al. 1998; Al-Gazali et al. 1999; Murshid 2000; Asindi and Shehri 2001), but for oral and facial clefts, the data were less consistent, with both a positive association (Zlotogora 1997; Kanaan et al. 2008) and no association reported (al-Bustan et al. 2002; Aljohar et al. 2008).

Consanguinity and Chromosome Aberrations Following the initial report of an excess of Kuwaiti children with Down syndrome born to consanguineous parents, a mechanism involving a recessively expressed gene coding for non-disjunction of chromosome 21 was proposed (Alfi et al. 1980). Additional support for this hypothesis was obtained from Kuwait (Naguib et al. 1989) and other non-Arab countries, but a number of subsequent studies in Arab populations have been unable to identify the existence of a predisposing gene for trisomy 21 (Hamamy et al. 1990; Zlotogora 1997; Chaabouni 1999; El Mouzan et al. 2008). Some degree of uncertainty as to the possible predisposing role of consanguinity remains, given the high rates of Down syndrome reported in Gulf

96


countries (Wahab et al. 2006), with conclusive results of either regional or global application dependent on large-scale epidemiological studies incorporating control for all appropriate non-genetic variables.

Consanguinity and Early Behavioural Disorders Many early studies into possible adverse effects of consanguinity focused on intellectual and developmental disability. In Arab populations, a significant but modest negative association was demonstrated between consanguinity and mean Intelligence Quotient (IQ) scores in children aged 10 years and 12 years, with the lowest mean scores and highest variance in the progeny of double first cousins (Bashi 1977). However, as previously discussed in other contexts, control for variables other than consanguinity was incomplete, and this observation also applies to studies that have reported an increased prevalence of speech disorders (Jaber et al. 1997b), learning and reading difficulties (Eapen et al. 1998; Abu-Rabia and Maroun 2005), hyperactivity (Al-sharbati et al. 2003), intellectual disability (Al-Ansari 1993; Farag et al. 1993; Salem et al. 1994; Temtamy et al. 1994; Abdulrazzaq et al. 1997), and recurrent febrile seizures (al-Eissa 1995) in firstcousin and other consanguineous progeny. Given the high overall rates of consanguineous marriages in Saudi Arabia, the comparatively low level of intellectual disability (8.9/1,000) reported in Saudi children aged 0–18 years was somewhat surprising (El-Hazmi et al. 2003). However, the authors noted that 83.2% of children with intellectual disability were not attending school, which may have resulted in under-enumeration of affected children. It is interesting that 70.9% of affected children were diagnosed with moderate to severe intellectual disability (El-Hazmi et al. 2003), which suggests both a high level of genetic causality and a significantly reduced life expectancy (Bittles et al. 2002b).

Consanguinity and Adult-Onset Disease Limited information has been published on the effects of consanguinity on adultonset disorders among Arabs, with no significant differences in the prevalence or the age of onset of diabetes mellitus, myocardial infarction, bronchial asthma or duodenal ulcer in “consanguineous” and non-consanguineous subjects (Jaber et al. 1997c). As each of these conditions can be categorized as a complex disease, with multiple potential interacting genes and environmental factors, and there was no control for socioeconomic status or clan/tribe endogamy, the outcome is not surprising. Similar caveats apply to the confusing picture reported for adult cancers, with a negative association between consanguinity and the overall risk of cancer (Denic et al. 2007), both a lower breast cancer rate in women with consanguineous parents


97

(Denic and Bener 2001) and no effect of parental consanguinity on the risk of breast cancer (Denic et al. 2005), and a hypothetical positive association between consanguinity and cervical cancer (Denic 2003). With life expectancy rapidly increasing in most Arab countries, cancer can clearly be identified as a disease where wellplanned and rigorously conducted epidemiological studies are urgently needed. Additional diagnostic problems may arise with adult behavioural disorders, and until discrete disease phenotypes can be reproducibly demonstrated, the lack of a significant association between consanguinity and schizophrenia reported in Sudan (Ahmed 1979) and Saudi Arabia (Chaleby and Tuma 1987), and the positive association of consanguinity with bipolar disease type 1 in Egypt (Mansour et al. 2009) merit acceptance with due caution. There is, however, convincing evidence of specific predisposing genes for Alzheimer disease in an Israeli Arab village isolate (Farrer et al. 2003), and it may be that studies that concentrate on individual families and discrete communities, rather than surveys organised on a national or regional basis, will prove to be the most rewarding in identifying individuals and communities at high risk of complex diseases.

Genetic Counselling for Consanguineous Couples Consanguinity is linked to ill-health, congenital malformations and intellectual disability in the minds of many lay people in Arab countries. Often there is no clear concept of how such conditions could be inherited, and the parents of affected children may have difficulty in accepting a genetic explanation for diseases that did not affect all of their children at the time of birth. Parents may also cite religious or folk beliefs to account for illness, with denial or resignation to the situation, and with divorce and remarriage accepted as possible solutions (Panter-Brick 1991; Hamamy and Bittles 2009). The belief that inherited disorders can arise only through cousin marriages on the paternal side of the family is also quite common, as Arab societies are patrilineal and in the minds of many people consanguinity may refer only to paternal blood relationships. Thus, during counselling, if a couple indicate that they are not related, it is imperative to specifically inquire about any shared biological relationships on their mothers’ sides of the families. In similar vein, families may opt to avoid cousin marriages when the disease is inherited as an autosomal dominant and are bewildered by the subsequent birth of an affected baby. Through school- and community-based education programmes and with improved, non-invasive diagnostic facilities, younger couples in many Arab countries are becoming increasingly aware of both the existence and the nature of genetic and congenital disorders, and strategies to prevent their occurrence (Hamamy and Alwan 1997; Alwan and Modell 1997). In Saudi Arabia, there is also strong evidence that university students are aware of the availability of premarital screening for genetic disorders (Al-Aama et al. 2008).

98


Premarital Counselling Premarital genetic counselling is a particularly important strategy in Arab communities. Despite a Fatwa issued by the Islamic Jurisprudence Council of the Islamic World League that allowed abortion up to 120 days after conception in pregnancies involving a foetus with a severe disorder or malformation not amenable to therapy (Alkuraya and Kilani 2001; Albar 2002; Al Aqeel 2007), medical termination of pregnancy is unacceptable on cultural, religious and legal grounds in many Arab countries, Tunisia being an exception (Hessini 2007; Chaabouni-Bouhamed 2008). In part, the reluctance to accept medical termination of pregnancy may reflect the School of Islamic Jurisprudence to which an individual or community belongs (Hamamy and Bittles 2009), besides differences in their cultural background and community organisation (El-Hazmi 2007). In many Arab countries, there are still inadequate numbers of appropriately trained clinicians, midwives and nurses, genetic counsellors and laboratory personnel capable of providing full premarital genetic counselling coverage. In addition, inconsistencies in genetic counselling protocols can arise, and guidelines on premarital counselling for consanguineous couples are not generally available to health care providers (Hamamy and Bittles 2009). Thus, an accurate risk estimate cannot always be provided by a counsellor because of unknown population basal parameters. Premarital counselling is, nevertheless, an effective strategy for the prevention of autosomal recessive conditions and can be of particular help in reducing the numbers of arranged marriages of high-risk couples. Following premarital counselling, even if couples had decided to proceed with marriage to a relative, a large majority reported that the counselling had influenced their final decision to some degree (Shiloh et al. 1995). Given the close structure of Arab families, premarital counselling can also provide educational benefits to other members of the extended family.

Premarital Screening and Carrier Testing Community programmes for premarital screening to detect b-thalassaemia carriers have been initiated in a number of Arab countries, including Jordan, Saudi Arabia, Bahrain, UAE and Tunisia (Al Arrayed 2005; Al-Gazali et al. 2005; Al-Gazali et al. 2006; El-Hazmi 2006). Besides their intended purpose, the programmes have additionally served to increase public awareness about genetic diseases in general and specific disease prevention options, and have helped to reduce the fear that consanguinity is a major risk factor in such disorders. Problems can exist in terms of carrier testing, because of difficulty in diagnosing the condition in the family, including the lack of a molecular diagnosis, the refusal of affected family members to undergo testing, or the death of an affected person


99

before sampling could be arranged. In countries with a strong tradition of medical paternalism, there may also be an expectation on the part of counsellees and their families that directive advice will be given on issues such as the choice of a marriage partner, reproductive options and medical termination of pregnancy (WHO 2002; Rantanen et al. 2008; Hamamy and Bittles 2009). Unfortunately, failure to provide such advice may be interpreted by families as a sign of self-doubt and a lack of knowledge on the part of the clinician (Eldahdah et al. 2007). As consanguineous marriage is a strong cultural belief, cousin couples may face specific problems in conveying the diagnosis of their disorder to other family members whose own future marital arrangements may be jeopardised. Some couples also express dissatisfaction when offered a percentage risk estimate rather than a definitive diagnostic opinion (Hamamy and Bittles 2009). Even though a decision not to proceed with an arranged marriage is taken voluntarily by the family on the grounds of a high risk to future offspring, in communities with a strong patrilineal and patrilocal tradition some stigmatisation may be directed at the female partner (Raz and Atar 2004).

Conclusions With increasing urbanisation, improved access to higher education, professional employment and wider social networks, some decline in the occurrence of arranged and consanguineous marriages seems probable, especially in the Arab diaspora. As previously indicated, this trend is underway in many, but by no means all, Arab countries, and in Arab societies in general consanguineous marriage remains culturally and socially respected. Many Arab countries are experiencing demographic transitions, including a substantial reduction in infant mortality rates. Therefore, it is important that action be taken to improve the education and training of Arab health care providers on issues concerning consanguineous marriage. As infant mortality rates decline, the proportion of ill-health and early deaths due to genetic and congenital disorders increases (Bittles 1995, 2001), necessitating robust, comprehensive national programmes for the control of inherited disorders. The need for a better understanding of the potential association between consanguinity and genetic disorders is crucial in Arab countries where up to 50% of all marriages may be intra-familial (Table 4.1). To date, there has been limited appreciation of the very important role and consequences of clan and tribal subdivisions in the transmission of disease genes, resulting in an over-emphasis of the adverse role of consanguinity. In populations that are sub-divided along ethnic, religious, clan and tribal lines, a recessive founder or de novo mutation of chronic effect can rapidly increase in frequency within a particular community. Hence, with the strict patterns of clan and tribe endogamy that still apply in most Arab societies, a child may have inherited a specific recessive disorder irrespective of whether its parents are consanguineous or non-relatives (Zlotogora et al. 2006).

100


Clear examples of community endogamy are seen in the distribution of tribespecific single-gene disorders in Saudi Arabia, for example, maple syrup urine disease, methylmalonic acidaemia, Sandhoff disease and Canavan disease (Ozand et al. 1990; Ozand et al. 1992; Rashed et al. 1994). Likewise, in an Israeli Arab village of 8,600 inhabitants, 19 mostly chronic autosomal recessive disorders have been identified with a prevalence of known and suspected AR disorders of 1/70 (Zlotogora et al. 2000). Different villages may exhibit quite different disease profiles, and the levels of village endogamy and consanguinity in some Arab communities are such that, even within a single village, it has been possible to identify and plot the origins and expansion patterns of four different b-globin mutations (Zlotogora et al. 2005), with no suggestion that this situation is unique to the study community. There is also a significantly increased chance that more than one detrimental recessive gene may be expressed in a family (Gordon et al. 1990), which can cause major difficulties in the provision of genetic counselling. Failure to recognise the significant role of population stratification in the prevalence and distribution patterns of genetic disorders has serious implications for genetic education and genetic counselling programmes. Subject to ethical considerations, in many cases the clan or tribe may be the most logical unit of population for interventions based on population screening and genetic counselling, since in effect each acts as a separate and largely discrete gene pool (Bittles 2008). This opinion is exemplified by the distribution pattern of b-thalassaemia in Oman. Of the estimated 185 major Omani tribes and sub-tribes, only some 10% of tribes are affected by b-thalassaemia and over 50% of all cases were diagnosed in a single tribe (Rajab and Patton 1997, 1999). Under these circumstances, the selection of subjects for case–control studies, association studies and clinical trials becomes critical. More specifically, in the investigation of consanguinity outcomes, comparisons drawn between the progeny of couples selected solely in terms of their current marital relationships will be of dubious validity unless they are members of the same tribe and clan (Bittles 2008). Conversely, where there is evidence of both consanguinity and family clustering, as in a study of male factor infertility in Lebanon (Inhorn et al. 2008), the associations drawn become much more persuasive. Given their particular family, clan and tribal structures, high rates of consanguineous marriage, large kindred size, and in many countries access to rapidly advancing health facilities, it can be expected that Arab populations will continue to be a major focus for research in medical and community genetics. The Arab Genetic Disease Database (Teebi et al. 2002) and the Catalogue of Transmission Genetics in Arabs established by the Centre for Arab Genomic Studies (Tadmouri et al. 2006) will greatly assist this progress and improve our knowledge of the underlying disease genomics and phenotypes. It is essential that equivalent emphasis be devoted to the investigation of the cultural, social and economic attributes of consanguineous unions, and the advantages that make them attractive marital options to families. With socioeconomic progress, the balance between the advantages and disadvantages of consanguinity is changing, and many infants with a genetic disorder who in earlier generations


101

would have died at a young age will survive into adulthood (Bittles 2001). A radical shift in disease impact of this nature places parents and the extended family in an invidious position with respect to future family marriage prospects and arrangements. There is evidence of the difficulties faced by families in arranging marriages with non-relatives, when multiple family members are affected by a serious inherited health disorder (Jalili and Smith 1988; Basel-Vanagaite et al. 2007). For such families, the only realistic option may be to resort to even higher rates of intrafamilial marriage, with the probability that equivalently increased numbers of affected offspring will be born. Against this background, the importance of genetic education and premarital genetic counselling programmes becomes increasingly obvious and effective in social, economic and health terms. Especially since it is probable that endogamy and consanguinity will be shown to play significant roles in the aetiology of many complex diseases, including common major disorders of adult-onset. It is imperative that programmes of this type, appropriate in design, structure and content to meet the needs of Arab communities, be developed and introduced as an issue of high priority.

References Abdulrazzaq YM, Bener A, Al-Gazali LI, Al-Khayat AI, Micallef R, Gaber T (1997) A study of possible deleterious effects of consanguinity. Clin Genet 51:167–173 Abolfotouh MA, Nofal LM, Safwat H (1990) Growth and nutritional status of preschool children attending the well-baby clinics. J Egypt Public Health Assoc 65:485–507 Abu-Rabia S, Maroun L (2005) The effect of consanguineous marriage on reading disability in the Arab community. Dyslexia 11:1–21 Ahmed AH (1979) Consanguinity and schizophrenia in Sudan. Brit J Psychiat 134:635–636 Al Aqeel A (2007) Islamic ethical framework for research into and prevention of genetic diseases. Nat Gen 39:1293–1298 Al Arrayed S (1994) Consanguinity in the state of Bahrain. In: El-Hazmi MAF (ed) Medical genetics in the setting of Middle Eastern populations. King Abdul Aziz City for Science and Technology, Riyadh, pp 97–101 Al Arrayed S (2005) Campaign to control genetic blood diseases in Bahrain. Community Genet 8:52–55 Al Hosani H, Salah M, Abu-Zeid H, Farag HM, Saade D (2005) The national congenital anomalies register in the United Arab Emirates. East Mediterr Health J 11:690–699 al Husain M, al Bunyan M (1997) Consanguineous marriages in a Saudi population and the effect of inbreeding on prenatal and postnatal mortality. Ann Trop Paediatr 17:155–160 Al-Aama JY, Al-Nabulsi BK, Alyousef MA, Asiri NA, Al-Blewi M (2008) Knowledge regarding the national premarital screening program among university students in western Saudi Arabia. Saudi Med J 29:1649–1653 al-Abdulkareem AA, Ballal SG (1998) Consanguineous marriage in an urban area of Saudi Arabia: rates and adverse health effects on the offspring. J Commun Health 23:75–83 al-Ansari A (1993) Etiology of mild mental retardation among Bahraini children: a communitybased case control study. Ment Retard 31:140–143 Al-Awadi S, Moussa MA, Naguib KK, Farag TI, Teebi AS, el-Khalifa M, el-Dossary L (1985) Consanguinity among the Kuwaiti population. Clin Genet 27:483–486

102


Al-Awadi SA, Naguib KK, Moussa MA, Farag TI, Teebi AS, el-Khalifa MY (1986) The effect of consanguineous marriages on reproductive wastage. Clin Genet 29:384–388 Albar M (1999) Counselling about genetic disease: an Islamic perspective. East Mediterr Health J 5:1129–1133 Albar M (2002) Ethical considerations in the prevention and management of genetic disorders with special emphasis on religious considerations. Saudi Med J 23:627–632 al-Bustan SA, el-Zawahri MM, al-Adsani AM, Bang RL, Ghunaim I, Maher BS, Weinberg S, Marazita ML (2002) Epidemiological and genetic study of 121 cases of oral clefts in Kuwait. Orthod Craniofac Res 5:154–160 al-Eissa YA (1995) Febrile seizures: rate and risk factors of recurrence. J Child Neurol 10:315–319 al-Eissa YA, Ba’Aqeel HS, Haque KN (1991) Low birthweight in Riyadh, Saudi Arabia: incidence and risk factors. Ann Trop Paediatr 11:75–82 Alfi O, Chang R, Azen S (1980) Evidence for genetic control of nondisjunction in man. Am J Hum Genet 32:477–483 Al-Gazali LI (1998) A genetic aetiological survey of severe childhood deafness in the United Arab Emirates. J Trop Ped 44:157–160 Al-Gazali LI, Dawodu AH, Sabarinathan K, Varghese M (1995) The profile of major congenital abnormalities in the United Arab Emirates (UAE) population. J Med Genet 32:7–13 Al-Gazali LI, Bener A, Abdulrazzaq YM, Micaleff R, Al-Khayat GT (1997) Consanguineous marriages in the United Arab Emirates. J Biosoc Sci 29:491–497 Al-Gazali LI, Sztriha L, Dawodu A, Bakir M, Varghese M, Varady E, Scorer J, Abdulrazzaq YM, Bener A, Padmanabhan R (1999) Pattern of central nervous system anomalies in a population with a high rate of consanguineous marriages. Clin Genet 55:95–102 Al-Gazali LI, Alwash R, Abdulrazzaq YM (2005) United Arab Emirates: communities and community genetics. Community Genet 8:186–196 Al-Gazali L, Hamamy H, Al-Arrayad S (2006) Genetic disorders in the Arab world. Brit Med J 333:831–834 Al-Idrissi I, Al-Kaff AS, Senft SH (1992) Cumulative incidence of retinoblastoma in Riyadh, Saudi Arabia. Ophthal Paediat Genet 13:9–12 Aljohar A, Ravichandran K, Subhani S (2008) Pattern of cleft lip and palate in hospital-based population in Saudi Arabia: retrospective study. Cleft Palate Craniofac J 45:592–596 Alkuraya FS, Kilani RA (2001) Attitude of Saudi families affected with hemoglobinopathies towards prenatal screening and abortion and the influence of religious ruling (Fatwa). Prenat Diagn 21:448–461 Al-Salem M, Rawashdeh N (1993) Consanguinity in North Jordan: prevalence and pattern. J Biosoc Sci 25:553–556 Al-sharbati MM, Al-Hussaini AA, Anthony SX (2003) Profile of child and adolescent psychiatry in Oman. Saudi Med J 24:391–395 Al-Thakeb FT (1985) The Arab family and modernity: evidence from Kuwait. Curr Anthropol 26:575–580 Alwan A, Modell B (1997) Community control of genetic and congenital disorders, EMRO Technical Publications 24. World Health Organization, Alexandra Alwan A, Modell B (2003) Recommendations for introducing genetics services in developing countries. Nat Rev Genet 4:61–68 Asindi A, Shehri A (2001) Neural tube defects in the Asir region of Saudi Arabia. Ann Saudi Med 21:26–29 Assaf S, Khawaja M (2009) Consanguinity trends and correlates in the Palestinian Territories. J Biosoc Sci 41:107–124 Assaf S, Khawaja M, DeJong J, Mahfoud Z, Yunis K (2009) Consanguinity and reproductive wastage in the Palestinian territories. Paediatr Perinat Epidemiol 23:107–115 Attias J, Al-Masri M, Abukader L, Cohen G, Merlov P, Pratt H, Othman-Jebara R, Aber P, Raad F, Noyek A (2006) The prevalence of congenital and early-onset hearing loss in Jordanian and Israeli infants. Int J Audiol 45:528–536


103

Basel-Vanagaite L, Taub E, Halpern GJ, Drasinover V, Magal N, Davodov B, Zlotogora J, Shohat M (2007) Genetic screening for autosomal recessive nonsyndromic mental retardation in an isolated population in Israel. Eur J Hum Genet 15:250–253 Bashi J (1977) Effects of inbreeding on cognitive performance. Nature 266:440–442 Bassili A, Mokhtar SA, Dabous NI, Zaher SR, Mokhtar MM, Zaki A (2000) Risk factors for congenital heart diseases in Alexandria, Egypt. Eur J Epidemiol 16:805–814 Becker SM, Al Halees Z, Molina C, Paterson RM (2001) Consanguinity and congenital heart disease in Saudi Arabia. Am J Med Genet 99:8–13 Benalle`gue A, Kedji F (1984) Consanguinite´ et sante´ publique: Etude alge´rienne. Arch Fr Pediatr 41:435–440 Bener A, Alali KA (2006) Consanguineous marriage in a newly developed country: the Qatari population. J Biosoc Sci 38:239–246 Bener A, Abdulrazzaq YM, Al-Gazali LI, Micallef R, Al-Khayat AI, Gaber T (1996) Consanguinoity and associated socio-demographic factors in the United Arab Emirates. Hum Hered 46:256–264 Bittar Z (1998) Major congenital malformations presenting in the first 24 hours of life in 3865 consecutive births in south of Beirut. Incidence and pattern. J Med Liban 46:256–260 Bittles AH (1995) When cousins marry: consanguineous marriage in the Middle East. Perspect Hum Biol 1:71–83 Bittles AH (2001) Consanguinity and its relevance to clinical genetics. Clin Genet 60:89–98 Bittles AH (2005) Endogamy, consanguinity and community disease profiles. Commun Genet 8:17–20 Bittles AH (2008) A community genetics perspective on consanguineous marriage. Commun Genet 11:324–330 Bittles AH, Grant JC, Sullivan S, Hussain R (2002a) Does inbreeding lead to decreased human fertility? Ann Hum Biol 29:111–131 Bittles AH, Petterson BA, Sullivan S, Hussain R, Glasson EJ, Montgomery PD (2002b) The influence of intellectual disability on life expectancy. J Gerontol A: Biol Sci Med Sci 57A:M470–M472 Bromiker R, Glam-Baruch M, Gofin R, Hammerman C, Amitai Y (2004) Association of parental consanguinity with congenital malformations among Arab newborns in Jerusalem. Clin Genet 66:63–66 Chaabouni H (1999) E´tude epidemiologique et genetique de la trisomie 21 en Tunisie. Tunisie Me´ 77:407–414 Chaabouni-Bouhamed H (2008) Tunisia: communities and community genetics. Community Genet 11:313–323 Chaleby K (1988) Traditional Arabian marriages and mental health in a group of outpatient Saudis. Acta Psychiatr Scand 77:139–142 Chaleby K, Tuma TA (1987) Cousin marriages and schizophrenia in Saudi Arabia. Brit J Psychiatr 150:547–549 Christianson A, Howson C, Modell B (2006) Global report on birth defects. The hidden toll of dying and disabled children. March of Dimes Birth Defects Foundation, White Plains, NY COSIT, Central Organization for Statistics and Information Technology (2005) Iraq living conditions survey 2004, vol. II: Analytical Report. Ministry of Planning and Development Cooperation, Baghdad Dawodu A, Al-Gazali L, Varady E, Varghese M, Nath K, Rajan V (2005) Genetic contribution to high neonatally lethal malformation rate in the United Arab Emirates. Community Genet 8:31–34 Denic S (2003) Consanguinity as a risk factor for cervical carcinoma. Med Hypoth 60:321–324 Denic S, Bener A (2001) Consanguinity decreases risk of breast cancer – cervical cancer unaffected. Brit J Cancer 85:1675–1679 Denic S, Bener A, Sabri S, Khatib F, Milenkovic J (2005) Parental consanguinity and risk of breast cancer: a population-based case-control study. Med Sci Monit 11:CR415–CR419

104


Denic S, Frampton C, Nicholls MG (2007) Risk of cancer in an inbred population. Cancer Detect Prev 31:263–269 Eapen V, Al-Gazali L, Bin-Othman S, Abou-Saleh M (1998) Mental health problems among schoolchildren in United Arab Emirates: prevalence and risk factors. J Am Acad Child Adolesc Psychiatr 37:880–886 El Mouzan MI, Al Salloum AA, Al Herbish AS, Qurachi MM, Al Omar AA (2008) Consanguinity and major genetic disorders in Saudi children: a community-based cross-sectional study. Ann Saudi Med 28:169–173 El-Badramany MH, Farag TI, Al-Awadi SA, Teebi AS (1997) Psychosocial and medical aspects of genetic counseling among Arabs: the example of Kuwait. In: Teebi AS, Farag TI (eds) Genetic disorders among Arab populations, vol 1. Oxford University Press, New York, pp 474–486 Eldahdah L, Ormond K, Nassar A, Khalil T, Zahed L (2007) Outcome of chromosomally abnormal pregnancies in Lebanon: obstetricians’ roles during and after prenatal diagnosis. Prenat Diagn 27:525–534 Elder MJ, De Cock R (1993) Childhood blindness in the West Bank and the Gaza Strip: prevalence, aetiology and hereditary factors. Eye 7:580–583 El-Hazmi MA (2006) Pre-marital examination as a method of prevention from blood genetic disorders. Community views. Saudi Med J 27:1291–1295 El-Hazmi M (2007) Islamic teachings of bioethics in relation to the practice of medical genetics. Saudi Med J 28:1781–1787 El-Hazmi M, Al-Swailem AA, Warsy A, Al-Swailem AM, Sulaimani R, Al-Meshari A (1995) Consanguinity among the Saudi Arabian population. J Med Genet 32:623–626 El-Hazmi M, Al-Swailem AA, Al-Mosa NA, Al-Jarallah AA (2003) Prevalence of mental retardation among children in Saudi Arabia. East Mediterr Health J 9:6–11 El-Islam MF (1976) Intergenerational conflict and the young Qatari neurotic. Ethos 4:45–56 El-Mouzan MI, Al-Salloum AA, Al-Herbish AS, Qurachi MM, Al-Omar AA (2007) Regional variations in the prevalence of consanguinity in Saudi Arabia. Saudi Med J 28:1881–1884 Farag TI, Al-Awadi SA, el-Badramany MH, Aref MA, Kasrawi B, Krishna Murthy DS et al (1993) Disease profile of 400 institutionalized mentally retarded patients in Kuwait. Clin Genet 44:329–334 Farrer LA, Bowirrat A, Friedland RP, Waraska K, Korczyn AD, Baldwin CT (2003) Identification of multiple loci for Alzheimer loci in a consanguineous Israeli-Arab community. Hum Mol Genet 12:415–422 Freundlich E, Hino N (1984) Consanguineous marriage among rural Arabs in Israel. Isr J Med Sci 20:1035–1038 Gev D, Roguin N, Freundlich E (1986) Consanguinity and congenital heart disease in the rural Arab population in northern Israel. Hum Hered 36:213–217 Gordon CR, Bar-Ziv Y, Frydman M, Zlotogora J, Gadoth N (1990) Mucolipidosis III and BardetBiedl syndrome in the same family: diagnostic pitfalls. Brain Dev 12:403–407 Gunaid AA, Ali Hummad N, Tamim KA (2004) Consanguineous marriage in the capital city Sana’a, Yemen. J Biosoc Sci 36:111–121 Hafez M, El-Tahan H, Awadalla M, El-Khayat H, Abdel-Gafar A, Ghoneim M (1983) Consanguineous matings in the Egyptian population. J Med Genet 20:58–60 Hamamy H, Al-Hakkak Z (1989) Consanguinity and reproductive health in Iraq. Hum Hered 39:271–275 Hamamy H, Alwan A (1994) Hereditary disorders in the Eastern Mediterranean Region. Bull World Health Organ 72:45–154 Hamamy H, Alwan A (1997) Genetic disorders and congenital abnormalities: strategies for reducing the burden in the region. East Mediterr Health J 3:123–132 Hamamy H, Bittles AH (2009) Genetic clinics in Arab communities: meeting individual, family and community needs. Public Health Genomics 12:30–40 Hamamy HA, al-Hakkak ZS, al-Taha S (1990) Consanguinity and the genetic control of Down syndrome. Clin Genet 37:24–29


105

Hamamy H, Jamhawi L, Al-Darawsheh J, Ajlouni K (2005) Consanguineous marriages in Jordan: why is the rate changing with time? Clin Genet 67:511–516 Hamamy H, Al-Hait S, Alwan A, Ajlouni K (2007a) Jordan: communities and community genetics. Commun Genet 10:52–60 Hamamy HA, Masri AT, Al-Hadidy AM, Ajlouni KM (2007b) Consanguinity and genetic disorders. Profile from Jordan. Saudi Med J 28:1015–1017 Hammami A, Chalbi N, Ben Abdallah M, Elgazzeh M (2005) Effects of consanguinity and social factors on mortality and fertility in Mauritania. Tunis Me´d 83:221–226 Hessini L (2007) Abortion and Islam: policies and practice in the Middle East and North Africa. Reprod Health Matters 15:1–10 Hoodfar E, Teebi AS (1996) Genetic referrals of Middle Eastern origin in a western city: inbreeding and disease profile. J Med Genet 33:212–215 Hussain R (1999) Community perceptions of reasons for preference for consanguineous marriages in Pakistan. J Biosoc Sci 31:449–461 Hussien FH (1971) Endogamy in Egyptian Nubia. J Biosoc Sci 3:251–257 Inhorn MC, Kobeissi L, Nassar Z, Lakkis D, Fakih MH (2008) Consanguinity and family clustering of male factor infertility in Lebanon. Fertil Steril (Epub ahead of print) Jaber L, Merlob P, Bu X, Rotter JI, Shohat M (1992) Marked parental consanguinity as a cause for increased major malformations in an Israeli Arab community. Am J Med Genet 44:1–6 Jaber L, Shohat T, Halpern GJ (1996) Demographic characteristics of the Israeli Arab community in connection with consanguinity. Isr J Med Sci 32:1286–1289 Jaber L, Merlob P, Gabriel R, Shohat M (1997a) Effects of consanguineous marriage on reproductive outcome in an Arab community in Israel. J Med Genet 34:1000–1002 Jaber L, Nahmani A, Shohat M (1997b) Speech disorders in Israeli Arab children. Isr J Med Sci 33:663–665 Jaber L, Shohat T, Rotter JI, Shohat M (1997c) Consanguinity and common adult diseases in Israeli Arab communities. Am J Med Genet 70:346–348 Jaber L, Halpern GJ, Shohat T (2000) Trends in the frequencies of consanguineous marriages in the Israeli Arab community. Clin Genet 58:106–110 Jalili IK, Smith NJD (1988) A progressive cone-rod dystrophy and amelogenesis imperfecta: a new syndrome. J Med Genet 25:738–740 Joseph SE (2007) “Kissing coins”: consanguineous marriage and early mortality in a reproductive isolate. Curr Anthropol 48:756–764 Jurdi R, Saxena PC (2003) The prevalence and correlates of consanguineous marriages in Yemen: similarities and contrasts with other Arab countries. J Biosoc Sci 35:1–13 Kanaan ZM, Mahfouz R, Tamim H (2008) The prevalence of consanguineous marriages in an underserved area in Lebanon and its association with congenital anomalies. Genet Test 12:367–372 Kerkeni E, Kerkeni E, Monastiri K, Saket B, Guediche MN, Ben Cheikh H (2007) Interplay of socio-economic factors, consanguinity, fertility, and offspring mortality in Monastir, Tunisia. Croat Med J 48:701–707 Khabori MA, Patton MA (2008) Consanguinity and deafness in Omani children. Int J Audiol 47:30–33 Khawaja M, Tewtel-Salem M (2004) Agreement between husband and wife reports of domestic violence: evidence from poor refugee communities in Lebanon. Int J Epidemiol 33:526–533 Khlat M (1985) Consanguineous marriages in Beirut: time trends, spatial distribution. Soc Biol 35:324–330 Khlat M (1988) Consanguineous marriage and reproduction in Beirut, Lebanon. Am J Hum Genet 43:188–196 Khlat M (1989) Inbreeding effects on fetal growth in Beirut, Lebanon. Am J Phys Anthropol 80:481–484 Khlat M (1997) Endogamy in the Arab world. In: Teebi AS, Farag TI (eds) Genetic disorders among Arab populations, 1st edn. Oxford University Press, New York, pp 63–80

106


Khlat M, Halabi S, Khudr A, Der Kaloustian VM (1986) Perception of consanguineous marriages and their genetic effects among a sample of couples from Beirut. Am J Med Genet 25:299–306 Khoury SA, Massad D (1992) Consanguineous marriage in Jordan. Am J Med Genet 43:769–775 Khoury SA, Massad D (2000) Consanguinity, fertility, reproductive wastage, infant mortality and congential malformations in Jordan. Saudi Med J 21:150–154 Khrouf N, Spang R, Podgorna T, Miled SB, Moussaoui M, Chibani M (1986) Malformations in 10, 000 consecutive births in Tunis. Acta Pediatr Scand 75:534–539 Khuri FI (1970) Parallel cousin marriage reconsidered: a Middle Eastern practice that nullifies the effects of marriage on the intensity of familial relationships. Man 5:597–618 Klat M, Khudr A (1986) Religious endogamy and consanguinity in marriage patterns in Beirut, Lebanon. Soc Biol 33:138–145 Lamdouar Bouazzaoui N (1994) Consanguinite´ et sante´ publique au Maroc. Bull Acad Natl Me´d 178:1013–1027 Maatouk F, Laamri D, Argoubi K, Ghedra H (1995) Dental manifestations of inbreeding. J Clin Pediatr Dent 19:305–306 Madi SA, Al-Naggar RL, Al-Awadi SA, Bastaki LA (2005) Profile of major congenital malformations in neonates in Al-Jahra region of Kuwait. East Mediterr Health J 11:700–706 Mahdi A (1992) Consanguinity and its effect on major congenital malformations. Iraqi Med J 40–42:70–176 Mansour H, Klei L, Wood J, Talkowski M, Chowdari K, Fathi W et al (2009) Consanguinity associated with increased risk for bipolar 1 disorder in Egypt. Am J Med Genet Part B: Neuropsychiatr Genet 150:879–885 Maziak W, Asfar T (2003) Physical abuse in low-income women in Aleppo, Syria. Health Care Women Int 24:313–326 Mokhtar MM, Abdel-Fattah MM (2001) Consanguinity and advanced maternal age as risk factors for reproductive losses in Alexandria, Egypt. Eur J Epidemiol 17:559–565 Mumtaz G, Tamim H, Kanaan M, Khawaga M, Khogali M, Wakim G, Yunis K (2007) Effect of consanguinity on birth weight for gestational age in a developing country. Am J Epidemiol 165:742–752 Murshid WR (2000) Spina bifida in Saudi Arabia: is consanguinity among the parents a risk factor? Pediatr Neurosurg 32:10–12 Nabulsi A (1995) Mating patterns of the Abbad tribe in Jordan. Soc Biol 42:162–174 Nabulsi MM, Tamim H, Sabbagh M, Obeid MY, Yunis KA, Bitar FF (2003) Parental consanguinity and congenital heart malformations in a developing country. Am J Med Genet A 116A:342–347 Naguib K, Al-Awai S, Moussa M, Farag T, Teebi A (1989) Effect of parental age, birth order and consanguinity on nondisjunction in the population of Kuwait. J Kuwait Med Assoc 23:37–43 Nelson J, Smith M, Bittles AH (1997) Consanguineous marriage and its clinical consequences in migrants to Australia. Clin Genet 52:142–146 Obeidat BR, Khader YS, Amarin ZO, Kassawneh M, Al Omari M (2008) Consanguinity and adverse pregnancy outcomes: the north of Jordan experience. Matern Child Health J [E-publication] Ozand PT, Gascon GC, al Aqeel A, Roberts G, Dhalla M, Subramanyam SB (1990) Prevalence of different types of lysosomal storage diseases in Saudi Arabia. J Inherit Dis 13:849–861 Ozand PT, Devol EB, Gascon GC (1992) Neuro-metabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre. J Child Neurol 7(Suppl):S4–S11 Panter-Brick C (1991) Parental responses to consanguinity and genetic disease in Saudi Arabia. Soc Sci Med 33:1295–1302 Patel PK (2007) Profile of major congenital anomalies in the Dhahira region, Oman. Ann Saudi Med 27:106–111


107

Pedersen J (2002) The influence of consanguineous marriage on infant and child mortality among Palestinians in the West Bank and Gaza, Jordan, Lebanon and Syria. Community Genet 5:178–181 Radovanovic Z, Shah N, Behbehani J (1999) Prevalence and social correlates of consanguinity in Kuwait. Ann Saudi Med 19:206–210 Rajab A, Patton MA (1997) Major factors determining the frequencies of hemoglobinopathies in Oman. Am J Med Genet 71:240–242 Rajab A, Patton MA (1999) Analysis of the population structure in Oman. Community Genet 2:23–25 Rajab A, Patton MA (2000) A study of consanguinity in the Sultanate of Oman. Ann Hum Biol 27:321–326 Rajab A, Vaishnav A, Freeman NV, Patton MA (1998) Neural tube defects and congenital hydrocephalus in the Sultanate of Oman. J Trop Pediatr 44:300–303 Rantanen E, Hietala M, Kristoffersson U, Nippert I, Schmidtke J, Swequeiros J, K€a€ari€ainen H (2008) What is ideal genetic counselling? A survey of current international guidelines. Eur J Hum Genet 16:445–452 Rashed M, Ozand PT, Al Aqeel A, Gascon GG (1994) Experience of King Faisal Hospital and Research Centre with Saudi organic acid disorders. Brain Dev 16(Suppl):1–6 Raz AE, Atar M (2004) Cousin marriage and premarital carrier matching in a Bedouin community in Israel: attitudes, service development and educational intervention. J Fam Plann Reprod Health Care 30:49–51 Riou SE, Younsi C, Chaabouni H (1989) Consanguinite´ dans la population du Nord de la Tunisie. Tunis Me´d 67:167–172 Saad FA, Jauniaux E (2002) Recurrent early pregnancy loss and consanguinity. Reprod Biomed Online 5:167–170 Saedi-Wong S, al-Frayh AR (1989) Effects of consanguineous matings on anthropometric measurements of Saudi newborn infants. Fam Pract 6:217–220 Saedi-Wong S, al-Frayh AR, Wong HYH (1989) Socio-economic epidemiology of consanguineous mating in the Saudi Arabian population. J Asian Afr Stud 24:247–251 Saha N, El Sheikh FS (1988) Inbreeding levels in Khartoum. J Biosoc Sci 20:333–336 Saha N, Hamad RE, Mohamed S (1990) Inbreeding effects on reproductive outcome in a Sudanese population. Hum Hered 40:208–212 Salem K, Lashin S, El Dib A (1994) Consanguinity and mental retardation. Med J Cairo Univ 62 (Suppl):177–186 Sawardekar KP (2005) Profile of major congenital malformations at Nizwa Hospital, Oman: 10-year review. J Paediatr Child Health 41:323–330 Seliem MA, Bou-Holaigah IH, Al-Sannaa N (2007) Influence of consanguinity on the pattern of familial aggregation of congenital cardiovascular anomalies in an outpatient population: studies from the eastern province of Saudi Arabia. Community Genet 10:27–31 Sharkia R, Zaid M, Athamna A, Cohen D, Azem A, Zalan A (2007) The changing pattern of consanguinity in a selected region of the Israeli Arab community. Am J Hum Biol 20:72–77 Shiloh S, Reznik H, Bat-Miriam-Katznelson M, Goldman B (1995) Pre-marital genetic counselling to consanguineous couples: attitudes, beliefs and decisions among counselled, noncounselled and unrelated couples in Israel. Soc Sci Med 41:1301–1310 Stern GH (1939) Marriage in early Islam. London, The Royal Asiatic Society, pp 165–166 Subramanyan R, Joy J, Venugopalan SA, Al Khusaiby SM (2000) Incidence and spectrum of congenital heart disease in Oman. Ann Trop Paediatr 20:337–340 Tadmouri GO, Al Ali MT, Al-Haj Ali S, Al Khaja N (2006) CTGA: the database for genetic disorders in Arab populations. Nucleic Acids Res 34(Database issue):D602–606 Tamim H, Khogali M, Beydoun H, Melki I, Yunis K (2003) Consanguinity and apnea of prematurity. Am J Epidemiol 158:942–946 Teebi A (1994) Autosomal recessive disorders among Arabs: an overview from Kuwait. J Med Genet 31:224–233

108


Teebi AS, Teebi SA, Porter CJ, Cuticchia AJ (2002) Arab genetic disease database (AGDDB): a population-specific clinical and mutation database. Hum Mutat 19:615–621 Temtamy SA, Kandil MR, Demerdash AM, Hassan WA, Meguid NA, Afifi HH (1994) An epidemiological/genetic study of mental subnormality in Assiut Governorate, Egypt. Clin Genet 46:347–351 Temtamy S, Abdel Meguid N, Mazen I, Ismail S, Kassem N, Bassiouni R (1998) A genetic epidemiological study of malformations at birth in Egypt. East Mediterr Health J 4:252–259 Tucker JE (1988) Marriage and family in Nablus, 1720–1856: toward a history of Arab marriage. J Fam Hist 13:165–179 Vardi-Saliternik R, Friedlander Y, Cohen T (2002) Consanguinity in a population sample of Israeli Muslim Arabs, Christian Arabs and Druze. Ann Hum Biol 29:422–431 Wahab AA, Bener A, Teebi AS (2006) The incidence patterns of Down syndrome in Qatar. Clin Genet 69:360–362 WHO (2002) Advisory committee on health research, genomics and world health. World Health Organization, Geneva Wong SS, Anokute CC (1990) The effect of consanguinity on pregnancy outcome in Saudi Arabia. J R Soc Health 110:146–147 Yunis K, Mumtaz G, Bitar F, Chamseddine F, Kassar M, Rashkidi J et al (2006) Consanguineous marriage and congenital heart defects: a case-control study in the neonatal period. Am J Med Genet A 140:1524–1530 Zakzouk S, El-Sayed Y, Bafaqeeh SA (1993) Consanguinity and hereditary hearing impairment among Saudi population. Ann Saudi Med 13:447–450 Zaoui S, Bie´mont C (2002) Fre´quence et structure des mariages consanguins dans le re´gion de Tlemcen (Ouest alge´rien). Cahiers Sante´ 12:289–295 Zlotogora J (1997) Genetic disorders among Palestinian Arabs: 1. Effects of consanguinity. Am J Med Genet 68:472–475 Zlotogora J, Shalev S, Habiballah H, Barjes S (2000) Genetic disorders among Palestinian Arabs: 3. Autosomal recessive in a single village. Am J Med Genet 92:343–345 Zlotogora J, Habiballa H, Odatalla A, Barges S (2002) Changing family structure in a modernizing society: a study of marriage patterns in a single Muslim village in Israel. Am J Hum Biol 14:680–682 Zlotogora J, Hujerat Y, Zalman L, Barges S, Filon D, Koren A, Shalev SA, Chakravarti A (2005) The origin and expansion of four different beta globin mutations in a single Arab village. Am J Hum Biol 17:659–661 Zlotogora J, Hujerat Y, Barges S, Shalev SA, Chakravti A (2006) The fate of 12 recessive mutations in a single village. Ann Hum Genet 71:202–208

Part III Selected Disease Entities Prevalent Among the Arabs

Chapter 5

Familial Mediterranean Fever and Other Autoinflammatory Disorders Hatem El-Shanti and Hasan Abdel Majeed

Autoinflammatory diseases are a group of disorders characterized by seemingly unprovoked inflammation in the absence of high-titer autoantibodies or antigenspecific T-cells (Stojanov and Kastner 2005). The autoinflammatory diseases include the hereditary periodic fever syndromes and are thought to be due to disturbances in the regulation of the innate immunity (Kastner 2005). Familial Mediterranean Fever (FMF) is the archetypal hereditary periodic fever syndrome and autoinflammatory disease. Other disorders include tumor necrosis factor receptorassociated periodic syndrome (TRAPS); hyperimmunoglobulinemia D with periodic fever syndrome (Hyper-IgD); pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; the cryopyrinopathies: familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID, also called chronic infantile neurologic cutaneous and articular syndrome, or CINCA syndrome); and chronic recurrent multifocal osteomyelitis (McGonagle and McDermott 2006; Milhavet et al. 2008).

Familial Mediterranean Fever (FMF, MIM 249100; MEFV, MIM 608107) FMF is characterized by recurrent self-limiting episodes of fever and painful polyserositis affecting mainly the peritoneum, pleura, and synovium. It was first described as a distinct disease entity, under the name of benign paroxysmal peritonitis, in 1945 (Siegal 1945). The international medical community adopted the name FMF, as suggested by the team led by Heller (Sohar et al. 1961), although the disorder had several other names including recurrent polyserositis, recurrent H. El-Shanti (*) Director, Shafallah Medical Genetics Center, Doha, Qatar Adjunct Associate Professor of Pediatrics, University of Iowa, Iowa City, Iowa, USA email: [email protected]


111

112

H. El-Shanti and H.A. Majeed

hereditary polyserositis, periodic disease and periodic peritonitis. FMF is an autosomal recessive disorder (Sohar et al. 1961), with considerable prevalence in specific ethnic groups, namely, non-Ashkenazi Jews, Armenians, Turks, and Arabs. The impact of FMF on patients is determined mainly by the presence or absence of its most deleterious complication, amyloidosis (Heller et al. 1961). However, the burden of the febrile and painful episodes as manifested in loss of school or work days, repetitive suffering, and unnecessary hospitalization, and surgery (Kasifoglu et al. 2009) is also substantial.

Clinical Aspects The classic clinical picture consists of recurrent febrile episodes that are usually of acute onset, variable frequency, sometimes without a recognized triggering factor but often occurring with menstruation, emotional stress, or strenuous physical activity (Samuels et al. 1998). These febrile episodes are short-lived, lasting 1–3 days but may last 4 days or longer, and usually abort abruptly. The episodes are often accompanied by pain due to peritonitis, pleuritis, or acute synovitis of large joints. The frequency of the attacks varies from once per week to long periods of remission. Over the course of the lifelong illness, an affected individual will probably experience several forms of the febrile and painful episodes, but the recurrence of one type over many years is common (Sohar et al. 1967). During the attack there is neutrophilia and a brisk acute-phase response, and histologically there is a massive sterile influx of polymorphonuclear leukocytes (PMNs) into the affected site (Sohar et al. 1967). Between attacks, patients feel well, although biochemical evidence for inflammation may persist (Kastner 2005). The episodes start, most commonly during childhood, with more than 80% of patients presenting before the age of 20 years and a very few after the age of 40 years (Barakat et al. 1986; Padeh 2005; Sohar et al. 1967). The painful abdominal (peritoneal) attack is the most frequent association with the febrile episode. It is experienced by the majority of patients (Padeh 2005) and is reported in about 50% of patients as the first symptom (Sohar et al. 1967). The abdominal pain can be diffuse or localized, ranging in intensity from mild bloating to real peritonitis with guarding, rigidity, tenderness, and rebound tenderness (Padeh 2005; Samuels et al. 1998). The organization of the peritoneal inflammatory exudate may result in fibrous adhesions and may give rise to mechanical intestinal obstruction (Michaeli et al. 1966). These adhesions are probably the cause of sterility in some women affected by FMF (Ehrenfeld et al. 1987; Ismajovich et al. 1973; Mijatovic et al. 2003; Rabinovitch et al. 1992). The articular involvement in FMF episodes is the second-most common association with the fever. The articular inflammation presents as an abrupt onset of acute arthritis, accompanied by high fever, redness, warmth, tenderness, and swelling (Barakat et al. 1986; Majeed and Rawashdeh 1997; Ozer et al. 1971; Schwabe and Peters 1974). It is often monoarticular and commonly affects the large joints of the

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

113

lower limbs. It usually lasts longer than other FMF manifestations and subsides gradually rather than abruptly and leaves no residual damage (Padeh 2005). The synovial fluid is sterile but contains large numbers of neutrophils (Heller et al. 1966; Sohar et al. 1967). Rarely, FMF patients develop protracted arthritis, synovitis, muscle atrophy, erosions, and juxta-articular osteoporosis (Heller et al. 1966; Salai et al. 1997; Sneh et al. 1977; Yalcinkaya et al. 1997). Non-steroidal antiinflammatory drugs (NSAIDs) are generally effective in FMF arthritis. Pleural attacks occur in 15–30% of FMF patients (Saatci et al. 1997). Usually, the attacks present as an acute one-sided febrile pleuritis resembling the peritoneal attacks in their abrupt onset, unpredictable occurrence, and abrupt and rapid resolution (Majeed et al. 1999; Ozer et al. 1971; Sohar et al. 1967). Breathing may be painful, there may be diminished breath sounds on auscultation, and there may be radiological evidence of pleural effusion or lung collapse. The characteristic skin lesion is the erysipelas-like erythema which may sometimes accompany the arthritis (Azizi and Fisher 1976; Sohar et al. 1967). Histological examination of the lesions reveals edema of the dermis, sparse perivascular infiltrate without vasculitis and C3 deposits seen by immunofluorescence (Barzilai et al. 2000). Muscle pain occurs in about 10% of FMF patients and is usually mild and confined to the lower extremities (Padeh 2005). It may be precipitated by physical exertion or prolonged standing, lasts few hours to 1 day and subsides with rest or NSAIDs (Majeed et al. 2000a). Rarely, a syndrome of protracted febrile myalgia may develop (Kotevoglu et al. 2004; Langevitz et al. 1994; Majeed et al. 2000a; Sidi et al. 2000). It is characterized by severe debilitating myalgia, prolonged fever, abdominal pain without peritoneal involvement, a high erythrocyte sedimentation rate (ESR), and hyperglobulinemia. If treated with NSAIDs alone, the syndrome may last for up to 8 weeks, but it will subside promptly if treated with corticosteroids (Kotevoglu et al. 2004; Langevitz et al. 1994; Majeed et al. 2000a; Sidi et al. 2000). Acute inflammation of the tunica vaginalis in FMF patients may mimic torsion of the testis and will present as a unilateral tender scrotal swelling (Eshel et al. 1988, 1994; Majeed et al. 2000c). This is not surprising as the tunica vaginalis is structurally part of the peritoneum. However, these episodes usually do not occur with an acute peritoneal attack and are usually unilateral (Majeed et al. 1999). Fever and pain are always present with these self-limiting and short-lived acute scrotum episodes. Uncommon manifestations include headache (Buskila et al. 1997; Gedalia and Zamir 1993), meningeal irritation and increased CSF proteins and cells (Barakat et al. 1988; Gedalia and Zamir 1993; Karachaliou et al. 2005; Schwabe and Monroe 1988; Vilaseca et al. 1982), impaired female fertility (Ehrenfeld et al. 1987; Ismajovich et al. 1973; Mijatovic et al. 2003), pericarditis (Kees et al. 1997), and transient microscopic hematuria. Vasculitides are found in FMF at a higher frequency than in the general population. Henoch–Schonlein purpura (HSP) has been reported in 3–11 % of FMF patients (Flatau et al. 1982; Gershoni-Baruch et al. 2003; Majeed et al. 1990; Schlesinger et al. 1985). A study identified more than expected homozygous and

114


heterozygous FMF mutations among children presenting with HSP (GershoniBaruch et al. 2003). Polyarteritis nodosa also occurs more commonly in patients with FMF (Sachs et al. 1987). Various types of glomerulonephritis have been reported in FMF (Said et al. 1992), but the data are insufficient to draw conclusions about its higher prevalence in FMF patients when compared to the general population even within the same ethnic group. The most significant complication of FMF is amyloidosis, which mainly affects the kidneys causing proteinuria and leading to renal failure (Heller et al. 1961). Chemically, it is the same type of reactive amyloidosis, with amyloid A deposits, which takes place with chronic infectious and non-infectious inflammatory conditions, such as tuberculosis, bronchiectasis, and rheumatoid arthritis (Pras et al. 1982). Family history of amyloidosis and consanguinity are factors causing a higher risk of development of amyloidosis in FMF patients (Saatci et al. 1993, 1997). Colchicine treatment greatly influenced the occurrence of amyloidosis as a complication of FMF. In a group of patients, clinically designated as phenotype II FMF patients, renal amyloidosis develops without being preceded by typical attacks of the disease (Balci et al. 2002; Konstantopoulos et al. 2001; Melikoglu et al. 2000; Tunca et al. 2005). A daily regimen of 1–2 mg of oral colchicine remains the recommended treatment since its introduction in 1972 (Ben-Chetrit and Levy 1998; Goldfinger 1972; Ozkan et al. 1972). Adherence to a daily dose of colchicine produces significant decrease in the frequency and severity of the attacks or even cessation of the attacks all together in about 95% of FMF patients (Zemer et al. 1974). Continuous prophylactic treatment with colchicine in FMF patients inhibits the development of amyloidosis (Cabili et al. 1985), even in the patients who do not experience a decrease in the frequency or severity of the attacks (Ben-Chetrit and Levy 1991). The diagnosis of FMF remains a clinical bedside diagnosis with well-outlined validated diagnostic criteria (Livneh et al. 1997); however, a positive response to colchicine is supportive of the diagnosis. An attempt at the revision of the diagnostic criteria, especially as it applies to children, produced a newer set of clinical diagnostic criteria although this set awaits independent validation (Yalcinkaya et al. 2009). There is slight predominance of males affected with FMF, because of either reduced penetrance in females (Shohat et al. 1992b) or more probably because of underestimation of the disease in females (Medlej-Hashim et al. 2005).

The Genetics The gene responsible for FMF, MEFV, is located on the short arm of human chromosome 16 (Gruberg et al. 1992; Pras et al. 1992, 1994; Shohat et al. 1992a), and was independently identified by two positional cloning consortia (French FMF Consortium 1997; International FMF Consortium 1997). With the cloning of the gene, four missense mutations in exon 10, namely M694V, V726A, M694I,


115

and M680I, were identified (French FMF Consortium 1997; International FMF Consortium 1997). These four mutations and E148Q in exon 2 are the most common MEFV mutations among the putative mutations identified to date (Bernot et al. 1998; Booth et al. 1998; Touitou 2001). Exon 10 remains the major site of mutations, with a smaller cluster in exon 2 (available at http://fmf.igh.cnrs.fr/ infevers) (Fig. 5.1) (Milhavet et al. 2008; Sarrauste de Menthiere et al. 2003; Touitou et al. 2004). The FMF carrier rate can be as high as 1 in 3 in the commonly affected ethnic groups, raising the possibility of selective heterozygote advantage (Al-Alami et al. 2003; Gershoni-Baruch et al. 2001; Kogan et al. 2001; Stoffman et al. 2000; Touitou 2001; Yilmaz et al. 2001). Although FMF is an autosomal recessive disease, pseudodominance is frequently observed, because of the high mutation frequency and also because of consanguinity, which is practiced frequently in the ethnic groups commonly affected by FMF (Aksentijevich et al. 1999; Yuval et al. 1995). Consistent with the biology of FMF, MEFV is expressed predominantly in granulocytes, monocytes, dendritic cells, and in fibroblasts derived from skin, peritoneum, and synovium (Centola et al. 2000; Diaz et al. 2004; Matzner et al. 2000). MEFV encodes a full-length 781 amino acid protein named pyrin (International FMF Consortium 1997) or marenostrin (French FMF Consortium 1997). Native pyrin protein is localized in different subcellular compartments in different cell types (Diaz et al. 2004). Wild-type pyrin is cytoplasmic, co-localizes with MEFV NM

000243.1(16p13.3)

DNA: 14600bp, mRNA: 3499bp, Protein: 781aa P180R N99N G196W D102D R202Q D103D S208Afs S108R A457V L110P G219G G632S V469L P221P L110L I640M Y688X Y471X E225D G111G I692del I641F E474E E230K G112fs M694del P646L E474K Y232H P124P P646P M694I Q476Q G236V E125E M694L L649P H478Y N130_13line S242S T309M M694V R652R F479L R314R S242R C>G G138G R653H K695M V487M S141I S242R C>A R314H K695R E656A Q489Q E319K E251K R143P K695N D66IN R501G N256Dfs E148Q V328A A701A S675N 1759+8C>T R501H R329H I259V E148V S702C G678E 1760–30A>T R501R T267I R151S S339F M680L S703S 1760–28T>A I506I R348H A268V E163A M680IG>A V704I 1760–4G>A I506V C352C A165A R278P M680IG>C P705S 1423V D510D –792C>T E167D P283L R354W P706P T68II P588P 1610+47A>T Q440E I513T –751A>T P175H P283R S363S S683S R708C I591T 1610+96C>T G514E –740C>T P369S 1260+10C>T T177I A289V L709R Y688C G592G –614C>G Q383K 1260+18C>G 1587+18C>T F299G L9L S179I A595V –382C>G 1587+29G>T G304R 910+29C>T P393P 1260+92G>A R42W P180P 1727-587>C 1792+39 G>A –330G>A Y65Y 1587+33C>G 911-22T>G R408Q 1261–11T>G T577S 1792+57 C>T –12C>G A89T 911-78T>C V415V 1261–28A>G 1356+44A>G 1540+69G>A L559F M582L 1793–14A>G

5’flanking Sizes (bp)

1 317

11 1520

2 633

12 4377

3 350

13 426

4 96

14 1662

5 231

15

16

468

1936

6 23

17

18

7 8 9 186 361 116 33 33

19

10

165

R717S I720M F721F V722M D723D V726A F743F F743L A744S S749C Q753Q I755V P758S R761H 1772V G779G P780T *9C>T *12T>C *21C>G

3’flanking

1667

CDS joints Positions Codons

277/278 93

910/911 304

1260/1261 420/421

1356/1357 452/453

1587/1588 529/530

This graph shows the variant usual name (i.e. as first published). Please refer to the variant detail by clicking on its name for possible edited nomenclature.

Fig. 5.1 MEFV and its variations

1610/1611 537

1726/1727 576

1759/1760 587

1792/1793 598

INFEVERS: May 25,2009 N Sequence variants:181

116


microtubules, and it is proposed that it regulates inflammatory responses at the level of the cytoskeletal organization (Mansfield et al. 2001; Papin et al. 2000). However, nuclear localization of full-length pyrin in synovial fibroblasts, dendritic cells and granulocytes has been demonstrated (Diaz et al. 2004). Several alternatively spliced forms have been described (Diaz et al. 2004; Papin et al. 2000). In addition, it appears that pyrin acts as an upstream regulator of interleukin (IL)-1b activation (Chae et al. 2003; Yu et al. 2005), having both inhibitory and potentiating effects on IL-1b production. There is also evidence that pyrin plays a role in regulating nuclear factor (NF)-kB activation and apoptosis (Chae et al. 2003; Dowds et al. 2003; Masumoto et al. 2003; Stehlik and Reed 2004; Yu et al. 2005).

Genotype/Phenotype Correlation Patterns The Tel Hashomer severity score (Pras et al. 1998), has been used to facilitate comparison of FMF phenotype severity among the different ethnic groups. Several studies have examined the correlation between certain mutations and phenotype severity in the different affected ethnic groups. Most studies showed correlation between M694V and severity of the disease or the presence of amyloidosis across all affected ethnic groups with the exception of the Turkish FMF patients (Brik et al. 1999; Cazeneuve et al. 1999; Dewalle et al. 1998; Livneh et al. 1999; Majeed et al. 2002; Mansour et al. 2001; Shinar et al. 2000; Shohat et al. 1999; Sidi et al. 2000; Yalcinkaya et al. 2000). The results of selected studies are summarized in Table 5.1. Upon reviewing the FMF genotype/phenotype correlation literature, we can conclude that there is no consistency in the correlation between a specific MEFV mutation and amyloidosis or other phenotypic feature across all populations, with the exception of M694V and amyloidosis or severity of the FMF symptoms. However, there is a specific pattern of severity or amyloidosis within the same population, such as in homozygosity for M694V in the North African Jews and M694V homozygosity in the protracted febrile myalgia syndrome in the Arabs. Overall, the studies that explored the reasons accounting for the fact that only a subset of FMF patients develops amyloidosis did not lead to definitive conclusions. These studies tested a limited number of variables in often small series. In addition the studies had variable designs which do not allow comparisons or meta-analytic approaches. A web-based project denoted “metaFMF” emerged with the goal of resolving discrepant published conclusions related to genotype/phenotype correlation patterns in FMF (Milhavet et al. 2008; Pugnere et al. 2003; Sarrauste de Menthiere et al. 2003; Touitou et al. 2004, 2007). This project that utilizes a standardized mode of data collection represents an international effort with significant contribution from the Arabic FMF investigator teams. The project evolved into an online mutation registry for autoinflammatory disorders (Milhavet et al. 2008; Sarrauste de Menthiere et al. 2003; Touitou et al. 2004) (available at http://fmf.igh.cnrs.fr/infevers).

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders Table 5.1 Summary of selected genotype/phenotype correlation studies Mutation Ethnic group Phenotype assessed 1 M694V/M694V Non-Ashkenazi Arthritis & Pleuritis Jews Amyloidosis 2 M694V/M694V Armenians Arthritis

3

M694V/M694V

4

M694V/M694V

5

Others M694V/M694V

6

M694V/M694V

Non-Ashkenazi Jews Arabs North African Jews, Armenians & Turks Non-Ashkenazi Jews Mixed Jewish

7

M694V/M694V

Mixed Jewish

8

M694V/M694V

Turks

9

M694V/M694V M680I/M680I M694V/M694V

M694I/M694I M694V/M694I 10 M694V/M694V

Arabs

Arabs

M694V/V726A

Amyloidosis Severity (no specific index) Amyloidosis Amyloidosis Severity Amyloidosis Tel Hashomer Severity Score Protracted febrile myalgia Severity (12 parameters) Amyloidosis Arthritis Amyloidosis Amyloidosis Amyloidosis Severity (modified score) Protracted febrile myalgia

117

Relation Increased 2X Dewalle et al. (1998) Increased Increased Cazeneuve et al. (1999) Increased Increased Brik et al. (1999) Increased Increased Shohat et al. (1999) No relation Increased Livneh et al. (1999) Increased Shinar et al. (2000) Increased Sidi et al. (2000) No relation Yalcinkaya et al. (2000) No relation Decreased Increased Mansour et al. (2001) Increased Increased Increased Majeed et al. (2002) Increased

FMF in the Arabs Currently, FMF is established as a common genetic disease among the Arabs and in the early 1980s it became recognized as a public health concern in some Arabic countries (Barakat et al. 1984a, b, 1986; Majeed and Barakat 1989). Since then, it became increasingly notable that FMF has a considerable impact on the health and welfare of children and adults in the Arabic countries (El-Shanti et al. 2006). FMF may be complicated by amyloidosis which leads to renal failure and it is associated with loss of school days or work hours and unnecessary hospitalizations and surgeries. In addition, the painful and febrile episodes are extremely uncomfortable for FMF patients. However, similar to other ethnic groups commonly affected by FMF, the mortality and morbidity associated with FMF are preventable with early identification of affected individuals followed by appropriate treatment and prophylaxis. Clinical and molecular studies involving a variety of Arabic subpopulations demonstrate the high prevalence of FMF and high MEFV mutation-carrier

118


frequency (Al-Alami et al. 2003; Gershoni-Baruch et al. 2001; Rawashdeh and Majeed 1996). However, the clinical and particularly the molecular aspects FMF have not been adequately studied in the Arabs when compared to other ethnic groups commonly affected by FMF.

Clinical Aspects The studies that elaborate on the clinical features of Arabic patients were carried out either prior to the identification of the MEFV as the gene responsible for FMF or did not incorporate molecular data in the analyzes (Barakat et al. 1986; Majeed 2000; Majeed and Barakat 1989; Majeed and Rawashdeh 1997; Majeed et al. 1990, 1999, 2000a, c; 2002, 2005a; Rawashdeh and Majeed 1996; Said and Hamzeh 1990; Said et al. 1988, 1989, 1992). The majority of these studies employed the original diagnostic criteria (short attacks of fever and abdominal pain recurring at varying intervals in the absence of any causative factor) proposed by Heller and coworkers (1958). However, more recent studies employed the validated diagnostic criteria of Livneh and coworkers (1997) as a standard for the diagnosis (Majeed 2000; Majeed et al. 1999; Majeed et al. 2000a, 2000c, 2002, 2005a). In addition, most of these studies were done after the establishment of colchicine as an effective treatment and this may have influenced the reported phenotype. We conclude that different diagnostic standards and colchicine therapy are the primary confounding factors that may have contributed to the reported clinical peculiarities of the FMF phenotype in the Arabs. In addition, several other confounding factors may have contributed to the difference in phenotype, such as under-reporting of symptoms, criteria for patient selection, reliance on family history, chance variations, and the lack of a definitive diagnostic test. About 80% of Arabic FMF patients present before the age of 10 years and abdominal pain is the most commonly reported presenting feature (Majeed et al. 1999). This earlier age at onset is probably explained by the skewed patient selection in the reported case series which is influenced by the clarity of symptoms and the presence of family history. Unlike the higher prevalence in men in other ethnic groups commonly affected by FMF, the male to female ratio in Arabs is almost equal (Majeed et al. 1999; Rawashdeh and Majeed 1996). This is probably due to the accurate estimation of the number of affected women, also influenced by patient selection. In addition, this finding does not support the suggestion that FMF may have incomplete penetrance in females (Shohat et al. 1992b). Arthritis is less common in the Arabic FMF children and adults (Barakat et al. 1986; Majeed and Barakat 1989; Majeed and Rawashdeh 1997; Majeed et al. 1999), as compared to that in Jews (Sohar et al. 1967; Zemer et al. 1991); however, it is similar to arthritis in Turks (Ozdemir and Sokmen 1969; Sayarlioglu et al. 2005) and Armenians (Cazeneuve et al. 1999; Schwabe and Peters 1974). The decreased frequency of arthritis in Arabs, Turks, and Armenians may be due to under-reporting of the symptoms, as well as due to delay in the diagnosis.


119

The pleural attacks (Majeed et al. 1999), peritoneal attacks (Barakat et al. 1986; Majeed and Barakat 1989; Rawashdeh and Majeed 1996), and myalgia (Majeed et al. 2000a) are not different from those in other ethnic groups commonly affected by FMF. About 20% of Jewish and Arab children with functional abdominal pain were homozygous for an MEFV mutation (Brik et al. 2001). In one early report, non-specific purpuric rash was reported more commonly than erysipelas-like erythema in Arabic FMF patients (Majeed et al. 1990), while erysipelas-like erythema is the most common in other ethnic groups commonly affected by FMF. This unusual finding is probably due to the small number in that series and the differences were probably not statistically significant. In addition, the erysipelas-like erythema was noted to be a common cutaneous manifestation of FMF in Arabs in a later case series (Majeed et al. 1999). The acute scrotal swelling reported in Arabic FMF patients sometimes occurred in the absence of peritonitis (Majeed et al. 1999) and is associated with a high rate of decreased favorable response to colchicine therapy in Arabic and Jewish FMF patients (Eshel et al. 1994, 1988; Majeed et al. 1999, 2000c). This therapy failure rate is alarming due to a report of testicular necrosis following recurrent scrotal attacks in the latter ethnic group (Livneh et al. 1994). Recurrent hyperbilirubinemia has been described in the early FMF literature but very few patients were clinically icteric (Priest and Nixon 1959). This probably explains why this feature is not mentioned in the large clinical series reported from all ethnic groups commonly affected by FMF. Recurrent hyperbilirubinemia has been described in two Arabic patients in 1994 (Neequaye and Jelly 1994) and in 1998 (Majeed et al. 1998). In these two reports, the hyperbilirubinemia was transient, occurring only during a peritoneal attack and clinical jaundice was mild with only a minimal rise in serum bilirubin (mainly conjugated) (Majeed et al. 1999). The etiology of the hyperbilirubinemia is unclear, but seems to be a benign process as no cases of acute or chronic liver failure have been reported. It has been noted that amyloidosis and chronic renal disease are less common in the Arabic FMF patients when compared to the other ethnic groups commonly affected by FMF (Bakir and Murtadha 1975; Barakat et al. 1986; Majeed and Barakat 1989; Majeed et al. 1999; Rawashdeh and Majeed 1996). The frequency of amyloidosis ranged from 0.4% in Jordanian FMF patients (Majeed et al. 1999) to 2% in a mixed Arabic population residing in Kuwait (Majeed and Barakat 1989). The frequency of amyloidosis in Sephardic Jews ranges from 26 to 42% (Gafni et al. 1968; Sohar et al. 1967), while in Armenians it is about 24% (Aivazian et al. 1977) and in Turks about 60% (Ozdemir and Sokmen 1969; Saatci et al. 1993). The low rate of occurrence of FMF-related amyloidosis in the Arabic patients is probably due to the fact that these figures were obtained after the worldwide establishment of colchicine as the standard of care for FMF patients (Barakat et al. 1986; Majeed and Barakat 1989; Majeed et al. 1999; Rawashdeh and Majeed 1996). In two studies from Lebanon, the frequency of amyloidosis was about 10% (Armenian and Khachadurian 1973; Khachadurian and Armenian 1974). This higher figure can be explained by the conduction of the two studies prior to the establishment of colchicine therapy in Lebanon and that some of the Lebanese FMF

120


patients in the studied cohorts were Armenian in origin. The frequency of amyloidosis in the Arabic FMF patients and the factors influencing its occurrence have been studied together with specific MEFV mutations and examination of genotype/ phenotype correlation patterns and is discussed in detail below. Besides amyloidosis, kidney involvement in the form of IgM nephropathy, IgA nephropathy, or rapid progressive glomerulonephritis has been described in Arabic FMF patients (Said and Hamzeh 1990, Said et al. 1988, 1989, 1992). However, the numbers in these case series are small to draw firm conclusions but may point to the higher prevalence of vasculitis or glomerulonephritis in FMF patients.

MEFV Mutations The mutation analysis studies that include a substantial number of Arabic FMF patients are limited in number and in methodology (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Chaabouni et al. 2007; Dode et al. 2000; GershoniBaruch et al. 2001, 2002a, b; Jarjour 2010; Majeed et al. 2002, 2005a; Mansour et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2001, 2002, 2004, 2005; Sabbagh et al. 2008). All of these studies examined for the five common mutations (E148Q, M680I, M694V, M694I, and V726A) using a combination of restriction endonuclease-based test, ARMS (Amplification Refractory Mutation System) test, DGGE (denaturing gradient gel electrophoresis), and selective exonic sequencing. A few studies examined for additional mutations but also in a selective manner (Ayesh et al. 2005; Chaabouni et al. 2007; Dode et al. 2000; Jarjour 2010; MedlejHashim et al. 2000, 2005; Sabbagh et al. 2008). A summary of selected MEFV mutation analysis studies that included Arabic FMF patients is provided in Table 5.2. However, despite their limitations, these studies point to the high MEFV mutation carrier frequency among the Arabs, which is similar to that among the other ethnic groups commonly affected by FMF (1 in 3–6 individuals). The most common MEFV mutation is the M694V (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Dode et al. 2000; Gershoni-Baruch et al. 2001, 2002a, b; Jarjour 2010; Majeed et al. 2002, Majeed et al. 2005a; Mansour et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2001, 2002, 2004, 2005; Sabbagh et al. 2008), although it is less common than in other ethnic groups commonly affected by FMF (Cazeneuve et al. 1999; Medlej-Hashim et al. 2005; Padeh et al. 2003; Yalcinkaya et al. 2000). The V726A is the second most common mutation in Arabs (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Dode et al. 2000; Gershoni-Baruch et al. 2001, 2002a, b; Jarjour 2010; Majeed et al. 2002, 2005a; Mansour et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2001, 2002, 2004, 2005; Sabbagh et al. 2008) similar to the findings in Armenians, Turks, and Jews (Cazeneuve et al. 1999; Padeh et al. 2003; Yalcinkaya et al. 2000). M694I is the third most common mutation in Arabs (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Gershoni-Baruch et al. 2002a; Majeed et al. 2002, 2005a; Mansour et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2005; Sabbagh

Table 5.2 Summary of selected MEFV mutational analysis studies that included Arabic patients with FMF Proportion (%) mutant alleles identified (n/N) Method of analysis Arabs Jews Armenians Turks 96% (47/49)a ns ns Brik et al. (1999) Restriction endonuclease digestion 90% (28/31)a Dode et al. (2000) Sequencing of exon 10, restriction endonuclease 49% (48/98) 70% (131/186) 90% (56/62) 75% (36/48) digestion & DGGE Medlej-Hashim et al. (2000) Restriction endonuclease digestion & ARMS 56% (47/84) ns ns ns Mansour et al. (2001) Sequencing of exon 10, restriction endonuclease 67% (97/143) ns ns ns digestion, DGGE & ARMS Gershoni-Baruch et al. (2001) Restriction endonuclease digestion 85% (121/142) 96% (144/150) ns ns Majeed et al. (2002) Sequencing of exon 10, restriction endonuclease 32% (176/556) ns ns ns digestion & ARMS Al-Alami et al. (2003) Sequencing of exon 10, restriction endonuclease 54% (31/58) ns ns ns digestion & ARMS Majeed et al. (2005a) Restriction endonuclease digestion & ARMS 47% (387/814) ns ns ns Ayesh et al. (2005) Sequencing of exon 10 & ARMS 49% (504/1022) ns ns ns Medlej-Hashim et al. (2005) Sequencing of exon 10, restriction endonuclease 50% (553/1116) ns ns ns digestion, SSCP & resequencing exons 1–9 Chaabouni et al. (2007) Restriction endonuclease digestion & ARMS 38% (105/278) ns ns ns Sabbagh et al. (2008) Strip assay 38.5% (205/532) ns ns ns Jarjour (2010) Strip assay 49% (150/306) ns ns ns ARMS Amplification refractory mutation system; DGGE Denaturing gradient gel electrophoresis; ns population not studied a Proportion of patients identified to have one or two mutations and not proportion of identified alleles

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders 121

122


et al. 2008) and appears to be found mainly in this ethnic group (Aksentijevich et al. 1999; Ben-Chetrit et al. 2002; Booth et al. 1998; French FMF Consortium 1997; Samuels et al. 1998). The M680I mutation found mostly in Armenians and Turks (Cazeneuve et al. 1999; Yalcinkaya et al. 2000) is the fourth common mutation in Arabs (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Gershoni-Baruch et al. 2002a; Majeed et al. 2002, 2005a; Mansour et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2005; Sabbagh et al. 2008). There are few studies that show that in Arabic patient series M680I is more common than M694I (GershoniBaruch et al. 2002a; Gershoni-Baruch et al. 2001; Jarjour 2010; Medlej-Hashim et al. 2000) or even the most common mutation among the population studied (Chaabouni et al. 2007). The E148Q mutation is the least penetrant and might be a polymorphism (Ben-Chetrit et al. 2000; Chaabouni et al. 2007; Jarjour 2010; Mattit et al. 2006; Medlej-Hashim et al. 2005; Sabbagh et al. 2008; Touitou 2001). It has been identified in Arabic FMF patients alone or in a complex allele with other exon ten mutations (Majeed et al. 2002, 2005a; Mansour et al. 2001; Medlej-Hashim et al. 2000, 2002), but is more commonly identified in healthy carriers (Al-Alami et al. 2003; Mattit et al. 2006). Table 5.3 provides a summary of the distribution of the five common MEFV mutations in the Arabic FMF patients in selected studies that provided clear mutant allele frequencies. The distribution of the five common MEFV mutations among healthy Arabic individuals has been the subject of two studies to date (Al-Alami et al. 2003; Mattit et al. 2006). In the first study, healthy cohorts from Jordan, Egypt, Syria, Saudi Arabia, and Iraq were examined for the five common MEFV mutations. The distribution of each mutation in each Arabic population and the collective distribution are shown in Table 5.4. This study concludes that E148Q has reduced penetrance in the Arabic population and thus, a proportion of the genetically affected individuals remain asymptomatic. It is of note that utilizing the restriction endonuclease digestion test for the detection of the E148Q mutation can lead to misdiagnosis in presence of the E148V mutation (Medlej-Hashim et al. 2002), which may have increased the number of E148Q identified in healthy Arabic cohorts (Al-Alami et al. 2003). M694I and M680I are more prevalent in affected individuals when compared to the healthy individuals, which points to their higher

Table 5.3 The distribution of the five common MEFV mutations in the Arabic FMF patients in selected studies Mutation M694V (%) V726A (%) M694I (%) M680I (%) E148Q (%) Medlej-Hashim et al. (2000) 20.2 14.3 1.2 9.5 7.1 Dode et al. (2000) 36 0 55.4 4.3 4.3 Gershoni-Baruch et al. (2001) 17.4 34.7 9.9 21.5 16.5 Gershoni-Baruch et al. (2002a) 16.7 26.7 13.3 22.5 5.8 Al-Alami et al. (2003) 35.5 29 16 9.7 0 Majeed et al. (2005a) 37.5 26 14 10 12.5 Ayesh et al. (2005) 49 16.7 11.9 4 8.5 The percentage value is the contribution of the mutation to the pool of the identified mutant alleles


123

Table 5.4 Distribution of the five common mutations, allele frequencies, and carrier rates among the healthy adult cohort from five Arabic countries Saudies Total Nationality and Egyptians Syrians Jordaniansa Iraqies (200) (176) (107) (939) number (231) (225) Number of 462 450 400 352 214 1,878 chromosomes M694V 2 6 13 0 0 21 V726A 8 5 14 9 1 37 M694I 4 0 2 0 0 6 M680I 0 1 1 0 0 2 E148Q 29 30 23 29 12 123 Total 43 42 53 38 13 189 Wild-type allele 0.907 0.907 0.8675 0.892 0.939 0.899 frequency “p” Mutant allele 0.093 0.093 0.1325 0.108 0.061 0.101 frequency “q” Calculated carriers 39(16.87%) 38(16.92%) 46(23%) 34(19.26%) 12(11.4%) 170 (rate) Observed number 43 42 37 38 13 173 of carriers a The calculations of the carrier rate and allele frequency are done under the assumption that there are no complex alleles

penetrance. The overall carrier rate for the five common MEFV mutations from this study is 1 in 5 which is very similar to the calculated carrier rate. Despite the high carrier rate, the heterozygote advantage for the MEFV mutations could not be demonstrated in the study probably because of the relatively small sample size. In the second study, examination of healthy Syrian controls for the five common mutations revealed a carrier status of 17.5% (1:5.8) (Mattit et al. 2006). One of the remarkable conclusions from these studies is that the percentage of unidentified disease-causing MEFV alleles is highest in the Arabic population when compared to the other ethnic groups commonly affected by FMF (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Chaabouni et al. 2007; Dode et al. 2000; Gershoni-Baruch et al. 2001; Jarjour 2010; Majeed et al. 2002, 2005b; Mansour et al. 2001; Medlej-Hashim et al. 2000, 2005; Sabbagh et al. 2008). This is clearly shown in one study that used a combination of methods including direct sequencing of exon 10, DGGE, and restriction endonuclease digestion in a cohort of well characterized FMF patients from the four commonly affected ethnic groups (Dode et al. 2000). While 51% of the alleles in Arabic FMF patients were not identified in this study, only 30, 25, and 9% of the alleles were not identified in nonAshkenazi Jews, Turks, and Armenians, respectively. A recent study that employed methods that detect 24 previously described mutations (ARMS test followed by resequencing of exon 10 and exploration of five other mutations in exons 2, 3, 4, 5, and 6) in Palestinians failed to detect 51% of the alleles, which is quite high considering the detailed methodology (Ayesh et al. 2005). It is unlikely that the diagnosis of FMF in these studies is inaccurate, as all published reports follow the validated diagnostic criteria (Livneh et al. 1997). In a recently published study on

124


83 FMF patients from Syria, 76% of mutant alleles were identified by testing for the five common mutations followed by resequencing of exon 10 in patients with one or no mutation (Mattit et al. 2006). This is the highest reported percentage of identifiable mutation in an Arabic cohort. However, an independent study on 153 patients from Syria who were screened for a similar number of mutations albeit utilizing a different technical approach identified only 49% of mutant alleles and 51% of the alleles remained undetermined (Jarjour 2010). The summary of selected studies shown in Table 5.2 indicates the high percentage of unidentifiable alleles in Arabic FMF patients, which suggests the presence of other mutations not identified by the applied methods.

Genotype/Phenotype Correlation Patterns There are a few genotype/phenotype correlation pattern studies involving Arabic FMF patients (Brik et al. 1999; Gershoni-Baruch et al. 2002a; Jarjour 2010; Majeed et al. 2002; Mansour et al. 2001; Medlej-Hashim et al. 2004). One study that included mixed Arabic and Jewish FMF patients denoted that in Arabic patients FMF tends to run a milder course and carries a better prognosis (Brik et al. 1999). This was attributed to the fact that M694V is less common among the Arabic FMF patient cohort. Another study concluded that Arabic FMF patients with the genotypes M694V/M694V or M694V/V726A tend to have a severe clinical course (Majeed et al. 2002). The genotype M694I/M694I is common in Arabic FMF patients and seems to be associated with milder disease. However, this study used a severity score modified from the Tel Hashomer severity score and both have not been statistically validated. Homozygosity of M694V or the complex allele V726A/E148Q was associated with most severe course and highest risk for amyloidosis in mixed Arabic, Ashkenazi, and Non-Ashkenazi Jewish FMF patients (Gershoni-Baruch et al. 2002a). In Lebanese patients, M694V and M694I were associated with higher risk of amyloidosis (Mansour et al. 2001; Medlej-Hashim et al. 2004). It appears that the phenotype associated with the M694I mutation is not consistent in the limited number of studies. The genotype/ phenotype correlation pattern studies performed in Arabic FMF patients are mentioned in Table 5.1. A new and simple severity score has recently been developed and has been statistically validated (Mor et al. 2005). It was utilized on one cohort from Syria to outline a genotype/phenotype correlation pattern (Jarjour 2010). There was a statistically significant higher severity score in patients homozygous for the M694V mutations, although the numbers are still small. It would be of interest to apply this severity score to large cohorts of Arabic FMF patients to outline the specific genotype/phenotype correlation patterns. As this severity score reflects on the actual burden of FMF, it will also be of interest to measure the burden of FMF on Arabic communities utilizing this tool.


125

Needs and Goals for the Future As a considerable proportion of the disease-causing MEFV alleles in the Arabic FMF patients remain unidentified, the need arises to perform extensive studies that take a comprehensive approach to the identification of MEFV mutations. These studies should explore regulatory sequences and conserved intronic sequences for disease-causing mutations. The exploration of other non-traditional mutation mechanisms should also be examined, such as analysis for large deletions or duplication. Furthermore, the exploration of the role of already described and potential modifier genes and polymorphisms within these genes should be carried out in conjunction with the appropriate genotype/phenotype relationship studies. It is of paramount importance to identify if there is a distinctive pattern of the relationship between MEFV and modifier gene genotypes on one hand and the phenotype in the Arabic FMF patient population on the other hand. It is of equal importance to identify if there is a correlation between the severity of the disease, its burden, and its common complications with any of the mutations in Arabic FMF patients. The severity of the disease should be a practical and actual measure of the disease burden and should not be affected by colchicine therapy, which is the standard of care for diagnosed patients. The achievement of these goals will lead to the establishment of adequate population screening protocols for early and presymptomatic identification of patients and the provision of prophylactic colchicine therapy. There is a paucity of the studies that measure and evaluate FMF as a public health consideration in the Arabic countries, and the need for such crosssectional studies cannot be overstated. There is a need to establish collaborative and standardized study protocols across the Arabic countries with substantial numbers of FMF patients to facilitate comparisons and allow the aggregation of data for robust statistical analysis. These protocols will also provide the guidelines for the appropriate screening approaches and the instatement of public policies that provide adequate preventive measures. The establishment of educational resources parallels the establishment of diagnostic laboratory testing and increases the awareness of physicians and medical personnel to FMF and its complications. As diagnostic laboratory testing is not specific and the molecular diagnosis is still limited, the clarity of the clinical diagnostic criteria is the hallmark for making an accurate and precise diagnosis. The development of these diagnostic skills among physicians requires the appropriate and continued medical educational resources to be available to health care providers. There is a need for the utilization of clinically well-characterized FMF patients in research endeavors that aim at exploring the pathogenesis of the disorder. The understanding of the pathogenesis of the disorder will serve all ethnic groups commonly affected by FMF and will promote the understanding of inflammation and the molecular correlates to the innate immunity.

126


TNF Receptor Associated Periodic Syndrome (TRAPS) (FPF, MIM 142680) TRAPS is a newly recognized autoinflammatory disease that actually subsumes several older diagnoses that were consolidated with the recent recognition that all are caused by mutations in the extracellular domain of the 55 kDa TNF receptor (TNFRSF1A) (McDermott et al. 1999), Figure 5.2 (Milhavet et al. 2008; Sarrauste de Menthiere et al. 2003; Touitou et al. 2004). Before the discovery of TNFRSF1A mutations, the dominant periodic fevers included a poorly understood, ethnically diverse group of illnesses, most of which had been described in case reports of single families. The most thoroughly characterized was a large pedigree of Irish and Scottish ancestry ascertained in Nottingham, England, whose illness was denoted familial Hibernian fever (McDermott et al. 1997; Williamson et al. 1982). A second large Australian family of Scottish ancestry with similar clinical findings was denoted as benign autosomal dominant familial periodic fever because of uncertainty over whether this family had the same condition as the first (Mulley et al. 1998). Although amyloidosis was observed in only 1 of 21 affected members of the first family and in none of the eight affected members of the second family,

TNFRSFIA NM 001065.2 (12p13.2) DNA: 13231bp, mRNA: 2096bp, Protein: 455aa G36E C55Y T371 F60L(I>C) Y38C F60V L39F F60S D42del F60L(C>A) C43R T6II D12E C43Y T6IN S86P Y20H C43S N65I C88R Y20D P46L H66Y C88Y H22Y G47G L67P R92W H22R T50M H69fs R92P H22Q T50K C70R R92Q S27S C52R C70S T94T C29F C52F C70G V95M C29Y C52Y C70Y C96Y C30R E54E C73R C98Y 472+1G>A C30S C55R C73W R104Q 472+6C>T K157K C30Y C55S S74C H105P 472+64C>T L167 G175del C30F E109A 473–72G>A ll70N C33G194–29G>A F112I 473–33C>T V173D –609 G/T 36 A>G C33Y 194–18 -17del 625+10G>A N116S 473–16 G>A –580 A/G 194–15C>T –383 A/C 39+1899(GT) (GA) 194–14G>A 740–97>C 323–32A>G 552–89A>T SI97S

5’flanking Sizes (bp)

1

11 7531

229

12

2

3

225 154

129

13 220

4 150

14 219

5 79

15 2142

6

16 141

74

17

7 302 8 114

18

200 29

Y331X

9

19 155

289

3’flanking

10 849

CDS joints 39/40 Positions Codons(- Leader Seq.) (+ Leader Seq.) 13/14

193/194 322/323 472/473 36 79 129 65 158 108

551/552 625/626 739/740 768/769 155 180 218 227/228 184 247 256/257 209

This graph shows the variant usual name (i.e. as first published). Please refer to the variant detail by clicking on its name for possible edited nomenclature.

Fig. 5.2 TNFRSF1A and its variations

1057/1058 324 353

INFEVERS: April 19, 2009 N Sequencevariants: 91


127

amyloidosis was a prominent feature in several other reported families of various ethnic backgrounds (Gertz et al. 1987). As is generally the case in the hereditary periodic fevers, patients experience febrile episodes accompanied by peritoneal or pleural inflammation, arthralgia or arthritis, and skin rash. However, in TRAPS, the attacks tend to be longer than in FMF. Many attacks last more than 1 week and some TRAPS patients have episodes lasting more than 1 month or experience nearly continuous inflammation. Conjunctival involvement and/or periorbital edema, as well as localized myalgia, are also much more frequent in TRAPS than in FMF. Another distinguishing feature in TRAPS, although it is not observed in all patients, is a rash that progresses centrifugally on the limbs. Finally, most patients with TRAPS respond poorly to colchicine, which is quite effective in FMF, but show significant improvement on corticosteroids, which are usually ineffective in FMF. Patients with traps TRAPS respond quite well to etanercept (TNF-alpha blocker) (Arostegui et al. 2005; Jesus et al. 2008; Morbach et al. 2009). TRAPS has not been reported in Arabs, probably because of lack of the diagnostic tools and for the decreased suspicion as it is an autosomal dominant disease. In addition, several instances in which autosomal dominant periodic fever syndrome was suspected in an Arabic family turned out to be FMF exhibiting pseudodominant transmission because of the high consanguinity rate and the high of frequency of mutation carriers. One report was of an Israeli Arab who had a de novo mutation in TNFRSF1A (Aganna et al. 2002). Mutations in TNFRSF1A should be always sought in Arab patients with atypical FMF or without identifiable mutations within MEFV.

Chronic Recurrent Multifocal Osteomyelitis (CRMO, MIM 259680; 609628) CRMO is a relatively rare childhood disease that presents with bone pain with or without associated fever (Giedion et al. 1972; Schultz et al. 1999). The disease course often lasts several years and is characterized by remissions and exacerbations. The inflammatory bone lesions are typically located at the metaphyses of tubular long bones, but they can occur at other sites including the mandible, sternum, clavicle, and vertebrae (Bjorksten and Boquist 1980; El-Shanti and Ferguson 2007; Ferguson and El-Shanti 2007; Girschick et al. 2005; Huber et al. 2002; Jansson et al. 2007; Jurik 2004; Schultz et al. 1999). Plain films reveal lytic bone lesions surrounded by sclerosis (Bjorksten and Boquist 1980; Jurik 2004). Bone histology reveals neutrophils early in the disease course, accompanied by multinucleated giant cells, scattered granulomatous foci, and osteoclastic bone resorption. Later, new bone formation, fibrosis, and lymphocytes predominate (Bjorksten and Boquist 1980). Cultures and stains for pathogens are negative, and treatment with antibiotics is rarely associated with clinical improvement (Bjorksten and Boquist

128


1980; Girschick et al. 1999; Schultz et al. 1999). Not long after the initial description of CRMO, its association with other chronic inflammatory disorders began to be reported. Disease associations included palmar–plantar pustulosis, psoriasis vulgaris, and inflammatory bowel disease, which suggested that an inflammatory pathway common to skin, bone, and gut is dysregulated in these disorders (Bergdahl et al. 1979; Bjorksten et al. 1978; Bognar et al. 1998; Laxer et al. 1988; Schultz et al. 1999). There is evidence that the etiology of sporadic CRMO has a genetic component, including several reports of affected siblings, affected parent and child, concordant monozygotic twins, and a report of a susceptibility locus on chromosome 18q21.3–18q22 (Ben Becher et al. 1991; Festen et al. 1985; Golla et al. 2002; Jansson et al. 2007). In addition, as many as half the patients have a first-degree or second-degree family member who is affected by a chronic inflammatory disorder, most often psoriasis (Jansson et al. 2007). In our cohort of 45 CRMO patients, 47% of first-degree relatives have a chronic inflammatory disorder (family history of psoriasis in 18%, inflammatory bowel disease in 13%, inflammatory arthritis in 11%, and severe acne in 7%; unpublished data). A syndromic form of CRMO was first described by Dr. Hasan Abdel Majeed and his colleagues in 1989 (Majeed et al. 1989) and was subsequently named after him as Majeed syndrome. Affected individuals present with periodic fevers, early-onset CRMO (age range 3 weeks to 19 months), a microcytic congenital dyserythropoietic anemia, and often a transiently occurring inflammatory dermatosis (Al-Mosawi et al. 2007; Majeed et al. 1989, 2000b, 2001). The congenital dyserythropoietic anemia presents during the first year of life and the resultant anemia varies in severity from mild to transfusion-dependent (Al-Mosawi et al. 2007; Majeed et al. 1989, 2000b, 2001). The dermatosis is most often Sweet syndrome. Hepatomegaly, neutropenia, and transient cholestatic jaundice may occur during the neonatal period (Al-Mosawi et al. 2007). The bone marrow exhibits increased erythropoiesis associated with evidence of dyserythropoiesis, including binucleated normoblasts (Majeed et al. 2001). The CRMO in Majeed syndrome is persistent with a few short remissions, frequent exacerbations, and prolonged duration. Like sporadic CRMO, there is a predilection for the metaphyses of the long bones, and radiographs demonstrate extensive lytic lesions with areas of sclerosis (Majeed et al. 2001). Cultures of the bone lesions are negative and prolonged antibiotic administration provides no benefit (Al-Mosawi et al. 2007; Majeed et al. 2001). Permanent joint deformities and growth disturbance may occur after years of continued inflammation (Majeed et al. 2001). Uniformly, there is marked clinical improvement with corticosteroids (AlMosawi et al. 2007; Majeed et al. 1989). Nonsteroidal anti-inflammatory drugs provide a moderate degree of improvement (Al-Mosawi et al. 2007; Majeed et al. 2001). Majeed syndrome is an autosomal-recessive disorder caused by mutations in LPIN2 (Ferguson et al. 2005). The gene responsible for Majeed syndrome was localized to the short arm of chromosome 18 using homozygosity mapping, because the first two described families were inbred. To date, three different


129

LPIN2 NM 014646.2(18p11.31) DNA: 94953 bp, mRNA: 6228 bp, protein: 896 aa

A331S P348L K387E

T180fs

L504F

E601K

S734L

R776S

5’flanking

3’flanking

11

12

13

14

15

16

17

18

19 110 111 112 113 114 115 116 117 118 119

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

779 916 1354 677 536 1575 399 651 340 Sizes (bp) 50868 6049 3147 10342 1001 1442 3241 2907 2097 404 100 188 94 153 115 104 302 108 124 346 70 90 83 145 149 87 230 201 96 CDS joints Positions

Codons

20 3443

2546/2547 -10/-9 698/699 1168/1169 1456/1457 1620/1621 1793/1794 2087/2088 2327/2328 288/289 192/193 590/591 822/823 1268/1269 1550/1551 1710/1711 1938/1939 2174/2175 2442/2443 96/97 64/65

233 197

390 274/275

486 423

517

540/541 598 570/571

This graph shows the variant usual name (i.e as first published). Please refer to the variant detail by clicking on its name for possible edited nomenclature.

696 646/647

776 725

849 814/815

INFEVERS: April 19, 2009 N Sequence variants:8

Fig. 5.3 LPIN2 and its variations

homozygous mutations in LPIN2 have been found in each of the reported families with Majeed syndrome, all of whom are Arabic (Al-Mosawi et al. 2007; Ferguson et al. 2005) (available at http://fmf.igh.cnrs.fr/infevers) (Figure 5.3) (Milhavet et al. 2008). There are two murine models of CRMO. The first model to be described is a spontaneous mutant mouse named the cmo (chronic multifocal osteomyelitis) mouse (Byrd et al. 1991; Ferguson et al. 2006; Hentunen et al. 2000). The cmo mouse develops tail kinks and hind foot deformities, which are the results of a robust mixed inflammatory infiltrate in the bone composed of PMNs, macrophages, lymphocytes, plasma cells, and osteoclasts (Ferguson et al. 2006; Hentunen et al. 2000). Later, there is presence of osteosclerosis as the inflammatory infiltrate is replaced by new bone and fibrosis (Ferguson et al. 2006; Hentunen et al. 2000). Subsequently, the mouse develops inflammation of the ears involving the dermis, epidermis, and cartilage (Ferguson et al. 2006). A second autosomal-recessive mouse model of CRMO was produced by chemical (N-ethyl-N-nitrosourea) mutagenesis; it was noted to have a similar but somewhat more severe phenotype than the cmo mouse and was named the Lupo mouse (Grosse et al. 2006). The gene defect was identified in both cmo and Lupo mice utilizing similar genetic approaches as two different missense mutations in pstpip2/Mayp (Ferguson et al. 2006; Grosse et al. 2006).

130


Hyperimmunoglobulinemia D with Periodic Fever Syndrome (Hyper-IgD) HIDS, MIM 260920) The hyper-IgD syndrome was recognized as a separate clinical entity in 1984 (van der Meer et al. 1984). Patients with the hyper-IgD syndrome have recurrent attacks of fever that usually start before the end of the first year of life (Drenth et al. 1994b). An attack is heralded by chills, followed by a sharp rise in body temperature, and lasts for 4–6 days, with gradual defervescence. It can be provoked by vaccination, minor trauma, surgery, or stress. Cervical lymphadenopathy and abdominal pain with vomiting, diarrhea, or both almost always accompany the attack. Symptoms that are common include hepatosplenomegaly, headache, arthralgias, arthritis of large joints, erythematous macules and papules, and even petechia and purpura (Drenth et al. 1994a). After an attack, patients are free of symptoms, although skin and joint symptoms disappear slowly. The attacks generally recur every 4–6 weeks, but the interval between them can vary substantially in an individual patient and from one patient to another. The hyper-IgD syndrome is inherited as an autosomal recessive trait (Drenth et al. 1994c). Most patients with the hyper-IgD syndrome are white and are from western European countries; some 60% are either Dutch or French. Although hyper-IgD syndrome is autosomal recessive, there has been no report from Arabic countries thus far. The hyper-IgD syndrome is diagnosed on the basis of characteristic clinical findings and continuously high IgD values (more than 100 IU per mL). During an attack, there is a brisk acute-phase response, with leukocytosis, high levels of serum C-reactive protein and serum amyloid A, and activation of the cytokine network (Drenth et al. 1995). A genome-wide search established the linkage of the susceptibility gene for the hyper-IgD syndrome to the long arm of chromosome 12 (Drenth et al. 1999; Houten et al. 1999a). This information, along with the fortuitous detection of mevalonic acid in a urine sample obtained during a febrile attack in a patient with the hyperIgD syndrome, led to the identification of mutations in the gene for mevalonate kinase as the cause of the syndrome (Drenth et al. 1999; Houten et al. 1999a). In patients with the hyper-IgD syndrome, the activity of mevalonate kinase is reduced to 5–15% of normal; as a result, serum cholesterol levels are slightly reduced, and during attacks, urinary excretion of mevalonic acid is slightly elevated. Less than 1% of patients have a complete deficiency of mevalonate kinase, which is associated with mevalonic aciduria, a rare inherited disorder characterized by developmental delay, failure to thrive, hypotonia, ataxia, myopathy, and cataracts. In mevalonic aciduria, the disease-associated mutations are mainly clustered within a specific region of the protein (Houten et al. 1999b). No uniformly successful treatment of the hyper-IgD syndrome is available. Patients with the hyper-IgD syndrome have febrile attacks throughout their lives, although the frequency of attacks is highest in childhood and adolescence. Patients may be free of attacks for months or even years. Amyloidosis has not been reported in association with the hyper-IgD syndrome.


131

Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome (PAPA, MIM 604416) This syndrome, first described in 1997, is a rare autoinflammatory disease mainly involving the joints and the skin (Lindor et al. 1997). It is inherited in an autosomal dominant pattern and the disease gene was mapped to chromosome 15 (Yeon et al. 2000). Subsequently, the CD2-binding protein 1, CD2BP1, also called the proline/ serine/thronine phosphatase interacting protein 1, PSTPIP1, was reported as the PAPA syndrome susceptibility gene (Wise et al. 2002). The CD2BP1 protein appears to interact with pyrin where PAPA-associated mutations lead to increased binding to pyrin (Shoham et al. 2003). As a result, CD2BP1 may sequester pyrin and therefore reduce pyrin’s inhibitory role in regulation of the IL-1b pathway and the innate immune response. Individuals with PAPA syndrome typically develop cystic acne, sterile abscesses, and cutaneous ulcers, including pyoderma gangrenosum-like lesions. They may also develop sterile abscesses at injection sites (Lindor et al. 1997). Histologic examination of skin shows a superficial and deep perivascular, interstitial, periadnexal infiltrate predominantly consisting of lymphocytic and neutrophilic leukocytes. At a young age, patients with PAPA syndrome develop a severe sterile, pyogenic, destructive arthritis that affects the non-axial skeleton (Lindor et al. 1997). Corticosteroids can provide relief for patients with PAPA syndrome but their adverse effects often limit their use. Biologic therapies provide a possible new avenue for treatment, such as the TNF-a inhibitor etanercept (Cortis et al. 2004).

The Cryopyrinopathies Familial cold autoinflammatory syndrome (FCAS, MIM 120100), Muckle–Wells syndrome (MWS, MIM 191900), and neonatal-onset multisystem inflammatory disease (NOMID, MIM 607115), also called chronic infantile neurologic cutaneous and articular syndrome, or CINCA syndrome, represent unique disease entities, which are also known as the cryopyrinopathies. The cryopyrinopathies share a number of similar phenotypic features and appear to represent a continuum of disease, with FCAS at the mild end and NOMID/CINCA syndrome representing the severe end of the spectrum. Genetic studies using linkage analysis of large families with FCAS and MWS identified the susceptibility loci for these two disorders at chromosome 1q44.4 (Hoffman et al. 2000). In 2001, it was shown that both FCAS and MWS were associated with mutations in the same gene, CIAS1 (Dode et al. 2002; Hoffman et al. 2001a). CIAS1 encodes for cryopyrin (also called PYPAF1, NALP3, and CATERPILLER 1.1). Subsequently, it was shown that mutations in CIAS1 are also associated with NOMID/CINCA syndrome

132


(Aksentijevich et al. 2002; Feldmann et al. 2002). To date, more than 50 mutations in CIAS1 have been identified. Almost all of these mutations, except three, are missense mutations that are localized to exon 3 of CIAS1, which encodes for the NACHT domain. These findings suggest that the mutated cryopyrin may have a dominant negative or gain-of-function effect over the wild-type product (Neven et al. 2004). FCAS, also known as familial cold urticaria and MWS are rare autosomal dominant disorders that are characterized by fever, urticarial-like eruption, and limb pain (Hawkins et al. 2004; Muckle and Wellsm 1962). Erythematous and edematous papules and plaques are the most common dermatologic manifestations of FCAS and MCS. They are present in almost all patients in the first 6 months of life (Hoffman et al. 2001b). In addition to skin findings during attacks, patients with FCAS also have fever, headache, nausea, sweating, drowsiness, extreme thirst, conjunctivitis, blurred vision, ocular pain, and polyarthralgia. Progressive sensorineural hearing impairment, nephropathy, and amyloidosis are reported in MWS (Muckle 1979; Muckle and Wellsm 1962). In the past, aside from avoidance of cold exposure, there was no effective treatment for patients with FCAS or MWS. Nonsteroidal anti-inflammatory drugs are often used for relief of arthralgias. Therapy with high dose corticosteroids is effective, but adverse effects usually limit long term use. Anakinra, an IL-1 receptor antagonist, has been shown not only to prevent a recurrence of episodes but also to decrease a chronic inflammatory response that can lead to systemic amyloidosis (Hawkins et al. 2003, 2004; Hoffman et al. 2004). NOMID/CINCA syndrome is a rare inflammatory disease that is characterized by the triad of disabling arthropathy, skin eruption, and central nervous system inflammation. Patients have progressively worsening visual, auditory, and nervous system manifestations. Only a few cases of NOMID/CINCA syndrome have been reported with autosomal dominant transmission, but most cases seem sporadic (Aksentijevich et al. 2002; Feldmann et al. 2002). Nonpruritic, migratory eruption of edematous papules and plaques, which fluctuates in intensity, arises in a large percentage of patients with NOMID/CINCA syndrome (Prieur 2001) About twothirds of affected newborns have the “urticaria-like eruption” at birth, and most develop it in the first 6 months of life. Patients with NOMID/CINCA syndrome commonly have short episodes of recurrent fevers. They also develop an assortment of neurologic abnormalities, including headaches, macrocephaly, cerebral atrophy, chronic aseptic meningitis, high-frequency hearing loss, and developmental delay (Mallouh et al. 1987). Arthropathy, varying greatly in severity between patients, may develop (Mallouh et al. 1987). High-dose steroids have been effective in attenuating pain and inflammation, but in general do not alleviate the other manifestations of disease. Recently, there have been several reports of patients with NOMID who had a dramatic response to treatment with the IL-1 receptor antagonist, anakinra (Goldbach-Mansky et al. 2006, 2008).


133

References Aganna E, Zeharia A, Hitman GA, Basel-Vanagaite L, Allotey RA, Booth DR, Hawkins PN, Thacker C, Syndercombe-Court D, McDermott MF (2002) An Israeli Arab patient with a de novo TNFRSF1A mutation causing tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 46(1):245–249 Aivazian AA, Zavgorodniaia AM, Abramian MK, Pashinian SA, Bagdasarian GB (1977) Immunogenesis of periodic disease. Klin Med (Mosk) 55(2):91–97 Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E, Chae JJ, Oddoux C, Wood G, Azzaro MP, Palumbo G et al (1999) Mutation and haplotype studies of Familial Mediterranean Fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet 64(4):949–962 Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, Stein L, Russo R, Goldsmith D, Dent P et al (2002) De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum 46(12):3340–3348 Al-Alami JR, Tayeh MK, Najib DA, Abu-Rubaiha ZA, Majeed HA, Al-Khateeb MS, El-Shanti HI (2003) Familial Mediterranean Fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Med J 24(10):1055–1059 Al-Mosawi ZS, Al-Saad KK, Ijadi-Maghsoodi R, El-Shanti HI, Ferguson PJ (2007) A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum 56(3):960–964 Armenian HK, Khachadurian AK (1973) Familial paroxysmal polyserositis. Clinical and laboratory findings in 120 cases. J Med Liban 26(6):605–614 Arostegui JI, Solis P, Aldea A, Cantero T, Rius J, Bahillo P, Plaza S, Vives J, Gomez S, Yague J (2005) Etanercept plus colchicine treatment in a child with tumour necrosis factor receptorassociated periodic syndrome abolishes auto-inflammatory episodes without normalising the subclinical acute phase response. Eur J Pediatr 164(1):13–16 Ayesh SK, Nassar SM, Al-Sharef WA, Abu-Libdeh BY, Darwish HM (2005) Genetic screening of Familial Mediterranean Fever mutations in the Palestinian population. Saudi Med J 26(5):732–737 Azizi E, Fisher BK (1976) Cutaneous manifestations of Familial Mediterranean Fever. Arch Dermatol 112(3):364–366 Bakir F, Murtadha M (1975) Periodic peritonitis. Report of 41 cases without amyloidosis. Trans R Soc Trop Med Hyg 69(1):111–117 Balci B, Tinaztepe K, Yilmaz E, Gucer S, Ozen S, Topaloglu R, Besbas N, Ozguc M, Bakkaloglu A (2002) MEFV gene mutations in Familial Mediterranean Fever phenotype II patients with renal amyloidosis in childhood: a retrospective clinicopathological and molecular study. Nephrol Dial Transplant 17(11):1921–1923 Barakat MH, El-Khawad AO, Gumaa KA, El-Sobki NI, Fenech FF (1984a) Metaraminol provocative test: a specific diagnostic test for Familial Mediterranean Fever. Lancet 1(8378):656–657 Barakat MH, El-Sobki NI, El-Khawad AO, Gumma KA, Fenech FF (1984b) Diagnosing Familial Mediterranean Fever letter. Lancet 2(8393):41–42 Barakat MH, Karnik AM, Majeed HW, El-Sobki NI, Fenech FF (1986) Familial Mediterranean Fever (recurrent hereditary polyserositis) in Arabs–a study of 175 patients and review of the literature. Q J Med 60(233):837–847 Barakat MH, Mustafa HT, Shakir RA (1988) Mollaret’s meningitis. A variant of recurrent hereditary polyserositis, both provoked by metaraminol. Arch Neurol 45(8):926–927 Barzilai A, Langevitz P, Goldberg I, Kopolovic J, Livneh A, Pras M, Trau H (2000) Erysipelaslike erythema of Familial Mediterranean Fever: clinicopathologic correlation. J Am Acad Dermatol 42(5 Pt 1):791–795

134


Ben Becher S, Essaddam H, Nahali N, Ben Hamadi F, Mouelhi MH, Hammou A, Hadj Romdhane L, Ben Cheikh M, Boudhina T, Dargouth M (1991) Recurrent multifocal periostosis in children. Report of a familial form. Ann Pediatr (Paris) 38(5):345–349 Ben-Chetrit E, Levy M (1991) Colchicine prophylaxis in Familial Mediterranean Fever: reappraisal after 15 years. Semin Arthritis Rheum 20(4):241–246 Ben-Chetrit E, Levy M (1998) Colchicine: 1998 update. Semin Arthritis Rheum 28(1):48–59 Ben-Chetrit E, Lerer I, Malamud E, Domingo C, Abeliovich D (2000) The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant? Hum Mutat 15(4):385–386 Ben-Chetrit E, Urieli-Shoval S, Calko S, Abeliovich D, Matzner Y (2002) Molecular diagnosis of FMF: lessons from a study of 446 unrelated individuals. Clin Exp Rheumatol 20(4 suppl 26): S25–S29 Bergdahl K, Bjorksten B, Gustavson KH, Liden S, Probst F (1979) Pustulosis palmoplantaris and its relation to chronic recurrent multifocal osteomyelitis. Dermatologica 159(1):37–45 Bernot A, da Silva C, Petit JL, Cruaud C, Caloustian C, Castet V, Ahmed-Arab M, Dross C, Dupont M, Cattan D et al (1998) Non-founder mutations in the MEFV gene establish this gene as the cause of Familial Mediterranean Fever (FMF). Hum Mol Genet 7(8):1317–1325 Bjorksten B, Boquist L (1980) Histopathological aspects of chronic recurrent multifocal osteomyelitis. J Bone Joint Surg [Br] 62(3):376–380 Bjorksten B, Gustavson KH, Eriksson B, Lindholm A, Nordstrom S (1978) Chronic recurrent multifocal osteomyelitis and pustulosis palmoplantaris. J Pediatr 93(2):227–231 Bognar M, Blake W, Agudelo C (1998) Chronic recurrent multifocal osteomyelitis associated with Crohn’s disease. Am J Med Sci 315(2):133–135 Booth DR, Gillmore JD, Booth SE, Pepys MB, Hawkins PN (1998) Pyrin/marenostrin mutations in Familial Mediterranean Fever. QJM 91(9):603–606 Brik R, Shinawi M, Kepten I, Berant M, Gershoni-Baruch R (1999) Familial Mediterranean Fever: clinical and genetic characterization in a mixed pediatric population of Jewish and Arab patients. Pediatrics 103(5):e70 Brik R, Litmanovitz D, Berkowitz D, Shamir R, Rosenthal E, Shinawi M, Gershoni-Baruch R (2001) Incidence of Familial Mediterranean Fever (FMF) mutations among children of Mediterranean extraction with functional abdominal pain. J Pediatr 138(5):759–762 Buskila D, Zaks N, Neumann L, Livneh A, Greenberg S, Pras M, Langevitz P (1997) Quality of life of patients with Familial Mediterranean Fever. Clin Exp Rheumatol 15(4):355–360 Byrd L, Grossmann M, Potter M, Shen-Ong GL (1991) Chronic multifocal osteomyelitis, a new recessive mutation on chromosome 18 of the mouse. Genomics 11(4):794–798 Cabili S, Zemer D, Pras M, Aviram A, Sohar E, Gafni J (1985) The prevention of amyloidosis in Familial Mediterranean Fever with colchicine. Proc Eur Dial Transplant Assoc Eur Ren Assoc 21:709–711 Cazeneuve C, Sarkisian T, Pecheux C, Dervichian M, Nedelec B, Reinert P, Ayvazyan A, Kouyoumdjian JC, Ajrapetyan H, Delpech M et al (1999) MEFV-Gene analysis in armenian patients with Familial Mediterranean Fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications. Am J Hum Genet 65(1):88–97 Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, Kingma DW, Horwitz ME, Mansfield E, Holland SM et al (2000) The gene for Familial Mediterranean Fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 95(10):3223–3231 Chaabouni HB, Ksantini M, M’Rad R, Kharrat M, Chaabouni M, Maazoul F, Bahloul Z, Ben Jemaa L, Ben Moussa F, Ben Chaabane T et al (2007) MEFV mutations in Tunisian patients suffering from Familial Mediterranean Fever. Semin Arthritis Rheum 36(6):397–401 Chae JJ, Komarow HD, Cheng J, Wood G, Raben N, Liu PP, Kastner DL (2003) Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell 11(3):591–604


135

Cortis E, De Benedetti F, Insalaco A, Cioschi S, Muratori F, D’Urbano LE, Ugazio AG (2004) Abnormal production of tumor necrosis factor (TNF) – alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome [corrected]. J Pediatr 145(6):851–855 Dewalle M, Domingo C, Rozenbaum M, Ben-Chetrit E, Cattan D, Bernot A, Dross C, Dupont M, Notarnicola C, Levy M et al (1998) Phenotype-genotype correlation in Jewish patients suffering from Familial Mediterranean Fever (FMF). Eur J Hum Genet 6(1):95–97 Diaz A, Hu C, Kastner DL, Schaner P, Reginato AM, Richards N, Gumucio DL (2004) Lipopolysaccharide-induced expression of multiple alternatively spliced MEFV transcripts in human synovial fibroblasts: a prominent splice isoform lacks the C-terminal domain that is highly mutated in Familial Mediterranean Fever. Arthritis Rheum 50(11):3679–3689 Dode C, Pecheux C, Cazeneuve C, Cattan D, Dervichian M, Goossens M, Delpech M, Amselem S, Grateau G (2000) Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of Familial Mediterranean Fever. Am J Med Genet 92(4):241–246 Dode C, Le Du N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G, Meyrier A, Watts RA, Scott DG, Nicholls A et al (2002) New mutations of CIAS1 that are responsible for Muckle–Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet 70(6):1498–1506 Dowds TA, Masumoto J, Chen FF, Ogura Y, Inohara N, Nunez G (2003) Regulation of cryopyrin/ Pypaf1 signaling by pyrin, the Familial Mediterranean Fever gene product. Biochem Biophys Res Commun 302(3):575–580 Drenth JP, Boom BW, Toonstra J, Van der Meer JW (1994a) Cutaneous manifestations and histologic findings in the hyperimmunoglobulinemia D syndrome International Hyper IgD Study Group. Arch Dermatol 130(1):59–65 Drenth JP, Haagsma CJ, van der Meer JW (1994b) Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine (Baltimore) 73(3):133–144 Drenth JP, Mariman EC, Van der Velde-Visser SD, Ropers HH, Van der Meer JW (1994c) Location of the gene causing hyperimmunoglobulinemia D and periodic fever syndrome differs from that for Familial Mediterranean Fever. International Hyper-IgD Study Group. Hum Genet 94(6):616–620 Drenth JP, van Deuren M, van der Ven-Jongekrijg J, Schalkwijk CG, van der Meer JW (1995) Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Blood 85(12):3586–3593 Drenth JP, Cuisset L, Grateau G, Vasseur C, van de Velde-Visser SD, de Jong JG, Beckmann JS, van der Meer JW, Delpech M (1999) Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet 22(2):178–181 Ehrenfeld M, Brzezinski A, Levy M, Eliakim M (1987) Fertility and obstetric history in patients with Familial Mediterranean Fever on long-term colchicine therapy. Br J Obstet Gynaecol 94 (12):1186–1191 El-Shanti HI, Ferguson PJ (2007) Chronic recurrent multifocal osteomyelitis: a concise review and genetic update. Clin Orthop Relat Res 462:11–19 El-Shanti H, Majeed HA, El-Khateeb M (2006) Familial Mediterranean Fever in Arabs. Lancet 367(9515):1016–1024 Eshel G, Zemer D, Bar-Yochai A (1988) Acute orchitis in Familial Mediterranean Fever. Ann Intern Med 109(2):164–165 Eshel G, Vinograd I, Barr J, Zemer D (1994) Acute scrotal pain complicating Familial Mediterranean Fever in children. Br J Surg 81(6):894–896 Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, Teillac-Hamel D, Fischer A, de Saint BG (2002) Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet 71(1):198–203

136


Ferguson PJ, El-Shanti HI (2007) Autoinflammatory bone disorders. Curr Opin Rheumatol 19(5):492–498 Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM, Pelet A, Munnich A, Lyonnet S, Majeed HA, El-Shanti H (2005) Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet 42(7):551–557 Ferguson PJ, Bing X, Vasef MA, Ochoa LA, Mahgoub A, Waldschmidt TJ, Tygrett LT, Schlueter AJ, El-Shanti H (2006) A missense mutation in pstpip2 is associated with the murine autoinflammatory disorder chronic multifocal osteomyelitis. Bone 38(1):41–47 Festen JJ, Kuipers FC, Schaars AH (1985) Multifocal recurrent periostitis responsive to colchicine. Scand J Rheumatol 14(1):8–14 Flatau E, Kohn D, Schiller D, Lurie M, Levy E (1982) Schonlein–Henoch syndrome in patients with Familial Mediterranean Fever. Arthritis Rheum 25(1):42–47 French FMF Consortium (1997) A candidate gene for Familial Mediterranean Fever. Nat Genet 17:25–31 Gafni J, Ravid M, Sohar E (1968) The role of amyloidosis in Familial Mediterranean Fever. A population study. Isr J Med Sci 4(5):995–999 Gedalia A, Zamir S (1993) Neurologic manifestations in Familial Mediterranean Fever. Pediatr Neurol 9(4):301–302 Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R (2001) Familial Mediterranean Fever: prevalence, penetrance and genetic drift. Eur J Hum Genet 9(8):634–637 Gershoni-Baruch R, Brik R, Shinawi M, Livneh A (2002a) The differential contribution of MEFV mutant alleles to the clinical profile of Familial Mediterranean Fever. Eur J Hum Genet 10(2):145–149 Gershoni-Baruch R, Shinawi M, Shamaly H, Katsinetz L, Brik R (2002b) Familial Mediterranean Fever: the segregation of four different mutations in 13 individuals from one inbred family: genotype-phenotype correlation and intrafamilial variability. Am J Med Genet 109 (3):198–201 Gershoni-Baruch R, Broza Y, Brik R (2003) Prevalence and significance of mutations in the Familial Mediterranean Fever gene in Henoch–Schonlein purpura. J Pediatr 143 (5):658–661 Gertz MA, Petitt RM, Perrault J, Kyle RA (1987) Autosomal dominant Familial Mediterranean Fever-like syndrome with amyloidosis. Mayo Clin Proc 62(12):1095–1100 Giedion A, Holthusen W, Masel LF, Vischer D (1972) Subacute and chronic “symmetrical” osteomyelitis. Ann Radiol (Paris) 15(3):329–342 Girschick HJ, Huppertz HI, Harmsen D, Krauspe R, Muller-Hermelink HK, Papadopoulos T (1999) Chronic recurrent multifocal osteomyelitis in children: diagnostic value of histopathology and microbial testing. Hum Pathol 30(1):59–65 Girschick HJ, Raab P, Surbaum S, Trusen A, Kirschner S, Schneider P, Papadopoulos T, MullerHermelink HK, Lipsky PE (2005) Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis 64(2):279–285 Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E et al (2006) Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 355(6):581–592 Goldbach-Mansky R, Shroff SD, Wilson M, Snyder C, Plehn S, Barham B, Pham TH, Pucino F, Wesley RA, Papadopoulos JH et al (2008) A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum 58(8):2432–2442 Goldfinger SE (1972) Colchicine for Familial Mediterranean Fever. N Engl J Med 287 (25):1302 Golla A, Jansson A, Ramser J, Hellebrand H, Zahn R, Meitinger T, Belohradsky BH, Meindl A (2002) Chronic recurrent multifocal osteomyelitis (CRMO): evidence for a susceptibility gene located on chromosome 18q21.3–18q22. Eur J Hum Genet 10(3):217–221


137

Grosse J, Chitu V, Marquardt A, Hanke P, Schmittwolf C, Zeitlmann L, Schropp P, Barth B, Yu P, Paffenholz R et al (2006) Mutation of mouse Mayp/Pstpip2 causes a macrophage autoinflammatory disease. Blood 107(8):3350–3358 Gruberg L, Aksentijevich I, Pras E, Kastner DL, Pras M (1992) Mapping of the Familial Mediterranean Fever gene to chromosome 16. Am J Reprod Immunol 28(3–4):241–242 Hawkins PN, Lachmann HJ, McDermott MF (2003) Interleukin-1-receptor antagonist in the Muckle–Wells syndrome. N Engl J Med 348(25):2583–2584 Hawkins PN, Lachmann HJ, Aganna E, McDermott MF (2004) Spectrum of clinical features in Muckle–Wells syndrome and response to anakinra. Arthritis Rheum 50(2):607–612 Heller H, Sohar E, Sherf L (1958) Familial Mediterranean Fever. AMA Arch Intern Med 102 (1):50–71 Heller H, Sohar E, Gafni J, Heller J (1961) Amyloidosis in Familial Mediterranean Fever. Arch Intern Med 107:539–550 Heller H, Gafni J, Michaeli D, Shahin N, Sohar E, Ehrlich G, Karten I, Sokoloff L (1966) The arthritis of Familial Mediterranean Fever (FMF). Arthritis Rheum 9(1):1–17 Hentunen TA, Choi SJ, Boyce BF, Dallas MR, Dallas SL, Shen-Ong GL, Roodman GD (2000) A murine model of inflammatory bone disease. Bone 26(2):183–188 Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD (2000) Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet 66(5):1693–1698 Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD (2001a) Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat Genet 29(3):301–305 Hoffman HM, Wanderer AA, Broide DH (2001b) Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol 108(4):615–620 Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayar J, Mueller JL, Anderson JP, Wanderer AA, Firestein GS (2004) Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 364(9447):1779–1785 Houten SM, Kuis W, Duran M, de Koning TJ, van Royen-Kerkhof A, Romeijn GJ, Frenkel J, Dorland L, de Barse MM, Huijbers WA et al (1999a) Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet 22 (2):175–177 Houten SM, Romeijn GJ, Koster J, Gray RG, Darbyshire P, Smit GP, de Klerk JB, Duran M, Gibson KM, Wanders RJ et al (1999b) Identification and characterization of three novel missense mutations in mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene biosynthesis. Hum Mol Genet 8(8):1523–1528 Huber AM, Lam PY, Duffy CM, Yeung RS, Ditchfield M, Laxer D, Cole WG, Kerr Graham H, Allen RC, Laxer RM (2002) Chronic recurrent multifocal osteomyelitis: clinical outcomes after more than five years of follow-up. J Pediatr 141(2):198–203 International FMF Consortium (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause Familial Mediterranean Fever. Cell 90:797–807 Ismajovich B, Zemer D, Revach M, Serr DM, Sohar E (1973) The causes of sterility in females with Familial Mediterranean Fever. Fertil Steril 24(11):844–847 Jansson A, Renner ED, Ramser J, Mayer A, Haban M, Meindl A, Grote V, Diebold J, Jansson V, Schneider K et al (2007) Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford) 46(1):154–160 Jarjour RA (2010) Familial Mediterranean fever in Syrian patients: MEFV gene mutations and genotype-phenotype correlation. Mol Bio Rep 37(1):1–5 Jesus AA, Oliveira JB, Aksentijevich I, Fujihira E, Carneiro-Sampaio MM, Duarte AJ, Silva CA (2008) TNF receptor-associated periodic syndrome (TRAPS): description of a novel TNFRSF1A mutation and response to etanercept. Eur J Pediatr 167(12):1421–1425 Jurik AG (2004) Chronic recurrent multifocal osteomyelitis. Semin Musculoskelet Radiol 8(3):243–253

138


Karachaliou I, Karachalios G, Charalabopoulos A, Charalabopoulos K (2005) Meningitis associated with Familial Mediterranean Fever. Int J Clin Pract Suppl 147:60–61 Kasifoglu T, Cansu DU, Korkmaz C (2009) Frequency of abdominal surgery in patients with Familial Mediterranean Fever. Intern Med 48(7):523–526 Kastner DL (2005) Hereditary periodic Fever syndromes. Hematology Am Soc Hematol Educ Program 2005:74–81 Kees S, Langevitz P, Zemer D, Padeh S, Pras M, Livneh A (1997) Attacks of pericarditis as a manifestation of Familial Mediterranean Fever (FMF). QJM 90(10):643–647 Khachadurian AK, Armenian HK (1974) Familial paroxysmal polyserositis (Familial Mediterranean Fever); incidence of amyloidosis and mode of inheritance. Birth Defects Orig Artic Ser 10 (4):62–66 Kogan A, Shinar Y, Lidar M, Revivo A, Langevitz P, Padeh S, Pras M, Livneh A (2001) Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state. Am J Med Genet 102(3):272–276 Konstantopoulos K, Kanta A, Tzoulianos M, Dimou S, Sotsiou F, Politou M, Loukopoulos D (2001) Familial Mediterranean Fever phenotype II in Greece. Isr Med Assoc J 3(11):862–863 Kotevoglu N, Sahin F, Ozkiris SO, Bankaoglu M, Sakiz D, Kuran B (2004) Protracted febrile myalgia of Familial Mediterranean Fever. Clin Exp Rheumatol 22(4 Suppl 34):S69–S70 Langevitz P, Zemer D, Livneh A, Shemer J, Pras M (1994) Protracted febrile myalgia in patients with Familial Mediterranean Fever. J Rheumatol 21(9):1708–1709 Laxer RM, Shore AD, Manson D, King S, Silverman ED, Wilmot DM (1988) Chronic recurrent multifocal osteomyelitis and psoriasis–a report of a new association and review of related disorders. Semin Arthritis Rheum 17(4):260–270 Lindor NM, Arsenault TM, Solomon H, Seidman CE, McEvoy MT (1997) A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc 72(7):611–615 Livneh A, Madgar I, Langevitz P, Zemer D (1994) Recurrent episodes of acute scrotum with ischemic testicular necrosis in a patient with Familial Mediterranean Fever. J Urol 151 (2):431–432 Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M (1997) Criteria for the diagnosis of Familial Mediterranean Fever. Arthritis Rheum 40 (10):1879–1885 Livneh A, Langevitz P, Shinar Y, Zaks N, Kastner DL, Pras M, Pras E (1999) MEFV mutation analysis in patients suffering from amyloidosis of Familial Mediterranean Fever. Amyloid 6(1):1–6 Majeed HA (2000) Differential diagnosis of fever of unknown origin in children. Curr Opin Rheumatol 12(5):439–444 Majeed HA, Barakat M (1989) Familial Mediterranean Fever (recurrent hereditary polyserositis) in children: analysis of 88 cases. Eur J Pediatr 148:636–641 Majeed HA, Rawashdeh M (1997) The clinical patterns of arthritis in children with Familial Mediterranean Fever. QJM 90(1):37–43 Majeed HA, Kalaawi M, Mohanty D, Teebi AS, Tunjekar MF, al-Gharbawy F, Majeed SA, al-Gazzar AH (1989) Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in three related children and the association with Sweet syndrome in two siblings. J Pediatr 115(5 Pt 1):730–734 Majeed HA, Quabazard Z, Hijazi Z, Farwana S, Harshani F (1990) The cutaneous manifestations in children with Familial Mediterranean Fever (recurrent hereditary polyserositis). A six-year study. Q J Med 75(278):607–616 Majeed HA, Halabi I, al-Taleb O (1998) Recurrent hyperbilirubinaemia, a feature of Familial Mediterranean Fever: report of a child and review of the literature. Ann Trop Paediatr 18(1):13–15


139

Majeed HA, Rawashdeh M, El-Shanti H, Qubain H, Khuri-Bulos N, Shahin HM (1999) Familial Mediterranean Fever in children: the expanded clinical profile. QJM 92(6):309–318 Majeed HA, Al-Qudah AK, Qubain H, Shahin HM (2000a) The clinical patterns of myalgia in children with Familial Mediterranean Fever. Semin Arthritis Rheum 30(2):138–143 Majeed HA, El-Shanti H, Al-Rimawi H, Al-Masri N (2000b) On mice and men: an autosomal recessive syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia. J Pediatr 137(3):441–442 Majeed HA, Ghandour K, Shahin HM (2000c) The acute scrotum in Arab children with Familial Mediterranean Fever. Pediatr Surg Int 16(1–2):72–74 Majeed HA, Al-Tarawna M, El-Shanti H, Kamel B, Al-Khalaileh F (2001) The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review. Eur J Pediatr 160(12):705–710 Majeed HA, El-Shanti H, Al-Khateeb MS, Rabaiha ZA (2002) Genotype/phenotype correlations in Arab patients with Familial Mediterranean Fever. Semin Arthritis Rheum 31(6):371–376 Majeed HA, El-Khateeb M, El-Shanti H, Abu Rabaiha Z, Tayeh M, Najib D (2005a) The spectrum of Familial Mediterranean Fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum 34(6):813–818 Majeed HA, El-Khateeb M, El-Shanti H, Rabaiha ZA, Tayeh M, Najib D (2005b) The spectrum of Familial Mediterranean Fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum 34(6):813–818 Mallouh A, Abu-Osba YK, Talab Y (1987) Infantile-onset arthritis and multisystem inflammatory disease: “a new syndrome”. J Pediatr Orthop 7(2):227–230 Mansfield E, Chae JJ, Komarow HD, Brotz TM, Frucht DM, Aksentijevich I, Kastner DL (2001) The Familial Mediterranean Fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. Blood 98(3):851–859 Mansour I, Delague V, Cazeneuve C, Dode C, Chouery E, Pecheux C, Medlej-Hashim M, Salem N, El Zein L, Levan-Petit I et al (2001) Familial Mediterranean Fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations. Eur J Hum Genet 9(1):51–55 Masumoto J, Dowds TA, Schaner P, Chen FF, Ogura Y, Li M, Zhu L, Katsuyama T, Sagara J, Taniguchi S et al (2003) ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis. Biochem Biophys Res Commun 303(1):69–73 Mattit H, Joma M, Al-Cheikh S, El-Khateeb M, Medlej-Hashim M, Salem N, Delague V, Megarbane A (2006) Familial Mediterranean Fever in the Syrian population: gene mutation frequencies, carrier rates and phenotype-genotype correlation. Eur J Med Genet 49 (6):481–486 Matzner Y, Abedat S, Shapiro E, Eisenberg S, Bar-Gil-Shitrit A, Stepensky P, Calco S, Azar Y, Urieli-Shoval S (2000) Expression of the Familial Mediterranean Fever gene and activity of the C5a inhibitor in human primary fibroblast cultures. Blood 96(2):727–731 McDermott EM, Smillie DM, Powell RJ (1997) Clinical spectrum of familial Hibernian fever: a 14-year follow-up study of the index case and extended family. Mayo Clin Proc 72 (9):806–817 McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, Mansfield E, Gadina M, Karenko L, Pettersson T et al (1999) Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97(1):133–144 McGonagle D, McDermott MF (2006) A proposed classification of the immunological diseases. PLoS Med 3(8):e297 Medlej-Hashim M, Rawashdeh M, Chouery E, Mansour I, Delague V, Lefranc G, Naman R, Loiselet J, Megarbane A (2000) Genetic screening of fourteen mutations in Jordanian Familial Mediterranean Fever patients. Hum Mutat 15(4):384

140


Medlej-Hashim M, Petit I, Adib S, Chouery E, Salem N, Delague V, Rawashdeh M, Mansour I, Lefranc G, Naman R et al (2001) Familial Mediterranean Fever: association of elevated IgD plasma levels with specific MEFV mutations. Eur J Hum Genet 9(11):849–854 Medlej-Hashim M, Salem N, Chouery E, Rawashdeh M, Delague V, Haffar M, Mansour I, Naman R, Lefranc G, Loiselet J et al (2002) Familial Mediterranean Fever: the potential for misdiagnosis of E148V using the E148Q usual RFLP detection method. Clin Genet 61(1):71–73 Medlej-Hashim M, Delague V, Chouery E, Salem N, Rawashdeh M, Lefranc G, Loiselet J, Megarbane A (2004) Amyloidosis in Familial Mediterranean Fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects. BMC Med Genet 5(1):4 Medlej-Hashim M, Serre JL, Corbani S, Saab O, Jalkh N, Delague V, Chouery E, Salem N, Loiselet J, Lefranc G et al (2005) Familial Mediterranean Fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet 48 (4):412–420 Melikoglu M, Ozdogan H, Korkmaz C, Kasapcopur O, Arisoy N, Akkus S, Fresko Z, Yazici H (2000) A survey of phenotype II in Familial Mediterranean Fever. Ann Rheum Dis 59 (11):910–913 Michaeli D, Pras M, Rozen N (1966) Intestinal strangulation complicating Familial Mediterranean Fever. BMJ 2:30–31 Mijatovic V, Hompes PG, Wouters MG (2003) Familial Mediterranean Fever and its implications for fertility and pregnancy. Eur J Obstet Gynecol Reprod Biol 108(2):171–176 Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H, Aksentijevich I, Lesage S, Waterham H, Wise C, Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H, Aksentijevich I, Lesage S, Waterham H, Wise C, Sarrauste de Menthiere C et al (2008) The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat 29(6):803–808 Mor A, Shinar Y, Zaks N, Langevitz P, Chetrit A, Shtrasburg S, Rabinovitz E, Livneh A (2005) Evaluation of disease severity in Familial Mediterranean Fever. Semin Arthritis Rheum 35 (1):57–64 Morbach H, Richl P, Stojanov S, Lohse P, Girschick HJ (2009) Tumor necrosis factor receptor 1-associated periodic syndrome without fever: cytokine profile before and during etanercept treatment. Rheumatol Int Muckle TJ (1979) The ‘Muckle–Wells’ syndrome. Br J Dermatol 100(1):87–92 Muckle TJ, Wellsm (1962) Urticaria, deafness, and amyloidosis: a new heredo-familial syndrome. Q J Med 31:235–248 Mulley J, Saar K, Hewitt G, Ruschendorf F, Phillips H, Colley A, Sillence D, Reis A, Wilson M (1998) Gene localization for an autosomal dominant familial periodic fever to 12p13. Am J Hum Genet 62(4):884–889 Neequaye J, Jelly AE (1994) Acute hepatitis in recurrent hereditary polyserositis (Familial Mediterranean Fever). J Trop Pediatr 40(4):243–245 Neven B, Callebaut I, Prieur AM, Feldmann J, Bodemer C, Lepore L, Derfalvi B, Benjaponpitak S, Vesely R, Sauvain MJ et al (2004) Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/ NOMID, MWS, and FCU. Blood 103(7):2809–2815 Ozdemir AI, Sokmen C (1969) Familial Mediterranean Fever among the Turkish people. Am J Gastroenterol 51(4):311–316 Ozer FL, Kaplaman E, Zileli S (1971) Familial Mediterranean Fever in Turkey. A report of twenty cases. Am J Med 50(3):336–339 Ozkan E, Okur O, Ekmekci A, Ozcan R, Tag T (1972) A new approach to the treatment of periodic fever. Med Bull Istanbul 5:44–49 Padeh S (2005) Periodic fever syndromes. Pediatr Clin North Am 52(2):577–609, vii Padeh S, Shinar Y, Pras E, Zemer D, Langevitz P, Pras M, Livneh A (2003) Clinical and diagnostic value of genetic testing in 216 Israeli children with Familial Mediterranean Fever. J Rheumatol 30(1):185–190


141

Papin S, Duquesnoy P, Cazeneuve C, Pantel J, Coppey-Moisan M, Dargemont C, Amselem S (2000) Alternative splicing at the MEFV locus involved in Familial Mediterranean Fever regulates translocation of the marenostrin/pyrin protein to the nucleus. Hum Mol Genet 9(20):3001–3009 Pras M, Bronshpigel N, Zemer D, Gafni J (1982) Variable incidence of amyloidosis in Familial Mediterranean Fever among different ethnic groups. Johns Hopkins Med J 150(1):22–26 Pras E, Aksentijevich I, Gruberg L, Balow JE Jr, Prosen L, Dean M, Steinberg AD, Pras M, Kastner DL (1992) Mapping of a gene causing Familial Mediterranean Fever to the short arm of chromosome 16. N Engl J Med 326(23):1509–1513 Pras E, Aksentijevich I, Levy E, Gruberg L, Prosen L, Dean M, Pras M, Kastner DL (1994) The gene causing Familial Mediterranean Fever maps to the short arm of chromosome 16 in Druze and Moslem Arab families. Hum Genet 94(5):576–577 Pras E, Livneh A, Balow JE Jr, Kastner DL, Pras M, Langevitz P (1998) Clinical differences between North African and Iraqi Jews with Familial Mediterranean Fever. Am J Med Genet 75(2):216–219 Priest RJ, Nixon RK (1959) Familial recurring polyserositis: a disease entity. Ann Intern Med 51:1253–1274 Prieur AM (2001) A recently recognised chronic inflammatory disease of early onset characterised by the triad of rash, central nervous system involvement and arthropathy. Clin Exp Rheumatol 19(1):103–106 Pugnere D, Ruiz M, Sarrauste de Menthiere C, Masdoua B, Demaille J, Touitou I (2003) The MetaFMF website: a high quality tool for meta-analysis of FMF. Nucleic Acids Res 31(1):286–290 Rabinovitch O, Zemer D, Kukia E, Sohar E, Mashiach S (1992) Colchicine treatment in conception and pregnancy: two hundred thirty-one pregnancies in patients with Familial Mediterranean Fever. Am J Reprod Immunol 28(3–4):245–246 Rawashdeh MO, Majeed HA (1996) Familial Mediterranean Fever in Arab children: the high prevalence and gene frequency. Eur J Pediatr 155(7):540–544 Saatci U, Bakkaloglu A, Ozen S, Besbas N (1993) Familial Mediterranean Fever and amyloidosis in children. Acta Paediatr 82(8):705–706 Saatci U, Ozen S, Ozdemir S, Bakkaloglu A, Besbas N, Topaloglu R, Arslan S (1997) Familial Mediterranean Fever in children: report of a large series and discussion of the risk and prognostic factors of amyloidosis. Eur J Pediatr 156(8):619–623 Sabbagh AS, Ghasham M, Abdel Khalek R, Greije L, Shammaa DM, Zaatari GS, Mahfouz RA (2008) MEFV gene mutations spectrum among Lebanese patients referred for Familial Mediterranean Fever work-up: experience of a major tertiary care center. Mol Biol Rep 35(3):447–451 Sachs D, Langevitz P, Morag B, Pras M (1987) Polyarteritis nodosa and Familial Mediterranean Fever. Br J Rheumatol 26(2):139–141 Said R, Hamzeh Y (1990) IgM nephropathy associated with Familial Mediterranean Fever. Clin Nephrol 33(5):227–231 Said R, Nasrallah N, Hamzah Y, Tarawneh M, al-Khatib M (1988) IgA nephropathy in patients with Familial Mediterranean Fever. Am J Nephrol 8(5):417–420 Said R, Hamzeh Y, Tarawneh M, el-Khateeb M, Abdeen M, Shaheen A (1989) Rapid progressive glomerulonephritis in patients with Familial Mediterranean Fever. Am J Kidney Dis 14 (5):412–416 Said R, Hamzeh Y, Said S, Tarawneh M, al-Khateeb M (1992) Spectrum of renal involvement in Familial Mediterranean Fever. Kidney Int 41(2):414–419 Salai M, Zemmer D, Segal E, Corat A, Heyman Z, Davidson B, Langevitz P, Livneh A (1997) Chronic massive knee effusion in Familial Mediterranean Fever. Semin Arthritis Rheum 27(3):169–172 Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood R, Kastner DL (1998) Familial Mediterranean Fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore) 77(4):268–297

142


Sarrauste de Menthiere C, Terriere S, Pugnere D, Ruiz M, Demaille J, Touitou I (2003) INFEVERS: the Registry for FMF and hereditary inflammatory disorders mutations. Nucleic Acids Res 31(1):282–285 Sayarlioglu M, Cefle A, Inanc M, Kamali S, Dalkilic E, Gul A, Ocal L, Aral O, Konice M (2005) Characteristics of patients with adult-onset Familial Mediterranean Fever in Turkey: analysis of 401 cases. Int J Clin Pract 59(2):202–205 Schlesinger M, Rubinow A, Vardy PA (1985) Henoch-Schonlein purpura and Familial Mediterranean Fever. Isr J Med Sci 21(1):83–85 Schultz C, Holterhus PM, Seidel A, Jonas S, Barthel M, Kruse K, Bucsky P (1999) Chronic recurrent multifocal osteomyelitis in children. Pediatr Infect Dis J 18(11):1008–1013 Schwabe AD, Monroe JB (1988) Meningitis in Familial Mediterranean Fever. Am J Med 85(5):715–717 Schwabe AD, Peters RS (1974) Familial Mediterranean Fever in Armenians. Analysis of 100 cases. Medicine (Baltimore) 53(6):453–462 Shinar Y, Livneh A, Langevitz P, Zaks N, Aksentijevich I, Koziol DE, Kastner DL, Pras M, Pras E (2000) Genotype-phenotype assessment of common genotypes among patients with Familial Mediterranean Fever. J Rheumatol 27(7):1703–1707 Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, Kastner DL (2003) Pyrin binds the PSTPIP1/CD2BP1 protein, defining Familial Mediterranean Fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci USA 100 (23):13501–13506 Shohat M, Bu X, Shohat T, Fischel-Ghodsian N, Magal N, Nakamura Y, Schwabe AD, Schlezinger M, Danon Y, Rotter JI (1992a) The gene for Familial Mediterranean Fever in both Armenians and non-Ashkenazi Jews is linked to the alpha-globin complex on 16p: evidence for locus homogeneity. Am J Hum Genet 51(6):1349–1354 Shohat M, Danon YL, Rotter JI (1992b) Familial Mediterranean Fever: analysis of inheritance and current linkage data. Am J Med Genet 44(2):183–188 Shohat M, Magal N, Shohat T, Chen X, Dagan T, Mimouni A, Danon Y, Lotan R, Ogur G, Sirin A et al (1999) Phenotype-genotype correlation in Familial Mediterranean Fever: evidence for an association between Met694Val and amyloidosis. Eur J Hum Genet 7(3):287–292 Sidi G, Shinar Y, Livneh A, Langevitz P, Pras M, Pras E (2000) Protracted febrile myalgia of Familial Mediterranean Fever. Mutation analysis and clinical correlations. Scand J Rheumatol 29(3):174–176 Siegal S (1945) Benign paroxysmal peritonitis. Ann Intern Med 23:1–21 Sneh E, Pras M, Michaeli D, Shanin N, Gafni J (1977) Protracted arthritis in Familial Mediterranean Fever. Rheumatol Rehabil 16(2):102–106 Sohar E, Pras M, Heller J, Heller H (1961) Genetics of Familial Mediterranean Fever. Arch Intern Med 107:529–538 Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean Fever. A survey of 470 cases and review of the literature. Am J Med 43(2):227–253 Stehlik C, Reed JC (2004) The PYRIN connection: novel players in innate immunity and inflammation. J Exp Med 200(5):551–558 Stoffman N, Magal N, Shohat T, Lotan R, Koman S, Oron A, Danon Y, Halpern GJ, Lifshitz Y, Shohat M (2000) Higher than expected carrier rates for Familial Mediterranean Fever in various Jewish ethnic groups. Eur J Hum Genet 8(4):307–310 Stojanov S, Kastner DL (2005) Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr Opin Rheumatol 17(5):586–599 Touitou I (2001) The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 9(7):473–483 Touitou I, Lesage S, McDermott M, Cuisset L, Hoffman H, Dode C, Shoham N, Aganna E, Hugot JP, Wise C et al (2004) Infevers: an evolving mutation database for auto-inflammatory syndromes. Hum Mutat 24(3):194–198


143

Touitou I, Sarkisian T, Medlej-Hashim M, Tunca M, Livneh A, Cattan D, Yalcinkaya F, Ozen S, Majeed H, Ozdogan H et al (2007) Country as the primary risk factor for renal amyloidosis in Familial Mediterranean Fever. Arthritis Rheum 56(5):1706–1712 Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, Tutar E, Ozen S, Topaloglu R, Yilmaz E et al (2005) Familial Mediterranean Fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 84(1):1–11 van der Meer JW, Vossen JM, Radl J, van Nieuwkoop JA, Meyer CJ, Lobatto S, van Furth R (1984) Hyperimmunoglobulinaemia D and periodic fever: a new syndrome. Lancet 1 (8386):1087–1090 Vilaseca J, Tor J, Guardia J, Bacardi R (1982) Periodic meningitis and Familial Mediterranean Fever. Arch Intern Med 142(2):378–379 Williamson LM, Hull D, Mehta R, Reeves WG, Robinson BH, Toghill PJ (1982) Familial Hibernian fever. Q J Med 51(204):469–480 Wise CA, Gillum JD, Seidman CE, Lindor NM, Veile R, Bashiardes S, Lovett M (2002) Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet 11(8):961–969 Yalcinkaya F, Tekin M, Tumer N, Ozkaya N (1997) Protracted arthritis of Familial Mediterranean Fever (an unusual complication). Br J Rheumatol 36(11):1228–1230 Yalcinkaya F, Cakar N, Misirlioglu M, Tumer N, Akar N, Tekin M, Tastan H, Kocak H, Ozkaya N, Elhan AH (2000) Genotype-phenotype correlation in a large group of Turkish patients with Familial Mediterranean Fever: evidence for mutation-independent amyloidosis. Rheumatology (Oxford) 39(1):67–72 Yalcinkaya F, Ozen S, Ozcakar ZB, Aktay N, Cakar N, Duzova A, Kasapcopur O, Elhan AH, Doganay B, Ekim M et al (2009) A new set of criteria for the diagnosis of Familial Mediterranean Fever in childhood. Rheumatology (Oxford) 48(4):395–398 Yeon HB, Lindor NM, Seidman JG, Seidman CE (2000) Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q. Am J Hum Genet 66(4):1443–1448 Yilmaz E, Ozen S, Balci B, Duzova A, Topaloglu R, Besbas N, Saatci U, Bakkaloglu A, Ozguc M (2001) Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population. Eur J Hum Genet 9(7):553–555 Yu JW, Wu J, Zhang Z, Datta P, Ibrahimi I, Taniguchi S, Sagara J, Fernandes-Alnemri T, Alnemri ES (2005) Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization. Cell Death Differ 13(2):236–249 Yuval Y, Hemo-Zisser M, Zemer D, Sohar E, Pras M (1995) Dominant inheritance in two families with Familial Mediterranean Fever (FMF). Am J Med Genet 57(3):455–457 Zemer D, Revach M, Pras M, Modan B, Schor S, Sohar E, Gafni J (1974) A controlled trial of colchicine in preventing attacks of Familial Mediterranean Fever. N Engl J Med 291 (18):932–934 Zemer D, Livneh A, Danon YL, Pras M, Sohar E (1991) Long-term colchicine treatment in children with Familial Mediterranean Fever. Arthritis Rheum 34(8):973–977

Chapter 6

Muscular Dystrophies and Myopathies in Arab Populations Mustafa A.M. Salih

Interest in neuromuscular disorders has grown rapidly in recent years as knowledge of their molecular basis has advanced and the search for potential treatment by gene or cell therapy has begun. (Allamand et al. 2000; Cordier et al. 2000; Dressman et al. 2002; Yakota et al. 2009). This chapter gives an overview of the epidemiologic, clinical, and laboratory studies of muscular dystrophies (MDs) and myopathies reported in Arab communities.

Epidemiology The data presented here, though scarce, came mainly from retrospective surveys of medical records in secondary- and tertiary-care hospitals, or from smaller prospective series of selected neuromuscular disorders. One of these was a 3-year search (January 1983–December 1985) for certain conditions in the sole neurology center in the Benghazi region of Libya (Radhakrishnan et al. 1987). This study included 34 patients with Duchenne muscular dystrophy (DMD): 25 were index cases; 19 MD (13 index cases); 4 had fascioscapulohumeral MD (3 index cases); 3 had opthamoplegia plus (all index cases); and 41 were index cases of hereditary motor and sensory neuropathy (HMSN). The estimated overall prevalence of MDs was 132/106 (1,000,000), DMD being the most common of them (60/106). The overall prevalence is less than half the figure (286/106) estimated by Emery (1991) in a world survey, whereas the prevalence of DMD was about twice as high (Table 6.1). This might have resulted from the inherent problems of ascertainment in the study from Benghazi, since histopathological confirmation (using light microscopy) was possible in about half of the cases, whereas facilities for electron microscopy and enzyme histochemistry were not available. M.A.M. Salih Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia e-mail: [email protected]


145

146

M.A.M. Salih

Table 6.1 Prevalence rate (per million population) of selected muscular dystrophies among Arabs compared to a world survey prevalence Muscular dystrophies Study Location/ Overall Duchenne Limb“DuchenneMyotonic country prevalence girdle like” dystrophy Benghazi, 132 60 37 – – Radhakrishnan Libya et al. (1987)a 44 – – 88 Al-Rajeh et al. Thugbah, 265b (1993) Saudi Arabia Romdhane et al. Kelibia, 315 – – – – (1993) Tunisia Emery (1991) World survey 286 32 17 years) than in DMD (10 times normal. Electromyography (EMG) showed myopathic features, whereas muscle biopsy was consistent with MD and also revealed type I fiber predominance (>75%) and normal dystrophin staining. Another series of 14 patients (nine females (F) and five males (M)) with SCARMD were also studied at KKUH, Riyadh (Salih et al. 1996b). Six of these (three M and three F) were siblings of two Saudi families, whereas another Syrian family had an affected boy and girl. Two other Saudi girls had positive family history, including three males and three females, one of whom died of the disease at 15 years. The remaining four patients were isolated cases and included three Saudis (one M and two F) and one Yemeni girl. Close parental consanguinity was found in five (63%) of the eight pairs of parents. Onset was between 3 and 9 years (median 3 years) and all of those aged >12 years lost ambulation except one male. The mean serum CK was 20 times the upper normal limit. In a remarkable similarity to what has been observed in Sudanese patients (Salih et al. 1983), ECG showed ST-segment depression and T-wave changes that tended to occur in fixed leads, pointing to the possibility of myocardial involvement with the dystrophic process (Armstrong 1985). Changes in QRS configuration, which suggested intraventricular conduction delay, were seen in four patients, similar to what has been reported in Tunisian SCARMD patients (Ben-Hamida et al. 1983). It is noteworthy that a specific deficiency of adhalin has been observed in skeletal muscle of the cardiomyopathic hamster, whereas a deficiency of multiple DAGs, including adhalin, was found in its cardiac muscle (Roberds et al. 1993b). These animals suffer from both myopathy and cardiomyopaty, with death occurring because of the latter. Muscle biopsy showed dystrophic features in all patients associated with type I fiber predominance, which agreed with findings in Tunisian and Sudanese series (Ben-Hamida et al. 1983; Salih et al. 1983). There was also good differentiation of the major fiber types in the routine ATPase (pH 9.4), similar to findings in Sudanese children (Salih et al. 1983) and to what appears in the muscle photomicrographs that were published in one of the Tunisian series (Ben-Hamida et al. 1983). Dystrophin was positive in all of the six cases that were tested (Fig. 6.2), whereas a specific deficiency of adhalin was detected in three of four patients (two girls and one boy). The adhalin deficient boy was an isolated case (aged 13 years) with rapidly progressing disease. Having identified SCARMD in Saudis, Syrians, and Yemenis, such studies provided further evidence that cases reported previously in the Arabian Peninsula (Dubowitz 1980; Farag and Teebi 1990), northwestern Africa (Ben Hamida and Fardeau 1980; Ben-Hamida et al. 1983), and Sudan (Salih 1980, 1982; Salih et al. 1983) belong to the same disease entity. In fact, historic data on the Sudanese kindred that had several patients affected with SCARMD revealed that it belonged

154

M.A.M. Salih

Fig. 6.2 A 13-year-old girl from the Central Region of Saudi Arabia who had SCARMD. (a) There is remarkable muscle hypertrophy, especially of the calf muscles associated with equinovarus deformity. Cautery marks (a form of alternative medicine) are evident. (b) Immunohistochemical staining of vastus lateralis (biopsied in 1992) showed normal sarcolemma dystrophin distribution (400). Staining for adhalin (a-sarcoglycan) was negative (not shown)

to the Kawahla tribe. This Sudanese tribe is known to descend from Kahil Ibn Asad Ibn Khuzaima and to have migrated from the central region of Saudi Arabia to Sudan after crossing the Read Sea during the twelfth and thirteenth centuries (Fig. 6.3) (Mohamed 1956; MacMichael 1967).

Limb-Girdle Muscular Dystrophy 2B (LG-MD 2B) This form of LGMD is associated with defects in the DYSF gene that encodes the protein dysferlin. The initial linkage of this subtype to chromosome 2q was reported by Bashir et al. (1994) in two unrelated consanguineous families, one Palestinian and one of Sicilian origin, manifesting autosomal recessive inheritance. Two other allelic phenotypes of dysferlin deficiency were later recognized. These are Miyoshi myopathy (MM), which is characterized by weakness affecting initially the gastrocnemius muscle from the late teens or early adulthood (Miyoshi et al. 1986), and distal anterior compartment myopathy characterized by anterior compartment (tibi alis anterior) myopathy (Salani et al. 2004). The term “dysferlinopathy” was coined by Bushby (1999) after MM and LGMD 2B were found to be allelic disorders. The co-existence of MM phenotype with LGMD in the same family had been reported earlier by Mahjneh et al. (1992) in a large kindred from Palestine. Cupler et al. (1998) described MM in a Saudi family with five siblings aged 3–25 years and in an 18-year-old woman and a 40-year-old man who were unrelated. The two sporadic and two of the familial cases showed classic findings of MM, including early adult onset, preferential involvement of gastrocnemius muscles,

6 Muscular Dystrophies and Myopathies in Arab Populations

155

Fig. 6.3 Map showing the migration of the ancestors of the family in whom SCARMD was initially described in Sudan. Three settlement areas (1, 2, 3) of the Kawahla tribe in the Sudan, to whom the family belongs, are shown. This tribe migrated from central Saudi Arabia (Mohamed 1956; MacMichael 1967). The village of the SCARMD family is marked (dots) in area 3

markedly elevated serum CK, and dystrophic appearing muscle without vacuoles. Interestingly, the three familial cases had elevated serum CK and only two of these also had early myopathic findings by EMG. In a study involving researchers from Saudi Arabia and Tunisia, Lui et al. (1998) identified a novel mutation in a skeletal muscle gene, dysferlin, at the locus 2p12–14 and documented that dysferlin mutations cause MM and LGMD 2B. An international collaborative study (Aoki et al. 2001), including patients from Sudi Arabia, described the exon–intron structure of the dysferlin gene and identified nine novel mutations associated with MM. The study also confirmed that dysferlin gene is mutated in both MM and LGMD 2B. It is noteworthy that no mutational hot spots have been reported, as yet, in any of the three Maghrebian countries (Morocco, Algeria, and Tunisia) despite the high prevalence of primary dysferlinopathy in this area (Urtizberea et al. 2008).

Limb-Girdle Muscular Dystrophy, Type 2C (LGMD2C) In an extension of the studies that demonstrated linkage homogeneity to 13q patients with SCARMD (DMD-like) phenotype from Morocco, Tunisia, and

156

M.A.M. Salih

Algeria (Ben Othmane et al. 1992; Azibi et al. 1993; El Kerch et al. 1994), Ben Othmane et al. (1995) also identified six Tunisian and one Egyptian families who showed linkage to the pericentromeric region of chromosome 13q. Ben Hamida et al. (1996) further highlighted the clinical features of the LGMD2C linked to chromosome 13q and realted to a 35 kDa DAG deficiency. They described the disease to be characterized by a variability of the age of onset, the severity of the evolution, and the severity of the myopathic changes at the muscle biopsy. This variability was also present in the expression of the a-sarcoglycan (adhalin) between the same sibships and between different families. The study of Kefi et al. (2003) emphasized the previous observations that all Tunisian patients were homozygous for del521T mutation in the g-sarcoglycan gene, and carried the same allele 122-bp of D13S232 marker indicating a founder effect. All the studied 132 LGMD2C patients had the same homozygous del521-T mutation in the g-sarcoglycan gene. However, this identical mutation was found to lead to mild, intermediate and severe phenotypes in different families. Immunohistochemical studies of muscle biopsy showed a total absence of g-sarcoglycan and a normal or slightly reduced a- and d-sarcoglycans, whereas the expression of b-sarcoglycan was variable. They accounted for this phenotypic variability by the possible involvement of a modifying gene controlling the course of the disease. Fendri et al. (2006) reported on three Tunisian patients belonging to the same consanguineous family and sharing similar SCARMD phenotype but heterogenous sarcoglycans immunohistochemical patterns. One patient had del521T homozygous mutation in exon 6 of the g-sarcoglycan gene (LGMD2C), and two had a 157G>A homozygous mutation in exon 2 of the adhalin (a-sarcoglycan) gene (LGMD2D). The authors highlighted the complexity of genetic counseling in inbred populations. It is noteworthy that the same del521T mutation was found in patients from Western India (Khadilkar and Benny 2008) and in Towareg tribe from Niger (A. Urtizberea, personal communication), possibly relating to the pattern of human migration. Piccolo et al. (1996) identified a different founder g-sarcoglycan gene mutation (C283Y) in the Romany Gypsies of Europe. These are believed to have originated from Northern Indian populations that arrived in Europe around 1,100 A.D. Another novel nonsense mutation: 93G > A (Trp31X) on exon 2 of the d-sarcoglycan gene was identified in a Moroccan patient who presented with progressive walking disturbances for several years, exercise intolerance, and leg pains (Vermeer et al. 2004).

Primary Adhalinopathy (a-sarcoglycanopathy, LGMD2D) Following the discovery of adhalin (a-sarcoglycan) gene in a French kindred (Roberds et al. 1994), an international collaborative study (Piccolo et al. 1995) examined 12 cases of autosomal recessive MD from various origins (France, Italy, Germany, Algeria, and Morocco). The authors first emphasized the fact that there are two types of myopathies with adhalin (a-sarcoglycan) deficiency: one with primary


157

defect of adhalin (primary adhalinopathy), and one in which absence of adhalin is secondary to a separate gene defect of chromosome 13. Both of the Algerian and Moroccan patients had SCARMD phenotype and revealed negative lodscores with the markers of the 17q21 region including the intragenic adhalin microsatellite. Mutations in the adhalin gene were detected in 10 new cases and the most severe clinical course was observed in patients who had homozygous null mutations. In three patients belonging to the same consanguineous family, Fendri et al. (2006) described two siblings with LGMD2D (a-sarcoglycanopathy). Onset was at 5 years and both patients became wheelchair-bound by the age of 18 years. A homozygous mutation (157G>A) in exon 2 of the a-sarcoglycan gene was found in the two siblings. A second-degree cousin of these patients had g-sarcoglycan gene mutation (LGMD2C). Adhalin (a-sarcoglycan) gene mutations were also found in Saudi Arabia in four families (M.A.M. Salih, unpublished work). Three of these were Saudi, whereas the other originated from Yemen. b-Sarcoglycanopathy (LGMD2E) Following the cloning of b-sarcoglycan gene in 1995 (Lim et al. 1995; Bonnemann et al. 1995), the first Tunisian family with b-sarcoglycanopathy (LGMD2E) was described, adding to the genetic heterogeneity of autosomal recessive LGMD in this population (Bonnemann et al. 1998). The family had SCARMD phenotype and immunohistochemical analysis showed absence of the sarcoglycan complex components. A homozygous mutation (G272 ! T, Arg 91Leu) was identified in exon 3 of the b-sarcoglycan gene. The Sudanese kindred with SCARMD phenotype that were first studied in 1977 (Salih 1980; Salih et al. 1983) were re-investigated applying molecular genetic tools (Salih et al. 2007). By the year 2007, a total of 17 individuals in 8 generations were ascertained to have died of the disease at a mean age of 21.65 + 9.96 years (range 12–39 years). In the ninth generation, an affected boy was evaluated at the age of 9 years and 4 months. Onset was at the age of 3 years and he was wheelchairbound at 8 years and 8 months. Apart from proximal muscle weakness and wasting, he showed tongue enlargement and calf muscle hypertrophy (Fig. 6.1a). Serum CK was 9.5 times normal and the histology of muscle biopsy showed dystrophic features. Re-examination of the stored muscle biopsy of one of the patients in the eight generation revealed negative staining for the sarcoglycans a (adhalin), b, g, and d. Molecular analysis showed mutation in the b–sarcoglycan gene (homozygous 2bp deletion at 112bp, changing Ser 38 to a Stop codon in exon 2). Genomic DNA analysis of the young boy in the ninth generation also showed a b–sarcoglycan gene deletion (2 bases (AG) in exon 2, creating a stop codon in position 48). The parents were heterozygous for the mutation. The phenotypic differences reported in the 1980s between the Sudanese and Tunisian families (Salih et al. 1983) seem to have been a reflection of the different sarcoglycans (b versus g) involved in the pathogenesis of the disease.

158

M.A.M. Salih

LGMD2I Type 2I of LGMD was originally described in a large consanguineous Tunisian family and linked to 19q (Driss et al. 2000). The disease is caused by mutations in Fukutin-related protein gene (FKRP). The phenotype is characterized by calf hypertrophy, marked elevation of creative kinase, and frequent cardiac and respiratory involvement (Poppe et al. 2003). Three Saudi families were found to be LGMD2I and harbor FKRP mutations (M.A.M. Salih, unpublished data).

Advances in the Molecular and Cell Biology of the Dystrophin-Associated Proteins Further studies in the characterization of the dystrophin associated proteins (DAPs) classified them into three groups (Ozawa et al. 2005): an intracellular peripheral membrane complex composed of dystrophin with dystrobrevins and the syntrophins and their associated molecules, and two transmembrane complexes, dystroglycan and sarcoglycan-sarcospan complex. The sub-sarcolemmal action filaments are connected to laminin, one of the main components of the extracellular matrix, through dystrophin and dystroglycan. This system seems to play an important role in protecting the sarcolemma during contraction and relaxation of muscle fibers. Dystroglycan is composed of two sub-units, a- and b-dystroglycan, both of which are transcribed from the same gene in chromosome 3p25 and are generated by posttranslational processing. a-dystroglycan is a heavily glycosylated protein and appears as a broad smeared band on western blots with an aberrant molecular weight of 156 kDa in skeletal muscle. Defects in the glycosylation of a-dystroglycan result in several forms of congenital MDas well as some types of LGMD. No naturally occurring mutations of the dystroglycan gene have been described so far. Nevertheless, a mild form of MD associated with b-dystroglycan deficiency has been described in a 4-year-old Saudi boy (Salih et al. 1996c). This patient had a myopathy starting at 1½ years of age that mainly affected the girdle and the proximal limb muscles. Investigations revealed normal findings on electrocardiogram (ECG), echocardiogram, and nerve conduction studies. Serum CK, measured on two occasions, was marginally raised at 248 and 255 IU/L (normal A). However, the analysis of polymorphisms segregating with the mutation did not suggest that the recurrence of this mutation resulted from a founder effect (S. Nicole and B. Fontaine, personal communication).

Congenital Myopathies Congenital myopathies are a group of muscle disorders which are caused by genetic defects in the contractile apparatus of muscle. They have been defined by distinctive static histochemical or ultrastructural changes on muscle biopsy (Ryan and North 2006; Cardomone et al. 2008). They usually present at birth or in childhood, with hypotonia and muscle weakness (Sewry et al. 2008). Central nuclei are the characteristic feature of the X-linked myotubular myoapthy, caused by mutations in the MTM1 gene, which encodes myotubulation (Laporte et al. 1996). This condition was reported by Tanner et al. (1999) in a 39-year-old Yemenese woman with histologic and clinical phenotype consistent with X-linked myotubular myopathy. The proband was found to be a carrier of the most common MTM1 gene mutation, which is associated with a severe phenotype in males. The patient had an extremely skewed X-inactivation pattern, thus explaining her abnormal phenotype, while her mother was a nonmanifesting carrier with extremely skewed X-inactivation pattern in the opposite direction. Another report on this disease came from Oman, describing one female newborn affected by X-linked myotubular myopathy (Menon et al. 2002). Myofibrillar myopathies include a group of neuromuscular disorders, characterized by structural changes in the myofibril, resulting from intracellular accumulation of proteins such as desmins (Cardomone et al. 2008). Being inherited as autosomal dominant or autosomal recessive, the phenotype is characterized by the development of proximal, distal, or generalized weakness. Additional features include the development of cardiomyopathy, cardiac conduction defects, and peripheral neuropathy (Cardomone et al. 2008). El-Menyar et al. (2004) reported a Qatari family with myofibrillar myopathy. The proband, a 22-year-old male, had been diagnosed 6 years earlier with tachybrady syndrome and had been on a permanent pacemaker since then. His parents were second cousins and he had three sisters.


167

One of these underwent heart transplantation for severe obstructive cardiomyopathy, while the other had a permanent pacemaker for complete heart block. El-Menyar et al. (2004) suggested that the clinical heterogeneity in the family could be explained by mutations in the desmin gene. Further analysis of data of all patients (T genotypes which is in strong association with the severity of asthma. Heshmat and El-Hadidi (2006) found that serum sCD30 levels correlate with the severity of AD and bronchial asthma. Temtamy studied a male infant affected with Omenn syndrome (MIM: 603554) confirmed by clinical, hematological and immunologic data. He was the offspring of first cousins (unpublished data). Adenosine deaminase deficiency was reported by El-Bassyouni and El-Sayed (2000). Ezzat et al. (2005) confirmed the association of DRB1 *04 and *14 alleles with juvenile rheumatoid arthritis susceptibility and DRB1 *08 with protection in 60 patients with polyarticular onset JRA. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (MIM: 240300) presenting with severe keratopathy in an Egyptian patient with a homozygous R139X mutation in the gene encoding the AIRE protein was reported by Tawfik et al. (2005). In a study of 50 children with chronic rheumatic heart disease (RHD) from the Nile Delta region of Egypt, Settin et al. (2007a) found that predisposition to RHD was influenced by genetic factors including cytokine gene polymorphisms, with possible susceptibility to severe disease with multi-valvular affection among cases with composite polymorphism (TNF-alpha (-308 )A/A and IL-10(-1082) A/A) and (TNF-alpha(308 )A/A and IL-10(1,082) G/G). Sixteen Egyptian children with non familial steroid-resistant nephrotic syndrome (SRNS) (MIM: 600995) were screened by PCR-single-strand conformation polymorphism analysis of NPHS2 gene followed by direct sequencing. NPHS2 mutations were evident in four patients (25%) who were bearing four novel mutations including two frame shift mutations (R238fs and P45fs) and two missense mutations (I136L and F216Y) (Bakr et al. 2008). Among the familial cases in a genetic study of 100 Egyptian children with cleft lip and palate, Temtamy and loutfy (1970) reported several syndromes including: van der Woode syndrome (OMIM: 119300), popliteal pterygium syndrome (MIM: 119500), orofaciodigital syndrome, otopalatodigital syndrome (MIM: 304120), Larsen syndrome, and Roberts syndrome. Mossalam et al. (1974) reported familial Waardenburg syndrome (OMIM: 193500). A case with Waardenburg–Klein syndrome (MIM: 148820) was described by Temtamy et al. (1981b). Anthropometry in Egyptian children with Seckel syndrome (MIM: 210600) was reported by Hosny et al. (1997). Hatem et al. (2003) studied two sibs with Seckel syndrome and associated CNS anomalies. Ismail and Helmy (2000) studied Silver–Russel syndrome (MIM: 180860). Zaki et al. (1989) reported the results of anthropometry and dermatoglyphics in Noonan syndrome (OMIM: 163950). Aglan (2002) provided control data of 16

254

S.A. Temtamy et al.

facial indices calculated in 100 normal Egyptian children using photoanthropometry and compared them to the age to be used to delineate abnormal facial features in dysmorphic cases. Aglan et al. (2003) recorded the similarities and differences in the phenotypic features and clinical findings between 14 cases with Noonan syndrome (NS) and six cases with cardiofaciocutaneous syndrome (MIM: 115150) in 20 Egyptian patients. Temtamy and Shoukry (1975) reported the first Egyptian case with Brachmann de Lange syndrome (MIM: 122470). Temtamy et al. (1994a) described 12 other Egyptian cases with emphasis on the orodental, ear and eye abnormalities and their relation to the severity of expression of the disorder. De Lange syndrome with hemimelia was reported by El-Ruby and Temtamy (1997). In a study of 50 patients with auricular abnormalities, four cases had renal anomalies and all four were diagnosed as MCA syndromes (de-Lange syndrome, Goldenhar and Crouzon syndrome) (Rashad and El-Fiky 2007). Temtamy et al. (1991b) illustrated the variability in Hallerman–Strieff syndrome (OMIM: 264090). Cerebrooculofacioskeletal (COFS) syndrome (OMIM: 214150) with familial 1;16 translocation was reported by Temtamy et al. (1996c). SanjadSakati syndrome (OMIM: 241410) was reported by El-Sawy et al. (2004). Temtamy and Shalash (1975) reported sibs with Bardet–Biedel syndrome (BB) (OMIM: 209900). Miniawi et al. (1981) provided a genetic study of 11 cases with BB syndrome. Temtamy et al. (1989a) added new observations to the syndrome. Farag et al. (1999) reported Prader–Willi syndrome (PW) (OMIM: 176270) with microdeletion in chromosome 15(15q11-q). Farag et al. (1999) also reported two patients with FISH-positive Williams syndrome (OMIM: 194050). In a genetic study of obesity in 50 children, Mazen et al. (2002) found 48% with exogeneous obesity, 30% with PW syndrome, 18% with BB syndrome, 2% with Fra X syndrome and 2% with Down syndrome. Positive parental consanguinity was seen in 58% of cases. Elsayed et al. (2005) studied three patients with BeckwithWiedemann syndrome (MIM130650) with hypomethylation of the KCNQ1OT gene and no abnormal methylation of the H19 gene. Elsobky et al. (2005) reported two cases of Cohen syndrome (MIM216550) from two separate families. Abdel-Salam et al. (2007a) described seven patients (five males and two females) with microcephaly, mild microphthalmia, microcornea, congenital cataracts and hypogenitalism (only in males), consistent with the diagnosis of Micro syndrome (OMIM: 600118). Mutation analysis for two of their patients showed homozygous nonsense mutation of RAB3GAP1 in one while the other showed no evidence of linkage to either RAB3GAP1 or RAB2GAP2.

Novel Syndromes The association of anetoderma, optic atrophy and metaphyseal dysplasia (MIM: 250450) was reported by Temtamy et al. (1974a).

8 Genetic Disorders in Egypt

255

Fig. 8.4 Temtany preaxial brachydactyly syndrome (Temtamy et al. 1998)

A new bone dysplasia with intrauterine growth retardation, facial dysmorphism and recurrent bone fractures and autosomal recessive inheritance was described by Temtamy et al. (1974b). Temtamy et al. (1975a) reported the Duane/radial dysplasia syndrome (MIM 607323). Temtamy and Sinbawy (1991) described two sibs, offspring of normal first cousins with congenital cataract, hypertrichosis, mental retardation, and normal chromosomes (CAHMR) (MIM 211770). Temtamy et al. (1991a) delineated a new type of megalocornea/mental retardation (MMR) syndrome (MMR2) (MIM 249310). A new autosomal recessive MCA/MR syndrome with craniofacial dysmorphism absent corpus callosum, ocular colobomas and connective tissue dysplasia was first delineated by Temtamy et al. (1996d) (Temtamy syndrome MIM 218340). It was noted in two sisters and a brother whose parents were normal first cousins. Temtamy et al. (1998c) reported a child with a new syndrome characterized by multiple congenital anomalies, mental retardation, sensorineural deafness, talon cusps of upper central incisors, growth retardation, bilateral symmetrical digital anomalies mainly in the form of preaxial brachydactyly and hyperphalangism of digits I–III (MIM 605282) (Fig. 8.4). Phocomelia and ipsilateral asymmetric crying face was described by Temtamy et al. (1998a).

256

S.A. Temtamy et al.

Ashour et al. (2003) described a patient, the offspring of first cousins with characteristic skin lesions, suggestive of lipoid proteinosis, and confirmed by skin biopsy. The patient had bilateral congenital cataract, myopic fundus, flat facies, pinched nose and fair hair. A paternal cousin and two second cousins were similarly affected.

References Online Mendelian Inheritance in Man, OMIM (TM): McKusick–Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD). World Wide Web URI: http:// www//ncbi-nlm.nih.gov./OMIM/ Abbasy AS (1951) Sickle cell anemia; first case reported from Egypt. Blood 6:555–558 Abd El, Aziz AM (2002) Phenotypic Variability in Sex-reversed Patients; XX Males and XY Females. Egypt J Med Hum Genet 3:99–110 Abdel Ghaffar TY, El Shakankiry H, Maher K, Gaber A, El-Monaiery M, Galal N, Mohamed H (2001) Mitochondrial hepatopathy associated with mitochondrial encephalomyopathy in two sibs: a case report. Egypt J Med Hum Genet 2:127–136 Abdel Hamed MF, Hussein HA, Helmy NA (2007) Detection of steroid sulfatase gene deletion (STS) in Egyptian males with X-linked ichthyosis. Egypt J Med Hum Genet 8:209–217 Abdel Mawgoud SA, El-Bassyouni HT, Afifi HH, Khalipha AG (2007) The role of DHA in amelioration of symptoms of Peroxisome biogenesis Disorders. Res J Med Med Sci 2:5–13 Abdel Salam E, Abdel-Magid IA, Barakat W (1985) Rate of consanguinity in Egyptian population. J Int Coll Pediatr 3:11 Abdel Salam E, Abdel-Maguid IE, Barakat W, Fathy M (1986) National screening of cystic fibrosis in Egypt. In: Proceedings of the International Conference on cystic fibrosis, Cairo, Egypt Abdel Salam E, Temtamy SA, Abdel El Salam M, Meguid NA, Abdel Meguid IE, Gerzawy A (1996) Study of the fragile X-syndrome in Institutes of mentally retarded in Egypt. Egypt J Pediatr 13:155–169 Abdel-Aleem A, Zaki MS (2008) Spinocerebellar ataxia type 2 (SCA2) in an Egyptian family presenting with polyphagia and marked CAG expansion in infancy. J Neurol 255:413–419 Abdel-Aleem A, Kalf-Suske M, Temtamy SA, Abdel Meguid N, Hassan S, Grzesckik KH (2002) Molecular genetic screening of GLI 3 gene in various polydactyly phenotpes in a group of Egyptian patients. Arab J Lab Med 28:131–146 Abdel-Aleem A, Effat L, Salah N, El-Gammal M, Anwar G, Mazen I (2003) The common FGFR3 gene mutation is detected in Egyptian patients with achondroplasia phenotype. Med J Cairo Univ 71:183–187 Abdel-Aleem AK, Abdel Salam GMH, Kayed HF, Zaki MS (2006) C677T polymorphism of the 5, 10-Methylenene tetrahydrofolate reductase (MTHFR) gene as a risk factor of neural tube defects among Egyptian families. Egypt J Med Hum Genet 7:139–154 Abdel-Aleem A, Zaki MS, Abdel Salam GMH, Shehab MI (2007) Novel truncating mutation in MECP2 gene in a sporadic case with typical Rett syndrome. JAC 18:61–66 Abdel-Ghaffar TY, Fateen E, Zaki I, Abou El-Einein A, Rakha O, El-Monaiery MS, Hassanein BM, Kamel MA (1998) Role of alpha one antitrypsin deficiency and hereditary tyrosinemia type I in liver diseases in Egyptian children. Sci J Al-Azhar Med Fac (Girls) 19:1110–1123 Abdelrazik N (2007) Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children’s Hospital experience. Hematology 12:577–585 Abdelrazik N, Ghanem H (2007) Failure of puberty in Egyptian beta thalassemic patients: experience in northeast region - Dakahlia province. Hematology 12:449–456


257

Abdelrazik N, Rashad H, Selim T, Tharwat L (2007a) Coagulation disorders and inhibitors of coagulation in children from Mansoura, Egypt. Hematology 12:309–314 Abdelrazik N, Reda M, El-Ziny M, Rabea H (2007b) Evaluation of bone mineral density in children with hemophilia: Mansoura University children hospital (MUCH) experience, Mansoura, Egypt. Hematology 12:431–437 Abdel-Salam GM, Zaki MS (2004) Hallervorden–Spatz syndrome. Variable imaging findings. Neurosciences 9:447–450 Abdel-Salam GM, Zaki MS, Lebon P, Meguid NA (2004a) Aicardi-Goutie`res syndrome: clinical and neuroradiological findings of 10 new cases. Acta Paediatr 93:929–936 Abdel-Salam GMH, Ashour AM, El-Essawy R, Kayed HF, El-Badry TH, El-Shazly N (2004b) Anophthalmi/Microphthalmia: clinical, ophthalmological and imaging findings. Med J Cairo Univ 72:427–441 Abdel-Salam GM, Shehab M, Zaki MS (2006) Isolated Dandy–Walker malformation associated with brain stem dysgenesis in male sibs. Brain Dev 28:529–533 Abdel-Salam GM, Hassan NA, Kayed HF, Aligianis IA (2007a) Phenotypic variability in Micro syndrome: report of new cases. Genet Couns 18:423–435 Abdel-Salam GMH, Afifi HH, Zaki MS, Aglan MS, Hegazy I, Torky A, Abdulla KH, Tantawy S, Issa MY, Micheal M, Kamal RM, El-Nekhely I, Temtamy SA (2007b) Congenital anomalies in Giza, Egypt: a cross-sectional study. In: The 5th Meeting of the African Society of Human Genetics in conjunction with the 1st Annual meeting of the Division of Human Genetics and Genome Research Division and The National Society of Human Genetics, NRC, Cairo, Egypt Abdullah NM, Temtamy SA, Fateen EM, Esmat AY, Abdel Salam RM (1994) Screening for biotinidase deficiency in Egyptian neonates and patients with neurological disorders. Arab J Lab Med 21:175–193 Aboul-Ezz EHA, Hilal E, El-Din GAS, Temtamy SA, Ismail SA, Nassar AM (1988a) Oral ultrastructure of xeroderma pigmentosa and Sjogren Larsson syndrome. Afr J Dermatol 1:15–26 Aboul-Ezz EHA, Hilal E, El-Din GAS, Temtamy SA, Nassar AH, Ismail SR (1988b) Oral and ultrastructural studies of the gingiva of a patient with glycogen storage disease. Bull NRC Egypt 13:273–284 Afifi HH, Aglan MS (2002) Anthropometric and Photoanthropometric analysis of males with Fragile X syndrome. JAC 13:447–464 Afifi HH, El-Bassyouni HT (2005) Mandibuloacral dysplasia: a report of two Egyptian cases. Genet Couns 16:353–362 Afifi HH, Mostafa MI, Zaki MS (2003) Cranioectodermal dysplasia: two new Egyptian cases with expansion of the phenotype. JAC 14:145–158 Afifi HH, Zaki MS, El-Kamah GY, El-Darouti M (2007) Elejalde syndrome: clinical and histopathological findings in an Egyptian male. Genet Couns 18:179–188 Aglan MS (2002) Facial photoanthropometry: quantification of dysmorphic features. Gaz Egypt Paed 50:383–397 Aglan MS, Afifi HH, El-Kotoury A, Ashour AM (2003) Noonan and Cardiofaciocutaneous syndromes: clinical evaluation of overlapping manifestations. JAC 14:499–513 Aglan MS, Shehab M, El-Badry TH (2004) Genetic studies of the oculo-auriculo-vertebral spectrum. JAC 15:67–90 Aglan MS, Abdel-Aleem AK, EL-Katoury AIS, Hafez MH, Saleem SN, Otaify GA, Temtamy SA (2009) Clinical, anthropometric, radiological and molecular characteristics of Egyptian achondroplasia patients. Egypt J Med Hum Genet 10:13–25 Al-Alami JR, Tayeh MK, Najib DA, Abu-Rubaiha ZA, Majeed HA, Al-Khateeb MS, El-Shanti HI (2003) Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Med J 24:1055–1059 Al-Anssary MK (1995) A genetic study of congenital malformations in a sample of newborns in Shatby University Maternity Hospital, Alexandria. University of Alexandria, Egypt

258

S.A. Temtamy et al.

Al-Daraji WI, Al-Mahmoud RM, Ilyas M (2008) Gastric changes following colchicine therapy in patients with FMF. Dig Dis Sci 53:2079–2082 Ali BR, Jeffery S, Patel N, Tinworth LE, Meguid N, Patton MA, Afzal AR (2007) Novel Robinow syndrome causing mutations in the proximal region of the frizzled-like domain of ROR2 are retained in the endoplasmic reticulum. Hum Genet 122:389–395 Ashour AM, El-Badry TH (2004) Comparison between isolated ectrodactyly and split hand/split foot as a part of syndromes: clinical and orodental studies. Egypt J Med Hum Genet 5:79–96 Ashour AM, Temtamy SA, El-Darouti M (2003) A probable new syndrome of lipoid proteinosis, congenital cataract and characteristic facies. Egypt J Med Hum Genet 4:27–33 Badawy IH, El-Bassyouni HT, Ashour AM, Khalifa AG, Fateen EM (2003) Galactosemia: clinical and nutritional study. Egypt Med J NRC 3:135–148 Badr El-Din MK (1960) A familial convulsive disorder with an unusual onset during intrauterine life, a case report. J Pediatr 56:655–657 Bakr A, Yehia S, El-Ghannam D, Hammad A, Ragab M, Sarhan A, Al-Husseni F, Al-Morsy Z (2008) NPHS2 mutations. Indian J Pediatr 75:135–138 Barrada Y, Guinena S, Abd-El-Naby TY (1954) Congenital and familial cerebro-cerebellar diplegia. Gaz Egypt Pediatr Assoc 11:315 Blacksin MF, Pletcher BA, David M (1998) Osteogenesis imperfecta with joint contractures: Bruck syndrome. Pediatr Radiol 28:117–119 Bonomi M, Proverbio MC, Weber G, Chiumello G, Beck-Peccoz P, Persani L (2001) Hyperplastic pituitary gland, high serum glycoprotein hormone alpha-subunit, and variable circulating thyrotropin (TSH) levels as hallmark of central hypothyroidism due to mutations of the TSH beta gene. J Clin Endocrinol Metab 86:1600–1604 Brancati F, Travaglini L, Zablocka D, Boltshauser E, Accorsi P, Montagna G, Silhavy JL, Barrano G, Bertini E, Emma F, Rigoli L, International JSRD Study Group, Dallapiccola B, Gleeson JG, Valente EM, Collaborators (113) (2008) RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders. Clin Genet 74:164–170 Craig JE, Barnetson R, Weatherall DJ, Thein SL (1993) Rapid detection of a 13.4-kb deletion causing delta beta thalassemia in an Egyptian family by polymerase chain reaction. Blood 81:861–863 Dardir AAM (2000) Clinical, genetic and environmental studies in birth defects. Ph.D. Thesis in Childhood Studies, Ain-Shams University, Cairo, Egypt De Bellis A, Quigley CA, Cariello NF, El-Awady MK, Sar M, Lane MV, Wilson EM, French FS (1992) Single base mutations in the human androgen receptor gene causing complete androgen insensitivity: rapid detection by a modified denaturing gradient gel electrophoresis technique. Mol Endocrinol 6:1909–1920 De Bellis A, Quigley CA, Marschke KB, El-Awady MK, Lane MV, Smith EP, Sar M, Wilson EM, French FS (1994) Characterization of mutant androgen receptors causing partial androgen insensitivity syndrome. J Clin Endocrinol Metab 78:513–522 Effat L, Kuzmin A, Goltsov N, Kasem N, Abdel Meguid N, Kotb S, Temtamy SA, Rushdy S, Woo SLC, Eisensmith RC, El-Awady M (1999) Haplotype and mutations at the PAH Locus in Egyptian families with PKU. Eur J Hum Genet 7:259–262 Effat LK, El-Harouni AA, Amr KS, El-Minisi TI, Abdel Meguid N, El-Awady M (2000) Screening of dystrophin gene deletions in Egyptian patients with DMD/BMD muscular dystrophies. Dis Markers 16:125–129 Effat LK, Essawi ML, Abd El Hamid MS, Hawari N, Gad YZ (2008) Screening for six Mediterranean mutations in 90 Egyptian patients with phenylketonuria. Bratisl Lek Listy 109:17–19 El Sherif RM, Fahmy NA, Nonaka I, Etribi MA (2007) Patterns of dystrophin gene deletion in Egyptian Duchenne/Becker muscular dystrophy patients. Acta Myol 26:145–150 El-Aleem AA, Bohm I, Temtamy SA, El-Awady M, Awadalla M, Schmidtke J, Stuhrmann M (1995) Direct Molecular analysis of the fragile X-Syndrome in a sample of Egyptian and German patients using non-radioactive PCR and Southern blot followed by chemiluminescent detection. Hum Genet 96:577–584


259

El-Ashry MF, Abd El-Aziz MM, Bhattacharya SS (2007) A clinical and molecular genetic study of Egyptian and Saudi Arabian patients with primary congenital glaucoma (PCG). J Glaucoma 16:104–111 El-Awady MK, Temtamy SA, Salam MA, Gad YZ (1987) Familial leydig cell hypoplasia as a cause of male pseudohermaphroditism. Hum Hered 37:36–40 El-Awady MK, El Shater SF, Ragaa E, Atef K, Shaheen IM, Megiud NA (2004) Molecular study on Y chromosome microdeletions in Egyptian males with idiopathic infertility. Asian J Androl 6:53–57 El-Badry T, Temtamy SA (2003) Orodental manifestations of Lenz microphthalmia syndrome. Egypt J Med Hum Genet 4:45–54 El-Bassyouni HT, El-Sayed K (2000) Adenosine Deaminase Deficiency. Sci J Al-Azhar Med Fac (Girls) 21:243–248 El-Bassyouni HT, Afifi HH, El-Awady MK, Meguid NA (1999a) Mucopolysaccharidosis type I: clinical and biochemical study. East Mediterr Health J 5:259–366 El-Bassyouni HT, Fateen EM, Meguid N, Salwa MY (1999b) A three year experience of screening Egyptian patients for inborn errors of metabolism. Egypt J Paed 16:17–24 El-Bassyouni HT, Abdel Mawgoud SA, Khalipha AG (2003) Peroxisomal disorders in Egyptian children: Estimation of very long chain fatty acids by GC/MS. Med J Cairo Univ 71:391–401 El-Bassyouni HT, Abdallah AA, Wafaa Ghoneim W, Hassan I (2004) Clinical and Biochemical Aspects of Mitochondrial Disorders in Egyptian Patients. Inter J Child Neuropsychiatry 1:41–50 El-Bassyouni HT, Ali OSM, Abdel Maksoud S (2005) Clinical and biochemical changes in Egyptian patients with Sjogren Larsson syndrome. Egypt J Med Hum Genet 6:135–144 El-Bassyouni HT, Ashour AM, Afifi M, Ezat A (2008a) Oxidative stress in nonsyndromic sensorineural hearing loss. J Arab Soc Med Res 3:77–81 El-Bassyouni HT, Ezzat A, Ashour AM, Afifi M (2008b) The therapeutic role of vitamin E and C on non syndromic sensorineural hearing loss. J Arab Soc Med Res 3:69–75 El-bastawisy HI, El-Bassyouni HT, Ezzat A, Bassyouni R, Afifi HH, Nowier SR (2005) Primary retinitis pigmentosa: a genetic and biochemical study in Egyptian patients. JAC 6:367–379 El-Beshlawy A (2005) The Egyptian experience with oral iron chelators. Hematology 10(Suppl 1): 174–175 El-Beshlawy A, Kaddah N, Omran N, Moustafa A, Al-Awady A, Abd-El-Azim K (1993) Detection of Thalassemia carrier among Egyptians. Proc EMS Ann Sci Cong 1:329–347 El-Beshlawy A, Ibrahim IY, Rizk S, Eid K (2002) Study of 22 Egyptian patients with DiamondBlackfan anemia, corticosteroids, and cyclosporin therapy results. Pediatrics 110:e44 El-Beshlawy A, Abd El Raouf E, Mostafa F, Talaat M, Isma’eel H, Aoun E, Hoffbrand AV, Taher A (2006a) Diastolic dysfunction and pulmonary hypertension in sickle cell anemia: is there a role for L-carnitine treatment? Acta Haematol 115:91–96 El-Beshlawy A, Ragab L, Youssry I, Yakout K, El-Kiki H, Eid K, Mansour IM, Abd El-Hamid S, Yang M, Mistry PK (2006b) Enzyme replacement therapy and bony changes in Egyptian paediatric Gaucher disease patients. J Inherit Metab Dis 29:92–98 El-Beshlawy A, Manz C, Naja M, Eltagui M, Tarabishi C, Youssry I, Sobh H, Hamdy M, Sharaf I, Mostafa A, Shaker O, Hoffbrand AV, Taher A (2008a) Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. Ann Hematol 87:545–550 El-Beshlawy A, Mostafa A, Youssry I, Gabr H, Mansour IM, El-Tablawy M, Aziz M, Hussein IR (2008b) Correction of aberrant pre-mRNA splicing by antisense oligonucleotides in betaThalassemia Egyptian patients with IVSI-110 mutation. J Pediatr Hematol Oncol 30:281–284 El-Bostany E, Omer IN, Al Jouni S, El-Ghoroury E. 2008. The spectrum of inherited bleeding disorders in pediatrics. In: The 13th Congress of the European Hematology Association, 12–15 June El-Defrawy H, Temtamy SA, Sabry S, Meguid NA, El Beltagi T (1991) Genetic study of primary developmental glaucoma. Bull Ophthalmol Soc Egypt 84:99–106

260

S.A. Temtamy et al.

El-Gammal MA, Eyada OK (2006) Eye anomalies in genetic diseases: study of 20 cases. Egypt J Med Hum Genet 7:23–45 El-Gammal M, Temtamy SA, Shawky R, Awadallah M, Rashed M, Aboul Ezz E, Youssef S, Hindawy A (2001) Amino acid and organic acid disorders in 50 high risk Egyptian children. Egypt J Med Hum Genet 2:15–31 El-Garf A, Mahmoud G, Gheith R, Abd El-Aaty G, Abd El-Aaty H (2003) Camptodactyly, arthropathy, coxa vara, and pericarditis syndrome among Egyptians. J Rheumatol 30:1081–1086 El-Gawhary S, El-Shafie S, Niazi M, Aziz M, El-Beshlawy A (2007) Study of beta-Thalassemia mutations using the polymerase chain reaction-amplification refractory mutation system and direct DNA sequencing techniques in a group of Egyptian Thalassemia patients. Hemoglobin 31:63–69 El-Gholmy A, Hashem N, Khalifa AS, Osman N, Abdel Hamid G (1965) Report of the first family of glycogen storage disease among Egyptians. J Egypt Med Assoc 48:130–41 El-Harouni AA, Abul-Ezz EHA, Fadaly GA, Abdel-Salam M, Hindawy A, Nassar AM, Ismail SR (1994) Neuromuscular disorders in Egyptian children: a clinical, genetic and ultrastructure study. New Egypt J Med 10:532–537 El-Harouni AA, Aboul-Ezz EHA, Meguid NA, Temtamy SA (1996a) Central nervous system involvement in progressive congenital muscular dystrophy (Fukuyama Type?) in two Egyptian Families. Egypt J Pediatr 13:83–92 El-Harouni AA, Aboul-Ezz EHA, Temtamy SA (1996b) Mitochondrial abnormalities in muscle and gingival biopsies from patients with different forms of mitochondrial myopatheis. Egypt I Pediatr 13:1–10 El-Harouni AA, Zaki MS, Fateen EM, Meguid NA (2002) GM2 Gangliosidosis: clinical, genetic and biochemical studies among Egyptian patients. Egypt J Neurol Psych Neurosurg 39:87–97 El-Harouni AA, Amr KS, Effat L, Eassawi ML, Ismail S, Gad YZ, El-Awady MK (2003) The milder phenotype of the dystrophin gene double deletions. Acta Neurol Scand 107:400 Elhawary NA, Kamal TM (2006) A Lymphotoxin-a Gene polymorphism and asthma in Egyptian children. Egypt J Med Hum Genet 7:7–14 Elhawary NA, Shawky RM, Hashem N (2004) Frameshift deletion mechanisms in Egyptian Duchenne and Becker muscular dystrophy families. Mol Cells 18:141–149 El-Hazmi MA, Warsy AS, al-Swailem AR (1995) The frequency of 14 beta-thalassemia mutations in the Arab populations. Hemoglobin 19:353–360 El-Hazmi MA, Warsy AS, Bashir N, Beshlawi A, Hussein JR, Temtamy S, Qubaili F (1999) Haplotypes of beta-globin gene as prognostic factors in sickle cell disease. East Mediterr Health J 5:1154–1158 El-Hefnawi H, Smith SM, Penrose LS (1965) Xeroderma pigmentosum. Its inheritance and relationship to the the ABO blood-group system. Ann Hum Genet 28:273–290 El-Kabbany Z, Elsayed SM, Rashad M, Tareef R, Galal N (2004) Dorfman–Chanarin syndrome in Egypt. Am J Med Genet A 129A:214 El-Kamah Gh, Temtamy SA (2003) Variability of cardiac and limb involvement in the Holt–Oram Syndrome. Kasr El Aini Med J 9:223–230 El-Kamah Gh, El-Beshlawy A, Sobh HA, Hussein IR (2003) Phenotypic scoring in thalassemia intermedia and the impact of underlying molecular defects. Med J Cairo Univ 4:323–327 El-Kamah Gh, El-Bassyouni HT, El-Darouty M (2005) Hypomelanosis of Ito: expanding the spectrum of the disease Clinico-pathological variability. Egypt Med J NRC 6:247–266 el-Khateeb EA (2008) Bullous congenital ichthyosiform erythroderma associated with hypocalcemic vitamin D-resistant rickets. Pediatr Dermatol 25:279–282 El-Mofty AM (1964) Cutaneous porphyria in Egyptians. Br J Dermatol 76:268–277 El-Nasr HS, El-Hefnawi H (1963a) Dyskeratosis congenita with pigmentation, dystrophia unguium and leukoplakia oris. J Egypt Med Assoc 46:1109–1122 El-Nasr HS, El-Hefnawi H (1963b) Congenital alopecia areata in a father inherited in his son. J Egypt Med Assoc 46:1353–1356


261

El-Nekhely I, Namaste S, Shriver EK (2008) Analysis of country situationsurvey: National plan of action. In: The 2nd Conference of the Middle East and North Africa Newborn Screening Initiative, Cairo, Egypt, 12–14 April EL-Rifai WM, Aboul-Ezz EHA, El-Sinbawy AH, El-Sawi A, El-Khayat HA, Temtamy SA (1993) Is deafness a feature of the Coffin–Siris syndrome? J Med Res I 14:263–276 El-Ruby M, Temtamy SA (1997) The De-Lange syndrome with bilateral hemimelia and normal karyotype. Report of a case. Review of limb malformations and genetics of this syndrome. Egypt J Pediatr 14:659–667 El-Ruby MO, Ramzy IM, Meguid NA (1998) Robinow syndrome with unusual manifestations. Egypt J Pediatr 15:13–22 El-Sawy MA, El-Kholy MS, El-Sedfy HH, Sleem MN (2004) Sanjad–Sakati syndrome, case report. Egypt J Med Hum Genet 5:61–66 Elsayed SM (2005) Dyggve–Melchior–Clausen Syndrome: case report. Egypt J Med Hum Genet 6:67–72 Elsayed SM, Rossignol S, Le Bouc Y (2005) Methylation Status of Tthe KCNQ1OT and H19 Genes in Beckwith–Wiedemann Syndrome. Egypt J Med Hum Genet 6:55–61 El-Shafei SS (1999) Cytogenetic and biochemical studies of the mentally handicapped in Alexandria. Bull High Inst Public Health 29:509–518 Elsobky E, Elsayed SM (2004) Extended metabolic screen in sick neonates and children. Egypt J Med Hum Genet 5:1–7 Elsobky E, Elsayed SM, Bahyeldeen L (2005) Cohen syndrome. Egypt J Med Hum Genet 6:207–212 Endo Y, Fateen E, Aoyama Y, Horinishi A, Ebara T, Murase T, Shin YS, Okubo M (2005) Molecular characterization of Egyptian patients with glycogen storage disease type IIIa. J Hum Genet 50:538–542 Essawi M, Nasr H, Mazen I, Gaafar K, Amr K, Hafez M, Gad YZ (2008) Low incidence of androgen receptor mutation among Egyptian children with androgen resistance. Egypt J Med Hum Gen 9:111–119 Essawi M, Gad YZ, El-Rouby O, Temtamy SA, Sabour YA, El-Awady M (1997) Molecular analysis of androgen resistance syndromes in Egyptian patients. Dis Markers 13:99–105 Essawi ML, Effat LK, Shanab GM, Al-Ettribi GM, El-Haronui AA, Karim AM (2007a) Molecular analysis of SMN1 and NAIP genes in Egyptian patients with spinal muscular atrophy. Bratisl Lek Listy 108:133–137 Essawi ML, Sharaf SAE, Effat LK, Hafez MH, Amr KS (2007b) Molecular characterization of 21-hydroxylase deficiency congenital adrenal hyperplasia in Egyptian children: A pilot study. Med J Cairo Univ suppl 75(Suppl 11):55–59 Etriby A, Girgis SM, Ibrahim A, el-Danasoury M, Kahil S (1966) Four male pseudo-hermaphroditic sisters. Dtsch Zahnarztl Z 21:608–614 Ezzat MH, Awwad KS, Shaheen KY, Abdel-Wahab SM, Osman TI (2005) The influence of HLA-DRB1 alleles on polyarticular onset juvenile rheumatoid arthritis susceptibility, severity, and prognosis. Egypt J Med Hum Genet 6:145–171 Fahmy W, Safwat AS, Bissada NK, Curry N, Guirguis N, Clarke HS, Fraig M, Finkbeiner A (2007) Multiple/bilateral renal tumors in patients with Birt–Hogg–Dube´ syndrome. Int Urol Nephrol 39:995–999 Farag HM, Kotb SM, Sweify GA, Fawzy RK, Ismail SR (1999) A diagnostic clinical genetic study of craniofacial dysmorphism. East Mediterr Health J 5:470–477 Farrag AF, Faraghaly WMA, Hoffman EP, Hamed SA (2000) DNA sequence analysis for structure/function and mutation studies in Duchenne/Becker muscular dystrophy patients Abstract). In: Conference of Egypyian Society of Neurology, Psychiatry and Neurosurgery, Assiut, Egypt, 4–6 October Fateen E, Ata H, Oraby A, Gouda A, Temtamy SA, Taodrous G, Dacremont G (1999) The diagnosis of medium chain acyl coenzye A dehydrogenase deficiency (MCADD). Egypt Arab J Lab Med 25:391–406

262

S.A. Temtamy et al.

Fateen E, Schulpis K, El- Sawi M, Tantawy A, Temtamy SA (2000) Determination of dihydopteridine reductase activity in PKU patients with persistent hyperphenylalanemia. Bull Egypt Soc Physiol Sci 20:82–103 Fateen E, El-Shafei S, El-Karaksy H, Mahmoud M, Roshdy S, El-Temtamy S, Shin Y (2004) Diagnosis and management of galactosemia: an Egyptian experience. Bratisl Lek Listy 105:303–309 Fried K, Mundel G (1974) Polysyndactyly and Marfan’s syndrome. J Med Genet 11:141–144 Gaber SA, Mazzola G, Berrino M, Canale L, Cornaglia M, Ghali I, Sergio Curtoni E, Amoroso A (1994) Human leukocyte antigen class II polymorphisms and genetic susceptibility of IDDM in Egyptian children. Diabetes Care 17:1341–1344 Gaber KR, Farag MK, Soliman SE, El-Bassyouni HT, El-Kamah G (2007) Maternal vitamin B12 and the risk of fetal neural tube defects in Egyptian patients. Clin Lab 53:69–75 Gabr M, Hashem N, Hashem M, Fahmi A, Safouh M (1960) Progeria, a pathologic study. J Pediatr 57:70–77 Gad YZ (2002) The I172N mutation in the CYP21 gene as an etiology for salt wasting congenital adrenal hyperplasia. New Egypt J Med 27:243 Gad YZ, Nasr H, Mazen I, Salah N, El-Ridi R (1997) 5a-reductase deficiency in patients with micropenis. J Inherit Metab Dis 20:95 Gad YZ, Mazen l, Lumbroso S, Temtamy SA, Sultan C (2003) A novel point mutation of the androgen receptor (F804L) in an Egyptian newborn with complete androgen insensitivity associated with congenital glaucoma and hypertrophic pyloric stenosis. Clin Genet 63:59 Gad YZ, Khairt R, Mazen I, Osman HG (2007) Detection of the G34R mutation in the 5 alpha reductase 2 gene by allele specific PCR and its linkage to the 89L allele among Egyptian cases. Sex Dev 1:293–296 Galal AH, El-Din AA, Soliman FA (2005) Genetic study of blepharoptosis among Egyptians. Bratisl Lek Listy 106:307–312 German J, Hashem N, El-Hefnawi M, Cleaver JE (1984) Xeroderma pigmentosum in Egypt. III. ABO blood grouping in 22 affected families. Ann Hum Genet 48:61–64 Ghaffer KA, Zahran FM, Fahmy HM, Brown RS (1999) Papillon-Lefe`vre syndrome: neutrophil function in 15 cases fron 4 families in Egypt. Oral Surg Oral Med Oral Pathol Oral Radiol Endoc 88:320–325 Gomaa A (2007) Genetic eye diseases and genetic counselling services in Egypt. Community Eye Health 20:11 Guinena Y, Naby SA, Taher Y (1954) Two cases of compression myelopathy secondary to multiple myelomatosis. J Egypt Med Assoc 37:939–946 Guirguis FK, Sawy ME, Khalil S, Mikhail MM, Zaky A, Helmy MA, Helmy-Khalil S (1985) HLA-A, -B and -C specificities in insulin dependent diabetes mellitus in the Egyptian population. Ann Biol Clin (Paris) 43:233–237 Habib Z, Boö¨k JA (1982) Thalassaemia in the Egyptian population. Hereditas 96:149–58 Habib Z, Boö¨k JA (1983) Consanguinity and incidence of thalassaemia in Egypt. Hereditas 99:215–217 Hafez M, Hashem N (1988) Perinatal screening of neural tube defects among Egyptians. Brain Dysfunct 1:90–102 Hafez M, El-Tahan H, Awadalla M, El-Khayat H, Abdel-Gafar A, Ghoneim M (1983) Consanguineous matings in the Egyptian population. J Med Genet 20:58–60 Hafez M, Mazen I, Ghali I, Sultan C, Lumbroso S (2003) A new mutation of 5-alpha-reductase type 2 (A62E) in a large Egyptian kindred. Horm Res 59:281–284 Hamza RT, Haider M, Teama S, Elhawary NA (2006) Association between polymorphisms within tumor necrosis factor genes and the development of bronchial asthma among Egyptian children. Egypt J Med Hum Genet 7:203–213 Hashem N (1965) The possible role of autosensitization in eczema, as demonstrated by a new experimental technique. J Pediatr 66:248–250 Hashem N (1972) Familial male pseudohermaphroditism. Hum Hered 22:225–238


263

Hashem N (1978) Preventive aspects of genetic morbidity. Volumes I,II,III. In: Proceedings of First International Conference, Cairo, Egypt, 30 March to 4 April Hashem N, Nour A (1969) Studies on glucose-6-phosphate dehydrogenase deficient Egyptian families. J Med Genet 6:150–156 Hashem N, Hirschhorn K, Sedlis E, Holt LE (1963) Infantile eczema. Evidence of autoimmunity to human skin. Lancet 2:269–270 Hashem N, Bootsma D, Keijzer W, Greene A, Coriell L, Thomas G, Cleaver JE (1980) Clinical characteristics, DNA repair, and complementation groups in xeroderma pigmentosum patients from Egypt. Cancer Res 40:13–18 Hashem N, Bosco P, Chiavetta V, Calı` F, Ceratto N, Romano V (1996) Preliminary studies on the molecular basis of hyperphenylalaninemia in Egypt. Hum Genet 98:3–6 Hashishe MM (1992) Genetic study of phenylketonuria. J Egypt Public Health Assoc 67:443–463 Hassan AM, Nassar S, Elbaz R, Hassan AA, Settin A (2005) TNF-a(-308), IL-10(-1082), IL-6(-174) and IL-1Ra(VNTR) Gene polymorphism in leprosy cases from the Nile delta region of Egypt. Egypt J Med Hum Genet 6:1–20 Hatem NL, Tayel S, Emara H (2003) Seckel syndrome: report of two cases. Egypt J Med Hum Genet 4:13–19 Hawass Z, Gad YZ, Ismail S et al. (2010) Ancestry and pathology in King Tutankhamun’s family. JAMA 303:638–647 Helal SI (2000) Genetic study of hereditary ataxias. M.D.Thesis in Neurology, Cairo University, Egypt Heshmat NM, El-Hadidi ES (2006) Soluble CD30 serum levels in atopic dermatitis and bronchial asthma and its relationship with disease severity in pediatric age. Pediatr Allergy Immunol 17:297–303 Hindawy A, Fateen EM, Hagras AM, Bazaraa HM (1999) Biotinidase deficiency in infants with convulsions. Arab J lab Med 25:381–390 Hosny LA, Ramzy MI, Aglan MS, Zaki ME, Meguid NA, Hussien FH (1997) Anthropometry in Egyptian children with Seckel syndrome. Egypt J Pediatr 14:137–148 Hussein L, Yamamah G, Saleh A (1992) Glucose-6-phosphate dehydrogenase deficiency and sulfadimidin acetylation phenotypes in Egyptian oases. Biochem Genet 30:113–121 Hussein IR, Temtamy SA, El-Beshlawy A, Fearon C, Shalaby Z, Vassilopoulos G, Kazazian gr HH (1993) Molecular characterization of B-Thalassemia in Egypt. Hum Mutat 2:48–52 Hussein IR, Temtamy SA, El-Beshlawy A, El-Awady M, El-Kammaly G, Baffico M, Romeo G (1997) Screening for B-thalassemia mutations in Egypt by reverse dot blot hybridization. Egypt J Genet Cytol 26:261–271 Hussein IR, Temtamy SA, El-Harouni A, El-Awady M, Selim LA, Eissawy M (1999) Molecular and genetic studies in DMD and BMD in Egyptian patients. Egypt J Paediatr 16:245–264 Hussein IR, El-Kamah Gh, El-Beshlawy A, Foda B (2003) The effect of -3.7 Alpha-globin gene deletion and Gamma-globin gene polymorphism on clinical variability of beta thalassemia in Egyptian patients. Med J Cairo Univ 4(Suppl II):299–304 Hussein G, Fawzy M, Serafi TE, Ismail EF, Metwally DE, Saber MA, Giansily M, Schved JF, Pissard S, Martinez PA (2007) Rapid detection of beta-Thalassemia alleles in Egypt using naturally or amplified created restriction sites and direct sequencing: a step in disease control. Hemoglobin 31:49–62 Hussein IR, El-Beshlawy A, Salem A, Mosaad R, Zaghloul N, Ragab L, Fayek H, Gaber K, El-Ekiabi M (2008) The use of DNA markers for carrier detection and prenatal diagnosis of haemophilia A in Egyptian families. Haemophilia 14:1082–1087 Hussien FH, Abdalla ZM, Sarry El-Din AM (1990) Achondroplastic old kingdom dwarf from Giza. In: The VIIIth European Meeting of the Paleopathology Association, Cambridge, 19–22 September Ibrahim NA (1997) Genetic syndromes associated with disorders of cranial volume and shape. MSc thesis, Department of Pediatrics, Faculty of Medicine, Cairo University

264

S.A. Temtamy et al.

Ibrahim MA, Temtamy SA, Fateen E, El-Barbary M, Tantawy A (1993) Sweat chloride in children with chronic chest disorders. Bull Egypt Soc Physiol Sci 13:374–389 Ibrahim MAAF, Shaheen MA, Elhawary NA, Abdel-Fattah RA (2005) Glutathione S-Transferase M1 genotype (GSTM1) plus prenatal exposure to smoke as risk factors for pediatric asthma. Egypt J Med Hum Genet 6:183–190 Ismail SR (1977) CNS Malformations: Incidence related to country and season of birth. J Egypt Soc Obstet Gynecol 3:81 Ismail SI, Helmy NA (2000) Silver–Russel syndrome: Clinical and cytogenetic studies in 25 patients. JAC 11:675–684 Ismail SR, Abdel-Rahim N, Hashishe MM, Abdallah EM (1996a) Newborn screening for certain treatable inborn errors of metabolism in Alexandria. J Egypt Public Health Assoc 71:495–520 Ismail SR, Hashine MM, Mourad MI, Abdel Kader M (1996b) Inheritance of non-syndromal genetic deafness. J Egypt Public Health Assoc 71:403–438 Ismail S, Zaki MS, El-Harouni AA (2003) Callosal dysgenesis: clinical and genetic studies in 55 Egyptian patients. Egypt J Neurol Psych Neurosurg 40:1–10 Kamel AM, Mossallam GI, Adel D, Gamil H, Ismail N, Moneer M (2007) HLA-DQA and DQB alleles and predisposition to insulin dependent diabetes mellitus. Egypt J Med Hum Genet 8:69–86 Karim M et al (1970) Congenital foetal malformations in UAR. Ain Shams Med J 21:527–533 Karim MA, Parsian AJ, Cleves MA, Bracey J, Elsayed MS, Elsobky E, Parsian A (2006) A novel mutation in BAP/SIL1 gene causes Marinesco-Sjo¨gren syndrome in an extended pedigree. Clin Genet 70:420–423 Khalifa AS, Fateen E, Tantawy AAG, Monir E, Cooper A (1999) Phenotype-genotype expression of Gaucher disease in Egyptian infants and children. Egypt J Pediatr 16:631–653 Khalifa AS, Ali HH, El-Garf WT (2000) Alpha-mannosidosis: a case report and review of literature. Egypt J Med Hum Genet 1:207–213 Khayat RG, Saxena PC (2000) Consanguinity and its effect on infant and childhood mortality in Egypt. http://www.divx.com. Knoblauch H, Urban M, Tinschert S (1999) Autosomal recessive versus autosomal dominant inheritance in Larsen syndrome: report of two affected sisters. Genet Couns 10:315–320 Ko¨hle C, Mo¨hrle B, M€ unzel PA, Schwab M, Wernet D, Badary OA, Bock KW (2003) Frequent co-occurrence of the TATA box mutation associated with Gilbert’s syndrome (UGT1A1*28) with other polymorphisms of the UDP-glucuronosyltransferase-1 locus (UGT1A6*2 and UGT1A7*3) in Caucasians and Egyptians. Biochem Pharmacol 65:1521–1527 Kozma C (2006) Dwarfs in ancient Egypt. Am J Med Genet A 140:303–311 Lissens W, Mahmoud KZ, El-Gindi E, Abdel-Sattar A, Seneca S, Van Steirteghem A, Liebaers I (2000) Molecular analysis of the cystic fibrosis gene reveals a high frequency of the intron 8 splice variant 5T in Egyptian males with congenital bilateral absence of the vas deferens. Mol Hum Reprod 6:669–670 Lumbroso S, Wagschal A, Bourguet W, Georget V, Mazen I, Servant N, Audran F, Sultan C, Auzou G (2004) A new mutation of the androgen receptor, P817A, causing partial androgen insensitivity syndrome: in vitro and structural analysis. J Mol Endocrinol 32:679–687 Mahmoud SF (1997) Lawrence-Seip syndrome: report of a case from Egypt. Cutis 60:91–3 Mahmoud LA, Ibrahim AA, Ghonem HR, Jouvenceaux A (1987) Human blood groups in Dakahlya, Egypt. Ann Hum Biol 14:487–493 Marin A, Cerutti N, Massa ER (1999) Use of the amplification refractory mutation system (ARMS) in the study of HbS in predynastic Egyptian remains. Boll Soc Ital Biol Sper 75:27–30 Mazen I, Zaki MS (2006) Unusual association of simplified gyral pattern and sparse hair in an Egyptian patient with microcephaly-lymphoedema. Clin Dysmorphol 15:245–247 Mazen I, Gad YZ, El-Awady MK (1996) Intersex disorders among Egyptian patients. JAC 7:607 Mazen I, Hosny LA, Aziz SS, Hammad SA, Shihab MIK, El-Salam MA, Awadalla M, Mohamed AM (2002) Genetic study of obesity in children. Egypt J Med Hum Genet 3:27–41


265

Mazen I, Gad YZ, Hafez M, Sultan C, Lumbroso S (2003a) Molecular analysis of 5a-reductase type 2 gene in eight unrelated Egyptian children with suspected 5a-reductase deficiency: prevalence of the G34R mutation. Clin Endocrinol 58:627 Mazen I, Hafez M, Mamdouh M, Sultan C, Lumbroso S (2003b) A novel mutation of the 5alphareductase type 2 gene in two unrelated Egyptian children with ambiguous genitalia. J Pediatr Endocrinol Metab 16:219–224 Mazen I, Lumbroso S, Abdel Ghaffar S, Salah N, Sultan C (2004) Mutation of the androgen receptor (R840S) in an Egyptian patient with partial androgen insensitivity syndrome: review of the literature on the clinical expression of different R840 substitutions. J Endocrinol Invest 27:57–60 Mazen I, Hiort O, Bassiouny R, El Gammal M (2008) Differential diagnosis of disorders of sex development in Egypt. Horm Res 70:118–123 McCaffrey RP, Awny AW (1970) Glucose- 6-phosphate dehydrogenase deficiency in Egypt: with a note on the methemoglobin reduction test. Blood 36:793–796 Meguid NA (1993) Frontonasal dysplasia, lipoma of the corpus callosum and tetralogy of Fallot. Clin Genet 44:95–977 Meguid NA, Aglan MS (2002) Clinical and anthropometric study in Egyptian children with Robinow Syndrome. Gaz Egypt Paed 50:399–413 Meguid NA, Ashour AM (2001) Holoprosencephaly and split hand/foot: an additional case with this rare association. Clin Dysmorphol 10:277–279 Meguid NA, Temtamy SA (1988) The Carpenter syndrome first report in an Egyptian girl presenting the kleeblattschaedel anomaly and review of literature. Egypt J Pediatr 5:250–541 Meguid NA, Temtamy SA (1991) The Neu–Laxova syndrome in two Egyptian families. Brief clinical report. Am J Med Genet 41:30–31 Meguid NA, Temtamy SA, Afifi HH, Aboul-Ezz EHA (1995) Clinical variability and chromosomal aberrations in EEC syndrome. Egypt J Pediatr 12:315–324 Meguid NA, Afifi HA, Ramzy MI, Hindawy AT, Temtamy SA (1997a) GAPO Syndrome: first Egyptian case with ultrastructural changes in the gingiva. Clin Genet 52:110–115 Meguid NA, El-Harouni A, Afifi HH, Temtamy SA (1997b) An autosomal recessive pterygium syndrome with severe muscular atrophy: Escobar type. JAC 8:81–87 Meguid NA, El-Harouni A, Temtamy SA (1997c) Genetic, therapeutic and immunologic studies of Schwartz-Jampel syndrome in Egypt. JAC 8:355–361 Meguid NA, Dardir AA, Aglan MS, Fateen EM, Rashad MM (2003a) Metachromatic Leukodystrophy: Biochemical and neurophysiologic studies. Egypt J Neurol Psych Neurosurg 40:139–146 Meguid NA, Temtamy SA, Mazen I (2003b) Transposition of external genitalia and associated malformations. Clin Dysmorphol 12:59–62 Meguid N, Abdel-Raouf ER, Dardir A, Mostafa K (2007) Prevalence of fragile X syndrome among school age Egyptian males. World J Pediatr 3(4):271–275 Metwally SS, Mosaad YM, Abdel-Samee ER, El-Gayyar MA, Abdel-Aziz AM, El-Chennawi FA (2004) IL-13 gene expression in patients with atopic dermatitis: relation to IgE level and to disease severity. Egypt J Immunol 11:171–177 Miniawi LK, Salam MA, Temtamy SA, Kamel WA, Hussein FH, Ghali I (1981) The Laurence– Moon–Bardet–Biedl (LMBB) syndrome, clinical and genetic studies of 11 cases. J Egypt Med Assoc 64:35–49 Mohamed MS (1995) An epidemiological study on consanguineous marriage among urban population in Alexandria. J Egypt Public Health Assoc 70:293–305 Mokhtar MM, Abdel-Fattah MM (2001) Consanguinity and advanced maternal age as risk factors for reproductive losses in Alexandria, Egypt. Eur J Epidemiol 17:559–565 Mokhtar MM, Nazmy NA, Mahrous HS (2002) Genetic study of abnormal sexual differentiation in Alexandria, Egypt. Egypt J Med Hum Genet 3:63–76 Mossalam L, El-Khodary AF, Temtamy SA (1974) Waardenburg’s Syndrome in Egypt. Ain Shams Med J 25:43

266

S.A. Temtamy et al.

Mostafa MI, Temtamy SA, El-Gammal MA, Mazen I (2005) Unusual pattern of inheritance and orodental changes in the Ellis–Van Creveld syndrome. Genet Couns 16:75–83 Moustafa MS, Temtamy SA, El-Gammal MY, Abdel-Sayed S, El-Salam MA, El-Baroudy R (1981) Genetic studies of congenital cataract. MetabPediatr Ophthalmol 314:233–244 Moustafa MS, Temtamy SA, El-Gammal M, Abdel-Sayed S, Meguid NA (1989) Genetic studies on retinitis pigmentosa. Bull Ophthalmol Soc Egypt 28:285–293 Naguib ML, Schrijver I, Gardner P, Pique LM, Doss SS, Abu Zekry MA, Aziz M, Nasr SZ (2007) Cystic fibrosis detection in high-risk Egyptian children and CFTR mutation analysis. J Cyst Fibros 6:111–116 Novelletto A, Hafez M, Di Rienzo A, Felicetti L, Deidda G, El-Morsi Z, al-Tonbary Y, El-Ziny M, Abd-El-Gelil N, Terrenato L (1989) Frequency and molecular types of deletional alphathalassemia in Egypt. Hum Genet 81:211–213 Novelletto A, Hafez M, Deidda G, Di Rienzo A, Felicetti L, El-Tahan H, El-Morsi Z, El-Ziny M, Al-Tonbary Y, Sittien A et al (1990) Molecular characterization of beta-thalassemia mutations in Egypt. Hum Genet 85:272–274 Omar A, Abdel Karim E, Gendy WE, Marzouk I, Wagdy M (2005) Molecular basis of betathalassemia in Alexandria. Egypt J Immunol 12:15–24 Pals-Rylaarsdam R, Liu G, Brickman W, Duranteau L, Monroe J, El-Awady MK, Gad YZ, Shenker A (2005) A novel double mutation in the luteinizing hormone receptor in a kindred with familial Leydig cell hypoplasia and male pseudohermaphroditism. Endocr Res 31:307–323 Pronk JC, Gibrson RA, Savoia A, Wyker M, Morgan NV, Melchionda S, Ford D, Temtamy SA, Ortega JJ, Jansen S, Havenga C, Cohn RJ, de Ravel TJ, Roberts I, Westerveld A, Eastron DF, Joenje H, Mathew CG, Arwert F (1995) Localization of the Fanconi anaemia complementation group A gene to chromosome. Nat Genet 11:338–340 Pusch CM, Broghammer M, Nicholson GJ, Nerlich AG, Zink A, Kennerknecht I, Bachmann L, Blin N (2004) PCR-induced sequence alterations hamper the typing of prehistoric bone samples for diagnostic achondroplasia mutations. Mol Biol Evol 21:2005–2011 Rady MS, Baffico M, Khalifa AS, Heshmat NM, Sciaratta El-Moselhy S, GV HIR, Temtamy SA, Romeo G (1997) Identification of Mediterranean B-Thalassemia mutations by reverse dot blot in Italians and Egyptians. Hemoglobin 21:59–69 Ramzy MI, El-Gammal MA (2004) Juvenile hyaline fibromatosis (Murray-puretic–Drescher syndrome) oral, systemic and histopathological findings in an Egyptian girl. Egypt J Med Hum Genet 5:69–78 Rashad M, El-Fiky SM (2007) Prevalence of renal anomalies in children with auricular malformations among attendance of genetics clinic in Ain Shams University. Egypt J Med Hum Genet 8:191–197 Rogers GR, Rizzo WB, Zlotogorski A, Hashem N, Lee M, Compton JG, Bale SJ (1995) Genetic homogeneity in Sjo¨gren–Larsson syndrome: linkage to chromosome 17p in families of different non-Swedish ethnic origins. Am J Hum Genet 57:1123–1129 Russell LJ, DiGiovanna JJ, Rogers GR, Steinert PM, Hashem N, Compton JG, Bale SJ (1995) Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nat Genet 9:279–283 Salem MSZ, El-Serafy OA (2001) Genetic study of isolated epilepsy among Egyptians. Egypt J Med Hum Genet 2:115–126 Salem MSZ, Rashid HM, Arnaoat HH, Assaf MI (2002) Genetically-determined predisposing factors in psoriasis. Egypt J Med Hum Genet 3:113–125 Sarry El-Din AM (2002) Congenital skeletal anomalies in paleopopulations. Review article. Human Genetics Department, National Research Centre, Cairo Satinoff MI, Wells C (1969) Multiple basal cell naevus syndrome in ancient Egypt. Med Hist 13:294–297 Scheidel W (1997) Brother-sister marriage in Roman Egypt. J Biosoc Sci 29:361–371 Settin A, El-Bendary M, Abo-Al-Kassem R, El Baz R (2006) Molecular analysis of A1AT (S and Z) and HFE (C282Y and H63D) gene mutations in Egyptian cases with HCV liver cirrhosis. J Gastrointestin Liver Dis 15:131–135


267

Settin A, Abdel-Hady H, El-Baz R, Saber I (2007a) Gene polymorphisms of TNF-alpha (-08), IL-10(-1082), IL-6(-174), and IL-1Ra(VNTR) related to susceptibility and severity of rheumatic heart disease. Pediatr Cardiol 28:363–371 Settin A, El-Baz R, Abd Rasool M, El-Khalegy H, El-Sayed O, El-Bendary M, Al-Nagar AS (2007b) Clinical and molecular diagnosis of Familial Mediterranean Fever in Egyptian children. J Gastrointestin Liver Dis 16:141–145 Shatla H, El-Shakankiry HM, Fateen E, Ahmed NS, Mustafa HA (1999) Prevalence of GM2 gangliosidosis among cases with early onset seizures and psychomotor retardation. Bull Egypt Soc Physiol Sci 19:249–273 Shawky RM, Elsayed SM (2000) Melnick-needles osteodystrophy with amenorrhea: the first Egyptian patient. Egypt J Med Hum Genet 1:163–171 Shawky RM, Elsayed SM (2004) Gaucher disease with pulmonary, cardiac and renal involvement: Improvement on fractionation of Cerezyme dose. Egypt J Med Hum Genet 5:55–59 Shawky RM, Elsayed SM (2005) Hypomelanosis of Ito associated with neuroblastoma. Egypt J Med Hum Genet 6:73–79 Shawky RM, Sadik DI (2007) Frontofacionasal dysplasia: another observation. Egypt J Med Hum Genet 8:225–227 Shawky RM, El-Sawy MA, Nowier SR (2000a) Study of Egyptian patients with multiple congenital anomalies and mental retardation. Egypt J Med Hum Genet 1:215–234 Shawky RM, El-Sedfy HH, Abd El-Hamid H (2000b) Phenotypic expression of hyperphenylalaninemia syndromes among Egyptians. Egypt J Med Hum Genet 1:1235–248 Shawky RM, Mokhtar GM, Abdel Hay A, Agaiby E (2000c) Some genetics aspects of congenital hydrocephalus. Egypt J Med Hum Genet 1:197–205 Shawky RM, Salem MSZ, Rifaat MM, Ali MA, Zico OAO, Abd Al-Azeem AA (2000d) Molecular mutations of retinoblastoma gene among Egyptian children. Egypt J Med Hum Genet 1:83–90 Shawky RM, Abd-El-Aleem KM, El-Sobki ES, El-Safoury HM, Khalifa OA (2001a) Detection of SRY gene in Egyptian children with ambiguous genitalia using FISH technique. Egypt J Med Hum Genet 2:1–14 Shawky RM, El-Aleem KA, Rifaat MM, Moustafa A (2001b) Molecular diagnosis of spinal muscular atrophy in Egyptians. East Mediterr Health J 7:229–237 Shawky RM, Riad MS, Osman HM, Bahaa NM (2001c) Screening for some inborn errors of amino acid metabolism which impair mental function. Egypt J Med Hum Genet 2:71–91 Shawky RM, Abdel Fattah SM, Abdelaziz EA, El-Sayed NS (2002a) Genetic study of Egyptian children with craniosynostosis. Egypt J Med Hum Genet 3(25–44):2002 Shawky RM, El-Aleem KA, Rifaat MM, el-Naggar RL, Marzouk GM (2002b) Rapid carrier screening using short tandem repeats in the phenylalanine hydroxylase gene. East Mediterr Health J 8:49–54 Shawky RM, Salem MSZ, Rifaat MM, Alazeem AA (2002c) Retinoblastoma gene mutations among Egyptian patients. Egypt J Med Hum Genet 3:101–111 Shawky RM, Zaky EA, EI-Sayed SM, Aly MR, El-Zawahry KA, Sedhom K (2002d) Juvenile hyaline fibromatosis. a case report. Egypt J Med Hum Genet 3:85–93 Shawky RM, Abd El Khalek KA, Abd-El Fattah SM, Moselhi SE, Rifaat MM, Kamal TM, Aly MR, EI-Garf WT (2003a) Biochemical and molecular study of Cystic Fibrosis among high risk group patients with chronic lung disease. Egypt J Med Hum Genet 4:97–111 Shawky RM, Khalifa AS, Elkholy MS, Refaat MM, Kamal TM, Elkholy SA, Hughes A, McGibbon D (2003b) Genotype phenotype correlation and hormone profile in sickle cell anaemia. Egypt J Med Hum Genet 4:63–75 Shawky RM, Khalifa AS, Mokhtar GM, Rifaat MM, Kamal TM, Elhawary NA, Elnewhy R (2003c) Prenatal diagnosis of b-thalassemia via automated DHPLC analysis of fetal cells in maternal circulation. Egypt J Med Hum Genet 4:1–12 Shawky RM, Zaky EA, Bahy-Eldeen L, Elsayed SM (2003d) Fibrodysplasia ossificans progressiva: a case report. Egypt J Med Hum Genet 4:43–47 Shawky RM, Sayed NS, Elhawary NA (2004) Mutations in transglutaminase 1 gene in autosomal recessive congenital ichthyosis in Egyptian families. Dis Markers 20:3252–332

268

S.A. Temtamy et al.

Shawky RM, Elsedfy HH, Mouharam W (2005) Martsolf syndrome. Egypt J Med Hum Genet 6:213–216 Shawky RM, Eldin LB, Helal SA, Eltonbary KY (2006a) Study of muscle biopsy in children with muscular dystrophy. Egypt J Med Hum Genet 7:215–225 Shawky RM, Elhawary NA, Elsedafy HH, Elsayed SM, Abdel-Hamid H (2006b) Updated listing of mutation map at the human phenylalanine locus among Egyptian population. Egypt J Med Hum Genet 7:15–22 Shawky RM, Elhawary NA, Salem MSZ, Elgebaly HH, El-Sayed NS (2006c) Gene analysis and carrier detection of Duchenne muscle dystrophy in Egyptian families. Egypt J Med Hum Genet 7:227–240 Shawky RM, Elsobky E, Elsayed SM, Mohram W (2006d) Femoral Hypoplasia–Unusual Facies Syndrome: femoral facial Syndrome (FFS): a recessive severe skeletal form. Egypt J Med Hum Genet 7:251–254 Shawky RM, Fateen EM, Zaghloul MS, Salem AA (2006e) Prevalence of some lipidosis among Egyptian children with neurodegenerative disorders. Egypt J Med Hum Genet 7:47–73 Shawky RM, El-Sedfy HH, Mahmoud AO, Rashad M, Bahaa Eldin EM (2007a) Study of amino acid disorders among a high risk group of Egyptian infants and children. Egypt J Med Hum Genet 8:173–189 Shawky RM, Talaat IM, El-Hakin IZ, Elsayed SM (2007b) MURCS association: a case report. Egypt J Med Hum Genet 8:219–224 Sinbawy AH, Temtamy SA, Meguid NA (1988) Familial ocular albinism with heterozygous expression. Bull Ophthalmol Soc Egypt 81:341–345 Snoeckx RL, Hassan DM, Kamal NM, Van Den Bogaert K, Van Camp G (2005) Mutation analysis of the GJB2 (connexin 26) gene in Egypt. Hum Mutat 26:60–61 Sourour EM (1987) A clinical genetic study of Robinow syndrome. M.Sc. Thesis in Human Genetics, Medical Research Institute, Alexandria University Stenn FF, Milgram JW, Lee SL, Weigand RJ, Veis A (1977) Biochemical identification of homogentisic acid pigment in an ochronotic Egyptian mummy. Science 197:566–568 Stevenson AC, Johnston HA, Stewart MIP, Golding DR (1966) Congenital malformations. A report of a series of consecutive births in 24 countries. WHO, Geneve, Switzerland Sullivan R (1995) A brief journey into medical care and disease in Ancient Egypt. J R Soc Med 88:141–145 Tainmont J (2007) History of osteogenesis imperfecta or brittle bone disease: a few stops on a road 3000 years long. B-ENT 3:157–173 Tawfik S, Azim MA, Peterson P, Donaldson MD (2005) Autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy presenting with severe keratopathy in an Egyptian patient with a homozygous R139X mutation. Horm Res 64:96–99 Temtamy SA (1966) Genetic factors in hand malformations. Ph.D Thesis in Human Genetics, The Johns Hopkins University, USA Temtamy SA (1982) Classification of hand malformations as isolated defects: an overview. J Genet Hum 30:281–290 Temtamy SA (1998) Prevention of genetic diseases and malformations in newborns. Minist Health Popul Sci J 2:22–27 Temtamy SA, Aglan MS (2008) Brachydactyly. Review article. Orphanet J Rare Dis 3:15 Temtamy SA, Loutfy A (1970) Some genetic and surgical aspects of cleft lip-cleft palate problem in Egypt. Cleft Palate J 7:578 Temtamy SA, McKusick VA (1978) The genetics of hand malformations. Alan R Liss, NewYork, for the National Foundation-March of Dimes, BD:OAS XIV 3, reprinted in 1987 and in 2001 Temtamy SA, Meguid NA (1989) Hypogenitalism in the acrocallosal syndrome. Am J Med Genet 32:301–305 Temtamy SA, Sanad MH (2001) Variable autistic features in Rubinstein–Taybi syndrome. New Egypt Med J 24:60–66


269

Temtamy SA, Shalash B (1974) Genetic heterogeneity of congenital cataract, microphthalmia and nystagmus. Birth Defects Orig Art Ser Urinary System and Others X:292 Temtamy SA, Shalash B (1975) Laurence–Moon–Bardet–Biedel: syndrome in sibs. Birth Defect: Orig Art Ser Malformation Syndromes XI:202 Temtamy SA, Shoukry SA (1975) Cornelia de Lange syndrome in and Egyptian Child. Birth Defects Orig Art Ser Malformation Syndr XI:362 Temtamy SA, Sinbawy AH (1991) Cataract, hirsuitism and mental retardation (CAHMR). A new autosomal recessive syndrome. Am J Med Genet 41:432–434 Temtamy SA, El-Meligy MR, Badrawy HS, Abdel Meguid MS, Safwat HM (1974a) Metaphyseal dysplasia, anetoderma and optic atrophy, an autosomal recessive syndrome. Birth Defects Orig Art Ser Skeletal Dysplasias X(12):61 Temtamy SA, El-Meligy MR, Osman N, Abdel Meguid MS, Salem S (1974b) A new bone dysplasia with autosomal recessive inheritance. Med Genet Today, Birth Defects Orig Art Ser X(10):165 Temtamy SA, El-Meligy MR, Salem S, Osman N (1974c) Hyperphosphatasia in an Egyptian child. Skeletal Dysplasias Birth Defects Orig Art Ser X(12):292 Temtamy SA, Loutfy AA, Hetta F, Raafat M, Attiya OM, Boulos SY (1974d) Familial male hermaphroditism. Urinary system and others. Birth Defects Orig Art Ser X:243 Temtamy SA, Shoukry AS, Ghaly L, El-Meligy B, Boulos SY (1975a) The Duane/radial dysplasia syndrome: an autosomal dominant disorder. New chromosomal and malformation syndromes. Birth Defects Orig Art Ser XI:344 Temtamy SA, Shoukry AS, Raafat M, Mihareb S (1975b) Marden–Walker syndrome. Evidence for autosomal recessive inheritance. Birth Defects Orig Art Ser Malformation Syndromes XI:104 Temtamy SA, Shoukry SA, El-Meligy MR (1975c) Pfeiffer Syndrome. Birth Defects Orig Art Ser Limb Malformation X:229 Temtamy SA, Shoukry SA, Fayad I, El-Meligy MR (1975d) Limb malformations in the colver-leaf skull anomaly. Birth Defects Orig Art Ser Malformation Syndr XI:247 Temtamy SA, Abdel-Hamid G, Salam MA, El-Badrawy F, Hussein FH, El-Miniawy LK, German J, Abul-Dahab Y (1981a) Genetic studies in rare limb malformations in Egyptian children. Med J Cairo Univ 49:71–86 Temtamy SA, Hussein FH, El Miniawi LK (1981b) The Waardenburg Syndrome in Egypt Revisited. In: Huber A, Klein D (eds) Neurogenetics and Neuroophtalmology, vol 5, Developments in neurology. Elsevier, Amsterdam, pp 407–422 Temtamy SA, Abdelsalam M, Meguid NA, Ismail SR (1987) Chromosomal aberrations in patients with multiple congenital anomalies and mental retardation. JMRI 8(Suppl):211–232 Temtamy SA, El-Salam MA, Meguid NA, Gerzawy AS, Hendawi A (1988) Fragile X-linked mental retardation in Egyptian males. Egypt J Pediatr 5:251–267 Temtamy SA, El-Salam MA, Aboul-Ezz EHA, Meguid NA, Zaki ME (1989a) New observations on the Laurence–Moon and Bardet–Biedl Syndromes. New Egypt J Med 3:715–720 Temtamy SA, Ismail SR, Nassar AM, Aboul-Ezz EHA (1989b) Orodental ultrasturcture studies of pulp and gingiva in two sibs with osteogenesis imperfecta. J Med Res Inst, Alexandria University 10:281–290 Temtamy SA, Youssef N, El-Sawi M (1989c) Sjogren-Larsson Syndrome in Egypt. Clinical and Genetic Study of 12 Cases. Egypt J Pediatr 6:125–138 Temtamy SA, El-Awady MK, Barakat MMA, Kheir El-Din AA, Fahim AT, Abdel-Hamid S (1990a) Screening for some inborn errors of metabolism causing mental retardation in Egyptians. New Egypt J Med 4:621–627 Temtamy SA, Salam MA, Zaki MA, Meguid NA, Aboul-Ezz E (1990b) Rubinstein–Taybi syndrome in Egyptians. J Med Res Inst 11:55–72 Temtamy SA, Abdel-Hamid J, Hussein F, Abdel-Salam N, Meguid NA, Aboul-Ezz EHA, Zaki ME (1991a) Megalocornea mental retardation syndrome (MMR): Delineation of a new entity (MMR-2) (Abstract). Am J Hum Genet Suppl 49:125, Proc. of 8th International Cong. of Hum. Genet.Washinghon DC, USA

270

S.A. Temtamy et al.

Temtamy SA, Meguid NA, Aboul-Ezz EHA (1991b) Genetic heterogeneity and phenotypic variability in Hallermann–Strief syndrome. Egypt J Pediatr 8:323–332 Temtamy SA, Salam AM, Hussein FH, Meguid NA, El-Gindy E (1991c) Clinical, biochemical and cytogenetic studies of mental retardation in Egyptian children. J Pub Health Assoc IXVI (Suppl):189–199 Temtamy SA, El-Sawy MA, Abul-Ezz EHA, El-Din MK, Fateen EM, Meguid NA, Samy G, Dacremont SC, Leroy JG, El-Bassyouni HT (1993) Screening for peroxisomal and sialic acid disorders in progressive neurologic disorders among Egyptian children. Appl Endocrinol Egypt 11:17–44 Temtamy SA, Aboul Ezz EHA, Sinbawy AH, Mouris AL, Meguid NA, El Sawi M (1994a) Orodental, ear and eye anomalies in Egyptian Brachman de Lange syndrome cases. J Egypt Health Assoc IXIX(3, 4):164–184 Temtamy SA, Fateen EM, Wahba S (1994b) A fluorometric leucocyte B- glucosidase assay for Gaucher’s disease in Egyptian children. Bull Egypt Soc Physiolsci 14:376–388 Temtamy SA, Kandil MR, Demerdash AM, Hassan WA, Meguid NA, Afifi HH (1994c) An epidemiological/genetic study of mental subnormality in Assiut governorate. Egypt Clin Genet 46:347–351 Temtamy SA, Aboul-Ezz EHA, Afifi HH, Kamel AK, Abdel Aleem A (1996a) Phenotypic overlap between Kabuki make up syndrome and Prader–Willi like phenotype of the fragile X-syndrome. Cairo Dent J 12:69–75 Temtamy SA, Aboul-Ezz EHA, Meguid NA (1996b) A Second family with oculotrichodysplasia syndrome (OTD) confirming the syndrome and its autosomal recessive inheritance. Egypt J Pediatr 13:105–118 Temtamy SA, Meguid NA, Mahmoud A, Hosny H, Shawky AM, Saad M (1996c) COFS Syndrome with familial 1, 16 tanslocation. Clin Genet 50:240–243 Temtamy SA, Salam MA, Aboul-Ezz EHA, Hussein HA, Helmy SAH, Shalash BA (1996d) New autosomal recessive multiple congenital abnormalities/mental retardation syndrome with craniofacial dysmorphism absent corpus callosum, iris colobomas and connective tissue dysplasia. Clin Dysomorphol 5:23–240 Temtamy SA et al (1997) New DNA techniques for identification of mutations in the beta globin gene in Egyptian Beta Thalassemia patients. Terminal Evaluation Report ICGEB collaborative research program. ICGEB ref. #: CRP/EGY 93-01. Principle investigator, Prof. Dr. Samia A Temtamy Temtamy SA, Mazen I, Hindawy A (1998a) The association of ipsilateral phocomelia and asymmetric crying facies. A mere association or a new syndrome? JAC 9:443–451 Temtamy SA, Meguid N, Mazen I, Ismail SR, Kassem NS, Bassiouni R (1998b) A genetic epidemiological study of malformations at birth in Egypt. East Mediterr Health J 4:252–259 Temtamy SA, Meguid NA, Ismail SA, Ramzy MI (1998c) A new multiple congenital anomaly, mental retardation syndrome with preaxial brachydactyly, hyperphalangism, deafness and orodental anomalies. Clin Dysmorphol 7:249–255 Temtamy SA, Meguid NA, Ismail SI, El Henawy MS, Kamel AK, Zaki MS (1998d) Genetic studies and computed cranial tomography in microcephaly. Egypt J Pediatr 15:1–12 Temtamy SA, Al-Diwany KM, Mohamed AM, Meguid NA, Badran N, El-Sayed L, Abu Hashem SH (2000a) Genetic counselling in children with limb malformations. Egypt J Med Hum Genet 1:55–72 Temtamy SA, Ismail SI, Meguid NA (2000b) Lenz microphthalmia syndrome: three additional cases with rare associated anomalies. Genet Couns 11:147–152 Temtamy SA, Nemat AM, Ramzy MI, Fateen E, Meguid NA, Abul-Ezz EHA (2000c) Ultrastructure of gingival biopsy in lysosomal storage disorders. Cairo Dent J 16:287–295 Temtamy SA, Aglan MS, Nemat A, Eid M (2003a) Expanding the phenotypic spectrum of the Baller–Gerold Syndrome. Genet Couns 14:299–312 Temtamy SA, El-Ruby MO, Nemat AH (2003b) Phenotypic variations versus genetic differences in the oral-facial-digital syndromes. Egypt J Med Hum Genet 4:79–96


271

Temtamy SA, Ismail SI, Nemat A (2003c) Mild facial dyspmorphism and qausidominant in heritance in Cenani–Lenz Syndrome. Clin Dysmorphol 12:77–85 Temtamy SA, Aglan MS, Ashour A, El Badry T, Helmy N, Hussien HA (2004a) Genetic studies of congenital contractures of limbs. Egypt J Med Hum Genet 5:1–58 Temtamy SA, El Kamah Gh, Ismail S, Mazen I, Darouti M (2004b) Report of four Egytian cases representing two new rare types of Ehlers–Danlos Syndrome. JAC 15:91–111 Temtamy SA, Ismail S, El-Kamah Gh, El-Bassyouni HT, Kotouri AIS, Ramzy M, Zaki ME (2004c) The phenomenon of multiple genetic disorders in the same individual or sibship Relevance to consanguinity. Med J Cairo Univ 27(Suppl II):157–173 Temtamy SA, Abdel-Hady SH, Salem FA, El-Ruby MO, Aglan MS, Tomarek RH, Al-Awady H (2006a) Genetic studies of limb reduction defects. Egypt J Med Hum Genet 7:155–192 Temtamy SA, Aglan MS, Ashour AM, Ramzy MI, Hosny LA, Mostafa MI (2006b) 3-M syndrome: a report of three Egyptian cases with review of the literature. Clin Dysmorphol 15:55–64 Temtamy SA, Ismail S, Helmy NI (2006c) Roberts syndrome: a study of 4 new Egyptian patients with comparison of clinical and cytogenetic studies. Genet Couns 17(1–13):2006 Temtamy SA, Minnikk MM, Abdel-Salam GMH, Hassan NA, Ala-Kokko L, Afifi HH (2006d) Oto-Spondylo-Megaepiphyseal Dysplasia (OSMED): Clinical and radiological findings in Egyptian sibs homozygous for premature stop codon mutation in the COL11A2 gene. Am J Med Genet 140:1189–1195 Temtamy SA, Aglan MS, Aboul-Ezz EHA, Ashour AM, El-badry TH (2007a) A study of 319 Egyptian cases with limb and skeletal Malformations. In: The 5th Meeting of the African Society of Human Genetics in conjunction with the 1st Annual meeting of the Division of Human Genetics and Genome Research Division and The National Society of Human Genetics, NRC, Cairo, Egypt Temtamy SA, Aglan MS, Ashour AM, Zaki MS (2007b) Adams–Oliver Syndrome: further evidence of an autosomal recessive variant. Clin Dysmorphol 16:141–149 Temtamy SA, Aglan MS, El-Gammal MA, Hosny LA, Ashour AM, El-Badry TH, Awad SA, Fateen E (2007c) Genetic heterogeneity in spondylo-epi-metaphyseal dysplasias: a clinical and radiological study. Egypt J Med Hum Genet 8:147–172 Temtamy SA, Ismail SR, El-Beshlawy AM, Mohamed AM, Kotb SM, Eid MM (2007d) Fanconi anemia: cytogenetic and clinical studies on a group of Fanconi anemia patients in Egypt. Haema 10:61–67 Temtamy SA, Aglan MS, Valencia M, Cocchi G, Pacheco M, Ashour AM, Amr KS, Helmy SMH, El-Gammal MA, Lapunzina P, Goodship JA, Ruiz-Perez VL (2008) Long interspersed nuclear element-1 (LINE1)-mediated deletion of EVC, EVC2, C4orf6, and STK32B in Ellis-van Creveld syndrome with borderline intelligence. Hum Mutat 29:931–938 Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench N, Hewitt C, Moynihan L, Roberts E, Woods CG, Markham A, Wong M, Widmer R, Ghaffar KA, Pemberton M, Hussein IR, Temtamy SA, Davies R, Read AP, Sloan P, Dixon MJ, Thakker NS (1999) Lossof-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 23:378–380 Usanga EA, Ameen R (2000) Glucose-6-phosphate dehydrogenase deficiency in Kuwait, Syria, Egypt, Iran, Jordan and Lebanon. Hum Hered 50:158–161 Valencia M, Lapunzina P, Lim D, Zannolli R, Bartholdi D, Wollnick B, Al-Ajlouni O, Eid S, Cox H, Buoni S, Hayek J, Martinez-Frias ML, Antonio P-A, Temtamy S, Aglan MS, Goodship JA, Ruiz-Perez VL (2009) Widening the mutation spectrum of EVC & EVC2¼ectopic expression of Weyers variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling. Hum Mutat 30:1667–1675 Valente EM, Brancati F, Silhavy JL, Castori M, Marsh SE, Barrano G, Bertini E, Boltshauser E, Zaki MS, Abdel-Aleem A, Abdel-Salam GM, Bellacchio E, Battini R, Cruse RP, Dobyns WB, Krishnamoorthy KS, Lagier-Tourenne C, Magee A, Pascual-Castroviejo I, Salpietro CD, Sarco D, Dallapiccola B, Gleeson JG; International JSRD Study Group (2006) AHI1

272

S.A. Temtamy et al.

gene mutations cause specific forms of Joubert syndrome-related disorders. Ann Neurol 59:527–534 Wahab AA, Janahi IA, Marafia MM (2004) Pseudo–Bartter’s syndrome in an Egyptian infant with cystic fibrosis mutation N1303K. J Trop Pediatr 50:242–4 Wang K, Pugh EW, Griffen S, Doheny KF, Mostafa WZ, Al-Aboosi MM, Al-Shanti H, Gitschier J (2001) Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3. Am J Hum Genet 68:1055–1060 Zaki ME, Temtamy SA, Hussein FH, El-Ruby MO (1989) Anthropometric and dermatoglyphic studies on Noonan syndrome. Proc Egypt Acad Sci 39:227–235 Zaki MS, El-Sabbagh MH, Saleem NA (2001) Neuronal migration disorders: clinical, neuroimaging and neurophysiologic studies. Gaz Egypt Ped Assoc 49:235–245 Zaki MS, Saleem SN, Helmy NA (2002) Clinico-radiological features of malformations of cerebral cortical development (MCD) in childhood and their genetic background. Med J Cairo Univ 70(Suppl):1–18 Zaki MS, El-Sabbagh MH, Aglan MS (2004) Familial congenital brachial palsy: a report of two affected Egyptian families. Genet Couns 15:27–36 Zaki MS, Kayed HF, Saleem SN, Abdel Salam GMH (2005) Holoprosencephaly spectrum in Egyptian patients: clinico-radiological and genetic aspects. Egypt Med J NRC 4:20–34 Zaki MS, Abdel-Aleem A, Abdel-Salam G, Marsh SE, Silhavy JL, Barkovich AJ, Ross ME, Saleem SN, Dobyns WB, Gleeson JG (2008) The molar tooth sign: a new Joubert syndrome and related cerebellar disorders classification system tested in Egyptian families. Neurology 70:556–565 Zakrzewski SR (2007) Population continuity or population change: formation of the ancient Egyptian state. Am J Phys Anthropol 132:501–509 Zekri AR, el-Bassuoni MA, Hammad OM, Sakr MA, Ibrahim AA (2004) Application of refractory fragment amplification system for detection of Egyptian variant of Familial Mediterranean Fever. Egypt J Immunol 11:103–110

Chapter 9

Genetic Disorders in Ancient Egypt Chahira Kozma

Ancient Egypt The ancient Egyptian civilization originated in North Eastern Africa along the banks of the Nile River around 3000 BCE. It ended in 30 BCE, when the Roman Empire conquered Egypt and made it a province. The ancient Egyptians left a superb legacy of mathematics, language, architecture, agriculture techniques, and monumental buildings. This legacy is preserved through an elaborate system of Hieroglyphic writing, artistic documentation on tombs and temple walls, and numerous masterpieces that have lasted until the present time. The hot and dry climate of Egypt as well as the process of artificial mummification left many skeletal and biological remains intact, including evidence of genetic conditions and in particular skeletal disorders (Kozma 2008). In general, the sources of evidence come from biological and artistic resources. Although written evidence, in the form of medical papyri, are abundant from ancient Egypt, they usually relate to remedies, incantations, and magic spells for the treatment of medical, surgical, and gynecological conditions. The medical papyri do not mention or describe congenital disorders.

Biological Evidence Due to the hot and dry climate of Egypt, a substantial number of biological remains are well preserved in the form of naturally mummified corps and complete or partial skeletons. In their ardent desire for immortality, the ancient Egyptians mastered the technique of artificial mummification and left thousands desiccated mummies, C. Kozma Department of Pediatrics, Georgetown University Hospital, 3800 Reservoir Rd N.W., Washington DC, USA e-mail: [email protected]; [email protected]


273

274

C. Kozma

which are available for modern-day studies. A substantial number of those biological remains that span thousands of years have been intensely researched by archeologists and scientists, making Egyptian paleopathology one of the best studied among ancient civilizations.

Dwarfs The pharaohs and nobles of ancient Egypt were enchanted to have in their households pygmies and dwarfs (Dasen 1993). The high value placed on dwarfs in ancient Egypt is highlighted by the praise given to Harkuf, a general who served King Pepi II (2278–2184 BCE), when he returned from an African expedition with precious treasures and a pygmy or a dwarf who could perform exotic dances. Pepi II wrote Harkhuf a letter expressing his delight at the prospect of seeing this man dance. The king urged Harkuf to take great care of this man and to post good guards to keep him from falling off the boat on the way to the royal residence. Harkuf was so delighted with the letter that he had it engraved on the cliffs outside of his tomb, where it can still be seen. An abbreviation of the letter of the child king, who was then about 8 years of age, is as follows: Come northward to the Residence immediately. Leave (everything) and bring this pygmy with thee, which thou hast brought living from the land of Akthiu (possibly Somalia), for the dances of the God, to rejoice and gladden the heart of thee. When he (the pygmy) goes down with thee to the vessel, appoint trustee people, who shall be about him on each side of the vessel; take care lest he fall into the water. If thou arrives of the Residence, this pygmy being with thee alive. My Majesty will do for thee a greater thing in accordance with the heart’s desire of My Majesty to see this pygmy.

The biological evidence of dwarfs is abundant from ancient Egypt and includes several complete and partial skeletons, which are located in Egyptian and British museums. Some of the skeletons have been adequately studied and published and some are known from excavators’ observations. The majority of skeletons represent achondroplasia (Hamada and Rida 1972). A skeleton of a female worker that dates back to the Old Kingdom was found in the necropolis of Giza, a major funerary complex where the pyramids are located. She had achondroplasia and was found with a fetus in situ. It is believed that she died during delivery.

The Badarian Skeleton The earliest biological evidence of dwarfs in ancient Egypt dates back to 4500 BCE, the Badarian Period. The partial skeleton was thoroughly studied when it was located in the Museum of the Royal College of Surgeons in England. Its current location is unknown. The skull and mandible are normal; however, the clavicles are slim. The small bones of the hands, the ribs, and the scapulae are normal. The head of the humerus is malformed. The radii and ulnae are small and symmetrical with

9 Genetic Disorders in Ancient Egypt

275

the radial tuberosity, and ligamentous prominences of the radii are pronounced. The head is malformed and lacks the usual even contour (Fig. 9.1). These abnormalities are not characteristic of achondroplasia and they represent another short-limbed dwarfism, possibly epiphyseal dysplasia (Jones 1932).

The Dwarf from the Tomb Complex of King Wadj The skeleton was located in a tomb in Saqqara, a vast funerary complex to the south of Cairo. It dates back to 3100–2800 BCE. It is located at Cairo University, Egypt. When unearthed, the tomb was unplundered and contained four different types of jars. The long bones are very short and the fibulae bowed (Fig. 9.2). To most Egyptologists, the changes are attributed to short-limb dwarfism, most likely achondroplasia (Emery 1954; Weeks 1970).

The Dwarfs from the Tomb of King Semerkhet These skeletons date back to 3050–2890 BCE and are located in the Natural History Museum in London (BMNH AF.11.4/427). The specimens consist of a skull, humerus, femur, three tibiae, and two fibulae. The shortened skull base contributes to the appearance of a depression in the middle third of the face. The nasal bones and the frontal processes of the maxilla are broad and the short face is accentuated by the prognathism of the alveolar portion of the maxilla. The long bones are very short and have relatively normal diameter of the shafts and epiphyses. The tibiae have slight medial bowing of the distal half. The humerus is short with the abnormal joint pathology associated with achondroplasia (Fig. 9.3). The secondary teeth and the fused epiphyses and apophyses indicate young adulthood (Putschar and Ortner 1985). The maximum length of the femur is 250 mm, of the humerus is 165 mm, of the fibula is 213 mm, and of the tibia is 215 mm.

The Dwarf Pereniankh The dwarf Pereniankh was an elite dwarf who lived between 2350 and 2175 BCE. His funerary statue, which is on display at the Egyptian Museum of Cairo, was found along with his skeleton in Giza not far from the great pyramids (Hawass 2004). The statue shows him seated on a chair and wearing a short kilt. His face is round and his neck is short and thick. His extremities, especially his legs, are short. Examination of his skeleton revealed the characteristic traits of achondroplasia including short and squat upper and lower limbs. It was estimated that he was about 40 years old when he died. The facial part of his skull is missing. The measurements of the long limbs of the skeleton and those of the statue matched, and it was

276 Fig. 9.1 The Badarian skeleton. (a) Skull, (b) Mandibles, (c) Clavicles, (d) Radii, (e) Ulnae, (f) Humeri, (g) Vertebrae

C. Kozma


277

Fig. 9.2 Left: A skeleton of a male achondroplastic dwarf from the Old Kingdom. Right: A skeleton of an average size person from the same burial complex for comparison. Courtesy of the Egypt Exploration Society, London

concluded that there was a realistic attempt to model Pereniankh’ skeletal disorder. His legs are slightly different in size, possibly because of elephantiasis. Both sides of his chair are inscribed with his name and titles, “the dancing dwarf in the Great Palace, the one who pleased his majesty everyday, Per-ni-ankh-w.”

Mucopolysaccaridoses The Natural History Museum in London has a pair of deformed humeri from early dynastic Egypt (BMNH AF.11.3/75). Both humeri are abnormally short. The diaphysis is normal in diameter, with a well-developed deltoid tuberosity. The humeral head exhibits severe malformation of the articular surface with pitting of the subchondral plate, particularly on the right. The left humerus is about 2 cm shorter than the right (Fig. 9.4). The external morphology of the humeral heads suggests an almost complete failure in the development of the epiphysis (Brothwell 1965). Ortner and Putschar argued against achondroplasia and suggested mucopolysaccharidoses because of the almost complete failure in the development of the epiphysis. The fusion of the distal humeral epiphyses and apophyses indicates a minimum age of about 14 or the possibility of young adulthood.

278 Fig. 9.3 Anterior view of skull and long bones of dwarfs. Specimen BMNH AF.11.41427. Courtesy of the Natural History Museum, London

C. Kozma


279

Fig. 9.4 Humeri with possible mucopolysaccaridoses. Specimen BMNH AF.11.3/75. Courtesy of the Natural History Museum in London

Osteogenesis Imperfecta A rare example of osteogenesis imperfecta comes from ancient Egypt and dates back to 1000 BCE. The skeleton was in a coffin and is currently in the British Museum (Registry No. 41603). It consists of skull bones, clavicles, ribs, long bones of the upper and lower extremities, and a few small bones of the hands (Fig. 9.5). In general, the bones are of a pale brown color, friable, and extremely light. The skull is described to have the Tam O’Shanter effect (a tight-fitting Scottish cap). The weight of the brain cannot be supported and settled into a beret-like effect. The skull has an enlarged vault with multiple wormian bones, elongated eye orbit, and multiple ossification centers. Most of the teeth were scattered among the bones. They are brittle, discolored, and have poorly developed roots. Furthermore, the teeth have a disorder of the tubular structure of the dentine, which is compatible with dentinogenesis imperfecta. The bones of the lower extremities are showing significant antero-lateral bowing and distortion due to multiple fractures. Radiographic examination of the bones showed the cortex to be composed of thin wavy lines, and the spongiosa being reduced to scattered amorphous wisps (Gray 1970).

The Stillborn Children of King Tutankhamen King Tutankhamen ruled Egypt from 1333 to 1324 BCE. It is believed that he was the son of Amenhotep IV (better known as Akhenaten) and Kia, a minor queen. King Tutankhamen married his half-sister, the daughter of Akhenaten and his famous wife, Queen Nefertiti. When his tomb was discovered in 1922–1923, two

280

C. Kozma

Fig. 9.5 A skeleton of a child with Ostegenesis imperfecta. Registry # 41603. Courtesy of the British Museum of London

miniature coffins containing two embalmed children, both stillborn, were found. The first fetus, a female, was estimated to be about 5 months of gestation. It measures less than 30 cm and is well preserved. The second fetus, also a female, is estimated to be between 7 and 9 months in gestational age. It is less well preserved than the other and measures 38.5 cm. When the body was examined and X-rayed in 1978, it was found to have scoliosis, spina bifida, and Sprengel


281

deformity (Harrison et al. 1979 ). Currently, both fetuses are being examined by CT scan for further clarification of any congenital anomalies. Because Egyptologists have long debated whether these mummies were the stillborn children of King Tut and Ankhesenamun, DNA analyses are being carried out by the Egyptian scientific community for further identification of their lineage (Lorenzi 2008).

The Pharaoh Siptah: Clubfoot Deformity vs. Polio or Cerebral Palsy? The mummy of the pharaoh Siptah (1194–1188 BCE) is on display in the Royal Mummy Room in the Egyptian Museum of Cairo. It shows a clear deformity of the left leg and foot due to poliomyelitis, clubfoot deformity, or cerebral palsy (Smith 2000). The left leg is significantly shortened, with the foot in vertical position (Fig. 9.6). The diagnosis of poliomyelitis continues to be debated after the mummy was reexamined (Aufderheide and Rodriquez-Martin 1998). It was observed that the left foot compensated for the shorter leg by dislocation of the tarsal and metatarsal bones, tendon, and muscles.

Facial and Skull Malformations Two examples of agenesis of the premaxilla are recorded from ancient Egypt. The first example is a skull that was located from a cemetery located to the south of the city of Assiut. It dates back to 700 BCE and belongs to a female who was past middle age. Examination of the skull reveals a marked reduction in the size of the hard palate due to absence of the premaxillary part as well as the horizontal plates of the palatine bones. Otherwise the skull is normal. The provenance of the second skull is unknown. It is from an adult female (Fig. 9.7). The premaxilla and the incisor teeth are absent. The mandibles show prognathism most likely related to the subnormal development of the maxilla (Derry 1938). The Nubian pathology collection in the Natural History British Museum has a complete cranium of an adult female with cleft palate (BMNH 210 72/291). The dental alveoli appear intact; however, most of the teeth were lost postmortem. The palatal defect is bilateral and involves the central and posterior portions of the palate (Filer 1995). An example of hydrocephalus comes from the Roman Period in Egypt. The skeleton is of a man who is at least 30 years of age. The facial bones are normal, but the circumference of the head measured 66 cm, the normal being around 55 cm. Examination of the skeleton revealed an evidence of a left-sided weakness and over development of the right arm perhaps from using a crutch in the form of a long staff (Derry 1913).

282

C. Kozma

Fig. 9.6 The mummy of pharaoh Siptah showing a deformity of the left leg and foot. The Egyptian Museum of Cairo

Vertebrae and Other Spine Anomalies A study done on 272 skeletons dating back to the Old Kingdom, during the time of the early pyramid builders, found that nine cases (3.33%) were affected with spina bifida occulta in the sacral region and six cases (2.22%) had transitional vertebrae at the lumbosacral joint, namely sacralisation and lumbarisation. Spina bifida occulta


283

Fig. 9.7 Agenesis of premaxilla. Notice the absent incisor teeth, hypoplastic maxilla, and prognathism

is the most common developmental defect of the vertebral column in historical skeletal series. This condition has to be differentiated from the more serious problem of spina bifida cystica, which is the neural tube defect (Sarry El-Din and Abd El-Shafy El Banna 2006). Several researchers have reported ankylosing spondylitis among several ancient Egyptian mummies as well as at least three pharaohs: Amenhotep II, Ramses II, and his son, Merenptah. The mummies were investigated with radiographic examinations. The mummy of Amenhotep II (1390–1352 BCE) showed calcification of the paraspinous ligaments and obliteration of the sacroiliac joint. Ramses II (1279–1212 BCE) lived and ruled Egypt until the advanced age of 87 years. His mummy was examined in Cairo as well in Paris. The ligaments along the spine were ossified and the sacroiliac joint was effaced. Many Egyptologists are of the opinion that Ramsess II seems relatively stiff when portrayed in various images. Radiographic imaging of Merenptah (1213–1203 BCE), who succeeded his father Ramsess II as a relatively old man, shows indications of severe hypertrophic arthritis, which is most likely due to ankylosing spondylitis (Feldtkeller et al. 2003).

Sickle Cell Anemia The existence of hemoglobinopathies, thalassemia, and sickle cell anemia, has long been suspected in ancient Egypt among mummies with severe anemia. A molecular investigation was done on six Egyptian Predynastic mummies (3200 BCE) located in Turin Museum, Italy. They had evidence of severe hemolytic anemia. DNA was extracted from dental samples, a modified PCR was applied, and the amplified

284

C. Kozma

DNA was studied by electrophoresis. In three individuals, there was a band at the level of the HbS mutated fragment, indicating the presence of sickle cell anemia. These molecular results represent additional confirmation of the presence of sickle cell anemia in ancient Egypt. Previous histological studies revealed sickle cells in a mummy from the same collection (Marin et al. 1999).

Arteriosclerosis Although arteriosclerosis is considered to be a new disease, at least 10–20% of mummies from ancient Egypt show evidence of arteriosclerosis. Radiological examination by various pathologists showed calcifications of the aorta, femoral, and carotid arteries. A sample of the aorta of Merenptah revealed extreme calcareous degeneration, with the formation of large bone-like plaques (Magee 1998). Mummification was an expensive process and was affordable by the rich and middle and upper classes, who enjoyed animal fats, abundant food, and perhaps were subjected to some stress. The mummy of Ramsess II showed arteriosclerosis. He exhibited tortuous calcareous temporal arteries. Calcification was found in his carotid arteries and deposits of calcium were identified by radiological examination between his first and second metatarsal bones (Francois and Lichtenberg 1994).

Alkaptonuria (Ochronosis) Several mummies from ancient Egypt have been diagnosed with possible alkaptonuria or ochronosis. Radiological examination of the spine of those mummies revealed dense shadows in the region of the lumbar disks with narrow, translucent zones adjacent to the dense zones and mineralization of the intervertebral disks. In one mummy, dating from 1500 BC, analysis showed extensive calcification of the intervertebral disks and articular narrowing in both hip and knee joints. Biopsy cores from the right hip showed parallel black zones in the region of the articular surfaces, leading to a clinical diagnosis of ochronosis. The black pigment was extracted, analyzed, and compared with an air-oxidized homogentisic acid polymer. The two substances were apparently identical. Chemical analysis of the dark substance supports the diagnosis of ochronosis, an autosomal recessive disorder (Stenn et al. 1977).

Artistic Evidence of Genetic Disorders Through representations and inscriptions on tomb and temple walls, thousands of funerary objects, and documents on papyri, the ancient Egyptians left an immense legacy about their culture, religion, Gods, governmental affairs, and personal and


285

daily life. As a result, we are well informed about the daily life of the ancient Egyptians and in particular achondroplastic dwarfs (Kozma 2006).

Dwarfs The artistic evidence of dwarfs is quite abundant and covers the full spectrum of Egyptian civilization (Dawson 1938). In fact, as early as Predynastic Times, many statuettes of dwarfs were found in burial places, suggesting that they were prized enough to accompany the deceased to the afterlife (Fig. 9.8). Among the treasures of King Tutankhamen, there is a female dwarf that has the typical characteristics of achondroplasia (Fig. 9.9). Achondroplastic dwarfs had magical significance. They were associated with the sun God and numerous figurines and amulets were formed in their shape. The function of the dwarfs was to protect the living and the dead from dangers facing them including diseases, venomous animals, snakes, and crocodiles. There were at least two dwarf Gods, Ptah and Bes. God Ptah was associated with regeneration and rejuvenation. God Bes was a protector of sexuality, childbirth, women, and children. Several high-ranking dwarfs achieved important status and had expensive tombs close to the pyramids. Many ordinary dwarfs were employed as personal attendants, animal tenders, jewelers, fishermen, and entertainers.

Fig. 9.8 Two Predynastic statuettes (Catalogues: 71.532, 71.534). They are naked with shaven heads, pointed ears, and their hands resting on their hips. The upper arms are short, fat, and twisted. The lower extremities are very short and malformed. The female pubic area is triangular and marked by holes. The sex of the male figurine is identified by a small protrusion. Courtesy of the Walters Art Museum, Baltimore, Maryland

286

C. Kozma

Fig. 9.9 Female dwarf from the tomb of Tutankhamen. The Egyptian Museum of Cairo, Egypt

In several New Kingdom papyri, dwarfs are described as rising up to the sky and going down to the underworld. In the Magical and Medical Papyri of the New Kingdom, the dwarf God is invoked to stand by the speaker: “O that dwarf of the sky, O that dwarf of the sky. O dwarf great of face, with high back and short thighs. O great pillars, extending from the sky to the underworld. O Lord of the great corps which rests in Heliopolis. O great living lord.” In incantation three against the snakes in the same papyrus, the name of the dwarf is invoked for protection from the snakes: “O, dwarf! My magical powers are against my enemies. To render the influence of the poison of the snakes harmless. May they be free from intrusion for ever” (Leitz 1999).

Dwarf Gods The dwarf Gods Ptah and Bes were the best known and were involved in magical practices to protect the living and the dead.

God Ptah God Ptah was the greatest of the Gods of Egypt. He was considered the first of all the Gods and the master architect of the universe. Ptah was a creator God who


287

brought all things to being by thinking of them with his mind and saying their names with his tongue. He was also the patron God of craftsmen, artisan designers, builders, architects, masons, and metal workers (Aterman 1999). As a craftsman, Ptah was said to have carved the divine bodies of the royalty. Ptah was especially revered by the artisan’s community of Deir-el-Medina, near Western Thebes. In his human form, he is depicted as a man with a beard, wrapped up like a mummy, with his hands emerging from the wrappings in front and holding the symbols for life, stability, and power. Ptah is occasionally depicted in the form of an achondroplastic dwarf (Melzer 1986). In this form, he is usually naked, with short limbs, a relatively long trunk, and a large head with prominent forehead. Sometimes he is shown grasping and biting snakes to highlight his protective role against harmful creatures threatening ancient Egyptians. In his dwarf form, he is very distinct from God Bes and in general does not carry weapons.

The God Bes God Bes was a very popular God. He was thought to help ensure fertility, keep women safe in childbirth, and look after children. Also, he was the dwarf God of music and warfare and the patron of many functions. Although his cult dates back to the Old Kingdom (about 2613–2160 BCE), he was most prominent in the New Kingdom (1550–1070 BCE), and his cult lasted until the Greco Roman Period, where he was a favored deity. His temple, which dates back to the Ptolemaic period, was excavated in the Baharia oasis in the middle of Egypt and was in use until the fourth century AD (Hawass 2000) Bes was very prominent in the religious concerns of the ordinary people of ancient Egypt. He was frequently incorporated in household items to protect people from dangers facing them, and to bring prosperity and protection to the home. His figures were placed inside houses, painted on walls, and incorporated into furniture such as beds and chairs, cosmetic containers, and medicine bottles. Bes is depicted as an achondroplastic dwarf with a grotesque mask and lion mane. Often, he is depicted brandishing a sword to keep evil away and holding or standing on serpents and crocodiles. He is represented with a large skull and a prominent forehead. He has proximal shortening of the upper and lower extremities. Often, he is shown in a hybrid nature combining animal and feline features, and wearing a monkey skin on his back. He was also featured in the Mammisi or birth houses, which were located near major temples. Although the role of Bes has evolved significantly through the Dynasties, his most important function was the protection of women during childbirth. In several papyri from 1539 to 1069 BCE, the magical power of dwarfs, perhaps of the God Bes, is appealed to protect women in childbirth and delivery of the placenta. In a magical papyrus at Leiden, there is a spell to facilitate birth, called “the spell of the dwarf ”: O good dwarf, come, because of the one who sent you . . . come down placenta, come down placenta, come down!

288

C. Kozma

The prayer was to be recited four times over a clay figure of the dwarf God that had been placed on the head of the woman in labor. In the spell of the vulva, the woman in labor pain screams: “To the man for a dwarf-statute of clay” (Borghouts 1971).

Elite Dwarfs There was a significant value placed on dwarfs in ancient Egypt. Several elite dwarfs, especially from the old kingdom (2686–2190 BCE), achieved important status. Their magnificent burial sites were located in the royal cemeteries, Giza and Saqqara. Their names, titles, and captions on their statues indicate their important roles in society and their close association with the king. Some of them were Seneb, Khnumhotep, and Djeho. Another elite dwarf is Pereniankh, who was described in the earlier section regarding biological evidence. The dwarf Seneb served during the fourth dynasty of pharaohs Khufu and Djeder (2575–2467 BCE). His statue is on display in the Egyptian Museum of Cairo. It represents an excellent portrait of ancient Egyptian art. Seneb, most likely an achondroplastic dwarf, is seated in the position of a scribe. His wife and children are of average size. The statue depicts a family group with a great sense of harmony and balance. Seneb has short hair, large eyes, and a pronounced nose and mouth. His upper and lower extremities show the proximal shortening characteristic of achondroplasia. His mild facial features can be suggestive of hypochondroplasia. However, ancient Egyptian artists often depicted achondroplastic dwarfs with normal faces possibly because of conventional reasons. Since his skeleton was never found, an accurate diagnosis cannot be made. As this example illustrates, physical handicap was not an impossible barrier to success in the ancient Egyptian society. The paintings on the walls of his tomb reveal the main stages of his carrier. Twenty titles are inscribed on his tomb such as: beloved of the lord, overseer of weaving of the palace, overseer of dwarfs (suggesting that there were other dwarfs in the palace), and overseer of the crew of the ship (Dasen 1988). The dwarf Khnumhotpe held the title of the “Keeper of the Royal Wardrobe.” He dates back to the Old Kingdom. His titles, which were found on his statue, suggest that he belonged to the household of a high official. His figurine, which measures 18 in and is made out of painted limestone, is on display in the Egyptian Museum of Cairo. He has a large cranial vault and elongated skull. Although his facial features are pronounced, they are essentially normal. He shows rhizomelic shortening of the upper extremities. His lower extremities are very short. His back is arched, his abdomen is protruded, and he has a stocky torso. The dwarf Djeho, an achondroplastic dwarf, lived during the 30th Dynasty. He has a very impressive representation in the Egyptian Museum of Cairo. His life-size naked figure, which measures 120 cm, is carved in a profile on the lid of his granite sarcophagus (Baines 1992). The figure shows an accurate depiction of the features


289

Fig. 9.10 The dwarf Djeho carved in profile. The Egyptian Museum of Cairo, Egypt

of achondroplasia. The dwarf Djeho has a prominent forehead, depressed nasal bridge, and an enlarged anterior–posterior diameter of his skull. His hands are short and reach to the hips. Both his both upper and lower extremities reveal proximal shortening. Other characteristics include mild kyphosis, protruded abdomen, and normal male genitalia (Fig. 9.10).

Ordinary Dwarfs Dwarfs were often depicted in Old Kingdom funerary art in the vast necropolises of Saqqara and Giza performing a variety of jobs. The repetition of certain pictures in tombs makes it possible to draw conclusion about their societal role at that period (Sampsell 2001). Dwarfs specialized in certain occupations including jewelry. A superb scene from the tomb of Mereruka at Saqqara, a vizier to king Teti and his son-in-law, depicts dwarfs making splendid pieces of jewelry among averagesize workers. On many reliefs, dwarfs look after household pets, especially dogs and monkeys. This role appears to be restricted to male dwarfs who often tamed monkeys. In their roles as personal attendants, dwarfs are often shown in a privileged relationship with their master. Several Egyptian queens from the Old Kingdom had female dwarfs as attendants. Dwarfs worked also as fishermen, keeper of the wardrobe, nurses to young children, and supervisors of clothing and linen.

290

C. Kozma

Pharaoh Akhenaten Akhenaten reigned in the mid-1300s BCE in ancient Egypt. He was married to Nefertiti, his principal wife who bore him six daughters. He also had other wives including Kia, who was probably the mother of King Tutankhamen. Akhenaten is famous for his religious reforms, where the polytheism of ancient Egypt was abandoned, and the new religion focused on monotheism and centered around Aten, the God of the solar disk. During his reign, both art and religion were subjected to dramatic and significant changes. Artistic representation of Akhenaten gives him a bizarre appearance with an elongated head, large breasts, slender limbs, protruding belly, and wide hips (Ghalioungui and Dawakhly 1965). He looked more feminine than masculine giving rise to multiple theories; none of them appears to be valid (Fig. 9.11). One speculation is that he suffered from sexual differentiation disorders. The fact that he had several children argued against this possibility. The other suggested diagnosis is Marfan syndrome due to his disproportionate limbs and elongated face. The argument against this diagnosis is that Akhenaten’s head shape was portrayed normal before he changed his name and adopted the new monotheistic religion. Furthermore, an altered shape of head in antiquity indicated a high

Fig. 9.11 Pharaoh Akhenaten. The Egyptian Museum of Cairo, Egypt


291

social status. The evidence of the cranial deformation is limited to artistic representations and not observed on skulls from that period. The artistic representation of Akhenaten and his family influenced the portrayal of people from that period and soon disappeared after his death. The accurate diagnosis of Akhenaten remains difficult since his mummy and the mummies of his close relatives have not been located and many of his monuments were destroyed and demolished soon after his death.

The Doorkeeper Roma The doorkeeper Roma lived in the 18–20th Dynasty (Ghalioungui and El Dawakhly, 1965–1080 BCE). A funerary stela shows him with a leg abnormality, which required him to use a cane. Despite his disability, he achieved a high status, acquired wealth, and was married with at least one child. His leg is wasted and shortened and accompanied by an equinus deformity of the foot (Fig. 9.12). The exact medical diagnosis and the cause of this deformity continue to be debated. Some favor that Roma’s deformity is the result of a congenital clubfoot deformity. The other view is that of a case of poliomyelitis contracted in childhood before the completion of skeletal growth causing extreme shortening of the leg with severe wasting (Nunn 1996).

The Queen of Punt The Queen of Punt, who is depicted in an unusual form due to severe lordosis and heavy deposits of fats, continues to represent a diagnostic dilemma, giving rise to numerous speculations. The land of Punt is thought to be near present-day Somalia and Eritrea. Queen Hatshepsut, who ruled Egypt between 1479 and 1457 BCE,

Fig. 9.12 The Doorkeeper Roma with his wife and child (1550–1080 BCE). Specimen ÆIN 134. Courtesy of New Carlsberg Glyptotek, Copenhagen

292

C. Kozma

Fig. 9.13 The sketch depicts the prince followed by the Queen of Punt, their two sons, and their daughter. Their hands are held in adoration and prayer gestures. While the prince and the two sons are normal, the queen and her daughter appear to be affected with a similar disorder

dispatched an expedition to the land of Punt to obtain precious commodities. The details of the expedition, including portraits of the prince and Queen of Punt and their children, are recorded on the walls of Deir El Bahri temple, in Upper Egypt in great details. The face of the queen is rough and rugged. She is obese with multiple skin folds and symmetrical deposits of fat on the trunk, limbs, and thighs. Her spine is bent forward because of significant lordosis. Her upper extremities and hands are normal except for the excess skin folds. Her legs are very short (Fig. 9.13). The queen’s daughter has a similarly but less-pronounced appearance, which may suggest a familial pattern (Mariette 1877). The illustration of the queen of Punt continues to arouse the curiosity of physicians and Egyptologists alike. Several differential diagnoses have been proposed to explain the queen pathology including Launois Bensaude lipomatosis, Dercum disease (significant fat accumulation), neurofibromatosis type I, lipodystrophy, achondroplasia, familial obesity, Proteus syndrome, elephantiasis, and X linked dominant hypophosphatemic rickets. Steatopygia has been suggested. It refers to significant fat accumulation in and around the buttocks and is usually seen as a normal variant in some tribes in South West Africa. Recently Farag and Iskandar coined a new pathology “Queen of Punt Syndrome” (Farag et al. 1999).

The Pygmies Dancers The three pygmy dancers, part of an ivory toy, are located in the Egyptian Museum of Cairo. A fourth dancing figure that belongs to the same set is in the Metropolitan Museum of Art in New York. The figures date back to the Middle Kingdom


293

(1990–1780 BCE). The statuettes are connected to a string and danced when the string was pulled. They represent a realistic depiction of pygmies who were imported to ancient Egypt from Central Africa for their dancing ability. They have round faces, broad noses, and thick lips as well as bulging buttocks and bowed legs, which is typical of pygmies of Southern Africa. Contrary to achondroplastic dwarfs, their bodies are stout and proportionately short (Martino 2005).

Conclusion The artistic and biological evidence provides a rich legacy and documentation of the positions of individuals with skeletal dysplasia and other genetic disorders in daily life in ancient Egypt, and their acceptance in society. Several Egyptologists and researchers have concluded that the image of individuals with dwarfs and those with disabilities in ancient Egypt is essentially positive (Sullivan 2001). In the tombs of some high officials, individuals with disabilities are depicted alongside the deceased. In the tomb of Baqt I, who was an elite man, there is a dwarf, a man with hunchback, and a man with clubfeet, who accompanied the tomb owner in the afterlife (Fig. 9.14). It is believed that these men had a prestigious status due to their proximity to the tomb owner, wearing pointed kilts, and being of a larger scale than the servants (Newberry 1893). Another indication of the positive attitude toward individuals with disabilities in ancient Egypt is revealed in moral teachings. The Papyrus Insinger that dates back to the Late Period portrays the wise person as being moral and pious: The blind one whom the God bless, his way is open The Lame one whose heart is on the way of the God, his way is smooth.

Fig. 9.14 The sketch depicts a dwarf, a man with a hunchback, and a man with clubfeet who accompany a noble man in the after life

294

C. Kozma

Ancient Egyptians had a strict code of ethics. The instructions of Amenemope, who lived during the reign of Amenhotpe III, taught and commanded respect for dwarfs and other individuals with handicapping conditions: Do not jeer at a blind man nor tease a dwarf Neither interfere with the condition of a cripple; Do not taunt a man who is in the hand of God, Nor scowl at him if he errs.

Additional instructions of Amenemope give positive images of attitudes toward human limits. It also teaches that care for the old, sick, and malformed is a moral duty, because “Man is clay and straw, the God is his builder. The Wise Man should respect people affected by reversal of fortune” (Simpson 1973).

References Aterman K (1999) From Horus the child to Hephaestus who limps: a romp through history. Am J Med Genet 83:53–63 Aufderheide AC, Rodriquez-Martin C (1998) The Cambridge encyclopedia of human paleopathology. Cambridge University Press, Cambridge, p 76 Baines J (1992) Merit by proxy: the biographies of the dwarf Djeho and his patron Tjaiharpta. JEA 78:241–257 Borghouts JF (1971) The magical tests of papyrus Leiden. Brill, Leiden, p 29 Brothwell DR (1965) Digging up bones. London, Trustees of the British Museum Natural History, p 164 Dasen V (1988) Dwarfism in Egypt and classical antiquity: iconography and medical history. Med Hist 32:253–276 Dasen V (1993) Dwarfs in ancient Egypt and Greece. Clarendon Press, Oxford, pp 17–159 Dawson WR (1938) Pygmies and dwarfs in ancient Egypt. J Egypt Archaeol 24:85–189 Derry DE (1913) A case of Hydrocephalus in an Egyptian of the Roman period. J Anat Physiol 47:436–458 Derry DE (1938) Two skulls with absence of the premaxilla. J Anat 72:295–298 Emery WB (1954) Great tombs of the First Dynasty; excavations at Saqqara. Oxford University Press, Oxford, p 36 Farag TI, Sabry MA, Iskandar A (1999) Queen of punt syndrome. Am J Hum Genet Supplement: Abstract A803 Feldtkeller E, Lemmel EM, Russell AS (2003) Ankylosing spondylitis in the pharaohs of ancient Egypt. Rheumatol Int 23:1–5 Filer J (1995) Egyptian bookshelf disease. Sources of evidence. The British Museum Press, London, p 36 Francois D, Lichtenberg R (1994) Mummies: a voyage through eternity. Harry N. Abrams, New York, p 83 Ghalioungui P, El Dawakhly Z (1965) Health and healing in ancient Egypt. Al-Maaref, Cairo, pp 19–20 Gray PHK (1970) A case of osteogenesis imperfecta with associated dentinogenesis imperfecta dating from antiquity. Clin Radiol 21:106–108 Hamada G, Rida A (1972) Orthopaedics and orthopaedic diseases in ancient and modern Egypt. Clin Orthop Relat Res 89:253–268 Harrison RG, Connolly RC, Ahmed S et al (1979) A mummified foetus from the tomb of Tutankhamun. Antiquity 53:19–21


295

Hawass Z (2000) Valley of the golden mummies. The temple of Bes. Harry N. Abrams, New York, p 169 Hawass Z (2004) The dancing dwarf. The Ambassadors Online Magazine. The forum for culture and civilization. Volume 7-Issue 2. http://ambassadors.net./selected.study.htm. Accessed 27 Feb 2009 Jones EWAH (1932) Studies in achondroplasia. J Anat 66:569–573 Kozma C (2006) Dwarfs in ancient Egypt. Am J Med Genet 140A:303–311 Kozma C (2008) Historial review: skeletal dysplasia in ancient Egypt. Am J Med Genet A 146A:3104–3112 Leitz C (1999) Magical and medical papyri of the New Kingdom. British Museum Press, London, pp 11–45 Lorenzi R (2008) Fetus mummies were likely King Tut’s. Discovery Channel. dsc.discovery.com/ news/2008/08/15/king-tut-fetus.html. Accessed 27 Feb 2009 Magee R (1998) Arterial disease in antiquity. Med J Aust 169:663–666 Mariette A (1877) Deir-el-Bahari, documents topographiques, historiques et ethnographiques recueillis dans ce temple pendant les fouilles exećuteés par Auguste Mariette-bey. Leipzig J C Hinrichs. Plate 5 Marin A, Cerutti N, Massa ER (1999) Use of the amplification refractory mutation system (ARMS) in the study of HbS in Predynastic Egyptian remains. Boll Soc Ital Biol Sper 75:27–30 Martino E (2005) Three dancing dwarves. J Endocrinol Invest 28:100 Melzer R (1986) Ptah, the dwarf God of ancient Egypt. Adler Mus Bull 12:1–3 Newberry PE (1893) Beni Hasan II. ASE 2, London, p XXXII Nunn JF (1996) Ancient Egyptian medicine. The pattern of disease. University of Oklahoma Press, Oklahoma, pp 64–95 Putschar WGJ, Ortner DJ (1985) Identification of pathological conditions in human Skeletal remains. Skeletal dysplasias. Smithsonian Institution Press, Washinton DC, pp 331–332 Sampsell BM (2001) Ancient Egyptian dwarfs. KMT 12:60–73 Sarry El-Din AM, Abd El-Shafy El Banna R (2006) Congenital anomalies of the vertebral column: a case study on ancient and modern Egypt. Int J Osteoarchaeol 6:200–207 Simpson WK (1973) In: Simpson WK, Simpson WK (eds) The Literature of Ancient Egypt. The instructions of Amenemope. Yale University Press, New Haven CT, pp 241–265, With translations by RO Faulkner, EF Wente, WK Simpson Smith GE (2000) The royal mummies (Catalogue Geńe´ral du Museé du Caire, 1912). (Duckworth Egyptology). Bath, Bath Press, p Plate LXII Stenn FF, Milgram JW, Lee SL, Weigand RJ, Veis A (1977) Biochemical identification of homogentisic acid pigment in an ochronotic Egyptian mummy. Science 197:566–568 Sullivan R (2001) Deformity-A modern Western prejudice with ancient origins. Proc R Coll Physicians Edinb 31:262–266 Weeks KR (1970) The Anatomical knowledge of the Ancient Egyptians and the representation of the figure in Egyptian Art. PhD Thesis, Yale University

Chapter 10

Genetic Diseases in Iraq Hanan Ali Hamamy

Geography and History Iraq occupies the northeastern corner of the Arab world; Iran lies to the East and Turkey lies to the North (Fig. 10.1). Its total land surface is 438,000 km2. The northern part is mountainous; the central region is occupied by the Tigris–Euphrates Plain; the south is characterized by marshes; and deserts predominate in the west. Despite its hot, parched, and windswept land, Mesopotamia became one of the earliest civilizations. Early in the fifth millennium, BC, farmers abandoned their villages in northern Mesopotamia and migrated southward to the Tigris–Euphrates Plain. These earliest inhabitants of southern Mesopotamia were known as the Ubaidians; they were later infiltrated by the Semitic nomads from the Syrian Desert and the Arabian Peninsula. The Sumerians did not arrive on the scene until about 3,500 B.C. (Kramer 1967), although their possible origin in southern Iraq cannot be excluded (Roux 1980). The cross-fertilization of the groups of people living in southern Mesopotamia brought about an ethnic and cultural fusion that was to initiate the Sumerian civilization. After lasting for about 1,500 years, the Sumerian capital Ur was destroyed and shortly thereafter the Akkadian civilization arose founded by the Amorites, who were Semites of the Arabian deserts. Later on, the Babylonian civilization in central Iraq and the Assyrian civilization in Northern Iraq emerged. These civilizations produced some of the earliest writings and some of the first sciences, mathematics, laws and philosophies of the world; hence the common epithet for Iraq: the “Cradle of Civilization.”

Hanan A. Hamamy Department of Genetic Medicine and Development, Geneva University Hospital, Geneva, Switzerland (formely Al-Mustansiriyah Medical College, Baghdad, Iraq) e-mail: [email protected]


297

298

Hanan A. Hamamy

Fig. 10.1 Iraq Map http://www.lib.utexas.edu/maps/iraq.html

The Population The population structure reveals ethno-linguistic diversity. The ancient population of Iraq has long been assimilated and absorbed by the successive waves of migration and settlement. The Iraqi genetic makeup of today reflects the admixture of these various groups. The last population census was carried out in 1997 with the exclusion of the autonomous Kurdish provinces in the North giving a figure of 20 millions. The 1999 estimate was 22.5 million (World Health Report 2000), whereas the total population for Iraq in 2005–2008 is estimated at around 28–29 millions (WHO, EMRO country profiles; World Bank Iraq data sheet). The population is composed of about 75–80% Arabs and 15–20% Kurds, the latter inhabiting the mountainous regions of the north and northeast. Although considerable intermingling has taken place, a major proportion still retains a separate character and continues to speak its own Kurdish language. Turks and Turkomen also inhabit the northern regions. Other ethnic groups are quite small and include the Yazidis living west and north of Mosul. The predominant religion is Islam (Shi’a and Sunni). The Christian communities of about 3% are chiefly descendants of the ancient population that was not converted to Islam when it took root in Iraq in the seventh century AD. They are subdivided among various Christian sects including Chaldeans, members of the Orthodox Church, and

10

Genetic Diseases in Iraq

299

Assyrians. The Assyrians, of Arab Semitic origin, are the original people of the Assyrian civilization in northern Mesopotamia who in about AD 175 were converted to Christianity. From a demographic perspective the population of Iraq as of many other Arab countries is characterized by marriage at a young age, advanced maternal and paternal ages with customary consanguineous marriage and large family sizes (Hamamy and Alwan 1994; Al-Gazali et al. 2006; Hamamy and Bittles 2008).

Basic Health Indicators and Genetic Services in Iraq Abundant natural and human resources enabled Iraq to attain the status of a middleincome country in the 1970s. The country developed good infrastructure and a wellperforming education and healthcare system, widely regarded as the best in the Middle East. Income per capita rose to over US$3,600 in the early 1980s. Since that time, successive wars and economic sanctions have stifled growth and development and debilitated basic infrastructure and social services. Despite the country’s rich resource endowment, Iraq’s human development indicators are now among the lowest in the region, and the income per capita has continued to drop with an estimated GDP per capita of $480–630 in 2003 (The World Bank). Some rise was estimated in 2004 to $1,180 GDP per capita (WHO, EMRO country profiles), and to $3,500 in 2007 (CIA World Factbook). Results of the 1999 UNICEF Iraq Child and Maternal Mortality survey among 23,105 eligible respondents in the south/center of Iraq showed that infant mortality rate (IMR) has increased from 47 deaths per 1,000 live births for the period 1984–1989, to 108 deaths per 1,000 live births for the period 1994–1999 (Ali and Shah 2000). Another report on IMR for 1978 and 1998 of 16 Arab countries in the Eastern Mediterranean region extracting its data from World Health Organization and United Nations Children’s Fund sources showed that IMR in all countries showed a sharp decline from 1978 to 1998 except in Iraq, where the IMR rose from 84 in 1978 to 95/1000 livebirths in 1998 [Shawky 2001]. The IMR in 2003 was estimated at 107.9 deaths per 1,000 livebirths (WHO, EMRO country profiles), 37 deaths per 1,000 livebirths in 2006 [UNICEF], and 45.4 deaths per 1,000 live births in 2008 [CIA World Factbook], and the estimated life expectancy at birth in 2005 was 58 years (WHO, EMRO country profiles). The average perinatal mortality rate for Iraq was estimated at 28 per 1,000 live births during the period 1980–1990 (the period before sanctions) and 108 per 1,000 live births during the period 1990–1999 following the 1991 Gulf war and the economic sanctions. The important causes of neonatal deaths are low birth weight, perinatal infections and birth asphyxia (Nasheit 2003). A cross-sectional study carried out in the Obstetric Department, Al-Kadhimiya Teaching Hospital in Baghdad involving 300 full-term newborns from January 1, 2002, through December 31, 2004, showed that ten anthropometric measurements

300

Hanan A. Hamamy

in Iraqi newborns were less than their published figures in other populations (Al-Mefraji et al. 2006). The decline in the health-care system following the successive wars and sanctions in Iraq touched all medical services including genetic services. The rapid progress in genetic services and research experienced by the world in the past 20 years did not involve Iraq, a wealthy country that has markedly regressed in this field. Community genetic services are currently scarce and patchy in Iraq with no national programs for the prevention of genetic diseases. The severe lack of medical genetic specialists in the country reflects on the scarcity of genetic clinic services. In Baghdad, one of the genetics unit founded in 1981 was linked to the Al-Yarmouk Teaching Hospital (Hamamy 1984) while another was linked to Baghdad University Medical College (Al-Taha 1996). Both units are not functioning properly following the wars and sanctions. A recent Genetic subspecialty Clinic at Al-Nahrain College of Medicine in Baghdad is offering basic genetic services. Hematology specialists and thalassemia centers in Baghdad, Mosul, Basrah, Dohuk and other governorates are offering their services to patients with hereditary blood disorders.

Consanguineous Marriages Social, religious, cultural, political and economic factors play roles in favoring consanguineous marriages among the new generations just as strongly as they did among the older generations, particularly in rural areas. In a study of consanguinity among the urban population of Baghdad (Hamamy et al. 1986), the coefficient of inbreeding (F) was estimated at 0.0225, and first cousin marriage rate at 29.2% (Table 10.1). Iraqi society, however, has a long tradition of consanguinity, and the cumulative estimate of (F) may exceed the estimated value which is calculated for a single generation (Bittles et al. 1993). The highest rates of marriages to close relatives are consistently reported in the more traditional rural areas and among the poorest and least educated in society (Bittles et al. 1993). It is thus expected that the consanguinity rate among the rural population in Iraq would exceed the rate reported from the urban population of Baghdad. Figures on nationwide consanguinity rates in Iraq are lacking. The 1999 UNICEF Iraq Child and Maternal Mortality survey among 23,105 respondents in Table 10.1 Consanguinity rates among 4491 families in Baghdad Hamamy et al. (1986)

Degree of consanguinity First cousin First cousin once removed Second cousin Further than second cousin Total

Consanguineous n % 1,311 29.2 453 10.1 321 514

7.1 11.4

2,599

57.9

Non-consanguineous n %

1,892

42.1

10


301

the south/center of Iraq showed a total consanguinity rate of 60% and 47% among 14,035 respondents in the Kurdish autonomous region (Sulaimaniya, Duhok and Arbil) (Ali and Shah 2000). A questionnaire was administered to 989 mothers attending the maternal and child health clinics to assess the role of consanguinity in reproductive health. Among consanguineous marriages as compared to non-consanguineous marriages, a higher rate of pregnancies per family, a lower rate of abortions, and a higher rate of infant deaths were reported (Table 10.2). The increased postnatal mortality among the offspring of consanguineous parents may be related to the action of deleterious recessive genes and multi-gene complexes inherited from a common ancestor. The higher parity rate among consanguineous couples counterbalances the higher infant mortality; as a result, there is equality in the number of living children among consanguineous and nonconsanguineous couples. Several studies have reported greater numbers of children born to consanguineous than to non-consanguineous couples where a positive association between consanguinity and fertility was confirmed (Bittles et al. 1991). A number of social factors may be strongly implicated, including younger parental age at marriage and in particular younger maternal age. It has also been suggested that the larger number of births in consanguineous mating is in part a planned reproductive compensation response by the parents in the face of increased early postnatal mortality. The incidence of major congenital malformations is significantly higher among children of consanguineous parents than among those of non-consanguineous parents; confirmed in the study conducted in Baghdad (Hamamy and Al-Hakkak 1989). The distribution of 166 cases of stratified congenital anomalies according to the consanguinity rates of their parents indicate that rates of different types of congenital anomalies increased with the degree of consanguinity, being highest in the first cousin mating (Table 10.3). This may be partly explained by the presence of a number of undiagnosed autosomal recessive conditions. Traditional cousin marriages may be discouraged for reasons other than their general risks for reproductive health and other than the relatively higher risks of childhood mortality and morbidity. On individual bases, when a severe autosomal recessive condition segregates in a family, genetic counseling becomes of utmost importance in prevention of the disorder by minimizing further intermarriages in the family. Iraqi families are inclined to large sibship size: total fertility rate in 2004 was estimated as six (WHO EMRO country profiles). Early genetic counseling after Table 10.2 Reproductive parameters among consanguineous and nonconsanguineous mating Hamamy et al. (1986)

Variables Number of families Average number of pregnancies/family Abortion rate Stillbirth rate Infant death rate

Consanguineous Non-consanguineous 572 417 4.5 3.8 8.9% 2.4% 3.5%

11.1% 2.4% 2.4%

302

Hanan A. Hamamy

Table 10.3 Distribution of 166 cases of stratified congenital anomalies according to consanguinity rates of their parents Hamamy and Al-Hakkak (1989) Anomalies First cousin Second cousin Not related Total n % n % n % n % 38 50 20 26.3 18 23.7 76 45.8 MCA+/MRa Hypotonia/motor retardation 35 70 12 24 3 6 50 30.1 Single congenital malformation 8 36.4 6 27.3 8 36.4 22 13.3 All anomalies 9 50 5 27.8 4 22.2 18 10.8 90 54.2 43 25.9 33 19.9 166 100 a MCA MR: multiple congenital anomalies with or without mental retardation

the birth of one affected child could prevent the birth of further affected children and reduce the prevalence of inherited disease by 50% (WHO 1985). Furthermore, diagnostic facilities for prenatal diagnosis of genetic disorders are not available, thus limiting the use of this prevention tool. Based on personal experience, efforts to minimize further intermarriages in families with segregating autosomal recessive disorders face many difficulties due to the existence of deeply rooted social beliefs. Repeated long counseling sessions involving various family members are usually required. The term “hereditary disorder” may arouse a multitude of feelings of hostility and denial, often leading to disregard of the risk information given to the family. Families fear that their daughters would be stigmatized and would not get married. Preliminary experience has revealed that response to genetic counseling could differ dramatically depending on the cultural and educational level of the parents; this factor may be more important than the severity of the disease in the family. An educated working mother would be alarmed by the birth of a single affected baby and would undertake any available procedure to prevent the birth of another. However, a poorly educated or illiterate woman might continue to conceive despite having several affected children, partly because of the pressure from the husband’s family (Hamamy 1984).

Population Genetics Investigation of the ABO gene frequencies among the Iraqi population revealed differences among various ethnic groups and geographic areas. These differences may be partly endogenous and partly caused by outer influences of neighboring populations (Table 10.4). Although the number of individuals studied is small, gene frequency distribution indicates that blood group (B) is more common than (A) in southern Iraq, while blood group (A) is more frequent than (B) in Mosul in Northern Iraq as well as among the Kurds, Turkomen and Assyrians. Rh (D) positivity was exhibited in 92 and 94.4% of the population of Mosul and Arbil respectively in North Iraq (Saleem and Mahmoud 1988; Rofoo et al. 1995), and 96.7% of the population of Basrah, in south Iraq (Al-Kasab et al. 1987).

10


Table 10.4 Distribution of ABO blood groups in Iraq Region or sector (reference) Number of individuals surveyed O Baghdad (Mourant et al. 1976) 1,403 36.3 Mosul (Mourant et al. 1976) 333 41.4 Mosul (Saleem and Mahmoud 1988) 3,177 34.7 Mosul Total 3,510 35.7 Basrah (Abdullah 1976) 6,400 36.8 Basrah (Al-Kasab et al. 1987) 610 46.4 Basrah (Abdullah 1981) 92 39.1 Basrah, Total 7,102 37.6 Ramadi (Al-Agidi et al. 1977) 63 46.1 Arbil (Rofoo et al. 1995) 23247 37.7% Kurds (Mourant et al. 1976) 1,529 35.3 Kurds (Al-Khafaji and Al-Rubeai 1976) Duhok 314 38.5 Sulaimaniya 3,916 36 Kirkuk 340 37.1 Baghdad 616 35.9 Arbil 1,059 39 Kurds, Total 7,774 36.4 Turkmen (Mourant et al. 1976) 128 36.7 Assyrians (Ikin et al. 1965) 99 39.4

303

% blood groups A B 31.1 25.6 30.6 18.9 28.8 23.9 29.3 22.8 27.8 29.1 24.1 26 21.7 32.6 27.4 28.9 23.8 25.4 32.4% 23.5% 30.2 19.6 34.7 34.3 35.9 37 33.2 33.7 38.3 27.3

21.3 23 22.1 20.8 22.9 22 17.2 25.3

AB 7 9 12.6 12.2 6.3 3.4 6.5 6 4.8 6.4% 14.9 5.4 6.7 5 6.3 4.9 7.9 7.8 8

Investigators from Mosul medical College (Ahmad and Taha 1983) studying N-acetylation frequency among 57 volunteers revealed that 58, 7 and 35% were slow, intermediate and rapid acetylators respectively. In Baghdad, among 67 volunteers, frequency of slow and rapid acetylators was 71.6 and 28.4% respectively (Najim et al. 2005). In North America and Europe, 50% of the population is reported to be slow inactivators, in contrast to the Japanese, who are predominately rapid inactivators (Emery and Mueller 1992). The results of a study of Phenylthiocarbamide [P.T.C.] taste sensitivity and threshold among 110 Iraqi Medical students of Arab ethnic origin indicated that the incidence of tasters was 78.2% (Shah and Sattar 1981). Among a sample of 21,462 Iraqi subjects, 2.9% were reported to have color blindness (Jamil et al. 1994).

Genetic Disorders in Iraq Data on the epidemiology and magnitude of genetic diseases in Iraq are scarce and patchy. The available information is predominantly derived from analysis of referred cases to genetics or other related units rather than from direct population surveys. Mendelian genetic disorders reported from Iraq are listed in Table 10.5.

304

Hanan A. Hamamy

Table 10.5 Mendelian disorders reported from Iraq Disease MIM No Autosomal Dominant Aarskog’s syndrome 100050 Achondroplasia 100800 Apert’s syndrome 101200 Saethre-Chotzen 101400 Albright hereditary osteodystrophy 103580 Stickler’s syndrome 108300 Gorlin-Goltz 109400 Cornelia De Lange 122470

Crouzon syndrome Nuclear cataract congenital MODY Coffin-Siris syndrome Frontal nasal dysplasia Holt Oram Opitz syndrome Kallmann’s syndrome Klippel-Trenaunay-Weber Treacher Collins Moebius syndrome Fascioscapulohumeral muscular dystrophy Limb girdle muscular dystrophy Neurofibromatosis Noonan syndrome Osteogenesis Imperfecta

123500 123580 125850 135900 136760 142900 145410 147950 149000 154500 157900 158900 159000 162200 163950 166200

Gardner’s syndrome Peutz-jegher syndrome Porphyria: acute intermittent Progeria Retinitis pigmentosa

175100 175200 176000 176670 180100

Ectrodactyly Tuberous sclerosis Waardenburg’s syndrome

183600 191100 193500

Freeman-Sheldon syndrome Autosomal Recessive hypotrichosis with monilethrix hairs and congenital scalp erosions Brachydactyly, Type C Carpenter syndrome Congenital adrenal hyperplasia alkaptonuria Retinal aplasia Bardet Biedl syndrome Seckel syndrome Familial carnitine deficiency Chondrodysplasia punctata

193700

References Al-Hakeem and Hamamy (1992) Sarsam and Izzat (1986) Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished Al-Yazachi (1986) Personal observation, unpublished; Al-Hakeem and Hamamy (1992), Al-Rawi et al. (1986) Personal observation, unpublished Personal observation, unpublished Alwan and Shamdeen (1989) Al-Mosawi (2006) Al-Hakeem and Hamamy (1992) Al-Hakeem and Hamamy (1992) Al-Hakeem and Hamamy (1992) Hamamy and Al-Taha (1989a) Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished Al-Azzawi et al. (1987) Al-Azzawi et al. (1987) Al-Sharbati et al. (1993) Hamamy and Al-Taha (1989b) Personal observation, unpublished; Al-Khaidhaire (1994) Safar and Sawa (1992) Al-Shawk et al. (1983) Al-Windawi and Al Naama (1984) Sarsam and Izzat (1986) Personal observation, unpublished; Al-Kanani (1990) Personal observation, unpublished Al-Rawi et al. (1986) Personal observation, unpublished; Al-Hakeem and Hamamy (1992), Al-Huwaizi (1987) Amin-Zaki et al. (1972) Al-Hakeem and Hamamy (1992) Schaffer et al. (2006)

113100 201000 201910 203500 204000 209900 210600 212140 215100

Baraitser and Burn (1983) Personal observation, unpublished Personal observation, unpublished Al-Mefraji (2008) Personal observation, unpublished Beales et al. (2001) Børglum et al. (2001) Shahar et al. (1988) Personal observation, unpublished (continued)

10


Table 10.5 (continued) Disease Cockayne syndrome Cohen syndrome Cystic fibrosis cystinosis Wolfram syndrome Epidermolysis bullosa Fanconi’s anemia

305

MIM No 216400 216550 219700 219800 222300 226600 227650

Galactosemia Gangliosidosis Glycogen storage disease Paget Disease, Juvenile Hypophosphatasia Icthyosiform erythroderma Icthyosis Kartagener’s syndrome Kartagener’s syndrome Laurence-Moon’s syndrome Meckel Gruber Familial Mediterranean fever Megalencephaly with Dysmyelination Microcephaly Microphthalmia Orofaciodigital syndrome II Hurler syndrome Sanfilippo’s syndrome Morquio’s syndrome Werdnig-Hoffman Duchenne-like, autosomal recessive (SARCMD) nephronophthisis Nephrotic syndrome: congenital Congenital nephrosis Niemann-Pick Disease, Type C1 primary hyperoxaluria Laron dwarfism

230400 230500 232200 239000 241500 242100 242300 244400 244400 245800 249000 249100 249240 251200 251600 252100 252800 252900 253000 253300 253700 256100 256300 256300 257220 259900 262500

Polycystic kidney; infantile Multiple pterygium syndrome Retinitis pigmentosa

263200 265000 268000

Smith-Lemli-Opitz Pendred syndrome Trichorhinophalyngeal Usher syndrome Xeroderma pigmentosum

270400 274600 275500 276900 278700

Xeroderma pigmentosa

278720

De-Sanctis-Cacchioni’s syndrome

278800

References Personal observation, unpublished Al-Hakeem and Hamamy (1992) Al-Hassani (1977) Al-Mosawi (2002) Nagi (1979) Personal observation, unpublished Personal observation, unpublished; Al-Hakeem and Hamamy (1992) Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished Cundy et al. (2002) Sarsam and Izzat (1986) Personal observation, unpublished Personal observation, unpublished Al-Hassani (1977) Al-Hassani (1977) Personal observation, unpublished Personal observation, unpublished Bakir and Murtadha (1975) Harbord et al. (1990) Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished Al-Rawi et al. (1986) Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished Teebi (1994) Al-Mosawi (2002) Al-Nadawi and Atra (1984) Nagi and Nouri (1974) Fensom et al. (1990) Al-Mosawi (2002) Personal observation, unpublished; Sarsam and Izzat (1986) Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished; Al-Kanani (1990) Personal observation, unpublished Al-Huwaizi (1990) Al-Hakeem and Hamamy (1992) Personal observation, unpublished Al-Jadiry et al. (1987), Al-Saleem et al. (1984) Al-Khatib and Abdul Hadi (1995), Al-Hadithi and Al Saleem (1991) Al-Jadiry et al. (1987) (continued)

306 Table 10.5 (continued) Disease Retinal detachment, cataract, facial dysmorphism, generalized osteoporosis, immobile spine and platyspondyly Megarbane Syndrome

Hanan A. Hamamy

MIM No 605822

References Schmidt et al. (2001)

606527 (AR or XR)

Megarbane et al. (2001)

X-linked Androgen insensitivity Hypohidrotic ectodermal dysplasia FG syndrome G6PD deficiency

300068 305100 305450 305900

Leber’s optic atrophy oculocerebrorenal syndrome Rennpening’s syndrome Fragile X syndrome Juberg-Marsidi Becker muscular dystrophy Duchenne muscular dystrophy

308900 309000 309500 309550 309580 310200 310200

Hamamy and Al-Taha (1989b) Personal observation, unpublished Al-Hakeem and Hamamy (1992) Al-Naama et al. (1984), Amin-Zaki et al. (1972), Hamamy and saeed (1981) Al-Kanani (1990) Al-Mosawi (2002) Al-Hakeem and Hamamy (1992) Al-Hakeem and Hamamy (1992) Al-Hakeem and Hamamy (1992) Personal observation, unpublished Personal observation, unpublished; Al-Azzawi et al. (1987) Yaseen (1995) Personal observation, unpublished

Congenital nystagmus 310700 Orofaciodigital syndrome I 311200 MIM based on McKusick OMIM, 11 December 2008

Congenital Malformations Studies on the birth prevalence of congenital and genetic disorders that are lethal or cause lifelong impairment if untreated indicated that, of the six World Health Organization (WHO) regions, the highest rate of 65 affected per 1,000 live births was reported in the Eastern Mediterranean region that includes the majority of Arab countries (Alwan and Modell 2003). These figures were supported by a recent March of Dimes report which estimated birth defects to be 69.9 per 1,000 live births in most Arab countries and 75.2 per 1,000 live births in Iraq, as opposed to 52.1 per 1,000 live births in Europe, North America, and Australia (Christianson and Howson 2006). The 1993 World Development Report (World Bank 1993) indicated that congenital malformations constitute 6.5% of the total disease burden for children less than 5 years of age in developing countries as well as 4% of 5 deaths for ages between 0 and 4 years. There are few published reports on the frequency of congenital malformations among newborns in Iraq.

10


307

In a study among 6,988 newly born infants in Ramadi obstetric and pediatric hospitals during the year 1990, the prevalence of gross congenital anomalies was reported to be 0.79% (Al-Ani and El Sebai 1994). During a prospective study of 5,974 consecutive birth from October 1993 to March 1994 at Basrah maternity and child hospital, the prevalence of major congenital malformations was given as 7.7 per total births (6.9 per 1,000 livebirths and 147per 1,000 stillbirths. Main defects included skeletal malformations [2.5 per 1,000], central nervous system abnormalities [1.84 per 1,000], known syndromes [1.25 per 1,000], urogenital system abnormalities [1 per 1,000], and skin abnormalities [0.33 per 1,000]. There were significant differences in congenital malformation rates in newborns of consanguineous versus non consanguineous parents. On the other hand there was no significant association with maternal age (Habeeb and Al-Sadoon 1995). Another study from Basrah on 392 livebirths in 2003–2004 showed that 1.78% had congenital defects (Shiyaa et al. 2006). Among 7,135 births in Baghdad Hospital, major congenital malformations were detected in 10.091 per 1,000 live births. Central nervous system and multiple malformations represented the commonest type. The rate of consanguineous marriages among parents of malformed babies was significantly higher than the rate among parents in the control group [64, 48% respectively], and the coefficient of inbreeding among parents of malformed babies and controls were 0.027 and 0.024 respectively. Consanguineous marriage was high among all types of congenital malformations except that of extremities (Mahdi 1992). In a prospective study on 24,250 schoolchildren in Baghdad–Alresafa, the frequency of cleft lip and/or cleft palate was 1.24 per 1,000 (Al Zubaidee and Hammash 1997). The scant data obtained through analyzing various etiological factors indicate an increased frequency of autosomal recessive disorders. Among 377 children with congenital anomalies referred to the genetic counseling clinic in Yarmouk Teaching Hospital in Baghdad between 1981 and 1986 (Hamamy 1989), etiological factors included 16.7% chromosomal aberrations, 40% single gene disorders, 2.9% multifactorial disorders and 2.9% environmental causes. The etiology remained undetermined in 37.5% of all cases. Among cases with single gene etiology, a high proportion of 66% was attributed to autosomal recessive conditions. In other words, 26.3% of all affected children suffered from autosomal recessive diseases. The consanguinity rate among parents of all children was remarkably high, at 77%, with 53% of first cousin marriages. Even when families with proven autosomal recessive conditions were excluded, the consanguinity rate among the rest of the parents was 68.2%. This figure is higher than the consanguinity rate of the general population, pointing to the possible contribution of autosomal recessive genes among cases with undetermined etiology. A similarly high rate of consanguinity (70%) was observed earlier among parents of a smaller group of congenitally malformed patients (Hamamy 1984). A compilation of all cases with congenital anomalies seen in the Al-Yarmouk Genetics Clinic from 1981 to 1990 showed a similar pattern (Table 10.6).

308

Hanan A. Hamamy Table 10.6 Etiological factors in 494 children with congenital anomalies referred to Al-Yarmouk Genetic Unit

Etiology Chromosome abnormality Mendelian disorders Multifactorial Environmental

% of total 18.4 40.9 4.7 36

Surgical intervention on 36 cases with neonatal intestinal obstruction during the period 1986–1996 showed that the main causes were imperforate anus (27.8%), duodenal atresia (13.9%) and colonic atresia and meconium ileus (11.1% each) (Nasir et al. 2000). Several rare congenital anomalies have been reported in Iraq, such as the case of accessory nose associated with unilateral complete congenital choanal atresia seen in Najaf, Iraq, (Al-Helo et al. 2008), posterior choanal atresia (Shehab et al. 1998), bilateral agenesis of parotid salivary glands in Sulaymania (Al-Talabani et al. 2008), and congenital prepubic sinus (Al-Wattar 2003). Eight hundred primary school children, 520 males and 280 females ranging in age from 7 to 12 years, studied for the presence of mitral valve prolapse (MVP) showed an incidence of 3.1%, with no significant sex difference. This study points out that MVP is more common in children in Mosul city than other parts of the world (Shaikhow and Al Jawadi 1989).

Mental Retardation A study of 185 mentally retarded children referred to the Children’s Department of Medical City in Baghdad between 1978 and 1983 (Al-Rawi et al. 1986) showed a parental consanguinity rate of 76%, with 46% being first cousins. This high proportion suggests the possible etiological role of autosomal recessive genes in mental retardation. A family history of mental retardation was reported in 27% of the cases. Down syndrome was detected in 8% of the cases, where 73.3% and 86.6% were born to mothers and fathers over 35 years, respectively. Other cases included microcephaly (4.9%), kernicterus (4.9%), phenylketonuria (3.8%), hypothyroidism (3.3%), tuberous sclerosis (1.6%), mucopolysaccharidosis (1.1%), Cornelia de Lange syndrome (0.5%), and familial spastic paraplegia (0.5%). Precise diagnosis in about 40% of all cases was undetermined. Another study (Al-Hakeem and Hamamy 1992) was undertaken in six special educational and rehabilitation institutions for the mentally handicapped in Baghdad. Down syndrome comprised 25.7% of the studied population. The male/female ratio of 3.8:1 detected in this study may point to the role played by X-linked recessive conditions as well as other factors leading to increased male preponderance in special institutions, such as the social trend of keeping the mentally retarded females at home rather than enrolling them in a special school.

10


309

Clinical evaluation of 138 boys with undiagnosed mental retardation together with cytogenetic analysis of 60 of them verified the etiology in 31.9% of all cases (Al-Hakeem and Hamamy 1992). Autosomal and X-linked recessive genes caused 10.8 and 14.6% of all cases, respectively. Diagnosed cases included a child with XYY karyotype and another with the fragile X syndrome. Among 21 patients with undiagnosed severe mental retardation (MR) recruited from Al-Rajaa institution for MR in Najaf province, 14 patients revealed obvious chromosomal abnormalities (67%). Of the established chromosomal abnormalities, 13 patients were found to have autosomal abnormalities (61%), while one patient had sex chromosomal abnormality. Structural autosomal abnormalities (ring chromosomes and translocation) represented the majority of cases. A single case of mosaic Down’s syndrome was seen (Yasseen and Al-Musawi 2001). New cases of mental retardation seen in a private pediatric clinic in Baghdad 1988–1997 amounted to 447 cases (2.6% of all new consultations). Male to female ratio was 1.4. The group of MR related to perinatal difficulties amounted to 50.1% of cases. Hypoxic injury was responsible for more than one fourth of all cases (Al-Thamery 1999). Biochemical tests confirmed the diagnosis of aminoacidopathy in 48% of 768 Iraqi children clinically suspected with inborn errors of metabolism. Cystinuria, galactosemia and phenylketonuria were the major groups of aminoacidopathy distributed in these children, followed by Hartnup disease, Fanconi syndrome, maple syrup urine disease, occulocerebrorenal disease, homocystinuria. tyrosinosis, mucopolysacharoidosis and histidinaemia, respectively (Abboud 1993).

Down Syndrome The birth incidence of Down syndrome in Iraq has not been cytogenetically investigated. The contribution of Down syndrome to the etiology of mental retardation ranged between 8 and 26% in different studies (Al-Rawi et al. 1986; Al-Hakeem and Hamamy 1992). The effect of consanguinity on the occurrence of Down syndrome was investigated in Baghdad (Hamamy et al. 1990). Eightythree infants and children with cytogenetically confirmed Down syndrome were distributed according to parental consanguinity (Table 10.7). The results showed that the rate of consanguinity was lower among parents of trisomic children than the Table 10.7 Distribution of 83 down syndrome cases according to parental consanguinity Hamamy et al. (1990) Consanguinity Trisomy Mosaicism Both No % No % No % Not related 53 77.9 8 53.3 61 73.5 First cousins 11 16.2 4 26.7 15 18.1 Second cousins 4 5.9 3 20 7 8.4 total 68 81.9 15 18.1 83 100

310

Hanan A. Hamamy

general population figures. The difference, however, was not apparent in cases of Down syndrome with mosaic chromosome pattern. Karyotype analysis of 150 cases of Down’s syndrome in Baghdad showed that 90.7, 5.3 and 4% were trisomic, mosaic and translocation Down’s syndrome respectively (Farman and Shakir 1976). An interesting finding was the demonstration of an increased rate of sister chromatid exchanges in lymphocytes of Down syndrome patients and their parents (Shubber et al. 1991). This genomic instability and deranged DNA repair mechanisms were accentuated by exposure to mutagenic agents. This may suggest a role for genomic instability in non-disjunction events. However, it may suggest that both non-disjunction and the genomic instability may have resulted from exposure to mutagenic or clastogenic environmental factors.

Infertility Problems Among the undiagnosed azoospermic men studied for genetic etiology, 39% had first cousin parents as compared to 30% among the general population of the same area. Klinefelter syndrome was diagnosed in 22.9% of 131 azoospermic men, while 3.1% of cases revealed a polymorphic large Y chromosome and 2.3% showed Kallmann syndrome (Hamamy and Al-Taha 1989a). In another study on 64 infertile males with azoospermia or oligospermia in Kufa, Iraq (Yasseen et al. 2001), Klinefelter syndrome was diagnosed in seven patients (11%), while an autosomal translocation was seen in one patient. The contribution of chromosome anomalies among 200 women with primary amenorrhea was studied (Hamamy and Al-Taha 1989b). The results revealed that chromosomal abnormalities were implicated in 8.5% of cases who have Turner syndrome. Testicular feminization syndrome was diagnosed in 6.9% while 8% of cases have presumably autosomal recessive disorders manifesting as primary amenorrhea with or without other stigmata such as deafness or alopecia. Absence of Mullarian derivatives was found in another 7% of cases with 46, XX karyotype suggestive of Rokitansky-Kuster-Hauser syndrome. One case of Noonan syndrome (0.5%) was seen. Unpublished data showed that 41% of parents of females with primary amenorrhea of unknown etiology were first cousins. The contribution of chromosome aberrations in spontaneous abortions was studied in 100 couples with repeated fetal death (Hamamy and Al-Taha 1996). The study revealed that one partner in eight couples (8%) had a chromosomal anomaly. In 4% of males, the polymorphic long Y chromosome was found. Although the number studied is small, an interesting finding was that a consanguinity rate of 67% was observed among couples who experienced infant deaths or congenitally malformed offspring in addition to fetal loss, as compared to a consanguinity rate of 42% among couples with early spontaneous abortion only. A negative correlation between early spontaneous abortion frequency and rate of

10


311

first cousin marriages has been observed among a sample of the population in Baghdad (Hamamy et al. 1986). An interesting finding in couples with unfavorable reproduction in Baghdad is the demonstration of an increased frequency of sister chromatid exchanges in their somatic cells (Hamamy et al. 1992). This indicates persisting DNA lesions resulting from various conditions which may include exposure to environmental mutagens and clastogens or a possible presence of inherent genetic instability. Association behavior of acrocentric chromosome in 57 infertile males assessed at Kufa University, Iraq, showed statistically significant difference in infertile male classes compared to control groups. This significant increase in the satellite association is proposed to have another indirect causal factor, which influenced spermatogenesis (Yasseen and Aunuiz 2002).

Blood Disorders Hemoglobinopathies and glucose-6 phosphate dehydrogenase (G6PD) deficiency are common in Iraq, a situation similar to most neighboring countries (Hamamy and Alwan 1994; Al-Gazali et al. 2006, Hamamy and Bittles 2008). Available data on the frequency of hemoglobinopathies in various regions in Iraq is presented in Table 10.8. Beta thalassemia major is an important health problem throughout Iraq, including the Dohuk region, where there are more than 250 registered patients, in a population of about one million. The problem is further accentuated by the high rate of consanguineous marriages estimated at 25.3% in the region. Among parents of 104 unselected beta-thalassemia major/intermedia patients, registered at the

Table 10.8 Distribution of hemoglobinopathies in Iraq Region (reference) Studied population

Basrah (Al Kasab et al. 1987) Basrah (Al Kasab et al. 1987) Basra (Hassan et al. 2003) Baghdad (Yahya et al. 1996) Dohuk (Al-Allawi, Al-Dousky, accepted) Sulaimaniya (Jalal et al. 2008)

bthalassemia carrier rate

bthalassemia major

athalassemia carrier rate

610 women 15–44 years 10–12 years

Sickle cell carrier rate 16%

Sickle Bdcarrier cell anemia rate 1.7% 2.6%

1,064 couples 14–60 years 502 pregnant women 1,182 premarital screening

4.6%

1,472 premarital screening

4.14%

4.4%

6.5% 1%

3.7%

3.3%

0.2% 1.2%

0.1%

0.27%

0.14%

312

Hanan A. Hamamy

Dohuk Thalassemia Care Center, consanguinity rate was 64.4% (Al-Allawi et al. 2006). Molecular studies of hemoglobinopathies in Iraq are scarce. In one study from Dohuk on 104 b-thalassemia patients, 12 different mutations were identified. The eight most frequent mutations constituting 81.7% of all defects included in order of frequency: IVSII-1 (18.3%), codon 44 (12.5%), codon 5 (10.6%), IVSI-1 (8.7%), IVSI-6 (8.7%), codon 39 (8.7%), codons 8/9 (7.7%), and IVSI-5 (6.7%). Less frequent mutations involved codons 8, 22, 30 and IVS-1-110. The molecular defects remained uncharacterized in 12 cases (1–1.5%). Hb A2 levels in the 102 cases with beta-thal minor ranged between 3.4 and 8.0% (mean of 5.45 0.98) (Al-Allawi et al. 2006). The Dohuk region lies at the extreme north of Iraq, midway between Iran, Turkey and Syria. This region includes four main towns surrounded by hundreds of small towns and villages, in a rough mountainous terrain. Its population is estimated at around one million, mainly Kurdish Muslims, with a small Kurdish Yezidi minority. The detection of 12 different mutations responsible for betathalassemia in this region reflects the interaction of the population throughout history during various occupations and migrations. To some extent, the pattern of these mutations is unique since the 12.5% frequency of codon 44 is much higher than has been reported in any of the surrounding countries or elsewhere, and is only surpassed by its frequency in Jewish Kurds originating from this same area (Al-Allawi et al. 2006). A new beta-chain silent variant in a family with multiple hemoglobin disorders was detected and named Hb Iraq-Halabja beta10 (A7) Ala!Val (GCC!GTC): (Deutsch et al. 1999). From Mosul in northern Iraq (Kheder and Bashir 1990), data on 37 obligatory beta-thalassemia carriers has indicated that three quarters had an elevated HB F level above 1%, with a range of 1.7–3.3%. It was found that the most common a-thalassemia genotypes in 51 individuals with unexplained hypochromia and/or microcytosis from the Dohuk region in northern Iraq were –a3.7/a a, followed by – –MED-I/a a, then – a 3.7/– a 3.7, respectively, detected in 84.3% of the above individuals. Other genotypes identified sporadically were – a 4.2/a a, apoly A1 a/a a (AATAAA>AATAAG), a Adana a/a a [Hb Adana, codon 59 (Gly a Asp) or HBA1:c.179G>A] and a Evanston a/a a [Hb Evanston, codon 14 (Trp a Arg) or HBA1:c.43 T>C]. Three cases (5.88%) remained uncharacterized even after sequencing. All nine Hb H cases carried the – a 3.7/– –MED-I genotype (Al-Allawi et al. accepted 2009). In Mosul, among 700 thalassemics, 105 transfusion dependent children, 2.5–18 years of age attended Ibn-Al-Atheer teaching hospital in Mosul City, Iraq, during 2005 (Al-Samarrai et al. 2008). In Sulaimaniya, a Kurdish city in Northern Iraq, Hb C trait, homozygous hereditary persistence of fetal hemoglobin, and Hb H disease were detected in 0.14, 0.07, and 0.07% respectively among 1,472 subjects attending the premarital checkup. Consanguinity rate in the studied population was 24.3%. Among the 1.5

10


313

million population of this city, there were 600 registered cases of beta-thalassemia major/intermedia (Jalal et al. 2008). Sickle cell anemia affected the weight and height of 75 males aged 18 years with sickle cell anemia (SCA); 77.3% showed weights below the 5th centiles and 46.6% had heights below the 5th centile (Mansour 2003). Reports indicate that the clinical severity of SCA in Southern Iraq is intermediate betweeen the African and Saudi types (Al-Shawi 1988; Al-Kasab 1980). A rare medical case was also reported for the first time in Iraq in a woman of 35 years of age born with cyanosis not accompanied with dyspnea, the cause of cyanosis was found to be a rare hemoglobin called methaemoglobin M (Bashir and Al Taee 1988). The frequency of glucose-6-phosphate-dehydrogenase (G6PD) deficiency in Iraq ranges between 8.4 and 13% (Table 10.9), with some variability in distribution among ethnic groups (Table 10.10) In the study on 305 males and 394 females using Beutler’s fluorescent spot test for screening (Hamamy and Saeed 1981), the extent of deficiency varied with age , being highest among children and lowest in those over 50 years. About 35% of female heterozygotes could be detected using this test. The level of G6PD enzyme activity was higher among neonates than among adults (Al-Naama et al. 1994).

Table 10.9 G6PD deficiency in Iraq Region (Ref) Males Baghdad (Amin Zaki et al. 1,043 1972) Baghdad (Hamamy and 305 Saeed 1981) Basrah (Al-Naama et al. 1994), level of enzyme activity was measured

Number Females Both 409 1452

% of G6PD deficiency Males Females Both 8.6 8.5 8.6

394

12.4

8.8

7.9

9.7

9.2 6.1 15.3

11.8

699 456 neonates

186 adults Baghdad (Hilmi et al. 2002) 758 Basra (Hassan et al. 2003) 1,064 couples

Table 10.10 G6PD deficiency in some ethnic groups in Iraq Ethnic group Number of samples examined Males Femalesa a b Arab 489 703 191 85 Kurd 211a 34b 45 Turkuman 142a 18b 53 Chaldean 131a 35 Assyrian 70a a Amin-Zaki et al. (1972) b Hilmi et al. (2002)

10.4

12.5

Frequency of G6PD deficiency Males Femalesa a b 9.4% 6% 8.4% 7.6%a 8.8%b 7.3% 6.3%a 5.6%b 6.6% 8.4%a 9.4% 11.4%a 8.5%

314

Hanan A. Hamamy

In a study from Basrah, human erythrocyte G6PD activity was estimated using a quantitative spectrophotometric technique (Al-Naama et al. 1984). The reference value for G6PD was found to be 6.9 2.6IU/g Hb (mean SD) using hemolysates of 166 male and female healthy individuals. Similarly, the activity of 6-phosphogluconate dehydrogenase was found to be 5.9 0.99 IU/gm Hb. Complete G6PD deficiency (zero activity) and partial deficiency (below 4.3 IU/g Hb) were detected in 9.05 and 3.95% of 177 tested individuals respectively. An overall incidence of G6PD deficiency was thus found to be 13% among both sexes in the Basrah population. An interesting positive association of G6PD deficiency with diabetes mellitus was observed in 318 diabetics in Baghdad (Saeed et al. 1985). The distribution of G6PD deficiency varied with age, sex and duration of diabetes. The underlying nature of this positive association remains unknown. The authors favor the idea that G6PD deficiency is the result of, rather than a predisposing cause in diabetes mellitus. Among 758 randomly selected healthy Iraqi males aged 18–60 years, the predominant non-deficient G6PD phenotype was G6PD B (92.6%), G6PD Aþ was found in a polymorphic frequency (1.3%). In 46 deficient cases, 31 were fully characterized, including 17 cases with features consistent with G6PD Mediterranean variant, while 12 had other biochemical features and were labeled as nonMediterranean variant. The remaining two deficient cases were characterized as G6PD A– variant (Hilmi et al. 2002). The prevalence rate of factor V Leiden as detected by DNA analysis was 3% among 100 Iraqi blood donors. Although this is much lower than the prevalence rates of 14.2, 13.6, and 12.25% reported in Lebanon, Syria, and Jordan, respectively and to a lesser extent than the rates in Turkey (7.4%) and Iran (5.5%), the Iraq rate is comparable to the prevalence of 2.5% reported in Saudi Arabia. This may be related to a common origin and closer links between the population of Iraq (including Baghdad) and that of the Arabian Peninsula throughout history (Al-Allawi et al. 2004). Among one hundred and fifty consecutive healthy blood donors from the regional blood bank in Dohuk-Iraq, Factor V Leiden and Prothrombin G20210A carrier states were found in 1.2% and 3% of the individuals respectively. The MTHFR C677T homozygous and heterozygous states were confirmed in 8% and 44% respectively. The study demonstrated that while the prevalence of Prothrombin and MTHFR mutations were rather consistent with the pattern seen in surrounding countries in the Mediterranean region, Factor V Leiden prevalence was the least ever reported from any other population in the region. The latter finding suggests that the contribution of Factor V Leiden to thrombotic states in Northern Iraq may not be as significant as it is in other countries in the region (Al-Allawi et al. personal communication).

Familial Mediterranean Fever (FMF) This genetic disorder affecting mainly people of Mediterranean origin has been reported in Iraq (Bakir and Murtadha 1975). The study on 41 cases included 26 Arabs, 10 Armenian, three Kurds and two Assyrians. In about half the cases, the

10


315

disease began in the first decade, and in 75% of cases, before the end of the second decade. As in other studies on Arabs (Barakat et al. 1986), the incidence of amyloidosis in this series was quite low. Another study on 80 cases of FMF in Iraq showed that amyloidosis occurred in only two cases (Bakir et al. 1979). Recently, molecular studies among a cohort of 176 healthy adult Iraqis showed that the FMF mutation E148Q was detected in 29 per 352 chromosomes. The V726A mutation was detected in 9 per 352 chromosomes. Mutations M694V, M694I and M680I were not detected. This gives a mutant allele frequency “q” of 0.108, and a calculated carrier rate of 11.4% (Al-Alami et al. 2003). A unique FMF haplotype common to Iraqi Jews, Arabs, and Armenians was observed supporting the view that a few major mutations account for a large percentage of the cases of FMF and suggest that some of these mutations arose before the affected Middle Eastern populations diverged from one another (Balow et al. 1997). A high frequency of carriers of FMF of 29–39% was found among Iraqi Jews (Stoffman et al. 2000).

Common Multifactorial Diseases Remarkable changes have taken place in the epidemiological pattern of disease in Iraq during the last four decades. Declining incidence of infectious and nutritional disorders has been associated with an apparent increase in morbidity and mortality from common multifactorial diseases such as hypertension, coronary heart disease, diabetes mellitus, and cancer. As in other Arab countries (Alwan and King 1992; Alwan 1993), diabetes and hypertension have emerged as major health problems. A study performed in a small village, population 15 years and over in southern Iraq, using glucose tolerance test, revealed an overall prevalence of diabetes of 4.8% (Al-Kasab et al. 1979). The figure is probably an underestimate since it does not provide information on impaired glucose tolerance, and also it may not reflect the situation in the urban population. A more recent study providing data on diabetes mellitus and impaired fasting glucose (IFG) in Basrah, Iraq for the period of April–May 2007 among 3,176 participants gave a combined prevalence of 7.43% for diabetes and 2.02% for IFG (Mansour et al. 2008). A study involving 1,175 diabetic patients in Baghdad revealed that type 1 diabetes was present in 16.5% of cases, and type 2 diabetes occurred in over 82.5% of cases. Maturity onset diabetes of youth (MODY), an autosomal dominant condition, was reported in less than 1% of cases (Alwan and Shamdeen 1989). The health system in Iraq underwent progressive decline since the embargo or the economic sanctions that followed the second gulf war in 1991. The war in 2003 exacerbated this decline by causing further damage to the infrastructure, with lack of security leading to impaired drug distribution. Electricity problems contributed to the difficulties in drug storage. Currently, the Iraqi health system is unable to

316

Hanan A. Hamamy

cope with the healthcare needs of its population. Of a population of 27 million Iraqis, the prevalence of type 2 Diabetes is reaching epidemic proportions, affecting an estimated two million people–7.43% of the overall Iraqi population. During the period January to December 2007, 2,688 patients with diabetes of 1–30 years duration and A1C 7% were seen at the diabetes out-patient clinic in Al-Faiha general hospital in Basrah. These patients responded to the question of “Why do you think that it is difficult to control your diabetes?” Main causes given in their response were no drug supply from primary health care center (PHC), drug shortage, high expense of drugs and migration (Mansour 2008). A survey study was conducted on 158 subjects aged over 25 years living in two villages near Mosul. The overall prevalence of diabetes was 10.1% (Mulla Abed and Waad Allah 1992). The prevalence of hypertension among an examined population sample over the age of 15 years was 12.3 and 9.5% for the urban and rural populations respectively (Alwan et al. 1982). Increase in age and obesity was accompanied by a progressive rise in the prevalence of hypertension. Detection rate was found to be quite low, since over 80% of cases were undiagnosed prior to the survey. The point prevalence of hypertension [HT] among 1,098 male workers was found to be 11.8% (Hussien and Jamil 1993). A cross-sectional study recruiting 1,427 school aged students (6–12 years) from eight primary schools in Baghdad during the period November 2001 to May 2002 showed that the overall prevalence of hypertension was 1.7% with no significant gender distribution (Subhi 2006).

Childhood Blindness From 1970 onward, genetically determined diseases accounted for 81% of childhood blindness (Al-Kanani 1990). The most commonly encountered conditions were congenital cataract (28.3%), retinitis pigmentosa (27.4%), congenital glaucoma (12.3%), and Leber’s optic atrophy (8.5%). The consanguinity rate of parents of the affected was, however, not significantly different from that of the general population.

Deafness In Baghdad, eight schools accepted deaf-mute children aged 6–16 years; in the academic year 1987–1988, 797 children from 702 families were enrolled. Family studies of the deaf-mute children indicated that deaf-mutism was acquired in 16.2% and congenital in 83.8%. Among the congenital group 39.3% are multiplex families with affected sibs and normal parents, strongly pointing to an autosomal recessive etiology. Moreover, among the singles families, rate of first cousin marriages was

10


317

49.5% as compared to 30.1% among the group with acquired deaf-mutism, implying the action of autosomal recessive genes (Harith 1990; personal). A comprehensive survey of 7,500 children in Mosul was carried out from December 1997 through to December 2000. The overall prevalence of hearing impairment was 10%. The proportions of those with sensorineural hearing loss and those with severe to profound bilateral sensory-neural hearing loss were 1.6% and 0.15% respectively. This prevalence rate of severe to profound sensory-neural hearing loss is considered high when compared to the rate in developed countries (Al-Allaf et al. 2003).

Short Stature Among 120 patients aged 6–18 years with short stature (Sarsam and Izzat 1986), familial isolated growth hormone deficiency was diagnosed in 40%. One family had four children with Laron dwarfism. Idiopathic panhypopituitarism was the etiological factor among 4.2% while 2.5% manifested a craniopharyngioma. The diagnosis of celiac disease confirmed by jejunal biopsy accounted for 16.7% of cases of short stature. An important etiological factor among girls was Turner syndrome, accounting for 15.8% of short stature cases among the girls. Hypothyroidism was documented in 6.7% of cases. Monogenic disorders seen in this study included achondroplasia, hypophosphatasia, and progeria.

Conclusions Iraq is considered a country in turmoil due to the devastating impact of three major wars and a long period of imposed economic sanctions in the past three decades. The decline in health services and basic health indicators has markedly hampered the development of genetic services and genetic research in the country, at a time when the rest of the Arab world and the World in general are making huge advances in this field. The data given in this chapter is derived from the few publications on genetic diseases that have been mostly retrieved from local journals [WHO, IMEMR]. This data reflects the minimum of the burden of genetic and congenital disorders in the country. Despite the scarcity of epidemiologic studies on the frequency of hereditary disorders in Iraq, the analysis of available data indicates that some disorders occur in high frequencies, causing considerable suffering, severe disabilities, and early death. Hemoglobin disorders and enzymopathies, autosomal recessive disorders in general, Down’s syndrome, and congenital malformations are generally considered examples of common problems. The magnitude of multifactorial disorders such as hypertension, diabetes mellitus and coronary artery disease is growing significantly.

318

Hanan A. Hamamy

More data on the types and frequencies of genetic disorders in Iraq is required. Emphasis should be directed toward research on the major causes of congenital malformations and the contribution of teratogenic factors. The impact of consanguinity on the rate of birth defects needs thorough investigations. The provision of genetic services in Iraq is currently inadequate given the prevalence and burden of genetic diseases. Improving this situation calls for major efforts including the implementation of projects that involve increasing the genetic literacy of the general public and the health care sector, designing comprehensive courses and campaigns to familiarize primary health care workers with counseling needs and skills and with referral guidelines for high-risk families, updating medical, nursing, and paramedical curricula to incorporate information on community genetics, and training clinical and laboratory genetic specialists to meet the short- and long-term goals of genetic disease prevention and management. National newborn screening programs for metabolic errors and hypothyroidism are needed, as well as national premarital screening programs for hemoglobinopathies. Community genetic programs could be structured according to local needs and in accordance with social, cultural and religious beliefs. Acknowledgment I am deeply grateful to Professor Nasir Al-Allawi, Professor of Hematology, Scientific supervisor of Hemoglobinopathy preventive program, College of Medicine, University of Dohuk, Iraq, for providing me with valuable data and references on hereditary blood disorders in Iraq.

References Abboud M (1993) Aminoacidopathies among Iraqi children suspected with inborn errors of metabolism. J Fac Med Baghdad 35(2):57–60 Abdullah NF (1976) Human blood groups in Basrah. Man (NS) 11:239–242 Abdullah NF (1981) Distribution of blood groups among the Iraqi Arabs. J Fac Med Baghdad 23(4):453–472 Ahmad RA, Taha IA (1983) Acetylation in Iraqi population. Iraqi Med J 31:53–57 Al-Agidi SK, Papiha SS, Roberts DF (1977) Immunoglobulin levels in Iraq. Clin Exp Immunol 29(2):247–255 Al-Alami JR, Tayeh MK, Najib DA, Abu-Rubaiha ZA, Majeed HA, Al-Khateeb MS, El-Shanti HI (2003) Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Med J 24(10):1055–1059 Al-Allaf A, Ali A, Muneer M (2003) Deafness in chilren and the need for cochlear implants. J Bahrain Med Soc 15(4):219–222 Al-Allawi N, Al-Dousky A. Frequency of Hemoglobinopathies and Service Indicators for their Preventive Program in the Dohuk Governerate-Iraq. Accepted for publication in East Mediterr Health J Al-Allawi N, Badi A, Imanian H, Nikzat N, Jubrael J, Najmabadi H (2009) Molecular characterization of α-thalassemia in the Dohuk region of Iraq. Haemoglobin 33(1):37–44 Al-Allawi N, Jubrael J, Baban N, Gedeon G. Thrombophilic Mutations in Blood Donors in DohukIraq. Personal communication Al-Allawi N, Jubrael J, Hilmi F (2004) Factor V Leiden in Blood Donors in Baghdad (Iraq). Clin Chem 50(3):677–678

10


319

Al-Allawi NA, Jubrael JM, Hughson M (2006) Molecular characterization of beta-thalassemia in the Dohuk region of Iraq. Hemoglobin 30(4):479–486 Al-Azzawi HT, Al-Salihi AR, Saleem IH, Fadhli AA, Zaidan ZA (1987) alpha Naphthyl acetate esterase activity in monocytes and lymphocytes of normal and muscular dystrophic individuals. Iraqi Med J 35(1):19–24 Al-Ani S, El Sebai HF (1994) Gross congenital malformations in neonates in Ramadi city during the year 1990: types, incidence, and possible teratogens J. Fac Med Baghdad 36(4):609–614 Al-Gazali L, Hamamy H, Al-Arrayad S (2006) Genetic disorders in the Arab world. BMJ 333 (7573):831–834 Al-Hadithi F, Al Saleem T (1991) Ocular manifestations of xeroderma pigmentosa in Iraq. Saudi J Ophthalmol 5(1):6–8 Al-Hakeem S, Hamamy H (1992) Genetic studies on institutionalized mentally retarded males with special reference to the FragileX syndrome. Extracted from MSc Thesis, Al-Mustansiriya Medical College, Baghdad Al-Hassani M (1977) Cystic fibrosis in Iraqi children. J Trop Paed 23:36–137 Al-Helo S, Taghi AS, Mahboba S (2008) Unusual case of accessory nose associated with unilateral complete congenital choanal atresia. Saudi Med J 29(9):1342–1343 Al-Huwaizi F (1987) Waardenburg’s syndrome in an Iraqi family. J Fac Med Baghdad 29 (1):81–85 Al-Huwaizi F (1990) Pendred’s syndrome in eleven Iraqi patients. Pendred’s syndrome in eleven Iraqi patients. J Community Med 3(2):123–126 Al-Jadiry A, Rustam H, Al-Saleem T, Ismail MA (1987) Xeroderma pigmentosum. Saudi med J 8:468–475 Ali MM, Shah IH (2000) Sanctions and childhood mortality in Iraq. Lancet 355(9218):1851–1857 Al-Kasab F (1980) Sickle cell disease in southern Iraq. Med J Basrah Univ 3(2):25–38 Al-Kasab F, Al-Kafajei A, Kutty P, Al-Windawi S, Antony R, Zuabie A, Al-Septi S (1987) Hematological profile of women in the reproductive age in southern Iraq. Iraqi Med J 35(1):33–38 Al-Kasab FM, Alkafajei AM, Medbigh SH (1979) The prevalence of diabetes mellitus in a rural community in Iraq. Int J Epidemiol 8(1):69–71 Al-Khafaji SD, Al-Rubeai MA (1976) The frequencies of the ABO and Rh(D) blood groups in the Kurdish population of Iraq. Ann Hum Biol 3(2):189–191 Al-Khaidhaire S (1994) A new concept in diagnosis of osteogenesis imperfecta. J Fac Med Baghdad 36(2):225–229 Al-Khatib A, Abdul Hadi T (1995) Squamous cell carcinoma of the skin of face in patients with xeroderma pigmentosum. J Fac Med Baghdad 37(3):397–400 Al-Kanani S (1990) Childhood blindness in Iraq J Fac Med Baghdad 32(1):103–108 Al-Mefraji SH (2008) May-Jun. Alkaptonuria in a 5-year-old boy in Iraq. East Mediterr Health J 14(3):745–746 Al-Mefraji SH, Al-Tawil NG, Karim LA (2006) Anthropometric measurements of a group of newborns in a teaching hospital in Baghdad. Saudi Med J 27(6):870–873 Al-Mosawi AJ (2006) Genetic drift. Letter from Baghdad: Coffin–Siris syndrome in a girl with absent kidney. Am J Med Genet 140(16):1789–1790 Al-Mosawi AJ (2002) The etiology of chronic renal failure in 54 Iraqi children. Pediatr Nephrol 17(6):463–464 Al-Naama MM, al-Naama LM, al-Sadoon TA (1994) Glucose-6-phosphate dehydrogenase, hexokinase and pyruvate kinase activities in erythrocytes of neonates and adults in Basrah. Ann Trop Paediatr 14(3):195–200 Al-Naama L, Al-Gailany K, Al-Kaysi G (1984) Human erythrocytes glucose 6-phosphate dehydrogenase and 6-phosphogluconate in Basrah area. J Fac Med Baghdad 26(1):101–109 Al-Nadawi M, Atra A (1984) Congenital nephrotic syndrome. J Fac Med Baghdad 26(3):97–102 Al-Rawi F, Al Naddawi M, Al Musawi Z (1986) Mental retardation in Iraqi children. J Fac Med Baghdad 28(4):29–36

320

Hanan A. Hamamy

Al-Samarrai AH, Adaay MH, Al-Tikriti KA, Al-Anzy MM (2008) Evaluation of some essential element levels in thalassemia major patients in Mosul district, Iraq. Saudi Med J 29(1):94–97 Al-Shawi TS (1988) A study of Sickle Cell Disease in young adult males in Iraq. MSc thesis. College of Medicine, University of Baghdad, Iraq Al-Shawk S, Mathur S, Al Nasiri N (1983) Peutz-Jeghers syndrome presenting with hypoproteinemia: a case report and review of the literature. Iraqi Med J 31:121–128 Al-Saleem T, Abulkiel A, Sabri Z, Alash N. (1984) Skin cancer in Iraq. J Fac Med Baghdad 28:29–36 Al-Sharbati MM, Al-Chalabi TS, Rummani SF (1993) School screening for scoliosis in Baghdad. Saudi Med J 14:298–302 Al-Taha S (1996) A survey of a genetic clinic patients for chromosomal, genetic syndromes and congenital malformations as detected by clinical and chromosomal studies1989–90vs 1992–93. J Fac Med Baghdad 38(2):137–140 Al-Talabani N, Gataa IS, Latteef SA (2008) Bilateral agenesis of parotid salivary glands, an extremely rare condition: report of a case and review of literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 105(3):e73–e75 Al-Thamery D (1999) Frequency of mental retardation in a private paediatric clinic in Baghdad. Ann Coll Med Mosul 25(1–2):35–40 Alwan A, King H (1992) Diabetes in the eastern Mediterranean region. World Health Stat Q 45 (4):355–359 Alwan AA, Al-Tahafi NA, Saleh AM (1982) Studies on the prevalence of hypertension in Iraqi rural and urban communities. Iraqi Med J 29–30:61–70 Alwan A, Shamdeen L (1989) Clinical Presentation of Iraqi diabetes in Iraq. Proceedings of the second Scientific Research exhibition, Ministry of higher education and Scientific Research, Baghdad Alwan AA (1993) Cardiovascular diseases in the eastern Mediterranean region. World Health Stat Q 46(2):97–100 Alwan A, Modell B (2003) Recommendations for introducing genetics services in developing countries. Nat Rev Genet 4:61–68 Al-Wattar KM (2003) Congenital prepubic sinus: an epispadiac variant of urethral duplication: case report and review of literature. J Pediatr Surg 38(4):E18 Al-Windawi S, Al Naama L (1984) Acute intermittent porphyria: 2 cases from Southern Iraq. J Fac Med Baghdad 26(4):85–91 Al-Yazachi MB (1986) Gorlin syndrome, Naevoid basal cell carcinoma. J Fac Med baghdad 28:69–76 Amin-Zaki L, el-Din ST, Kubba K (1972) Glucose-6-phosphate dehydrogenase deficiency among ethnic groups in Iraq. Bull World Health Organ 47(1):1–5 Al-Zubaidee A, Hammash M (1997) Cleft lip and palate in children of Baghdad’s Al-Resafa schools. J Fac Med Baghdad 39(1):53–60 Bakir F, Murtadha M (1975) Periodic peritonitis. Report of 41 cases without amyloidosis. Trans R Soc Trop Med Hyg 69(1):111–117 Bakir F, Murtadha M, Issa N (1979) Amyloidosis and Periodic Peritonitis (Familial Mediterranean Fever). West J Med 131(3):193–195 Balow JE Jr, Shelton DA, Orsborn A, Mangelsdorf M, Aksentijevich I, Blake T, Sood R, Gardner D, Liu R, Pras E, Levy EN, Centola M, Deng Z, Zaks N, Wood G, Chen X, Richards N, Shohat M, Livneh A, Pras M, Doggett NA, Collins FS, Liu PP, Rotter JI, Kastner DL et al (1997) Highresolution genetic map of the familial Mediterranean fever candidate region allows identification of haplotype-sharing among ethnic groups. Genomics 44(3):280–291 Baraitser M, Burn J (1983) Recessively inherited brachydactyly type C. J Med Genet 20:128–129 Barakat MH, Karnik AM, Majeed HW, el-Sobki NI, Fenech FF (1986) Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs—a study of 175 patients and review of the literature. Q J Med 60(233):837–847

10


321

Bashir F, Al Taee M (1988) Congenital methemoglobinemia due to haemoglobinopathy-M. Jordan Med J 21(1):61–68 Beales PL, Katsanis N, Lewis RA, Ansley SJ, Elcioglu N, Raza J, Woods MO, Green JS, Parfrey PS, Davidson WS, Lupski JR (2001) Genetic and mutational analyses of a large multiethnic Bardet-Biedl cohort reveal a minor involvement of BBS6 and delineate the critical intervals of other loci. Am J Hum Genet 68:606–616 Bittles AH, Mason WM, Greene J, Rao NA (1991) Reproductive behavior and health in consanguineous marriages. Science 252(5007):789–794 Bittles AH, Grant JC, Shami SA (1993) Consanguinity as a determinant of reproductive behaviour and mortality in Pakistan. Int J Epidemiol 22(3):463–467 Børglum AD, Balslev T, Haagerup A, Birkebaek N, Binderup H, Kruse TA, Hertz JM (2001) A new locus for Seckel syndrome on chromosome 18p11.31–q11.2. Eur J Hum Genet 9 (10):753–757 Christianson A, Howson C, Modell B (2006) Global Report on Birth Defects. The Hidden Toll of Dying and Disabled Children. White Plains, N.Y, March of Dimes Birth Defects Foundation CIA World Factbook https://www.cia.gov/library/publications/the-world-factbook/geos/iz.html Cundy T, Hegde M, Naot D, Chong B, King A, Wallace R, Mulley J, Love DR, Seidel J, Fawkner M, Banovic T, Callon KE, Grey AB, Reid IR, Middleton-Hardie CA, Cornish J (2002) A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum Mol Genet 11:2119–2127 Deutsch S, Darbellay R, Offord R, Frutiger A, Kister J, Wajcman H, Beris P (1999) Hb IraqHalabja beta10 (A7) Ala–>Val (GCC–>GTC): a new beta-chain silent variant in a family with multiple Hb disorders. Am J Hematol 61(3):187–193 Emery A, Mueller R (1992) Elements of medical genetics. Churchill Livingstone, Edinburgh Farman N, Shakir A (1976) Karyotypic analysis of 150 cases of Down’s syndrome in Iraq. J Ment Def Res 20:83–87 Fensom AH, El Kalla S, Bizzari R, Fahmy NA, Semrin A, Benson PF, Shubbar AI (1990) Clinical Presentation and Diagnosis of Niemann- Pick Disease Type C. Emirates Med J 8:215–219 Habeeb S, Al-Sadoon I (1995) The incidence of congenital malformation and associated risk factors in Basrah city. J Fac Med Baghdad 37(4):520–526 Hamamy H, Al-Bayati N, Al-Kubaisy W (1986) Consanguineous marriages in Iraqi urban population and the effect on pregnancy outcome and infant mortality. Iraqi Med J 34:76–80 Hamamy H, Alwan A (1994) Hereditary disorders in the Eastern Mediterranean Region. Bull World Health Organ 72(1):145–154 Hamamy H, Bittles A (2008) Genetic Clinics in Arab Communities: Meeting Individual, Family and Community Needs. Public Health Genomics 12(1):10.1159/000153428 Hamamy H, Shubber EK, al-Allak BM (1992) Sister chromatid exchange frequencies in a group of individuals with unfavorable reproductive health. Eur J Obstet Gynecol Reprod Biol 43(1):45–49 Hamamy H, Al-Taha S (1989a) Cytogenetic Investigations in a Referred Population of Azoospermic Males. J Fac Med Baghdad 31(3):311–315 Hamamy H, Al-Taha S (1989b) Cytogenetic Investigations in 201 Females with Primary Amenorrhea. J Fac Med Baghdad 31(3):317–322 Hamamy H (1984) Chromosome Studies and Genetic Counseling in Iraq: One Year’s Experience. Saudi Med 5:46–52 Hamamy H (1989) Genetic factors and congenital malformations. Proceedings of the Fifth Conference of the Scientific Research Council, Baghdad 5(2):1–8 Hamamy HA, al-Hakkak ZS, al-Taha S (1990) Consanguinity and the genetic control of Down syndrome. Clin Genet 37(1):24–29 Hamamy HA, al-Hakkak ZS (1989) Consanguinity and reproductive health in Iraq. Hum Hered 39 (5):271–275 Hamamy HA, Saeed TK (1981) Glucose-6-phosphate dehydrogenase deficiency in Iraq. Hum Genet 58(4):434–435

322

Hanan A. Hamamy

Harbord MG, Harden A, Harding B, Brett EM, Baraitser M (1990) Megalencephaly with dysmyelination, spasticity, ataxia, seizures and distinctive neurophysiological findings in two siblings. Neuropediatrics 21:164–168 Harith A (1990) The aetiological contribute to severe sensorineural hearing impairment in children. J Community Med 3(2):111–121 Hassan MK, Taha JY, Al-Naama LM, Widad NM, Jasim SN (2003) Frequency of haemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency in Basra. East Mediterr Health J 9(1–2):45–54 Hilmi FA, Al-Allawi NA, Rassam M, Al-Shamma G, Al-Hashimi A (2002) Red cell glucose6-phosphate dehydrogenase phenotypes in Iraq. East Mediterr Health J 8(1):42–48 Hussien H, Jamil H (1993) The prevalence rate of hypertension among a group of industrial population-Iraq. J Community Med 6(1):51–55 Ikin EW, Mourant AE, Lehman H (1965) The blood groups and hemoglobin of the Assyrians of Iraq. Man 65:110–111 Jalal S, Al-Allawi N, Faraj A, Ahmed N (2008) Prevalence of hemoglobinopathies in SulaimaniIraq. Dohuk Med J 2(1):17–79 Jamil L, Yaldo M, Jamil H (1994) A study of the prevalence rate of obvious eye diseases in Baghdad city-Iraq. J Fac Med Baghdad 36(4):671–676 Kheder HH, Bashir FZ (1990) Beta thalassemia trait in Mosul. Saudi Med J 11(6):460–462 Kramer SN (1967) Editors of time-life books. Time-Life Books, New York, Cradle of Civilizations Mahdi A (1992) Consanguinity and its effect on major congenital malformations. Iraqi Med J 40–42:170–176 Mansour AA (2008) Patients’ opinion on the barriers to diabetes control in areas of conflicts: The Iraqi example. Confl Health 2:7 Mansour AA, Wanoose HL, Hani I, Abed-Alzahrea A, Wanoose HL (2008) Diabetes screening in Basrah, Iraq: a population-based cross-sectional study. Diabetes Res Clin Pract 79(1): 147–150 Mansour AA (2003) Influence of sickle hemoglobinopathy on growth and development of young adult males in Southern Iraq. Saudi Med J 24(5):544–546 Megarbane A, Ruchoux MM, Loeys B, Ayoub N, Nuytinck L (2001) Short stature, abnormal face, joint laxity, dislocation, hernias, delayed bone age, and severe psychomotor retardation in two brothers: previously undescribed MCA/MR syndrome. Am J Med Genet 104(3):221–224 Mourant AE, Kopec AC, Domaniewska-Sobczak K (1976) The distribution of the human blood groups and other polymorphism. Oxford University Press, London Abed M, Waad Allah S (1992) The prevalence of diabetes mellitus in a rural community in Northern Iraq. Med J Basrah Univ 10(1–2):63–69 Nagi NA (1979) Diabetes insipidus, diabetes mellitus, optic atrophy and deafness. A clinical and genetic study. Postgrad Med J 55(644):377–380 Najim RA, Al-waizt M, Al-Razzuqi RA (2005) Acetylator phenotype in Iraqi patients with allergic contact dermatitis. Ann Saudi Med 25(6):473–476 Nasheit NA (2003) Perinatal and neonatal mortality and morbidity in Iraq. J Matern Fetal Neonatal Med 13(1):64–67 Nasir GA, Rahma S, Kadim AH (2000) Neonatal intestinal obstruction. East Mediterr Health J 6(1):187–193 Rofoo F, Hashim H, Al Jaff H (1995) Disribution of ABO and RH blood group systems among Arbil population. Zanco J Med Sci 2(1):21–25 Roux G (1980) Ancient Iraq. Penguin Books, London Saeed TK, Hamamy HA, Alwan AA (1985) Association of glucose-6-phosphate dehydrogenase deficiency with diabetes mellitus. Diabet Med 2(2):110–112 Safar S, Sawa T (1992) Gardner’s syndrome: the place of colectomy in the management: a study of two families. J Fac Med Baghdad 34(4):453–460

10


323

Saleem M, Mahmoud N (1988) Distribution of A B O and Rh D blood group systems among Mosul population. Ann Coll Med Mosul 14(1):61–65 Sarsam H, Izzat M (1986) Short stature in Iraq. J Fac Med Baghdad 28(4):37–47 Schaffer JV, Bazzi H, Vitebsky A, Witkiewicz A, Kovich OI, Kamino H, Shapiro LS, Amin SP, Orlow SJ, Christiano AM (2006) Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions. J Invest Dermatol 126(6):1286–1291 Schmidt H, Rudolph G, Hergersberg M, Schneider K, Moradi S, Meitinger T (2001) Retinal detachment and cataract, facial dysmorphism, generalized osteoporosis, immobile spine and platyspondyly in a consanguinous kindred–a possible new syndrome. Clin Genet 59(2):99–105 Shah G, Sattar N (1981) The incidence of phenyl thiocarbamide [PTC] taste threshold and sensitivity in Iraqi Arabs. Med J Basrah Univ 4(2):121–131 Shahar E, Brand N, Shapira Y, Barash V, Gutman A (1988) Familial carnitine deficiency: further evidence for autosomal recessive transmission with variable expression. J Neurol Neurosurg Psychiatry 51(2):298–300 Shaikhow S, Al Jawadi A (1989) Incidence of mitral valve prolapse in children. J Fac Med Baghdad 31(2):181–184 Shawky S (2001) Infant mortality in Arab countries: sociodemographic, perinatal and economic factors. East Mediterr Health J 7(6):956–965 Shehab N, Al Hubaitty A, Al Hiyalli Y (1998) Choanal atresia. Ann Coll Med Mosul 24(1–2):50–53 Shiyaa N, Balasim R, Habib O (2006) Pregnancy outcome and fate of neonates: a hospital-based study. J Bahrain Med Soc 18(1):19–22 Shubber EK, Hamami HA, Allak BM, Khaleel AH (1991) Sister-chromatid exchanges in lymphocytes from infants with Down’s syndrome. Mutat Res 248(1):61–72 Stoffman N, Magal N, Shohat T, Lotan R, Koman S, Oron A, Danon Y, Halpern GJ, Lifshitz Y, Shohat M (2000) Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups. Eur J Hum Genet 8(4):307–310 Subhi MD (2006) Blood pressure profiles and hypertension in Iraqi primary school children. Saudi Med J 27(4):482–486 Teebi A (1994) Autosomal recessive disorders among Arabs: an overview from Kuwait. J Med Genet 31:224–233 UNICEF. http://www.unicef.org/infobycountry/iraq_statistics.html WHO Index Medicus for the Eastern Mediterranean Region. http://www.who.int/library/databases/emro/en/index.html WHO Advisory Group Report [1985]: Community approaches to the control of hereditary diseases HDP/WG/85-10 WHO, EMRO country profiles. http://www.emro.who.int/emrinfo/index.asp?Ctry=irq World bank http://web.worldbank.org/WBSITE/EXTERNAL/COUNTRIES/MENAEXT/IRAQEXTN/0, menuPK:313111pagePK:141159piPK:141110theSitePK:313105,00.html World Bank. World Development Report (1993) Investing in health. Oxford University Press, New York World Bank Iraq data sheet http://www.iraqslogger.com/downloads/DATASHEETIraqDec2006. pdf World Health Report, 2000 http://www.who.int/whr/2000/en/annex02_en.pdf Yahya H, Khalel K, Al-Allawi N, Helmi F (1996) Thalassaemia genes in Baghdad, Iraq. East Mediterr Health J 2:31–35 Yaseen N (1995) Inheritance pattern of nystagmus in Iraqi families. Med J Tikrit Univ 1(1):25–35 Yasseen A, Aunuiz A, Al-Mosawi M (2001) Chromosome studies in male patients suffering from infertility. Saudi Med J 22(3):223–226 Yasseen A, Aunuiz A (2002) High frequency of satellite association in metaphases of infertile male patients. Saudi Med J 23(4):427–431 Yasseen AA, Al-Musawi TA (2001) Cytogenetics study in severely mentally retarded patients. Saudi Med J 22(5):444–449

Chapter 11

Genetic Disorders in Jordan Majed Dasouki and Hatem El-Shanti

The Country and Population Like many of its modern neighboring Arab countries, Jordan was part of the Ottoman Empire until the end of World War I. Under the mandate of the British government in 1923, Jordan became a political entity known as “Transjordan.” However, Jordan gained its independence and was declared a Kingdom in 1946. In 1948, Jordan witnessed a mass migration of at least 700,000 Palestinians as a result of the creation of the state of Israel. The union of Transjordan and the West Bank (of Palestine) in 1950 produced the current name of the Hashemite Kingdom of Jordan. As a result of the 1967 war, the West Bank fell under Israel’s occupation and another wave of Palestinian refugees moved to Jordan adding to its population. Geographically, Jordan is almost entirely landlocked, with the port of Aqaba in the far south being its only outlet to the red sea. Palestine and Israel separate Jordan from the Mediterranean sea, Saudi Arabia lies to the south and east, Iraq to the northeast, and Syria to the north (Fig. 11.1). Three climate zones characterize Jordan, running from the west to the east of the country. These zones include the Jordan Valley which is largely below sea level and considered semitropical; the highlands east of the Jordan Valley which can be considered to have a Mediterranean climate; and the low-lying desert to the east of the highlands. Jordan is about the size of the state of Indiana, USA. Over 80% of Jordan’s land is characterized by semi-desert conditions with some scattered wetlands including the Azraq Basin. Administratively, Jordan is divided into 12 governorates, which are grouped into three regions – the North region (Irbid, Jarash, Ajloun, and Mafraq), the Central region (Amman, Zarqa, Balqa, and Madaba), and

H. El-Shanti (*) Director, Shafallah Medical Genetics Center, Doha, Qatar Adjunct Associate Professor of Pediatrics, University of Iowa, Iowa City, Iowa, USA e‐mail: [email protected]


325

326

M. Dasouki and H. El-Shanti

IRAQ

SYRIA

Irbid West Bank Amman GAZA

ISRAEL

JORDAN SAUDI ARABIA

Al Aqabah

Fig. 11.1 Geographic map of Jordan showing neighboring countries

the South region (Karak, Tafielah, Ma’an, and Aqaba) (Fig. 11.1). The major cities are Amman (the capital), Zarqa, and Irbid. Jordan is a small country with limited natural resources and a 13% unemployment rate in 2008. The bulk of Jordan’s labor force is engaged in providing services, 20% in industry and only 2.7% in agriculture. Jordan’s major exports include clothing, fertilizers, potash, phosphates, vegetables, and pharmaceuticals. The Hashemite Kingdom of Jordan experienced a significant growth in its population, which increased from half a million in 1952 to 5.85 millions in 2008, with about two millions inhabiting the capital “Amman.” In addition to the influx of Palestinians in 1948 and 1967, Jordan had few other major population influxes following the Lebanese civil war and most recently the Iraqi invasion of Kuwait in 1990 and the United State’s invasion of Iraq in 2003. Overall, these population shifts resulted in about tenfold increase in the population, over a 50-year period and resulted in a partial or total admixture of the incoming individuals with the basal population. In 2008, the average number of persons per family was 5.4 and infant

11

Genetic Disorders in Jordan

327

mortality rate (per 1,000 live births) was 19. Life expectancy for males was 71.6 years compared with 74.4 years for females (www.moh.gov.jo). Jordanian citizens make up 93% of the population and 95–98% of Jordan’s people are Arabs. The remaining non-Arabs of the population are mainly Circassians, Chechens, Armenians, Kurds and Gypsies. The majority of Jordanians are Muslims while 6% are Christians. Jordan has an overall literacy rate of 91.1%. Health services in Jordan are provided though the Ministry of Health hospitals, Armed forces Health Centers and the private sector.

Genetic Services Genetic services in Jordan began on a small scale with the establishment of a cytogenetics laboratory at the University of Jordan in the late 1980s. It continues to provide basic chromosomal analysis, in addition to a few molecular-based cytogenetic tests. The first clinical genetics clinic also began at the University of Jordan in 1992 and was staffed by one medical geneticist. It lasted for a short period of time. In 1994, another cytogenetics laboratory and medical genetics clinic were then started at Jordan University of Science and Technology and lasted for 10 years. The cytogenetics laboratory is still functional. Since the mid 1990s, a few additional laboratories at the Ministry of Health hospitals and commercial laboratories began offering limited cytogenetic, biochemical and molecular genetics services. Also, clinical genetics services were incorporated into the National Center for Diabetes, Endocrinology and Genetics, since its inception in1997 until the current time. Currently, there are no board-certified practicing medical geneticists in Jordan. However, Jordan’s manpower includes a few Ph.D. level molecular geneticists and cytogeneticists who trained in the US, as well as locally trained staff. Prenatal genetic diagnosis is practiced on a very small scale in Jordan. In the private health sector, there are a few in vitro fertilization (IVF) centers which offer limited pre-implantation genetic diagnosis.

Consanguinity Similar to many Arabic countries, the traditional practice of consanguineous marriages is very common in Jordan with rates as high as 60% (Al-Salem and Rawashdeh 1993; Khoury and Massad 1992; Nabulsi 1995) and first cousin marriages being the most common. While the rates of consanguineous marriages had changed over the last few decades, they continue to be high (Hamamy et al. 2005). Several studies suggested that consanguinity among Jordanians contributed to the increased incidence of various common and rare autosomal recessive disorders (identity by descent; IBD), birth defects, infant mortality, reproductive wastage, adverse pregnancy outcomes in general, and childhood mental retardation (Aqrabawi 2008;

328


Cook and Hanslip 1966; Hamamy et al. 2007a, 2007b; Janson and Dawani 1994; Janson et al. 1990; Khoury and Massad 2000; Obeidat et al. 2008) but not to the frequency of pre-eclampsia or its severity (Badria et al. 2001; Badria and Amarin 2003). The “2007” Jordan: Population and Family Health Survey (http://pdf.usaid. gov/pdf_docs/PNADN523.pdf) showed that 40% of married women aged 15–49 reported consanguinity, with 5% being double first cousin marriages and patrilineal consanguineous marriages being more common than matrilineal ones. Demographic characteristics that favor consanguinity include: rural (49%) vs. urban (38%), North and South regions vs. Central region (43 and 45%, respectively, vs. 37%) and Badia areas compared to non-Badia areas (47 vs. 39%), less educated (47%) than higher educated (31%). Also, women in Amman, Zarqa, Madaba, and Aqaba are more likely to enter into non-consanguineous marriages than women in other governorates. Age at marriage and the woman’s socioeconomic status are inversely related to consanguinity while duration of marriage was not a significant factor. The high consanguinity rate in Jordan and throughout the Arab world in general had a significant impact on medical practice, research, and health policy. Facilitated by the high incidence of consanguinity and large family sizes, several new genetic syndromes and new features of previously recognized syndromes had been described in the medical literature. The advent and application of novel molecular genetics technologies coupled with international collaborative research efforts led to the discovery of the genetic basis for several novel genetic disorders. There are no specific studies that address the magnitude of economic and psychosocial burden genetic disorders have on individuals or the population as a whole. Although the 2008 report from the Jordan Ministry of Health (www.moh.gov.jo) indicates that only 0.17% of all health visits were related to genetic disorders (congenital malformations and chromosomal disorders). We believe that the burden on the public health system is more significant than suggested by this report. To overcome the health burden imposed by consanguinity, preventive strategies should focus on several factors including increasing public awareness and adequate education of health professionals on genetic diseases, carrier testing when applicable and premarital and preconception testing and counseling for common disorders. Preimplantation genetic diagnosis, and prenatal diagnosis and termination of pregnancy (within the allowed limits of religion) should also be made available and be integral parts of this strategy (Teebi and El-Shanti 2006). In a national effort to prevent or control certain common genetic disorders such as thalassemia, premarital examinations had been mandated by law since 2004. Due to limited resources including the unavailability of trained genetic health professionals this law had a limited impact if any on the incidence or severity of genetic disorders in Jordanian communities. Only 18% of ever-married women and/or their husbands underwent premarital medical examinations according to the 2007 Jordan: Population and Family Health Survey. Despite these significant limitations, it appears that premarital examination is more frequent among women of older ages at first marriage, women with higher education, those residing in urban areas, in the Central region and in the non-Badia areas than among other women.

11


329

Chromosomal Disorders In 785 chromosomal analyses done in Northern Jordan, the investigators found 105 children (13.3% ) with trisomy 21 (four with de novo Robertsonian translocations), 16 with sex chromosome aneupolidies (2%) including six with Klinefleter syndrome and ten with Turner syndrome. Structural chromosomal abnormalities were identified in 22 patients (2.8%). The overall yield of chromosomal abnormalities in their experience was 18.2% (El-Shanti and Al-Alami 2002). Advanced maternal age carries with it some known maternal and fetal health risks including hypertension, diabetes mellitus, antepartum hemorrhage, large babies, trisomy 21 and twin pregnancy (Amarin and Akasheh 2001). In this study, and both the advanced maternal age and young age groups, combined incidence of chromosomal aneuploidies was 2.2% while 4.2% of the babies had congenital malformations.

Neurological Disorders Based on the World Bank and WHO disability prevalence estimate of 10% in any given population, Jordan’s National Demographic Committee (NDC) estimated that the incidence of disability in Jordan’s population is slightly over 10%. Among those disabled, 75% of all projected disabilities are mild, 20% are moderate and 5% are severe. In Jordan, the application of those percentages for expected numbers of children with mild, moderate and severe disability to the population of 0–18-year-olds (2,375,222) results in projections of 178,141 children with mild disabilities, 47,504 with moderate disabilities and 11,876 with severe disabilities (http://www.ncfa.org.jo/admin/publications/NCFA%20Report%20English.doc). Physical and cognitive disability of various degrees occur in many neurogenetic disorders. Recognition of these disorders usually helps with the management and prognosis of these disorders. Studies of neurogenetic disorders among Jordanians are limited and are largely descriptive. However, there is an increasing number of such studies that shed light on the pathogenesis of some of these disorders. High perinatal morbidity or meningitis in infancy leading to a combination of severe mental retardation and cerebral palsy and a high degree of consanguinity favored genetic causes of mental retardation in a group of 203 severely mentally retarded children born during 1975–1985 (Janson et al. 1990). In a group of 29 children with neuromigrational disorders evaluated at a tertiary medical center, lissencephaly was found to be the most common disorder (58.6%) and was frequently associated with consanguinity (88.2%) and positive family history (76.4%) (Al-Qudah 1998). These findings strongly suggest a monogenic basis for lissencephaly. Other central nervous system anomalies included: pachygyria (13.8%), neuronal heterotopias (10.3%), schizencephaly (13.8%) and

330


hemi- megalencephaly (3.4%). Neuromigrational disorders and associated abnormalities were frequently seen (48.2%). Primary Microcephaly (MCPH) is a genetically heterogeneous congenital disorder characterized by a small head circumference at least four SD below the age and sex average, normal brain structure and otherwise normal physical growth and normal karyotype. Some degree of non-progressive mental retardation, as well as seizures, may occur in affected children. A genome-wide scan was performed on five families from the Netherlands and Jordan, with 14 microcephalic individuals (Wallerman et al. 2003). Mapping and haplotype analysis suggests that the gene causing microcephaly, MCPH5, is located on chromosome 1. Hyperekplexia is a rare non-epileptic disorder characterized by excessive startle response to acoustic, visual, or other stimuli. Patients with hyperekplexia are often misdiagnosed as having epilepsy. The disorder was described in nine Jordanian families (Masri and Hamamy 2007). All families were referred with the diagnosis of uncontrolled seizures with onset of the disease in the neonatal period and with variable and atypical presenting features. The inheritance profile in 4 families was compatible with autosomal recessive and in one family with autosomal dominant inheritance. In the remaining four families, the disorder appeared to be sporadic. Childhood epilepsy is a relatively common disorder and etiologically heterogeneous. A case-control study from Irbid, Jordan, demonstrated that positive family history for epilepsy, head trauma, febrile convulsions and abnormal perinatal history correlated with epilepsy while consanguinity did not show a similar correlation (Daoud et al. 2003). Predictors for seizure recurrence included partial seizure and positive family history while sex, age, duration of seizure and consanguinity were not strong predictors (Daoud et al. 2004). In 55 infants with epilepsy, various etiologies (hypoxic-ischemic encephalopathy, cortical malformations, neurocutaneous syndromes, metabolic disorders and craniosynostosis) were identified in about 50% of babies (Masri et al. 2008a). Again, parental consanguinity, family history of global developmental delay, family history of epilepsy and a positive perinatal history were strong predictors of infantile epilepsy. An unusual autosomal recessive Pallido-pyramidal syndrome is characterized by clinical signs and symptoms of subacute, juvenile onset, severe levodoparesponsive Parkinsonism, cortico-spinal tract disease, dementia and supranuclear upgaze paresis was termed Kufor–Rakeb syndrome (Najim al-Din et al. 1994). Significant atrophy of the globus pallidus and the pyramids as well as generalized brain atrophy in later stages were demonstrated on brain MRI. Using linkage analysis, it was first mapped to chromosome 1p36 (Hampshire et al. 2001) and then assigned as PARK9 locus (Lees and Singleton 2007; Williams et al. 2005). Loss of function mutation (exon 16, 22bp dup) in the predominantly neuronal P-type ATPase gene, ATP13A2, was then identified as the cause of this Parkinsonism syndrome (Ramirez et al. 2006). In 11 consanguineous families with 17 individuals with recessively inherited young-onset parkinsonism evaluated for mutations in the parkin and PINK1 genes, homozygous exon 4 parkin gene deletion & 2 novel PINK1 gene mutations (P416R and S419P) were identified (Myhre et al. 2008).

11


331

Autosomal recessive ataxias are a heterogeneous group of rare disorders characterized by early onset ataxia associated with neurologic, ophthalmologic or systemic signs. A 13-year-old girl with Ataxia Telangiectasia developed craniopharyngioma and non-Hodgkin’s lymphoma (Masri et al. 2006). The ataxias associated with myoclonus, epilepsy and progressive neurological degeneration are usually included with the progressive myoclonus epilepsies, one of which is UnverrichtLundborg disease. Using a genome-wide screen for linkage, a distinct locus for autosomal recessive ataxia to chromosome 12 q12 was mapped in an inbred Jordanian family with four affected siblings (El-Shanti et al. 2006a). The clinical phenotype was characterized by ataxia noted at the onset of walking with dysarthria and bulbar features, but no cerebellar hypoplasia on MRI. All four patients developed a fine tremor that progressed to a coarse action tremor, as well as atonic seizures. Seizures and tremors improved upon treatment with Valproic acid while the ataxia did not improve. In affected members of three reported families a homozygous mutation in the PRICKLE1 (R104Q) was identified which is consistent with a founder effect (Bassuk et al. 2008; Berkovic et al. 2005; El-Shanti et al. 2006a). A 10 generation inbred family with 50 affected individuals distributed over five consecutive generations with spastic paraplegia was reported (El-Shanti et al. 1999b). The mode of inheritance is either autosomal recessive or autosomal dominant with incomplete penetrance or variable expression of the age at onset. The age at onset seems to decrease with successive generations, either due to a true anticipatory phenomenon or to increased awareness. The distribution and frequency of common pediatric myopathies in Jordan was reported (Al-Qudah and Tarawneh 1998). Seventy-three percent of the myopathies were due to muscular dystrophy, half of which were accounted for by congenital muscular dystrophy (CMD). High rates of consanguinity and positive family history of muscular dystrophy were reported in those families suggesting autosomal recessive basis. Other muscular dystrophies such as Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic dystrophy (MD), limb-girdle muscular dystrophy (LGMD), and facio-scapulo-humeral dystrophy (FSHD) were also identified in decreasing order. Several new neurogenetic syndromes were also reported in some Jordanian families (Christodoulou et al. 2000; Hamamy et al. 2007c; Hiyasat et al. 2002; Middleton et al. 1999). A previously unrecognized autosomal or X-linked recessive syndrome in two brothers who had facial dysmorphism, sloping shoulders, enamel hypoplasia, severe myopia, deafness and borderline intelligence was described (Hamamy et al. 2007c). Autosomal recessive, “Jerash type” distal hereditary motor neuropathies characterized by progressive weakness and atrophy of the lower limbs plus pyramidal features and early childhood onset in seven consanguineous families was described (Middleton et al. 1999). The responsible gene was mapped by linkage analysis to chromosome 9p21.1-p12 (Christodoulou et al. 2000). “D-CHRAMPS syndrome”: Cerebellar hypoplasia, Hypergonadotrophic hypogonadism, Retinitis pigmentosa, Alopecia, Microcephaly, Psychomotor retardation, and Short stature syndrome is a novel disorder which was reported but its gene locus had not been mapped yet (Hiyasat et al. 2002).

332


Eye Diseases Studies of color blindness showed a prevalence of 8.72% in males and 0.33% in females with calculated color blindness gene allele frequencies of 0.087 in males, 0.003 in females and 0.016 in the total population (Al-Aqtum and Al-Qawasmeh 2001). The pattern of childhood blindness reflects a high frequency of genetic causes, especially autosomal recessive inheritance coupled with high consanguinity rates (Al-Salem and Rawashdeh 1992). In Northern Jordan it was found that 43% of blindness was caused by genetic disorders including tapetoretinal degenerations, glaucomas and congenital cataracts (Al-Salem et al. 1996). A large, highly inbred family from the Jordan valley consisting of about 2,000 living subjects in whom affected members had Leber congenital amaurosis (LCA) was described (Al-Salem 1997). A 31-member subset of this family was investigated and a homozygous (Q2646X) mutation in RETGC was identified (El-Shanti et al. 1999a). Isolated dominantly inherited ectopia lentis due to mutations in the fibrillin one gene had been reported previously. Two large consanguineous families with autosomal recessive isolated ectopia lentis were first reported (Al-Salem 1990). By homozygosity mapping, the gene was first mapped to chromosome 1p13.2–q21.1 then a homozygous truncating mutation (p.Y595X) was found in the ADAMTSL4 gene which disrupts the integrity of the lenticular zonular fibers (Ahram et al. 2009). Wolfram syndrome (DIDMOAD-Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness) is an autosomal recessive neurodegenerative disorder with locus heterogeneity. Sixteen patients from four different Jordanian families were studied; none of them had diabetes insipidus and several patients had profound upper gastrointestinal ulceration and bleeding (Ajlouni et al. 2002; Al-Sheyyab et al. 2001; Al-Till et al. 2002; Hadidy et al. 2004; Jarrah et al. 1999). Linkage to WFS1 (4p16.1) was excluded in three families which then showed linkage to 4q22–24 (WFS2) (El-Shanti et al. 2000). A pathogenic (E37Q) mutation in the ERIS (endoplasmic reticulum intermembrane small protein) gene was demonstrated in these families, which creates a new splice site and produces a smaller protein (Amr et al. 2007). Unlike Wolframin (WFS1), ERIS was not found to be mutated in isolated deafness.

Inborn Errors of Metabolism A small number of inborn errors of metabolism in Jordanians had been formally reported in the medical literature. The true spectrum and frequency of various metabolic disorders in Jordanians remains unknown. While basic screening for common biochemical genetic disorders is generally available, arriving at a specific diagnosis for many metabolic disorders is not possible without sending biological samples outside Jordan which is expensive and often times logistically difficult. Therefore, development of local and regional expertise in various groups of

11


333

metabolic disorders is necessary to provide timely and relatively inexpensive services. Recently, a limited national newborn screening program targeting congenital hypothyroidism and phenylketonuria began. According to the 2008 Jordan’s Ministry of Health report, there are 148 Jordanian patients with PKU who attend its clinics. These patients had 636 visits during 2008 which resulted in an average of 4.3 visits per year per patient. The prevalence of PKU in Jordan is therefore estimated at 0.26/10,000 individuals. Congenital adrenal hyperplasia was studied and it was found that 85% had classical presentation with salt wasting type in two thirds of these patients (Al-Maghribi 2007). In a family with several affected siblings, Aspartoacylase (Canavan disease) was reported and an exon 1 (p.G27R) mutation was identified (Masri and Hamamy 2006). The Centre for Arab Genomic Studies Work Group (2006) conducted a retrospective study for metabolic disorders described at Al-Wasl Hospital in Dubai between 1997 and 2006 (http://www.cags. org.ae/) and identified a few metabolic disorders among Jordanians living in the UAE, including one child with glycogen storage disease and two with maple syrup urine disease (MSUD). Pyruvate Kinase deficiency was reported in two unrelated patients with chronic hemolytic anemia which improved after splenectomy (Karadsheh 1993). A case of Wolman disease was diagnosed based on the radiological evidence of bilateral adrenal calcifications and foam cells in the bone marrow (Mahdi et al. 1991). Decreased “acid esterase” activity in skin fibroblasts confirmed the diagnosis. The concurrence of Papillon–Lefevre syndrome (PLS) and type 1 oculocutaneous albinism (OCA1) was reported in two Jordanian brothers. Both were found with compound heterozygous mutations in the cathepsin C (CTSC; c.3181G>A) and tyrosinase genes [c.817G>C/p.W272C] (Hattab and Amin 2005; Hewitt et al. 2004). These two genes are closely linked within 1Mb region on chromosome 11q14.2–14.3. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is thought to be common among Jordanians. In a group of 333 males, Usanga and Amin found 3.6% to be deficient (Usanga and Ameen 2000). The frequencies of GDPD A- and G6PD B- variants were 0.006 and 0.031 respectively. Some Jordanian patients with various metabolic disorders underwent therapeutic bone marrow transplantation (Abdel-Rahman et al. 2008). Polymorphisms in transferrin C, haptoglobin and mitochondrial DNA (mtDNA) had also been studied (Gonzalez et al. 2008; Janaydeh et al. 2004; Saha 1985). Lysosomal storage disorders (LSD) represent a large group of metabolic disorders characterized by deficiency of one of the several lysosomal acid hydrolases which leads to substrate accumulation in various organs including the brain and reticulo-endothelial system. The lipidoses (Gaucher and Fabry disease) are the most common types of LSD. Gaucher disease was reported in ten Jordanian patients (http://www.lsdregistry.net/gaucherregistry/). Two brothers with infantile Pompe disease were also recognized (personal observation). Trimethylaminuria (TMAU) is an autosomal recessive metabolic disorder characterized by an odor resembling that of rotten or decaying fish which occurs due to excess excretion of trimethylamine in body fluids (urine, breath, sweat, and reproductive fluids). Affected individuals have either an increased percent of total trimethylamine (free trimethylamine [TMA] plus the non-odorous metabolite

334


TMA N-oxide) excreted in the urine as unmetabolized free TMA or the concentration of unmetabolized TMA in the urine. Defects in the FMO3 (flavin monooxygenase 3) gene cause TMAU. TMAU was found in 1.7% (2/116) Jordanian, 3.8% Ecuadorian and 11.0% (11/100) New Guinean individuals excreting 80% or less of their total trimethylamine as the N-oxide (Mitchell et al. 1997). Drug metabolism was assessed in Jordanians as well. CYP2D6 (Debrisoquine4-hydroxylase) is responsible for Dextromethorphan O-demethylation to dextrophan. Using thin layer chromatography, Irshaid et al. (1993) found that 2.9% of Jordanian volunteers were poor metabolizers of Dextromethorphan resulting in a 0.17 allele frequency. CYP2C19 is a clinically important enzyme that metabolizes a wide variety of drugs, including the anticonvulsant mephenytoin, anti-peptic ulcer drugs such as omeprazole, certain antidepressants, and the antimalarial drug proguanil. Mutation in the CYP2C19 gene causes poor metabolism of these drugs. In a group of 194 unrelated, healthy volunteers, 4.6% were found to be poor metabolizers giving an allele frequency of 0.215 which is similar to what had been observed in European populations (Hadidi et al. 1995).

Cardiovascular Disorders Congenital heart disease (isolated or syndromic) is a relatively common birth defect. In a group of 60 babies with cleft lip and/or cleft palate, 47% had congenital heart disease. Congenital heart disease was more frequent (60%) in the group of babies with combined cleft lip and cleft palate (Aqrabawi 2008). No chromosomal studies were done in any of these patients.

Pulmonary Disorders A raised protein level in the meconium of an infant with cystic fibrosis (CF) was described by Buchanan and Rapoport (1952) in an infant with meconium ileus (Buchanan and Rapoport 1952). Nazer prospectively screened 7,682 Jordanian neonates using this technique (Nazer 1992). Three of the four babies who had abnormally elevated meconium albumin levels had abnormal sweat chloride test. Therefore, the incidence of CF in Jordanians is about 1:2,560 live births. The clinical profile of CF appears to be different and more severe than it is in western countries. In Northern Jordan, a high frequency of pancreatic insufficiency (75%), history of meconium ileus (6.6%) and high mortality during infancy (23%) were found (Rawashdeh and Manal 2000). Twenty-four different CFTR gene mutations were identified in this population of 202 individuals with CF. The DF508 mutation accounted for only 7.4% of all CFTR mutations (Rawashdeh and Manal 2000). Similar findings were reported, in 72 children, where 20 different CFTR gene mutations were identified including five novel ones (296 þ 9A-T, T338M,

11


335

T760M, 3679delA, and G1244D) (Kakish 2001). Kakish also suggested an association between CF and infantile hypertrophic pyloric stenosis, which he observed in two children (Kakish 2002). Ciliary dyskinesia associated with hydrocephalus and mental retardation in a large three generation consanguineous Jordanian family with four affected brothers and possibly their maternal uncle was described (Al-Shroof et al. 2001). Chromosome analysis was normal while electron microscopy of the nasal cilia from three affected siblings showed features of primary ciliary dyskinesia. Computed tomographic scans of the brains of all four affected siblings showed hydrocephalus. Family history was consistent with autosomal recessive inheritance if the maternal uncle’s history was excluded and it was suggested that this phenotype is caused by a novel gene (Al-Shroof et al. 2001). Pulmonary alveolar microlithiasis (PAM) is a rare slowly progressive autosomal recessive lung disease characterized by the deposition of calcium phosphate microliths throughout the lungs. It is caused by mutations in SLC34A2 (Corut et al. 2006). PAM was recently described in an 8-month-old male infant presenting with worsening respiratory distress and cyanosis (Dahabreh and Najada 2009). Chest X-ray and CT scan showed diffuse reticulo-nodular densities and open lung biopsy showed diffused alveolar calcium deposits.

Gatrointestinal Disorders Many variants of alpha-1-antitrypsin (PI) had been described, and worldwide gene frequencies for allelic variants M (M1, M2, M3, M4), S, Z, F, I, and V were tabulated (Roychoudhury and Nei 1988). The frequencies of the three common subtypes of PI M were studied in Jordan (Saleh et al. 1986). In comparison with other populations, PI*M3 was found to be low (0.038) and PI*M2 rather high (0.155). A highly significant difference in Lactose malabsorption (hypolactasia) was demonstrated between Jordanian Bedouins (24%), and Jordanians from the urban/ agricultural zone of western Jordan and Palestine (75%) using Lactose tolerance tests with breath hydrogen determination (Hijazi et al. 1983). These findings suggested that milk dependence in nomadic desert populations resulted in selective pressures in favor of the lactase persistence gene and hypolactasia gene frequencies were increased in people migrating from the desert border in Jordan to the Mediterranean shore. A single allele, carrying the T13910 variant 14 kb upstream of lactase LCT gene, fully correlates with Lactase Persistence (LP) in many global populations (Enattah et al. 2008). Sequencing of analysis of 56 random Jordanian DNA samples known to be of mixed origin revealed three LP mutations (C/T13910, T/G13915, T/C13913) The allele frequencies for each of these mutations was 0.054, 0.054, and 0.009 respectively. The total LP gene mutation allele frequency was 0.117. Dermatitis, diarrhea, alopecia, and growth failure are the cardinal clinical features of acrodermatitis enteropathica (AE), a rare autosomal recessive disorder caused by insufficient uptake of zinc by the intestine. AE can be fatal unless the diet

336


is supplemented with zinc. The AE gene was mapped to chromosome 8q24.3 using a genome-wide screen done on 17 individuals from a consanguineous Jordanian family (Wang et al., 2001). The intestinal zinc transporter (SLC39A4) was found to be the gene responsible for AE (Kury et al. 2002; Wang et al. 2002). This gene is expressed in the apical membrane of mouse intestinal enterocytes. The Jordanian family was found to have a homozygous “G630R” mutation. Juvenile polyposis syndrome is an autosomal dominant disorder that predisposes gene carriers to various types of tumors. The risk of malignant transformation in the hamartomatous gastrointestinal polyps seen in JPS patients is approximately 20%. BMPR1 and SMAD4 are the only genes known thus far to cause JPS (Handra-Luca et al. 2005). Two Jordanian siblings having JPS while their father had non-polyposis colon cancer at the age of 35 have been described (Al-Jaberi and El-Shanti 2002).

Genitourinary Disorders The estimated prevalence of chronic renal failure in children in Jordan is 51 per million population and the incidence as 10.7 new cases per million child population per year (Hamed 2002). The most common causes of chronic renal failure were urological abnormalities and malformations (42%) followed by hereditary renal disorders (42%). He also reported on renal cysts and associated malformations in pediatric autopsy material (Hamed et al. 1998). In Jordanian adults who underwent renal biopsies, focal segmental glomerulosclerosis was the most common histological diagnosis (Wahbeh et al. 2008). Congenital nephrotic syndrome (Finnish type) is a serious renal disease in Jordanian children with 100% mortality by 5 years of age (Hamed 2003; Hamed and Shomaf 2001). Thirty such children were diagnosed based on their clinical findings and light microscopic examinations of their renal biopsies. Chronic renal insufficiency developed in 17, and five of them needed chronic peritoneal dialysis. Galloway-Mowat syndrome is an autosomal recessive disorder characterized by an early onset of the nephrotic syndrome and central nervous system anomalies. Mutations in podocyte proteins, such as nephrin, alpha-actinin 4, and podocin, are associated with proteinuria and nephrotic syndrome. The genetic defect in Galloway-Mowat syndrome is as yet unknown. Two Jordanian children were diagnosed as having Galloway–Mowat syndrome (Srivastava et al. 2001).

Autoimmune, Autoinflammatory and Rheumatologic Disorders The distribution of the different HLA phenotypes and genotypes was determined through a comprehensive study (Sanchez-Velasco et al. 2001). Twenty alleles for the locus HLA-A and 46 for the HLA-B locus were detected, which indicates the existence of high polymorphism in this area. The results suggest that both

11


337

HLA class I and class II polymorphism of the Jordanian population demonstrates considerable heterogeneity, which reflects ancient and recent admixture with neighboring populations, and important human migratory trends throughout the history. The association of the different HLA phenotypes and genotypes with multiple sclerosis (MS) has been the subject of one study (Brautbar et al. 1982). It showed that there is a lack of association of A3 and B7 and MS in the Jordanian population. Chediak–Higashi Syndrome (CHS) is a rare autosomal recessive disorder of the immune system, characterized by chronic infections, neutropenia, partial oculocutaneous albinism, and bleeding diatheses with partial neuropathy. Eight patients with CHS from three unrelated families were reported from Jordan, with a review of the clinical literature (Al-Sheyyab et al. 2000). A similar but unrelated group of disorders, designated as Griscelli syndromes, has been reported from Jordan (Masri et al. 2008b). Familial Mediterranean Fever (FMF) is characterized by recurrent self-limiting episodes of fever and painful polyserositis affecting mainly the peritoneum, pleura and synovium. FMF is an autosomal recessive disorder, with considerable prevalence in specific ethnic groups, namely, non-Ashkenazi Jews, Armenians, Turks, and Arabs (El-Shanti et al. 2006b). There is a plethora of reports regarding the clinical, genetic and mutational spectrum in the Jordanian population (Al-Alami et al. 2003; Al-Wahadneh and Dahabreh 2006; El-Shanti et al. 2006b; El-Shanti 2001, 2003; Majeed et al. 2000a; Majeed et al. 2005; Majeed et al. 2002; Majeed et al. 1999; Medlej-Hashim et al. 2000, 2005; Milhavet et al. 2008; Rawashdeh and Majeed 1996; Touitou et al. 2007). It is important to identify if there is a distinctive pattern of the relationship between MEFV and the FMF phenotype. Achieving this goal will lead to the establishment of adequate population screening protocols for early and presymptomatic identification of patients and the provision of prophylactic colchicine therapy. Chronic recurrent multifocal osteomyelitis (CRMO) is a relatively rare childhood disease that presents with pain in the bone with or without associated fever (El-Shanti and Ferguson 2007; Ferguson and El-Shanti 2007). A syndromic form of CRMO was first described by Dr. Hassan Abdel Majeed and his colleagues in 1989 (Majeed et al. 1989) and was subsequently named after him as the Majeed syndrome. Affected individuals present with periodic fevers, early-onset CRMO (age range 3 weeks to 19 months), microcytic congenital dyserythropoietic anemia, and often transiently occurring inflammatory dermatosis (Al-Mosawi et al. 2007; Majeed et al. 1989, 2000b, 2001). Like sporadic CRMO, there is a predilection for the metaphyses of the long bones, and the radiographs demonstrate extensive lytic lesions with areas of sclerosis (Majeed et al. 2001). The congenital dyserythropoietic anemia presents during the first year of life and the resultant anemia varies in severity from mild to transfusion-dependent (Al-Mosawi et al. 2007; Majeed et al. 1989, 2000b, 2001). The dermatosis is most often Sweet syndrome. Majeed syndrome is an autosomal recessive disorder caused by mutations in LPIN2 (Ferguson et al. 2005). The gene responsible for Majeed syndrome was localized to the short arm of chromosome 18 using homozygosity mapping, because the first two described families were inbred. To date, three different homozygous mutations

338


in LPIN2 have been found in each of the reported families with Majeed syndrome, all of whom are Arabic (Al-Mosawi et al. 2007; Ferguson et al. 2005) (available at http://fmf.igh.cnrs.fr/infevers). Behcet disease (BD) is a multisystem inflammatory disease characterized by recurrent orogenital ulceration, ocular inflammation, and skin lesions. The etiology of the disease is currently unknown but evidence suggests that there is a strong genetic component mediating the chronicity of the disorder. There is a strong BD society in Jordan that provides support, services and information to patients and families (Tamimi and Madanat 2003). Several studies have involved Jordanian BD patients to examine associations between specific clinical aspects of the disease and DNA polymorphisms (Takemoto et al. 2008; Verity et al. 1999a, b), as well as association studies in search of etiologic genetic factors (Ahmad et al. 2005; Baranathan et al. 2007; Verity et al. 2000; Wallace et al. 1999, 2007; Yang et al. 2004). In addition, there are several descriptive reports on the BD patient population (Madanat et al. 1993, 2003; Madanat and Madanat 2008).

Endocrinological Disorders Diabetes Mellitus is quite prevalent in Jordan and that is attributed to changes in dietary habits and life style (Ajlouni et al. 2008). Surveys of the prevalence of the different types of DM, its associations and complications has been professionally carried out in Jordan (Abdallah et al. 2007; Abdel-Aal et al. 2008; Abu Ali et al. 2008; Ajlouni et al. 1998a, 1999; Al-Till et al. 2005; Awadallah and Hamad 2000; Jbour et al. 2003b; Khatib et al. 2006; Radaideh et al. 2004). A genotypic and phenotypic variant of a syndromic form of DM, Wolfram syndrome (DIDMOAD; Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness) has been described from Jordan and its clinical picture has been clearly outlined (Ajlouni et al. 2002; Al-Sheyyab et al. 2001; Al-Till et al. 2002; Hadidy et al. 2004; Jarrah et al. 1999). The variant was mapped to the long arm of chromosome 4 (El-Shanti et al. 2000) and the gene encoding for the responsible protein, ERIS, was identified 8 years later (Amr et al. 2007). The effect of metformin on the androgenic profile of diabetic and normal men was prospectively studied (Shegem et al. 2002, 2004). Similar to all neighboring countries, as well as the developed world, obesity is forcefully emerging as a public health problem in Jordan (Ajlouni et al. 1998b). According to a recent study, age-standardized prevalence of obesity in Northern Jordan was 28.1% for men and 53.1% for women. Irrespective of age or measure used, women always had a considerably higher prevalence of obesity than men. There has been a significant increase in the prevalence of obesity over a period of ten years for both men and women aged 60 years and above only. This study demonstrated alarming rates of obesity and of its associated comorbidities among Jordanians (Khader et al. 2008). Other studies, done in Jordan, indirectly showed that obesity is remarkably increasing (Hasan et al. 2001; Jaddou et al. 2003; Khader et al. 2007; Majali et al. 2003).

11


339

Kallman syndrome is a genetically heterogeneous disorder associated with hypogonadism and anosmia. The clinical picture of 32 patients from 12 families was delineated and the presenting features were outlined (Abujbara et al. 2004). A standard clinical smell testing protocol was devised from the National Center for Diabetes, Endocrinology and Genetics to allow for accurate and culturally appropriate evaluation of anosmia (Ahmad et al. 2007). Congenital adrenal hyperplasia has been studied in Jordan and atypical forms were reported (Ajlouni et al. 1996; Arnaout 1992). The classic type, due to the 21hydroxylase deficiency has been reported on recently, especially in relation to the development of sexual organs (Al-Maghribi 2007). In a recent study aimed to display the spectrum of initial presentation and etiology among children with precocious puberty and to assess any association between the clinical features and the underlying cause of the condition, congenital adrenal hyperplasia was diagnosed in four boys and four girls, and hypothyroidism in three girls (Taher et al. 2004). Rare causes of hypogonadism were reported (Hiyasat et al. 2002; Jbour et al. 2003a), as well as a rare family with true hermaphroditism (Jarrah et al. 2000).

Genodermatosis Although autosomal recessive disorders of skin are often diagnosed such as epidermolysis bullosa, ectodermal dysplasia and ichthyosis, these are not usually reported in the literature. A case of lamellar ichthyosis was reported secondary to the development of acute lymphocytic leukemia (Al-Sheyyab et al. 1996). Alopecia with partial, total or universal has been reported in Jordanians in association of other abnormalities. Two Christian Jordanian sisters and their brothers were reported with primary hypogonadism, partial alopecia and defective Mullerian development (only in the sisters) (Al-Awadi et al. 1985). Five children from two unrelated families were reported with alopecia universalis, laryngomalacia, short stature and gonadal dysgenesis (El-Shanti 2004; El-Shanti et al. 2003). One more patient was reported upon from Toronto with the same syndromic features (Teebi et al. 2004). AE is caused by insufficient uptake of zinc by the intestine. The AE gene was mapped to chromosome 8q24.3 using a consanguineous Jordanian family (Wang et al. 2001). The Jordanian family was found to have a homozygous “G630R” mutation, once the gene was identified (Wang et al. 2002).

Skeletal and Dental Disorders Nine Jordanian families having 20 individuals affected with amelogenesis imperfecta (AI) and 41 unaffected were studied by light and scanning electron microscopy along with amino acid analysis of the enamels (Nusier et al. 2004). The authors

340


proposed to classify the disorder as “autosomal recessive generalized thin hypoplastic AI,” giving importance to the mode of inheritance, as well as the clinical form (Nusier et al. 2004). The cathepsin C gene (CTSC) encodes a cysteine lysosomal protease belonging to the papain family, called dipeptidyl peptidase I. The enzymatic function of this protease is the removal of amino terminal dipetides of the protein substrate. In the immune cells, the protease plays a role in removing the activation dipeptide from many of the leukocyte and mast cell granule-associated proteinases, which is considered an essential step for the PMN mediated killing of pathogens. Mutations in the CTSC gene have been implicated in PLS, Haim-Munk syndrome, and prepubertal periodontitis where early onset periodontitis is a common manifestation. Several families with these disorders were reported and mutations within CTSC were found (Hart et al. 2000; Hattab and Amin 2005; Hattab et al. 1995; Nusier et al. 2002). Two siblings with Ellis-Van Creveld were presented to include their oral findings, summarized as multiple broad labial frenula with abnormal attachments, congenital missing incisors and anomalous teeth (Hattab et al. 1998). The same group presented the oral findings in a case resembling Grebe chondrodysplasia (Hattab et al. 1996). Progressive pseudorheumatoid dysplasia (PPD) is an autosomal recessive skeletal dysplasia with radiographic changes in the spine similar to Spondyloepiphyseal dysplasia tarda with clinical, though not radiographic, resemblance to rheumatoid arthritis (El-Shanti et al. 1997). It is a prevalent condition among the Arabs and has been reported from Jordan. The gene responsible for this disorder was mapped to the long arm of chromosome 6 (El-Shanti et al. 1998), and later identified as WISP3 (Hurvitz et al. 1999). Several other reports of different other skeletal disorders originated from Jordan, such as mulitple enchondromatosis (Mahafza 2004), Raine syndrome (Mahafza et al. 2001) and Holt–Oram syndrome (Boehme and Shotar 1989).

Hematological and Oncologic Disorders The hemoglobinopathies constitute a large heterogeneous group of hemoglobin disorders, including b-thalassemia, a-thalassemia and sickle cell anemia. The prevalence of these disorders is significantly high in the Jordanian population (Bashir et al. 1992a, b), which mandated premarital testing for b-thalassemia. There are several manuscripts that describe different clinical aspects and care of children with b-thalassemia (Abu Alhaija et al. 2002; Al-Rimawi et al. 2005, 2006; Al Qaddoumi 2006; Barkawi et al. 1991; Hattab et al. 2001). The spectrum of mutations in the b-globin gene was the subject of several studies (Adekile et al. 1994; Al Qaddoumi 2006; el-Hazmi et al. 1995; Sadiq et al. 2001; Sadiq and Huisman 1994). On the other hand, there are several studies of the clinical and molecular aspects of a-thalassemia (Adekile et al. 1994; Al Qaddoum 2006). Sickle cell anemia is not

11


341

systematically studied, despite its considerable prevalence (Al-Rimawi et al. 2006; Al-Salem 1991; Al-Salem and Ismail 1990; Barkawi et al. 1991; Bashir et al. 1992a, b; Talafih et al. 1996). Rare forms of anemias have been subjects of several reports, such as the congenital dyserythropoietic anemia of Majeed syndrome (Majeed et al. 2001), selective vitamin B12 malabsorption anemia (Al-Alami et al. 2002, 2005) and Fanconi anemia (Al-Sheyyab et al. 1998). Glucose-6-dehydrogenase (G-6-PD) deficiency is quite prevalent in the Jordanian population but due to its mild symptoms it has not gained significant systematic studying of its clinical and molecular aspects except in recent years (Karadsheh et al. 2005a, b; Kurdi-Haidar et al. 1990; Talafih et al. 1996; Usanga and Ameen 2000). Several studies looked at variants and at mutations and their distribution in the population (Karadsheh et al. 2005a, b). Molecular screening for G6PD mutations in two Jordanian populations revealed six different mutations and higher incidences of G6PD deficiency and G6PD A- (376A!G þ 202G!A) mutation in Jordan Valley than in the Amman area (Karadsheh et al. 2005b). One manuscript deals with treatment issues relative to the acute hemolytic anemia (Al-Rimawi et al. 1999). Bleeding disorders, whether rare or common, are reported from Jordan with some depth in studying their etiology (Al-Sheyyab et al. 2001; Awidi 1992; Qublan et al. 2006; Rosenberg et al. 2005). The frequency of factor V Leiden has been studied, somewhat extensively, probably due to its role in technology assisted pregnancy (Awidi et al. 1999; Eid and Rihani 2004; Eid and Shubeilat 2005; Nusier et al. 2007; Qublan et al. 2006, 2008; Verity et al. 1999a). It appears that about 20% of the population are heterozygous and 5% are homozygous for the Leiden allele (Eid and Shubeilat 2005). The ABO blood group allele frequency was studied in the Jordanian population as part of larger studies (Hosseini-Maaf et al. 2003, 2005). There are a mediocre number of reports regarding cancer genetics despite the high impact of cancer on the Jordanian society. There is one study exploring the frequency of P53 gene polymorphism in healthy Jordanians and comparison to the frequency of the polymorphisms in cancer patients (Mahasneh and Abdel-Hafiz 2004). A study that investigated the presence of germ-line mutations in BRCA1 among 135 breast cancer patients revealed six germ-line mutations (Atoum and Al-Kayed 2004); however, it followed two studies of risk factors relating to breast cancer (Atoum and Al-Hourani 2004a, b). The investigation of hormone receptor positivity among Jordanian patients with breast cancer showed that the prevalence of hormone receptor positivity in breast cancer of Jordanian women is lower than that of the western populations (Almasri and Al Hamad 2005; Sughayer et al. 2006). A major study that investigated methylation patterns in colorectal carcinoma from three Middle Eastern countries including Jordan showed that it has differing gene methylation patterns and mutation frequencies that indicate dissimilar molecular pathogenesis, probably reflecting different environmental exposures (Chan et al. 2005). Studies on the molecular aspects of lymphomas in Jordan included a study on Bcl-2 rearrangements (Almasri et al. 2005), the presence of ‘The transforming mutation’ E17K/AKT1in B-cell lymphomas (Mahmoud et al. 2008), and the Frequency of t(14;18) in follicular carcinoma (Ismail et al. 2009).

342


Conclusion Jordan is a developing country with limited natural resources. Jordan has one of the highest rates of consanguinity among the Arab countries which is clearly associated with a significant number of recognizable and novel genetic disorders. Over the last few decades, health care services improved significantly in Jordan while the health needs of its people continue to grow, as well. Care for patients with chronic diseases including genetic disorders is becoming increasingly important. The available genetic services appear to be limited, fragmented and do not meet the need of the people of Jordan. While significant gains in knowledge about the spectrum of genetic disorders among Jordanians had been achieved, the magnitude and breadth of the health, financial and socioeconomic effects had not been adequately studied or appreciated. Making early identification, education, prenatal genetic diagnosis readily available along with allocation of adequate technical, financial and manpower resources should help control the huge impact genetic disorders have on Jordan’s population.

References Abdallah S, Ahmad AT, Batieha A, Ajlouni K (2007) Diabetes mellitus: the leading cause of haemodialysis in Jordan. East Mediterr Health J 13(4):803–9 Abdel-Aal NM, Ahmad AT, Froelicher ES, Batieha AM, Hamza MM, Ajlouni KM (2008) Prevalence of dyslipidemia in patients with type 2 diabetes in Jordan. Saudi Med J 29 (10):1423–8 Abdel-Rahman F, Hussein A, Rihani R, Hlalah O, El Taani H, Sharma S, Nserat T, Sarhan M (2008) Bone marrow and stem cell transplantation at King Hussein cancer center. Bone Marrow Transplant 42(Suppl 1):S89–S91 Abu Alhaija ES, Hattab FN, al-Omari MA (2002) Cephalometric measurements and facial deformities in subjects with beta-thalassaemia major. Eur J Orthod 24(1):9–19 Abu Ali RM, Al Hajeri RM, Khader YS, Shegem NS, Ajlouni KM (2008) Sexual dysfunction in Jordanian diabetic women. Diabetes Care 31(8):1580–1 Abujbara MA, Hamamy HA, Jarrah NS, Shegem NS, Ajlouni KM (2004) Clinical and inheritance profiles of Kallmann syndrome in Jordan. Reprod Health 1(1):5 Adekile AD, Gu LH, Baysal E, Haider MZ, al-Fuzae L, Aboobacker KC, al-Rashied A, Huisman TH (1994) Molecular characterization of alpha-thalassemia determinants, beta-thalassemia alleles, and beta S haplotypes among Kuwaiti Arabs. Acta Haematol 92(4):176–81 Ahmad T, Zhang L, Gogus F, Verity D, Wallace G, Madanat W, Fayyad F, James T, Neville M, Kanawati C et al (2005) CARD15 polymorphisms in Behcet’s disease. Scand J Rheumatol 34(3):233–7 Ahmad AT, Jbara MA, Hiyasat D, Bateiha A, Ajlouni KM (2007) The standard clinical smell testing protocol of the National Center for Diabetes, Endocrinology and Genetics in Amman, Jordan: JOR test. Am J Otolaryngol 28(6):388–91 Ahram D, Sato TS, Kohilan A, Tayeh M, Chen S, Leal S, Al-Salem M, El-Shanti H (2009) A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. Am J Hum Genet 84(2):274–8 Ajlouni KM, Arnaout MA, Qoussous Y (1996) Congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency with skeletal abnormalities. J Endocrinol Invest 19(5):316–9

11


343

Ajlouni K, Jaddou H, Batieha A (1998a) Diabetes and impaired glucose tolerance in Jordan: prevalence and associated risk factors. J Intern Med 244(4):317–23 Ajlouni K, Jaddou H, Batieha A (1998b) Obesity in Jordan. Int J Obes Relat Metab Disord 22(7): 624–8 Ajlouni K, Qusous Y, Khawaldeh AK, Jaddou H, Batiehah A, Ammari F, Zaheri M, Mashal A (1999) Incidence of insulin-dependent diabetes mellitus in Jordanian children aged 0-14 y during 1992–1996. Acta Paediatr Suppl 88(427):11–3 Ajlouni K, Jarrah N, El-Khateeb M, El-Zaheri M, El Shanti H, Lidral A (2002) Wolfram syndrome: identification of a phenotypic and genotypic variant from Jordan. Am J Med Genet 115(1):61–5 Ajlouni K, Khader YS, Batieha A, Ajlouni H, El-Khateeb M (2008) An increase in prevalence of diabetes mellitus in Jordan over 10 years. J Diabetes Complications 22(5):317–24 Al Qaddoumi AA (2006) Co-inheritance of alpha and beta-thalassemia in a Jordanian family. Clin Lab Sci 19(3):165–8 Al-Alami JR, Tayeh MK, Al-Sheyyab MY, El-Shanti HI (2002) Linkage analysis of a large inbred family with congenital megaloblastic anemia. Saudi Med J 23(10):1251–6 Al-Alami JR, Tayeh MK, Najib DA, Abu-Rubaiha ZA, Majeed HA, Al-Khateeb MS, El-Shanti HI (2003) Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Med J 24(10):1055–9 Al-Alami JR, Tanner SM, Tayeh MK, de la Chapelle A, El-Shanti H (2005) Homozygous AMN mutation in hereditary selective intestinal malabsorption of vitamin B12 in Jordan. Saudi Med J 26(7):1061–4 Al-Aqtum MT, Al-Qawasmeh MH (2001) Prevalence of colour blindness in young Jordanians. Ophthalmologica 215(1):39–42 Al-Awadi SA, Farag TI, Teebi AS, Naguib K, el-Khalifa MY, Kelani Y, Al-Ansari A, Schimke RN (1985) Primary hypogonadism and partial alopecia in three sibs with mullerian hypoplasia in the affected females. Am J Med Genet 22(3):619–22 Al-Jaberi TM, El-Shanti H (2002) Diversity in polyp pathology and distribution of Familial Juvenile Polyposis Syndrome. Saudi Med J 23(3):328–31 Al-Maghribi H (2007) Congenital adrenal hyperplasia: problems with developmental anomalies of the external genitalia and sex assignment. Saudi J Kidney Dis Transpl 18(3):405–13 Almasri NM, Al Hamad M (2005) Immunohistochemical evaluation of human epidermal growth factor receptor 2 and estrogen and progesterone receptors in breast carcinoma in Jordan. Breast Cancer Res 7(5):R598–604 Almasri NM, Al-Alami J, Faza M (2005) Bcl-2 gene rearrangement in Jordanian follicular and diffuse large B-cell lymphomas. Saudi Med J 26(2):251–5 Al-Mosawi ZS, Al-Saad KK, Ijadi-Maghsoodi R, El-Shanti HI, Ferguson PJ (2007) A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum 56(3):960–4 Al-Qudah AA (1998) Clinical patterns of neuronal migrational disorders and parental consanguinity. J Trop Pediatr 44(6):351–4 Al-Qudah AA, Tarawneh M (1998) Congenital muscular dystrophy in Jordanian children. J Child Neurol 13(8):383–6 Al-Rimawi HS, Al-Sheyyab M, Batieha A, El-Shanti H, Abuekteish F (1999) Effect of desferrioxamine in acute haemolytic anaemia of glucose-6-phosphate dehydrogenase deficiency. Acta Haematol 101(3):145–8 Al-Rimawi HS, Jallad MF, Amarin ZO, Obeidat BR (2005) Hypothalamic-pituitary-gonadal function in adolescent females with beta-thalassemia major. Int J Gynaecol Obstet 90(1):44–7 Al-Rimawi HS, Abdul-Qader M, Jallad MF, Amarin ZO (2006) Acute splenic sequestration in female children with sickle cell disease in the North of Jordan. J Trop Pediatr 52(6):416–20 Al-Salem M (1990) Autosomal recessive ectopia lentis in two Arab family pedigrees. Ophthalmic Paediatr Genet 11(2):123–7 Al-Salem M (1991) Benign ocular manifestations of sickle cell anemia in Arabs. Indian J Ophthalmol 39(1):9–11

344


Al-Salem M (1997) Leber’s congenital amaurosis in 22 affected members of one family. J Pediatr Ophthalmol Strabismus 34(4):254–7 Al-Salem M, Ismail L (1990) Ocular manifestations of sickle cell anaemia in Arab children. Ann Trop Paediatr 10(2):199–202 Al-Salem M, Rawashdeh N (1992) Pattern of childhood blindness and partial sight among Jordanians in two generations. J Pediatr Ophthalmol Strabismus 29(6):361–5 Al-Salem M, Rawashdeh N (1993) Consanguinity in north Jordan: prevalence and pattern. J Biosoc Sci 25(4):553–6 Al-Salem M, Arafat AF, Ismail L, Jaradat M (1996) Causes of blindness in Irbid, Jordan. Ann Saudi Med 16(4):420–3 Al-Sheyyab M, El Shanti H, Todd D, Shurman A (1996) Autosomal recessive lamellar ichthyosis and acute lymphoblastic leukemia. Eur J Hum Genet 4(2):105–7 Al-Sheyyab M, El-Shanti H, Ghariebeh N, Ektiesh F, Daoud AS (1998) Fanconi’s anemia and primary hypothyroidism. Ann Saudi Med 18(1):58–9 Al-Sheyyab M, Daoud AS, El-Shanti H (2000) Chediak–Higashi syndrome: a report of eight cases from three families. Indian Pediatr 37(1):69–75 Al-Sheyyab M, Jarrah N, Younis E, Shennak MM, Hadidi A, Awidi A, El-Shanti H, Ajlouni K (2001) Bleeding tendency in Wolfram syndrome: a newly identified feature with phenotype genotype correlation. Eur J Pediatr 160(4):243–6 Al-Shroof M, Karnik AM, Karnik AA, Longshore J, Sliman NA, Khan FA (2001) Ciliary dyskinesia associated with hydrocephalus and mental retardation in a Jordanian family. Mayo Clin Proc 76(12):1219–24 Al-Till M, Jarrah NS, Ajlouni KM (2002) Ophthalmologic findings in fifteen patients with Wolfram syndrome. Eur J Ophthalmol 12(2):84–8 Al-Till MI, Al-Bdour MD, Ajlouni KM (2005) Prevalence of blindness and visual impairment among Jordanian diabetics. Eur J Ophthalmol 15(1):62–8 Al-Wahadneh AM, Dahabreh MM (2006) Familial Mediterranean fever in children: a single centre experience in Jordan. East Mediterr Health J 12(6):818–23 Amarin VN, Akasheh HF (2001) Advanced maternal age and pregnancy outcome. East Mediterr Health J 7(4–5):646–51 Amr S, Heisey C, Zhang M, Xia XJ, Shows KH, Ajlouni K, Pandya A, Satin LS, El-Shanti H, Shiang R (2007) A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2. Am J Hum Genet 81(4):673–83 Aqrabawi HE (2008) Facial cleft and associated anomalies: incidence among infants at a Jordanian medical centre. East Mediterr Health J 14(2):356–9 Arnaout MA (1992) Late-onset congenital adrenal hyperplasia in women with hirsutism. Eur J Clin Invest 22(10):651–8 Atoum MF, Al-Hourani HM (2004a) Comparison of some risk factors between non-familial and familial breast cancer females in Jordan. Saudi Med J 25(2):168–71 Atoum MF, Al-Hourani HM (2004b) Lifestyle related risk factors for breast cancer in Jordanian females. Saudi Med J 25(9):1245–8 Atoum MF, Al-Kayed SA (2004) Mutation analysis of the breast cancer gene BRCA1 among breast cancer Jordanian females. Saudi Med J 25(1):60–3 Awadallah S, Hamad M (2000) The prevalence of type II diabetes mellitus is haptoglobin phenotype-independent. Cytobios 101(398):145–50 Awidi AS (1992) Rare inherited bleeding disorders secondary to coagulation factors in Jordan: a nine-year study. Acta Haematol 88(1):11–3 Awidi A, Shannak M, Bseiso A, Kailani MA, Kailani MA, Omar N, Anshasi B, Sakarneh N (1999) High prevalence of factor V Leiden in healthy Jordanian Arabs. Thromb Haemost 81(4):582–4 Badria LF, Amarin ZO (2003) Does consanguinity affect the severity of pre-eclampsia? Arch Gynecol Obstet 268(2):117–20 Badria LF, Abu-Heija A, Zayed F, Ziadeh SM, Alchalabi H (2001) Has consanguinity any impact on occurrence of pre-eclampsia and eclampsia? J Obstet Gynaecol 21(4):358–60

11


345

Baranathan V, Stanford MR, Vaughan RW, Kondeatis E, Graham E, Fortune F, Madanat W, Kanawati C, Ghabra M, Murray PI et al (2007) The association of the PTPN22 620W polymorphism with Behcet’s disease. Ann Rheum Dis 66(11):1531–3 Barkawi M, Bashir N, Sharif L (1991) Sickle cell-thalassemia in a Jordanian family. Trop Geogr Med 43(1–2):94–9 Bashir N, Barkawi M, Sharif L (1992a) Sickle cell/beta-thalassemia in North Jordan. J Trop Pediatr 38(4):196–8 Bashir N, Barkawi M, Sharif L, Momani A, Gharaibeh N (1992b) Prevalence of hemoglobinopathies in north Jordan. Trop Geogr Med 44(1–2):122–5 Bassuk AG, Wallace RH, Buhr A, Buller AR, Afawi Z, Shimojo M, Miyata S, Chen S, GonzalezAlegre P, Griesbach HL et al (2008) A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. Am J Hum Genet 83(5):572–81 Berkovic SF, Mazarib A, Walid S, Neufeld MY, Manelis J, Nevo Y, Korczyn AD, Yin J, Xiong L, Pandolfo M et al (2005) A new clinical and molecular form of Unverricht-Lundborg disease localized by homozygosity mapping. Brain 128(Pt 3):652–8 Boehme DH, Shotar AO (1989) A complex deformity of appendicular skeleton and shoulder with congenital heart disease in three generations of a Jordanian family. Clin Genet 36(6): 442–50 Brautbar C, Amar A, Cohen N, Oksenberg J, Cohen I, Kahana E, Bloch D, Alter M, Grosse-Wilde H (1982) HLA-D typing in multiple sclerosis: Israelis tested with European homozygous typing cells. Tissue Antigens 19(3):189–97 Buchanan DJ, Rapoport S (1952) Chemical comparison of normal meconium and meconium from a patient with meconium ileus. Pediatrics 9(3):304–10 Chan AO, Soliman AS, Zhang Q, Rashid A, Bedeir A, Houlihan PS, Mokhtar N, Al-Masri N, Ozbek U, Yaghan R et al (2005) Differing DNA methylation patterns and gene mutation frequencies in colorectal carcinomas from Middle Eastern countries. Clin Cancer Res 11(23): 8281–7 Christodoulou K, Zamba E, Tsingis M, Mubaidin A, Horani K, Abu-Sheik S, El-Khateeb M, Kyriacou K, Kyriakides T, Al-Qudah AK et al (2000) A novel form of distal hereditary motor neuronopathy maps to chromosome 9p21.1-p12. Ann Neurol 48(6):877–84 Cook R, Hanslip A (1966) Mortality among offspring of consanguineous marriage in a rural area of East Jordan. J Trop Pediatr Afr Child Health 11(4):95–9 Corut A, Senyigit A, Ugur SA, Altin S, Ozcelik U, Calisir H, Yildirim Z, Gocmen A, Tolun A (2006) Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am J Hum Genet 79(4):650–6 Dahabreh M, Najada A (2009) Pulmonary alveolar microlithiasis in an 8-month-old infant. Ann Trop Paediatr 29(1):55–9 Daoud AS, Batieha A, Bashtawi M, El-Shanti H (2003) Risk factors for childhood epilepsy: a casecontrol study from Irbid, Jordan. Seizure 12(3):171–4 Daoud AS, Ajloni S, El-Salem K, Horani K, Otoom S, Daradkeh T (2004) Risk of seizure recurrence after a first unprovoked seizure: a prospective study among Jordanian children. Seizure 13(2):99–103 Eid SS, Rihani G (2004) Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in 200 healthy Jordanians. Clin Lab Sci 17(4):200–2 Eid SS, Shubeilat T (2005) Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR G677A among 594 thrombotic Jordanian patients. Blood Coagul Fibrinolysis 16(6):417–21 el-Hazmi MA, Warsy AS, al-Swailem AR (1995) The frequency of 14 beta-thalassemia mutations in the Arab populations. Hemoglobin 19(6):353–60 El-Shanti HE (2001) Familial Mediterranean Fever. Saudi Med J 22(2):104–9 El-Shanti HI (2003) Familial mediterranean Fever and renal disease. Saudi J Kidney Dis Transpl 14(3):378–85 El-Shanti H (2004) Further delineation of El-Shanti syndrome. Eur J Pediatr 163(12):761–2

346


El-Shanti H, Al-Alami J (2002) The pattern of peripheral blood chromosomal abnormalities in Northern Jordan. Saudi Med J 23(12):1552–4 El-Shanti HI, Ferguson PJ (2007) Chronic recurrent multifocal osteomyelitis: a concise review and genetic update. Clin Orthop Relat Res 462:11–9 El-Shanti HE, Omari HZ, Qubain HI (1997) Progressive pseudorheumatoid dysplasia: report of a family and review. J Med Genet 34(7):559–63 El-Shanti H, Murray JC, Semina EV, Beutow KH, Scherpbier T, Al-Alami J (1998) Assignment of gene responsible for progressive pseudorheumatoid dysplasia to chromosome 6 and examination of COL10A1 as candidate gene. Eur J Hum Genet 6(3):251–6 El-Shanti H, Al-Salem M, El-Najjar M, Ajlouni K, Beck J, Sheffiled VC, Stone EM (1999a) A nonsense mutation in the retinal specific guanylate cyclase gene is the cause of Leber congenital amaurosis in a large inbred kindred from Jordan. J Med Genet 36(11):862–5 El-Shanti HE, Daoud AS, Batieha A (1999b) A clinical study of a large inbred kindred with pure familial spastic paraplegia. Brain Dev 21(7):478–82 El-Shanti H, Lidral AC, Jarrah N, Druhan L, Ajlouni K (2000) Homozygosity mapping identifies an additional locus for Wolfram syndrome on chromosome 4q. Am J Hum Genet 66 (4):1229–36 El-Shanti H, Ahmad M, Ajlouni K (2003) Alopecia universalis congenita, XY gonadal dysgenesis and laryngomalacia: a novel malformation syndrome. Eur J Pediatr 162(1):36–40 El-Shanti H, Daoud A, Sadoon AA, Leal SM, Chen S, Lee K, Spiegel R (2006a) A distinct autosomal recessive ataxia maps to chromosome 12 in an inbred family from Jordan. Brain Dev 28(6):353–7 El-Shanti H, Majeed HA, El-Khateeb M (2006b) Familial mediterranean fever in Arabs. Lancet 367(9515):1016–24 Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF et al (2008) Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. Am J Hum Genet 82(1):57–72 Ferguson PJ, El-Shanti HI (2007) Autoinflammatory bone disorders. Curr Opin Rheumatol 19(5): 492–8 Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM, Pelet A, Munnich A, Lyonnet S, Majeed HA, El-Shanti H (2005) Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet 42(7):551–7 Gonzalez AM, Karadsheh N, Maca-Meyer N, Flores C, Cabrera VM, Larruga JM (2008) Mitochondrial DNA variation in Jordanians and their genetic relationship to other Middle East populations. Ann Hum Biol 35(2):212–31 Hadidi HF, Irshaid YM, Woosley RL, Idle JR, Flockhart DA (1995) S-mephenytoin hydroxylation phenotypes in a Jordanian population. Clin Pharmacol Ther 58(5):542–7 Hadidy AM, Jarrah NS, Al-Till MI, El-Shanti HE, Ajlouni KM (2004) Radiological findings in Wolfram syndrome. Saudi Med J 25(5):638–41 Hamamy H, Jamhawi L, Al-Darawsheh J, Ajlouni K (2005) Consanguineous marriages in Jordan: why is the rate changing with time? Clin Genet 67(6):511–6 Hamamy H, Al-Hait S, Alwan A, Ajlouni K (2007a) Jordan: communities and community genetics. Community Genet 10(1):52–60 Hamamy HA, Masri AT, Al-Hadidy AM, Ajlouni KM (2007b) Consanguinity and genetic disorders. Profile from Jordan. Saudi Med J 28(7):1015–7 Hamamy HA, Teebi AS, Oudjhane K, Shegem NN, Ajlouni KM (2007c) Severe hypertelorism, midface prominence, prominent/simple ears, severe myopia, borderline intelligence, and bone fragility in two brothers: new syndrome? Am J Med Genet A 143(3):229–34 Hamed RM (2002) The spectrum of chronic renal failure among Jordanian children. J Nephrol 15(2):130–5 Hamed RM (2003) Congenital nephrotic syndrome. Saudi J Kidney Dis Transpl 14(3):328–35

11


347

Hamed RM, Shomaf M (2001) Congenital nephrotic syndrome: a clinico-pathologic study of thirty children. J Nephrol 14(2):104–9 Hamed RM, Tamimi S, Al-Shamayleh A, Kamal MF, Tarawneh M, Toffaha A (1998) Renal cysts and associated malformations in pediatric autopsy material. Ann Saudi Med 18(5):451–3 Hampshire DJ, Roberts E, Crow Y, Bond J, Mubaidin A, Wriekat AL, Al-Din A, Woods CG (2001) Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36. J Med Genet 38(10):680–2 Handra-Luca A, Condroyer C, de Moncuit C, Tepper M, Flejou JF, Thomas G, Olschwang S (2005) Vessels’ morphology in SMAD4 and BMPR1A-related juvenile polyposis. Am J Med Genet A 138A(2):113–7 Hart TC, Hart PS, Michalec MD, Zhang Y, Marazita ML, Cooper M, Yassin OM, Nusier M, Walker S (2000) Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation. J Med Genet 37(2):95–101 Hasan MA, Batieha A, Jadou H, Khawaldeh AK, Ajlouni K (2001) Growth status of Jordanian schoolchildren in military-funded schools. Eur J Clin Nutr 55(5):380–6 Hattab FN, Amin WM (2005) Papillon-Lefevre syndrome with albinism: a review of the literature and report of 2 brothers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 100(6):709–16 Hattab FN, Rawashdeh MA, Yassin OM, al-Momani AS, al-Ubosi MM (1995) Papillon-Lefevre syndrome: a review of the literature and report of 4 cases. J Periodontol 66(5):413–20 Hattab FN, al-Khateeb T, Mansour M (1996) Oral manifestations of severe short-limb dwarfism resembling Grebe chondrodysplasia: report of a case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81(5):550–5 Hattab FN, Yassin OM, Sasa IS (1998) Oral manifestations of Ellis-van Creveld syndrome: report of two siblings with unusual dental anomalies. J Clin Pediatr Dent 22(2):159–65 Hattab FN, Hazza’a AM, Yassin OM, al-Rimawi HS (2001) Caries risk in patients with thalassaemia major. Int Dent J 51(1):35–8 Hewitt C, Wu CL, Hattab FN, Amin W, Ghaffar KA, Toomes C, Sloan P, Read AP, James JA, Thakker NS (2004) Coinheritance of two rare genodermatoses (Papillon-Lefevre syndrome and oculocutaneous albinism type 1) in two families: a genetic study. Br J Dermatol 151 (6):1261–5 Hijazi SS, Abulaban A, Ammarin Z, Flatz G (1983) Distribution of adult lactase phenotypes in Bedouins and in urban and agricultural populations of Jordan. Trop Geogr Med 35 (2):157–61 Hiyasat D, Dehyyat MA, Ajlouni S, Mubaidin AF, Till M, Hadidi A, El-Shanti H, Ajlouni KM (2002) Cerebellar hypoplasia, hypergonadotrophic hypogonadism, retinitis pigmentosa, alopecia, microcephaly, psychomotor retardation, and short stature: "D-CHRAMPS syndrome". Eur J Pediatr 161(3):170–2 Hosseini-Maaf B, Hellberg A, Rodrigues MJ, Chester MA, Olsson ML (2003) ABO exon and intron analysis in individuals with the AweakB phenotype reveals a novel O1v-A2 hybrid allele that causes four missense mutations in the A transferase. BMC Genet 4:17 Hosseini-Maaf B, Smart E, Chester MA, Olsson ML (2005) The Abantu phenotype in the ABO blood group system is due to a splice-site mutation in a hybrid between a new O1-like allelic lineage and the A2 allele. Vox Sang 88(4):256–64 Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Furga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV et al (1999) Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 23(1):94–8 Irshaid YM, al-Hadidi HF, Rawashdeh NM (1993) Dextromethorphan O-demethylation polymorphism in Jordanians. Eur J Clin Pharmacol 45(3):271–3 Ismail SI, Sughayer MA, Al-Quadan TF, Qaqish BM, Tarawneh MS (2009) Frequency of t(14;18) in follicular lymphoma patients: geographical or technical variation. Int J Lab Hematol 31:535–545 Jaddou HY, Bateiha AM, Al-Khateeb MS, Ajlouni KM (2003) Epidemiology and management of hypertension among Bedouins in Northern Jordan. Saudi Med J 24(5):472–6

348


Janaydeh M, Hamad M, Awadallah S (2004) The relationship between haptoglobin polymorphism and serum ceruloplasmin ferroxidase activity. Clin Exp Med 3(4):219–23 Janson S, Dawani H (1994) Chronic illness in preschool Jordanian children. Ann Trop Paediatr 14(2):137–44 Janson S, Jayakoddy A, Abulaban A, Gustavson KH (1990) Severe mental retardation in Jordanian children. A retrospective study. Acta Paediatr Scand 79(11):1099–1104 Jarrah NS, El-Shanti H, Shennak MM, Ajlouni KM (1999) A case of Wolfram syndrome in triplets: some newly recognized features. Ann Saudi Med 19(2):132–4 Jarrah N, El-Shanti H, Khier A, Obeidat FN, Haddidi A, Ajlouni K (2000) Familial disorder of sex determination in seven individuals from three related sibships. Eur J Pediatr 159(12):912–8 Jbour AK, Mubaidin AF, Till M, El-Shanti H, Hadidi A, Ajlouni KM (2003a) Hypogonadotrophic hypogonadism, short stature, cerebellar ataxia, rod-cone retinal dystrophy, and hypersegmented neutrophils: a novel disorder or a new variant of Boucher–Neuhauser syndrome? J Med Genet 40(1):e2 Jbour AS, Jarrah NS, Radaideh AM, Shegem NS, Bader IM, Batieha AM, Ajlouni KM (2003b) Prevalence and predictors of diabetic foot syndrome in type 2 diabetes mellitus in Jordan. Saudi Med J 24(7):761–4 Kakish KS (2001) Cystic fibrosis in Jordan: clinical and genetic aspects. Bahrain Med Bull 23(4):157–159 Kakish KS (2002) Cystic fibrosis and infantile hypertrophic pyloric stenosis: is there an association? Pediatr Pulmonol 33(5):404–5 Karadsheh NS (1993) Pyruvate kinase (PK) deficiency in Jordan. Haematologica 78(2):80–3 Karadsheh NS, Gelbart T, Schulten HJ, Efferth T, Awidi A (2005a) Relationship between molecular variants and clinical manifestions in twelve glucose-6-phosphate dehydrogenasedeficient patients in Jordan. Acta Haematol 114(2):125–6 Karadsheh NS, Moses L, Ismail SI, Devaney JM, Hoffman E (2005b) Molecular heterogeneity of glucose-6-phosphate dehydrogenase deficiency in Jordan. Haematologica 90(12):1693–4 Khader Y, Bateiha A, El-Khateeb M, Al-Shaikh A, Ajlouni K (2007) High prevalence of the metabolic syndrome among Northern Jordanians. J Diabetes Complications 21(4):214–9 Khader Y, Batieha A, Ajlouni H, El-Khateeb M, Ajlouni K (2008) Obesity in Jordan: prevalence, associated factors, comorbidities, and change in prevalence over ten years. Metab Syndr Relat Disord 6(2):113–20 Khatib FA, Jarrah NS, Shegem NS, Bateiha AM, Abu-Ali RM, Ajlouni KM (2006) Sexual dysfunction among Jordanian men with diabetes. Saudi Med J 27(3):351–6 Khoury SA, Massad D (1992) Consanguineous marriage in Jordan. Am J Med Genet 43(5):769–75 Khoury SA, Massad DF (2000) Consanguinity, fertility, reproductive wastage, infant mortality and congenital malformations in Jordan. Saudi Med J 21(2):150–4 Kurdi-Haidar B, Mason PJ, Berrebi A, Ankra-Badu G, al-Ali A, Oppenheim A, Luzzatto L (1990) Origin and spread of the glucose-6-phosphate dehydrogenase variant (G6PD-Mediterranean) in the Middle East. Am J Hum Genet 47(6):1013–9 Kury S, Dreno B, Bezieau S, Giraudet S, Kharfi M, Kamoun R, Moisan JP (2002) Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet 31(3):239–40 Lees AJ, Singleton AB (2007) Clinical heterogeneity of ATP13A2 linked disease (Kufor-Rakeb) justifies a PARK designation. Neurology 68(19):1553–4 Madanat WY, Madanat AY (2008) Worsening of osteomalacia in a patient successfully treated for neuro-Behcet’s disease with infliximab. Clin Exp Rheumatol 26(4 Suppl 50):S128–9 Madanat WY, Prokaeva TB, Kotel’nikova GP, Alekberova ZS (1993) Endocarditis with left atrial thrombus formation in Behcet’s disease mimicking myxoma. J Rheumatol 20(11): 1982–4 Madanat W, Sharaiha Z, Khasawneh S, Zureikat H, Fayyad F (2003) Gastro-intestinal manifestations of Behcet’s disease. Adv Exp Med Biol 528:455–7 Mahafza WS (2004) Multiple enchondromatosis Ollier’s disease with two primary brain tumors. Saudi Med J 25(9):1261–3

11


349

Mahafza T, El-Shanti H, Omari H (2001) Raine syndrome: report of a case with hand and foot anomalies. Clin Dysmorphol 10(3):227–9 Mahasneh AA, Abdel-Hafiz SS (2004) Polymorphism of p53 gene in Jordanian population and possible associations with breast cancer and lung adenocarcinoma. Saudi Med J 25(11): 1568–73 Mahdi AH, al-Mashhadani SA, al-Nasser M (1991) Wolman’s disease in a Jordanian infant. Ann Trop Paediatr 11(3):305–8 Mahmoud IS, Sughayer MA, Mohammad HA, Awidi AS, EL-K MS, Ismail SI (2008) The transforming mutation E17K/AKT1 is not a major event in B-cell-derived lymphoid leukaemias. Br J Cancer 99(3):488–90 Majali H, Batieha AM, Jaddou HY, Khawaldeh A, Ajlouni KM (2003) Socio-economic discrepancies in growth status of Jordanian children in military-run schools at the turn of the twentieth century. Saudi Med J 24(5):548–9 Majeed HA, Kalaawi M, Mohanty D, Teebi AS, Tunjekar MF, al-Gharbawy F, Majeed SA, al-Gazzar AH (1989) Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in three related children and the association with Sweet syndrome in two siblings. J Pediatr 115(5 Pt 1):730–4 Majeed HA, Rawashdeh M, el-Shanti H, Qubain H, Khuri-Bulos N, Shahin HM (1999) Familial Mediterranean fever in children: the expanded clinical profile. QJM 92(6):309–18 Majeed HA, Al-Qudah AK, Qubain H, Shahin HM (2000a) The clinical patterns of myalgia in children with familial Mediterranean fever. Semin Arthritis Rheum 30(2):138–43 Majeed HA, El-Shanti H, Al-Rimawi H, Al-Masri N (2000b) On mice and men: an autosomal recessive syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia. J Pediatr 137(3):441–2 Majeed HA, Al-Tarawna M, El-Shanti H, Kamel B, Al-Khalaileh F (2001) The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review. Eur J Pediatr 160(12):705–10 Majeed HA, El-Shanti H, Al-Khateeb MS, Rabaiha ZA (2002) Genotype/phenotype correlations in Arab patients with familial Mediterranean fever. Semin Arthritis Rheum 31(6):371–6 Majeed HA, El-Khateeb M, El-Shanti H, Rabaiha ZA, Tayeh M, Najib D (2005) The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum 34(6):813–8 Masri A, Hamamy H (2006) Canavan disease: a first case from Jordan. J Pediatr Neurol 4:143–146 Masri AT, Hamamy HA (2007) Clinical and inheritance profiles of hyperekplexia in Jordan. J Child Neurol 22(7):895–900 Masri AT, Bakri FG, Al-Hadidy AM, Musharbash AF, Al-Hussaini M (2006) Ataxia-telangiectasia complicated by craniopharyngioma–a new observation. Pediatr Neurol 35(4):287–8 Masri A, Badran E, Hamamy H, Assaf A, Al-Qudah AA (2008a) Etiologies, outcomes, and risk factors for epilepsy in infants: a case-control study. Clin Neurol Neurosurg 110(4):352–6 Masri A, Bakri FG, Al-Hussaini M, Al-Hadidy A, Hirzallah R, de Saint BG, Hamamy H (2008b) Griscelli syndrome type 2: a rare and lethal disorder. J Child Neurol 23(8):964–7 Medlej-Hashim M, Rawashdeh M, Chouery E, Mansour I, Delague V, Lefranc G, Naman R, Loiselet J, Megarbane A (2000) Genetic screening of fourteen mutations in Jordanian familial Mediterranean fever patients. Hum Mutat 15(4):384 Medlej-Hashim M, Serre JL, Corbani S, Saab O, Jalkh N, Delague V, Chouery E, Salem N, Loiselet J, Lefranc G et al (2005) Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet 48(4):412–20 Middleton LT, Christodoulou K, Mubaidin A, Zamba E, Tsingis M, Kyriacou K, Abu-Sheikh S, Kyriakides T, Neocleous V, Georgiou DM et al (1999) Distal hereditary motor neuronopathy of the Jerash type. Ann NY Acad Sci 883:439–42 Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H, Aksentijevich I, Lesage S, Waterham H, Wise C, SarraustedeMenthiere C et al (2008) The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat 29(6):803–8

350


Mitchell SC, Zhang AQ, Barrett T, Ayesh R, Smith RL (1997) Studies on the discontinuous N-oxidation of trimethylamine among Jordanian, Ecuadorian and New Guinean populations. Pharmacogenetics 7(1):45–50 Myhre R, Steinkjer S, Stormyr A, Nilsen GL, Abu Zayyad H, Horany K, Nusier MK, Klungland H (2008) Significance of the parkin and PINK1 gene in Jordanian families with incidences of young-onset and juvenile Parkinsonism. BMC Neurol 8:47 Nabulsi A (1995) Mating patterns of the Abbad tribe in Jordan. Soc Biol 42(3–4):162–74 Najim al-Din AS, al-Kurdi A, Dasouki M, Wriekat AL, al-Khateeb M, Mubaidin A, al-Hiari M (1994) Autosomal recessive ataxia, slow eye movements and psychomotor retardation. J Neurol Sci 124(1):61–6 Nazer HM (1992) Early diagnosis of cystic fibrosis in Jordanian children. J Trop Pediatr 38(3): 113–5 Nusier M, Zhang Y, Yassin O, Hart TC, Hart PS (2002) Demonstration of altered splicing with the IVS3–1G –> a mutation of cathepsin C. Mol Genet Metab 75(3):280–3 Nusier M, Yassin O, Hart TC, Samimi A, Wright JT (2004) Phenotypic diversity and revision of the nomenclature for autosomal recessive amelogenesis imperfecta. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 97(2):220–30 Nusier MK, Radaideh AM, Ababneh NA, Qaqish BM, Alzoubi R, Khader Y, Mersa JY, Irshaid NM, El-Khateeb M (2007) Prevalence of factor V G1691A (Leiden) and prothrombin G20210A polymorphisms among apparently healthy Jordanians. Neuro Endocrinol Lett 28(5):699–703 Obeidat BR, Khader YS, Amarin ZO, Kassawneh M, Al Omari M (2008) Consanguinity and Adverse Pregnancy Outcomes: The North of Jordan Experience. Matern Child Health J Qublan HS, Eid SS, Ababneh HA, Amarin ZO, Smadi AZ, Al-Khafaji FF, Khader YS (2006) Acquired and inherited thrombophilia: implication in recurrent IVF and embryo transfer failure. Hum Reprod 21(10):2694–8 Qublan H, Amarin Z, Dabbas M, Farraj AE, Beni-Merei Z, Al-Akash H, Bdoor AN, Nawasreh M, Malkawi S, Diab F et al (2008) Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial. Hum Fertil (Camb) 11(4):246–53 Radaideh AR, Nusier MK, Amari FL, Bateiha AE, El-Khateeb MS, Naser AS, Ajlouni KM (2004) Thyroid dysfunction in patients with type 2 diabetes mellitus in Jordan. Saudi Med J 25(8): 1046–50 Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, Goebel I, Mubaidin AF, Wriekat AL, Roeper J et al (2006) Hereditary Parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38(10): 1184–91 Rawashdeh MO, Majeed HA (1996) Familial Mediterranean fever in Arab children: the high prevalence and gene frequency. Eur J Pediatr 155(7):540–4 Rawashdeh M, Manal H (2000) Cystic fibrosis in Arabs: a prototype from Jordan. Ann Trop Paediatr 20(4):283–6 Rosenberg N, Hauschner H, Peretz H, Mor-Cohen R, Landau M, Shenkman B, Kenet G, Coller BS, Awidi AA, Seligsohn U (2005) A 13-bp deletion in alpha(IIb) gene is a founder mutation that predominates in Palestinian-Arab patients with Glanzmann thrombasthenia. J Thromb Haemost 3(12):2764–72 Roychoudhury AK, Nei M (1988) Human Polymorphic Genes: World Distribution. Oxford University Press, New York Sadiq MF, Huisman TH (1994) Molecular characterization of beta-thalassemia in north Jordan. Hemoglobin 18(4–5):325–32 Sadiq MF, Eigel A, Horst J (2001) Spectrum of beta-thalassemia in Jordan: identification of two novel mutations. Am J Hematol 68(1):16–22 Saha N (1985) Distribution of transferrin C subtypes among the Bedouin and non-Bedouin populations of Jordan. Hum Hered 35(5):341–2

11


351

Saleh H, Davrinche C, Charlionet R, Rivat C (1986) Alpha-1-antitrypsin phenotypes in a population of Jordan. Hum Hered 36(3):192–4 Sanchez-Velasco P, Karadsheh NS, Garcia-Martin A, Ruiz de Alegria C, Leyva-Cobian F (2001) Molecular analysis of HLA allelic frequencies and haplotypes in Jordanians and comparison with other related populations. Hum Immunol 62(9):901–9 Shegem NS, Nasir AM, Jbour AK, Batieha AM, El-Khateeb MS, Ajlouni KM (2002) Effects of short term metformin administration on androgens in normal men. Saudi Med J 23(8):934–7 Shegem NS, Alsheek Nasir AM, Batieha AM, El-Shanti H, Ajlouni KM (2004) Effects of short term metformin administration on androgens in diabetic men. Saudi Med J 25(1):75–8 Srivastava T, Whiting JM, Garola RE, Dasouki MJ, Ruotsalainen V, Tryggvason K, Hamed R, Alon US (2001) Podocyte proteins in Galloway–Mowat syndrome. Pediatr Nephrol 16 (12):1022–9 Sughayer MA, Al-Khawaja MM, Massarweh S, Al-Masri M (2006) Prevalence of hormone receptors and HER2/neu in breast cancer cases in Jordan. Pathol Oncol Res 12(2):83–6 Taher BM, Ajlouni HK, Hamamy HA, Shegem NS, Madanat AY, Ajlouni KM (2004) Precocious puberty at an endocrine centre in Jordan. Eur J Clin Invest 34(9):599–604 Takemoto Y, Naruse T, Namba K, Kitaichi N, Ota M, Shindo Y, Mizuki N, Gul A, Madanat W, Chams H et al (2008) Re-evaluation of heterogeneity in HLA-B*510101 associated with Behcet’s disease. Tissue Antigens 72(4):347–53 Talafih K, Hunaiti AA, Gharaibeh N, Gharaibeh M, Jaradat S (1996) The prevalence of hemoglobin S and glucose-6-phosphate dehydrogenase deficiency in Jordanian newborn. J Obstet Gynaecol Res 22(5):417–20 Tamimi J, Madanat W (2003) Jordan friends of Behcet’s disease patients society. A fruit of joint efforts between doctors and patients. Adv Exp Med Biol 528:609–11 Teebi AS, El-Shanti HI (2006) Consanguinity: implications for practice, research, and policy. Lancet 367(9515):970–1 Teebi AS, Dupuis L, Wherrett D, Khoury A, Zucker KJ (2004) Alopecia congenita universalis, microcephaly, cutis marmorata, short stature and XY gonadal dysgenesis: variable expression of El-Shanti syndrome. Eur J Pediatr 163(3):170–2 Touitou I, Sarkisian T, Medlej-Hashim M, Tunca M, Livneh A, Cattan D, Yalcinkaya F, Ozen S, Majeed H, Ozdogan H et al (2007) Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis Rheum 56(5):1706–12 Usanga EA, Ameen R (2000) Glucose-6-phosphate dehydrogenase deficiency in Kuwait, Syria, Egypt, Iran, Jordan and Lebanon. Hum Hered 50(3):158–61 Verity DH, Vaughan RW, Madanat W, Kondeatis E, Zureikat H, Fayyad F, Kanawati CA, Ayesh I, Stanford MR, Wallace GR (1999a) Factor V Leiden mutation is associated with ocular involvement in Behcet disease. Am J Ophthalmol 128(3):352–6 Verity DH, Wallace GR, Vaughan RW, Kondeatis E, Madanat W, Zureikat H, Fayyad F, Marr JE, Kanawati CA, Stanford MR (1999b) HLA and tumour necrosis factor (TNF) polymorphisms in ocular Behcet’s disease. Tissue Antigens 54(3):264–72 Verity DH, Vaughan RW, Kondeatis E, Madanat W, Zureikat H, Fayyad F, Marr JE, Kanawati CA, Wallace GR, Stanford MR (2000) Intercellular adhesion molecule-1 gene polymorphisms in Behcet’s disease. Eur J Immunogenet 27(2):73–6 Wahbeh AM, Ewais MH, Elsharif ME (2008) Spectrum of glomerulonephritis in adult Jordanians at Jordan university hospital. Saudi J Kidney Dis Transpl 19(6):997–1000 Wallace GR, Verity DH, Delamaine LJ, Ohno S, Inoko H, Ota M, Mizuki N, Yabuki K, Kondiatis E, Stephens HA et al (1999) MIC-A allele profiles and HLA class I associations in Behcet’s disease. Immunogenetics 49(7–8):613–7 Wallace GR, Kondeatis E, Vaughan RW, Verity DH, Chen Y, Fortune F, Madanat W, Kanawati CA, Graham EM, Stanford MR (2007) IL-10 genotype analysis in patients with Behcet’s disease. Hum Immunol 68(2):122–7 Wallerman O, Van Eeghen A, Ten Kate LP, Wadelius C (2003) Evidence for a second gene for primary microcephaly at MCPH5 on chromosome 1. Hereditas 139(1):64–7

352


Wang K, Pugh EW, Griffen S, Doheny KF, Mostafa WZ, al-Aboosi MM, el-Shanti H, Gitschier J (2001) Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3. Am J Hum Genet 68(4):1055–60 Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J (2002) A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet 71(1):66–73 Williams DR, Hadeed A, al-Din AS, Wreikat AL, Lees AJ (2005) Kufor Rakeb disease: autosomal recessive, levodopa-responsive parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementia. Mov Disord 20(10):1264–71 Yang X, Ahmad T, Gogus F, Verity D, Wallace GR, Madanat W, Kanawati CA, Stanford MR, Fortune F, Jewell DP et al (2004) Analysis of the CC chemokine receptor 5 (CCR5) Delta32 polymorphism in Behcet’s disease. Eur J Immunogenet 31(1):11–4

Chapter 12

Genetic Disorders in Kuwait Nawal Makhseed

The Country and Population Kuwait is situated northeast of Saudi Arabia at the northern end of the Persian Gulf, south of Iraq (Fig. 12.1). The country’s total area is 17,820 km2, mainly flat desert with few oases. It is rich in oil, which constitutes the major source of wealth in Kuwait. Following the war to end the Iraqi occupation in 1991, the population has declined from more than two million to only 1.2 million because of the departure of many non-Kuwaiti residents, mainly the Palestinians, who constituted about 22% of the Kuwaiti population before the Iraqi occupation of Kuwait. The current population of Kuwait is estimated at 2,985 million. Of the total population, the Kuwaiti Nationals constitute 35%, other Arab nationals 22%, Asians 39%, and 4% are Bedoons, who are mostly Bedouins without determined citizenship. http://www.asiarooms.com/travel-guide/kuwait/kuwait-overview/kuwaitpopulation. html The Kuwaiti nationals can be divided into several groups. These groups reflect the tribal origins of the Kuwaiti society. The first tribe of settlers was the Anaza (led by the Sabah family) and the later settlers include the Bahar, Hamad, and Babtain families, originated in Nejd (central Arabia). Another group, the Kenaat (including the Mutawa family and its offshoot, the Saleh), came to Kuwait from Iraq and remain distinct from the Nejdi families. There are also few large families of Persian origin including the Behbahanis. The remaining citizens are few former Palestinians and other Arabs, the most being originally Bedouins who have been granted citizenship. The Bedouins are the nomadic Arabs of the desert who live on the fringes of the Arabian Peninsula, which includes parts of Kuwait, Saudi Arabia,

N. Makhseed Department of Pediatrics, Jahra Hospital, Ministry of Health, Kuwait e-mail: [email protected]


353

354

N. Makhseed

Fig. 12.1 Map of Kuwait

Qatar, United Arab Emirates, Oman, Iraq, Jordan, and Syria as well as Negev and Sinai desert (Teebi 1994). Birth rate is about 21 per 1,000 (Population Bureau). Population growth rate has been around 3.4% in the last few years since the year 2000. Islam is the predominant religion among Kuwaitis, with more than 70% being Sunnite Muslims and the rest being Shite Muslims. In Kuwait it was estimated that 8–12.5% of all marriages contracted are polygamous (Chaleby 1985).

Genetic Services A small unit of Genetics was established in late 1960s but discontinued in 1970 because of the lack of qualified personal. The service was resumed as a weekly genetic clinic at Al-Sabah hospital, and in the late 1980s the Kuwait Medical Genetic Center (KMGC) was operational. It constituted clinical genetics section

12

Genetic Disorders in Kuwait

355

and cytogenetic laboratory. After 1983, community genetics clinics were developed. In 1993, Molecular genetics laboratory and Fluorescence in situ Hybridization (FISH) laboratory were added to the genetic center.

Consanguineous Marriages and Their Implications Al-Awadi et al. (1985b) found the rate of consanguineous mating was to be 54.3% with estimated population incidence rates from 52.9 to 55.7%. First-cousin marriages were the most common type, particularly paternal first cousins. Double firstcousin marriages also exist (Teebi 1994). The average inbreeding coefficient was 0.0219. This high rate is seen mostly among Bedouins as well as some wealthy families, for social, economic, and geographical factors. It was also found that other Arab communities living in Kuwait also have high rates of consanguinity according to studies conducted in Kuwait or in their countries of origin (Teebi 1994). Frequency of consanguineous marriages among Egyptians, and Jordanian, living in Kuwait was estimated to be 23.3 and 36.2% respectively (Al-Nassar et al. 1989). Radovanovic et al. (1999) studied the frequency, social correlates, and trend of consanguineous marriages. A questionnaire was administered to a representative sample of 482 households of Kuwaiti nationals from the most developed area (the Capital) and the least developed area (Jahra). It was concluded that the frequency of total first- and second-cousin marriages was much higher in Jahra governorate (42.1%) than in the Capital (22.6%). Over the last decade, the inbreeding has decreased in the Capital but not in Jahra. It was also found that Bedouin origin and year of marriage were the only variables significantly related to consanguinity.

Fertility Studies on the fertility rate in Kuwait conducted by different researchers from 1970 to 2004 showed a decline in the fertility rate in Kuwait as shown in (Table 12.1). Table 12.1 Fertility rates in Kuwait Year Total fertility rate 1970 7 1975 7.2 1980–1984 6.62 1985 6.5 1986 4.4 1990–1994 5.96 2000–2004 5.63 2007 3.58

References Kohli and Al-Omain (1993) Kohli and Al-Omain (1993) Courbage and Khlat (1993) Kohli and Al-Omain (1993) Kohli and Al-Omain (1993) Courbage and Khlat (1993) Courbage and Khlat (1993) Al-Kandari and Alshuaib (2007)

356

N. Makhseed

Al-Kandari (2007) studied the fertility and its relationship with socio-cultural factors in the Kuwaiti society. He concluded from a questionnaire administered to 7,749 married women who were 15–78 years of age that the fertility rate was 3.58 per woman. Fertility was higher among Sunni Muslim women, those of Bedouin ethnicity, and those in a consanguineous marriage. There was a significant negative relationship between fertility and respondents’ educational level, occupation, age at marriage, socioeconomic status, and type of marriage (consanguineous or not). There was a positive relationship between fertility and the respondents’ age and family income.

Genetic Disorders Reported From Kuwait Chromosomal Abnormalities Al-Naggar et al. (1999) studied the profile of chromosomal abnormalities at Al-Jahra Hospital region of Kuwait. This hospital was serving at that time an Arab population of 300,000, 80% of whom belong to the Bedouin community. The study population included 177 cases of chromosomal abnormalities diagnosed among 49,174 live births registered at the hospital from January 1983 to December 1989. Among the 177 cases with chromosomal abnormalities, 95% had numerical chromosomal abnormalities, and 5% had structural abnormalities. Of them, 145 cases had classic trisomy 21 with an incidence of 2.9/1,000 live births, 16 cases had trisomy 18 (0.3/1,000 live births), five cases had trisomy 13 (0.1/1,000 live births), one case had trilpoidy 69, XXY (0.02/1,000 live births), and one had Turner syndrome (0.05/1,000 live births). Nine cases with structural abnormalities were enumerated, and the incidence of each was 0.02/1,000 live births. Two cases of translocation trisomy 21 (0.04/1,000 live births) and three cases of cri-du-chat (0.06/1,000) were found. This study has shown that Bedouin had a double-fold increased risk of common trisomies and advanced maternal age was also a risk factor while the paternal age was an inconsistent risk factor.

Down Syndrome Al-Awadi et al. (1990) had shown during 7 years period, from 1980 to 1986, that there were 635 confirmed cases of Down syndrome at KMGC registry. Regular trisomy 21 was found in 96.2% of them, 1.9% had different translocation, 1.4% with mosaicism, and 0.5% had nonclassical karyotypes. These results were compared with major worldwide cytogenetic surveys of 17,738 Down syndrome cases. 92.9% were regular trisomy 21, 4.3% translocation, 2.2% mosaicism, and 0.5% nonclassical karyotype. Studies in Kuwait have shown a high incidence of Down syndrome (3.6/1,000) among highly inbred Bedouin community in the Jahra area of Kuwait, whereas in an area with a mixed Arab population, the incidence was

12


357

1.7/1,000 live births. This was explained on the basis of possible gene effects on nondisjunction (Farag and Teebi 1988a). Alfi et al. (1980) reported that Down syndrome was four times more frequent among children of closely related parents. Another study in Kuwait (Naguib et al. 1989) suggested an association between consanguinity and occurrence of nondisjunction, although a single-gene defect was not observed. It was also reported in two studies that it is not uncommon among Bedouins in Kuwait to find examples of recurrent aneuploidies in the same family (Farag and Teebi 1988b). Recurrent regular trisomy 21 was reported in several unrelated inbred Bedouin families, the age of the mother in each of these families was less than 34 years, and this provides a further evidence of an aneuploidy gene effect among inbred populations (Farag and Krishna Murthy 1994; Quaife and AlGazali 1994). Trisomy 18 Naguib et al. (1987b) reported that the incidence of trisomy 18 in 1986 was 4.61/ 10,000, which is significantly higher than the international incidence as well as the incidence in previous years. The male-to-female sex ratio was 1:1.8, the median maternal age 32.5, and the median paternal age 40. Later, Naguib et al. (1999a, b) reported that the average Trisomy18 birth incidence rate was 8.95 per 10,000 live births based on 59 cases who were ascertained clinically and cytogenetically from 1994 to 1997. Trisomy 18 cases were mostly females with a male–female ratio of 1:2.1. Maternal age above 30 years was found to be a significant factor for Trisomy18, and such cluster of high prevalence may indicate a possible environmental and to a lesser extent, genetic predisposition to aneuploidy nondisjunction. Male Infertility Mohammed et al. (2007) conducted a study on 289 infertile men who had cytogenetic studies and molecular testing. Chromosomal anomalies and Y microdeletion were detected in 10.4% of them. The distribution of the chromosomal abnormalities found in the infertile men in Kuwait: 23 patients (8%) had sex chromosome abnormalities where 69% of them had Klinefelter or a variant of it, 13% had XXY syndrome, 8.7% were XX males, 4.4% had 45,X/46X, i(YP) karyotype, and 4.4% had 45, XY karyotype. Only seven patients of the total (2.6%) had Y-microdeletion in the AZF b and AZF c regions. Testicular biopsy was carried out in 31 azoospermic patients; five had Sertoli-cell-only syndrome and 26 had spermatogenic arrest. Alkhalaf et al. (2002) analyzed 118 infertile patients using cytogenetic analysis. The overall incidence of chromosomal abnormalities was 11%, with common chromosomal abnormalities detected in 12 patients. One of those was an infertile male with the karyotype 46,XY, del (21)(pter; q11.2). Krishna Murthy et al. (2002) reported that paternal balanced translocation t(1p;19p)(p32; q13) was associated with recurrent fetal loss.

358

N. Makhseed

Female Infertility Alkhalaf (2007) reported a novel chromosomal translocation, t(2;10) (p21;pl5), which was associated with increased chromosomal fragility in two young women with a history of early recurrent spontaneous abortions (7–10 weeks). However, the relationship between this novel translocation and DNA fragility was not well understood. Xp25 deletion was reported to be associated with infertility. Naguib et al. (1988) reported that a mother and two daughters with Xp25 deletion were fertile. Consistent inactivation of the deleted X chromosome in the proposita and, an early menopause in the mother, were noted.

Mental Retardation (MR) Farag et al. (1993a) conducted a 4-year clinicogenetic survey of 400 institutionalized mentally retarded (IQ < 50) patients in Kuwait. In 203 patients (50.75%), a constitutional disorder was found: chromosomal abnormality in 37 (9.25%); Mendelian disorders in 137 (34.5%); multiple congenital anomalies and mental retardation in 22 (5.55%); and central nervous system malformation in seven cases (1.75%). In 157 patients (39.35), a pre, peri, or postnatal cause was ascertained. No etiological diagnosis was detected in 40 patients (10%). Phenylketonuria was found to have a frequency between 1.6% and 1.865% among institutionalized mentally retarded patients (Teebi et al. 1987a).

Neural Tube Defects (NTD) El-Alfi et al. (1968) reported that the prevalence of anencephaly in Kuwait was high at 3.2/1,000 births among 4,625 deliveries at the Maternity hospital. Al-Awadi et al. (1984) reported 18 years later a marked decline in the prevalence of anencephaly to 1.33/1,000 births during 1983. The highest incidence (2.05/1,000 births) was among deliveries in Jahra hospital, 80% of the population served at this hospital belonged to the Bedouin community, and the lowest incidence (0.85/1,000 births) was among deliveries in Farwania hospital, which serves a mixed Arab and nonArab population, with only 15% belonging to Bedouin community. Meckel syndrome is an autosomal recessive form of neural tube defect anomalies, frequently diagnosed among neonates in Kuwait (Teebi 1994) with an incidence of 1:3,530 live births (Teebi et al. 1992). It is mostly ascertained among those of Bedouin ancestry. Farag et al. (1990) reported a variant of Meckel syndrome in a Bedouin family with five affected sibs lacking polydactyly. Other cases of Meckel syndrome were ascertained in a study of cleft lip with or without cleft palate (Naguib et al. 1989).

12


359

Hematological Disorders The hemoglobinopathies are the commonest single-gene disorders known and are so common in some regions of the world that the majority of the population carries at least one genetic abnormality affecting the structure or synthesis of the hemoglobin molecule (Flint et al. 1993).

Sickle Cell Disease and Thalassemias Adekile (2001) reported the incidence of sickle cell trait to be at 3% of the Kuwaiti population. Marouf et al. (2002) reported that most commonly identified hemoglobinopathies were beta-thalassemia minor (14%), sickle cell trait (6%), sickle cell anemia (0.9%), S beta zero thal (0.8%), and S beta + thal (0.8%). Two rare hemoglobin variants, Hb DPunjab and Hb E, were encountered.

Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD deficiency) In 1999, Samilchuk et al. reported that the frequency of G6PD-deficient genotypes was 4.5% (5.73% in males and 2.56% in females). Alfadhli et al. (2005) conducted a study to investigate the mutation spectrum of the G6PD gene among the Kuwaitis. Seventy-two men and seven women were screened for gene mutation. The results showed that G6PD Mediterranean (563C!T), and A- (202G!A,376A!G) genotypes were characterized as the most common variants among the G6PDdeficient population, representing 0.742 and 0.124 allele frequencies, respectively. The two previously described mutations, G6PD Chatham (1003G!A) and Aures (143T!C), were found at lower frequencies (0.101 and 0.034, respectively). The allele frequencies for these four G6PD variants among the randomly selected Kuwaitis were 0.035, 0.0074, 0.0046, and 0.0023 for Mediterranean, A-, Chatham, and Aures, respectively.

Endocrine Disorders Congenital Hypothyroidism There is no national newborn screening for congenital hypothyroidism in Kuwait. It is currently done at a low scale for newborns at three of the governmental hospitals. However, newborn screening is done for babies born at private hospitals in Kuwait. In one of the regional hospitals in Kuwait, 25 children were diagnosed on clinical grounds with congenital hypothyroidism from 1981 to 1987 (Daoud et al. 1989). The calculated incidence was 1:3,476 live births. Seven patients were

360

N. Makhseed

diagnosed in the first month, 6 in the following months, and 12 diagnosed after the age of 6 months. Thyroid scan was done for 13 patients, four had thyroid aplasia, three had ectopia, and six had thyroid in normal position.

Congenital Adrenal Hyperplasia (CAH) Lubani et al. (1990a) reported that in one hospital, 60 patients were diagnosed over a 10-year period (1978–1988). The prevalence of CAH was estimated to be 1:9,000 live births, which is higher than that reported from Europe and Canada. However, there was presumptive evidence of CAH resulting in the death of 20 other children, giving a prevalence of 1:7,000. There were more girls affected than boys with 68 and 32% of the total respectively. Seventy-five percent of the girls and 57.9% of the boys were salt losers. Biochemical analysis showed that 90% had 21-hydroxylase deficiency, 5% had 3-beta-hydroxy-steroid dehydrogenase deficiency, and 5% had 11-beta-hydroxylase deficiency.

Familial Hypophosphatemic Rickets (FHR) Lubani et al. (1990b) reported that 24 cases of FHR were diagnosed from 1982 to 1988, nine were diagnosed during screening of families with an index case. The average annual incidence was 0.2/1,000 live births. Age of onset ranged between 10 months and 14 years. Almost all patients presented with growth retardation and bowing of the legs. Those diagnosed early responded well to treatment; those diagnosed late had final height below the third centile.

Diabetes Mellitus Shaltout et al. (2002) has reported that the incidence of Type 1 diabetes in Kuwait is high compared with the neighboring Arab countries. Abdullah (2005) conducted an epidemiological study on type 1 diabetes among Arab children (6% to the modern Phoenician-influenced populations examined.

Y-Chromosome Diversity in Lebanon Nine hundred and twenty six Lebanese men were typed with Y-chromosomal SNP and STR markers. Male genetic variation within Lebanon was found to be more strongly structured by religious affiliation than by geographic origin. It was found that Y-haplogroup J*(J2) was more frequent in the putative Muslim source region (the Arabian Peninsula) than in Lebanon. It was also more frequent in Lebanese Muslims than Lebanese non-Muslims. Conversely, haplogroup R1b was more frequent in the putative Christian source region (Western Europe) than in Lebanon. It was also more frequent in Lebanese Christians than in Lebanese non-Christians. It is therefore suggested that the Islamic expansion from the Arabian Peninsula at the beginning of the seventh century AD introduced their lineages into the communities that later became the Lebanese Muslims, and the Crusaders in the eleventh to thirteenth centuries CE introduced the western European lineages into the Lebanese Christians (Zalloua et al. 2008b).

Consanguinity The degree of “genetic impermeability” varies widely according to the ethnic and religious groups. It is important to note that marriages are quite frequent between members of different Christian communities. In this respect, the Druze seem to be the most isolated group, even though Sunnites, Shiites, and Armenians also try to avoid marriage outside their own community. The prevalence of preferential patriarchal parallel-cousin marriage is recognized as a specific trait of the Arabs. This type of marriage has been so common that the

13

Genetic Disorders in Lebanon

393

popular name in Arabic for father-in-law is “uncle” (father’s brother), for motherin-law is “uncle’s wife” (wife of father’s brother), and for husband or wife is “uncle’s son” or “uncle’s daughter” (son or daughter of paternal uncle). In the studies of Khlat and Khudr (1984), the classical predominance of patrilateral parallel-cousin marriage is no longer evident in the most recent generations, which displays an equal preference for all types of cousin marriage. Harfouche (1965) studied the social structure of low-income families in Lebanon among three communities: Maronites, Sunnites, and Armenians. She found that the incidence of consanguineous marriage was highest among the Maronites (31%), second among the Sunnites (24%), and third among the Armenians (10%). Marriage between first cousins is common among Maronites and Sunnites, whereas among Armenians the rule is to avoid consanguineous marriages, especially between first cousins. In these three ethnic groups, the average rate of consanguineous marriages was 21%. A study of the general Lebanese population, by Loiselet et al. (1971), showed the highest incidence of consanguineous marriages to be among the Druze (41%), followed by the Shiites(28%), and the Sunnites (27%). The other groups (Maronites, Greek Orthodox, and Armenians) were found to have an incidence of 10%. The average incidence of consanguineous marriages in Lebanon according to this second study (Loiselet et al. 1971) was 18%. Since neither study is extensive, the different sampling methods may explain the differences in the details of the results. However, both studies lead to similar general conclusions about the extent of consanguinity. Khlat (1988a) has found that the overall cross-sectional proportion of consanguineous marriages in Lebanon is 25%. She has also shown, in a separate study, that the actual rate slightly declines with time and that this decline mainly reaches marriages between distant relatives, whereas the prevalence of first-cousin marriages remains relatively stable (Khlat et al. 1986; Khlat 1988b, c). Moreover, the perception of consanguineous marriages is still very positive in the population (Khlat et al. 1986) and the trend toward modernization in Beirut does not seem to weaken endogamy (Khlat and Halabi 1986).

Population Genetics Few major investigations have attempted to explore the genetic structure of the Lebanese population. One of these involved a study of dermatoglyphics (Naffah 1974), while the others investigated the types and distributions of certain genetic markers and protein variants (Lefranc et al. 1976).

Dermatoglyphics The dermatoglyphic studies that were carried out among the seven major communities of the Lebanese population pursued two aims: to compare anthropologically the different segments of the population and to obtain control data for the study

394

V.M. Der Kaloustian

of dermatoglyphics in congenital or hereditary anomalies (Naffah 1974). Dermatoglyphics have the advantage of being polygenic, which makes them more useful than monogenic traits in the study of relations between populations. On the basis of its dermatologic characteristics, and in spite of small and often insignificant variations between communities, the Lebanese population is, on the whole, quite homogeneous. Compared with others, there is a great similarity to the Mediterranean populations, especially those of the Near and Middle East. Although the general characteristics are those of a White population, certain peculiarities bring them closer to eastern Mongoloid populations. The Lebanese communities farthest from the average, according to their dermatoglyphic patterns, are the Armenians, the Shiites, and the Druze. The first two have the most Asian characteristics, while the last is closer to Western populations. No plausible explanation is available for these findings (Naffah 1974).

Genetic Markers and Protein Variants The different religious and ethnic communities of the country were considered to be relatively impermeable isolates because of the rarity of marriages between their members. The genetic distances were studied using random samples obtained from several laboratories for various medical analyses. The aim was to characterize the population as a whole and the differences between the communities composing it (Lefranc et al. 1976). The results of this study were similar to those of Naffah (1974) on dermatoglyphics. It was noted that, as a whole, the population of Lebanon is clearly Caucasian, but with certain Asian traits: a frequency of the B blood group (ABO system) higher than anywhere in Europe, a relative rarity of the Hp1 allele (haptoglobins) (Lalouel et al. 1976), and especially the presence of the haplotype Gm of the immunoglobulins, combining the Gm1 characteristic to the whole of Gm10, 11, 14, and 25 (Lefranc et al. 1976). The genetic distances between communities were calculated on the basis of the following seven markers: ABO, Rh, haptoglobins, Gc globulins, erythrocyte phosphatases, and Gm and Inv groups of immunoglobulins. The distances thus obtained are small in comparison with the distances measured between Mongolian and Caucasian communities (Lalouel et al. 1976). A study of the HLA system revealed no difference between the different communities of the country, except for the Armenians (Serre 1976).

Angiotensin-Converting Enzyme Gene Polymorphism (ACE; OMIM +106180) Angiotensin-converting enzyme (ACE) gene polymorphism insertion (I) or deletion (D) is linked to various functional effects and associated with common

13


395

diseases. In a study by Sabbagh et al. (2007b) of the distribution of the genotypes of the ACE in the Lebanese population, the prevalence of the D/D, I/D, and I/I genotypes was found to be 39.1, 45.1, and 38.3%, respectively. In another study, Saab et al. (2007) found that the frequency of the I allele in the Lebanese population was 27% and the corresponding I/I genotype was at a frequency of 7.37%.

Arylamine N-acetyltransferase 1 (NAT1) Genotypes in a Lebanese Population (OMIM *108345) Chronic exposure to carcinogenic chemicals (e.g., cigarette smoke) does not inevitably lead to cancer. This fact initiated numerous studies aimed at understanding the basis for individual susceptibility. Epidemiologic studies suggested that genetic variation in the N-acetylation of aromatic amine carcinogens may present a predisposition or a resistance to these carcinogens. In this line, there was an increasing interest in NAT1 because of its potential roles in carcinogen metabolism and cancer risk. A polymerase chain reaction-restriction fragment length polymorphism genotype assay was used to determine the frequency of NAT1 alleles in a Lebanese population. Of 84 NAT1 alleles assayed, 56% were found to be NAT1*4. Alleles NAT1*3, *10, and *14 were found at frequencies of 0.036, 0.107, and 0.238, respectively. Nearly 50% of the population were heterozygous for a NAT1*14 allele. The high frequency of NAT1*14 in the Lebanese population, if confirmed, might be useful to determine if the occurrence of cancer or other disorders is associated in either a positive or negative manner with this allele (Dhaini and Levy 2000).

HLA Class I and II Allele Frequencies The frequencies of HLA class I and class II antigens differed among the various religious communities of the Lebanese population. The frequency of DR10 in the Druze was 26%, significantly higher than in other communities (0–8%). The frequency of B41 was similar in the Druze and Greek Orthodox (11–12%), and to a certain extent in the Shiites (5%), but higher than that in other communities (0–1%). The degree of similarity of the HLA frequencies among the various communities ranged from 77 to 96% (Abdelnoor et al. 2001). Frequencies of HLA polymorphisms were examined at the molecular level. HLA class II genotyping of DRB1 and DQB1 loci revealed that DRB1*1101, DRB1*0401 and DRB1*0301 were the three most common DRB1 alleles observed, with respective frequencies of 0.302, 0.164, and 0.096. In the DQB locus group, DQB1*0301 (with an allele frequency of 0.384) was highly predominant, followed by the DQB1*0501, DQB1*0201, and DQB1*0302, with respective allele frequencies of 0.199, 0.195, and 0.103 (Samaha et al. 2003).

396

V.M. Der Kaloustian

HPA-1 Platelet Antigen Alleles (Integrin, Beta-3; ITGB3; OMIM +173470) Human platelet antigen (PA) systems are involved in the development of cardiovascular diseases, alloimmunization, and the rejection of organ transplantation. HPA-1 is considered to be the most important antigenic system in the Caucasian population. In a study of the 1a and 1b alleles of HPA-1, Sabbagh et al. (2007c) observed that of the genotypes 1a/1a, 1a/1b, and 1b/1b, the most prevalent was 1a/1a (68.85%), followed by 1a/1b (30.24%), and 1b/1b (3.91%). The allelic frequencies for 1a and 1b were 0.81 and 0.19, respectively. The prevalence of the HPA-1b which is higher in the Lebanese population as compared with other ethnic groups may predispose to a higher risk of alloimmunization (Sabbagh et al. 2007c).

Immunoglobulins IGHA2*M1 and IGHA2*M2 Soua et al. (1989) found the frequencies of IGHA2*M1 and the IGHA2*M2 alleles to be 0.79 and 0.20, respectively in the Lebanese population.

Immunoglobulin l Constant Polymorphism of immunoglobulin l constant region (IGLC) genes was studied in French, Lebanese, and Tunisian populations (Ghanem et al. 1988). The human IGLC polymorphisms appear as EcoR1 restriction-fragment-length variations – 8, 13, 18 or 23 kb. These polymorphic fragments are related to a number of IGLC genes varying from six to nine per haploid genome. Family studies confirmed the allelic nature of four of the different EcoR1 restriction fragments observed. Frequencies of the corresponding alleles in French, Lebanese, and Tunisian populations were determined and compared. The decrease of the 8-kb fragment (allele A1) frequency and the increase of that of the 13-kb and 18-kb fragments (alleles A2 and A3) appeared to be correlated to an African Black contribution in the gene pool. This contribution was more important in Tunisia than in Lebanon.

Genetic Diseases in Lebanon Table 13.1 lists the genetic diseases reported from Lebanon. Some of these diseases are relatively more common than others, or are characteristic of the ethnic composition and the geographic situation of the country. This group of diseases includes familial paroxysmal polyserositis (familial Mediterranean fever–FMF), familial

13


397

hypercholesterolemia (FH), hypothyroidism, the Dyggve–Melchior–Clausen syndrome, Sandhoff disease, juvenile Tay–Sachs disease, and various genetic hematologic diseases such as glucose-6-phosphate dehydrogenase deficiency, thalassemia major, and sickle-cell anemia. Moreover, a few rare conditions have been reported in the literature for the first time from Lebanon (Table 13.1).

Adrenal Hyperplasia, Congenital, 21-Hydroxylase Deficiency (OMIM +201910) Twenty-five unrelated Lebanese families with members affected by congenital adrenal hyperplasia (CAH) due to steroid 21-hydoxylase deficiency were tested for six point mutations, large deletions, gene conversion events, and duplications. In the classical forms, the most frequent mutation was that of a splice site in intron 2, accounting for 39% of the disease alleles. Gene conversion events accounted for 14% of the alleles. No large deletions were found. In the non-classical forms, the V281L mutations in exon 7 represent 86% of the tested alleles. The genotype–phenotype correlations were as expected (Delague et al. 2000b). The spectrum of mutations reflects the genetic diversity of the Lebanese population. However, no correlation could be noted between certain mutations and specific religious communities, except for the D8nt mutation, which was present only in the Christian Maronite group (Delague et al. 2000b).

Albinism, Oculocutaneous, Type 1 (OCA1; OMIM #203100) Thirty Lebanese subjects with oculocutaneous albinism were tested for the mutations in the tyrosinase gene. Mutations were found in 47%, while no mutation was identified in 53%. Fourteen different mutations were identified, of which eight were novel while six had been previously reported. Mutations were mainly seen in patients with clinical findings suggestive of OCA1A (64% of patients with OCA1A versus 25% of patients with OCA1B). Nine novel mutations were found. The new mutations for OCA1A were: cd84 T!G, Tyr!Stop; cd272 T!C, Trp!Arg; cd342 T!C, Asn!Asn; del15 bp IVS2; cd346 G!A, Gly!Glu; cd359 A!T, Gln!Leu. The new mutations for OCA1A were: cd360 A!G, Ser!Gly; del A cd402; cd433 A!G, Tyr!Cys (Zahed et al. 2005).

Ankylosing Spondylitis (OMIM #106300) A novel HLA-*B27 subtype was identified in a Lebanese patient suffering from ankylosing spondylitis. This variant differs from the common HLA-B*2705 at five nucleotype positions. These changes lead to three amino acid differences in the

398

V.M. Der Kaloustian

a2 domain: Thr to Ile at position 94, Leu to Ile at position 95, and Asn to Arg at position 97 (Tamouza et al. 2001).

Apnea of Prematurity The association of consanguinity with the incidence of apnea of prematurity was studied in Greater Beirut. The odds ratio of apnea of prematurity for first-degree consanguineous parents as compared with other marriages was 2.9. In addition to the recognized etiologic factors for apnea of prematurity, the authors suggested that genetic factors also play a role (Tamim et al. 2003).

Apolipoprotein E Gene Polymorphism (APOE, OMIM +107741) The Lebanese population showed similarities to earlier reported ApoE genotype distributions (high E3 allele frequency) but also peculiar differences to some Arab countries and other populations. The prevalence of genotypes E3/3, E3/4. and E2/3 was found to be 69, 26, and 22%, respectively, and 0.6% for each of E2/4 and E4/4 genotypes (Mahfouz et al. 2006).

Arthropathy, Progressive Pseudorheumatoid, of Childhood; PF (#208230) Wynne-Davies et al. (1982) reported fifteen patients with an inherited skeletal dysplasia, considerably more crippling than the usual form of spondylo-epiphyseal dysplasia tarda. Four of the patients were Arabs.This condition has a striking clinical resemblance to rheumatoid arthritis. However, in addition, it has platyspondyly and the radiological findings are different from those of rheumatoid arthritis. The authors present this as a new condition, but they also acknowledge that it may be the same as the case referred to by Maroteaux in 1974 as “les dysplasies spondylo-e´piphysio-me´taphysaires complexes.” The radiologic changes indicate bone dysplasia with flattened vertebral bodies. There is abnormality of the acetabular portion of the pelvis. There is also expansion of the ends of the proximal phalanges. Teebi and Al-Awadi (1986) reported a patient with these skeletal anomalies, born to double consanguineous Lebanese parents. They agreed with Wynne-Davis et al. that the condition most probably follows the autosomal recessive pattern of inheritance.

13


399

Ataxia, Cerebellar, Autosomal Recessive 2 (SCAR2; OMIM %213200) Me´garbane´ et al. (1999a) described a family with children affected with nonprogressive autosomal recessive congenital cerebellar ataxia associated with short stature. Later, the disease locus was assigned to a 12.1 cm interval on chromosome 9q34-qter, between D9S67 and D9S312 (Delague et al. 2001).

Ataxia, Cerebellar, Autosomal Recessive 5 (SCAR5; OMIM %606937) Me´garbane´ et al. (2001a) reported a large inbred Lebanese Druze family with children affected by a new condition. This consisted of severe developmental delay, proportionate short stature, microcephaly, cerebellar spastic ataxia, cerebellar atrophy, optic atrophy, speech defect, and an abnormal osmiophillic pattern of the skin vessels. The gene was later mapped to chromosome 15q24-q26 (Delague et al. 2002).

Ataxia Telangiectasia (AT, OMIM #208900) Ataxia telangiectasia (AT) is a rare autosomal recessive disease characterized by progressive cerebellar ataxia, immunodeficiency, susceptibility to lymphoreticular malignancies, hypersensitivity to ionic radiation, and chromosomal instability. Two different mutations, were found in two Israeli Druze clans of Lebanese origin. One of the clans emigrated from Southeast Lebanon 500 years ago. In this clan, a point mutation was found at position 1339 (C!T), changing the codon at position 447 (CAG) to a stop codon (TAG). The other clan moved from the center of Lebanon 300–400 years ago. In this clan, deletions of GG and TACG were found, respectively, at positions 6,672 and 6,677 (Fares et al. 2004).

Bardet–Biedl Syndrome (BBS, OMIM #209900) SNP homozygosity mapping was performed in an extended consanguineous family living in a small Lebanese village. This led to the identification of a novel BBS gene (BBS10). In one sibship of the pedigree, a BBS2 homozygous mutation was identified, while in three other sibships, a homozygous missense mutation was identified in a gene encoding a vertebrate-specific chaperonine-like protein (BBS10). The single patient in the last sibship was a compound heterozygote for the above-mentioned mutation and another one in the same gene. No triallelism was found in this family (Laurier et al. 2006).

400

V.M. Der Kaloustian

Bartter Syndrome Type 4, Infantile, with Sensorineural Deafness (OMIM #602522) The hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness (Bartter syndrome type 4) represents a genetic and clinical entity distinct from hyperprostaglandin E syndrome/antenatal Bartter syndrome. The characteristic sign of the disease in these patients is the constant association with congenital hearing loss (Jeck et al. 2001).

Behçet Syndrome (OMIM %109650) Behçet syndrome is characterized by recurrent oral and genital ulcers, skin lesions, and uveitis. In a study by Arayssi et al. (2008), polymorphisms of TNF (Tumor Necrosis Factor) alleles were not found to be associated with the clinical manifestations and the severity of the disease. The study confirmed the association of HLAB51 with Behçet syndrome and suggested an association between the 1031CC genotype and the disease in Lebanese patients.

Brown–Vialetto–Van Laere Syndrome (OMIM %211530) Brown–Vialetto–Van Laere syndrome is characterized by pontobulbar palsy, bilateral nerve deafness, cranial nerve disorders involving the motor components of the 7th and 9th to 12th cranial nerves and, less commonly, the spinal motor nerves and upper motor neurons. A large inbred Lebanese family was reported by Me´garbane´ et al. (2000) with four patients of both sexes. This strongly suggested autosomal recessive inheritance.

Cataract, Posterior Polar (CTPP4, OMIM #610623) Heterozygous and homozygous mutations in PITX3 were reported in a large Lebanese family by Bidinost et al. (2006). This was the first report of homozygous PITX3 mutations in humans. The phenotype of the two siblings who were homozygous for the C-terminal deletion of the gene was much more severe than that of the heterozygous family members. In addition to posterior polar cataracts, as in heterozygotes, the homozygotes had microphthalmia, blindness, and various neurologic manifestations as mental retardation, choreiform movements, decreased deep tendon reflexes of the lower extremities, and increased muscle tone.

13


401

Charcot–Marie–Tooth Disease, Type CMT4A (OMIM #214400) A novel GDAP1 homozygous mutation was identified in a 9-year-old Lebanese girl with an autosomal recessive severe peripheral demyelinating phenotype (CMT4A) associated with axon loss. The affected girl carried a mutation in exon 5 (c.668T!A, leading to the substitution of the leucine 223 residue to a stop codon (p.L223X) (De Sandre-Giovannoli et al. 2003).

Charcot–Marie–Tooth Disease, CMT4F (OMIM # 214400) Delague et al. (2000a) reported a large inbred Lebanese family affected with autosomal recessive CMT4 in whom they excluded linkage to the already-known loci. Clinical features and the results of histopathologic studies confirmed that the disease affecting this family constitutes a previously unknown demyelinating autosomal recessive CMT subtype, known as CMT4F. MAG was excluded as a candidate gene.

Charcot–Marie–Tooth Disease, CMT4H (OMIM #609311) A new form of autosomal recessive demyelinating Charcot–Marie–Tooth neuropathy was identified in a Lebanese family (De Sandre-Giovannoli et al. 2005). The gene was mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11. A mutation was identified in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein). FRABIN is a GDP/GTP nucleotide exchange factor (GEF), specific to Cdc42, a member of the Rho family of small guanosine triphosphate (GP)-binding proteins (Rho GTPases) (Delague et al. 2007).

Chondrodysplasia with Multiple Dislocations Me´garbane´ and Ghanem (2004) reported the offspring of consanguineous parents, affected with left hip dislocation, dislocated knees, inguinal hernias, short long bones, pectus excavatum, dislocation of the radial heads, prominent joints, limitation of motion of the elbows, brachydactyly, genua valga, and pes planovalgus. They considered that the findings in their patient represented a newly recognized syndrome.

Chondrodysplasia with Multiple System Anomalies Me´garbane´ et al. (2008b) reported a consanguineous Lebanese family with a sib pair presenting with developmental delay, dysmorphic facial appearance, a narrow

402

V.M. Der Kaloustian

chest, a prominent abdomen, and short limbs. Differential diagnosis suggested to the authors that this is a new type of chondrodysplasia.

Cohen Syndrome (OMIM #216550) Cohen syndrome is a rare autosomal recessive disorder with a variable clinical picture mainly characterized by developmental delay, mental retardation, microcephaly, typical facial dysmorphism, progressive pigmentary retinopathy, severe myopia, and intermittent neutropenia. Mutations were reported in the COH1 gene from various countries. Three siblings from Lebanon were also tested. Mutation c.9406-1G!T was identified. It affected the splice-acceptor site of intron 51. Direct sequencing of cDNA revealed that a cryptic splice site is activated in exon 52 and is used as the acceptor site instead of the mutant one in intron 51. The defective splicing leads to deletion of 16 exonic bases and results in a frameshift in the COH1 mRNA (Hennies et al. 2004).

Cohen Syndrome, Cutis Verticis Gyrate and Sensorineural Deafness (OMIM 605685, *607817) In 2001, Me´garbane´ et al. (2001b) described a syndrome in two brothers of a Lebanese family. They presented with microcephaly, cutis verticis gyrata, retinitis pigmentosa, cataracts, hearing loss, and mental retardation [OMIM 605685]. The parents did not give a history of consanguinity. They later discovered (Me´garbane´ et al. 2009) that both brothers had a homozygous novel splice site mutation in the VPS13B (COH1) gene. The mutation that they identified, c.9406-1G!C, affects the same nucleotide as an earlier described mutation associated with Cohen syndrome, c.9406-1G!T, but leads to a different nucleotide change. However, both nucleotide changes result in the same abnoramal splicing and the activation of a cryptic splice site near the 5’ end of exon 52, with a consecutive 16-bp frameshift deletion in the VPS13B mRNA.

Consanguinity and Birth Weight A study on 10,289 consecutive live-born singleton newborns admitted to eight hospitals in Beirut, Lebanon, during the years 2000 and 2001, revealed a statistically significant negative association between parental consanguinity and birth weight at each gestational age (Mumtaz et al. 2007).

13


403

Consanguinity and Congenital Heart Malformations The association of isolated congenital heart defects with parental consanguinity was examined in 759 Lebanese patients with different types of defects. The subjects were patients of the Children’s Cardiac Registry Center (CCRC) at the American University of Beirut Medical Centrer. The proportion of first-cousin marriages among cardiac subjects was compared to that of the National Collaborative Perinatal Neonatal Network (NCPNN). The proportion of overall parental consanguinity and first-cousin matings among CCRC subjects (34.7 and 20.2%, respectively) were significantly higher than those reported by the NCPNN. A significantly higher rate of parental consanguinity was found in all categories of cardiac malformations, except lesions of the great vessels and coronary arteries (P < 0.05) (Nabulsi et al. 2003).

Consanguinity and Kidney Disease Nine hundred and twenty-five patients were surveyed in all of the dialysis centers of Lebanon. The etiology of the kidney disease was unknown in more than half of the patients. Consanguinity was present in the parents of 26% of them. More patients with consanguineous parents with unknown etiology of their renal disease were diagnosed, and dialysis was initiated before the age of 30, when compared with those whose parents were not consanguineous (45 vs. 33%(P < 0.02) and 42 vs. 27%(P < 0.01), respectively). Parental consanguinity-associated kidney diseases affected all religious communities, but particularly the Muslim and the Druze with 36 and 39%, respectively, versus 17% of the Christians (Barbari et al. 2003).

Cystic Fibrosis (CF, #219700; CFTR, *602421) Cystic fibrosis is considered to be rare in the Arab populations of the Middle East and little data had been reported until 1997 (Bitar and Idriss 1969). Twenty families were reported from Lebanon in 1979, with children affected with this condition. These were mainly from the Maronite, Greek Catholic, Greek Orthodox, Shiite, and Sunnite communities. A 50% rate of consanguineous marriages was found, independent of the community of origin. Screening of all the exons of the CFTR gene was performed. Ten different mutations were found for 87.5% of 32 unrelated CF alleles. These included two novel putative mutations: E672del and IVS21-28G!A. Three mutations, DF508 (37.5%), W1282X (15.6%), and N1303K (9.4%) accounted for 62.5% of the CF alleles. Moreover, during this study, two novel polymorphisms (IVS1a+17del5 and 2691T/C) were discovered (Desgeorges et al. 1997). Farra et al. (2008) described a novel mutation in two Lebanese Muslim siblings. This is a frameshift mutation 4016insG. It generates a stop codon instead of Arginine-1301.

404

V.M. Der Kaloustian

Deafness, Autosomal Recessive 1 (DFNB1, OMIM #220290) In a Lebanese family with DFNB1 deafness, the same mutation was detected in all the affected children on both Cx26 alleles. This was a deletion of a guanosine (G) in a sequence of six G extending from position 30 to 35 (position 1 being the first base of the initiator codon). This 30delG mutation creates a frameshift which results in a premature stop codon at nucleotide position 38 (Denoyelle et al. 1997). Mustapha et al. (2001) investigated 48 Lebanese pedigrees with non-syndromic recessive deafness. Of these, 37 were Muslims, ten were Christians, and one was Druze. Mutations were DFNB1, DFNB3, DFNB4, DFNB5, DFNB6, DFNB7, DFNB9, DFNB10, DFNB12, DFNB13, DFNB14, DFNB17, DFNB21, DFNB22. 7 families were not categorized. The details of the results are summarized in a table published in their paper. 30delG was the prevalent mutation in the GJB2 gene. Moreover, in a Christian Maronite family, they found affected subjects who were compound heterozygotes for two novel mutations. One of these was a missense mutation replacing arginine by histidine at codon 32 (R32H), and the other was an insertion of an adenine in position 291 (291insA), thus creating a stop codon (Mustapha et al. 2001).

Deafness, Autosomal Recessive 9 (DFNB9, OMIM #601071) Chaib et al. (1996) reported a new form of autosomal recessive non-syndromic deafness in a consanguineous Lebanese Muslim Sunnite family from an isolated village of Northern Lebanon. This gene named by the authors as DFNB6, maps to chromosome 2p23-22. However, it was noted that Fukushima et al. (1995) had already made this designation for another locus. Thus, various reliable sources and databases changed the name of this locus from DFNB6 to DFNB9. In all affected members of four unrelated Lebanese kindreds, Yasunaga et al. (1999) found a missense mutation in a novel human gene which they called otoferlin (OTOF; OMIM *603681). The mutation consisted of a homozygous T!A transversion at position 2,416 in exon 18 of the OTOF gene, causing a Tyr-to-stop substitution at codon 730.

Deafness, Autosomal Recessive 13 (DFNB13, OMIM %603098) Mustapha et al. (1998) reported a consanguineous Lebanese family with members affected with severe progressive sensorineural hearing loss. The family was Christian Maronite, from an isolated region in Northern Lebanon. Linkage analysis revealed a new locus [DFNB13], located in the chromosomal region 7q34-q36, between the markers D7S2468/D7S2505, on the proximal side, and D7S2439, on the distal side.

13


405

Deafness, Autosomal Recessive 21 (DFNB21, OMIM #603629) Mustapha et al. (1999) reported a Lebanese family with members affected with severe sensorineural non-syndromic deafness. The family was Muslim Shiite. Linkage analysis revealed a new locus [DFNB21] located at 11q23-q25. The TECTA gene was already mapped to this site. This gene encodes a-tectorin, a protein with 2,155 amino acids, which is a component of the tectorial membrane. This gene is responsible for a dominant form of deafness, DFNA8/2. In this new family, sequence analysis of the TECTA gene revealed a G!A transition in the donor splice site (GT) of intron 9, which leads to a truncated protein of 971 amino acids. This established that a-tectorin mutations can be responsible for both dominant and recessive forms of deafness.

Deafness Syndrome, Branchiogenic (OMIM %609166) Me´garbane´ et al. (2003c) reported a Lebanese brother and sister with an apparently “new” syndrome presenting with congenital hearing loss, meatal atresia, preauricular tags and pits, branchial cysts or fistulae, strabismus, difficulty in opening the mouth wide, abnormal fifth fingers, short stature, learning disability, and patchy skin depigmentation in one. They belonged to the Muslim Sunnite community and were the offsprings of consanguineous parents. The father, his sister, and his halfbrother had unilateral auricular pits and/or branchial cysts and short stature. The authors concluded that this condition might be a new dominant branchiogenicdeafness syndrome.

Diabetes Mellitus (IDDM, T1D, OMIM %222100) In a study of HLA DRB1/DQB1 haplotypes on genetic susceptibilities to type 1 diabetes (T1D), it was found that in Lebanese subjects DRB1*030101, DRB1*130701, and DQB1*02201 were positively associated with T1D, and DRB1*110101, DQB1*030101, and DQB1*050101 were negatively associated with T1D (Stayoussef et al. 2009).

Diabetes Mellitus (NIDDM, T2D, OMIM #125853) In a study on patients from Bahrain and Lebanon, the association of HLA class II with type 2 diabetes (T2DM), DRB1*070101 and DQB1*0201 were found to be susceptibility-conferring haplotypes (Almawi et al. 2006).

406

V.M. Der Kaloustian

Dyggve–Melchior–Clausen Syndrome (OMIM #223800) Several families affected with this syndrome were reported from Lebanon (Naffah and Taleb 1974; Spranger et al. 1975; Naffah 1976). Three other patients of Lebanese origin affected with this condition were discovered in South Africa (Beighton 1978, 1990; Bonafede and Beighton 1978). This condition is evidently relatively more frequent in the Lebanese population. Lebanese patients showed two mutations in the DYM gene: IVS 3 194-1 G!A, and IVS 11 1252-1G!A (Thauvin-Robinet et al. 2002; El Ghouzzi et al. 2003; Paupe et al. 2004; Neumann et al. 2006).

Ectodermal Dysplasia, Hypohidrotic, X-Linked (XHED, OMIM #305100) Tomb et al. (2009) reported a Lebanese family with three male siblings affected with hypohidrotic ectodermal dysplasia. Molecular testing revealed a misssense mutation of codon 155.

Ectodermal Dysplasia, Hypohidrotic, Autosomal Recessive (OMIM #224900) Me´garbane´ et al. (2008c) reported a Lebanese patient with severe hypohidrotic ectodermal dysplasia and a novel homozygous mutation of the EDAR gene. The mutation was IVS9+1G!A. This mutation results in a total absence of the EDAR protein.

Ectopia Lentis, Spontaneous Filtering Blebs, Craniofacial Dysmorphism (OMIM %601552) Six members of a consanguineous Lebanese Druze family were reported with ectopia lentis and various craniofacial dysmorphisms. The ectopia lentis was associated with a variable degree of angle closure secondary to iridocorneal adhesions, patchy areas of atrophy in both irides, and avascular elevations of the bulbar conjunctiva. The craniofacial dysmorphisms consisted of downward slanting palpebral fissures, a large beaked nose, a triangular and retracted chin, and dental malocclusion. The pedigree was most compatible with autosomal recessive inheritance with pseudodominance (Shawaf et al. 1995).

13


407

Later, in 2001, the same condition was reported in members of another Lebanese Druze family (Haddad et al. 2001).

Enterocolitis, Necrotizing Nexrotizing enterocolitis (NEC) is a multifactorial condition with various risk factors. A Lebanese consanguineous family was reported where three siblings presented with severe early and lethal enterocolitis (Me´garbane´ and Sayad 2007). In 1974, Fried and Vure reported an Ashkenazi Jewish family, in which three of four children with consanguineous parents died within a few weeks after birth of severe enterocolitis. Although a common environmental origin of the disease cannot be dismissed, consanguinity in both families suggests a disease with autosomal recessive inheritance.

Epidermolysis Bullosa, Junctional (EBJ), Herlitz Type (OMIM #226700) Two female newborns, born to two first-degree consanguineous couples, presented a lethal form of EBJ. The two patients were homozygous for a new missense mutation of LAMA3 gene (exon 32:4300 insA), encoding the a3 subunit of laminin-5. The resulting mRNA, rapidly degraded, results in an extremely reduced synthesis of a3 polypeptide, truncated in its C-terminal domain (Ayoub et al. 2005).

Epilepsy Syndromes In a study in Lebanon on various epilepsy syndromes based on the criteria of the International League Against Epilepsy classification, it was concluded that genetic factors are important not only in idiopathic epilepsies and febrile seizures, but also in cryptogenic and symptomatic epilepsies (Choueiri et al. 2001).

Factor V Leiden (F5, OMIM *612309) Factor V Leiden is the most common genetic risk factor for deep venous thrombosis (DVT). In the Eastern Mediterranean countries, a high prevalence of factor V Leiden mutation was reported in healthy individuals (7–14%) with the highest

408

V.M. Der Kaloustian

frequency in Lebanon (14%); among patients with DVT, 40% had a factor V Leiden mutation. Positive family history was statistically associated with an increased risk for factor V Leiden mutation (Irani-Hakime et al. 2000; Taher et al. 2001). Moreover, a recently identified polymorphism, HR2 (His1299Arg), was reported to be a possible risk factor for the development of venous thromboembolism. The prevalence of factor V R2 (H1299R) polymorphism was also studied in the Lebanese population (Zaatari et al. 2006). Of a total of 125 controls studied, 13 (10.4%) had the HR2 haplotype, 11 (8.8%) were heterozygous (R1/R2), and two (1.6%) were homozygous (R2/R2).

Factor XI Deficiency (OMIM *264900) A new mutation of the F11 gene was reported for the first time. The patient was a Lebanese woman from the Greek-Orthodox community, who was found to have a prolonged activated partial thromboplastin time (aPTT) in her preoperative workup (de Moerloose et al. 2004).

Factor XIII, A1 (F13A1; OMIM +134570) Factor XIIIa gene (F13A1) V34L polymorphism was studied in 205 healthy unrelated Lebanese individuals (Mahfouz et al. 2008). The prevalence of wild type, heterozygous, and homozygous genotypes was found to be 74.2, 22.4, and 3.4%, respectively. The data in this study serve as a baseline for future investigations of the prevalence of Factor XIIIa V34L polymorphism in association with cardiovascular diseases.

Familial Mediterranean Fever (FMF) – Famillial Paroxysmal Polyserositis (FPP) – “Armenian” or “Periodic” disease (OMIM #249100) This genetic disorder, affecting primarily people of Mediterranean origin, was originally reported from Lebanon by Reimann et al. (1954). It occurs mainly in Armenians and Sephardic Jews (Schwabe and Peters 1974), but is present also among Arabs, Turks, Ashkenazi Jews, and other Mediterranean populations. Khachadurian and Armenian (1974) reported 120 cases of FPP from Lebanon. In their series, there was a predominance of Armenians; 53% of their patients were Armenian, 34% Muslim Arabs, 9% Christian Arabs, and 4% Syriacs. In another series of 72 patients, Naffah et al. (1975) found the Armenians to represent 45% of all cases. These are very high proportions, since the Armenians

13


409

represent only around 8% of the population of the country. Around 25% of their patients were Christian Arabs and 25% Muslim Arabs (21% Shiites and 4% Sunnites); 4% of the cases were of Kurdish origin. No case was found among the Druze community. In both series (Khachadurian and Armenian 1974; Naffah et al., 1975), published from Lebanon, the incidence of amyloidosis is very low and the average survival is longer, suggesting that the disorder in Armenians is distinct from that in Sephardic Jews (Sohar et al. 1967; Schwabe and Peters 1974). Pras et al. (1992), and Fischel-Ghodsian et al. (1992), found that the FMF gene maps to 16p in all ethnic groups, including Armenians, and Ashkenazi and nonAshkenazi Jews. Studying 14 Armenian and nine non-Ashkenazi Jewish families with FMF, Sohat et al. (1992) found linkage to the a-globin complex on 16p in both groups, with no evidence for genetic heterogeneity either between or within the groups. Mansour et al. (2001) tested Lebanese patients for 15 mutations in the MEFV gene: A761H, A744S, V726A, K695R, M694V, M694I, M694del, M6801 (G!C), M6801 (G!A) in exon 10, F479L in exon 5, P369S in exon 3, T267I, E167D and E148Q in exon 2. Mutations were detected in patients belonging to all communities, including the Maronite, Greek Orthodox, Greek Catholic, Syriac, and Shiite. The most frequent mutations were M694V and V726A (27 and 20% of the total alleles, respectively). The M694I, E148Q, and M6801 mutations accounted for 9, 8, and 5%, respectively. Each one of the K695R, E167D and F479L mutations were observed once. All the remaining mutations were not encountered. Thirty-three of the alleles did not carry any of the studied mutations. Over 50 mutations have been identified in MEFV, in 640 Lebanese patients studied by Medlej-Hashim et al. (2005). The percentages of the various mutations were as follows: M694V (30.3%), V726A (19.4%) M694I (12.8%), M680I (7.4%), E148Q (8.3%), R761H (3.1%), rare mutations (2.3%), and undetermined (16.4%) Rare mutations include the R653H, K659R, A744S, S108R, E167D, E148V, and T177I. Three novel mutations, T177I, S108R, and E474K, were also identified in the Lebanese population (Medlej-Hashim et al. 2005). Haplotype analysis of Lebanese FMF patients was performed using four microsatellite loci to study founder effects for the five most frequent mutations within the MEFV gene (M694V, M694I, V726A, and E148Q). The results suggested that each of these mutations have probably arisen from unique mutation events and that the carrier chromosomes derived from a common ancestor. The estimated ages of the most recent common ancestor for each of the five mutations were 7,000, 8,500, 15,000, 23,000, and 30,000 years for M694V, M694I, V726A, M680I, and E148Q, respectively. These results confirmed that Muslim sub-populations (Shiites and Sunnites), as well as Christian ones, including Armenians who were formerly settled in the southeastern part of Asia Minor (Cilicia), are all derived from an ancient common ancestral population (Jalkh et al. 2008). In another study, Sabbagh et al. (2008a) reported that five of the most common mutations, M694V, E148Q, V726A, M694I, and M6801(G/C), accounted for 26.1, 22.2, 21.3, 9.6, and 7.7%, respectively. The A744S, F479L, R761H, and I692del were found in 2.9% of the patients. P369S and M680I (G/A) were present in 1.2%

410

V.M. Der Kaloustian

of the patients. K695R was absent. This spectrum of MEFV mutations revealed a higher degree of heterogeneity in this population than others. Considering the relatively high frequency of the E148Q, the authors questioned whether it is a mutation rather than a polymorphism.

Gaucher Disease, Type I (OMIM #230800) Gaucher disease type I is caused by a mutation in the glucocerebrosidase (GBA) gene. A previously unidentified mutation (L371V) was reported in a Lebanese family (Shamseddine et al. 2004). In another Lebanese family compound heterozygosity was reported in two patients. The two mutations were a rare one, 259T (R48W), and a more common one, L444P (El-Zahabi et al. 2007).

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency: Favism (OMIM +305900) This acute hemolytic disease occurs in Lebanon because of the presence of a relatively high number of persons with G6PD deficiency and because fava beans are an important element of the Lebanese cuisine. In 1964, Taleb et al. studied the blood of 548 Lebanese men. They found 17 cases of G6PD deficiency, representing around 3.09% of the general population. Of 105 Druze and 36 Armenians tested in this series, none had the deficiency. This may be explained by the fact that both of these population groups have lived for centuries in mountainous areas, away from malarial endemicity. In spite of the absence of the deficiency in these two groups, because of the small number of individuals tested, the differences in incidence between the communities were not statistically significant. G6PD Mediterranean has a change from cytosine to thymine, at position 563 (in exon 6), which causes a change from serine to phenylalanine in the amino acid at position 188 (Vulliamy et al. 1988). There is a second silent mutation of TAC to TAT at codon 437 in exon 11 (C to T at nucleotide 1311). This mutation is a polymorphism. Beutler and Kuhl (1990) studied the distribution of the nucleotide polymorphism C1311T in diverse populations. Only one of 22 male subjects from Mediterranean countries, who had the G6PD Mediterranean-563T genotype, had a C at nucleotide 1311. In contrast, G6PD Mediterranean-563T males from the Indian subcontinent had the usual C at nucleotide 1311. Beutler and Kuhl (1990) interpreted these findings as suggesting that the same mutation at nucleotide 563 arose independently in Europe and in Asia. Similar studies were performed by Kurdi-Haidar et al. (1990) in 21 unrelated individuals with G6PD Mediterranean from Saudi Arabia, Iraq, Iran, Jordan, Lebanon, and Israel. All but one had the 563

13


411

mutation and, of these, all but one had the C-to-T change at nucleotide 1311. Among 24 unrelated persons of Middle Eastern origin with normal G6PD activity, four had the silent mutation at position 1311 in the absence of the deficiency mutation at position 563. Kurdi-Haidar et al. (1990), concluded that most Middle Eastern subjects with the G6PD Mediterranean phenotype have the same mutation as that found in Italy, that the silent mutation is an independent polymorphism in the Middle East, with a frequency of about 0.13, and that the mutation leading to the G6PD Mediterranean deficiency probably arose on a chromosome that already carried the silent mutation. In 2000, Usanga and Ameen found the percentage of G6PD deficiency among Lebanese males to be 2.13%.

Glycogen Storage Disease I (OMIM +232200) Trioche et al. (1999) reported a patient affected with glycogen storage disease I, born to a father of Lebanese origin and a French mother. She was compound heterozygote for mutations W70X and T108I. The father carried the W70X mutation. With this, there is a 288G!A transversion resulting in the creation of a premature stop codon at codon 70. This mutation abolishes a Bsr I restriction site.

Heart Block, Familial, Type IB (PFHB1B, OMIM %604559) Edouard Ste´phan, in 1954, was the first to report a bundle branch block in three members of the same family. He then published several other papers (Ste´phan 1974, 1978; Ste´phan et al. 1997) on this large Lebanese kindred, and designated the disorder as “hereditary bundle branch defect (HBBD).” The gene was mapped by de Meeus et al. (1995) at 19q13.3, narrowing the critical region to a 13-cM interval.

Heart Defects, Congenital A molecular study of congenital heart defects in Lebanese patients revealed that there is a differential duplication of an intronic region in the NFATC1 gene in patients with ventricular septal defect, suggesting that NFATC1 is a potential VSD-susceptibility gene (Yehya et al. 2006). The independent effect of consanguinity on the prevalence of congenital heart defects was investigated in newborns admitted to nine hospitals located in Beirut, and members of the NCPNN. Infants born to first-cousin marriages had a 1.8 times higher risk of having a CHD diagnosed at birth compared to those born to unrelated

412

V.M. Der Kaloustian

parents. In particular, first-cousin marriage was a significant risk factor for ventricular septal defect, atrial septal defect, hypoplastic left heart, and single ventricle. No association was found with d-transposition of the great arteries, coarctation, pulmonary atresia, atrioventricular septal defect, and tetralogy of Falllot (Yunis et al. 2006).

Hypercholesterolemia, Familial, FH (OMIM #143890) Khachadurian and his collaborators (Khachadurian 1964, 1968, 1972; Khachadurian and Uthman 1973) studied 31 families with 52 patients fulfilling the criteria for the homozygous form of FH. The high incidence of conasanguineous marriages in Lebanon is partly responsible for the large number of homozygous cases encountered. The frequency of homozygotes is 10 times higher than in other parts of the world. It was on the basis of these studies in Lebanon that Khachadurian, in 1964, first established the existence of homozygous FHC. Lehrman et al. (1987) analyzed the nature of the low-density lipoprotein receptor (LDLR) gene mutation present in high frequency in Lebanon. They demonstrated that the mutation involves a shortening of the receptor protein in three of its five domains: the region of clustered 0-linked carbohydrates, the membrane-spanning region, and the cytoplasmic tail. The defect was considered to be due to a single nucleotide substitution in the gene, creating a premature termination codon at amino acid 660, thus eliminating 180 residues from the mature protein. The termination codon occurred in the middle of a cysteine-rich sequence that is part of the domain homologous to the epidermal growth factor precursor (LDLR, CYS660TER). Lehrman et al. (1987) refer to this mutation as “the Lebanese allele.” The mutation creates a new restriction site, permitting diagnosis by Southern blotting of genomic DNA. Oppenheim et al. (1991) found the “Lebanese” allele in five Israeli–Arab kindreds with hypercholesterolemia. Figueiredo et al. (1992) analyzed ten Brazilian families with patients affected with hypercholesterolemia. They found the Lebanese allele in five families.

Hypercholesterolemia, Autosomal Recessive; ARH (OMIM #603813) A rare autosomal recessive form of hypercholesterolemia (ARH), that clinically resembles FH but is not due to mutations in the LDLR gene, was described by Khachadurian and Uthman in 1973. The patients affected with this condition have markedly impaired LDLR function in the liver, but normal or slightly reduced function in the cultured fibroblasts (Garcia et al. 2001).

13


413

The ARH locus was mapped to a 1-cM interval on chromosome 1p35 and mutations were identified in a gene encoding a putative adaptor protein (ARH). This protein has a tissue-specific role in LDLR function, and is required in the liver but not in fibroblasts (Garcia et al. 2001).

Hyperhomocysteinemia (OMIM #603174) and MTHFR (OMIM *60793) Certain mutations in the MTHFR (5,10-methylenetetrahydrofolate reductase) gene may result in homocysteinemia. A study by Sabbagh et al. (2008b) in Lebanon on the two most common MTHFR polymorphisms of C677T and A1298C revealed that for C677T the prevalence of the C/C, C/T, and T/T genotypes was 65.3, 30.8, and 3.9%, respectively. The overall carrier rate was 34.6% and the allelic frequency was 0.19. The A1298C genotypic prevalence of A/C, A/A, and C/C was 50.2, 25.9, and 23.9%, respectively. The overall carrier rate was 74.14% and the allelic frequency was 0.49. This study revealed that the Lebanese population has the highest prevalence of the MTHFR A1298C polymorphism.

Hyperlipoproteinemia, Type I (OMIM #238660) Hyperlipoproteinemia Type I is a rare autosomal recessive disorder. It is associated with repeated episodes of abdominal pain, recurrent pancreatitis, eruptive xanthomatosis, hepatosplenomegaly, and lipemia retinalis. This condition is caused by a deficiency of the lipoprotein lipase. LPL is the gene coding for this enzyme. A novel mutation in the LPL gene causing hyperchylomicronemia with recurrent hepatitis was reported in two Lebanese probands. The mutation was in exon 5. Both patients were homozygous for the 776A!T mutation, resulting in the D174V substitution (Abifadel et al. 2004).

Hypogonadism, Hypergonadotropic, with Partial Alopecia (OMIM %241090) In 1985, Al-Awadi et al. observed two Lebanese sisters with hypergonadotropic hypogonadism and partial alopecia. The hair was present only in the center of the scalp. One of the sisters had streak ovaries, and the other did not have gonads. The parents were first cousins once removed. In 2003, Me´garbane´ et al. (2003a) reported from Lebanon two sisters with primary hypergonadotropic hypogonadism, microcephaly, flat occiput, congenital

414

V.M. Der Kaloustian

partial alopecia with abnormal hair structure, m€ ullerian hypoplasia, and absent or streak ovaries. The parents were first cousins.

Hypogonadism, Hypogonadotropic, with Alopecia Salti and Salem (1979) reported a Lebanese family in which several members, both female and male, had hypogonadism with partial alopecia. Studies in three affected members have revealed that the hypogonadism is of the hypogonadotropic type. The parents are consanguineous and the condition most probably follows an autosomal recessive pattern of inheritance.

Hypothyroidism In 1963, Najjar et al. reported 47 hypothyroid children from 42 families living in an area in Lebanon where goiter is endemic. Three important differences from sporadic cretinism in nonendemic areas were found: There was a low incidence of athyreosis, the sex ratio failed to show the usual predominance of females, and the rate of consanguinity and familial incidence were high.

Ichthyosis, Lamellar, 3 (OMIM #604777) In a Lebanese patient with lamellar ichthyosis type 3, a mutation was identified in the CYP4F22 gene. This was a 980delC, resulting in a frameshift (Lefe`vre et al. 2006).

Imerslund–Gr€ asbeck Syndrome (IGS, OMIM #281100) Selective malabsorption of the intrinsic factor and vitamin B12/cobalamin (cbl) complex is known as Imerslund–Gr€asbeck syndrome. The disease is due to mutations in the CUBN gene, encoding cubilin. Four children of one family from Lebanon have been reported (Ro¨ssler et al. 2003).

Jervell and Lange–Nielsen Syndrome 2 (JLNS2, OMIM #612347) The Jervell and Lange–Nielsen syndrome is an autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death. It is a heterogeneous condition, with genes mapped at 11p15.5 (JLNS1) and 21q22.1-p22.2 (JLNS2). JLNS2 is due to mutations in the KCNE1 gene

13


415

(OMIM+176261) which encodes a transmembrane protein involved in the activity of a potassium channel. Schulze-Bahr et al. (1997) found mutations in the KCNE1 gene in the members of a Lebanese family affected with JLNS2.

Lipodystrophy, Congenital, Generalized, Type 2 (BSCL2, Berardinelli–Seip Type 2, OMIM #269700) Congenital generalized lipodystrophy type 2, or Berardinelli–Seip syndrome, is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. The first patients from Lebanon were published in 1973 and 1975 (Salem et al. 1973; Najjar et al.1975). A new gene locus, BSCL2, linked to 11q13, was identified in Lebanese and Norwegian patients. All the Lebanese patients were found to be homozygous for the same mutation. This is a 5-bp deletion in exon 4, which shifts the reading frame after amino acid 105, introducing a premature stop codon at position 111 (Magre´ et al. 2001).

Mannose-6-Phosphate Receptor Recognition Defect: Lebanese Type (OMIM %154570) Five healthy individuals belonging to three generations of a Lebanese family were found to have highly elevated plasma lysosomal enzyme levels inherited as a dominant Mendelian trait. The same enzymes were within normal limits in other extracellular fluids. The physicochemical properties of the elevated plasma enzymes were different from those of both control and I-cell disease, while the pattern and extent of elevation was similar to that found in mucolipidoses II and III. Secretion of lysosomal hydrolases into cell media by fibroblasts from one of the individuals was increased two to seven times more that that from controls (Alexander et al. 1984). Mannose-6-phosphate receptors in fibroblasts of the same individual were found to be functioning normally, but the cells had only half-normal levels of phosphodiester glycosidase activity. Pynocytosis of b-hexosaminidase (hexB) secreted by these fibroblasts into Sandhoff’s disease fibroblasts was 18% of control. The apparent KD for binding of these hexB to man-6-P receptors was 3.7 109 M compared to 1.25 109 M for control enzyme. Treatment of this abnormal hex B with exogenous placental phosphodiester glycosidase increased its binding to man-6-P receptors threefold. Secretion rates of seven lysosomal enzymes from these fibroblasts were, on average, twice as great as rates measured for two I-cell disease heterozygote fibroblast lines. The results suggest that these fibroblasts are heterozygous for phosphodiester glycosidase deficiency (Alexander et al. 1986).

416

V.M. Der Kaloustian

Me´garbane´ Syndrome (OMIM 606527) Two brothers with short face, beaked nose, flat nasal bridge, flat philtrum, bilateral ptosis, joint laxity and dislocation, hernias, and severe psychomotor retardation were reported by Me´garbane´ et al. (2001b). Their parents were first-cousin Iraqi Muslims. The authors suggested that this condition was most likely inherited as an autosomal recessive.

Mesomelic Dysplasia, Upper-Limb (OMIM %191440) Me´garbane´ and Ghanem (2005) reported a Lebanese boy with upper-limb mesomelic dysplasia. The father was also affected. This is the second report of this condition in the literature. It was first reported by Fryns et al. in 1988.

Methylenetetrahydrofolate Reductase (MTHFR): C677T Mutation (OMIM *607093) The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene plays a role in precipitating mild hyperhomocysteinemia, and is a risk factor for vascular thrombosis. The frequency of this mutation among 589 healthy Lebanese subjects was investigated. The prevalence of the mutated homozygous (T/T) and heterozygous (C/T) C677T MTHFR genotypes was 11.04 and 39.73%, respectively, giving an allele frequency of 0.309. The prevalence of the T/T genotype was similar with respect to gender. However, a higher prevalence was noted among Christian (13.08%) compared to Muslim (7.66%) subjects (P < 0.001). Moreover, heterogeneity in its distribution was seen in the different Lebanese provinces, and was directly related to the Christian/Muslim composition of each province (Almawi et al. 2004).

Neuropathy, Hereditary Sensory and Autonomic, Type II (OMIM #201300) Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by proximal and distal sensory loss caused by the reduction or absence of peripheral sensory nerves. This condition is due to mutations in the HSN2 gene. Screening of this gene in an HSAN type II Lebanese family showed a 1-bp deletion mutation found in a homozygous state in all affected individuals (Rivie`re et al. 2004).

13


417

Odontoonychodermal Dysplasia (OMIM #257980) Odontoonychodermal dysplasia is a condition characterized by dry hair, severe hypodontia, a smooth tongue with reduced fungiform and filiform papillae, keratoderma of the palms and soles, hyperkeratosis of the skin, and onychodysplasia. This condition was first reported from Lebanon (Fadhil et al. 1983). Other cases and variants were also reported later, from Lebanon and elsewhere (Zirbel et al. 1995; Arnold et al. 1995; Me´garbane´ et al. 1998, 2004). In 2007, Adaimy et al. reported three consanguineous Lebanese Muslim Shiite families that included six individuals affected with this condition. They identified the same c.697G!T (p.Glu233X) homozygous nonsense mutation in exon 3 of the WNT10A gene in all patients.

Osseous Dysplasia with Severe Short Stature, Multiple Dislocations, and Delayed Bone Age Two Lebanese children with consanguineous parents were reported with anisospondyly, absence of ossification of the odontoid apophysis, fusion of the neural arches of the cervical vertebrae, partial agenesis of the coccyx, abnormal and subluxated radial heads, bilateral dislocation of the hips, dysplastic acetabulae, hypoplasia of the femoral heads, short femoral necks, short long bones with thin diaphyses, widening of the medullary canal and thinning of the cortical one, slightly enlarged metaphyses, and diffuse osseous demineralization. The bone age was delayed (Me´garbane´ and Ghanem 2004; Me´garbane´ 2007).

Osteopetrosis, Autosomal Recessive (OPTB1, TCIRG1, OMIM #259700 and OPTB5, OSTM1, OMIM #259720) Four Lebanese families were reported, with children of consanguineous parents, affected with osteopetrosis (Souraty et al. 2007). The clinical findings included failure to thrive, a prominent forehead, exophthalmia, optic atrophy, neurological manifestations, hepatosplenomegaly with elevated hepatic enzymes and acid phosphatase, anemia, thrombocytopenia, hypocalcemia, and an early fatal outcome (Souraty et al. 2007). Mutations were identified in two genes: the T-cell immunoregulator-1 (TCIRG1) and the osteopetrosis-associated transmembrane protein 1 (OSTM1). Analysis of the TCIRG1 gene revealed two different types of mutations in the probands of two of these Lebanese families. A homozygous deletion of a single nucleotide was found in exon 7 at nucleotide 4668 of the gene. This lead to a frameshift starting at codon 235 and premature termination after 43 extraneous amino acids

418

V.M. Der Kaloustian

5(1235fs 43). In the third Lebanese family, the proband was homozygous for the G to C change at position +5 of the donor splice site of intron 5 (IVS5 + 5-exon skipping). The proband of the fourth family showed a single point mutation in exon 1, leading to a nonsense mutation (80433T!A, C12X) [Souraty et al. 2007].

Plasminogen Activator Inhibitor-1 (PAI-1) gene 4G/5G alleles In a study on the PAI-1 gene in the Lebanese population, it was found that the 4G/ 5G genotype was the most prevalent (45.6%), followed by 5G/5G (36.9%), and 4G/ 4G (17.5%). Compared to other ethnic communities, the Lebanese population was found to have a relatively high prevalence of the rare 4G allele, which may predispose this population to develop cardiovascular diseases and other thrombotic disorders (Shammaa et al. 2008).

Premature Ovarian Failure with POF1B Mutation (OMIM #300604) In five sisters of a Lebanese family, affected with premature ovarian failure, Lacombe et al. (2006) identified a point mutation in the POF1B gene, localized in exon 10. The substitution of a nucleotide (G!A) at position 1,123 results in an arginine!glutamine mutation of the protein sequence at position 329 (mutation R329Q).

Pseudohermaphroditism (Pseudovaginal Perineoscrotal Hypospadias) Eight patients with male pseudohermaphroditism were reported from a large Muslim Shiite village in Southern Lebanon, with a high rate of consanguinity. The affected individuals had 5-a-reductase deficiency (5aRD). They had a 46,XY chromosomal pattern. At birth, they had an external female phenotype, bilateral testes, and normal male internal genitalia. There is masculinization at puberty, followed by a change in gender role. Molecular studies revealed a homozygous point mutation in exon 1, with a T!A substitution, leading to a leucine to glutamine (Leu-Gln) substitution at position 55 (Hochberg et al. 1996).

Sandhoff Disease (OMIM #268800) ) Out of 11 cases clinically diagnosed in Lebanon as infantile Tay–Sachs disease, nine were enzymatically diagnosed to be affected with Sandhoff disease. The presence of

13


419

this condition was noted to be particularly in the Christian Maronite and Muslim Sunnite communities (Der Kaloustian et al. 1981). Thus, the frequency of the mutation for this disease is thought to be significantly higher in Lebanon than elsewhere. In Lebanese Maronites living in Cyprus, a novel mutation (a deletion of A at nt76) was found (Hara et al. 1994). Population screening in Cyprus revealed a high frequency of nt76 mutation carriers in the Maronite community. However, no mutation was identified in two Sunnite Muslim obligate carriers and eight Maronite individuals who were designated biochemically as carriers but were negative for both the nt76 and IVS8 nt5 mutations (Drousiotou et al. 2000).

Sickle-Cell Anemia (OMIM #603903) and Thalassemia Major (OMIM+141900) Cabannes et al. (1965) studied 3,000 Lebanese individuals and uncovered nine HbS heterozygotes. These consisted of one Maronite, one Greek Orthodox, four Shiites, and three Sunnites. No case was found among the Armenian and Druze communities. The same study showed the presence of the b-thalassemia trait in many regions and communities of Lebanon. The incidence of this trait is 2%, with slight variation from one group to the other. Dabbous and Firzli (1968) reviewed their 10-year experience in the Pediatric Hematology Clinic of the American University Hospital in Beirut, and noted that the sickling phenomenon was present almost exclusively in Muslim patients. Although the total admissions represented 49% Muslims and 51% Christians, all the patients affected with sickle-cell disease were Muslims. Out of 49 patients with sickle cells, eight had sickle-thalassemia, 17 had sickle-cell trait, and 25 had siclkecell anemia. Nineteen were Lebanese, seven Syrian, fourteen Palestinian, five Saudi Arabian, two Bahraini, and two Qatari. The authors (Dabbous and Firzli 1968) think that the sickle-cell gene was introduced in the country in the thirteenth and fourteenth centuries, when the various Muslim groups from the neighboring areas settled in the coastal towns west of Mount Lebanon proper, while the majority of the Christian and Druze withdrew to find shelter at higher altitudes in the mountains. It is of interest to note that malaria (until its eradication in the 1950s) was known to occur at low altitude in Lebanon, and endemic foci existed in the coastal plains and inner plateau, the same areas inhabited by the Muslims in general. Thus, it seems most likely that the preponderance of the HbS gene in Muslims is due to its introduction into the country by Muslim settlers in the fourteenth and fifteenth centuries, and its persistence and propagation in these communities to the malaria that existed in the regions inhabited by Muslims. Even though all subjects with sickle-cell disease (SCD) have the same singlebase-pair mutation, the severity of the clinical and hematological manifestations is extremely variable. A study examined for the first time in Lebanon the correlation

420

V.M. Der Kaloustian

between the clinical manifestations of SCD and the b-globin gene haplotypes. Most reported haplotypes were found in the population, with the Benin haplotype as the most prevalent one. When the patients were divided according to their HbF levels, into three groups (Group A: HbF < 5%; Group B: HbF between 5 and 15%; and Group C: HbF >15%), the highest levels of HBF were associated with the most severe clinical cases. These results suggested that fetal hemoglobin levels are one of the parameters that affect the severity of SCD (Inati et al. 2003). Taleb et al. (1969) published a study on hemoglobinopathies in Lebanon. They found six cases of sickle-cell anemia (four Lebanese), 13 cases of b-thalassemia major (all Lebanese), and one case of sickle-thalassemia (Lebanese). Shahid et al. (1974) described a family in which four siblings had HbH disease. Both parents were Sunnite Muslims and originated from a small village in Southern Lebanon. Strahler et al. (1983) found, from a Lebanese source and by reverse-phase high-performance liquid chromatography, a hemoglobin with substitution of valine by alanine at position 126 of the b-globin chain. They named it hemoglobin Beirut. Later, Blibech et al. (1986) found the same hemoglobin in an Algerian family. Patients with b-thalassemia from a Lebanese population with a high rate of consanguineous marriages were studied by Chehab et al. (1984). The clinical course of the anemia suggests that this population consists of the severe Mediterranean type; 23 unrelated homozygous b-thalassemia patients investigated for globin synthetic ratios consisted of 18 b+ and 5 b with a non-a/a range of 0.158–0.465 and 0.25–0.41, respectively. The percentage of Gg chains in HbF was determined for 21 of these patients and a mean value of 59% Gg-chain content was found. A study by Chehab et al. (1987) of the molecular lesions of b-thalassemia in Lebanon revealed the presence of eight different mutations in 25 patients. The IVS1 position 110 mutation predominated with a frequency of 62% and was almost invariably associated with Mediterranean chromosome haplotype I. Five other mutations commonly found in the Mediterranean area occurred with frequencies of 2–8%. In addition, a G!C substitution in IVS1 position 5 was demonstrated in a patient with Mediterranean haplotype II. A new mutation at codon 29 was found in two other patients with haplotype II. A study by Zahed et al. (1997), suggested that thalassemia was most frequent among the Sunnite Muslims, followed by the Shiite Muslims and the Maronites. The most frequent mutation was IVSI-110 (40%), followed by other common Mediterranean mutations (IVSI-1, IVSII-1, IVSI-6). The most heterogeneous religious group seemed to be the Sunnite Muslims, with 13 mutations, while only two mutations were detected among the Christian Maronites. No mutation was found among the Armenians. Another study by Zahed et al. (2000) on the molecular basis of b-thalassemia revealed a very important degree of heterogeneity. Eighteen different mutations were identified among a total of 277 chromosomes. There was evidence of clustering of certain mutations in particular geographic regions or among specific religious

13


421

groups. Seventy-two of the patients were Muslims and the Sunnite Muslims were the most heterogeneous at the molecular level. While the most common mutations were found in all religious groups, they found that IVSI-5 (G!C) and cd8(-AA) were exclusive to the Sunnite. They also reported that two mutations were exclusive to the Shiites. These were cd30 (G!C) and cd29 (C!T). Haplotype analysis revealed 11 different haplotypes. The five most common mutations were each found on two different haplotypes. Some mutations had a particular geographic distribution. For example, cd29 was mainly found in the Beqa’a valley, cd30 was found in Southern Lebanon (Zahed et al. 2000), while 290 bp del was found in the Shiites in Beirut and 88 was found among the Druze in Mount Lebanon (Makhoul et al. 2005). Both studies revealed similar findings by haplotype analysis of the mutant b-globin gene (Zahed et al. 1997, 2000). Moreover, they identified a rare 5’ subhaplotype (haplotype 12, previously reported in South Africa and Asia) linked to IVSI-110 in three unrelated Maronite individuals. The great majority of the Lebanese chromosomes with the IVS-I-110 mutation are associated with the RFLP haplotype I and sequence haplotype HT1. This is probably the ancestral structure from which the mutation first emerged. The remainder of the IVS-I-110 alleles are linked to the 50 subhaplotype 12 RFLP haplotype and/or HTR sequence haplotype (Zahed et al. 2002). Approximately one-third of thalassemic patients in Lebanon have thalassemia intermedia. In these patients three factors were analyzed: mild b-globin gene, mutations, deletions in the a-globin gene, and the presence of a polymorphism for the enzyme Xmn I in the Gg-promoter region. It was found that the most important contributing factor is the b-genotype: 68% of these patients have a mild b+ mutation (IVSI-6, cd29, 88 or 87), while 26% of the patients are positive for the Xmn I polymorphism associated with increased production of HbF, which showed a strong linkage to particular mutations (IVSII-1, cd8 and cd30) (Qatanani et al. 2000). In a thalassemic patient with a mild phenotype, a mutation was reported representing the insertion of a G nucleotide at codons 8/ 9 [(+G)AAG-TCT(Lys-Ser)!AAG-G-TCT(beta0)] of the beta-globin gene (Zalloua et al. 2003). Six (IVS-I-110, IVS-I-1, IVS-I-6, IVS-II-1, cd5, and C!T substitution at cd29) out of 20 b-globin defects identified accounted for more than 86% of the total. The Sunnite Muslims presented the greatest heterogeneity with 16 different mutations. The Shiite Muslims followed with 13 mutations, and the Maronites, who represented 11.9% of all b-thalassemia subjects, carried seven different mutations. The Druze were found to have six different mutations. One of these mutations, the rare b+ promoter mutation of C!T at position 88, seemed to be unique for this religious group (Makhoul et al. 2005). Zahed and Bou-Dames (1997) published the results of interviews of 83 couples at risk for a hemoglobin disorder, mostly b-thalassemia, in an effort to evaluate their attitude regarding first-trimester prenatal diagnosis. Fifty-nine percent were in favor, 23% were uncertain, and 18% were opposed, because of their religious

422

V.M. Der Kaloustian

convictions against termination of pregnancy. Another important factor influencing their choice was the cost of the test.

Sjo¨gren–Larsson Syndrome (SLS, OMIM #270200) Sjo¨gren–Larsson syndrome is an autosomal recessive disorder, presenting with congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. It is caused by mutations in the gene encoding fatty aldehyde dehydrogenase (FALDH), located on 17p11.2. Sequence analysis of the gene in a Lebanese family with affected persons revealed a homozygous in-frame deletion of three Cs and an insertion of 21 bp at nucleotide position 941 (nt941del3, ins21) (Silleń et al. 1998). This mutation has been found previously in a family of mixed European origin (De Laurenzi et al. 1996).

Smith–Lemli–Opitz syndrome (SLOS, OMIM #270400) Smith–Lemli–Opitz syndrome is a multiple congenital anomalies/mental retardation syndrome. The condition is due to the deficient activity of the enzyme 7-dehydrocholesterol (7-DHC) reductase. Akl et al. (1977) reported a patient with bilateral focal renal dysplasia. Siblings affected with this condition and with consanguineous parents of Syrian-Lebanese origin were reported, with a novel mutation in the DHCR7 gene. The patients were homozygotes for a missense mutation, causing a C!T transition at position 1,649 in exon 9, substituting a leucine for a proline residue (P467L) (Nezarati et al. 2002).

Spondyloepimetaphyseal Dysplasia with Multiple Dislocations (OMIM %603546) Me´garbane´ et al. (2003b) reported a new Lebanese patient with spondyloepimetaphyseal dysplasia with multiple dislocations, and reviewed the literature.

Tay–Sachs Disease, juvenile (OMIM #272800) Hechtman et al. (1989) evaluated the expression of the hexosaminidase isozymes in fibroblast cell lines obtained from two siblings of Lebanese Christian origin who presented with juvenile-onset Tay–Sachs disease. In the normal control fibroblasts,

13


423

the a-subunit of hexosaminidase A (Hex A) is synthesized as a 67-kDa precursor, which is cleaved in lysosomes to a mature 54-kDa peptide. The patient’s fibroblasts were capable of synthesizing the 67-kDa precursor but failed to convert it to the mature subunit. The a-subunit precursor synthesized by the cells of the patients could not be phosphorylated, nor was the patient’s a-subunit precursor secreted into the medium in response to NH4Cl, which caused accumulation of both a- and b-subunit precursor in the medium of the normal control fibroblasts. The patients had 0.32 and 0.36% of HexA-associated cleaving activity, compared to normal control fibroblasts, whereas this percentage is less than 0.016% for infantile Tay–Sachs disease fibroblasts. The occurrence of this form of Tay–Sachs disease in Lebanon in three unrelated Lebanese immigrant families in Canada, together with the fact that the grandparents of the unrelated probands come from villages in both the northern and the southern regions of Lebanon, lead the authors (Hechtman et al. 1989) to speculate that a gene causing juvenile-onset Tay–Sachs disease may not be infrequent in Lebanon. Again, in a Lebanese proband with juvenile-onset Tay–Sachs disease Trop et al. (1992) found, by direct sequencing of PCR products, a G!A transition at nucleotide749 in exon 7. The mutation caused a glycine-to-aspartic acid change at amino acid 250. Boustany et al. (1991) found in a Lebanese Maronite patient with the juvenile form of Tay–Sachs disease a specific mutation in the heterozygous state. The mutation consisted of a G!A transition at nucleotide 1511 of the a-chain of hexosaminidase A, resulting in substitution of histidine for arginine at position 504. Cultured fibroblasts synthesized an a-subunit that could acquire mannose 6-phosphate and be excreted, but which failed to associate with the b-subunit to form the enzymatically active heterodimer (Paw et al. 1990).

Usher Syndrome Type 1C (USH1C, OMIM #276904) Usher syndrome is the most common form of inherited deafness associated with retinitis pigmentosa. It is heterogeneous, both clinically and genetically. On the basis of the clinical phenotype, it is classified into three main types: USH1, USH2, and USH3. USH1 is the most genetically heterogeneous, with at least eight loci (Ahmed et al. 2003). Linkage analysis of seven Lebanese families with Usher syndrome revealed that two were of type I (USH1) and five with type II (USH2). The seventh was of the USH1C type (Saouda et al. 1998). Patients with USH1C and residing in New England were studied and their haplotypes compared. One patient had haplotypes found in previously reported USH1C Acadian families residing in south-western Louisiana. One patient was Lebanese-American (DeAngelis et al. 2001). The latter had the same haplotype as a previously reported USH1C family residing in Lebanon (Saouda et al. 1998).

424

V.M. Der Kaloustian

Vitamin K-Dependent Clotting Factors, Deficiency of (Familial Multiple Coagulation Factor Deficiency, FMFD, OMIM #277450) Familial multiple coagulation factor deficiency is a very rare disorder with only 14 cases described in the literature by 2002 (Fregin et al. 2002). Clinical symptome of the disease are episodes of intracerebral hemorrhage in the first weeks of life, sometimes leading to a fatal outcome. Clinical details of a Lebanese and a German family were presented with a suggestion of autosomal recessive inheritance (Oldenburg et al. 2000). The same group reported a second gene locus to the centromeric region of chromosome 16 (Fregin et al. 2002). Previously, a missense mutation in the g-glutamyl carboxylase gene was found to cause combined deficiency of all vitamin K-dependent blood coagulation factors (Brenner et al. 1998).

Weill–Marchesani Syndrome, Autosomal Recessive (WMS; OMIM #277600) Weill–Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and lens abnormalities. This condition presents with clinical homogeneity, but with both autosomal recessive and autosomal dominant inheritance. Faivre et al. (2002) reported in two consanguineous families (a Lebanese and a Saudi Arabian) linkage of the autosomal recessive variety of WMS to chromosome 19p13.3-p13.2, in a 12.4-cM interval. In 2004, Dagoneau et al. (2004) reported null mutations in the gene encoding ADAMTS10 in the Lebanese and Saudi Arabian families. The nucleotide change in the Lebanese family resulted in a nonsense mutation (R237X) with 709C!T/ 709C!T.

Wolfram Syndrome (DIDMOAD, WFS1, OMIM #222300) Wolfram syndrome (WFS) is a rare hereditary heterogeneous neurodegenerative disorder. It is also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). Thirty-one Lebanese patients, all derived from consanguineous marriages, were studied. Even though the accurate prevalence of this condition is not established in this study, it was suggested that it is much more prevalent in the Lebanese than in other populations, possibly because of the high rate of consanguinity. WFS1 gene mutations were detected in three families (23.5%), with two different putative mutations. No abnormalities were detected in the mitochondrial DNA (Medlej et al. 2004).

13


425

Delivery of Care to Patients with Genetic Diseases and Genetic Programs Genetic counseling and care to patients with genetic diseases were provided by two genetics units, both located in Beirut and founded in 1968. The first of these, The National Unit of Human Genetics was at the American University Medical Centre. It had facilities for clinical genetics, cytogenetics, biochemical genetics, and prenatal diagnosis. A multidisciplinary consultant staff provided genetic counseling in a genetics clinic and consultations on the wards. The second unit comprised cytogenetics and biochemical genetics laboratories at the Faculty of Medicine, St. Joseph University, Beirut (Faculte´ de Me´decine, Universite´ St. Joseph, Beyrouth) as well as at the Genetics Clinic of the Hoˆtel Dieu de France Hospital in Beirut. These two units catered not only to patients from various regions of Lebanon, but also to those from countries of the Middle East. Both units benefited from the effective support of a governmental agency, the Lebanese National Council for Scientific Research (LNCSR). They both had a productive scientific period, with a substantial number of publications. The unit at the American University of Beirut had also programs for M.Sc. and Ph.D. in human genetics, and a fellowship program in clinical genetics. Unfortunately, because of the Lebanese civil war, the two units were dismantled to a great extent, keeping only a skeleton of services, mostly in Cytogenetics. In the phase of reconstruction of the country during the past two decades, both universities are making special efforts to reorganize their genetic services and give them high priority. Fortunately, these efforts lead to the production of a new generation of very capable and productive specialists with outstanding contributions, and a marked presence in the region and internationally. The Cytogenetics Laboratory at the American University of Beirut Medical Center (AUBMC) is the only laboratory in Lebanon that performs prenatal diagnosis of chromosome abnormalities (Eldahdah et al. 2007).

References Abboud MR, Alexander D, Najjar SS (1985) Diabetes mellitus, thiamine-dependent megaloblastic anemia, and sensorineural deafness associated with deficient alpha-ketoglutarate dehydrogenase activity. J Pediatr 107:537–541 Abdelnoor AM, Abdelnoor M, Heneine W, Khauli R, Kobeissy F, Mansur S, Malak R, Sharara H (2001) Major histocompatibility complex class I and II antigen frequencies in selected groups of Lebanese. Transplant Proc 33:2839–2840 Abdul-Karim R, Iliya F, Iskandar G (1964) Consecutive hydrocephalus: report of two cases. Obstet Gynecol 24:376–378 Abifadel M, Jambart S, Allard D, Rabe`s J-P, Varret M, Derre´ A, Chouery E, Salem N, Junien C, Aydeńian H, Boileau C (2004) Identification of the first Lebanese mutation in the LPL gene and description of a rapid detection method. Clin Genet 65:158–161

426

V.M. Der Kaloustian

Adaimy L, Chouery E, Me´garbane´ H, Mroueh S, Delague V, Nicholas E, Belguith H, de Mazancourt P, Me´garbane´ A (2007) Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia. Am J Hum Genet 81:821–828 Afifi AK, Der Kaloustian VM, Mire JJ (1972a) Muscular abnormality in xeroderma pigmentosum. J Neurol Sci 17:435–442 Afifi AK, Rebeiz J, Mire J, Andonian SJ, Der Kaloustian VM (1972b) The myopathology of the prune belly syndrome. J Neurol Sci 15:153–166 Afifi AK, Najjar SS, Mire-Salman J, Bergman RA (1974) The myopathology of the Kocher– Debre´–Se´me´laigne syndrome. Electromyography, light and electron-microscopy study. J Neurol Sci 22:445–470 Afifi AK, Mire-Salman J, Najjar S (1976) The myopathology of congenital generalized lipodystrophy, light and electron microscopic observation. Johns Hopkins Med J 39(Suppl):61–68 Ahmed ZM, Riazuddin S, Riazuddin S, Wilcox ER (2003) The molecular genetics of Usher syndrome. Clin Genet 63:431–444 Akl KF, Khudr GS, Der Kaloustian VM, Najjar SS (1977) The Smith–Lemli–Opitz syndrome. Report of a case with bilateral focal renal dysplasia. Clin Pediatr 16:665–668 Al-Awadi SA, Farag TI, Teebi AS, Naguib K, El-Khalifa MY, Kelani Y, Al-Ansari A, Schimke RN (1985) Primary hypogonadism and partial alopecia in three sibs with mullerian hypoplasia in the affected females. Am J Med Genet 22:619–622 Alexander D, Assaf M, Khudr A, Haddad I, Barakat A (1985) Fructose-1, 6-diphosphatase deficiency: diagnosis using leukocytes and detection of heterozygotes with radiochemical and spectrophotometric methods. J Inherit Metab Dis 8:174–177 Alexander D, Dudin G, Talj F, Bitar F, Deeb M, Khudr A, Abboud M, Der Kaloustian VM (1984) Five related Lebanese individuals with high plasma lysosomal hydrolases: a new defect in mannose-6-phosphate receptor recognition? Am J Hum Genet 36:1001–1014 Alexander D, Deeb M, Talj F (1986) Heterozygosity for phosphodiester glycosidase deficiency: a novel human mutation of lysosomal enzyme processing. Hum Genet 73:53–59 Almawi WY, Finan RR, Tamim H, Daccache JL, Irani-Hakime N (2004) Differences in the frequency of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene among the Lebanese population. Am J Hematol 76:85–87 Almawi WY, Wakim-Ghorayeb SF, Arekat MR, Najm P, Keleshian SH, Al-Sayed N, Blanchon B, Samaha HR, Irani-Hakime N (2006) Association of selective HLA class II susceptibilityconferring and protective haplotypes with type 2 diabetes in patients from Bahrain and Lebanon. Clin Vaccine Immunol 13:1296–1298 Arayssi TK, Hamdan AR, Touma Z, Shameseddeen W, Hourani HB, Farra CG (2008) TNF polymorphisms in Lebanese patients with Behçet’s disease. Clin Exp Rheumatol 26(4 suppl 50):S130–131 Armenian H (1982) Genetic and environmental factors in the aetiology of familial paroxysmal polyserositis. An analysis of 150 cases from Lebanon. Trop Geogr Med 34:183–187 Armenian HK, Khachadurian AK (1973) Familial paroxysmal polyserositis. Clinical and laboratory findings in 120 cases. J Med Liban 26:605–614 Armenian HK, Uthman SM (1975) Familial paroxysmal polyserositis (FPP). J Med Liban 28:439–442 Arnold WP, Merks MAW, Steijlen PM (1995) Variant of odontoonychodermal dysplasia? Am J Med Genet 59:242–244 Ayoub N, Tomb R, Charlesworth A, Meneguzzi G (2005) E´pidermolyse bulleuse jonctionnelle. Identification d’une nouvelle mutation dans 2 familles libanaises. Ann Dermatol Venereol 132:550–553 Baghdassarian SA, Tabbara KF (1975) Childhood blindness in Lebanon. Am J Ophthalmol 79:827–830 Baraka A, Bikhazi G, Abu-Haidar G (1974) Succinylcholine block in a patient with atypical serum cholinesterase. Middle East J Anaesthesiol 4:53–59

13


427

Barakat AY, Butler MG (1987) Renal and urinary tract abnormalities associated with chromosome aberrations. Int J Pediatr Nephrol 8:215–226 Barakat AY, Francis YK, Mufarrij AA (1986) Hypokalemic alkalosis, hyperreninemia, aldosteronism, normal blood pressure and normal juxtaglomerular apparatus – a new syndrome of renal alkalosis. Int J Pediatr Nephrol 7:99–100 Barbari A, Stephan A, Masri M, Karam A, Aoun S, El Nahas J, Bou Khalil J (2003) Consanguinity-associated kidney disease in Lebanon: an epidemiological study. Mol Immunol 39:1109–1114 Beighton P (1978) Inherited disorders of the skeleton. Churchill-Livingstone, Edinburgh, pp 50–52 Beighton P (1990) Dyggve–Melchior–Clausen syndrome. J Med Genet 27:512–515 Ben Ezra D, Abulafia H, Maftzir G, Yatziv S, Paez J, Zelikovitch A (1982) Radial aplasia, chromosomal aberration, and anterior chamber cleavage manifestations in two siblings. Birth Defects Orig Artic Ser 18:571–575 Beutler E, Kuhl W (1990) The NT 1311 polymorphism of G6PD: G6PD Mediterranean mutation may have originated independently in Europe and Asia. Am J Hum Genet 47:1008–1012 Bidinost C, Matsumoto M, Chung D, Salem N, Zhang K, Stockton DW, Khoury A, Megarbane A, Bejjani B, Traboulsi EI (2006) Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities. Invest Ophthal Vis Sci 47:1274–1280 Bitar E (1966) La goutte au Liban. J Med Liban 19:235–241 Bitar E, Ghayad E, Ghoussoub K, Sinno W, Chams H, Khoury A, Baloglou P, Kallab K, Halaby C, Chemaly R et al (1986) Behçet’s disease: A propos of 32 cases. Rev Rhum Mal Osteoartic 53:621–624 Bitar JG (1970) Unconjugated hyperbilirubinemia (Gilbert’s syndrome). J Med Liban 23:485–489 Bitar JG, Idriss H (1969) Cystic fibrosis of the pancreas. J Med Liban 22:181–185 Bitar JG, Lightwood R (1967) The Wiskott-Aldrich syndrome associated with mucoviscidosis in the same patient. J Pediatr 71:123–126 Bitar JG, Takla R (1971) Hepatic glycogenoses. J Med Liban 24:483–490 Bitar J, Khalife´ R, Matta C, Najjar S, Tawil H (1969) Ataxia telangiectasia. J Med Liban 22:187–190 Bitar JG, Salem AA, Nasr AT (1970) Celiac disease in the Middle East. J Med Liban 23: 423–444 Blibech R, Mrad H, Kastally R, Brissart MA, Potron G, Arous N, Riou J, Blouquit Y, Bardakdjian J, Lacombe C, Rosa J, Galacteros F (1986) Hemoglobin Beirut (alpha 2 beta 2 (126) val-to-ala) in an Algerian family. Hemoglobin 10:651–654 Bonafede RP, Beighton P (1978) The Dyggve–Melchior–Clausen syndrome in adult siblings. Clin Genet 14:24–30 Boustany RM, Tanaka A, Nishimoto J, Suzuki K (1991) Genetic cause of a juvenile form of Tay–Sachs disease in a Lebanese child. Ann Neurol 29:104–107 Brenner B, Sańchez-Vega B, Wu S-M, Lanir N, Stafford DW, Solera J (1998) A missense mutation in g-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors. Blood 12:4554–4559 Brook CG, Wagner H, Zachmann M, Prader A, Armendares S, Frenk S, Aleman P, Najjar SS, Slim MS, Genton N, Bozie C (1973) Familial occurrence of persistent M€ ullerian structures in otherwise normal males. Br Med J 1:771–773 Buresi C, Ghanem N, Huck S, Lefranc G, Lefranc M-P (1989) Exon duplication and triplication in the human T-cell receptor gamma constant region genes and RFLP in French, Lebanese, Tunisian, and Black African populations. Immunogenetics 29:161–172 Cabannes R, Taleb N, Ghorra F, Schmitt-Beurrier A (1965): Etudes des types he´moglobiniques dans la population du Liban. Nouv Rev Fr Hematol 5:851–856

428

V.M. Der Kaloustian

Chaib H, Place C, Salem N, Chardenoux S, Vincent C, Weissenbach J, El-Zir E, Loiselet J, Petit C (1996) A gene responsible for a sensorineural nonsyndromic recessive deafness maps to chromosome 2p22-23. Hum Mol Genet 5:155–158 Chehab FF, Khouri FP, Deeb SS (1984) Globin synthetic ratios in homozygous beta-thalassemia patients from Lebanon. Hemoglobin 8:151–162 Chehab FF, Der Kaloustian V, Khouri FP, Deeb SS, Kan YW (1987) The molecular basis of betathalassemia in Lebanon: application to prenatal diagnosis. Blood 69:1141–1145 Choueiri RN, Fayad MN, Farah A, Mikati MA (2001) Classification of epilepsy syndromes and role of genetic factors. Pediatr Neurol 24:37–43 Chu ET, Rosenwasser LJ, Dinarello CA, Rosen FS, Geha RS (1984) Immunodeficiency with defective T-cell response to interleuken 1. Proc Natl Acad Sci USA 81:4945–4949 Courbage Y, Fargues P (1973) La situation de´mographique au Liban. Publications de l’Universite´ Libanaise, Beyrouth Dabbous IA, Firzli SS (1968) Sickle cell anemia in Lebanon. Its predominance in Mahommedans. Z Morphol Anthropol 59:225–231 Dagoneau N, Benoist-Lasselin C, Huber C, Faivre L, Me´garbane´ A, Alswaid A, Dolfus H, Alembik Y, Munnich A, Legeai-Mallet L, Cormier-Daire V (2004) ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am J Hum Genet 75:801–806 Darwish M, Armenian HK (1987) A case-control study of rheumatoid arthritis in Lebanon. Int J Epidemiol 16:420–424 DeAngelis MM, McGee TL, Keats BJB, Slim R, Berson EL, Dryja TP (2001) Two families from New England with Usher syndrome type 1C with distinct haplotypes. Am J Ophthalmol 131:355–358 De Laurenzi V, Rogers GR, Hamrock DJ, Marekov LN, Teinert PM, Compton JG, Markova N, Rizzo WB (1996) Sjo¨gren–Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nat Genet 12:52–57 De Meeus A, Stephan E, Debrus S, Jean M-K, Loiselet J, Weissenbach J, Demaille J, Bouvagnet P (1995) An isolated cardiac conduction disease maps to chromosome 19q. Circ Res 77:735–740 De Moerloose P, Germanos-Haddad M, Boehlen F, Neerman-Arbez M (2004) Severe factor XI deficiency in a Lebanese family: identification of a novel missense mutation (Trp501Cys) in the catalytic domain. Blood Coagul Fibrinolysis 15:269–272 De Sandre-Giovannoli A, Chaouch M, Boccaccio I, Bernard R, Delague V, Grid D, Vallat JM, Le´vy N, Me´garbane´ A (2003) Phenotypic and genetic exploration of severe demyelinating and secondary axonal neuropathies resulting from GDAP1 nonsense and spicing mutations. J Med Genet 40:e87 De Sandre-Giovannoli A, Delague V, Hamadouche T, Chaouch M, Krahn M, Boccaccio I, Maisonobe T, Chouery E, Jabbour R, Atweh S, Grid D, Me´garbane´ A, Le´vy N (2005) Homozygosity mapping of autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy (CMT4H) to a novel locus on chromosome 12p11.21-q13.11. J Med Genet 42:260–265 De Vaumas E (1954) Le Liban, Etude de Geógraphie Physique. Firmin-Didot, Paris De Vaumas E (1955) La re´partition confessionnelle au Liban et l’e´quilibre de l’Etat Libanais. Rev Geógr Alp 42:511–603 Deeb Z, Frayha RA (1976) Multiple vacuum discs: an early sign of ochronosis. Radiologic findings in two brothers. J Rheumatol 3:82–87 Delague V, Bareil C, Tuffery S, Bouvargnet P, Chouery E, Koussa S, Maisonobe T, Loiselet J, Me´garbane´ A (2000a): Mapping of a new locus for autosomal recessive demyelinating Charcot-Marie-Tooth disease to 19q13.1-13.3 in a large consanguineous Lebanese family: exclusion of MAG as a candidate gene. Am J Hum Genet 67:236–243 Delague V, Souraty N, Khallouf E, Tardy V, Chouery E, Halaby G, Loiselet J, Morel Y, Me´garbane´ A (2000b) Mutational analysis in Lebanese patients with congenital adrenal hyperplasia due to a deficit in 21-hydroxylase. Horm Res 53:77–82

13


429

Delague V, Bareil C, Bouvagnet P, Salem N, Chouery E, Loiselet J, Me´garbane´ A, Claustres M (2001): Nonprogressive autosomal recessive ataxia maps to chromosome 9q34-9qter in a large consanguineous Lebanese family. Ann Neurol 50:250–253 Delague V, Bareil C, Bouvagnet P, Salem N, Chouery E, Loiselet J, Me´garbane´ A (2002): A new autosomal recessive non-progressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities (CAMOS) maps to chromosome 15q24q26 in a large consanguineous Lebanese Druze family. Neurogenetics 4:23–27 Delague V, Jacquier A, Hamadouche T, Poitelon Y, Baudot C, Boccaccio I, Chouery E, Chaouch M, Kassouri N, Jabbour R, Grid D, Me´garbane´ A, Haase G, Le´vy N (2007) Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive CharcotMarie-Tooth type 4H. Am J Hum Genet 81:1–16 Denoyelle F, Weil D, Maw MA, Wilcox SA, Lench NJ, Allen-Powell DR, Osborn AH, Dahl H-HM, Middleton A, Houseman MJ, Dode´ C, Marlin S, Boulila-ElGaed A, Grati M, Ayadi H, BenArab S, Bitoun P, Lina-Granade G, Godet J, Mustapha M, Loiselet J, El-Zir E´, Aubois A, Joannard A, Levilliers J, Garabe´dian E´-N, Mueller RF, McKinlay Gardner RJ, Petit C (1997) Prelingual deafness: high prevalence of a 30delG mutation in the connexion 26 gene. Hum Mol Genet 12:2173–2177 Der Kaloustian VM, Baghdassarian SA (1972) The autosomal recessive variety of congenital stationary night-blindness with myopia. J Med Genet 9:67–69 Der Kaloustian VM, Mnaymneh WA (1973) Bilateral tibial aplasia with lobster-claw hands. A rare genetic entity. Acta Paediatr Scand 62:77–78 Der Kaloustian VM, Musallam SS (1975) Treatment of acrodermatitis enteropathica with oral zinc sulfate. Letter to the editor. Pediatrics 55:744 Der Kaloustian VM, Kronfol NM, Takla R, Habash A, Khazin A (1971) Leprechaunism. Am J Dis Child 122:442–445 Der Kaloustian VM, Afifi AK, Sinno AA, Mire J (1972a) The Rubinstein–Taybi syndrome. Am J Dis Child 124:897–902 Der Kaloustian VM, Sinno AA, Nassar SI (1972b) Acrocephalopolysyndactyly, type II (Carpenter’s syndrome). Am J Dis Child 124:716–718 Der Kaloustian VM, De Weerd-Kastelein EA, Kleijer WJ, Keijzer W, Bootsma D (1974a) The genetic defect in the De Sanctis–Cacchione syndrome. J Invest Dermatol 63:392–396 Der Kaloustian VM, Slim MS, Mishalany HG (1974b) Familial congenital duodenal atresia. Pediatrics 54:118 Der Kaloustian VM, Musallam SS, Sanjad SA, Murib A, Hammad WD, Idriss ZH (1976) Oral treatment of acrodermatitis enteropathica with zinc sulfate. Am J Dis Child 130: 421–423 Der Kaloustian VM, Naffah J, Loiselet J (1980) Genetic diseases in Lebanon. Am J Med Genet 7:187–203 Der Kaloustian VM, Khoury MJ, Hallal R, Idriss ZH, Deeb ME, Wakid NW, Haddad FS (1981) Sandhoff disease: a prevalent form of infantile Gm2 gangliosidosis in Lebanon. Am J Hum Genet 33:85–89 Der Kaloustian VM, Freij BJ, Kurban AK (1982) Prolidase deficiency: an inborn error of metabolism with major dermatological manifestations. Dermatologica 164:293–304 Der Kaloustian VM, Jarudi NI, Khoury MJ, Afifi AK, Bahuth NB, Deeb ME, Shammas J, Mikati MA (1985a) Familial spinocerebellar degeneration with corneal dystrophy. Am J Med Genet 20:325–339 Der Kaloustian VM, Ratl H, Malouf J, Hatem J, Slim M, Tomeh A, Khouri J, Kutayli F (1985b) Tetralogy of fallot with pulmonary atresia in siblings. Am J Med Genet 21:119–122 Der Kaloustian VM, Khudr A, Firzli S, Dabbous I (1987a) Psychosocial and economic profile of a sample of families with thalassemic children in Lebanon. J Med Genet 24:772–777 Der Kaloustian VM, Masri R, Khudr A, Talj F, Libbus B, Nabulsi M, Khouri FP (1987b) Down syndrome in two siblings with 47, XY,+21 and 46, XY/46, XY,-21,+t(21q;21q). Hum Genet 75:97

430

V.M. Der Kaloustian

Desgeorges M, Me´garbane´ A, Guittard C, Carles S, Loiselet J, Damaille J, Claustres M (1997) Cystic fibrosis in Lebanon: distribution of CFTR mutations among Arab communities. Hum Genet 100:279–283 Dhaini HR, Levy GN (2000) Arylamine N-acetyltransferase 1 (NAT1) genotypes in a Lebanese population. Pharmacogenet Genomics 10:79–83 Drousiotou A, Stylianidou G, Anastasiadou V, Christopoulos G, Mavrikiou E, Georgiou T, Kalakoutis G, Oladimeji A, Hara Y, Suzuki K, Furihata K, Ueno I, Ioannou PA, Fensom AH (2000) Sandhoff disease in Cyprus: population screening by biochemical and DNA analysis indicates a high frequency of carriers in the Maronite community. Hum Genet 107:12–17 Dudin G, Alexander D, Talj F, Deeb M, Musallam S, Der Kaloustian VM (1984a) Interstitial deletion of band q12 of chromosome 5. Clin Genet 25:455–456 Dudin G, Traboulsi E, Khouri F, Der Kaloustian VM (1984b) Hereditary retinoblastoma and 13qmosaicism. Cytogenet Cell Genet 38:235–237 El Ghouzzi V, Dagoneau N, Kinning E, Thauvin-Robinet C, Chemaitilly W, Prost-Squarcioni C, Al-Gazali LI, Verloes A, Le Merrer M, Munnich A, Trembath RC, Cormier-Daire V (2003) Mutations in a novel gene Dymeclin (FLJ20071) are responsible for Dyggve–Melchior– Clausen syndrome. Hum Mol Genet 12:357–364 Eldahdah LT, Ormond KE, Nassar AH, Khalil T, Zahed LF (2007) Outcome of chromosomally abnormal pregnancies in Lebanon: obstetricians’ roles during and after prenatal diagnosis. Prenat Diagn 27:525–534 El-Rassy I, Bou-Abdallah J, Al-Ghadban S, Bitar F, Nemer G (2008) Absence of NOTCH2 and Hey2 mutations in a familial Alagille syndrome case with a novel frameshift mutation in JAG1. Am J Med Genet 146A:937–939 El-Zahabi LM, Makarem J, Habbal Z, Otrock ZK, Taher A, Shamseddine A (2007) Gaucher disease: different clinical manifestations associated with a rare muttion (R48W) in a Lebanese family. Mol Genet Metab 91:402–404 Epstein PA, Kidd DD (1981) Dermo-distortive urticaria: an autosomal dominant dermatologic disorder. Am J Med Genet 9:307–315 Fadhil M, Ghabra TA, Deeb M, Der Kaloustian VM (1983): Odontoonychodermal dysplasia: a previously apparently undescribed ectodermal dysplasia. Am J Med Genet 26:123–131 Faivre L, Me´garbane´ A, Alswaid A, Zylberberg L, Aldohayan N, Campos-Xavier AB, Bacq D, Legeai-Maller L, Bonaventure J, Munnich A, Cormier-Daire V (2002) Homozygosity mapping of a Weill–Marchesani syndrome locus to chromosome 19p13.3-p11.2. Hum Genet 110: 366–370 Fares F, Ran SA, David M, Zelnik N, Hecht Y, Khairaldeen H, Lerner A (2004) Identification of two mutations for ataxia telangiectasia amon the Druze community. Pren Diagn 24:358–362 Farra C, Medawar R, Mroueh S, Souaid M, Cabet F, Awwad J (2008) Cystic fibrosis: a new mutation in the Lebanese population. J Cyst Fibros 7:429–432 Fayad MN, Yacoub A, Salman S, Khudr A, Der Kaloustian VM (1987) Juvenile hyaline fibromatosis: two new patients and review of the literature. Am J Med Genet 26:123–131 Figueiredo MS, Dos Santos JE, Alberto FL, Zago MA (1992): High frequency of the Lebanese allele of the LDLr gene among Brazilian patients with familial hypercholesterolemia. J Med Genet 29:813–815 Fischel-Ghodsian N, Bu X, Oztas S, Prezant TR, Danon Y, Shohat T, Rotter JI, Shohat M (1992) The gene for familial Mediterranean fever maps to the short arm of chromosome 16 in both Armenians and non-Ashkenazi Jews. Am J Hum Genet 41(Suppl):A187 Frayha R, Nasr F (1971) Juvenile ankylosing spondylitis. J Med Liban 24:401–409 Frayha RA, Nassar VH, Dagher F, Salti IS (1972) Familial parathyroid carcinoma. J Med Liban 25:299–309 Frayha RA, Salti IS, Abu Haidar GI, Al-Khalidi U, Hemady K (1973) Hereditary xanthinuria and xanthine urolithiasis: an additional 3 cases. J Urol 109:871–873 Frayha RA, Salti IS, Arnaout A, Khachadurian A, Uthman SM (1977) Hereditary xanthinuria. Report of three patients and short review of the literature. Nephron 19:328–332

13


431

Frayha R, Melhem R, Idriss H (1979) The Kniest (swiss cheese cartilage) syndrome. Description of a distinct arthropathy. Arthritis Rheum 22:286–289 Fregin A, Rost S, Wolz W, Krebsova A, Muller CR, Oldenburg J (2002) Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16. Blood 100:3229–3232 Freij BJ, Der Kaloustian VM (1986) Prolidase deficiency. A metabolic disorder presenting with dermatologic signs. Int J Dermatol 25:431–433 Freij BJ, Levy HL, Dudin G, Mutasim D, Deeb M, Der Kaloustian VM (1984) Clinical and biochemical characteristics of prolidase deficiency in siblings. Am J Med Genet 19:561–571 Fried K, Vure E (1974) A lethal autosomal recessive entero-colitis of early infancy. Clin Genet 6:195–196 Fryns J-P, Hofkens G, Fabry G, Van Den Berghe H (1988) Isolated mesomelic shortening of the forearm in father and daughter: a new entity in the group of mesomelic dysplasias. Clin Genet 33:57–59 Fukushima K, Ramesh A, Srisailapathy CRS, Ni L, Wayne S, O’Neill ME, Van Camp G, Coucke P, Jain P, Wilcox ER, Smith SD, Kenyon JB, Zbar RIS, Smith RJH (1995) An autosomal recessive nonsyndromic form of sensorineural hearing loss maps to 3p – DFNB6. Genome Res 5:305–308 Fuleihan DS, Der Kaloustian VM, Najjar SS (1971) The Russell–Silver syndrome. Report of three siblings. J Pediatr 78:654–657 Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S, Bertolini S, Cossu F, Grishin N, Barnes R, Cohen JC, Hobbs HH (2001) Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 292:1394–1398 Ghanem N, Dariavach P, Bensama M, Chibani J, Lefranc G, Lefranc MP (1988) Polymorphism of immunoglobulin lambda constant region genes in populations from France, Lebanon and Tunisia. Exp Clin Immunogenet 5:186–195 Ghayad E, Tohme A (1995) Behçet disease in Lebanon. J Med Liban 43:2–7 Haddad R, Uwaydat S, Dakroub R, Traboulsi EI (2001) Confirmation of the autosomal recessive syndrome of ectopia lentis and distinctive craniofacial appearance. Am J Med Genet 99:185–189 Hajjar ET, Vincenti F, Salti IS (1974) Gluten-induced enteropathy. Osteomalacia as its principal manifestation. Arch Intern Med 134:565–566 Hara Y, Ioannou P, Drousiotou A, Stylianidou G, Anastasiadou V, Suzuki K (1994) Mutation analysis of a Sandhoff disease patient in the Maronite community in Cyprus. Hum Genet 94:136–140 Harboyan G, Mamo J, Der Kaloustian V, Karam F (1971) Congenital corneal dystrophy with progressive sensorineural hearing loss. Arch Ophthalmol 85:27–32 Harfouche JK (1965) Social structure of low income families in Lebanon. Khayat’s, Beirut, p 41 Hechtman P, Boulay B, Bayleran J, Andermann E (1989) The mutation mechanism causing juvenile-onset Tay-Sachs disease among Lebanese. Clin Genet 35:364–375 Hennies HC, Rauch A, Seifert W, Schumi C, Moser E, Al-Talj E, Tariverdian G, Chrzanowska KH, Krajewska-Walasek M, Rajab A, Giugliani R, Neumann TE, Eckl KM, Karbasiyan M, Reis A, Horn D (2004) Allelic heterogeneity in the COH1 gene explains clinical variability in Cohen syndrome. Am J Hum Genet 75:138–145 Herman RH, Overhold EL, Hagler L (1969) Familial life-long persistent fever of unknown origin responding to dexamethasone and uronic acids. Am J Med 46:142–153 Hirbli KI, Aboujaoude´ JH, Ghorra FS, Barakat-el-Khoury WM (1990) Pre´valence et incidence du diabe`te sucre´ au Liban. Diabe`te Me´tab 16:479–483 Hitti PK (1967) Lebanon in history – from the earliest times to the present, 3rd edn. McMillan, London Hochberg Z, Chayen R, Reiss N, Falik Z, Makler A, Munichor M, Farkas A, Goldfarb H, Ohana N, Hiort O (1996) Clinical, biochemical, and genetic findings in a large pedigree of male and female patients with 5a-reductase 2 deficiency. J Clin Endocrinol Metab 81:2821–2827 Idriss ZH, Der Kaloustian VM (1973) Acrodermatitis enteropathica. Clin Pediatr 12:393–395

432

V.M. Der Kaloustian

Idriss ZH, Najjar SS, Der Kaloustian VM, Shammaa M (1975) Congenital erythropoietic porphyria. Am J Dis Child 129:701–702 Inati A, Taher A, Bou Alawi W, Koussa S, Kaspar H, Shbaklo ZPA (2003) b-globin gene cluster haplotypes and HbF levels are not the only modulators of sickle cell disease in Lebanon. Eur J Haematol 70:79–83 Irani-Hakime N, Tamim H, Kreidy R, Almawi WY (2000) The prevalence of factor V R506Q mutation-Leiden among apparently healthy Lebanese. Am J Hematol 65:45–49 Jaatoul NY, Haddad NE, Khoury LA, Afifi AK, Bahuth NB, Deeb ME, Mikati MA, Der Kaloustian VM (1982) The Marden–Walker syndrome. Am J Med Genet 11:259–271 Jalkh N, Geńin E, Chouery E, Delague V, Medlej-Hashim M, Idrac C-A, Me´garbane´ A, Serre J-L (2008) Familial Mediterranean fever in Lebanon: founder effects for different MEFV mutations. Ann Hum Genet 73:41–47 Jeck N, Reinalter SC, Henne T, Marg W, Mallmann R, Pasel K, Vollmer M, Klaus G, Leonhardt A, Seyberth HW, Konrad M (2001) Hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness. Pediatrics 108:e5 Khachadurian AK (1962) Essential pentosuria. Am J Hum Genet 14:249–255 Khachadurian AK (1963) Nonalimentary fructosuria. Pediatrics 32:455–457 Khachadurian AK (1964) The inheritance of essential familial hypercholesterolemia. Am J Med 37:402–407 Khachadurian AK (1968) Migratory polyarthritis in familial hypercholesterolemia (type II hyperlipoproteinemia). Arthritis Rheum 11:385–393 Khachadurian AK (1972) A general review of clinical and laboratory features of familial hypercholesterolemia (type II hyperbetalipoproteinemia). In: Proceedings of the 19th Colloqium. Peeters protides of the biological fluids. Pergamon Press, 1971 Khachadurian A, Abu Feisal K (1958) Alkaptonuria. Report of a family with severe cases in four successive generations, with metabolic studies in one patient. J Chronic Dis 7:455–465 Khachadurian AK, Armenian HK (1974) Familial paroxysmal polyserositis (familial Meditrerranean fever). Incidence of amyloidosis and mode of inheritance. Birth Defects Orig Artic Ser 10 (4):62–66 Khachadurian AK, Khachadurian LA (1964) The inheritance of renal glycosuria. Am J Hum Genet 16:189–194 Khachadurian AK, Somerville I (1965) Diabetes mellitus in Lebanon. A retrospective clinical study of 560 patients. J Chronic Dis 18:1309–1315 Khachadurian AK, Sutherland JV (1975) Affective psychoses in Lebanon. J Med Liban 28:159–167 Khachadurian AK, Uthman SM (1973) Experience with homozygous cases of familial hypercholesterolemia. A report of 52 patients. Nutr Metab 15:132–140 Khachadurian AK, Freyha R, Shamma’a MM, Baghdassarian SA (1971) A-b-lipoproteinemia and colour-blindness. Arch Dis Child 46:871–873 Khlat M (1988a) Consanguineous marriage and reproduction in Beirut, Lebanon. Am J Hum Genet 43:188–196 Khlat M (1988b) Consanguineous marriages in Beirut: time trends, spatial distribution. Soc Biol 35:324–330 Khlat M (1988c) Social correlates of consanguineous marriages in Beirut: a population-based study. Hum Biol 60:541–548 Khlat M, Halabi S (1986) Modernization and consanguineous marriage in Beirut. J Biosoc Sci 18:489–495 Khlat M, Khudr A (1984) Cousin marriages in Beirut, Lebanon. Is the pattern changing? J Biosoc Sci 16:369–373 Khlat M, Halabi S, Khudr A, Der Kaloustian VM (1986) Perception of consanguineous marriages and their genetic effects among a sample of couples from Beirut. Am J Med Genet 25:299–306 Kurban AK, Azar HA (1969) Familial continuous skin peeling. Br J Dermatol 81:191–195

13


433

Kurdi-Haidar B, Mason PJ, Bereebi A, Ankra-Badu G, Al-Ali A, Oppenheim A, Luzzatto L (1990) Origin and spread of the glucose-6-phosphate dehydrogenase variant (G6PD-Mediterranean) in the Middle East. Am J Hum Genet 47:1013–1019 Lacombe A, Lee H, Zahed L, Choucair M, Muller J-M, Nelson SF, Salameh W, Vilain E (2006) Disruption of POF1B binding to nonmuscle actin filaments is associated with premature ovarian failure. Am J Hum Genet 79:113–119 Lalouel JM, Loiselet J, Lefranc G, Chaiban D, Chakhachiro L, Rivat L, Rapartz C (1976) Genetic differentiation among Lebanese communities. Acta Anthropogenet 1:15–33 Laurier V, Stoetzel C, Muller J, Thibault C, Corbani S, Jalkh N, Salem N, Chouery E, Poch O, Licaire S, Danse JM, Amati-Bonneau P, Bonneau D, Me´garbane´ A, Mandel JL, Dolifus H (2006) Pitfalls of homozygosity mapping: an extended consanguineous Bardet–Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism. Eur J Hum Genet 11:1195–1203 Lefe`vre C, Bouadjar B, Ferrand V, Tadini E, Me´gharbane´ A, Lathrop M, Prud’homme JF, Fischer J (2006) Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3. Hum Mol Genet 15:767–776 Lefranc G, Loiselet J, Rivat L, Ropartz C (1976) Gm, Km and ISf allotypes in the Lebanese population. Acta Anthropogenet 1:34–45 Lehrman MA, Schneider WJ, Brown MS, Davis CG, Elhammer A, Russell DW, Goldstein JL (1987): The Lebanese allele at the low density lipoprotein receptor locus. Nonsense mutation produces truncated receptor that is retained in endoplasmic reticulum. J Biol Chem 262:401–410 Loiselet J, Jarjouhi L (1974) L’intole´rance au lactose chez l’adulte Libanais. J Med Liban 27:339–350 Loiselet J, Srouji G (1968): Re´partition de la cholineste´rase mutant parmi les communaute´s libanaises. Comparaison avec la re´partition d’autres ge`nes. Ann Genet 11:152–156 Loiselet J, Karayacouboglu J, Boustany N, Khouri R (1971) Les lipides sanguins chez un groupe de jeunes Libanais. J Med Liban 24:311–328 Magre´ J, Dele´pine M, Khallouf E, Gedde-Dahl T Jr, Van Maldergem L, Sobel E, Papp J, Meier M, Me´garbane´ A, BSCL Working Group, Lathrop M, Capeau J (2001) Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365–370 Mahfouz RAR, Sabbagh AS, Zahed LF, Mahfoud ZR, Kalmoni RF, Otrock ZK, Taher AT, Zaatari GS (2006) Apolipoprotein E gene polymorphism and allele frequencies in the Lebanese population. Mol Biol Rep 33:145–149 Mahfouz RAR, Sabbagh AS, Shammaa DMR, Otrock ZK, Zaatari GS, Taher AT (2008) Factor XIII gene V34L mutation in the Lebanese population: Another unique feature in this community? Mol Biol Rep 35:375–378 Majdalani E, Vassoyan J (1974) A propos d’une observation de lymphohistiocytose familiale he´mophagique. Arch Fr Pediatr 31:297–302 Makhoul NJ, Wells RS, Kaspar H, Shbaklo H, Taher A, Chakar N, Zalloua PA (2005) Genetic heterogeneity of beta thalassemia in Lebanon reflects historic and recent population migration. Ann Hum Genet 69:55–66 Malouf J, Alam S, Kanj H, Mufarrij A, Der Kaloustian VM (1985a) Hypergonadotropic hypogonadism with congestive cardiomyopathy: an autosomal recessive disorder? Am J Med Genet 20:483–489 Malouf J, Ratl H, Der Kaloustian VM (1985b) Apical hypertrophic cardiomyopathy in a father and daughter. Am J Med Genet 22:75–80 Mamo JG, Tabbara KF (1976) Homocystinuria in Lebanon. J Med Liban 24:473–482 Mansour AM, Traboulsi EI, Khawwam E, Dudin GE, Der Kaloustian VM (1984) Eye findings in interstitial deletion of band q12 of chromosome 5. Ophthalmic Paediatr Genet 4:117–119 Mansour I, Delague V, Cazeneuve C, Dode´ C, Chouery E, Pêcheur C, Medlej-Hashim M, Salem N, El Zein L, Levan-Petit I, Lefranc G, Goossens M, Delpech M, Amselem S, Loiselet J, Grateau E,

434

V.M. Der Kaloustian

Me´garbane´ A, Naman R (2001) Familial Mediterranean fever in Lebanon: mutation spectrum, evidence of cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694I mutations. Eur J Hum Genet 9:51–55 McLaren D, Zekian B (1971) Failure of enzymatic clearance of beta-carotene: the cause of vitamin A deficiency in a child. Am J Dis Child 121:278–280 Medlej R, Wasson J, Baz P, Azar S, Salti I, Loiselet J, Permutt A, Halaby G (2004) Diabetes mellitus and optic atrophy: a study of Wolfram syndrome in the Lebanese population. J Clin Endocrinol Metab 89:1656–1661 Medlej-Hashim M, Serre J-L, Corbani S, Saab O, Jalkh N, Delague V, Chouery E, Salem N, Loiselet J, Lefranc G, Me´garbane´ A (2005) Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet 48:412–420 Me´garbane´ A (2007) Osseous dysplasia with severe short stature, multiple dislocations, and delayed bone age: report on a second Lebanese patient. Am J Med Genet 143A:1782–1787 Me´garbane´ A, Ghanem I (2004) A newly recognized chondrodysplasia with multiple dislocations. Am J Med Genet 130A:107–109 Me´garbane´ A, Ghanem I (2005) Severe autosomal dominant upper-limb mesomelic dysplasia: report of a second family. Clin Genet 68:567–569 Me´garbane´ A, Sayad R (2007) Early lethal autosomal recessive enterocolitis: report of a second family. Clin Genet 71:89–90 Me´garbane´ A, Noujeim Z, Fabre M, Der Kaloustian VM (1998) New form of hidrotic ectodermal dysplasia in a Lebanese family. Am J Med Genet 75:196–199 Me´garbane´ A, Delague V, Salem N, Loiselet J (1999a) Autosomal recessive congenital cerebellar hypoplasia and short stature in a large inbred family. Am J Med Genet 87:88–90 Me´garbane´ A, Haddad FA, Haddad-Zebouni S, Achram M, Eich G, Le Merrer M, Superti-Furga A (1999b) Homozygosity for a novel DTDST mutation in a child with a ‘broad bone-platyspondylic’ variant of diastrophic dysplasia. Clin Genet 56:71–76 Me´garbane´ A, Desguerres L, Rizkallah E, Delague V, Nabbut R, Barois A, Urtizberea A (2000) Brown-Vialetto-Van Laere syndrome in a large inbred Lebanese family. Am J Med Genet 92:117–121 Me´garbane´ A, Delague V, Ruchoux MM, Rizkallah E, Maurage CA, Viollet L, Rouaix-Emery N, Urtizberea A (2001a) New autosomal recessive cerebellar ataxia disorder in a large inbred Lebanese family. Am J Med Genet 101:135–141 Me´garbane´ A, Ruchoux MM, Loeys B, Ayoub N, Nuytinck L (2001b) Short stature, abnormal face, joint laxity, dislocation, hernias, delayed bone age, and severe psychomotor retardation in two brothers: previously undescribed MCA/MR syndrome. Am J Med Genet 104: 221–224 Me´garbane´ A, Waked N, Chouery E, Moglabey YB, Saliba N, Mornet E, Serre JL, Slim R (2001c) Microcephaly, cutis verticis gyrata of the scalp, retinitis pigmentosa, cataracts, sensorineural deafness, and mental retardation in two brothers. Am J Med Genet 98:244–249 Me´garbane´ A, Gannage´-Yared MH, Khalife´ AA, Fabre M (2003a) Primary hypergonadotropic hypogonadism, partial alopecia, and m€ ullerian hypoplasia: report of a second family with additional findings. Am J Med Genet 119A:214–217 Me´garbane´ A, Ghanem I, Le Merrer M (2003b) Spondyloepimetaphyseal dysplasia with multiple dislocations, leptodactylic type: report of a new patient and review of the literature. Am J Med Genet 122A:252–256 Me´garbane´ A, Rassi S, Chouery E, Delague V, de Nanclares P, Leal G, Tabet M, Castano L, Loiselet J (2003c) A new dominant branchiogenic-deafness syndrome with internal auditory canal hypoplasia and abnormal extremities. Am J Med Genet 120A:276–282 Me´garbane´ H, Haddad M, Delague V, Renoux J, Boehm N, Me´garbane´ A (2004) Further delineation of the odonto-onycho-dermal dysplasia syndrome. Am J Med Genet 129A:193–197

13


435

Me´garbane´ A, Chouery E, Ghanem I (2008a) A multiplex family with possible metaphyseal Spahr-type dysplasia and exclusion of RMRP and COL10A1 as candidate genes. Am J Med Genet 146A:1865–1870 Me´garbane´ A, Dagher R, Melki I (2008b) Sib pair with previously unreported skeletal dysplasia. Am J Med Genet 146A:2916–2919 Me´garbane´ H, Cluzeau C, Bodemer C, Freitag S, Chalabi-Atallah M, Me´garbane´ A, Smahi A (2008c) Unusual presentation of a severe autosomal recessive anhydrotic ectodermal dysplasia with a novel mutation in the EDAR gene. Am J Med Genet 146A:2657–2662 Me´garbane´ A, Slim R, N€ urnberg G, Ebermann I, N€ urnberg P, Bolz HJ (2009) A novel VPS13B mutation in two brothers with Cohen syndrome, cutis verticis gyrate and sensorineural deafness. Eur J Hum Genet 17(8):1076–1079 Mikaelian DO, Der Kaloustian VM, Shahin NA, Barsoumian VM (1970) Congenital ectodermal dysplasia with hearing loss. Arch Otolaryngol 92:85–89 Mikati MA, Melhem RE, Najjar SS (1981) The syndrome of hyperostosis and hyperphosphatemia. J Pediatr 99:900–904 Mikati MA, Dudin G, Der Kaloustian VM, Benson PF, Fensom AH (1982) Maple syrup urine disease with increased intracranial pressure. Am J Dis Child 136:642–643 Mikati MA, Barakat AY, Sulh HB, Der Kaloustian VM (1984) Renal tubular insufficiency, cholestatic jaundice, and multiple congenital anomalies – a new multisystem syndrome. Helvet Paediatr Acta 39:463–471 Mikati MA, Najjar SS, Sahli IF, Melhem RE, Mansour S, Der Kaloustian VM (1985) Microcephaly, hypergonadotrophic hypogonadism, short stature, and minor anomalies: a new syndrome. Am J Med Genet 22:599–608 Mishalany HG, Der Kaloustian VM (1971) Familial multiple level intestinal atresia: report of two siblings. J Pediatr 79:124–125 Mishalany HG, Najjar FB (1968) Famillial jejunal atresia. Three cases in one family. J Pediatr 73:753–755 Mishalany HG, Der Kaloustian VM, Ghandour MH (1970) Familial congenital duodenal atresia. Pediatrics 46:629–634 Mishalany HG, Idriss ZH, Der Kaloustian VM (1978) Pyloroduodenal atresia (diaphragm type): an autosomal recessive disease. Pediatrics 62:419–420 Mitchell GA, Brody LC, Looney J, Steel G, Suchanek M, Dowling C, Der Kaloustian V, Kaiser-Kupfer M, Valle D (1988) An initiator codon mutation in ornithine-d-aminotransferase causing gyrate atrophy. J Clin Invest 81:630–633 Mossman J, Patrick AD, Fensom AH, Tansley LR, Benson PF, Der Kaloustian VM, Dudin G (1981) Correct prenatal diagnosis of a Hurler fetus where amniotic fluid cell cultures were of maternal origin. Prenat Diagn 1:121–124 Mossman J, Young EP, Patrick AD, Fensom AH, Ellis M, Benson PF, Der Kaloustian VM (1983) Prenatal tests for Sanfilippo disease type B in four pregnancies. Prenat Diagn 3:347–350 Mudawwar F, Geha R (1975) Severe combined immunodeficiency in Lebanon. J Med Liban 28:467–476 Mumtaz G, Tamim H, Kanaan M, Khawaja M, Khogali M, Wakim G, Yunis K (2007) Effect of consanguinity on birth weight for gestational age in a developing country. Am J Epidemiol 165:742–752 Mustapha M, Chardenoux S, Nieder A, Salem N, Weissenbach J, El-Zir E, Loiselet J, Petit C (1998) A sensorineural progressive autosomal recessive form of isolated deafness, DFNB13, maps to chromosome 7q34-q36. Eur J Hum Genet 6:245–250 Mustapha M, Well D, Chardenoux S, Elias S, El-Zir E, Beckmann JS, Loiselet J, Petit C (1999) An a-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21. Hum Mol Genet 8:409–412 Mustapha M, Salem N, Delague V, Chouery E, Ghassibeh M, Rai M, Loiselet J, Petit C, Me´garbane´ A (2001) Autosomal recessive non-syndromic hearing loss in the Lebanese

436

V.M. Der Kaloustian

population: prevalence of the 30delG mutation and report of two novel mutations in the connexion 26 (GJB2) gene. J Med Genet 38(10):E36 Nabulsi MM, Tamim H, Sabbagh M, Obeid MY, Yunis KA, Bitar FF (2003) Parental consanguinity and congenital heart malformations in a developing country. Am J Med Genet 116A:342–347 Naffah J (1973) Rubinstein–Taybi syndrome with ring E chromosome. Abstract, 4th International Conference on Birth Defects, Vienna Naffah J (1974) Dermatoglyphics and flexion creases in the Lebanese population. Am J Phys Anthropol 41:391–409 Naffah J (1976) The Dyggve–Melchior–Clausen syndrome. Am J Hum Genet 28:607–614 Naffah J, Der Kaloustian VM (1975): Un remaniement complexe inte´ressant les chromosomes 3 et 5 chez un enfant polymalforme´. Ann Geńe´t 18:121–124 Naffah J, Taleb N (1974) Deux nouveaux cas de syndrome Dyggve-Melchior-Clausen avec hyperplasie de l’apophyse odontoı¨de et compression spinale. Arch Fr Pe´diatr 31:985–992 Naffah J, Ghosn G, Gharios N (1972) A propos de trois nouveaux cas dans une meˆme fratrie du syndrome de Meckel ou dysence´phalie splanchnokystique de Gr€ uber. Arch Fr Pe´diatr 23:109–1081 Naffah J, Bitar E, Nasr W, Khoury K (1975) Etude geńe´tique de la polyse´rite paroxystique familiale – 72 cas. Nouv Presse Me´d 4:1031–1033 Najjar S (1963) Pendred’s syndrome in two families living in an endemic goiter area. Br Med J 5348:31–33 Najjar SS (1964) Hypothyroidism in children from an endemic goiter area. J Pediatr 64:372–380 Najjar SS, Jarrah A (1964) Pigmentation in Addison’s disease. Am J Dis Child 107:198–201 Najjar SS, Mahmud J (1968) Diabetes insipidus and diabetes mellitus. J Pediatr 73:251–253 Najjar SS, Nachman HS (1965) The Kocher-Debre´-Se´me´laigne syndrome:hypothyroidism with muscular “hypertrophy. J Pediatr 66:901–908 Najjar SS, Yunoszai K, Der Kaloustian VM (1963) Hypothyroidism in children. A review of 47 cases. J Med Liban 16:181–186 Najjar SS, Farah FS, Kurban AK (1968) Tumoral calcinosis and pseudoxanthoma elasticum. J Pediatr 72:243–247 Najjar SS, Der Kaloustian VM, Nassif SI (1970) Genital anomaly, mental retardation, and cardiomyopathy: a new syndrome? J Pediatr 83:286–288 Najjar SS, Takla RJ, Nassar VH (1974) The syndrome of rudimentary testes: occurrence in five siblings. J Pediatr 84:119–122 Najjar SS, Salem GM, Idriss ZH (1975) Congenital generalized lipodystrophy. Acta Paediatr Scand 64:273–279 Najjar SS, Der Kaloustian VM, Ardati KO (1984) Genital anomaly and cardiomyopathy: a new syndrome. Clin Genet 26:371–373 Najjar SS, Saikaly MG, Zaytoun GM, Abdelnoor A (1985) Association of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. The Wolfram or DIDMOAD syndrome. Arch Dis Child 60:823–828 Neumann LM, El Ghouzzi V, Paupe V, Weber H-P, Fastnacht E, Leenen A, Lyding S, Klusmann A, Mayatepek E, Pelz J, Cormier-Daire V (2006) Dyggve–Melchior–Clausen syndrome and Smith–McCort dysplasia: clinical and molecular findings in three families supporting genetic heterogeneity in Smith–McCort dysplasia. Am J Med Genet 140A:421–426 Newton FH, Rosenberg RN, Lampert PW, O’Brien JS (1971) Neurological involvement in Urback–Wiethe’s disease (lipoid proteinosis): a clinical, ultrastructural, and chemical study. Neurology 21:1205–1213 Nezarati MM, Loeffler J, Yoon G, MacLaren L, Fung E, Snyder F, Utermann G, Graham GE (2002) Novel mutation in the D-sterol reductase gene in three Lebanese sibs with Smith–Lemli–Opitz (RSH) syndrome. Am J Med Genet 110:103–108 Oldenburg J, von Brederlow B, Fregin A, Rost S, Wolz W, Eberl W, Eber S, Lenz E, Schwaab R, Brackmann HH, Effenberger W, Harbrecht U, Schurgers LJ, Vermeer C, M€ uller CR (2000)

13


437

Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex. Thromb Haemost 84:937–941 Oppenheim A, Friedlander Y, Dann EJ, Berkman N, Pressman Schwartz S, Leitersdorf E (1991) Hypercholesterolemia in five Israeli Christian-Arab kindreds is caused by the “Lebanese” allele at the low density lipoprotein receptor gene locus and by an additional independent major factor. Hum Genet 88:75–84 Parkman R, Rappeport J, Geha R, Belli J, Cassady R, Levey R, Nathan DG, Rosen FS (1978) Complete correction of the Wiskott–Aldrich syndrome by allogenic bone marrow transplantation. N Engl J Med 298:921–926 Paupe V, Gilbert T, Le Merrer M, Munnich A, Cormier-Daire V, El Ghouzzi V (2004) Recent advances in Dyggve–Melchior–Clausen syndrome. Mol Genet Metab 83:1–59 Paw BH, Moskowitz SM, Uhrhammer N, Wright N, Kaback MM, Neufeld EF (1990) Juvenile Gm2 gangliosidosis caused by substitution of histidine for arginine at position 499 or 504 of the a-subunit of b-hexosaminidase. J Biol Chem 265:9452–9457 Pipkin AC, Pipkin SB (1950) A pedigree of generalized lentigo. J Hered 4:79–82 Pras E, Aksentijevitch I, Gruberg L, Below JE Jr, Prosen L, Dean M, Steinberg AD, Pras M, Kastner DL (1992) Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med 326(23):1509–1513 Qatanani M, Taher A, Koussa S, Naaman R, Fisher C, Rugless M, Old J, Zahed L (2000) b-thalassaemia intermedia in Lebanon. Eur J Haematol 64:237–244 Reimann HA, Moadie´ J, Semerjian S, Sahyoun PF (1954) Periodic peritonitis – heredity and pathology. Report of seventy-two cases. J Am Med Assoc 154:1254–1259 Rivie`re J-B, Verlaan DJ, Shekarabi M, Lafrenie`re RG, Beńard M, Der Kaloustian VM, Shbaklo Z, Rouleau GA (2004) A mutation in the HSN2 gene causes sensory neuropathy type II in a Lebanese family. Ann Neurol 56:572–575 Ro¨ssler J, Breitenstein S, Havers W (2003) Late onset of Imerslund–Gr€asbeck syndrome without proteinuria in four children of one family from the Lebanon. Eur J Pediatr 162:808–809 Rutland J, de Longh RV (1990) Random ciliary orientation: a cause of respiratory tract disease. N Engl J Med 323:1681–1684 Saab YB, Gard PR, Overall AD (2007) The geographic distribution of the ACE II genotype: a novel finding. Genet Res 89:259–267 Sabbagh AS, Daher RT, Otrock ZK, Abdel Khalek RN, Zaatari GS, Mahfouz RA (2007a) ApoB-100 R3500Q mutation in the Lebanese population: prevalence and historical review of the literature. Mol Biol Rep 34:267–270 Sabbagh AS, Otrock ZK, Mahfoud ZR, Zaatari GS, Mahfouz RAR (2007b) Angiotensin-converting enzyme gene polymorphism and allele frequencies in the Lebanese population: prevalence and review of the literature. Mol Biol Rep 34:47–52 Sabbagh AS, Taher AT, Zaatari GS, Mahfouz RAR (2007c) Gene frequencies of the HPA-1 platelet antigen alleles in the Lebanese population. Transfus Med 17:473–478 Sabbagh AS, Ghasham M, Abdel Khalek R, Greije L, Shammaa DMR, Zaatari GS, Mahfouz RA (2008a) MEFV gene mutations spectrum among Lebanese patients referred for Familial Mediterranean Fever work-up: experience of a major tertiary care center. Mol Biol Rep 35:447–451 Sabbagh AS, Mahfoud Z, Taher A, Zaatari G, Daher R, Mahfouz RA (2008b) High prevalence of MTHFR gene A1298C polymorphism in Lebanon. Genet Test 12:75–80 Salam M (1963) Phenylketonuria in a child from the Middle East. Am J Dis Child 105:102–103 Salam M, Idriss H (1964) Infantile amaurotic familial idiocy and gargoylism in siblings. Pediatrics 34:658–663 Salem GM, Salti IS, Abu Haydar FR (1972) Peutz–Jeghers syndrome: report of two cases from Lebanon associated with endocrine abnormalities. J Med Liban 25:475–480 Salem G, Najjar SS, Zeynoun ST, Farah FS (1973) Lipodystrophy. J Med Liban 26:259–267 Salti IS, Mufarrij IS (1981) Familial Cushing disease. Am J Med Genet 8:201–204 Salti IS, Salem Z (1979) Famillial hypogonadotropic hypogonadism with alopecia. Can Med Assoc J 121:428–430

438

V.M. Der Kaloustian

Salti I, Kattuah N, Alam S, Wehby V, Frayha R (1976) The effect of allopurinol on oxypurine excretion in xanthinuria. J Rheumatol 3:201–204 Samaha H, Rahal EA, Abou-Jaoude M, Younes M, Dacchache J, Hakime N (2003) HLA class II allele frequencies in the Lebanese population. Mol Immunol 39:1079–1081 Saouda M, Mansour A, Bou Moglabey Y, El Zir E, Mustapha M, Chaib H, Nehme´ A, Me´garbane´ A, Loiselet J, Petit C, Slim R (1998) The Usher syndrome in the Lebanese population and further refinements of the USH2A candidate region. Hum Genet 103:193–198 Schulze-Bahr E, Haverkamp W, Wedekind H, Rubie C, Ho¨rdt M, Borggrefe M, Assmann G, Breithardt G, Funke H (1997) Autosomal recessive long-QT syndrome (Jervell Lange-Nielsen syndrome) is genetically heterogeneous. Hum Genet 100:573–576 Schwabe AD, Peters RS (1974) Familial Mediterranean fever in Armenians: analysis of 100 cases. Medicine 53:453–462 Serre JL (1976) L’apport de l’e´tude des syste`mes HLA dans la description de la reálite´ anthropobiologique des communaute´s libanaises. The`se de 3e`me cycle, Universite´ Paris VII Serre JL, Lefrance G, Loiselet J, Jacquard H (1979) HLA markers in six Lebanese religious subpopulations. Tissue Antigens 14:251–255 Shahid M, Abu Haydar N (1962) Sickle cell disease in Syria and Lebanon. Acta Haematol 27:268–273 Shahid MJ, Khouri FP, Ballas SK (1972) Fanconi’s anaemia: report of a patient with significant chromosomal abnormallities in bone marrow cells. J Med Genet 9:474–478 Shahid MJ, Khouri FP, Sahli IF (1974) Haemoglobin H disease and thalassaemia. J Med Genet 11:275–279 Shammaa DMR, Sabbagh AS, Taher AT, Zaatari GS, Mahfouz RAR (2008) Plasminogen Activator Inhibitor-1 (PAI-1) gene 4G/5G alleles frequency distribution in the Lebanese population. Mol Biol Rep 35:453–457 Shammas HF, Tabbara KF, Der Kaloustian VM (1976) Atypical serum cholinesterase in a family with congenital distichiasis. J Med Genet 13:514–515 Shammas HF, Tabbara KF, Der Kaloustian VM (1979) Distichiasis of the lids and lymphedema of the lower extremities: a report of ten cases. J Pediatr Ophthalmol Strabismus 16:129–132 Shamseddine A, Taher A, Fakhani S, Zhang M, Scott R, Habbal MZ (2004) Novel mutation, L371V, causing multigenerational Gaucher disease in a Lebanese family. Am J Med Genet 125A:257–260 Shawaf S, Noureddin B, Khouri A, Traboulsi EI (1995) A family with a syndrome of ectopia lentis, spontaneous filtering blebs, and craniofacial dysmorphism. Ophthalmic Genet 16:163–169 Shohat M, Bu X, Shohat T, Fischel-Ghodsian N, Magal N, Nakamura Y, Schwabe AD, Schlezinger M, Danon Y, Rotter J (1992) The gene for familial Mediterranean fever in both Armenian and non-Ashkenazi Jews is linked to the a-globin complex on 16p: evidence for locus homogeneity. Am J Hum Genet 51:1349–1354 Silleń A, Anton-Lamprecht I, Braun-Quentin C, Kraus CS, Sayli BS, Ayuso C, Jagell S, K€ uster W, Wadelius C (1998) Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjo¨gren–Larsson syndrome. Hum Mutat 12:377–384 Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean fever: a survey of 470 cases and review of the literature. Am J Med 43:227–253 Solh HM, Azoury RS, Najjar SS (1983) Peutz–Jeghers syndrome associated with precocious puberty. J Pediatr 103:593–595 Soua Z, Ghanem N, Ben Salem M, Lefranc G, Lefranc M-P (1989) Frequencies of the human immunoglobulins IGHA2*M1 and IGHA2*M2 alleles corresponding to the A2m(1) and A2m (2) allotypes in the French, Lebanese. Tunisian and Black African populations. Nucleic Acids Res 17:3625 Souraty N, Noun P, Djambas-Khayat C, Chouery E, Pangrazio A, Villa A, Lefranc G, Frattini A, Me´garbane´ A (2007) Molecular study of six families originating from the Middle-East and presenting with autosomal recessive osteopetrosis. Eur J Med Genet 50:188–199

13


439

Soussou I, Der Kaloustian VM, Slim MS (1974) Familial imperforate anus: report of a family. Dis Colon Rectum 17:562–564 Spranger J, Maroteaux P, Der Kaloustian VM (1975) The Dyggve–Melchior–Clausen syndrome. Radiology 114:415–421 Stayoussef M, Benmansour J, Al-Jenaidi FA, Nemr R, Ali ME, Mahjoub T, Almawi WY (2009) Influence of common and specific HLA-DRB1/DQB1 haplotypes on genetic susceptibilities of three distinct Arab populations to type 1 diabetes. Clin Vaccine Immunol 16:136–138 Ste´phan E (1954) Bloc auriculo-ventriculaire chez trois membres d’une meˆme famille. Rev Med Moyen Orient 11:246–248 Ste´phan E (1974) Familial atrioventricular block. Letter to the editor. JAMA 228:697 Ste´phan E (1978) Hereditary bundle branch system defect. Survey of a family with 4 affected generations. Am Heart J 95:89–95 Ste´phan E, de Meeus A, Bouvagnet P (1997) Hereditary bundle branch defect: right bundle branch blocks of different causes have different morphologic characteristics. Am Heart J 133:249–256 Strahler JR, Rosenbloom BB, Hanash SM (1983) A silent, neutral substitution detected by reversephase high-performance liquid chromatography: hemoglobin Beirut. Science 221:860–862 Sulh HM, Steinmann B, Rao VH, Dudin G, Zeid JA, Slim M, Der Kaloustian VM (1984) EhlersDanlos syndrome type IV D: an autosoomal recessive disorder. Clin Genet 25:278–287 Tabbara KF, Khouri FP, Der Kaloustian VM (1973) Rieger’s syndrome with chromosomal anomaly. Can J Ophthalmol 8:488–491 Taher A, Khalil I, Shamseddine A, El-Ahdab F, Bazarbachi A (2001) High prevalence of factor V Leiden mutation among healthy individuals and patients with deep venous thrombosis in Lebanon: is the Eastern Mediterranean region the area of origin of this mutation? Thromb Haemost 86:723–724 Taleb N, Shahid M (1967) Les ane´mies me´diterraneénnes (thalasse´mies). J Med Liban 20:127–139 Taleb N, Loiselet J, Ghorra F, Sfeir A (1964): Sur la de´ficience en glucose-6-phosphate de´shydrogeńase dans les populations autochtones du Liban. C R Acad Sci (Paris) 258:5749–5751 Taleb N, Loiselet J, Macaron C (1969) Aspects de la sicklane´mie au Liban. J Med Liban 22:551–558 Tamim H, Khogali M, Beydoun H, Melki I, Yunis K (2003) Consanguinity and apnea of prematurity. Am J Epidemiol 158:942–946 Tamouza R, Mansour I, Bouguacha N, Klayme S, Djouadi K, Laoussadi S, Azoury M, Dulphy N, Ramasawmy R, Krishnamoorthy R, Toubert A, Naman R, Charron D (2001) A new HLA-B*27 allele (B*2719) identified in a Lebanese patient affected with ankylosing spondylitis. Tissue Antigens 58:30–33 Teebi AS, Al-Awadi SA (1986) Spondyloepiphyseal dysplasia tarda with progressive arthropathy: a rare disorder frequently diagnosed among Arabs. J Med Genet 2:189–191 Thauvin-Robinet C, El Ghouzzi V, Chemaitilly W, Dagoneau N, Boute O, Viot G, Me´garbane´ A, Sefiani A, Munnich A, Le Merrer M, Cormier-Daire V (2002) Homozygosity mapping of a Dyggve–Melchior–Clausen syndrome gene to chromosome 18q21.1. J Med Genet 39: 714–717 Tomb R, Soutou B, Zalloua P (2009) Dysplasie ectodermique anhidrotique familiale: une mutation rare du ge`ne EDA1. Anhidrotic ectodermal dysplasia. Report of a rare mutation in EDA1. Ann Dermatol Veńe´reól 136:28–31 Traboulsi EI, Nasr AM, Fahd SD, Jabbour NM, Der Kaloustian VM (1984) Waardenburg’s recessive anophthalmia syndrome. Ophthalmic Paediatr Genet 4:13–18 Traboulsi EI, Azar DT, Jarudi N, Der Kaloustian VM (1985a) Ocular findings in the candidiasisendocrinopathy syndrome. Am J Ophthalmol 99:486–487 Traboulsi EI, el-Baba F, Barakat AY, Faris BM (1985b) The retinopathy of primary hyperoxaluria. Retina 5:151–153 Traboulsi EI, Faris BM, Der Kaloustian VM (1986a) Persistent hyperplastic primary vitreous and recessive oculo-dento-osseous dysplasia. Am J Med Genet 24:95–100

440

V.M. Der Kaloustian

Traboulsi EI, Jurdi-Nuwayhid F, Frangieh GT, Der Kaloustian VM (1986b) Retinoblastoma in Lebanon. Ophthalmic Paediatr Genet 7:29–34 Trioche P, Francoual J, Chalas J, Capel L, Bernard O, Labrune P (1999) Identification of three novel mutations (Q54P, W70X and T108I) in the glucose-6-phosphatase gene of patients with glycogen storage disease type Ia. Mutation in Brief #256. Online. Hum Mutat 14:91 Trop I, Kaplan F, Brown C, Mahuran D, Hechtman P (1992) A gly 250-to-asp substitution in the a-subunit of hexosaminidase A causes juvenile-onset Tay-Sachs disease in a LebaneseCanadian family. Hum Mutat 1:35–39 Usanga EA, Ameen R (2000) Glucose-6-phosphate dehydrogenase deficiency in Kuwait, Syria, Egypt, Iran, Jordan and Lebanon. Hum Hered 50:158–161 Vincenti F, Hajjar ET, Salti IS (1973): Tumerous hyperparathyroidism in hypophosphatemic vitamin D-resistant rickets. J Med Liban 26:583–594 Vulliamy TJ, D’Urso M, Battistuzzi G, Estrada M, Foulkes NS, Martini G, Calabro V, Poggi V, Giordano R, Town M, Luzzatto L, Persico MG (1988) Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci USA 85:5171–5175 Wiles CR, Taylor TF, Sillence DO (1992) Congenital synspondylism. Am J Med Genet 42:288–95 Wynnes-Davies R, Hall C, Ansell BM (1982) Spondylo-epiphyseal dysplasia tarda with progressive arthropathy: a ‘new’ disorder of autosomal recessive inheritance. J Bone Joint Surg 64B:442–443 Yasunaga S, Grati M, Cohen-Salmon M, El-Amraoui A, Mustapha M, Salem N, El-Zir E, Loiselet J, Petit C (1999) A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness. Nat Genet 21:363–369 Yehya A, Souki R, Bitar F, Nemer G (2006) Differential duplication of an intronic region in the NFATC1 gene in patients with congenital heart disease. Genome 49:1092–1098 Yunis K, Ghina M, Bitar F, Chamseddine F, Kassar M, Rashkidi J, Ghaith M, Tamim H (2006) Consanguineous marriage and congenital heart defects: a case-control study in the neonatal period. Am J Med Genet 140A:1524–1530 Zaatari GS, Otrock ZK, Sabbagh AS, Mahfouz RAR (2006) Prevalence of factor V R2 (H1299R) polymorphism in the Lebanese population. Pathology 38:442–444 Zahed L, Bou-Dames J (1997) Acceptance of first-trimester prenatal diagnosis for the haemoglobinopathies in Lebanon. Prenat Diagn 17:423–428 Zahed L, Talhouk R, Saleh M, Abou-Jaoudeh R, Fisher C, Old J (1997) The spectrum of b-thalassemia mutations in the Lebanon. Hum Hered 47:241–249 Zahed L, Quatanani M, Nabulsi M, Taher A (2000) b-thalassemia mutations and haplotype analysis in Lebanon. Hemoglobin 24:269–276 Zahed L, Demont J, Bouhass R, Trabuchet G, H€anni C, Zalloua P, Perrin P (2002): Origin and history of the IVS-I-110 and codon 39 beta-thalassemia mutations in the Lebanese population. Hum Biol 74:837–84 Zahed L, Zahreddine H, Noureddine B, Rebeiz N, Shakar N, Zalloua P, Haddad F (2005) Molecular basis of oculocutaneous albinism type ! in Lebanese patients. J Hum Genet 50: 317–319 Zahed L, Pramparo T, Farra C, Mikati M, Zuffardi O (2007) A patient with duplication (7) (p22.1pter) characterized by array-CGH. Am J Med Genet 143A:168–171 Zalloua PA, Aoun E, Koussa S, Asfahani WS, Taher A (2003) The codons 8/9(+G) mutation found for the first time in the Lebanese population. Hemoglobin 27:1–5 Zalloua PA, Platt DE, El Sibai M, Khalife J, Makhoul N, Haber M, Xue Y, Izaabel H, Bosch E, Adams SM, Arroyo E, Lo´pez-Parra AM, Aler M, Picornell A, Ramon M, Jobling MA, Comas D, Bertranpetit J, Wells RS, Tyler-Smith C, and the Genographic Consortium (2008a) Identifying genetic traces of historical expansions: Phoenician footprints in the Mediterranean. Am J Hum Genet 83:633–642 Zalloua PA, Xue Y, Khalife J, Makhoul N, Debiane L, Platt DE, Royyuru AK, Herrera RJ, Soria Hernanz DF, Blue-Smith J, Wells RS, Comas D, Bertranpetit J, Tyler-Smith C,

13


441

Zalloua PA, Xue Y, Khalife J, Makhoul N, Debiane L, Platt DE, Royyuru AK, Herrera RJ, Soria Hernanz DF, Blue-Smith J, Wells RS, Comas D, Bertranpetit J, Tyler-Smith C, and the Genographic Consortium (2008b) Y-chromosomal diversity in Lebanon is structured by recent historical events. Am J Hum Genet 82:873–882 Zaynoun ST, Kurban AK (1974) Lipoid proteinosis. J Med Liban 90:85–90 Zirbel GM, Ruttum MS, Post AC, Esterly NB (1995) Odonto-onycho-dermal dysplasia. Br J Dermatol 133:797–800

Chapter 14

Genetic Disorders in Libya Tawfeg Ben-Omran

The Country Libya is a Mediterranean North African country (Fig. 14.1). The country stretches along the northeast coast of Africa between Tunisia and Algeria on the west and Egypt on the east; to the south are Sudan, Chad, and Niger. Libya’s coastline is about 1,770 km with an estimated surface area of 1,775,500 km2. About 93% of the land is desert or semi-desert. Tripoli (the capital) is the country’s major city. For most of Libyan history, Libyans have been subjected to varying degrees of foreign control. In antiquity, the Phoenicians, Carthaginians, Greeks, Romans, Vandals, and Byzantines ruled all or parts of Libya. Although the Greeks and Romans left impressive ruins at Cyrene, Leptis Magna, and Sabratha, only little remains today to testify the presence of these ancient cultures. The Arabs conquered Libya in the seventh century A.D. In the following centuries, most of the people adopted Islam, the Arabic language, and the culture. The Ottoman Turks conquered the country in the sixteenth century. Libya remained part of their Empire until the Italian invasion in 1911, and after years of Libya’s resistance, incorporated Libya as its fourth coastal colony. In 1934, Italy adopted the name “Libya” (used by the Greeks for all of North Africa except Egypt) as the official name of the colony, which consisted of the provinces of Cyrenaica, Tripolitania, and Fezzan. Libya declared its independence on December 24, 1951; it was the first country to achieve independence through the United Nations as the Kingdom of Libya, and retained this status till September 1, 1969; since then it has been ruled by a Revolution Council led by the leader Muammar el-Qaddafi.

T. Ben-Omran Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation and Weill Cornell Medical College, Doha-Qatar e‐mail: [email protected]


443

444

T. Ben-Omran

Fig. 14.1 Map of Libya

Libya’s economy still depends mainly upon exported crude oil. After the first major oil discovery in 1959, Libya had become one of the major oil-exporting countries resulting in rapid expansion in the economy. Libyans are generally affluent with the highest per capita income in Africa.

The Population Libya has a relatively small population. Ninety percent of the people live in less than 15% of the land, primarily along the cost. According to the census conducted in 1984, the total population of Libya is 3.7 million. However, due to an impressive decline in the mortality rate coupled with the continuation of a high birth rate, as well as the country’s strong economic performance in the late 1970s, fuelling an influx of contracting and services staff as well as expatriate professionals, there was a rapid increase in population. Recently, according to 2008 estimates, the total population of Libya was 6.18 million, with 39% of the population below the age of 15. More than half of the population is urban; most of them live in the coastal area in the main cities, namely Tripoli (2.4 million) and Benghazi (0.75 million). The estimated birth rate is 25.6 births per 1,000 populations (158,000 births per annum). Approximately 98.3% of all births are in health establishments. Infant mortality rate is 17.6 per 1,000 live births; under-five mortality is 20.1 per 1,000 population, with a growth rate of 1.83%. Life expectancy at birth is 72.5 years. Libyans are primarily a mixture of Arabs and Berbers. Small Tebou and Touareg tribal groups in southern part of Libya lead nomadic or semi-nomadic lives.

14

Genetic Disorders in Libya

445

Genetic Services Although Libya has made a considerable progress in the prevention and elimination of infectious diseases, genetic disorders remain a major health problem in the country. The burden of these disorders is largely underestimated by healthcare authorities; this is because of a lack of published studies. In addition, there is a lack of data for some of the most common genetic disorders as most available studies are hospital-based; hence the lack of well-designed epidemiological studies. The first Genetic Clinic in Libya was established in the main Children Hospital in Benghazi in 1982, along with a small diagnostic cytogenetic laboratory in histology department, at the Faculty of Medicine. Between 1982 and 1985, over 400 patients with various genetic disorders had been registered in this clinic. Currently, most patients with genetic disorders are seen by different pediatric subspecialties (mainly endocrinologists, neonatologists, and neurologists etc) in the main children hospitals (mainly in Tripoli and Benghazi). There are very limited diagnostic facilities for genetic and metabolic disorders. Most samples are currently sent to one of two laboratories in Germany and France.

Consanguinity It is estimated that 48.4% of marriages in Libya are consanguineous; 30% of the total marriages are between first cousins (Broadhead and Sehgal 1981). The Libyan population is characterized demographically by large family size (6.1 children) and high birth rates. The high rate of consanguineous marriages in Libya gives rise to an inbred population in particular isolated areas in the Green and Nafossa mountains, as well as oases in southern part of Libya with increased risk of autosomal recessive disorders. Polygamy is not uncommon in Libya however it is not advocated by Libyan law.

Genetic Disorders Reported from Libya In general, the magnitude of genetic disorders and birth defects in Libya is underestimated. In a study by Mir et al. (1992), congenital anomalies were present in 2.38% of all infants. A recent study by Singh and al-Sudani (2000) showed the incidence of major congenital anomalies (MCAs) to be 7.4 per 1,000 live births and 9.3 per 1,000 total births. The incidence of perinatal death in births with MCAs was 49.1% as against 2.7% for all births. Gahukamble et al. (2002) conducted a retrospective analysis of the records of newborns with gastrointestinal atresias over a 16-year period. This showed that more than 25% of patients with atresias had atresias that were genetically influenced. In addition, Gahukamble et al. (2003) reported an unusual occurrence of foregut atresias in two consecutive siblings and a pair of monozygous twins.

446

T. Ben-Omran

Chromosomal Disorders Down syndrome incidence in Libya was found to be 1:517 live births (Verma et al. 1990; Khan 1992). Cytogenetically, about 96% were regular trisomy 21. The relatively high incidence was attributed in part to late maternal age. The mean age was 35.62 years, and 82.0% of mothers were over 30 years. The existence of genetic factors predisposing to nondisjunction was not excluded as a contributing factor.

Disorders of the Central Nervous System (CNS) Benamer (2007) reviewed all publications related to the incidence and prevalence of neurological disorders including neurogenetic disorders in Libya (Table 14.1). This study highlighted that neurogenetic disorders are a common health problem and represented a significant portion of all neurological disease burden in the country (13% of the total estimated neurological cases: 1,566 cases). This can be attributed to the demographic structure of the Libyan population (similar to other many Arabic countries).

Neural Tube Defects (NTD) In a study by Kishan et al. (1985), a total of 48,974 births (live and still births) were studied (between 1982 and 1984) for Neural Tube Defects (NTD). There were 32 cases of anencephaly with an incidence of 0.65 per 1,000 live births. Associated Central Nervous System (CNS) malformations were observed in 12 cases (37.5%). There were 18 cases of spina bifida with an incidence of 0.36 per 1,000 live births.

Table 14.1 Reported neurogenetic disorders in Libya MIM # Disease/Syndrome 208900 Ataxia telangiectasia 123400 Creutzfeldt-Jakob disease 212895 Early onset cerebellar ataxia with retained tendon reflexes 229300 Friedreich’s ataxia 118200 Hereditary sensory and motor neuropathy 270685 Hereditary spastic paraplegia 182600 164500 Late onset cerebellar ataxia Motor neuron disease Muscular dystrophy 253300 Spinal muscular atrophy

Reference Sridharan et al. (1985) Radhakrishnan et al. (1988a, b) Sridharan et al. (1985) Sridharan et al. (1985) Radhakrishnan et al. (1988a, b) Sridharan et al. (1985) Sridharan et al. (1985) Radhakrishnan et al. (1986) Radhakrishnan et al. (1987) Radhakrishnan et al. (1988a, b)

14


447

Hereditary Ataxias Sridharan et al. (1985) performed a study over a 2-year period between 1982 and 1984. He found 52 cases with various types of hereditary ataxias and paraplegia. Hereditary Spastic Paraplegia was diagnosed in 24 patients (12 males and 12 females) from 10 families. Autosomal recessive inheritance was found in 15 patients from 6 families (8 males and 7 females). Early Onset Cerebellar Ataxia with Retained Tendon Reflexes (MIM 212895) was diagnosed in 13 patients (6 males and 7 females) from 9 families. One family was diagnosed with Late Onset Cerebellar Ataxia with retinal pigmentary degeneration with autosomal dominant inheritance. Friedreich Ataxia (MIM 229300) was diagnosed in three patients. Ataxia Telangiectasia (MIM 208900) was diagnosed in one patient. This study showed the approximate prevalence of hereditary ataxia and paraplegia of 4.8/100,000 population.

Neuromuscular Disorders In a study (from 1983 to 1985) Radhakrishnan et al. (1987) found 34 cases with Duchenne muscular dystrophy (MIM 310200), 19 with limb girdle muscular dystrophy (MIM 253600), and 4 with facioscapulohumeral muscular dystrophy (MIM 158900). In addition, they found 41 cases with hereditary motor and sensory neuropathy (MIM 118200) and 3 cases with opthalmoplegia-plus (chronic progressive external opthalmoplegia and skeletal muscle involvement). The overall prevalence was estimated to be approximately 13.2/100,000 population. Richard et al. (2008) studied 23 families with congenital myasthenic syndrome originating from Libya, Tunisia, Algeria, and Morocco. Direct sequencing of the acetylcholine receptor epsilon subunit gene (CHRNE) was performed. The epsilon1293insG mutation was identified in 14 families (about 60% of the initial 23). This study concluded that epsilon1293insG mutation is likely to be derived from an ancient single founder mutation in the North African population.

Spinal Muscular Atrophy (SMA) (MIM 253300) Radhakrishnan et al. (1988a, b) reported 24 patients with Spinal Muscular Atrophy (SMA) (13 males and 11 females, age between 20 days and 45 years) among 519,000 subjects from a study carried over 4 years (1983–1986). There were 6 patients with infantile form with an incidence 1/12,500 live births/year, 12 with chronic childhood form (prevalence 2.3/100,000 population), and 6 with adultonset type (prevalence 1.2/100,000 population). The incidence is much lower than that in the Arabian Peninsula.

448

T. Ben-Omran

Hereditary Hematological Disorders Since ethnically Libyan population represents a mixture of African Negroes and South Mediterranean racial types, it is expected to find both sickle cell anemia and thalassemia in Libya. Jain (1983) studied 1,350 Libyan individuals visiting two University Hospitals in Benghazi (1978–1979) searching for hemoglobinopathies and Glucose-6-phosphate dehydrogenase deficiency (G6PD). G6PD was found in 147 individuals (10.8%), 16 were homozygous for beta-thalassemia (1.2%), 130 were heterozygous for betathalassemia (9.6%), homozygozity for sickle cell anemia in 5 individuals (0.36%), 61 with sickle cell trait (4.5%), and only 3 had sickle cell-thalassemia (0.2%).

Inborn Errors of Metabolism (IEM) and Lysosomal Storage Disorders The prevalence of this group of disorders in Libya is underestimated, partly due to the lack of a national neonatal screening program as well as the lack of clinical and diagnostic facilities for inborn errors of metabolism (IEM). In addition, most clinicians lack awareness of IEM especially in rural areas and there is no system for appropriate referrals or regular follow-up for this group of patients. There are some selective screening programs existing in Libya: for example, all infants of diabetic mothers are screened for congenital hypothyroidism, any infant with cataract would be screened for galactosemia, and all infants with positive family history of IEM are screened as well for similar diseases. From a recent study (unpublished data) to estimate the cost-effectiveness of establishing a neonatal screening program for phenylketonuria (PKU) in Libya, the estimated incidence of IEM in Libya is shown in Table 14.2. In a recent retrospective study by Eldeep et al. (2009). In this study 1503 (856 neonates and 647 children) patients were admitted to the pediatric intensive care unit Elkhadra Children Hospital in Tripoli. Inborn errors of metabolism account for Table 14.2 The estimated incidence of endocrine/IEM in Libya

MIM# 201910 230400 243500 251000

261600 606054 276700

Disorder Congenital hypothyroidism Congenital adrenal hyperplasia Galactosemia Glycogen storage disease Isovaleric acidemia Methylmalonic acidemia Mitochondrial disorders Nonketotic hypoglycemia Phenylketonuria Propionic acidemia Tyrosinemia Urea cycle defects

Estimated incidence 1:4,000 1:5,000 1:1,000 1:130,000 1:130,000 1:40,000 1:70,000 1:130,000 1:7,000 1:40,000 1:50,000 1:50,000

14


449

3% of total admissions. The total number of deaths was 136 patients (71 neonates & 65 children). The main cause of death among all admissions was congenital anomalies (38%) followed by IEM (36%). Phenylketonuria (MIM 261600) Since newborn screening has not been established yet in Libya, most patients come to attention in late infancy or childhood because of developmental delay or frank mental retardation. Elrfifi et al. (unpublished data) reported 19 patients (7 males, 12 females) with classical PKU. Most cases were product of consanguineous marriage with 4 families have 2 affected children each. The mean age of diagnosis was 28 months (ranging from 7 months to 9 years). The mean phenylalanine level at diagnosis was 1200 mmol/L (ranging from 600–2400 mmol/L). All late treated patients presented with developmental delay, in addition to developmental delay 3 had eczema, 5 patients presented with athetotic movements in the upper limbs, only one female patient diagnosed at 9 years had convulsion. The authors concluded that quality of life and IQ can be improved in late diagnosed and treated patients with PKU who continue on phenylalanine-restricted diet. Tyrosinemia type I (MIM 276700) There are 14 cases with tyrosinemia type I (personal observation with Dr. Alobaidy), among whom 11 are doing well on NTBC treatment, three died. Lysosomal Storage Disorders There are 31 patients diagnosed with Gaucher disease. Between 1997 and 2006, seven patients were diagnosed from Benghazi (personal observation with Dr. Shembesh). Two mutations (L444P and N370S) were found. Another 11 patients with Gaucher disease (personal communication with Dr. Zarroug) diagnosed at Tripoli Medical Center (age ranges from 18 months to 17 years), including 2 young ladies (23 and 24 years of age). In addition to Gaucher disease, there are nine patients with MPS type 1 (three with Hurler and six with Hurler-Scheie) and one family with three children affected with MPS type II. All patients receiving enzyme replacement therapy are doing well. Fabry disease seems less commonly seen in Libya with only two patients diagnosed at Tripoli medical center (personal communication with Dr. Shebani) possibly an under-diagnosed condition.

Familial Hypercholesterolemia Sheriff et al. (1994) reported Libyan family with hypercholesterolemia and increased high-density lipoprotein cholesterol in Plasma. The family with 11

450

T. Ben-Omran

members, of which 9, including both parents, 5 sons, and 2 daughters, show a marked increase in high density lipoprotein (HDL) cholesterol alone with low plasma concentrations of triglycerides. They concluded that the marked increase in HDL cholesterol possibly linked to a decrease in heparin-releasable hepatic lipase activity.

Endocrine Disorders Congenital Hypothyroidism A recent study (unpublished data) showed an estimated incidence of congenital hypothyroidism of 1:4,000 (Table 14.2).

Insulin-dependent Diabetes Mellitus Kadiki and Roaeid (2002) studied the incidence of insulin-dependent diabetes mellitus (IDDM) in children up to14 years old in Benghazi (based on prospective registration of IDDM new cases for the period 1991–2000). A total of 276 (males 117 and females 159) new cases were ascertained with apparent female preponderance. The average annual incidence per year was 7.8/100,000 population. There was an increase in incidence rate over that reported for the period 1981–1990 (7.8 vs. 7.0). It was concluded from this study that IDDM is probably the commonest chronic disease of childhood in Libya.

Genodermatosis Xeroderma Pigmentosum (XP MIM 278720) Khatri et al. (1999) studied the clinical profile of 42 cases with Xeroderma Pigmentosum (XP) (23 girls and 19 boys from 29 families) between 1981 and 1994. Consanguinity was seen in 92.8% (39 of 42), and 57% (24 of 42) were first cousins. The incidence of XP was approximately 15–20 per million of the population as against the worldwide incidence of approximately 4 per million. This study concluded that XP has a relatively high incidence in Libya. Similar high incidence has also been reported in Egypt, Tunisia, and other Arab countries. It is characterized by high percentage of consanguinity in parents of the patients, female preponderance, early onset of initial manifestations, severe ocular and oral lesions in a high percentage of patients, and early death. The malignant skin tumors seen were squamous cell carcinoma in 23 patients, basal cell carcinoma in 17 patients, and basosquamous carcinoma in 2 patients.

14


451

Lipoid proteinosis (MIM 247100) Lipoid proteinosis is an autosomal recessive disorder associated with variable scarring and infiltration of skin and mucosae. It is caused by loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1). Chan et al. (2003) reported a 10-year-old boy with lipoid proteinosis from a consanguineous family. Molecular studies showed a homozygous nonsense mutation (Q32X) in exon 2 of the ECM1gene. DNA analysis from the affected individual’s five siblings revealed that four were heterozygous carriers.

Congenital Sensorineural Deafness Lucotte (2007) studied the prevalence of carriers for 35delG mutation in the connexin 26 gene (MIM 121011) in seven populations from the Mediterranean area, including Libya, and compared the mutation in 17 other published populations in the same area. The study revealed a prevalence of the 35delG mutation is 1/41 in Libya. Otman and Abdelhamid (2005) reported a 36-year-old African man born in the Southern part of Libya with Waardenburg syndrome type 2 (MIM 247100). He presented with congenital deafness and white forelock, variable-sized hypopigmented, depigmented patches and hyperpigmented islands within the areas of hypomelanosis affecting the upper parts of the trunk, both arms and forearms. Shembesh et al. (1986) reported three Libyan children from one consanguineous family with the syndrome of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD, MIM 222300). Two children presented with diabetic ketoacidosis, while one was discovered during screening of the family.

Miscellaneous Disorders/Syndromes Other published disorders/syndromes or those through personal observation are included in Table 14.3.

Comments It is obvious from the available data that genetic and congenital disorders are common in Libya, in particular, recessively inherited disorders. This is attributed to several factors, similar in most Arab countries, including large family size, high maternal and paternal age, and high rate of consanguinity (nearly 30% of Libyan youth advocate consanguinity: from The Pan Arab Population and Family Health

452

T. Ben-Omran

Table 14.3 Other published disorders/syndromes, or through personal observation MIM # Disease/Syndrome Reference Autosomal recessive Ehlers Danlos syndrome (type I) Banerjee et al. (1988) 123400 Creutzfeldt-Jakob disease Radhakrishnan et al. (1988a, b) 225500 Ellis-van Creveld syndrome Personal observation 231070 Geroderma osteodysplastica Newman et al. (2008) 176670 Hutchinson-Gilford progeria syndrome Khalifa (1989) 249000 Meckel-Gruber syndrome Mehabresh (unpublished) 277700 Werner’s syndrome Radhakrishnan et al. (1991)

Project Report in 2008), in addition to the lack of public health preventive measures toward congenital and genetically determined disorders and inadequate genetic services and antenatal health care. There is discrepancy between the magnitudes of genetic and congenital disorders and the currently available genetic services if exist. Libyan healthcare system may use the available infrastructure in establishing different preventive measures, for example establishing a national neonatal screening program. It is recommended to establish specialized genetic and metabolic preventive services at least for now in the main pediatric hospitals in Tripoli Benghazi and Zawia as first step, in addition to implementing different strategies for the prevention of genetic and metabolic disorders within the primary healthcare system, some efforts being introduced privately in Musrata city (personal communication). Also, we emphasize on education through school health, mass media and educational campaigns to raise awareness of the public and decision makers toward introducing different preventive programs, similar to some Arab countries, which include: l

l

l

Premarital and preconception screening and counseling for common inherited disorders including hemoglobinopathies and common autosomal recessive conditions in the country Newborn screening for metabolic disorders and congenital hypothyroidism as well as for clinically detected conditions Prenatal screening for chromosome abnormalities, like Down syndrome, and congenital malformations such as NTD

References Banerjee G, Agarwal RK, Shembesh NM, Mauhoub Mansoor El (1988) Missed diagnosis, Ehlers Danlos syndrome – masquerading as primary muscle disease. Postgrad Med J 64:126–127 Benamer HT (2007) Neurological disorders in Libya: an overview. Neuroepidemiology 29:143–149 Broadhead RL, Sehgal KC (1981) Consanguinity and congenital abnormalities in East Libya. Garyounis Med J 4:3–5 Chan I, El-Zurghany A, Zendah B, Benghazil M, Oyama N, Hamada T, McGrath JA (2003) Molecular basis of lipoid proteinosis in a Libyan family. Clin Exp Dermatol 28:545–548

14


453

Eldeep A, Benyones R, Dougman K, Esahli H (2009) A five years review of admission patterns and outcomes in a pediatric intensive care unit in Elkhadra hospital. Jamahiriya Medical Journal 9(3):205–209 Elrfifi K, Zeglam A, Ben-Omran T, Aboureyana F, Al-Hmadi S. Intelligence quotient (IQ) of late treated phenylketonuric patients: Is brain damage still preventable? (Unpublished) Gahukamble DB, Adnan AR, Al-Gadi M (2002) Atresias of the gastrointestinal tract in an inbred, previously unstudied population. Pediatr Surg Int 18:40–42 Gahukamble DB, Adnan AR, Al Gadi M (2003) Distal foregut atresias in consecutive siblings and twins in the same family. Pediatr Surg Int 19:288–292 Jain RC (1983) Abnormal haemoglobin, thalassaemia and G-6-PD deficiency in Libya. Br J Haematol 54:154–155 Kadiki OA, Roaeid RB (2002) Incidence of type 1 diabetes in children (0–14 years) in Benghazi Libya (1991–2000). Diabetes Metab 28:463–467 Khalifa MM (1989) Hutchinson-Gilford progeria syndrome: report of a Libyan family and evidence of autosomal recessive inheritance. Clin Genet 35:125–132 Khan MA (1992) Development outcome of Down’s syndrome in eastern Libya. Indian J Med Sci 46:268–274 Khatri ML, Bemghazil M, Shafi M, Machina A (1999) Xeroderma pigmentosum in Libya. Int J Dermatol 38:520–524 Kishan J, Soni AL, Elzouki AY, Mir NA (1985) Neural tube defects. Indian Pediatr 22:545–547 Lucotte G (2007) High prevalences of carriers of the 35delG mutation of connexin 26 in the Mediterranean area. Int J Pediatr Otorhinolaryngol 71:741–746 Mehabresh MI, Benseriti GA. Meckel-Gruber like syndrome with (Encephalocele, nephrocalcinosis congenital hearth disease-VSD and no polydactyly). Elfath children-hospital, BenghaziLibya Mir NA, Galczek WC, Soni A (1992) Easily identifiable congenital malformations in children: survey of incidence and pattern in 32, 332 live born neonates. Ann Saudi Med 12:366–371 Newman WG, Clayton-Smith J, Metcalfe K, Cole R, Tartaglia M, Brancati F, Morara S, Novelli A, Liu X, Siminovitch KA, Mundlos S, Tassabehji M, Black GC (2008) Geroderma osteodysplastica maps to a 4 Mb locus on chromosome 1q24. Am J Med Genet A 146A:3034–3037 Otman SG, Abdelhamid NI (2005) Waardenburg syndrome type 2 in an African patient. Indian J Dermatol Venereol Leprol 71:426–427 Radhakrishnan K, Mousa ME (1988) Creutzfeldt-Jakob disease in Benghazi, Libya. Neuroepidemiology 7:42–43 Radhakrishnan K, Ashok PP, Sridharan R, Mousa ME (1986) Descriptive epidemiology of motor neuron disease in Benghazi, Libya. Neuroepidemiology 5:47–54 Radhakrishnan K, el-Mangoush MA, Gerryo SE (1987) Descriptive epidemiology of selected neuromuscular disorders in Benghazi, Libya. Acta Neurol Scand 75:95–100 Radhakrishnan K, Thacker AK, Maloo JC (1988a) A clinical, epidemiological and genetic study of hereditary motor neuropathies in Benghazi, Libya. J Neurol 235:422–424 Radhakrishnan K, Thacker AK, Maloo JC, Gerryo SE, Mousa ME (1988b) Descriptive epidemiology of some rare neurological diseases in Benghazi, Libya. Neuroepidemiology 7:159–164 Radhakrishnan K, Maloo JC, Thacker AK, Mousa ME (1991) Werner’s syndrome: a Libyan family with nine affected members. Ann Saudi Med 11:712–715 Richard P, Gaudon K, Haddad H, Ammar AB, Genin E, Bauche´ S, Paturneau-Jouas M, M€ uller JS, Lochm€uller H, Grid D, Hamri A, Nouioua S, Tazir M, Mayer M, Desnuelle C, Barois A, Chabrol B, Pouget J, Koenig J, Gouider-Khouja N, Hentati F, Eymard B, Hantaı¨ D (2008) The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa. Neurology 9:1967–1972 Shembesh NM, Sehgal KC, el-Mauhoub M, Elzouki AA (1986) DIDMOAD syndrome in a Libyan family. Ann Trop Paediatr 6:47–50 Sheriff DS, El Fakhri M, Ghwarsha K (1994) Libyan family with hypercholesterolemia and increased high-density lipoprotein cholesterol in plasma. Clin Chem 40(12):2313–2316

454

T. Ben-Omran

Singh R, al-Sudani O (2000) Major congenital anomalies at birth in Benghazi, Libyan Arab Jamahiriya, 1995. East Mediterr Health J 6:65–75 Sridharan R, Radhakrishnan K, Ashok PP, Mousa ME (1985) Prevalence and pattern of spinocerebellar degenerations in northeastern Libya. Brain 108:831–843 Verma IC, Mathews AR, Faquih A, el-Zouki AA, Malik GR, Mohammed F (1990) Cytogenetic analysis of Down syndrome in Libya. Indian J Pediatr 57:245–248

Chapter 15

Genetic Disorders in Morocco Abdelaziz Sefiani

The Country and Population Morocco is a North African country with a population of nearly 35 million and an area about 710,000 km2. Morocco has international borders with Algeria in the East, the Mediterranean sea in the North, and Mauritania in the South. The Berbers were the earliest known inhabitants of Morocco; they have inhabited the country since the earliest recorded time. Through the centuries, Berbers have mixed with many other ethnic groups: the Phoenicians, Carthaginians, Romans (first century BC), Vandals (fifth century AD), Byzantines (sixth century), and finally the Arabs who began bringing their civilization in the seventh century. This admixture of populations grew richer by the African migration from the South. Contrary to many Arab countries, Morocco was not under the Ottoman rule. On religious grounds, Morocco is homogeneous Sunnite Muslim ethnic group (>99%) with a Jewish minority. In 1948, approximately 265,000 Jews lived in Morocco; most of them left the country for Palestine. The Jewish population is currently down to 4,000. The beginning of the twentieth century knew different migration waves of Moroccans toward countries of the North. Currently nearly three million Moroccans live outside the country, mainly in Europe. These populations benefit from the health and research structures of the host countries, allowing the identification of several hereditary diseases and gene mutations in patients from Moroccan origin.

A. Sefiani Department of Medical Genetics, National Institute of Heath/University Mohammed V Souissi, Rabat 27, Avenue Ibn Batouta, BP 769, 11400, Rabat, Morocco e-mail: [email protected]


455

456

A. Sefiani

Genetic Services In Morocco, like other developing countries, malformations and genetic disorders are an important cause of morbidity and mortality, but the interest for genetic diseases is relatively recent. The Moroccan Health policy focused for many years on infectious diseases and malnutrition diseases. To date, a large number of genetic disorders were reported in the Moroccan population, in particular those which do not require high specialized biological investigations for their diagnosis. In the 1980s, molecular genetic data in some patients became available. For the majority of these diseases, the prevalence was not available. The first medical genetic centers were set up at the end of the 1990s and genetics was recognized as individualized medical specialty and new field medical practice in 1996. This chapter presents genetic diseases reported in Moroccan patients, for which, molecular data are available; most of them are indexed in the Moroccan Human Mutation Database at the address: http://www.sante.gov.ma/Departements/INH/MoHuMuDa

Consanguinity and Genetic Diseases in Morocco Morocco is one of the Mediterranean countries where consanguineous marriages are still frequent. It is an integral part of the cultural and social life. This contributes to morbidity and mortality of newborns and apparently increases prevalence of recessive genetic disorders and congenital malformations. The prevalence of consanguinity in Morocco reported to date varies in the range of 19.81–28.00% (Bouazzaoui 1994; Hami et al. 2006; Cherkaoui et al. 2006; Talbi et al. 2007). These studies were mainly limited to one region or reflect the activity of a specific medical center. A recent national study conducted by Jaouad et al. (2009) estimates the prevalence of consanguinity in Morocco to be 15.25% with a mean inbreeding coefficient of 0.0065. The rate of consanguineous marriage in 176 families reported in this study with autosomal recessive (AR) diseases was 59.09%.

Chromosomal Abnormalities The type and the frequency of the chromosomal anomalies in Morocco are not different from what is described elsewhere. According to a study carried out between 1993 and 2006 in the Department of Medical Genetics (DGM) of the Moroccan National Institute of Health, among the 3,778 cases studied for cytogenetics disorders, 1,133 (29.98%) had chromosomal abnormalities (unpublished data). The most common clinical reasons for performing cytogenetic investigations were suspected Down’s syndrome (23.66%), recurrent miscarriage (13.84%), short stature (7.49%), and dysmorphic features with developmental delay (7.38%). The frequency of Down’s syndrome in Moroccan population with abnormal

15

Genetic Disorders in Morocco

457

chromosomes is similar to that of other surveys. This could be attributed to its easy detection at the clinical level. Concerning structural chromosomal aberrations, translocation was the most common followed by deletion, marker chromosome, and ring chromosome in the order of frequency. Some balanced chromosomal anomalies discovered in Moroccan patients had a scientific interest. The translocation t(3;10)(p24;q32) reported in a large consanguineous Moroccan family was associated in homozygote state with recessive microcephaly, micropolygyria and corpus callosum agenesia. The breakpoint disturbs the EOMES gene, which leads to this new AR syndrome (Baala et al. 2007). A der(22;22)(q10;10q) was associated with an unexpected fertility in a Moroccan man which confirms that paternal uniparental disomy 22 has no clinical consequences (Ouldim et al. 2008).

Genetic Disorders in Morocco Neurosensorial Diseases Hearing Loss Nonsyndromic sensorineural hearing loss is mainly AR. Despite extensive genetic heterogeneity, the gene that encodes connexin 26, GJB2 (DFNB1) has been recognized to account for a large proportion of cases of nonsyndromic AR deafness. Like other Mediterranean populations, GJB2 35delG was found to be the most frequent mutation in Moroccan hearing-impaired children. This mutation was responsible for almost half of the hearing loss among Moroccan patients (Ratbi et al. 2007a). This finding underlines the advantages of a systematic search for this mutation among deaf children when environmental causes are considered irrelevant. The identification of this genetic anomaly signs the etiologic diagnosis of deafness, which allows a relevant genetic advice, and a better treatment of patients. Glaucoma Two AR mutations c.4339delG and p.Gly61Glu of CYP1B1, the gene encoding cytochrome P450 1B1, were reported by Belmouden et al. (2002) in Moroccan patients. Juvenile and adult primary glaucoma are characterized by autosomal dominant inheritance. Many loci are known. The mutation p.Thr377Met in myocilin gene (MYOC) was reported in one Moroccan patient by Melki et al. (2003). The phenotype associated with mutation in MYOC is highly variable even within the same kindred, ranging from normal through ocular hypertension to severe open angle glaucoma. The same author reported the homozygous mutation p.Met98Lys of OPTN in three families. Primary Open Angle Glaucoma secondary glaucomas arise as a consequence of disease or abnormality either elsewhere in the eye or in other systems: secondary

458

A. Sefiani

causes of childhood glaucoma: anterior segment disorders such as aniridia, neurofibromatosis type 1, Sturge-Weber syndrome. Secondary causes of juvenile and adult glaucoma such as: nail patella syndrome, Marfan syndrome, homocystinuria.

Retinitis Pigmentosa The mode of inheritance of Retinitis pigmentosa (RP) is determined by family history. RP can be inherited in an autosomal dominant, AR or X-linked manner. X-linked RP can be either recessive, affecting males only, or dominant, affecting both males and females; females are always more mildly affected. Some digenic and mitochondrial forms have also been described. At least 35 different genes or loci are known to cause nonsyndromic RP. Ebermann et al. (2007) found a homozygous mutation of MERTK gene in one Moroccan family. Therapy with vitamin A palmitate may slow retinal degeneration but is not recommended for those under age 18 years and should be routinely monitored in women of childbearing age because of potential teratogenic effects. Use of UV-A and UV-B blocking sunglasses is recommended. Diamox therapy may reduce cystoid macular edema. CPF 550 lenses may increase eye comfort by reducing glare and adaptation time from light to dark. Various other optical aids include magnifiers, closed-circuit television, and high-intensity, wide-beam flashlights.

Leber Congenital Amaurosis It is generally inherited as an AR trait but some autosomal dominant families have been described. There is genetic heterogeneity with more than nine genes identified. These genes are expressed preferentially in the retina or in the retinal pigment epithelium. Their putative functions are quite diverse and include retinal embryonic development (CRX), photo-receptor cell structure (CRB1), phototransduction (GUCY2D), protein trafficking (AIPL1, RPGRIP1), and vitamin A metabolism (RPE65). Mutations of many of these genes were reported in Moroccan population (see Table 15.1), in particular a recurrent mutation c.387delC (p.Asn129fsX165) of GUCY2D Aboussair et al. (2010).

Neuromuscular Diseases Dystrophinopathies Both X-linked recessive Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) diseases are caused by dystrophin deficiency in skeletal and heart muscles, leading to progressive necrosing lesions. The dystrophin gene is located in Xp21.2; it encodes several isoforms. The clinical diagnosis can be confirmed by

15


Table 15.1 Genetic diseases with gene mutations reported in Moroccan patients Disease Gene Achalasia Addisonianism Alacryma syndrome AAAS Analbuminenia ALB Apolipoprotein E APOE Arterial tortuosity syndrome SLC2A10 Ataxia with vitamin E deficiency Alpha-TTP gene Atrial-septal-defect with atrioventricular conduction NKX2-5 defects Autism Chromosomal aberration Bare lymphocyte type I TAP2 Bare lymphocyte type I SLC2A10 Bare lymphocyte type II, complementation group D RFXAP b-Thallassemia HBB Bloom syndrome DNA helicase RecQ Cataract congenital cerulean type 3 CRYGD Chanarin-Dorfman syndrome CGI-58 Charcot-Marie-tooth disease, axonal, type 2B RAB7 Charcot-Marie-tooth disease, axonal, type 2B1 LMNA Charcot-Marie-tooth disease, axonal, type 4C SH3TC2 Charcot-Marie-tooth disease type 4A GDAP1 Charcot-Marie-tooth disease type 4B2 SBF2 Charcot-Marie-tooth disease X-linked CX32 Colorectal adenomatous polyposis AR MYH Cone-rode dystrophy 3 ABCA4 Congenital adrenal hyperplasia, due to 21-hydroxylase CYP21A2 deficiency Congenital disorder of glycosylation type IIe COG7 Creutzfeld-Jakob disease PRNP Cystic fibrosis CFTR D-Bifunctional protein deficiency HSD17B4 Deafness, autosomal recessive 59 PJVK Deafness, neurosensory, autosomal recessive GJB2 Diabetes mellits type A insuline- resistance INSR Diamond-Blackfan anemia RPS19 DGS Di-Georges syndrome Dyggve-Melchior-Clausen syndrome Dymeclin Ectodermal dysplasia, anhidrotic EDAR Ectodermal dysplasia, anhidrotic AAAS Ectodermal dysplasia, anhidrotic EDARADD Epidermolysis pillosa with pyloric atresia ITGB4 Epilepsy, myoclonic, unverricht and lundborg CSTB Fabry disease GLA Facioscapulohumeral muscular dystrophy FSHMD1A Factor V deficiency F5 Factor XI deficiency F11 Familial hypercholesterolemia LDLR Familial hyperchilomicronemia LPL Familial mediterranean fever MEFV Fragile X mental retardation syndrome FMR1 Fructose 1-6 bipphosphatase deficiency FBP1 Furamase deficiency FH

459

OMIM 6¼ 231550 103600 107741 208050 277460 108900 209850 604571 208050 209920 141900 210900 608983 275630 600882 605588 601596 214400 604563 302800 608456 604116 201910 608779 123400 219700 261515 610220 220290 610549 105650 188400 223800 224900 231550 224900 226730 254800 301500 158900 227400 264900 144010 238600 249100 300624 229700 606812 (continued)

460 Table 15.1 (continued) Disease g-glutamylcysteine synthetase Deficiency, hemolytic anemia due to Glaucoma 1, open angle A Glaucoma 3, primary congenital A Glaucoma, primary open angle Goldberg-Shprintzen megacolon syndrome Goldberg-Shprintzen syndrome Growth hormone-releasing hormone receptor deficiency Hemochromatosis Hemophilia A Hereditary spastic paraplegia Huntington disease-like Hurler syndrome Ichthyosis lamellar type 2 Incontinencia pigmenti Infertility associated with multi-tailed spermatozoa and large heads Leber congenital amaurosis Leber congenital amaurosis Leber congenital amaurosis Leber congenital amaurosis Leber congenital amaurosis Lipodystrophy, congenital generalized, type 1 Lowe-oculo-cerebro-renal syndrome Lysinuric protein intolerance 3-M syndrome Malignant hyperthermia Mental retardation, X-linked Mental retardation, X-linked 3-Methylglutoconic aciduria type 1 Microcephaly polymicrogyria corpus collosum agenesis Mitochondrial DNA depletion syndrome Morquio syndrome A Mowat-Wilson syndrome Mucopolysaccharidosis type IIIC Multiple endocrine neoplasia type IIA Muscular dystrophy, Becker type Muscular dystrophy, congenital merosin-deficient Muscular dystrophy, Duchenne type Muscular dystrophy, limb-girdle type 2C LGMD2C Muscular dystrophy, limb-girdle type 2D LGMD2D Mycobacterium tuberculosis, susceptibility to infection by Nephrosis congenital, type 1 Neuropathy hereditary with spastic paraplegia Niemann-Pick disease type B Noonan syndrome Oculocutaneous albinism type 1 Ommen Otospondylomegaepiphyseal dysplasia Papillon-Lefevre syndrome

A. Sefiani

Gene GCLC

OMIM 6¼ 230450

MYOC CYP1B1 OPTN EDNRB KIAA1279 GHRHR HFE F8C SPG7 JPH3 IDUA ABCA12 NEMO AURKC

137750 231300 137760 235730 609367 139191 235200 306700 600584 606438 607014 601277 308300 243060

AIPL1 GUCY2D RPGRIP1 LCA6 RPE65 AGPAT2 OCRL SLC7A7 CUL7 RYR1 PQBP1 TM4SF2 AUH TBR2 RRM2B GALNS ZFHX1B HGNSAT RET Dystrophin LAMA2 Dystrophin SCGC SGCA IL12RB1

604393 204000 605446 604537 204100 608594 309000 222700 231520 145600 300463 300210 250950 604615 251880 253000 235730 252930 171400 300376 607855 310200 253700 608099 209950

NPHS1 Cct5 SMPD1 PTPN11 TYR RAG 1 COL11A2 CTSC

256300 256840 607616 163950 203100 603554 215150 245000 (continued)

15


Table 15.1 (continued) Disease Parkinson disease 8 Parkinson disease autosomal recessive juvenile Persistant Mullerian duct syndrome type I Phosphoglycerate deshydrogenase deficiency Polycystic kidney disease, autosomal recessive Prader-Willi syndrome Protease inhibitor 1 a-1 antitrypsin deficiency Retinitis pigmentosa Retinitis punctata albescens Retinal cone dystrophy Rett syndrome Schindler disease Short stature, idiopathic, autosomal Sjogren-Larsson syndrome Spastic paraplegia 7, autosomal recessive Spinal muscular atrophy type I Spinal muscular atrophy type II Spinal muscular atrophy type III Spinal muscular atrophy type IV Stickler syndrome, autosomal recessive Thiopurine S-methyl transferase Thromboembolism susceptibility due to factor V Leiden Ullrich congentital muscular dystrophy Usher syndrome type IB Vitamin D-dependent rickets type II Walker-Warburg syndrome Williams-Beuren syndrome Xeroderma-pigmentosum/cockayne syndrome complex Xeroderma-pigmentosum/cockayne syndrome complex

461

Gene LRRK2 PARK2 AMH PHGDH

OMIM 6¼ 607060 600116 261550 601815

FCYT SNRPN SERPINA1 MERTK RLBP1 KCNV2 MECP2 NAGA GHSR FALDH SPGT SMN1 SMN1 SMN1 SMN1 COL9A1 TPMT F5 COL6A3 Myosin VIIA VDR POMT2 ELN XPG XPC

263200 176270 107400 604705 136880 610356 312750 609241 604271 270200 607259 253300 253550 253400 271150 120210 187680 227400 254090 276900 277440 236670 194050 133530 278720

several methods. Creatine phosphokinase levels are 50–200-fold (DMD) or 10–35fold (BMD) above standard values. Muscular biopsy shows dystrophic features (necrotic and regenerative fibers). Immunohistochemical studies show a total absence of dystrophin (DMD) or altered quantity and/or quality (BMD). Deletions in the dystrophin gene represent 65% of mutations in DMD/BMD patients. In a previous study carried out by Sbiti et al. (2003b), the frequency of deletions in Moroccan DMD/BMD patients was about 51.3%. All these deletions were clustered in the two known hot-spots regions, and in 81% of cases were detected in the region from exon 43 to exon 52. These findings are comparable to those reported in other studies.

Limb-Girdle Muscular Dystrophy The mode of inheritance of limb-girdle muscular dystrophy (LGMD) is mainly AR. Elkerch et al. (2001) showed that nearly 50% of the Moroccan LGMD is due to the mutation del521T of SGCG gene (LGMD2C), with a maghrebin founder effect, as

462

A. Sefiani

has been previously shown in Tunisian and Algerian families. Few families have been reported with mutations of SGCA gene responsible of LGMD2D (personal unpublished data).

Congenital Muscular Dystrophy Approximately 50% of Congenital muscular dystrophy (CMD) is caused by complete merosin deficiency; diagnosis is made by detection of complete merosin deficiency on immunostaining of muscle biopsy and abnormal white matter signal on MRI after 4 months of age. Molecular genetic testing allows for genetic confirmation of some forms of CMD. The CMDs are inherited in an AR manner with the exception of Ullrich CMD, for which autosomal dominant inheritance have been reported. Allamand and Guicheney (2002) reported a homozygous mutation of LAMA2 in Moroccan patient with congenital merosin-deficient muscular dystrophy.

Facioscapulohumeral Muscular Dystrophy Facioscapulohumeral muscular dystrophy (FSHD) is inherited in an autosomal dominant manner. Approximately 70–90% of individuals have inherited the disease-causing deletion from a parent, and approximately 10–30% of affected individuals have FSHD as the result of a de novo deletion. It is diagnosed by a molecular genetic test showing a deletion of integral copies of a 3.3-kb DNA repeat motif named D4Z4. Molecular genetic testing detects about 95% of affected individuals. FSHD is probably relatively prevalent in Morocco, but up today only two large Moroccan families were reported with molecular abnormalities (personal unpublished data).

Spinal Muscular Atrophy The SMN1 (survival motor neuron 1) gene is the primary disease-causing gene. Approximately 95–98% of individuals with a clinical diagnosis of Spinal muscular atrophy (SMA) lack exon 7 of SMN1 gene. Approximately 2–5% of individuals with a clinical diagnosis of SMA are compound heterozygotes for deletion of SMN1 exon 7 and an intragenic mutation of SMN1. Targeted mutation analysis is used to detect deletion of exon 7 of SMN1 by a PCR and artificial restriction site creation. In Moroccan population, a previous study conducted by Bouhouche et al. (2003) showed a high incidence of SMN1 gene deletion in adult-onset SMA Moroccan patients. Among 54 suspected SMA patients (types I–IV), all of Moroccan origin, Sbiti et al. (2003a) found the exon 7 of the SMN1 gene homozygously absent in 100% of type I, 90% of type II, 74% of type III and 80% of type IV SMA patients (Bouhouche et al. 2007a).

15


463

Sbiti et al. from the DGM at INH Rabat have used the SMA genetic test to investigate 50 patients with unknown etiology of congenital hypotonia. The deletion of SMN1 gene was found in 16 patients (32%) Unpublished data. Charcot-Marie-Tooth Disease Charcot-Marie-Tooth (CMT) with AR inheritance is a heterogeneous group of inherited motor and sensory neuropathies. Bouhouche et al. (2007b) reported a novel mutation 233C >T in the GDAP1 gene, that was associated with a common haplotype suggesting a Moroccan founder mutation. They reported also patients with CMT2B1 disease that had the mutation 298C > T in the LMNA gene (Bouhouche et al. 2007a). The GDAP1 gene has been associated with both demyelinating and axonal phenotypes; Azzedine et al. (2003) reported already described S194X and a novel R310Q mutation in this gene. X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary motor and sensory neuropathy caused by mutations in the connexin 32 gene (Cx32). Meggouh et al. (1998) reported the first de novo mutation 499delG of the Cx32 gene in a Moroccan patient. Hereditary Spastic Paraplegia Hereditary spastic paraplegia (HSP) may be transmitted in an autosomal dominant manner, an AR manner, or an X-linked recessive manner. At least 35 different genes/loci are associated with HSP. Molecular genetic testing is available on a clinical basis for some types of HSP. Elleuch et al. (2006) reported a dominant frameshift mutation of SPG7 in a Moroccan patient.

Hematological Diseases Haemoglobinopathies are a result of an abnormal structure of the hemoglobin molecule, affecting one of the globin chains. This group of disease is most common in African populations, the Mediterranean basin, and Southeast Asia. Among this group, thalassemia, which is probably the most common single gene disorder worldwide, has a high incidence in the Moroccan population, even though it has not been fully characterized in this country. Thalassemia Mutation/haplotype study of the gene encoding the hemoglobin subunit b (HBB) has been performed on the Moroccan population. Six major mutations were found: Cd 39 (C > T) c.118C > T, Cd 8 (-AA) c.-25_26delAA, IVSI-6T > C c.92+6T > C,

464

A. Sefiani

IVSI-1G > A c.92+1G > A, Cd 6 (-A) c.-20delA, -29(A > G) c.-79 A > G, accounting for 75% of the 86 independent chromosomes studied (Lemsaddek et al. 2003). These data are consistent with the geographical location of the country and historical links with both the Mediterranean and the Sub-Saharan Africa communities. Based on these results, a genetic testing of the HBB gene has been set up to detect the major Moroccan mutations, and it is useful for genetic counseling, presymptomatic diagnosis of at-risk family members and possibly prenatal diagnosis.

Sickle Cell Anemia The term sickle cell disease encompasses a group of symptomatic disorders associated with mutations in the HBB gene and defined by the presence of hemoglobin S (Hb S). The other forms of sickle cell disease result from co-inheritance of Hb S with other abnormal globin beta chain variants, the most common forms being sickle-hemoglobin C disease (Hb SC) and two types of sickle b-thalassemia (Hb S b+-thalassemia and Hb S b+-thalassemia). Other globin beta chain variants such as D-Punjab and O-Arab also result in sickle cell disease when co-inherited with Hb S. HBB sequence analysis may be used following mutation analysis if it is uninformative or as the primary test to detect mutations associated with b-thalassemia hemoglobin variants. Sicke cell anemia is frequent in Morocco but to date, molecular studies in the Moroccan population have only been done on a few cases.

Hemophilia Hemophilia A and B are clinically undistinguishable. The factor VIII gene located in chromosome Xq28, involved in Hemophilia A, shows in 45% of patients an inversion occurring in intron 22 responsible of the gene disruption. A study by Belmahi et al. (1997) showed that among 11 patients studied, 5 had the inversion of intron 22. The same author reported a study performed in 10 Moroccan families with 47 women at risk to be carriers (Belmahi et al. 2001). Among them 27 wished to know her statute and the study found that only 12 were carriers. Other mutations are predominantly point mutations with about 5% being large or small deletions and insertions. Approximately 2% of patients with severe phenotype of hemophilia A do not have a detectable mutation of factor VIII gene. Detection of women carriers of the mutation is essential for genetic counseling.

G6PD Deficiency This deficit is most prevalent in Africa (affecting up to 20% of the population), but is common also around the Mediterranean (4–30%). Even if G6PD deficiency seems frequent in Morocco, there is no recent data available for the real frequency of this disease or the gene mutations in the Moroccan patients.

15


465

Endocrine and Metabolic Diseases Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia (CAH) is an AR disease. It has been revealed that the 21-OH gene (CYP21A2) and its non functional pseudogene (CYP21A1P) are located on chromosome 6 (6p21.3), sharing a high homology of about 98%. Most of the mutations causing 21-hydroxylase deficiency result from intergenic recombinations between CYP21A2 and closely linked CYP21A1P pseudogene. Rare mutations not generated by gene conversion account for 5–10% of 21-hydroxylase deficiency alleles. Abid et al. (2008) reported that the mutation IVS2-13A/C > G of CYP21A2 gene was the most common mutation in Morocco and the p.I172N was associated with the simple virilizing form (Elleuch et al. 2006). The p.Q318X was the second most frequent mutation with a regional distribution: the mutation was especially detected (75%) in patients from the midland of Morocco (Fez). A novel p.L353R mutation was associated with the p.V281L mutation on the same chromosome in one patient at homozygous state.

Familial Hypercholesterolemia Familial hypercholesterolemia (FH) is caused by mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B gene (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. There is a heterogeneous mutational spectrum of FH in Morocco. El Messal et al. (2003) and Chater et al. (2006) identified in Moroccan patients four mutations previously described (C113R, D151, P664L, C690S), five new mutations (C25X, G266C, 313+5G > T, A480E, D558A) and two large specific deletions (FH Morocco-1 and FH Morocco-2) in the LDLR gene.

Mucopolysaccharidosis Alif et al. reported a recurrent mutation p.Pro533Arg of the gene IDUA in Moroccan patients with Mucopolysaccharidosis (MPS) I (Alif et al. 2000); this mutation, which is rare in Europeans, was identified in 92% of mutant alleles. The predominance of this mutation could permit the screening of healthy heterozygotes and genetic counseling for families of Moroccan descent. MPS IIIC is caused by the inherited deficiency of the lysosomal membrane enzyme acetyl-coenzyme A: a-glucosaminide Nacetyltransferase (N-acetyltransferase), which leads to impaired degradation of heparan sulfate. The gene encoding this enzyme is HGSNAT. Recurrent mutation c.(318+1G > A;794C > A) in this gene, was found in three unrelated Moroccan patients and a Spanish patient (Hrebcek et al. 2006). Besides adding new data on the molecular spectrum of MPS IIIC, the

466

A. Sefiani

results obtained in this study will allow carrier detection and prenatal molecular diagnostics with great benefits for the Sanfilippo families. Furthermore, having detected that c.(318 + 1G > A;794C > A) is a recurrent mutation, alleles might be of great epidemiological relevance. As there is no known consanguinity among the patients studied here, c.(318 + 1G > A;794C > A) may represent a founder mutation in the context of the Moroccan population, which, if confirmed, should render the mutation a primary target in molecular studies of MPS IIIC in Morocco.

Dermatologic Diseases Xeroderma Pigmentosum Cells from individuals with Xeroderma pigmentosum (XP) with defective nucleotide excision repair are hypersensitive to killing by UV in comparison to normal cells. XP is known to be associated with mutations in XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG), ERCC1, and POLH (XP-V). Mutations in XPA and XPC account for approximately 50% of XP. Sarasin et al. (2007) studied 32 XP patients mostly from North Africa, and found that XPC mutations were present in 28 probands. They identified the same homozygous frameshift mutation c.1643_1644delTG (p.Val548AlafsX25) in 81% of XPC patients from North Africa. Haplotype analysis of the XPC gene demonstrated a common founder effect for this mutation in the Mediterranean region. XPC appears to be the major disease-causing gene concerning XP in Morocco. Since this unique XPC mutation is responsible for a huge proportion of XP cases, these data will help to set up a first simple XP molecular test, at least, in North Africa.

Hypohydrotic/Anhydrotic Ectodermal Dysplasia Kabbaj et al. (1998) studied a large Moroccan family in which anhidrotic ectodermal dysplasia is transmitted as an AR trait. Fourteen family members, both males and females, were affected and they all had a common ancestor. Linkage analysis by homozygosity mapping permits to find out that dominant and recessive HED are localized to the same chromosomal region which is 2q11-q13 (Kabbaj et al. 1998). The study of another large Moroccan family with autosomal dominant HED by Baala et al. (1999) mapped the disease gene to chromosome 1q42.2–q43, and identified a novel missense mutation in the death domain (DD) of EDARADD gene (c.335T4G, p.Leu112Arg) (Bal et al. 2007). The functional consequences of the dominant (p.Leu112Arg) mutation were studied knowing that EDAR is activated by its ligand, ectodysplasin, and uses EDARADD to build an intracellular complex and activate nuclear factor kappa B (NF-kB). They demonstrated that the p.Leu112Arg mutation completely abrogated NF-kB activation. These results

15


467

confirm that NF-kB activation is impaired in HED and support the role of EDARADD DD as a downstream effector of EDAR signaling.

Incontinentia Pigmenti The diagnosis of Incontinencia Pigmenti (IP) is based on clinical findings and molecular genetic testing of IKBKG (NEMO), the only gene known to be associated with IP. A deletion that removes exons 4 through 10 of IKBKG is present in about 80% of probands. Tnacheri Ouazzani et al. (2007) reported a case of deletion of gene NEMO in an infant girl aged 2 months who had typical skin lesions associated with severe impairment of her left eye.

Cancer Genetics Breast Cancer Several founder mutations are common in specific populations: 185delAG mutation of BRCA1 and 6174delT mutation of BRCA2 in Ashkenazi Jewish women. The 185delAG was reported in one Moroccan family suffering from breast cancer with no Jewish ancestries known (personal unpublished data). Most missense mutations in BRCA1/2 are of uncertain significance. Reference to websites such as the Breast Cancer Information Core (BIC) database may help with interpretation. Other autosomal dominant cancer-predisposing syndromes with an increased risk of breast cancer include: Peutz-Jeghers syndrome (gastrointestinal hamartomas, mucocutaneous pigmentation, and predisposition to gastrointestinal, breast and other cancers), Li-Fraumeni syndrome (soft tissue sarcomas, lung cancer and adreno-cortical carcinoma), Cowden syndrome (which is associated with macrocephaly, tricholemmomas, mucosal neuromas), ataxia telangiectasia (heterozygous carriers are at 3.6-fold risk of breast cancer).

Colorectal Cancer Until recently, familial adenomatous polyposis was considered to be solely due to autosomal dominant inheritance of germline mutations in the APC gene at 5q22.2. But there is emerging evidence that a significant proportion of attenuated FAP cases are due to AR inheritance of mutations in MUTYH (MYH), a DNA repair gene involved in the repair of oxidation damage, at 1p34.1. Early estimates are that, about 25% of those with >9 adenomas and no evidence of dominant family history are due to MUTYH mutations. Homozygous mutations p.Tyr165Cys of MYH and 1186_1187insGG were reported in Moroccan patients with attenuated polyposis.

468

A. Sefiani

Multiple Endocrine Neoplasia Type 2 This autosomal dominant cancer predisposition syndrome is characterized by the association of medullary thyroid cancer (MTC) and phaeochromocytoma. It is caused by activating germline mutations in the RET protooncogene. Multiple Endocrine Neoplasia Type 2 (MEN2) is subdivided into three subtypes, MEN2A, MEN2B, and familial MTC, all with a high risk of MTC arising in the C-cells of the thyroid. Ainahi et al. (2006) and Benazzouz et al. (2006) reported three MEN2 Moroccan families with the heterozygous mutation p.Cys634Tyr.

Familial Mediterranean Fever The Familial Mediterranean Fever is an autosomal recessive hereditary disease. The responsible gene MEFV is encoding the protein marenostrin or pyrin which play an essential role in the regulation of the inflammatory reactions. MEFV gene contains ten exons and most of the mutations have been found on the last exon. Up to date, 152 mutations and polymorpisms have been reported in, where V726A, M694V, M694I, M680I and E148Q are the most common mutations. Identification of MEFV gene mutations is an important step to have a firm diagnosis, to establish a genetic counseling, and to improve management and treatment of patients. Familial Mediterranean Fever (FMF) predominantly affects populations living in the Mediterranean region, with two common mutations: M694V and M694I. Belmahi et al. (2006) determined the mutational spectrum in Maghrebins patients with FMF; the most frequent MEFV mutations in this cohort were M694V and M694I. These mutations account for different proportions of the MEFV mutations in Algerian (5%, 80%), Moroccon (49%, 37%), and Tunisian (50%, 25%) patients. M694I mutation is specific to the Arab population from Maghreb. Other rare mutations were observed: M680L, M680I, A744S, V726A, and E148Q. We estimated the frequency of MEFV mutation carriers among the Arab Maghrebian population at around 1%, which is significantly lower than in non-Ashkenazi Jews, Armenians or Turks.

Cystic Fibrosis Over 1,500 CFTR sequence changes have been described, F508del being the most frequent mutation, along with geographic and ethnic variations in their distribution and frequency. Little is known about the spectrum and frequency of CFTR gene mutations in Moroccan patients; some data are available on cystic fibrosis (CF) in Moroccan patients living in Europe. Ratbi et al. (2008) carried out a preliminary study by screening healthy Moroccan individuals for 32 CFTR gene mutations. Two subjects were heterozygous for F508del and eight others for the (T)5 variant

15


469

(Ratbi et al. 2008). The prevalence of CF in Morocco would then range from 1/1,680 to 1/4,150 considering the effect of consanguinity for other mutations would further increase. The mutation 1811+1.6kbG > A was also reported in consanguineous Moroccan family (personal unpublished data). A Moroccan male having infertility by congenital bilateral absence of the vas deferens had CFTRdup11_13 in one allele and the (T)5 variant in the other one (Ratbi et al. 2007b). These findings indicate that the Moroccan population is at risk for CF and CFTR-related disorders.

Infertility Associated with Multi-tailed Spermatozoa and Large Heads One or more of abnormalities of sperm count, motility, or morphology is found in almost 90% of infertile males. An important proportion of the cases is believed to have a genetic component, yet few causal genes have been identified so far. A previous study by Dieterich et al. (2007), demonstrated that a homozygous mutation c.144delC in the Aurora Kinase C gene (AURKC) led to the production of large-headed polyploid multi-flagellar spermatozoa, a primary infertility phenotype observed in Moroccan patients. This founder mutation results in premature termination of translation, yielding a truncated protein that lacks the kinase domain. The absence of AURKC causes male infertility owing to the production of largeheaded multiflagellar polyploid spermatozoa. In another study, Dieterich et al. (2009), a carrier frequency of 1/50 was established on individuals from the Maghreb, comparable to that of Y-microdeletions, thus far the only known recurrent genetic event altering spermatogenesis. Acknowledgments The author wishes to express his appreciation to Dr. Imane Cherkaoui Jaouad, Dr. Siham Chafaı¨ Elalaoui, Dr. Laila Rifai and Prof. Ilham Ratbi who have helped immeasurably in the preparation of this chapter.

References Abid F, Tardy V, Gaouzi A, El Hessni A, Morel Y, Chabraoui L (2008) CYP21A2 gene mutation analysis in Moroccan patients with classic form of 21-hydroxylase deficiency: high regional prevalence of p.Q318X mutation and identification of a novel p.L353R mutation. Clin Chem Lab Med 46(12):1707–1713 Aboussair N, Berahou A, Perrault I, Elalaoui SC, Megzari A, Rozet JM, Kaplan J, Sefiani A (2010) First North African observation of Leber congenital amaurosis secondary to CEP290 gene mutation. J Fr Ophtalmol (in press) Ainahi A, Kebbou M, Timinouni M, Benabdeljalil N, Fechtali T, Oufara S, El Antri S (2006) Study of the RET gene and his implication in thyroid cancer: Morocco case family. Indian J Cancer 43:122–126

470

A. Sefiani

Alif N, Hess K, Straczek J, Sebbar S, Belahsen Y, Mouane N, Abkari A, Nabet P, Gelot MA (2000) Mucopolysaccharidosis type I in Morocco: clinical features and genetic profile. Arch Pediatr 7 (6):597–604 Allamand V, Guicheney P (2002) Merosin-deficient congenital muscular dystrophy, autosomal recessive (MDC1A, MIM#156225, LAMA2 gene coding for alpha2 chain of laminin). Eur J Hum Genet 10(2):91–94 Azzedine H, Ruberg M, Ente D, Gilardeau C, Pe´rie´ S, Wechsler B, Brice A, LeGuern E, Dubourg O (2003) Variability of disease progression in a family with autosomal recessive CMT associated with a S194X and new R310Q mutation in the GDAP1 gene. Neuromuscul Disord 13(4): 341–346 Baala L, Hagj Rabia S, Zlotogora J, Kabbaj K, Chhoul H, Munnich A, Lyonnet S, Sefiani A (1999) Both recessive and dominant forms of anhidrotic/hypohydrotic ectodermal dysplasia map to chromosome 2q11-13. Am J Hum Genet 64:651–653 Baala L, Briault S, Etchevers HC, Laumonnier F, Natiq A, Amiel J, Boddaert N, Picard C, Sbiti A, Asermouh A, Attie´-Bitach T, Encha-Razavi F, Munnich A, Sefiani A, Lyonnet S (2007) Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis. Nat Genet 39(4):454–456 Bal E, Baala L, Cluzeau C, El Kerch F, Ouldim K, Hadj-Rabia S, Bodemer C, Munnich A, Courtois G, Sefiani A, Smahi A (2007) Autosomal dominant anhidrotic ectodermal dysplasia at the EDARRAD locus. Hum Mutat 28:703–709 Belmahi L, Viemont M, Benouachane T, M’seffer-Alaoui F, Delpech D, Sefiani A (1997) Recherche des inversions du ge`ne F8c dans l’he´mophilie A au Maroc: a` propos de 11 cas. Rev Mar Rhuma 8:64–70 Belmahi L, Benouchane T, Viemont M, Maani K, Hadj Khalifa H, M’Seffer Alaoui F, Delpech M, Sefiani A (2001) Sept. Carriers detection in hemophilia A, about 27 cases. Maroc Medical, tome 23, n 3 Belmahi L, Sefiani A, Fouveau C, Feingold J, Delpech M, Grateau G, Dode´ C (2006) Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever. C R Biol 329(2):71–74 Belmouden A, Melki R, Hamdani M, Zaghloul K, Amraoui A, Nadifi S, Akhayat O, Garchon HJ (2002) A novel frameshift founder mutation in the cytochrome P450 IBI (CY1BI) gene is associated with primary congenital glaucoma in Morocco. Clin Genet 62 (4):334–339 Benazzouz B, Chraı¨bi A, Doghmi Y, El Bacha S, Boutayeb S, Kadiri A, Hilal L (2006) Characterization of RET proto-oncogene C634Y mutation in a Moroccan family with multiple endocrine neoplasia type 2A. Ann Endocrinol 67:21–26 Bouazzaoui N (1994) Consanguinity and public health in Morocco. Bulletin de l’Acade´mie Nationale de Me´decine 178:1013–1025 Bouhouche A, Benomar A, Birouk N, Bouslam N, Ouazzani R, Yahyaoui M, Chkili T (2003) High incidence of SMN1 gene deletion in Moroccan adult-onset spinal muscular atrophy patients. J Neurol 250(10):1209–1213 Bouhouche A, Birouk N, Azzedine H, Benomar A, Durosier G, Ente D, Muriel MP, Ruberg M, Slassi I, Yahyaoui M, Dubourg O, Ouazzani R, LeGuern E (2007a) Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): phenotype-genotype correlations in 13 Moroccan families. Brain 130(Pt 4):1062–1075 Bouhouche A, Birouk N, Benomar A, Ouazzani R, Chkili T, Yahyaoui M (2007b) A novel GDAP1 mutation P78L responsible for CMT4A disease in three Moroccan families. Can J Neurol Sci 34(4):421–426 Chater R, Aı¨t Chihab K, Rabe`s JP, Varret M, Chabraoui L, El Jahiri Y, Adlouni A, Boileau C, Kettani A, El Messal M (2006) Mutational heterogeneity in low-density lipoprotein receptor gene related to familial hypercholesterolemia in Morocco. Clin Chim Acta 373 (1–2):62–69

15


471

Cherkaoui M, Baali A, Larrouy G, Sevin A, Boe¨tsch G (2006) Consanguinity, fertility of couples and mortality of children in the high Atlas population (commons of Anougal and Azgour, Marrakesh, Morroco). Int J Anthropol 20:199–206 Dieterich K, Soto Rifo R, Faure AK, Hennebicq S, Ben Amar B, Zahi M, Perrin J, Martinez D, Se`le B, Jouk PS, Ohlmann T, Rousseaux S, Lunardi J, Ray PF (2007) Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nat Genet 39 (5):661–665 Dieterich K, Zouari R, Harbuz R, Vialard F, Martinez D, Bellayou H, Prisant N, Zoghmar A, Guichaoua MR, Koscinski I, Kharouf M, Noruzinia M, Nadifi S, Sefiani A, Lornage J, Zahi M, Viville S, Se`le B, Jouk PS, Jacob MC, Escalier D, Nikas Y, Hennebicq S, Lunardi J, Ray PF (2009) The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population. Hum Mol Genet 18(7):1301–1309 Ebermann I, Walger M, Scholl HP, Charbel Issa P, L€ uke C, N€ urnberg G, Lang-Roth R, Becker C, N€urnberg P, Bolz HJ (2007) Truncating mutation of the DFNB59 gene causes cochlear hearing impairment and central vestibular dysfunction. Hum Mutat 28(6):571–577 El Messal M, Aı¨t Chihab K, Chater R, Vallve´ JC, Bennis F, Hafidi A, Ribalta J, Varret M, Loutfi M, Rabe`s JP, Kettani A, Boileau C, Masana L, Adlouni A (2003) Familial hypercholesterolemia in Morocco: first report of mutations in the LDL receptor gene. J Hum Genet 48(4):199–203 Elkerch F, Sbiti A, Azibi K, Leturcqu F, Boudouma M, Kaplan JC, Sefiani A (2001) La gammasarcoglycanopathie par la mutation del521T au Maroc. a` propos de 20 cas. Rev Magh Pe´diat 11 (4):189–192 Elleuch N, Depienne C, Benomar A, Hernandez AM, Ferrer X, Fontaine B, Grid D, Tallaksen CM, Zemmouri R, Stevanin G, Durr A, Brice A (2006) Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia. Neurology 66(5):654–659 Hami H, Soulaymani A, Mokhtari A (2006) Endogamy, isonymy and consanguinity in the region of the Gharb-Chrarda-Beńi Hssen (Morocco). Antropo Revista de Antropologia fisica 11:223–233. www.didac.ehu.es/antropo Hrebcek M, Mrazova L, Seyrantepe V, Durand S, Roslin NM, Noskova L et al (2006) Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C Syndrome). Am J Hum Genet 79:807–819 Jaouad IC, Elalaoui SC, Sbiti A, Elkerch F, Belmahi L, Sefiani A (2009) Consanguineous marriages in Morocco and the consequence for the incidence of autosomal recessive disorders. J Biosoc Sci 41(5):575–581 Kabbaj K, Baala L, Chhoul H, Sefiani A (1998) Autosomal recessive anhidrotic ectodermal dysplasia in a large Moroccan family. J Med Genet 35:1043–1044 Lemsaddek W, Picanco I, Seuanes F, Mahmal L, Benchekroun S, Khattab M, Nogueira P, Osorio-Almeida L (2003) Spectrum of Thalassemia mutations and HbF levels in the heterozygous Moroccan population. Am J Hematol 73:161–168 Meggouh F, Benomar A, Rouger H, Tardieu S, Birouk N, Tassin J, Barhoumi C, Yahyaoui M, Chkili T, Brice A, LeGuern E (1998) The first de novo mutation of the connexin 32 gene associated with X linked Charcot-Marie-Tooth disease. J Med Genet 35(3):251–252 Melki R, Idhajji A, Driouiche S, Hassani M, Boukabboucha A, Akhayat O, Garchon H, Belmouden A (2003) Mutational analysis of the Myocilin gene in patients with primary open-angle glaucoma in Morocco. Ophthalmic Genet 24(3):153–160 Ouldim K, Sbiti A, Natiq A, El-Kerch F, Cherkaoui S, Sefiani A (2008) Unexpected fertility and paternal UPD 22. Fertil Steril 90(5):2013.e13–2013.e15 Ratbi I, Hajji S, Ouldim K, Aboussair N, Feldmann D, Sefiani A (2007a) The mutation 35delG of the gene of the connexin 26 is a frequent cause of autosomal-recessive non-syndromic hearing loss in Morocco. Arch Pediatr 14(5):450–453 Ratbi I, Legendre M, Niel F, Martin J, Soufir JC, Izard V, Costes B, Costa C, Goossens M, Girodon E (2007b) Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod 22(5):1285–1291

472

A. Sefiani

Ratbi I, Geńin E, Legendre M, Le Floch A, Costa C, Cherkaoui-Deqqaqi S, Goossens M, Sefiani A, Girodon E (2008) Cystic fibrosis carrier frequency and estimated prevalence of the disease in Morocco. J Cyst Fibros 7(5):440–443 Sarasin A, Bourillon A, Bourrat E, Armier J, Pham D, Blanchet-Bardon C, Khadir K, Zghal M, Robert CC, Grandchamp B, Stary A, Benchikhi H, Soufir N (2007) Mutation avec effet fondateur dans le Xeroderma Pigmentosum du groupe C chez les malades d’Afrique du Nord: l’espoir d’un diagnostic preńatal et pre´symptomatique simplifie´ (communication orale). Ann Dermatol Venereol 134:7S1–7S70 Sbiti A, Arazam A, Sefiani A (2003a) Le diagnostic molećulaire des amyotrophies spinales infantiles et son inte´reˆt dans les hypotonies congeńitales au Maroc: a` propos de 32 cas. Rev Maghr Pe´diatr 13:129–133 Sbiti A, El Kerch F, Sefiani A (2003b) Analysis of dystrophin gene deletions by multiplex PCR in Moroccan patients. J Biomed Biotechnol 2:158–160 Talbi J, Khadmaoui A, Soulaymani A, Chafik A (2007) Study of consanguinity in Moroccan population. Influence on the profile of health. Antropo Revista de Antropologia fisica 15:1–11. www.didac.ehu.es/antropo Tnacheri Ouazzani B, Guedira K, Dali H, Laghmari M, Ibrahimy W, Daoudi R, Sefiani A, Chakir M, Jiddane M, Mohcine Z (2007) Incontinentia pigmenti: a case study. J Fr Ophtalmol 30(8):e24

Chapter 16

Genetic Disorders in Oman Anna Rajab

The Country and Population Oman is situated in the southeast of the Arabian Peninsula along the east coast of the Persian Gulf and its territory being 309,500 km2. It has its borders with United Arab Emirates to the North, Saudi Arabia to the West and Yemen to the South West. After the accession of His Majesty Sultan Qaboos Bin Said in 1970, Oman opened the doors wide to the modern world. Since 1970, progress has been extremely rapid. Schools, roads, hospitals, electricity and telecommunications have been brought to the remotest regions. Main sources of Oman’s income are oil, gas, fisheries, agriculture, industry and tourism. The National census (2006) showed that the total population was 1,850,000. In general, the Omani population is characterized by a rapid rate of growth, large family size with an average of seven children per family. Oman was one of the fastest growing nations with natural population growth of 3.7% per year during 1980–1993. After a comprehensive birth-spacing campaign was started, the population growth dropped to less than 2% per year. Oman is generally considered a very young nation (See Population pyramid Fig. 16.1). There are eight main geographical areas in Oman referred to as “Manataq” which are further divided into districts referred as “Walayat” (see Fig. 16.2 Map of Oman).

Oman History The earliest archeological evidence of settlements in Oman dates back to about 12,000 BC, towards the end of the Ice Age. The tribes that took possession of Arabia in the beginning of the New Era were composed of two main stocks. One of these A. Rajab Consultant Clinical Geneticist, Genetic Unit, Ministry of Health, Sultanate of Oman e-mail: [email protected]


473

474

A. Rajab 80 + 75-79 70-74 65-69 60-64 55-59 50-54 45-49 40-44 35-39 30-34 25-29 20-24 15-19 10-14 5-09 0-04 10%

8%

6%

4%

2%

00%

2%

Males

4%

6%

8%

10%

Females

Fig. 16.1 Population pyramid of Omani nationals (2007)

stocks was Kahtan (Bani Hina), who colonized the Yemen and moved up north into Oman territories after the collapse of the Mareb dam in Yemen in fifth century AD. The other was Adnan (Bani Ghafir, descended from Ismael) who occupied the northern part of Arabian Peninsula (Carter 1982). In history, Bani Hina and Bani Ghafir have been opponents and have been competing for the territories for pastures and watering places. Later on, more Arab tribes (Northern Arabs) came from Iraq and settled in the north of Oman. Oman’s sailors and merchants traded from one end of the monsoon to the other, from China to East Africa as far back as the eighth century AD and forged their ways in ancient times to the markets of India and the distant shores of China. For centuries, Muscat was an important place of trade with India, Red Sea and East Africa. As Oman lies on the cross-roads between the East and the West, mixing

16

Genetic Disorders in Oman

475

Fig. 16.2 Map of Oman

with populations from neighboring Asian and African countries occurred because of immigration, trade, introduction of slaves and mercenaries.

Medical and Genetic Services in Oman In the past 30 years, Oman has witnessed remarkable social and economic growth, which is best reflected in the well-organized and efficient health care system. There has been a significant decrease in the incidence of communicable diseases and in the mortality and morbidity rates of infants and children under 5 years (Fig. 16.3). In the past, the scale of the problem of congenital/genetic disorders was hidden in the high infant mortality because most affected infants died without being diagnosed. Now, the majority are diagnosed and provided with best possible management. As a result, the number of surviving affected children increases by the annual

476

A. Rajab 100 80 60 40

IMR U5 SBR

20 0 1980

1985

1990

1995

2000

2005

Fig. 16.3 Changes in infant mortality rates (IMR), mortality under 5 years (U5) and Stillbirth (SBR) at 5-year intervals observed during the past 25 years (1980–2005) from the Ministry of Health information system data

birth cohort causing a considerable burden on the health-care services (Alwan and Modell 1997). Conditions with high lethality in perinatal period may be underrepresented as well as conditions seen in specialized clinics such as deafness, blindness, dermatological, orthopedic, neurological, psychiatric and numerous genetic diseases presenting outside of pediatric age group. The Ministry of Health in Oman is wishing to promote the potential benefits of the genomic advances for the health of Omani population, considering the context of the added value of the genetic technology to health-care delivery and recognizing the urgent need for the application of genomics in the Sultanate of Oman. High level of consanguinity (Rajab and Patton 2000) and the presence of genetic isolates create favorable circumstances for genetic studies. Specialized National Genetic Health Center is under construction in the capital city of Muscat and is expected to open its doors in 2010. Emphasis in Oman is on community genetic services which combine the skills of community medicine and medical genetics. The community approach is an accepted policy in Oman, and the approach for an early identification and prevention of genetic disease is aimed to be applied for the population at risk. Genetic Services in Oman are in the process of being incorporated into Primary Health Care. Educational packages and advocacy sessions delivered regularly to increase population genetic literacy. The first Community Genetic service in Oman was established in 1999 as National Program for the control genetic blood disorders. It is an integrated strategy combining the best possible patient care as a first objective coupled with community education, high-risk population screening and genetic counseling. Clinical genetic services in Oman commenced from 1993, cytogenetic laboratory from year 2000 and molecular genetic services were established in 2007.

Genetic Disorders in Oman Hospital-based data on genetic disease was collected in Oman from 1990 and presented in Tables 16.3–16.12. The number of diagnosed condition was notably

16


477

growing over years parallel to the improvement in diagnostic expertise and growth of diagnostic capacity. It is understood that, before comprehensive care became available, the illness and death of the children may have been attributed to other causes. As an example, limited access to detailed studies of various metabolic defects such as mitochondrial and glycosulation defects may be the cause of underdiagnosis and may not be a reflexion of disease rarity (Bappal et al. 2001).

Chromosomal Rearrangements Chromosomal rearrangements in 28.3% of 1,800 pediatric samples were studied in Cytogenetic Laboratory of Ministry of Health (Goud et al. 2005) with trisomies, tetrasomies and monosomies, translocations, autosomal aneploidies in the order of frequency. The birth prevalence of Down syndrome in Oman was 1:350 live births during 2000–2008 (Rajab et al. unpublished).

Single Gene Defects Autosomal Recessive Diseases Autosomal recessive conditions are by far the commonest and remain the major contributors to childhood morbidity, mortality and handicap (Tables 16.1–16.10). The complexity of dealing with autosomal recessive disorders is that it sums to a large number when a large variety of rare disorders are put together. The birth prevalence of various recessive disorders is largely unknown. The figures of recessive disorders frequently ascertained in pediatric practice derived from 1993–2002 hospital-based data presented in Table 16.1 (Rajab et al. 2005a, b). Some of the genetic conditions in Oman are confined to a common population group and reflect their ethnic and genetic diversity. It is evident from Fig. 16.4 that a number of autosomal recessive conditions could be placed on the map reflecting the places of residence of specific population groups.

Hemoglobinopathies Hemoglobin disorders represent highest population prevalence for single genes reflecting natural selection due to advantage for survival in heterozygous state against malaria. In Oman, the estimated birth prevalence of infants with hemoglobin disorders is 3.5–4.7/1,000 (Daar et al. 1998; Rajab and Patton 1997; Rajab and Patton 1999; White et al. 1993). Around 10% of Omani nationals are carriers of gene of sickle-cell anemia (OMIM 6039030), 2–3% carry the gene of b-thalassaemia (OMIM 141900) and 45% are carriers of a-thalassaemia (OMIM 141800).

478

A. Rajab Table 16.1 Commonly ascertained autosomal recessive diseases in Oman among 420,000 live births (1993–2002) Autosomal recessive diseases No of patients born 1993–2002 Spinal muscular atrophy (Wernig-Hoffman 56 disease) Congenital adrenal hyperplasia 55 Polycystic kidneys 34 Cystic fibrosis 32 Primary microcephaly 31 Renal tubular acidosis 28 Congenital nephrotic syndrome (Finish type) 25 Nesidoblastosis 24 Apple-peel bowel syndrome 21 Zellweger syndrome 19 Metachromatic leukodystrophy 18 Congenital generalized lipodystrophy 18 Ellis–Van creveld syndrome 18 Scwartz–Jampel syndrome 15 Bardet–Biedl syndrome 14 Robinow syndrome 12 Oculocutaneous albinism 14 Epidermolysis bullosa 15 Galactosialidosis 9 Cerebro-oculo-musculo-skeletal syndrome 9 Meckel-Gruber syndrome 9 Carbohydrate-deficient glycoprotein syndrome 8 Mucopolysacharidoses 8 Rajab et al. 2005a, Community Genet (8):27–30 Copyright permission from S. Karger AG, Basel 28.05.2005

the Sultanate of Observed incidence 1 in 10,000 birth 1 in 10,000 birth 1 in 12,000 birth 1 in 15,000 birth 1 in 15,000 birth 1 in 20,000 birth 1 in 20,000 birth 1 in 20,000 birth 1 in 20,000 birth 1 in 20,000 birth 1 in 25,000 birth 1 in 25,000 birth 1 in 25,000 birth 1 in 30,000 birth 1 in 30,000 birth 1 in 35,000 birth 1 in 30,000 birth 1 in 30,000 birth 1 in 50,000 birth 1 in 50,000 birth 1 in 50,000 birth 1 in 50,000 birth 1 in 50,000 birth

Currently, about 400 patients with thalassaemia major and 3,000 affected with various sickle cell disorders reside in the Sultanate. The birth prevalence of hemoglobin disorders are presented in Table 16.2.

Inborn Errors of Metabolism Various groups of metabolic diseases were observed in hospital practice (Bappal et al. 2001; Joshi et al. 2002; Joshi and Venugopalan 2007).Metabolic endocrinipathies, disorders of aminoacids, organic acids and long-chain fatty acids, various lysosomal storage disorders and mitochondrial cytopathies, observed in hospital practice, are presented in Table 16.3.

Neurogenetic Disorders A number of handicapping genetic disorders observed included microcephalic syndromes, syndromes with brain structural anomalies, neuronal migration defects,

16


479

RS = Robinow Syndrome CAH = Congenital Adrenal Hyperplasia CGL = Congenital Generalised Lipodystrophy CDGS = Carbohydrate-Deficient Glycoprotein Syndrome MGS = Meckel-Gruber Syndrome

EVC = Ellis Van Creveld Syndrome SC-J = Schwartz Jampel Syndrome GS = Galactosialidosis BBS = Bardet-Biedl Syndrome

Fig. 16.4 Geographical areas of oman representing high density of (90% of cases) autosomal recessive conditions. Rajab et al. 2005a, b Community Genet (8):27–30. Copyright permission from S. Karger AG, Basel 28.05.2005

Table 16.2 Birth prevalence of b-chain disorders in Oman (Rajab and Patton 1999) Region Total birth AS (%) No. AS b-thal No. Total % Total No. of 1989–1992 trait b-thal b-thal trait b-thal trait (%) trait and AS and AS Musandam 2,174 14.3 311 5.4 117 19.7 428 Dakhliya 22,107 14.3 3,161 3.3 730 17.6 3,891 North 15,076 13.3 2005 2.4 362 15.7 2,367 Sharqiya Dhahir 13,712 11.0 1,508 3.3 452 14.3 1,961 Capital 30,339 9.1 2,761 4.2 1,274 13.3 4,035 South Bathna 26,551 10.0 2,655 2.2 584 12.2 3,239 South 14,059 8.5 1,195 3.5 492 12 1,687 Sharqiya North Batna 37,347 5.6 2,091 4.5 1,681 10.1 3,772 Dhufar 12,053 0 0 0 0 0 0 Wustah 2,110 0 0 0 0 0 0 Total

175,538

8.9

15,688

3.2

5,692

12.2

21,380

480

A. Rajab

Table 16.3 Inborn errors of metabolism from hospital data Disorder OMIM Metabolic endocrinopathies Congenital adrenal hyperplasia 201910, 202110, 107910 Metabolic rickets 277440, 264700, 600785, 241520 Apparent mineralocorticoids excess 218030 Nesidioblastosis 256450 Maple syrup urine disease 248600 Tyrosinaemia 276700 Dihydropterin synthetase deficiency 261640 Homocystinuria 236200 Glutaric aciduria 231670, 231680 Organic acidurias Propionic 606054 Isovaleric 243500 Lysosomal storage disorders Mucopolysaccharidoses 607014, 607015, 252300 Multiple sulphatase deficiency 272200 Mucolipidosis I and II 256500 and 256550 Glycogen storage diseases 232200, 230800, 232400, 232300, 232700 Galactosialidosis 256540 GM1–Gangliosidodis 230500 Long-chain fatty acid oxidation defects Zellweger Syndrome 214100 Refsum disease 266500 Mitochondrial diseases Kearns-Sayre syndrome 530000 Congenital lactic acidosis Bappal et al. 2001 Pyruvate carboxylase deficiency 266150 pyruvate dehydrogenase deficiency 208800 Abnormality of fatty alcohol metabolism Sjogren–Larsen syndrome 270200

neurodegenerative diseases, seizure disorders and neuromuscular disorders (Table 16.4).

Osteodysplasias and Spondylodysplasias Various diseases of bone, skeletal dysplasias and chondrodysplasias from hospitalbased registry are presented in Table 16.5.

Diseases Affecting Kidneys, Liver and Gut Various types of cystic renal dysplasias, congenital nephropathies, renotubular disorders and disorders affecting liver and gut are presented in Table 16.6.

16


481

Table 16.4 Genetic diseases with neurologic dysfunction, brain structural defects and neuromuscular disorders Disorder OMIM Nonsyndromic mental retardation 249500 Syndromes with mirocephaly Primary microcephaly 608716, 251200 Lethal microcephaly Rajab et al. 2007a, b Microcephaly with pontocerebellar hypoplasia Rajab et al. 2003 Cohen microcephaly 216550 Microcephalic Primordial Dwarfism 210710 Syndromes with brain malformations and poor outcome Walker–Warburg syndrome 236670 Pena–Shokeir syndrome 214150 Meckel–Gruber syndrome 249000 Fryns syndrome 220950 Jouber syndrome 213300 Conditions with regression/ neurologic deficit/seizures Baten’s disease 256730 Tay–Sach’s disease 272800 Niemann–Pick’s disease 257220 Leukodystriophies 251100, 254200, 264090 Progressive myoclonic epilepsy 310370 Hereditary spastic paraplegia 270800 Hyperekplexia 149400 Genetic form of cerebral palsy Rajab et al. 2006 Neuromuscular disorders Spinal muscular dystrophies 253300, 253400, 253900 Congenital myopathies 255310, 161100, 601462 Charcot–Marie–Tooth neuropathy 214400 Facioscapulohumeral dystrophy 158900 Limb girdle muscular dystrophies 608099, 160500, 253601

Table 16.5 Skeletal dysplasias and diseases affecting bone structure Condition Asphyxiating thoracic dystrophy EllisVan–Creveld syndrome Hypochondrogenesis Grebe chondrodysplasia Robinow syndrome Spondyloepiphyseal dysplasia Omani type 3-M dwarfism (Dolichospondylic Dysplasia) Osteogenesis Imperfecta Pycnodysostosis Bamatter syndrome Osteopetrosis

OMIM 208500 225500 200610 200700 268310 608637 273750 610195 265800 231070 259700

Immunodeficiencies and Chromosomal Instability Syndromes Various syndromes with defects of immune system and DNA repair observed in Oman are presented in Table 16.7.

482

A. Rajab Table 16.6 Disease affecting kidneys, liver and gut Apple-peel bowel syndrome Infantile polycistic kidneys Focal segmental glomerulosclerosis Finish type congenital nephrosis Steroid-resistant nephrotic syndrome Nephronophtysis Cystinosis Hyperoxaluria Distal renal tubular acidosis Bartter syndrome Familiar intrahepatic cholestasis Crigler-Najjar syndrome type I Wilson disease

243600 263200 603278 256300 600995 256100, 602088 219800 259900 602722 607364 211600 218800 277900

Table 16.7 Diseases with impaired immunity and increased chromosomal fragility Immunodeficiencies and chromosomal instability OMIM Ataxia-telangiectasia 208900 Bloom syndrome 210900 Chronic granulomatous disease 233700 Common variable immunodeficiency 240500 Cyclic neutropenia 610738 Hemophagocytic lymphohistiocytosis type 1 267700 Fanconi anemia 227650 Nijmegen syndrome 251260 SCID 102700 Xeroderma pigmentosusm 278700

Table 16.8 Dematological diseases Dematological disorders Epidermolysis bullosa Hypohydrotic ectodermal dysplasia Lamellar ichthyosis Ichthyosis congenita

OMIM 226700, 226670 224900 242300 242500

Genodermatoses Common dermatological conditions observed in Oman are presented in Table 16.8.

Diseases Affecting Vision and Hearing Diseases associated with visual and hearing deficit represented in Table 16.9.

16

Genetic Disorders in Oman Table 16.9 Congenital blindness and deafness Congenital blindness and deafness Optic atrophy Congenital nonsyndromic sensoryneural deafness (Simsek et al. 2001) Leber congenital amaurosis Usher syndrome

483

OMIM 258500 220290 204000 276900

Miscellaneous Recessive Disorders Table 16.10 Table 16.10 Various autosomal recessive diseases from hospital records Autosomal recessive disorders OMIM Bardet–Biedl syndrome 209900 Congenital insensitivity to pain with anhydrosis 256800 Congenital generalized lipodystrophy 269700, 608594, 608154 Cutis laxa with growth and developmental delay 219200 Escobar syndrome 265000 Long Q-T syndrome 152427 Neonatal progeroid syndrome 271900 Oculocutaneous albinism 606952 Schwartz–Jampel syndrome 255800

Autosomal Dominant Conditions Table 16.11 Table 16.11 Autosomal dominant disorders Disorder Achondroplasia Adult polycystic kidney disease Allagille syndrome Craniosynostoses, acrocephalosyndactily Deafness congenital nonsyndromic Epidermolysis bullosa simplex Fanconi renotubular syndrome Hereditary angioedema Huntington’s chorea Hyper-IgE syndrome Neurofibromatosis Sotos syndrome Spinocerebellar ataxia Tuberous Sclerosis

OMIM 100800 601313 118450 101400 600965 131800 134600 106100 143100 147060 162200 117550 117360 191100

484

A. Rajab Table 16.12 X-linked conditions observed in Oman Disorder Anhydrotic ectodermal dysplasia Alport syndrome Bruton agammaglobulinaemia Hemophilia A Hemophilia B Duchenne muscular dystrophy Lissencephaly (LIS 4A) OTC deficiency Testicular feminization Syndrome X-linked forms of mental retardation

OMIM 305100 301050 300300 306700 306900 310200 300121 311250 300068 300624, 312750, 301040

X-Linked Conditions The commonest X-linked condition in Oman is G6PD deficiency found in 28% of males and 12% females (Daar and Pathare 2006). In a majority of Omanies, G6PD deficiency is benign (Daar et al. 1996; White et al. 1993) which suggest that asymptomatic forms A+ and B+ G6PD types predominate. Neonatal jaundice and hemolytic crises are seen in a small proportion of patients, mainly in Northern parts of Oman (Table 16.12).

Novel Phenotypes and Variants, and Novel Genotypes Two novel forms of lipodystrophy have been described in Omani families. The fist was a novel phenotype of congenital generalized lipodystrophy with effect on both, skeletal and nonskeletal muscle with the locus mapped to 9q (Rajab et al. 2002; Heathcote et al. 2002). Apart from generalized Lipodystrophy, there were reduced exercise tolerance, percussion myotonia and nonskeletal muscle hyperthrophy, such as hypertrophic pyloric stenosis, prominent veins (phlebomegaly), hyperthrophy of urethers, tonque, esophagus and myocardium (Rajab et al. 2010). The second novel form of Congenital Generalized Lipodystrophy with deafness was described in three Omani children with low birth weight, short stature, retarded bone age, tendency to fractures, striated metaphyses, sensorineural deafness and delayed cognitive development (Rajab et al. 2003). The recognized features of Bernadinelli-Seip lipodystrophy such as abnormalities of lipids and insulin, hepatosplenomegaly, acanthosis and hirsutism were not found. Microcephaly, a lethal form of prenatal onset was described in four siblings in an Omani family (Rajab et al. 2007a). Gene found in Amish families with lethal microcephaly was excluded. Low birth-weight, disproportionately small head, fetal distress, apnoea, seizures and facial features reminiscent of Amish microcephaly were noted. Brain imaging revealed a simplified gyral pattern with normal to

16


485

slightly thinned cortical gray matter, thin corpus callosum, mild brainstem and cerebellar hypoplasia. All patients died within hours to weeks after birth following severe apnoea attacks and central hypoventilation. A new form of Escobar variant with pursed mouth, creased tongue, ophthalmologic features and scoliosis was described in children from Oman and was found to be acetylcholine receptor pathway mutations explaining various fetal akinesia deformation sequence disorder (Rajab et al. 2005b, Michalk et al. 2008). Another phenotype of arthrogryposis type Escobar from Oman presenting at birth with severe contractures are found to be prenatal myasthenia caused by disruption of the acetylcholine receptor fetal subunit (Hoffmann et al. 2006). An autosomal recessive form of spastic cerebral palsy with wicrocephaly and mental retardation have been reported in two interrelated sibships presenting with mental retardation and spasticity. The phenotypic features were resembling such of cerebral palsy following birth asphyxia with no history of birth asphyxia in any of the patients (Rajab et al. 2006).Genetic study is underway for suggestive linkage to the locus of hereditary spastic paraplegia. Extensive Brain Calcifications in two interrelated Omani families were described in eight children manifesting autosomal recessive genetic disorder (Rajab et al. 2009). Brain imaging revealed extensive scattered calcifications of basal ganglia and cortex, similar to Aicardi–Goutieres Syndrome (AGS) or “Coats’ Plus” syndrome. However, the clinical features in the present families diverge substantially from these two syndromes. Growth delay, mild developmental delay and poor school performance were present in all the affected individuals, but progressive deterioration of neurological function was not apparent, nor were there significant cortical white matter disease or retinopathy. Genome-wide linkage and fine-mapping analyses indicate a genetic locus for this disorder on Chromosome 2 with a LOD score of 6.17. In all, the Chromosome 2 locus is novel and the clinical presentation displays features distinguishing the disorder from either Coats’ or AGS, making this a new variant or possibly a new disorder of inherited brain calcification. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11–21 was described in three siblings with postnatal microcephaly, mental retardation, optic atrophy, seizures, spasticity and growth failure. A simplified frontal gyral pattern with cerebellar hypoplasia, corpus callosum and midbrain hypoplasia was found on MRI scan (Rajab et al. 2003). A novel type of spondyloepiphyseal dysplasia was described in nine individuals from two consanguineous sibships (OMIM 608637) missence mutation in C6ST-1 gene R304Q (Rajab et al. 2004; Tiele et al. 2004). The clinical features include near to normal length at birth, short stature with final height of 110–130 cm, severe shortening of the upper segment due to severe progressive kyphoscoliosis, severe arthritic changes with joint dislocations, rhizomelic limbs, genu valgum, cubitus valgus, mild brachydactyly, camptodactyly, microdontia and normal intelligence osteoarthropathy and spinal involvement resulted in physical handicap in early adulthood, and female patients were disabled earlier than males. Comparison of these patients with other skeletal dysplasias suggests that they represent a previously undescribed variant of spondyloepiphyseal dysplasia.

486

A. Rajab

Positional cloning and a gene of Autosomal Recessive Robinow syndrome were first discovered in a study of Omani patients (Afzal et al. 2000a, b). It is allelic to dominant brachydactily type B, and caused by mutation of ROR2. Scwartz–Jampel Syndrome (chondrodystrophic myotonia) in an Omani family with three affected created a base for genetic study with identification of SJS locus to chromosome 1p36 and the discovery of perlecan, the major proteoglycan of basement membranes being altered in patients with Schwartz–Jampel syndrome (Nicole et al. 1995, 2000). Geroderma osteodysplastica patients from Oman (OMIM 231070) were described. Subsequent analysis of SCYL1BP1 in three Omani GO patients from families reported by Rajab et al. (2008) identified homozygosity for a 2-bp deletion in exon 1 of the SCYL1BP1 gene, affecting the deduced methionine start codon (Hennies et al. 2008). Protein blot analysis of fibroblast lysate from the Omani patient revealed complete absence of SCYL1BP1, indicating a loss-of-function effect. Wrinkly skin syndrome (autosomal recessive cutis laxa) multicenter study included patients from Oman (Rajab et al. 2008). Impaired glycosylation caused by mutations in the vesicular H+ATPase subunit ATP6V0A2 was detected in Omani families. (Kornak et al. 2008). Cohen syndrome is a disorder described in Finland characterized by microcephaly, mental retardation, unique facial features, neutropenia and ophthalmologic findings. A novel mutations of the COH1 gene in an Omani familywere found (Hennies et al. 2004; Mochida et al. 2004), providing the evidence that COH1 is responsible for Cohen syndrome in a wide geographic distribution. Hemophagocytic Lymphohistiocytosis type 1 studies in Oman were performed in Sultan Qabus University. Mutations in FHL1 gene (Del 9q 21.5-22; Pro 89!Thr, Arg225!Pro; trp374!stop codon; 50delT; mutation L17X; 12 bp inframe deletion (codon 284–287); Pro188!leu; Thr173!met change) were found in Omani families (Ohadi et al. 1999; Muralitharan et al. 2005, 2007). Hypopituitarism and hypoglycaemia in an Omani family in three affected children was found to have novel LHX3 mutation (Rajab et al. 2008). They also were of short stature, short neck, osteopenia, soft hyperelastic skin, hypermobile joints, spinal vertebral anomalies, deep palmar and plantar creases, learning difficulties and sensorineural deffness. Three M syndrome (DOLICHOSPONDYLIC DYSPLASIA) (OMIM 273750) from Omani families was studied with the identification of a new aminocaid change in exon 23 (Q1469R) on 6p 21.1 (Huber et al. 2009) Bardet–Biedl syndrome families from Oman were enrolled in the multicenter study with identification of FLJ23560 as BBS10 on chromosome 12q21.2 (White et al. 2007). The original phenotype of Bardet–Biedl syndrome with nephrosis, severe brain malformations and early lethality was observed (unpublished data). Allopecia universalis congenita (OMIM 203655) in Omani families was found to map to 8p21.2 with mutation 2776+1, G.A in exon 12 (Cichon et al. 1998). Grebe acromesomelic dysplasia (OMIM 200700) mutations were studied in Omani families with identification of a new deletion of G1144 on chromosome 20q11.2 (Al-Yahyaee et al. 2003)

16


487

New mutation of the gene regulating factor X function was found in Omani family with bleeding disorder. Familial CRM+ FX deficiency was found to be from impaired prothrombinase activity of factor X (Gly381Asp Factor X) (Pinotti et al. 2003). Paroxysmal nonkinesigenic dyskinesia (OMIM 118800) in Omani family was studied with identification of a novel mutation (c.20C>T: A7V; c.26C>T: A9V) of Myofibrillogenesis regulator 1 gene (MR-1) (Hempelmann et al. 2006). Spinal muscular atrophy (OMIM 553300) study conducted at Sultan Qabus University identified deletions of exons 5,6,7 and 8 on chromosome on 5q12.2q13.3 in Omani families (Simsek et al. 2003; Haider et al. 2001).

Comment As children with handicapping genetic disorders now survive, the population of patients on long-term therapy has steadily expanded causing a considerable burden on the health-care and social services. National strategies for the prevention and management of disorders and birth defects can be defined according to the epidemiological situation, local needs and priorities, as well as available resources. Few important adjustments in health-care delivery are being implemented based on availability of medical genetic expertise, comprehensive genetic diagnostic laboratory services, and genetic and genomic research. In addition, integrated support to the families affected by genetic illness, education in genetic health, and continuous medical education on medical genetics and ethics would be required for medical and paramedical professionals. The challenge faced by public health geneticists is to define novel prevention strategies ethically compatible with the cultural background and social circumstances and religious beliefs of the population, and the legal system of the country. The prime objective of genetic service is to maximize the chances for every couple to have a healthy child, and to offer early and proper management for the affected individual.

References Afzal AR, Rajab A, Fenzke CD, Oldridge M, Elanko N, Ternes-Pereira E, Tuysuz B, Murday V, Patton MA, Wilkie A, Jeffery S (2000a) Recessive Robinow syndrome, allelic to dominant brachydactily type B, is caused by mutation of ROR2. Lett Nat Genet 25(4):419–422 Afzal AR, Rajab A, Fenske C, Crosby A, Lahiri N, Ternes-Pereira E, Murday VA, Houlston R, Patton MA, Jeffrey S (2000b) Linkage of recessive Robinow syndrome to a 4 cM interval on chromosome 9q22. Hum Genet 106(3):351–354 Alwan AA, Modell B (1997) Community control of genetic and congenital disorders. EMRO technical publications series 24. World Health Organisation Regional Office for the Eastern Mediterranean. (218 pp) ISBN 92-9021-220-9. ISSN 1020-0428

488

A. Rajab

Al-Yahyaee SAS, Al-Kindi MN, Habbal O, Kumar DS (2003) Clinical and molecular ana´lysis of Grebe acromesomelic dysplasia in an Omani family. Am J Med Genet 121A:9–14 Bappal B, George M, Nair R, Khusaiby SA, De Silva V (2001) Factitious hypoglycemia: a tale from the Arab world. Pediatrics 107(1):180–181 Carter JRL (1982) Tribes of Oman, 1st edn. Peninsula Publishing, London Cichon S, Anker M, Vogt IR, Rohleder H, P€ utzst€ uck M, Hillmer A, Farooq SA, Al-Dhafri KS, Ahmad M, Haque S, Rietschel M, Propping P, Kruse R, No¨then MM (1998) Cloning, genomic organization, alternative transcripts and mutational analysis of the gene responsible for autosomal recessive universal congenital alopecia. Hum Mol Genet 7(11):1671–1679 Daar S, Vulliamy TJ, Kaeda J, Mason PJ, Luzzatto L (1996) Molecular characterization of G6PD deficiency in Oman. Hum Hered 46(3):172–176 Daar S, Hussein HM, Merghoub T, Krishnamoorthy R (1998) Spectrum of beta-thalassemia mutations in Oman. Ann N Y Acad Sci 850:404–406 Daar S, Pathare AV (2006) Combined therapy with desferrioxamine and deferiprone in betathalassemia major patients with transfusional iron overload. Ann Hematol 85(5):315–319 Goud MT, Harassi S, Al-Khalili S, Salmani KK, Al-Busaidi SM, Rajab A (2005) Incidence of chromosomal abnormalities in the Sultanate of Oman. Saudi Med J 26(12):1951–1957 Haider MZ, Moosa A, Dalal H, Habib Y, Reynold L (2001) Gene deletion patterns in spinal muscular atrophy patients with different clinical phenotypes. J Biomed Sci 8(2):191–196 Heathcote K, Rajab A, Magre J, Syrris P, Besti M, Patton M, Delepine M, Lathrop M, Capeau J, Jeffery S (2002) Molecular analysis of Berardinelli-Seip congenital lipodystrophy in Oman: evidence for multiple loci. Diabetes 51(4):1291–1293 Hempelmann A, Kumar S, Muralitharan S, Sander T (2006) Myofibrillogenesis regulator 1 gene (MR-1) mutation in an Omani family with paroxysmal nonkinesigenic dyskinesia. Neurosci Lett 402(1–2):118–120 Hennies HC, Rauch A, Seifert W, Schumi C, Moser E, Al-Taji E, Tariverdian G, Chrzanovska KH, Krajevska-Walasek M, Rajab A, Guigliani R, Neumann TE, Eckl KM, Karsbasyan M, Reis A, Horn D (2004) Allelic heterogeneity in the COH1 gene explain clinical variability in Cohen syndrome. Am J Hum Genet 75:138–145 Hennies HC, Kornak U, Zhang H, Egerer J, Zhang X, Seifert W, K€ uhnisch J, Budde B, N€atebus M, Brancati F, Wilcox WR, M€ uller D, Kaplan PB, Rajab A, Zampino G, Fodale V, Dallapiccola B, Newman W, Metcalfe K, Clayton-Smith J, Tassabehji M, Steinmann B, Barr FA, N€ urnberg P, Wieacker P, Mundlos S (2008) Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin. Nat Genet 40(12):1410–1412 Hoffmann K, M€uller JS, Stricker S, Megarbane A, AnnaRajab TH, Lindner MC, Chouery E, Adaimy L, IsmatGhanem VD, Boltshauser E, Talim B, Horvath R, Robinson PN, Lochm€ uller H, H€ubner C, Mundlos S (2006) Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal subunit. Am J Hum Genet 79:303–312 Huber C, Delezoide AL, Guimiot F, Baumann C, Malan V, Le Merrer M, Da Silva DB, Bonneau D, Chatelain P, Chu C, Clark R, Cox H, Edery P, Edouard T, Fano V, Gibson K, GillessenKaesbach G, Giovannucci-Uzielli ML, Graul- Neumann LM, van Hagen JM, van Hest L, Horovitz D, Melki J, Partsch CJ, Plauchu H, Rajab A, Rossi M, Sillence D, Steichen-Gersdorf E, Stewart H, Unger S, Zenker M, Munnich A, Cormier-Daire V (2009) A large-scale mutation search reveals genetic heterogeneity in 3M syndrome. Eur J Hum Genet 17(3):395–400 Joshi SN, Hashim J, Venugopal P (2002) Pattern of inborn errors of metabolism in an Omani population of the Arabian Peninsula. Ann Trop Paediatr 22(1):93–96 Joshi SN, Venugopalan P (2007) Clinical characteristics of neonates with inborn errors of metabolism detected by Tandem MS analysis in Oman. Brain Dev 29(9):543–546 Kornak U, Reynders E, Dimopoulou A, Van Reeuwijk J, Fischer B, Rajab A, Budde B, N€ urnberg P, Foulquier F, ARCL Debre´-type Study Group, Lefeber D, Urban Z, Gruenewald S, Annaert W, Brunner HG, van Bokhoven H, Wevers R, Morava E, Matthijs G, Van Maldergem L, Mundlos S (2008) Impaired glycosylation and cutis laxa caused by mutations in the vesicular H(+)ATPase subunit ATP6V0A2. Nat Genet 40:32–34

16


489

Michalk A, Stricker S, Becker J, Rupps R, Pantzar T, Miertus J, Botta G, Naretto VG, Janetzki C, Yaqoob N, Ott CE, Seelow D, Wieczorek D, Fiebig B, Wirth B, Hoopmann M, Walther M, Ko¨rber F, Blankenburg M, Mundlos S, Heller R, Hoffmann K (2008) Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Am J Hum Genet 82(2):464–476 Mochida GH, Rajab A, Eyaid W, Lu A, Al-Nouri D, Kosaki K, Noruzinia M, Sarda P, Ishihara J, Bodell A, Apse K, Walsh CA (2004) Broader geographical spectrum of Cohen syndrome due to COH1 mutations. J Med Genet 41(6):e87 Muralitharan S, Al Lamki Z, Dennison D, Christie BS, Wali YA, Zachariah M, Romana M, Bayoumi R, Krishnamoorthy R (2005) An inframe perforin gene deletion in familial hemophagocytic lymphohistiocytosis is associated with perforin expression. Am J Hematol 78(1):59–63 Muralitharan S, Wali YA, Dennison D, Lamki ZA, Zachariah M, Nagwa EB, Pathare A, Krishnamoorthy R (2007) Novel spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis in ethnic omani patients. Am J Hematol 82(12):1099–1102 Nicole S, Ben Hamida C, Beighton P, Bakouri S, Belal S, Romero N, Viljoen D, Ponsot G, Sammoud A, Weissenbach J, Fardeau M, Ben Hamida M, Fontaine B, Hentati F (1995) Localization of the Schwartz-Jampel syndrome (SJS) locus to chromosome 1p34–p36.1 by homozygosity mapping. Hum Molec Genet 4:1633–1636 Nicole S, Davoine C-S, Topaloglu H, Cattolico L, Barral D, Beighton P, Ben Hamida C, Hammouda H, Cruaud C, White PS, Samson D, Urtizberea JA, Lehmann-Horn F, Weissenbach J, Hentati F, Fontaine B (2000) Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nature Genet 26:480–483 Ohadi M, Lalloz MR, Sham P, Zhao J, Dearlove AM, Shiach C, Kinsey S, Rhodes M, Layton DM (1999) Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am J Hum Genet 64(1):165–171 Pinotti M, Camire RM, Baroni M, Rajab A, Marchetti G, Bernardi F (2003) Impaired prothrombinase activity of factor X Gly381Asp results in severe familial CRM+ FX deficiency. J Tromb Haemost 89:243–248 Rajab A, Patton M (1997) Major factors determining frequncies of haemoglobinopathies in Oman. Letter to the editor. Am J Med Genet 71:240–242 Rajab A, Patton M (1999) Development and use of a national haemoglobinopathy register in Oman. Letter to the editor. Community Genet 2:47–48 Rajab A, Patton M (2000) A study of consanguinity in the Sultanate of Oman. Ann Hum Biol 3:321–326 Rajab A, Heathcote K, Joshi S, Jeffery S, Patton M (2002) Heterogeniety or congenital generalised lipodystrophy in seventeen patients from Oman. Am J Med Genet 110:219–225 Rajab A, Khaburi M, Spranger S, Kunze J, Spranger J (2003a) Congenital generalized lipodystrophy, mental retardation, deafness, short stature, and slender bones: a newly recognized syndrome? Am J Med Genet 121A:271–276 Rajab A, Mochida GH, Hill A, Ganesh V, Bodell A, Riaz A, Grant PE, ShugartYY WCA (2003b) A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology 60:1664–1667 Rajab A, Kunze J, Mundlos S (2004) Spondyloepipheseal dysplasia omani type: a new recessive type of SED With progressive spinal involvement. Am J Med Genet 126A:413–419 Rajab A, Bappal B, Al-Shaikh H, Al-Khusaibi S, Mohammed AJ (2005a) Common autosomal recessive diseases in Oman derived from a hospital-based registry. Community Genet 8:27–30 Rajab A, Hoffmann K, Ganesh A, Sethu AU, Mundlos S (2005b) Escobar variant with pursed mouth, creased tongue, ophthalmologic features and scoliosis in 6 children from Oman. Am J Med Genet 134A:151–157 Rajab A, Yoo S-Y, Abdulgalil A, Kathiri S, Ahmed R, Moshida GH, Adria Bodell A, Barkovich J, Walch CA (2006) An autosomal recessive form of spastic cerebral palsy (CP) with microcephaly and mental retardation. Am J Med Genet 140A:1504–1510

490

A. Rajab

Rajab A, Manzini MC, Mochida GH, Walsh CA, Ross ME (2007a) A novel form of lethal microcephaly with simplified gyral pattern and brain stem hypoplasia. Am J Med Genet A 143(23):2761–2767 Rajab A, Manzini C, Mochida G, Walsh C, Ross E (2007b) A novel form of lethal microcephaly with simplified gyral pattern and brain stem hypoplasia. Am J Med Genet A 143(23): 2761–2767 Rajab A, Kornak U, Budde BS, Hoffmann K, Jaeken J, N€ urnberg P, Mundlos S (2008) Geroderma osteodysplasticum hereditaria and wrinkly skin syndrome in 22 patients from Oman. Am J Med Genet A 146A:965–976 Rajab A, Kelberman D, de Castro SC, Biebermann H, Shaikh H, Pearce K, Hall CM, Shaikh G, Gerrelli D, Grueters A, Krude H, Dattani MT (2009a) Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Hum Mol Genet 17(14):2150–2159 Rajab A, Aldinger KA, El-Shirbini HA, Dobyns WB, Ross ME (2009b) Recessive developmental delay, small stature, microcephaly and brain calcifications with locus on chromosome 2. Am J Med Genet A 149A(2):129–137 Rajab A, Al-Harasi S, Neitzel H, Sperling K. Down syndrome in The Sultanate of Oman (in preparation) Rajab A, Straub V, McCann LJ, Seelow D, Varon R, Barresi R, Schulze A, Lucke B, L€utzkendorf S, Karbasiyan M, Bachmann S, Spuler S, Schuelke M (2010) Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations. PloS Genetics 6(3):e1000874 Simsek M, Al-Wardy N, Al-Khayat A, Shanmugakonar M, Al-Bulushi T, Al-Khabory M, Al-Mujeni S, Al-Harthi S (2001) Absence of deafness-associated connexin-26 (GJB2) gene mutations in the Omani population. Hum Mutat 18(6):545–546 Simsek M, Al-Bulushi T, Shanmugakonar M, Al-Barwani HS, Bayoumi R (2003) Survival motor neuron (SMN) genes for molecular allele-specific amplification of exon 7 in the diagnosis of spinal muscular atrophy. Genet Test 7(4):325–327 Tiele H, Sakano M, Kitagawa K, Rajab A, Hohne W, Ritter H, Leschik G, Nurnberg P, Mundlos S (2004) Loss of chonroitin 6-0-sulfotransferase-1 function result in severe human chondrodysplasia with progressive spinal involvement. PNAS 101(27):10155–10160 White JM, Christie BS, Nam D, Daar S, Higgs DR (1993) Frequency and clinical significance of erythrocyte genetic abnormalities in Omanis. J Med Genet 30:396–400 White DR, Ganesh A, Nishimura D, Rattenberry E, Ahmed S, Smith UM, Pasha S, Raeburn S, Trembath RC, Rajab A, Macdonald F, Banin E, Stone EM, Johnson CA, Sheffield VC, Maher ER (2007) Autozygosity mapping of Bardet-Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10. Eur J Hum Genet 15(2):173–178

Chapter 17

Genetic Disorders Among the Palestinians Bassam Abu-Libdeh and Ahmad Said Teebi

History of Palestine The land of Palestine is among the most storied and fought-over parts of the world. Having drawn together in city-states, one of which was Jericho, the Canaanites were the earliest known inhabitants of Palestine, with roots there extending as far back as the third millennium BC. Located at the intersection of routes connecting three continents, Asia, Africa, and Europe, Palestine became a natural meeting place, as well as a battleground, for culture and religious influences from Syria, Mesopotamia, Egypt, and Asia Minor. Although the Hebrews, Semitic tribes from Mesopotamia, began to steadily immigrate into Palestine after the fourteenth century BC, it was not until around 1125 BC, more than 150 years after Moses led his people out of serfdom in Egypt, that they finally defeated the Canaanites. A more formidable opponent to the Hebrews proved to be the Philistines, who had established an independent state on the southern coast of Palestine and controlled the Canaanite town of Jerusalem. Owing to their military superiority, they soundly defeated the Israelites around 1050 BC. The Union of the Israelite tribes under King David, however, enabled the Hebrews to defeat the Philistines approximately 50 years later and assimilate with the Canaanites. After David’s death in 922 BC, the kingdom was divided into two sections, Israel, which fell to Assyria in 722 BC, and Judah, which fell to Babylonia in 586; as a result, Jerusalem was destroyed and most of the Jews were exiled. Not long afterward, however, Cyrus the Great of Persia conquered Babylonia and allowed the Jews to return, permitting them significant autonomy in the process. Persian rule was eventually ended when Alexander the Great of Macedonia took the region in 333 BC. After his successors’ attempts to impose Hellenistic (Greek) culture and religion, the Jews revolted three

B. Abu-Libdeh (*) Associate Professor of Pediatrics & Genetics, Al-Quds Medical School, Chief of Pediatrics & Genetics, Makassed Islamic Charitable Hospital, Jerusalem, Israel e-mail: [email protected]


491

492

B. Abu-Libdeh and A.S. Teebi

times between 141 BC and AD 135; the last of these insurrections ultimately resulted in Jews being banned from Jerusalem. Judea was renamed Syria Palistina. A period of prosperity followed in which most of the population became Hellenized and Christianized. Roman rule ended when Arab armies invaded Palestine and captured Jerusalem in AD 638, beginning 1,300 years of Muslim presence in what became to be known as Filastin. Palestine was holy to the Muslims because it was their first qiblah (the direction they face when praying) and because the prophet Mohammad was believed to have been nocturnally transported there from Mecca and to have been consequently ascended to heaven from the area thought to be the place of Solomon’s Temple, where the Dome of the Rock was later built. Although the Muslims guaranteed security and allowed religious freedom to all inhabitants of the region, the majority converted to Islam and adopted Arab culture. Palestine enjoyed, along with the rest of the Muslim empire at the time, a golden age of science, art, philosophy, and literature. Muslims continued in this renaissance until the empire, Palestine included, declined under the Mamelukes. It was also under the Mamelukes that the period of greatest turbulence overtook Palestine. During the eleventh century AD, various religious leaders in Europe spurred an uprising to conquer the “Holy Land” from the Muslims. Although the Crusades were at first dominated by religious aims, worldly motives such as capturing land and expanding trade also played a part. The Crusades were played out in eight major campaigns; the cast of victors and possessors of land changed frequently. The most severe damage to the Christian cause was inflicted by Saladin, a Muslim warrior and sultan of Egypt, who in the Third Crusade regained for his empire the stronghold of Jerusalem, a triumph the Christians were unable to reverse after the end of these wars. The Ottoman Turks then defeated the Mamelukes in the thirteenth century and ruled Palestine until 1917. The country was divided into districts, which were mainly administered by the Arab Palestinians. The Christian and Jewish communities were allowed a large measure of autonomy nevertheless. After a period of stagnation under the Ottoman Empire, the region was revitalized economically and socially in the nineteenth century by growing European interest in new markets and land. The rise of European nationalism, and especially of anti-Semitism during the 1880s, encouraged Jews living in Europe to seek reinstitution in Palestine or “the Promised Land.” Zionism was thus born. Aided by the Arabs, the British captured Palestine from the Turks in 1917–1918. In the Balfour Declaration of 1917, Britain promised the Jews, whose help was needed in World War I, a Jewish “national home” in Palestine, even though Palestinian Arabs made up more than 95% of the population at the time. Helped by large-scale immigration between the two world wars, the state of Israel was established on May 14, 1948. The West Bank, including East Jerusalem, was put under the control of neighboring country Jordan, while Egypt took command of the Gaza Strip. However, these two territories were both captured by Israel in 1967. The war resulted in the displacement of 60–70% of the Palestinians, whose number in diaspora is now estimated to be 5 million, scattered to neighboring countries, mainly Jordan. Later on, they spread to other countries, particularly the Arabian Gulf states and North America. Their number in Israel is

17

Genetic Disorders Among the Palestinians

493

Fig. 17.1 Map of old Palestine including present-day Israel and the Palestinian territories of West Bank and Gaza, and Jordan

1.1 millions and 3.7 millions in Palestinian Territories of the West Bank and Gaza (Palestinian Central Bureau of Statistics 2003) The Palestinians have maintained their identities and the desire to return to their homeland. The Oslo accord of 1993 resulted in the establishment of a Palestinian autonomy in the Palestinian territories of the West Bank and Gaza. Historical data are summarized from Mattar (1993), Bram and Dickey (1993), and Harden (1962).

494


Consanguinity and Family Patterns According to the latest statistics of the Palestinian Central Bureau of Statistics, consanguinity is generally high among Palestinians. In general, around 50% of total marriages are consanguineous with little variation between the West Bank and Gaza Strip, with 43.4% and 49.3%, respectively. There has been no significant decline in this rate between the years 2000 and 2006 in spite of the public education and media campaign to discourage this kind of marriage (Fig. 17.2). This can be attributed to political, economic, and social factors that play a major role in deciding the type of marriage (Palestinian Central Bureau of Statistics 2009). A study from Israel (Freundlich and Hino 1984) conducted among the Arab rural population in the western Galilee showed unusually high overall figures (39%). They were highest in the Druze population (49%), lower among Muslims (40%), and still lower among Christians (29%). The most common type of consanguineous marriage was that between first cousins, particularly paternal first cousins. A study by Jaber et al. (1994) from Israel also showed an overall prevalence of consanguineous mating of 44.3%, with an average family inbreeding coefficient of 0.0192. The study group represented Arabs from urban, suburban, and rural areas with an average inbreeding coefficient of 0.01625, 0.01794, and 0.01958, respectively. First-cousin marriage constituted more than 50% of all consanguineous marriages. In the village of Taybe near Tel-Aviv, one of the largest and most developed Arab villages in Israel, consanguineous mating was apparent in 236 families out of 610 families randomly chosen (Jaber et al. 1992). Most of these were first-cousin-type marriages (170 families). In this study (Jaber et al. 1992) a significant increase in the incidence of malformation was noted in relation to the closeness of the parental relationship. For an index-case group, the prevalence of major malformations was 5.8% in the product of intervillage marriage, 8.3% in the intravillage nonrelated

60%

Percentage

50% 40%

West Bank Gaza

30% 20% 10% 0% 2000

2004 Year

2006

Fig. 17.2 Consanguineous marriages percentage in the West Bank and Gaza

17


495

marriages, 15.1% in a distant consanguineous group, and up to 15.8% in the progeny of first-cousin marriage ( p < 0.001). Palestinian families generally prefer large numbers of children. The average number of offspring per woman in the West Bank and Gaza was 7.8 (Courbage and Khlat 1993). The small family unit (parents and children) maintains strong ties with extended family, from which they obtain support and pride. The typical Palestinian village includes several clans (called hamula, pl. hamayil) with patrilineal structure. Each individual carries and uses at least four names: the first name, the father’s name, the paternal grandfather’s name, and the family name. It is usually possible to trace kinship using the father’s first name (Lewitter et al. 1983). One finds an excess of popular names that relate to Islamic (Mohammad, Ahmad, etc.) or Christian (Jiryis, Hanna, Butros, etc.) traditions.

Genetic Markers and Polymorphism The genetic profile of Palestinians was studied for the first time by Arnaiz-Villena et al. (2001) by using human leukocyte antigen (HLA) gene variability and haplotypes. The comparison with other Mediterranean populations by using neighborjoining dendrograms and correspondence analysis reveals that Palestinians are genetically very close to Jews and other Middle East populations, including Turks (Anatolians), Lebanese, Egyptians, Armenians, and Iranians. Hammer et al. used haplotypes constructed from Y-chromosome markers to trace the paternal origins of the Jewish Diaspora. A set of 18 biallelic polymorphisms was genotyped in 1,371 males from 29 populations, including 7 Jewish (Ashkenazi, Roman, North African, Kurdish, Near Eastern, Yemenite, and Ethiopian) and 16 non-Jewish groups from similar geographic locations. They concluded that Jewish and Middle Eastern non-Jewish populations share a common pool of Y-chromosome biallelic haplotypes (Hammer et al. 2000). Mitochondrial DNA haplotypes were studied in the Jews and Arabs (Ritte et al. 1993). Results showed little differentiation with only Ethiopian Jews distinguishable. The remaining groups were genetically similar to Europeans. The genetic similarity of Palestinians to the Jordanians is well illustrated in studies of taste reaction to phenylthiourea (Omari 1986b), serum protein polymorphisms (Cleve et al. 1992; Nevo et al. 1993), color vision (Omari 1986a), tongue curling and folding (Omari 1986a), mid-digital hair (Omari 1986b), and ridge count and other dermato-glyphic parameters (Omari 1985, 1991, 1992, 1993). No significant differences were found between Jordanians and Palestinians (West Bank versus East Bank of Jordan River) in regard to blood groups (Omari 1986a). Data from this study are compared to those of a study on the Druze community from northern Israel (Nevo 1988). The blood group markers are similar among Jews and Arabs and have little, if any, African admixture (Banerjee et al. 1981; Omari 1986a). Of note is the high incidence of the O allele (Saha and Banerjee 1986). Gc allele frequencies were also similar for

496


Arab Druze and Muslims; the gene frequencies reported were as follows: Gc1F 0.1212 and 0.223, Gc1S 0.602 and 0.544, and Gc2 0.186 and 0.231, respectively (Cleve et al. 1978; Nevo and Cleve 1983). While the Druze are believed to have separated from other Muslims some eight centuries ago, the gene frequencies suggest that there has been no significant genetic divergence between the two communities. The frequency of alleles of a-1 antitrypsin in Palestinian was found to be different from that reported in European populations (Nevo et al. 1982). The latter work also includes a description of a new allele, PiV-S.

Genetics Disorders Among the Palestinians Only a few population epidemiological studies were conducted to discover the incidence of congenital malformations and genetic disorders among Palestinians. Similar to other Arabs (Teebi 1994), the Palestinians apparently have increased frequencies of congenital malformation and autosomal recessive disorders. This became more evident with the decreasing load of infections and nutritional problems. There is also as apparent high frequency of new autosomal recessive disorders and variants among Palestinians. The high frequency of autosomol recessive disorders at large is partly explained by the high rate of consanguinity, which also explains the high frequency of monogenic disorders in mentally retarded individuals from Palestine (Janson et al. 1990). In this study, parental consanguinity in cases of severe mental retardation was 67.5% (Janson et al. 1990) compared to 50% in the general population. In the mixed Arab population of Kuwait, genetic causes accounted for over 50% of cases of mental retardation (Farag et al. 1993).

Chromosomal Abnormalities The only cytogenetics laboratory in Palestine is located at Makassed Hospital in Jerusalem. It was established in 1996 and since then till 2008, 3,704 peripheral blood samples were processed for chromosome analysis for different indications. The most frequent abnormality detected was trisomy 21 followed by sex reversal, Turner syndrome and Klinefelter syndrome. Table 17.1 summarizes these patterns (Abu-Libdeh, unpublished data).

Common Autosomal Recessive Disorders Reported Among Palestinians Hemoglobinopathies Several autosomal recessive disorders are reported or observed to be highly prevalent in the general population. Hemoglobinopathies, mainly b Thalassemais (thal) are prevalent among Palestinians and represent a potentially preventable national

17


497

Table 17.1 Patterns of cytogenetic abnormalities on peripheral blood samples of Palestinians undergoing karyotyping at the cytogenetic laboratory at Makassed Hospital in Jerusalem between 1996 and 2008 Total Abn Trio Trio. Trio. Trans KF TS Sex Bal Others samples 21 18 13 DS Synd revers Trans 1996 169 31 17 1 2 1 1 0 6 1 2 1997 232 46 27 1 3 1 3 2 2 2 5 1998 268 50 28 1 2 0 5 5 5 2 2 1999 257 53 35 2 1 1 3 2 4 1 4 2000 265 48 24 5 0 0 5 4 7 0 3 2001 240 40 22 0 1 2 1 4 5 2 3 2002 196 39 23 1 0 1 3 2 7 2 0 2003 279 56 33 4 0 0 1 9 8 1 0 2004 291 61 36 2 1 0 4 6 5 2 5 2005 384 82 44 4 2 1 3 6 20 2 0 2006 365 56 38 3 3 1 3 2 0 2 4 2007 350 57 39 2 0 0 2 2 4 3 5 2008 408 72 60 3 3 1 2 1 0 1 1 Total 3704 691 426 29 18 9 36 45 73 21 34 Abn ¼ abnormal samples, Trio 21 ¼ trisomy 21, Trio 18 ¼ trisomy 18, Trio 13 ¼ trisomy 13, Trans. DS ¼ translocation Down syndrome, KF Synd ¼ Klinefelter syndrome, TS ¼ Turner syndrome, Sex revers ¼ Sex reversal, Bal Trans ¼ balanced translocation

health problem. The frequency of the b-thal trait among Muslim and Christian Palestinians and Bedouins is variable and ranges between 3% and 4% and up to more than 10% in some areas (Filon et al. 1994, 1995). Carrier screening performed on 1,650 secondary school students from Gaza for b thal showed an overall frequency of 4.3% (Sirdah et al. 1998). The frequency of b thal in the microcytic subjects was 27.1%. Assuming a carrier frequency of 4% in the general population, then the incidence is estimated at 1/2,500. This incidence has been declining over the last decade, mainly because of the mandatory premarital thalassemia screening that was adopted on May 2000 (Younis 2006). One additional factor for the decline was the introduction of an active antenatal diagnosis program for thalassemia at Makassed Hospital in Jerusalem. During the period of Jan/1999–Jul/2005, 25 cases of homozygous b thalassemia were diagnosed antenatally with subsequent termination of the pregnancy according to the wishes of the parents (Ayesh et al. 2005a). In 1990, there were 21 new cases affected with thalassemia, rising to 33 cases in 1995. In the year 2000, the number was 16, falling to 7 in 2003 and 5 in 2004 (Younis 2006). Marked genetic heterogeneity was observed among Palestinians, among whom 17 mutations were detected (Darwish et al. 2005; Ayesh et al. 2005a, b) Most of the detected mutations are the Mediterranean type, as seen in neighboring countries. The four most common mutations with their relative frequencies were as follows: IVSI-110 (22.2%), IVSI-6 (13.6%), Cd37 (12%), and IVSI-I (9.7%) (Ayesh et al. 2005a,b). Darwish et al. (2005) reported that IVSI-6 was the most common mutation with a frequency of 28.7% among their patient population. However, their sample was not representing the whole population (Suheil Ayesh, personal communication). Other studies have shown slight differences in the relative frequencies of the most common mutations with IVSI-110 being the most

498


common and accounting for 37.5% of all b thal alleles in Gaza (Filon et al. 1995). The IVS1-110 mutation is the most prevalent mutation in Lebanon and Egypt, accounts for 22% of the b-thal alleles in Israel and is present in both Kurdish Jews and Arabs (Filon et al. 1994). In Bedouins, most of the b-thal gene mutations were found in those who live in malarial regions near the Huleh and Jazreel valleys in northern Israel. A unique poly-A deletion (AATAAAA – A), accounting for 2.5% of all mutations in Gaza, has not been reported in any other country (Filon et al. 1995). A new b-hemoglobin variant, Hb Taybe, named for the Arab village of Taybe, was reported (Galacteros et al. 1994). This hemoglobin (a 38 or 39 THR deleted) is silent in the hetorozygote state and produces severe hemolytic anemias in the homozygous form. HbS and HbO-Arabs are present in several large Palestinian kindred in the ArabIsraeli village of Jesser El-Zarka (Rachmilewitz et al. 1985). This village traces its ancestry to immigrants from Jordan, the West Bank city of Nablus, and the south of Sudan. One Jewish family and eight Palestinian Arab families were found to have the Benin haplotype of the b-globin gene and the ninth family had the CAR haplotype (Central African Republic) (Rund et al. 1990).

Familial Mediterranean Fever One other relatively common disease is Familial Mediterranean Fever (FMF) and the incidence among Palestinians was estimated to be at least 1:2,000 (Barakat et al. 1989; Majeed and Barakat 1989; Said et al. 1992). Such a high incidence is close to that observed in Armenians and Sephardic Jews (Sohar et al. 1967). The spectrum of mutations and genotypes in the pyrin gene in Palestinian FMF patients is similar to that among other patients in neighboring countries. The five most frequent mutations are M694V (49%), V726A (16.7%), M694I (11.9%), E148Q (8.5%), and M680I (4.4%) that account for 90% of all detected mutations. The remaining nine mutations (P369S, R408Q, A744S, M680Ib, R653H, 695R, E167D, F479L, and R761H) were much less represented and had frequencies C in exon 4 of the CHX10 gene. This mutation produces p.Arg200Pro substitution (Faiyaz-Ul-Haque et al. 2007). The two families belonged to the same Bedouin tribe. Recently, two more families from the same tribe presenting with similarly affected individuals were also found to have the mutation. Carriers were identified and premarital counseling within the same tribe was highly recommended. Two families affected with this disorder had a successful preimplantation genetic diagnosis (PGD).

524

A.S. Teebi and T. Ben-Omran

Fig. 18.3 A new born with nonsyndromic microphthalmia/ anophthalmia ascertained to have CHX10 mutation

Fig. 18.4 A child with TeebiShaltout syndrome (TSS) from Qatar. Note the characteristic facial features with small eyes and mouth

Teebi-Shaltout Syndrome (MIM 272950) To date, three related families with four affected siblings were diagnosed. The families belonged to the same tribe. Another family with two affected children was also ascertained. The origin of this family is from Pakistan. Features included characteristic facies with small mouth opening and deep-set eyes, camptodactyly of fingers, long big toe, and caudal appendage among others (Figs. 18.4–18.6). Families reported here are currently recruited for gene mapping and cloning.

Epidermolysis Bullosa, Junctional Type (MIM226700) To date, five related families with five affected children (two females and three males) were diagnosed. The families belonged to the same Bedouin tribe. Two of the families had homozygous splice mutation c.3609þ1G>A of the LAMA3 gene.

18

Genetic Disorders in Qatar

525

Fig. 18.5 Hands of a child with TSS. Note the camptodactyly

Fig. 18.6 The foot of a child with TSS. Note the long first toe and syndactyly between second and third

Endocrine Disorders According to the neonatal screening program, incidence of endocrine disorders, which include CH and congenital adrenal hyperplasia, was found to be 1:2,801 which is similar to that in Germany (1:2,784) (Lindner et al. 2007). Hemoglobinopathies Thalassemias in particular b-thalassemia (b-thal) are frequently diagnosed in Qatar. In the main pediatric department at HMC in Doha, at least 60 patients with thalassemia major are seen on a regular basis. Adult patients are seen elsewhere by hematologists. The frequency of heterozygotes is estimated to be 2–3%. Recently, Al-Obaidli et al. (2007) studied at molecular level 31 clinically recognized patients with b-thal including three with sickle cell disease and b-thal, and

526


Fig. 18.7 Three siblings with Peters plus syndrome with overlapping features with Malpuech syndrome including eyes abnormalities, clefting, and caudal appendage

additional six cases referred because of unexplained microcytic anemia. They found 12 different b-thal alleles and 2 undefined alleles which highlights ethnic diversity in the small population of Qatar. Sickle cell disease is also relatively common in Qatar. At least 70 patients are followed up by the pediatric department of HMC. The frequency of sickle cell trait is estimated to be 3%. Sickle cell is amongst the disorders that are included recently in the neonatal screening program, and both sickle cell and thalassemias are included in the National Premarital Screening and Counseling program in Qatar.

Miscellaneous Disorders/Syndromes Many autosomal recessive disorders/syndromes either previously reported from Qatar or diagnosed by our group are included in Table 18.2. This reflects a wide range of disorders seen in Clinical Genetics and Metabolic Clinics. One of those disorders is the Peters plus syndrome overlapping with Malpuech syndrome features including facial clefting and caudal appendage in four siblings of consanguineous parents (Fig. 18.7). The family was confirmed to have Peters plus by finding homozygosity of splice site mutation in intron 6 of the B3GALTL gene (c459þ1G>A)(unpublished). Another disorder is a new disorder with the constellation of lissencephaly, IgG subclass immunodeficiency and easy bruisability with other connective tissue abnormalities, in a male child of first cousin parents (Ehlayel et al. 2009). A presumably new subtype of familial intracracranial calcification is recently reported (El-Said et al. 2010).

Comments The frequency of genetic disorders in Qatar has apparently increased, warranting attention and careful planning, in order to reduce their effects and incidence in

18


Table 18.2 Reported or diagnosed disorders/syndromes Disease/syndrome Aicardi-Goutierers Ataxia-telangiectasia

Autosmal recessive isolated ectopia lentis Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome Bartsocas-Papas syndrome Bruck syndrome Cohen syndrome Chondrodysplasia, Grebe type Donnai-Barrow syndrome Ellis-van creveld syndrome Epidermolysis bullosa, dystrophic type Familial hypertrophic synovitis Fanconi anemia Galactosyltransferase-I deficiency (facioskeletal type of Ehlers-Danlos) Gerodermia osteodysplastica Hypergonadotropic hypogonadism, partial alopecia Johanson-Blizzad syndrome Laron syndrome (growth hormone insensitivity syndrome) Leprechaunism Mal de Meleda disease Lethal multiple pterygium syndrome Multiple pterygium syndrome (Eskobar) Myofibrillar myopathy Meckel-Gruber syndrome Autosomal recessive microcephaly Noncompaction cardiomyopathy Peters Plus syndrome Retinitis pigmentosa Rhizomelic chondrodysplasia punctata Seckel syndrome Severe childhood autosomal recessive muscular dystrophy Stuve-Wiedemann syndrome The Carey-Fineman-Ziter syndrome Walker-Warburg syndrome Weaver syndrome Woodhouse-Sakati syndrome Wolcott-Rallison syndrome Xeroderma pigmentosum

Zellweger syndrome

527

References Osundwa and Dawod (1994) Ehlayel et al. (2008) Ahram et al. (2009) Massoud et al. (1998)

Kantarci et al. (2007)

Hammoudeh and Siam (1993) Faiyaz-Ul-Haque et al. (2004)

Hone et al. (1995)

El-Menyar et al. (2004)

El-Menyar et al. (2007)

Salih et al. (1984, 1996)

Fawzi et al. (2000)

Engelmann et al. (2008)

MIM # 225750 208900

225100 276820 263650 259450 216550 200700 222448 225500 226600 208250 227650 130070 604327 278250 241090 243800 262500 246200 248300 253290 265000 601419 249000 608716 300183 261540 608381 227650 210600 253700 608099 601559 254940 236670 277590 241080 226980 278700 278720 278730 278780 214100

528


future. The pattern of the diseases is somewhat similar to other Arab countries with clustering of autosomal recessive conditions because of the effect of consanguinity, which is high in the population of Qatar. In Qatar, owing to the mixed population, a number of autosomal recessive disorders are found segregating the population in relatively higher frequencies, many of which are traced back to a common origin. There is a golden opportunity to learn classical genetics in Qatar from real-life experiences as well as to find new genes through research of rare and previously unknown disorders in Qatar and other Arab countries.

References Abdul Wahab A, Dawod ST, al Thani G (2000) Cystic fibrosis in a large kindred family in Qatar. Ann Trop Paediatr 20:203–207 Abdul Wahab A, Al Thani G, Dawod ST, Kambouris M, Al Hamed M (2001) Heterogeneity of the cystic fibrosis phenotype in a large kindred family in Qatar with cystic fibrosis mutation (I1234V). J Trop Pediatr 47:110–112 Abdul Wahab A, Janahi IA, Eltohami A, Zeid A, Ul Haque NF, Teebi AS (2003) A new type of Ehlers-Danlos syndrome associated with tortuous systemic arteries in a large kindred from Qatar. Acta Paediatr 92:456–462 Abdul Wahab A, Janahi IA, El-Shafie SS (2004) Achromobacter xylosoxidans isolated from the sputum of a patient with cystic fibrosis mutation I1234V with Pseudomonas aeruginosa. Saudi Med J 25:810–811 Abdul-Wahab A, Bessisso MS, Elsaid MF (2002) Sandhoff disease (GM2 Gangliosidoses) in a premature patient with bronchopulmonary dysplasia. Saudi Med J 23:602–605 Ahram D, Sato TS, Kohilan A, Tayeh M, Chen S, Leal S, Al-Salem M, El-Shanti H (2009) A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. Am J Hum Genet 84:274–278 Al-Jawadi O, Al-Hilali A (1998) Haemoglobin A2 concentration in glucose-6-phosphate-dehydrogenase-deficient patients. Acta Haematol 100:99–100 Al-Obaidli A, Hamodat M, Fawzi Z, Abu-Laban M, Gerard N, Krishnamoorthy R (2007) Molecular basis of thalassemia in Qatar. Hemoglobin 31:121–127 Bener A, Alali KA (2006) Consanguineous marriage in a newly developed country: the Qatari population. J Biosoc Sci 38:239–246 Bener A, Hussain R (2006) Consanguineous unions and child health in the State of Qatar. Paediatr Perinat Epidemiol 20(5):372–378 Bener A, Hussain R, Teebi AS (2007) Consanguineous marriages and their effects on common adult diseases: studies from an endogamous population. Med Princ Pract 16(4):262–267 Bener A, El-Ayoubi HR, Chouchane L, Ali AI, Al-Kubaisi A, Al-Sulaiti H, Teebi AS (2009) Impact of consanguinity on cacer in a highly endogamous population. Asian Pac J Cancer Prev 10:35–40 Ehlayel M, Ben-Omran T, Teebi AS (2009) Lissencephaly, IgG subclass immunodeficiency, and a connective tissue disorder: a new syndrome? Neurol 256:2087–2090 Ehlayel M, de Beaucoudrey L, Fike F, Nahas SA, Feinberg J, Casanova JL, Gatti RA (2008) Simultaneous presentation of 2 rare hereditary immunodeficiencies: IL-12 receptor beta1 deficiency and ataxia-telangiectasia. J Allergy Clin Immunol 122(6):1217–1219 El-Menyar AA, Bener A, Al Suwaidi J (2004) Cardiovascular manifestations of myofibrillar myopathy. Anadolu Kardiyol Derg 4:336–338 El-Benhawi MO, George WM (1988) Incontinentia pigmenti. Cutis 41:259–262, Review

18


529

El-Menyar AA, Gendi SM, Numan MT (2007) Noncompaction cardiomyopathy in the State of Qatar. Saudi Med J 28:429–434 El-Said MF, Bener A, Lindner M, Alzyoud M, Shahbek N, Abdelrahman MO, Abdoh G, Bessisso MS, Zschocke J, Hoffmann GF (2007) Are heterocygotes for classical homocystinuria at risk of vitamin B12 and folic acid deficiency? Mol Genet Metab 92:100–103 El-Said MF, Badii R, Bessisso MS, Shahbek N, El-Ali MG, El-Marikhie M, El-Zyoid M, Salem MS, Bener A, Hoffmann GF, Zschocke J (2006) A common mutation in the CBS gene explains a high incidence of homocystinuria in the Qatari population. Hum Mutat 27:719 El-Said MF, Cow YJ, Livingstone JH, Ben-Omran T (2010) New Subtype of familial intracranial calcification in a mother and two children. Am J Med Genet (in press) Engelmann G, Meyburg J, Shahbek N, Al-Ali M, Hairetis MH, Baker AJ, Rodenburg RJ, Wenning D, Flechtenmacher C, Ellard S, Smeitink JA, Hoffmann GF, Buchanan CR (2008) Recurrent acute liver failure and mitochondriopathy in a case of Wolcott-Rallison syndrome. J Inherit Metab Dis 31:540–546 Faiyaz-Ul-Haque M, Zaidi SH, Al-Ali M, Al-Mureikhi MS, Kennedy S, Al-Thani G, Tsui LC, Teebi AS (2004) A novel missense mutation in the galactosyltransferase-I (B4GALT7) gene in a family exhibiting facioskeletal anomalies and Ehlers-Danlos syndrome resembling the progeroid type. Am J Med Genet A 128A:39–45 Faiyaz-Ul-Haque M, Zaidi SH, Al-Mureikhi MS, Peltekova I, Tsui LC, Teebi AS (2007) Mutations in the CHX10 gene in non-syndromic microphthalmia/anophthalmia patients from Qatar. Clin Genet 72:164–166 Faiyaz-Ul-Haque M, Zaidi SH, Wahab AA, Eltohami A, Al-Mureikhi MS, Al-Thani G, Peltekova VD, Tsui LC, Teebi AS (2008) Identification of a p.Ser81Arg encoding mutation in SLC2A10 gene of arterial tortuosity syndrome patients from 10 Qatari families. Clin Genet 74:189–193 Faiyaz-Ul-Haque M, Zaidi SH, Al-Sanna N, Alswaid A, Momenah T, Kaya N, Al-Dayel F, Bouhoaigah I, Saliem M, Tsui LC, Teebi AS (2009) A novel missense and a recurrent mutation in SLC2A10 gene of patients affected with arterial tortuosity syndrome. Atherosclerosis 203:466–471 Fawzi M, Bessisso M, Omar F (2000) Walker-Warburg syndrome: a case report of a Qatari patient. Qatar Med J 9(2):66–67 Gan-Schreier H, Kebbewar M, Fang-Hoffmann J, Wilrich J, Abdoh G, Ben-Omran T, Shahbek N, Bener A, Al Rifai H, Al Khal AL, Lindner M, Zschocke J, Hoffmann GF (2010) Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards. J Pediatr 156(3): 427–432 Hammoudeh M, Siam AR (1993) Familial hypertrophic synovitis. Clin Rheumatol 12:401–404 Hone J, Accili D, Psiachou H, Alghband-Zadeh J, Mitton S, Wertheimer E, Sinclair L, Taylor SI (1995) Homozygosity for a null allele of the insulin receptor gene in a patient with leprechaunism. Hum Mutat 6:17–22 Kantarci S, Al-Gazali L, Hill RS, Donnai D, Black GC, Bieth E, Chassaing N, Lacombe D, Devriendt K, Teebi A, Loscertales M, Robson C, Liu T, MacLaughlin DT, Noonan KM, Russell MK, Walsh CA, Donahoe PK, Pober BR (2007) Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nat Genet 39:957–959 Kapoor RR, Flanagan SE, Fulton P, Chakrapani A, Chadefaux B, Ben-Omran T, Banerjee I, Shield JP, Ellard S, Hussain K (2009) Hyperinsulinism-hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations. Eur J Endocrinol 161 (5):731–735 Lindner M, Abdoh G, Fang-Hoffmann J, Shabeck N, Al-Sayrafi M, Al-Janahi M, Ho S, Abdelrahman MO, Ben-Omran T, Bener A, Schulze A, Al-Rifai H, Al-Thani G, Hoffmann GF (2007) Implementation of extended neonatal screening and a metabolic unit in the State of Qatar: developing and optimizing strategies in cooperation with the Neonatal Screening Center in Heidelberg. J Inherit Metab Dis 30:522–529

530


Massoud AA, Ammaari AN, Khan AS, ven Katraman B, Teebi AS (1998) Bartsocas-Papas syndrome in an Arab family with four affected sibs: further characterization. Am J Med Genet 27:16–21 Nogueira GJ (1992) Pre- and neonatal hydrocephalus in the Middle East: experience in Qatar. Childs Nerv Syst 8:40–44 Osundwa VM, Dawod ST (1994) The occurrence of ataxia-telangiectasia and common variable immunodeficiency in siblings: case report. Ann Trop Paediatr 14(1):71–73 Robida A, Folger GM, Hajar HA (1997) Incidence of congenital heart disease in Qatari children. Int J Cardiol 27:19–22 Saad FA, Jauniaux E (2002) Recurrent early pregnancy loss and consanguinity. Reprod Biomed Online 5:167–170 Salih MA, Ekmejian A, Ibrahim M, Omer A (1984) Respiratory insufficiency in a severe autosomal recessive form of muscular dystrophy. Ann Trop Paediatr 4:45–48 Salih MA, Mahdi AH, al-Rikabi AC, al-Bunyan M, Roberds SL, Anderson RD, Campbell KP (1996) Clinical and molecular pathological features of severe childhood autosomal recessive muscular dystrophy in Saudi Arabia. Dev Med Child Neurol 38:262–270 Teebi AS, Ben-Omran T (2008) Genetic drift and founder effect: rediscovering genetics from Qatar. Second International Genetic Conference, Al-Ain, UAE. Abstract Wahab AA (2003) Cystic fibrosis mutation I1234V in a Qatari lady. J Trop Pediatr 49:54–55 Wahab AA, Janahi IA, Hebi S, al-Hamed M, Kambouris M (2002) Cystic fibrosis in a child from Syria. Ann Trop Paediatr 22:53–55 Wahab AA, Janahi IA, Marafia MM, El-Shafie S (2004a) Microbiological identification in cystic fibrosis patients with CFTR I1234V mutation. J Trop Pediatr 50:229–233 Wahab AA, Janahi IA, Marafia MM (2004b) Pseudo-Bartter’s syndrome in an Egyptian infant with cystic fibrosis mutation N1303K. J Trop Pediatr 50:242–244 Wahab A, Al Thani G, Dawod ST, Kambouris M, Al Hamed M (2004c) Rare CFTR mutation 1525-1G>A in a Pakistani patient. J Trop Pediatr 50:120–122 Wahab AA, Bener A, Teebi AS (2006) The incidence patterns of Down syndrome in Qatar. Clin Genet 69:360–362 White JM, Byrne M, Richards R, Buchanan T, Katsoulis E, Weerasingh K (1986) Red cell genetic abnormalities in peninsular Arabs: sickle cell haemoglobin, G6PD deficiency, and alpha and beta thalassemia. J Med Genet 23:245–251 Zaidi SH, Meyer S, Peltekova VD, Lindinger A, Teebi AS, Faiyaz-Ul-Haque M (2009) A novel non-sense mutation in the SLC2A10 gene of an arterial tortuosity syndrome patient of Kurdish origin. Eur J Pediatr 168:867–870 Zirie M, Mohammed I, El-Emadi M, Haider A (2001) Multiple endocrine neoplasia type iia: report of a family with a study of three generations in Qatar. Endocr Pract 7:19–27 Zschocke J, Kebbewar M, Gan-Schreier H, Fischer C, Fang-Hoffmann J, Wilrich J, Abdoh G, Ben-Omran T, Shahbek N, Lindner M, Al Rifai H, Al Khal AL, Hoffmann GF (2009) Molecular neonatal screening for homocystinuria in the Qatari population. Hum Mutat 20

Chapter 19

Genetic Disorders in Saudi Arabia Zuhair N. Al-Hassnan and Nadia Sakati

Introduction The 23rd of September 1932 marks in history the foundation of modern Saudi Arabia, when a royal decree affirmed the unity of the nation and named the country the Kingdom of Saudi Arabia (KSA). Spreading over 2,150,000 km2, KSA occupies almost 80% of the Arabian Peninsula. It is surrounded by the Red Sea on the west and the Arabian Gulf on the east; the coastlines of which stretch more than 2,300 km. Along the Red Sea lies Tihama coastal plain, to the east of which is the chain of Sarawat Mountains that extend beyond the southern and northern borders of Saudi Arabia. In the central part of the country lies the Najd plateau where the capital city, Riyadh, is located. Deserts cover more than half the total area of Saudi Arabia; the largest is the Empty Quarter in the Eastern Province (Saudi Geographical Society). According to the 2007 National Demographic Survey, the population of Saudi Arabia is 24 millions, 73% (17.5 millions) are Saudis of whom 37% are under the age of 15 years. The growth rate of the population is estimated to be 2.3% and the average size of Saudi family is 6.1. The country is divided into 13 regions (Fig. 19.1); of which the most populated are Makkah and Riyadh (Central Department of Statistics & Information). The structure of the Saudi population is largely tribal. Recent decades, however, have seen a change in the demographics of the population influenced by several educational, economic, and social factors. There has been a significant reduction in the illiteracy rate (14.7% in 2004 compared to 28.4% in 1992). Some large tribes have their branches extending to neighboring countries such as Jordan, Iraq, and Yemen, while their origins have remained in Saudi Arabia. Other tribes have

Z.N. Al-Hassnan (*) Associate Prof. of Genetics, College of Medicine, Alfaisal University Consultant, Department of Medical Genetics, MBC-75, King Faisal Specialist Hospital & Research Center, P.O. BOX 3354, Riyadh 11211, Saudi Arabia e-mail: [email protected]


531

532

Z.N. Al-Hassnan and N. Sakati

Fig. 19.1 Map of Saudi Arabia showing the 13 regions Source: Central Department of Statistics & Information

largely immigrated to major cities and Bedouins have moved to small settlements (Hijar). Nevertheless, in spite of this geographic admixture, the consanguinity rate has remained high. In 1995, the overall rate of consanguinity was found to be 57.7%, with 28.4% first-cousin marriages (El-Hazmi et al. 1995a). A recent study revealed very similar results with a prevalence of consanguinity of 56% and firstcousin marriages of 33.6%. There were, however, significant variations in the prevalence of consanguinity between regions as well as between rural and urban settlements (El-Mouzan et al. 2007).

Health Care System and Health Indicators The Health Care System in the Kingdom is divided into three sectors: Ministry of Health (MOH), other governmental health services, and private sector. The financial appropriations for MOH from the government budget is on an average 6%. On the basis of the most recently published MOH Health Statistics Book (2007), there were 387 hospitals across the country; 225 (58%) belongs to MOH, 39 (10%) to other governmental sectors, and 123 (32%) to private. The overall occupancy of hospitals was 53,519 beds; divided into 31,420 (59%) beds in MOH, 10,828 (20%)

19

Genetic Disorders in Saudi Arabia

533

in other governmental sectors, and 11,271 (21%) in private hospitals, which converts into a rate of one bed for 453 people. With respect to the number of physicians, there were 47,919 physicians, giving a rate of one physician for 476 people, 21.6% of them were Saudis, whereas 44.1% of the 51,188 nurses in the MOH hospitals were Saudis (MOH Health Statistics Book 2007). The other health indicators in 2007 were as follows: the crude birth rate/1,000 people was 24.5; the stillbirth rate was 16.3/1,000 live birth; and the infants mortality rate was 17.4/1,000 Saudi live birth. There were 337,177 deliveries in the MOH and other governmental hospitals (MOH Health Statistics Book 2007). Concerning the heath care provided to patients with genetic disorders in Saudi Arabia, King Faisal Specialist Hospital and Research Center (KFSH&RC) represents the leading comprehensive genetic service in the country. The clinical care provided covers diagnostic, therapeutic, and preventive interventions with the presence of: molecular, biochemical and cytogenetics laboratories, advanced treatment modalities including stem cell transplantation, organ transplantation, and enzyme replacement therapy, and the availability of preventive interventions via prenatal diagnosis, preimplantation genetic diagnosis, and carrier screening, in addition to well-established genetic counseling services. Though less comprehensive, genetic services are also provided in other hospitals: MOH tertiary centers, National Guard and Military medical services. On the other hand, the Medical Genetic Fellowship and the Genetic Counseling Training Programs at KFSH&RC have kept the momentum for continuing highly specialized local training for Saudi physicians and genetic counselors.

Genetic Disorders in Saudi Arabia Over the past decade, there has been a remarkable upsurge of interest to study genetic disorders in Saudi Arabia. This is evident by the number of relevant publications and the contributions to the entries in Online Mendelian Inheritance in Man (OMIM) database, which have increased noticeably. As an example, searching PubMed for “Saudi” and “gene” reveals only ten publications for the year 1990 while there were 73 in 2008. In OMIM, the number of entries for the word “Saudi” was 160 (accessed, 28 March 2009) describing 115 genetic disorders; of note, 107 (93%) were autosomal recessive. Clinical observations and anecdotal data note a clear geographic distribution of many autosomal recessive genetic disorders mirroring the tribal distribution across the country. Several disorders have high prevalence in certain tribes and their founder mutations represent the majority of mutant alleles. Examples are propionic acidemia and very long chain acyl-CoA dehydrogenase deficiency (VLCAD). Others, however, have very evident geographic distribution such as sickle-cell anemia and b-thalassemia. In the following sections, we present short synopses of genetic disorders we have observed in our clinical practice or have been published and focus on seven groups of inherited diseases of: (1) metabolism; (2) hematology; (3) neurology;

534


(4) congenital malformations; (5) endocrinology; (6) ophthalmology; and (7) rheumatology. A separate section on novel syndromes described in the Saudi population follows.

Inherited Metabolic Diseases Inherited metabolic disorders (IMD) are amongst the most common genetic disorders in Saudi Arabia. The introduction of metabolic screening using tandem mass spectrometry (MS/MS) (Rashed et al. 1995b; Rashed et al. 1997) in the presence of clinical expertise at KFSH&RC for more than two decades has provided a great opportunity to study IMD. In 1999, the incidence of IMD that can be detected by MS/MS was found to be 1:1,381 after screening 27,624 blood spots (Rashed et al. 1999b). However, a more recent data from the Saudi National Newborn Screening (NBS) Program indicate that the collective incidence of the 16 disorders that are screened for is much higher reaching one in almost 850 newborns (Al-Odaib, personal communication). Of those 16 diseases, methylmalonic acidemia (MMA), maple syrup urine disease (MSUD), and propionic acidmeia (PA) are commonly detected metabolic disorders. Examining the neurometabolic diseases in general, however, revealed that the most frequently diagnosed disorders among 473 conditions were lysosomal storage diseases (LSDs), followed by organic acid disorders, and aminoacidopathies (Ozand et al. 1992a). The high incidence of IMD has provided an opportunity for reviewing the clinical profiles of these disorders from various aspects, including unusual findings in PA (Ozand et al. 1994a), emergency presentation of MSUD, PA, and MMA (Henriquez et al. 1994), the high frequency of infections in PA (Al Essa et al. 1998f), in addition to the brain imaging features in Canavan disease (Brismar et al. 1990a), MSUD (Brismar et al. 1990b), PA & MMA (Brismar and Ozand 1994), glutaric acidemia type I (GAI) (Brismar and Ozand 1995), and 3-methylglutaconic aciduria (Al-Essa et al. 1999a). Research for developing new analytical methods for various metabolites has also flourished. Examples include MMA (Al-Dirbashi et al. 2005), glyceric aciduria (Rashed et al. 2002), tyrosinemia type I (Rashed et al. 2005; Al-Dirbashi et al. 2006), cystinuria (Al-Dirbashi et al. 2007), and peroxisomal disorders (Al-Dirbashi et al. 2008). LSDs comprise a prevalent group of IMD. In 125 referred cases with LSD, mucopolysaccharidosis (MPS) type IVA (Morquio disease), Niemann–Pick disease type B, Sandhoff disease, and neuronal ceroid lipofuscinosis (NCL) were frequently encountered as compared to other storage diseases (Ozand et al. 1990a). Also, Maroteaux-Lamy syndrome (MPS type VI) is a common MPS in Saudi Arabia. Sly disease (MPS type VII), which was reported in a case (Stangenberg et al. 1992), has been diagnosed in several infants with nonimmune hydrops fetalis. Niemann–Pick disease is one of the most common LSD in Saudi Arabia; the disease manifests

19


535

with severe phenotype involving the nervous system, and two mutations (H421Y and K576N) account for approximately 85% of the alleles (Simonaro et al. 2002). A third novel mutation (W533R) was also reported (Hellani et al. 2004). Gaucher disease, both types I and III, has been diagnosed in several patients, and causative mutations have been identified (Kaya et al. 2008a). The other relatively common LSD is Canavan disease which was reported in 12 Saudi infants almost two decades ago (Ozand et al. 1990b) and several mutations have been identified (Kaya et al. 2008b). Other reported LSDs are GM1 gangliosidosis type 2 (Gascon et al. 1992a), galactosialidosis (Ozand and Gascon 1992b), sialidosis type 1 (Gascon et al. 1992b), the AB variant of GM2 gangliosidosis (Schepers et al. 1996), and Wolman disease (Al Essa et al. 1998c). Organic acidurias (OA) are a common group of IMD with an estimated frequency of 1/740 births (Rashed et al. 1994). In addition to MMA and PA, data from NBS indicate that 3-methylcrotonyl-CoA carboxylase deficiency, GAI, and 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency are also common in Saudi Arabia. The prevalent mutations in the latter disorder have been reported (Mitchell et al. 1998; Al-Sayed et al. 2006). In addition, biotinidase deficiency has been diagnosed frequently (Joshi et al. 1999) and mutations have been reported (Pomponio et al. 2000). Other less-encountered OAs are 3-ketothiolase deficiency (Ozand et al. 1994b), malonic aciduria (Ozand et al. 1994c), 4-hydroxybutyric aciduria, (Rahbeeni et al. 1994), 3-methylglutaconic aciduria (al Aqeel et al. 1994), pyroglutamic aciduria (Al-Jishi et al. 1999), glutaric aciduria type II (al-Essa et al. 2000b), D-glyceric and L-glyceric acidurias (Rashed et al. 2002), and L-2-hydroxyglutaric aciduria (Sass et al. 2008). Aminoacidopathies, in particular, homocystinuria (HCU) (Al-Essa et al. 1998e), MSUD, and phenylketonuria (PKU) are frequent. A large series of 45 patients with HCU with a focus on ophthalmic complications was reviewed (Harrison et al. 1998). The NBS data indicate that the incidence of MSUD is one of the highest worldwide. Biopterin-dependent PKU due to deficiency of 6-pyruvoyl tetrahydropterin synthase, particularly prevalent in one tribe, is not a rare variant in comparison to classic PKU (al Aqeel et al. 1991). Although it has not been included in the NBS program, tyrosinemia type I has been diagnosed in several cases (Al-Dirbashi et al. 2006). Other amino acid disorders that have been reported in Saudis are: tyrosinemia type II (Tallab 1996; Al-Essa et al. 1998a), nonketotic hyperglycinemia (Haider et al. 1996); alkaptonuria (Al Essa et al. 1998b), methylenetetrahydrofolate reductase (MTHFR) deficiency (Al-Essa et al. 1999c), cystinuria (Al-Dirbashi et al. 2007), and hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome (Al-Hassnan et al. 2008). On the other hand, two urea cycle detects (UCD) are included in the NBS program: argininosuccinic aciduria (ASA) and citrullinemia (Cit). ASA is relatively more common than other UCD in Saudi Arabia (Rashed et al. 1999a), with a common mutation (Q354X) in 50% of tested cases (Al-Sayed et al. 2005). The other UCD have also been diagnosed but less frequently with arginase deficiency, reported in a single case (Grody et al. 1992), being rarely encountered.

536


Glycogen storage diseases (GSD), notably type I and III, are also commonly diagnosed in Saudi patients. Moreover, rare GSD variants have been described including phosphorylase b kinase deficiency (Sanjad et al. 1993), phosphofrucokinase deficiency (Al-Hassnan et al. 2007a), and Fanconi–Bickel syndrome (Taha et al. 2008). Fructose-1,6-bisphosphatase deficiency is another condition of hypoglycemia that is specifically prevalent in one tribe; the disorder mutations have been recently reported (Faiyaz-Ul-Haque et al. 2009b). Clinical observation indicates that a large group of patients have been clinically suspected to have mitochondrial disorders. Yet, in spite of extensive workup, a specific molecular defect is not reached in the majority of patients suggesting that mitochondrial disorders in Saudi Arabia are mostly due to autosomal recessive nuclear gene defects yet to be elucidated. Reports of such disorders are thus scarce. In children with stroke, mitochondrial disorders were the underlying risk factor in 4 (3.8%) of 104 children, nevertheless, the specific molecular defect was not identified (Salih et al. 2006). A novel mtDNA mutation in a patient with MELAS (Abu-Amero et al. 2006c) and a homozygous R19H substitution in COX6B1 gene in two brothers with cytochrome c oxidase deficiency (Massa et al. 2008) have been reported. Certain defects of fatty acid oxidation disorders (FAOD) and peroxisomal disorders are especially frequent. VLCAD is probably the most common FAOD in Saudi Arabia. In addition, medium-chain acyl-CoA dehydrogenase deficiency (MCAD) was once thought to be rare in Arabs; however, recent data suggest that its incidence is close to what has been observed in Caucasians approaching one in 18,000. One mutation (T121I) was identified in 72% of the cases (Al-Hassnan et al. 2006). In addition, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Rashed et al. 1995a), carnitine palmityl transferase I deficiency (Al-Aqeel et al. 2001), carnitine transporter defect (Rahbeeni et al. 2002), and carnitine acylcarnitine translocase deficiency (Al Aqeel et al. 2003) have been reported in Saudis. With respect to peroxisomal disorders, the clinical phenotype of both Zellweger syndrome (al-Essa et al. 1999b), and X-linked adrenoleukodystrophy (Al-Essa et al. 2000a) have been described in Saudi patients. The molecular defects in the peroxisomal biogenesis disorders seem to be heterogeneous with several PEX genes implicated including PEX5, PEX13, and PEX26. Hyperpipecolic acidemia (Al-Essa et al. 1999d) and rhizomelic chondrodysplasia punctata type II (Barr et al. 1993) were also described. A novel biotin-responsive basal ganglia disease was described by Ozand et al. (1998) in ten patients who had an onset of subacute encephalopathy that progressed to severe cogwheel rigidity, dystonia, and quadriparesis. On brain MRI, patients displayed central bilateral necrosis in the head of the caudate, with complete or partial involvement of the putamen. The patients responded dramatically to high dose of biotin (Ozand et al. 1998). Using linkage analysis, causative mutations in SLC19A3 gene were identified (Zeng et al. 2005). The list of reported IMD includes as well bile acid synthesis defect (HSD3B7 gene defect) (Clayton et al. 1987), hyperinsulinism and hyperammonemia syndrome (al-Shamsan et al. 1998), isolated sulfite oxidase deficiency (Seidahmed et al. 2005), and cerebrotendinous xanthomatosis (Price Evans et al. 2007).

19


537

Blood Disorders The sickle-cell hemoglobin (Hb S) was first reported in Saudi Arabia in 1963 (Lehmann et al. 1963). Years later, a study has characterized sickle cell–b0 thalassemia (S–b0 thal) in Eastern Saudi Arabia (Pembrey et al. 1980). Then Hb S, a- and b-thalassemia, glucose-6-phosphate dehydrogenase deficiency (G6PD), and other enzymopathies were shown to occur at a variable prevalence in different regions of the country (el-Hazmi 1987a) The comprehensive national survey of the distribution of the Hb S and thalassemia genes on more than 30,000 blood samples showed that the Hb S, a- and b-thalassemia gene frequency ranges were: 0.005–0.145, 0.01–0.40, and 0.01–0.15, respectively, in various areas of Saudi Arabia. The highest frequency (0.149) of Hb S was found in the Eastern Province and the lowest (0.001) was in the Central Region (el-Hazmi and Warsy 1996, 1999). Studies have shown extensive polymorphism of the b-globin gene existing at a variable frequency in different regions of the country (el-Hazmi 1986a). Individuals from the southwest of the Arabian peninsula have the same b S-chromosome haplotype previously found in west African, Jamaican, and African Americans, whereas those from the eastern oases of Saudi Arabia and from the west and the east coast of India showed a different haplotype not found in Africa (Kulozik et al. 1986). Patients from the Eastern Province who have sickle-cell anemia (SCA) have high circulating levels of fetal hemoglobin (HbF) and, as a consequence, have a mild form of the disease. A cytosine-to-thymine substitution at the cap site of the G-g-globin gene of the HbF chromosome was found in nearly 100% of patients with sickle-cell disease or trait while it was present in 22% of normal Saudis (Miller et al. 1987). Homozygosity for haplotype 31 (Saudi Arabian) confers high HbF levels and hence milder phenotype (Morgan et al. 1996). Patients from the Eastern Province generally had a mild clinical presentation, while in the South West and North West Provinces majority of the patients suffered from a severe disease (el-Hazmi 1992a). The polymorphism in the b-globin gene cluster was shown to be significantly related to the expression of the b S-gene and clinical severity of SCA (el-Hazmi et al. 1992c). On the other hand, studying the Xmn I polymorphic site revealed that 10% of g-genes in normal individuals were linked to the 7.0-kb fragment while in the SCA patients and Hb S heterozygotes the frequency of the polymorphic site was 0.932 and 0.625, respectively (el-Hazmi 1989). The first report on the types of mutations in Saudi b-thalassemia patients revealed that the most commonly encountered mutations were IVS1-110, IVS2-1, codon 39, IVS1-5, and IVSI 30 end (–25) (el-Hazmi et al. 1995b). The spectrum of mutations found in the Western Region is significantly different from that previously reported in the Eastern Region (Hasounah et al. 1995). In the latter, ten mutations were detected in 91% of the subjects with four novel alleles. IVS21G > A, IVS1-5G > A, and codon 39 mutations were found to be the most frequent (Al-Ali et al. 2005a). a-Thalassemia exists at a high prevalence in several regions of Saudi Arabia. On 504 cord blood samples from Qatif area, the prevalence of a-thalassemia was

538


39.99% (Quadri et al. 2000). The deletion type of a-thalassemia from the Eastern and Northwestern Regions of the country was studied. The arrangements alpha/ alpha alpha and a/a were common. A rightward deletion was detected in a majority of the cases. Leftward deletions, both homozygous and heterozygous, were also identified. Triple a-gene arrangements alpha alpha alpha anti 3.7/ were observed at a low frequency in both regions (el-Hazmi 1987b). The nondeletional a-thalassemia allele, a (T-Saudi), which is due to a single-base mutation (AATAAA–AATAAG) in the polyadenylation signal of the a-2 gene, is responsible for the clinical phenotype of Hb H disease in some Saudi individuals with five a-genes (a-T Saudi alpha/(alpha alpha alpha)T Saudi) (Pressley et al. 1980; Thein et al. 1988). Moreover, reported a-thalassemia mutations in Saudi patients have included three a-genes on one chromosome (alpha alpha alpha anti3.7) and two on the other (el-Hazmi and Warsy 1992b), and homozygosity of a3.7(a3.7/a3.7) (Katol et al. 2006). Similarly, G6PD deficiency is a frequently identified hematological disorder in Saudi Arabia. In 31 different areas, screening 24,407 Saudis for G6PD deficiency detected a frequency of 0.0905 and 0.041 in males and females, respectively (Warsy and El-Hazmi 2001). G6PDA-Mediterranean (G-6-PD-B+) is the major variant producing the severe deficiency state in our population. The frequency of the variants, however, shows significant differences among the regions with the highest being in areas which are endemic to malaria and have high frequencies of SCA and thalassemia, namely, the Eastern and the Southern Regions (el-Hazmi et al. 1986b; el-Hazmi and Warsy 1990). Of note, screening 40 G6PD-deficient females in the Eastern Region identified 34 (84%) homozygous cases for the Mediterranean mutation (Al-Ali et al. 2002). Several hemoglobin variants have been identified and published. In 1980, a report described the first finding of Hb O Arab in Saudi Arabia (El-Hazmi and Lehmann 1980). Hb Setif, initially described in an Algerian family, was detected in Saudi individuals (Al-Awamy et al. 1985). A new Hb variant in the heterozygous state, Hb Al-Hammadi Riyadh (codon 75 (GAC ! GTC); a75(EF4)Asp ! Val (a2)) corresponding to an A to T transversion on the second exon of the a2-globin gene was described in a boy from Riyadh (Burnichon et al. 2006). Hb Jeddah (a68 (E17)Asn ! His (a1)), which is a previously unrecognized a chain variant, was reported in combination with Hb S in three families from Saudi Arabia, Yemen, and United Arab Emirates (Markley et al. 2008). In addition to the extensively studied hemoglobinpathies, other inherited blood disorders have also been identified and reported. In a study on 1,691 Saudi individuals, the overall frequency of partial glutathione reductase (GR) deficiency was 24.5 and 20.3% in males and females, respectively (Warsy and el-Hazmi 1999). GR deficiency was encountered in combination with SCA, G6PD deficiency, and thalassemia (el-Hazmi and Warsy 1985). Molecular analysis on three Saudi brothers with early childhood thrombocytopenia was suggestive of an X-linked disorder distinct from the classical Wiskott–Aldrich syndrome phenotype (Knox-Macaulay et al. 1993). Selective intestinal malabsorption of vitamin B12 causing juvenile megaloblastic anemia was reported in two Saudi sisters (Al Essa

19


539

et al. 1998d), and causative mutations were identified (Tanner et al. 2004). In a family consisting of four brothers with thrombocytosis, segregation analysis excludes THPO gene which suggests the existence of a new locus whereby the disease is transmitted as a recessive, possibly X-linked trait (Stuhrmann et al. 2001). Two families with “factor X (FX)-Riyadh” were described with a novel missense mutation (Q51K) of FX gene. Affected members of both families exhibit prolongation in prothrombin time with normal partial thromboplastin time and low assay levels of FX (Al-Hilali et al. 2007). Other reported hematological disorders in Saudi families have been: hereditary pyropoikilocytosis (Mallouh et al. 1984); congenital afibrinogenemia (Elseed and Karrar 1984); congenital dyserythropoietic anemia type I (al-Fawaz and al-Mashhadani 1995); protein C deficiency (Abu-Amero et al. 2003a); hereditary hemorrhagic telangiectasia (El-Harith et al. 2006); thiamineresponsive megaloblastic anemia in a girl who was homozygous for a mutation in the thiamine transporter gene SLC19A2 (Alzahrani et al. 2006b); and combined factor V and factor VIII deficiency which was recently reported in a family who segregated a mutation in the MCFD2 gene (Zhang et al. 2008).

Neurological Disorders Numerous publications have addressed the genetics of inherited neurological disorders in Saudi Arabia. Spinal muscular atrophy (SMA) appears to be a common neuromuscular disease in the Saudi population; the carrier frequency was estimated to be 1in 20 in a pilot study (Al Jumah et al. 2007). The deletion rate of the SMN1 gene in Saudi SMA patients was found to be similar to what has been reported in other ethnic groups; homozygous deletions of exons 7 and 8 of the SMN1 gene were found in 94 and 87%, respectively (Al-Jumah et al. 2003). Previous work showed that the incidence of NAIP gene deletion is higher in the more severe SMA cases and the dual deletions of the SMN and NAIP genes are more common in Saudi SMA type I patients compared to patients of other ethnic groups (Al Rajeh et al. 1998). The molecular profile in Duchenne and Becker muscular dystrophies (DMD/BMD) were reported too. In 41 Saudi patients with DMD/BMD, the intragenic dystrophin gene deletions were found to occur with the same frequency compared to other ethnic groups (Al-Jumah et al. 2002). Severe childhood autosomal recessive muscular dystrophy (SCARMD), which appears to be more common than DMD in Saudi Arabia, was described in 14 patients. Muscles were dystrophinpositive while adhalin, the dystorphin-associated glycoprotein, was deficient (Salih et al. 1996a). Various other neuromuscular diseases have also been reported. Congenital muscular dystrophy (CMD) with diffuse periventricular white-matter abnormalities was reported in 11 children with a homogeneous clinical syndrome characterized by weakness of all muscle groups, normal nerve conduction velocity, and dystrophic changes on muscle biopsy (Cook et al. 1992). Two siblings with CMD were found to have a deleted laminin a2-chain as a result of a splice site mutation in the

540


LAMA2 gene. These patients appeared mildly affected compared to others who completely lack this protein (Allamand et al. 1997). A Saudi kindred with four affected individuals with a recessive hereditary motor and sensory neuropathy (HMSN) was described. The genetic study confirmed linkage to a previously identified locus on chromosome 11q23 and refined the location of the gene to a 3.3-cM region (Salih et al. 2000). Charcot–Marie–Tooth disease type 4B1 was diagnosed in a patient who was found to have two different homozygous mutations in the MTMR2 gene; an in-frame deletion and an E276X mutation (Bolino et al. 2000). Three patients with fast-channel congenital myasthenia syndrome were described. Homozygous mutation (P250Q) in the CHRND gene was identified (Shen et al. 2002). Hyaline body myopathy was reported in a kindred with 11 affected members who had the disease inherited in an autosomal dominant pattern (Bohlega et al. 2003b). Through linkage analysis and candidate gene approach, sequencing MYH7 revealed an H1904L substitution (Bohlega et al. 2004). In children with congenital muscle weakness and childhood-onset fatal dilated cardiomyopathy, a homozygous titin deletion in exons encoding the C-terminal M-line region was identified. This represents the first congenital and purely recessive titinopathy, and the first to involve both cardiac and skeletal muscle (Carmignac et al. 2007). Mutations in the acetylcholinesterase collagen-like tail subunit gene (COLQ) causing congenital myasthenic syndrome were recently reported in Saudi patients (Mihaylova et al. 2008). Neurodegenerative disorders are amongst the most common reasons for referrals to Genetics and Neurology services in tertiary hospitals in the Kingdom. The impact of high consanguinity is again observed; three notable examples are illustrative. An autosomal recessive juvenile Huntington disease-like neurodegenerative disorder was reported in five siblings (Al-Tahan et al. 1999). The disease manifests at approximately 3–4 years and is characterized by both pyramidal and extrapyramidal abnormalities, including chorea, dystonia, ataxia, gait instability, spasticity, seizures, mutism, and intellectual impairment. Brain MRI findings include progressive frontal cortical atrophy and bilateral caudate atrophy. Huntington CAG trinucleotide-repeat analysis was normal. The inheritance pattern and localization to 4p15.3 were consistent with the identification of a novel, autosomal recessive, neurodegenerative Huntington-like disorder (Kambouris et al. 2000a). Pelizaeus– Merzbacher disease is a hypomyelinating leukoencephaloathy disorder that is inherited in X-linked fashion. However, an autosomal recessive form, Pelizaeus– Merzbacher-like disease (PMLD), has been recently described in a Saudi family who was found to segregate a frameshift mutation (P131fs144X) in GJA12 gene (Bugiani et al. 2006). The third example is SAP-B deficiency (SAPBD) which is the metachromatic leukodystrophy (MLD) variant, caused by mutated PSAP gene, in which arylsulfatase-A (ASA) is normal. Out of 16 patients with MLD who were evaluated in one center, seven patients from three families were diagnosed to have ASA-deficient MLD, while nine children from four unrelated Saudi families were found to have SAPBD. PSAP analysis found that the four families segregate the same homozygous mutation (C241S) which was previously reported in an Arab patient suggesting that SAPBD is likely to be more

19


541

common than classic MLD in the Saudi population (Al-Hassnan et al. 2009). Likewise, and to the contrary to what has been observed in other populations, mutated CLN6 is likely to be a common cause of NCL in comparison to CLN1 and CLN2. Another rare NCL variant due to mutated MFSD8 (CLN7) gene has been reported recently (Aldahmesh et al. 2009b). The genetics of mental retardation has not been well studied in the Saudi population yet. Few publications, however, provided introductory views on this aspect. Screening 305 Saudi patients with mental retardation/developmental delay/ clinical suspicion of fragile X syndrome by cytogenetic methods detected 24 males (7.86%) and two females (0.65%) who were found to express fragile X site; a frequency that is similar to other reports of fragile X syndrome in preselected patients (Iqbal et al. 2000). Rett syndrome was also described in five Saudi girls (al-Jarallah et al. 1996). In one family, three siblings were reported to have mental retardation, calcification of the choroid plexus, and increased CSF protein (Singh et al. 1993). A pedigree with multiple affected individuals with microcephaly and seizures was reported to have a novel nonsense mutation in ASPM gene (Shen et al. 2005). A consanguineous family with four affected children presented with generalized tonic–clonic epilepsy, ataxia, and mental retardation. MRI and muscle biopsy of one patient revealed, respectively, posterior white matter hyperintensities and vacuolization of the sarcotubular system. The defective gene was localized by homozygosity mapping to a 19 Mb interval in 16q21–q23 (Gribaa et al. 2007). Other novel and unusual neurogenetic disorders have been reported too. The selective deficiency of b-dystroglycan with muscular dystrophy, a borderline elevation of serum creatine kinase level, early-onset proximal symmetrical muscle weakness and wasting without calf hypertrophy was described as a likely novel form of muscular dystrophy (Salih et al. 1996b). Juvenile primary lateral sclerosis was reported in three affected members of a Saudi family who were homozygous for a 2-bp deletion (1867delCT) in ALS2 gene (Yang et al. 2001). In a family that had an autosomal recessive form of spinocerebellar ataxia with axonal neuropathy (SCAN1), the presenting symptom was disturbance of gait in the teen years with signs of peripheral axonal motor and sensory neuropathy, distal muscular atrophy, pes cavus, and normal intelligence. Linkage analysis mapped the mutant gene to 14q31–q32. TDP1 was identified as one of the candidate genes in the region and a homozygous mutation (H493R) was detected (Takashima et al. 2002). In three affected individuals from a family displaying pure novel autosomal recessive hereditary spastic paraplegia and sensorineural deafness, the paraplegic trait was linked to a 1.8-Mb region of chromosome 13q14. The deafness did not link to this region and did not cosegregate with the paraplegic trait (Hodgkinson et al. 2002). In three families with chorea-acanthocytosis, three different homozygous mutations in VPS13A were identified (Bohlega et al. 2003a). Ataxia telangiectasia-like disorder (ATLD) was diagnosed in ten patients from three unrelated families. They presented with an early-onset slowly progressive ataxia plus ocular apraxia with an absence of tumor development, telangiectasia, raised a-fetoprotein or reduced immunoglobulin levels. All patients were homozygous for a novel missense mutation (W210C) in the MRE11 gene (Fernet et al. 2005). The carrier

542


frequency of this particular mutation was found to be 0.5% in a cohort of 428 Saudis (Alsbeih et al. 2008). In two affected members of a large consanguineous family with early-onset parkinsonism, a homozygous T313M substitution in PINK1 gene was identified. Both patients had onset at age 34 and 30 years, respectively, without cognitive impairment or major axial symptoms (Chishti et al. 2006). CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) was reported in a family who was found to have a mutation in Notch 3 (Bohlega et al. 2007).

Malformation Syndromes Alleleic homogeneity has not always been the rule. Explained by the diverse tribal components of the Saudi population, locus heterogeneity was, rather, found in many autosomal recessive diseases. Two exemplifying disorders are Bardet–Biedl syndrome (BBS) and Joubert syndrome. In BBS, which is a common disorder, at least five loci have been linked to Saudi pedigrees and mutations have been identified: a splicing mutation in the BBS4 gene in one family (Katsanis et al. 2002); a 4-bp deletion in the BBS7 gene in nine families (Badano et al. 2003); a 6-bp in-frame deletion in the BBS8 gene (TTC8) in two families (Ansley et al. 2003); a missense mutation in the BBS3 gene (ARL6) in another family (Fan et al. 2004), and a nonsense mutation in the BBS5 gene in two affected siblings (Li et al. 2004). With respect to Joubert syndrome, three independent mutations in the AHI1 gene in three families (Ferland et al. 2004), and a mutation in the CC2D2A gene in two others (Gorden et al. 2008) were identified. Similarly, the molecular basis of Meckel–Gruber syndrome, which is a common multiple malformations syndrome in Saudi Arabia, is yet to be identified; screening known causative genes in some families have been negative. Though less frequently, Walker–Warburg syndrome has also been diagnosed in several families, and in two affected siblings, a homozygous 63-kb intragenic deletion in the LARGE gene was recently discovered (van Reeuwijk et al. 2007). Cockayne syndrome has been diagnosed in several cases too and was reported in three sisters with varying clinical presentation (Mahmoud et al. 2002). In addition, other conditions with malformations have been encountered and described. Almost two decades before, osteodysplastic variant of primordial dwarfism was reported in an infant (Shebib et al. 1991). Severe microcephaly, lymphedema, and attention deficit disorder were described in a sister and brother from a nonconsanguineous family. An X-linked dominant inheritance could not be excluded (Kozma et al. 1996). In a family with first-cousin parents and three affected children with lissencephaly, a splice acceptor site mutation in the RELN gene was found (Hong et al. 2000). Recently, a nonsense mutation (E220X) in the PCNT2 gene was identified in two patients with Seckel syndrome (Griffith et al. 2008). Reports of rare dysmorphic syndromes in Saudi patients have also described: Johanson–Blizzard syndrome in three affected family members (Mardini et al.

19


543

1978); Borjeson–Forssman–Lehmann syndrome in a sibship (Robinson et al. 1983); Donnai–Barrow syndrome in a male infant (Gripp et al. 1997), Sotos syndrome in 14 children (al Rashed et al. 1999); Alstrom syndrome in four families who had their mutations identified (Aldahmesh et al. 2009a).

Endocrine Disorders Congenital adrenal hyperplasia (CAH) and congenital hypothyroidism are the most commonly detected disorders in the NBS program. The clinical findings and biochemical defects in CAH have been illustrated. Over a 10-year period, 78 Saudi children were diagnosed with CAH in a university hospital; 20 (25.6%) of them had 11b-hydroxylase deficiency (Al-Jurayyan 1995). In another retrospective review of 120 patients with ambiguous genitalia, CAH was the underlying cause in 41 of 63 patients with ambiguity because of endocrine causes; the most common of which was 21-hyroxylase deficiency. 3b-Hydroxylase deficiency was the cause in two patients (Al-Mutair et al. 2004). CAH due to 3b-hydroxysteroid dehydrogenase type II deficiency was also reported in four children (Bin-Abbas et al. 2004a). Among eight patients with congenital lipoid adrenal hyperplasia from six unrelated families, seven were found to be homozygous for an R182H mutation in the steroidogenic acute regulatory protein (STAR) (Chen et al. 2005). Clinical and molecular studies have extended to various endocrine disorders. Persistent hyperinsulinaemic hypoglycemia of infancy (PHHI) is relatively common in Saudi Arabia (al-Rabeeah et al. 1995; Bin-Abbas et al. 2003) with an estimated incidence of 1 in 2,675 live births (Mathew et al. 1988). Using homozygosity mapping, the locus of PHHI was detected in five consanguineous families (Thomas et al. 1995a) and, in 14 affected children, two homozygous point mutations were found in the SUR gene (Thomas et al. 1995b; Dunne et al. 1997). In two families with isolated growth hormone (GH) deficiency, splicing mutations were identified in the GH1 gene (Cogan et al. 1993; Phillips and Cogan 1994). Mutations in the GH receptor (GHR) gene were also identified in four individuals with Laron syndrome (Wojcik et al. 1998). Three unrelated kindreds were diagnosed to have pseudohypoaldosteronism type I. A 2-bp deletion at codon 68 resulting in a frameshift was identified in the a subunit of the SCNN1A gene (Chang et al. 1996). Idiopathic hypogonadotropic hypogonadism was described in a large family with six affected members (Bo-Abbas et al. 2003). Linkage analysis localized the gene to 19p13.3 (Acierno et al. 2003) and an L148S substitution was identified in the GPR54 gene (Seminara et al. 2003). Three siblings were reported to have a specific thyroid phenotype associated with a reduction in type II iodothyronine deiodinase activity. The patients had abnormal thyroid function tests with high TSH, total T4, free T4, and total triiodothyronine metabolite, whereas total and free T3 were low. Affected individuals were found to be homozygous for an R540Q mutation in the SECISBP2 gene (Dumitrescu et al. 2005).

544


Further, published work on Saudi patients with inherited endocrine disorders have included: the syndrome of alacrima–achalasia–addisonianism (triple-A syndrome) in an 8-year-old girl (Lanes et al. 1980); X-linked hypophosphataemic rickets in a family with 13 affected members with identified locus on Xp22.3–p21.3 (Thakker et al. 1992); hereditary 1,25-dihydroxyvitamin D3-resistant rickets in two children who had novel point mutations (G46D and I268T respectively) in the vitamin D receptor (VDR) gene (Lin et al. 1996; Malloy et al. 2004); Wolfram syndrome in a 10-year-old child who was homozygous for a 7-bp repeat insertion at nucleotide 1610 of the WFS1 gene (Inoue et al. 1998); GH, prolactin, and thyrotropin deficiency with a novel recessive mutation (P239S) in the Pit-1 gene (Pernasetti et al. 1998); hypothalamic hypopituitarism with the syndrome of septooptic dysplasia in ten children (Bin-Abbas et al. 2004b); anterior hypopituitarism with mutated PIT1/POU1F1 gene (Taha et al. 2005); recurrent goiters in two siblings, one of whom had metastatic follicular thyroid carcinoma, with a homozygous splicing mutation in thyroglobulin gene (Alzahrani et al. 2006a); adrenal insufficiency, complete sex reversal, and agenesis of corpus callosum in 46, XY patient who had homozygous mutation (V359A) in the CYP11A1 gene (al Kandari et al. 2006); multiple endocrine neoplasia type 1 (MEN 1) syndrome with a splicing mutation (Alzahrani et al. 2008); primary cortisol resistance in three siblings who were homozygous for a G679S mutation in the glucocorticoid receptor-a (GR-a) gene (Raef et al. 2008).

Rheumatological and Musculoskeletal Disorders The first series of Saudi patients with familial arthropathy with a triad of camptodactyly, arthropathy, and coxa vara (CAC syndrome) were reported in three children (Bahabri et al. 1994). Other cases were later described (Suwairi et al. 1997; Bahabri et al. 1998). The gene locus was mapped to chromosome 1q25–31 (Bahabri et al. 1998) and, in seven children from four unrelated families diagnosed with camptodactyly–arthropathy–coxa vara–pericarditis (CACP), five novel mutations in the PRG4 gene were uncovered (Alazami et al. 2006). In addition, diverse rheumatological/skeletal disorders have been reported. Progressive pseudorheumatoid arthropathy was diagnosed in two families who were found to have homozygosity for a 1-bp deletion at nucleotide 246 of the WISP3 gene (Hurvitz et al. 1999). In two large affected consanguineous families of Saudi and Lebanese origin consistent with autosomal recessive Weill–Marchesani syndrome, a genome-wide search mapped the disease gene to 19p13.3–p13.2 (Faivre et al. 2002). Three of 12 affected siblings were homozygous for a splicing mutation in the ADAMTS10 gene (Dagoneau et al. 2004). The clinical findings in a patient with Wolcott–Rallison syndrome were reported (Al-Gazali et al. 1995) and further cases have also been described (Abdelrahman et al. 2000; Bin-Abbas et al. 2001, 2002). The phenotype of infantile systemic hyalinosis in 19 patients were reviewed; 13 (68%) were

19


545

products of first-cousin marriages and five families had more than one affected child (Al-Mayouf et al. 2005). Almost three decades ago, osteopetrosis was reported in children of three Saudi families who were observed to have striking facial similarities and cerebral calcifications (Ohlsson et al. 1980). Other Saudi cases were later reported (Ohlsson et al. 1986; Al Rajeh et al. 1988), and the long-term clinical, biochemical, and radiological features of 35 children with carbonic anhydrase II (CA II) deficiency syndrome were reviewed (Awad et al. 2002). A splice junction mutation at the exon 2–intron 2 boundary of the CA II gene was previously shown to be the unique mutation in patients of Arab descent. The malignant osteopetrosis variant is also prevalent in Saudi Arabia (Solh et al. 1995). On the hand, we have observed a frequent occurrence of various forms of lethal skeletal dysplasias. The most notable examples have been short rib-polydactyly syndromes, and severe osteogenensis imperfecta, the molecular basis of both conditions is yet to be elucidated in our population. Reported skeletal and rheumatological disorders in Saudi patients have covered: tibial aplasia with ectrodactyly syndrome in four siblings (Mufti and Wood 1987); Rowbinow syndrome (Nazer et al. 1990); hyperostosis with hyperphosphatemia in two sisters born to consanguineous parents (Narchi 1997); cartilage hair hypoplasia with identified mutation in RMRP (Ridanp€a€a et al. 2002); spondyloepiphyseal dysplasia and bilateral femoral fractures with homozygosity for a 4-bp deletion (1563delGAAA) in the EIF2AK3 gene (Brickwood et al. 2003); familial Mediterranean fever with identified common mutations (Al-Alami et al. 2003); Meier– Gorlin in a girl who was found to have GH deficiency (Faqeih et al. 2008); and Grebe-type chondrodysplasia in three affected children from a consanguineous family who had a novel mutation (C429R) in the GDF5 gene (Faiyaz-Ul-Haque et al. 2008).

Ophthalmological Disorders Several novel loci and mutations have been identified in Saudi families with inherited eye disorders. Autosomal recessive congenital fibrosis of extraocular muscles (CFEOM) was diagnosed in 18 members of three consanguineous families. By genetic linkage analysis, the disorder was not linked to the classic CFEOM chromosome 12 locus, but to 11q13.1 (Engle et al. 1997). The same disease-associated haplotype was found in two of the three families suggesting founder effect (Wang et al. 1998). An R72V substitution was identified in the ARIX gene in two consanguineous families with CFEOM2, (Nakano et al. 2001). In two other consanguineous families with horizontal gaze palsy and progressive scoliosis, homozygosity for two mutations (3325þ1G and S705P) in the ROBO3 gene were identified (Jen et al. 2004). Later, several affected individuals from consanguineous families with novel homozygous mutations were reported (Bosley et al. 2005; Abu-Amero et al. 2009). A novel ROBO3 mutation was also reported in a girl with synergistic convergence (Khan et al. 2008). Sequence analysis of the CYP1B1 gene in families with primary

546


congenital glaucoma revealed several mutations with G61E, R469W, and D374N being the most common Saudi variants. However, affected individuals from five families had no CYP1B1 mutations (Bejjani et al. 1998, 2000). Twelve affected patients with recessive cornea plana were homozygous for one of two mutations in the KERA gene; a novel deletion (1634delC) or a previously reported nonsense mutation (R313X). An additional KERA mutation (R279X) has been reported previously in one Saudi family (Khan et al. 2006b). In three affected siblings with a phenotype resembling blepharophimosis–ptosis–telecanthus–epicanthus inversus, linkage analysis excluded FOXL2 as the underlying gene (Khan et al. 2006a). Congenital total white cataract with microcornea was diagnosed in three affected siblings who were homozygous for a novel nonsense mutation (R54C) in the CRYAA gene (Khan et al. 2007). Moreover, the molecular lesions of several retinal disorders have been described. By linkage analysis, a novel locus on 14q24 for Leber congenital amaurosis was identified in a consanguineous family and the locus was designated LCA3 (Stockton et al. 1998). Four consanguineous kindreds were diagnosed with fundus albipunctatus; in one family, a homozygous R150Q alteration was found in RLBP1, the gene associated previously with both recessive retinitis pigmentosa (RP) and retinitis punctata albescens (Katsanis et al. 2001). Autosomal recessive RP without glaucoma was described in an individual who was homozygous for an R368H mutation in the CYP1B1 gene (Vincent et al. 2002). Novel missense mutation was detected in two brothers who had Norrie disease (Khan et al. 2004). Recently, autosomal recessive congenital hereditary endothelial dystrophy was reported in nine members of a family who were homozygous for a novel mutation (T271M) in the SLC4A11 gene (Shah et al. 2008). Clinical reports on inherited ophthalmological disorders in Saudi patients have also included Stargardt disease in one consanguineous family (Allikmets et al. 1997) and brittle cornea syndrome in nine Saudi families who also had blue sclerae, joint laxity, and skin hyperelasticity (Al-Hussain et al. 2004).

Other Inherited Disorders The genetic basis of mendelian cardiovascular diseases in Saudi Arabia is just starting to be unraveled. Cardiomyopathies, arryhthmogenic disorders, and congenital heart diseases, have been observed to affect multiple cases in consanguineous families. Dilated cardiomyopathy, for example, was diagnosed in 55 children from 41 families; in 19 (46%) families, parents were first cousins suggesting an autosomal recessive inheritance (Seliem et al. 2000). Similarly, the long QT syndrome (LQTS), which is classically inherited as autosomal dominant in the absence of deafness, was described in two consanguineous Saudi families who segregated a novel homozygous splicing mutation in the KCNQ1 gene. This novel mutation is very likely to be a founder mutation (Bhuiyan et al. 2008). Mendelian cardiovascular diseases have also been encountered. Twelve patients from eight different

19


547

families were initially reported as a novel syndrome (Al Fadley et al. 2000) which was later found to be arterial tortuosity syndrome (ATS). Two mutations, a novel (R105C) and a recurrent (S81R), were recently described in SLC2A10 gene in seven patients of two unrelated families with ATS (Faiyaz-Ul-Haque et al. 2009a). Expectedly, genetic causes of known cardiovascular diseases extend beyond known loci. The rare cardiomyopathy disorder, Naxos disease, was diagnosed in two Saudi patients whose disease was not linked to the previously identified plakoglobin gene (Stuhrmann et al. 2004). Likewise, various inherited skin disorders have also been diagnosed in Saudi families. The genetic causes of junctional epidermolysis bullosa (EB) were elucidated in seven families form several Middle Eastern countries including Saudi Arabia. Mutations in genes encoding one of the three polypeptides of laminin-5: LAMB3; LAMA3; and LAMC2, were identified. In a 15-month-old Saudi girl with non-Herlitz type junctional EB, homozygosity for a Q1368X mutation in the LAMA3 gene was found (Nakano et al. 2002). Autosomal recessive EB simplex has been reported too (Abanmi et al. 1994). Progressive hair loss was observed in a consanguineous family in which four siblings are affected (Al Aboud et al. 2002); a homozygous truncating mutation in the P2RY5 gene was found (Pasternack et al. 2008). Dyschromatosis universalis hereditaria (DUH) was diagnosed in a consanguineous family with four affected siblings. Genome-wide scan identified a new locus for dyschromatosis on chromosome 12q21–q23 which revealed the first locus for autosomal recessive DUH (Stuhrmann et al. 2008). Unusual forms of connective tissue disorders are not uncommon too. Congenital cutis laxa, in particular, appears to be frequently diagnosed in Saudi Arabia. The disorder was diagnosed in two sisters who also had severe intrauterine growth retardation and congenital dislocation of the hip (Reisner et al. 1971). Seven more cases were later described (Sakati et al. 1983; Allanson et al. 1986). Reports of familial skin disorders have also included: wrinkly skin syndrome in two sibs (Karrar et al. 1983); porokeratosis punctata palmaris et plantaris in seven members of a family (Lestringant and Berge 1989); ichthyosis congenita, harlequin fetus type in two affected siblings (Prasad et al. 1994); congenital insensitivity to pain in five members of one family (Karkashan et al. 2002); Kindler syndrome (hereditary acrokeratotic poikiloderma) in one kindred (al aboud et al. 2002); Netherton syndrome in four siblings (Saif and Al-Khenaizan 2007); and congenital atrichia in a family who was found to have a homozygous insertion (c.2661dupG) in the human hairless gene (HR) (Betz et al. 2007). Informative work on the genetics of gastroenterological disorders in Saudi Arabia has been published with notable examples. Cystic fibrosis (CF) had been thought to be very rare in Arabs; however, the disease was documented in 13 Saudi children two decades ago (Nazer et al. 1989) and later in 70 patients from 46 families (Banjar et al. 1999). Eight novel mutations have been identified with the 1548delG being the most prevalent (Banjar et al. 1999; Kambouris et al. 2000b). Screening six mutations, though, would account for 70% of Saudi CFTR alleles (El-Harith et al. 1998). In Saudi patients with congenital chloride diarrhea (CLD), a major founder effect was observed: 94% of the CLD-associated chromosomes

548


carried a nonsense mutation (G187X) in the SLC26A3 gene (Ho¨glund et al. 1998). In Wilson disease, causative mutations have been studied and variants in exons 21 and 19 of the ATP7B gene appear to be unique for Saudis (Majumdar et al. 2000, 2003; Al Jumah et al. 2004). The first report of arthrogryposis, renal tubular dysfunction, and cholestasis (ARC) syndrome form Saudi Arabia was described in a consanguineopus family with several affected infants (Abdullah et al. 2000). Linkage analysis on this family and other similarly affected patients identified the defective gene, VPS33B (Gissen et al. 2004). In a1-antitrypsin deficiency, the frequency of the two most common deficiency alleles, protease inhibitor (PI)*S and PI*Z, was estimated in Saudi individuals (de Serres et al. 2006) as was the frequency of the two major alleles: C282Y and H63D in hereditary hemochromatosis gene (Alsmadi et al. 2006). A clinical report described Crigler–Najjar syndrome in concurrence with Robinow syndrome in two siblings of first-cousin Saudi parents (Nazer et al. 1990). Studies on the genetics of immunodeficiency disorders in Saudi patients have been very enlightening. A multisystem disorder with partial albinism, immunodeficiency, and progressive demyelination was described in eight Saudi kindreds (Harfi et al. 1992). This disorder, referred originally as PAID syndrome, was later confirmed to be Griscelli syndrome caused by mutated RAB27A gene (de Saint Basile 2007). Noteworthy, novel genes have been discovered to cause various forms of immunodeficiency in Saudi patients: CD40 gene in autosomal recessive immunodeficiency with hyper-IgM (Ferrari et al. 2001); IL12B gene in interleukin-12 deficiency (Picard et al. 2002); IRAK4 gene and recurrent pyogenic bacterial infections (Picard et al. 2003); IFNGR2 gene and severe mycobacterial disease (Vogt et al. 2005); and NOLA3 gene in autosomal recessive dyskeratosis congenita (Walne et al. 2007). Molecular studies have also revealed: a novel intronic mutation in ADA gene in four patients from three families who had adenosine deaminase deficiency (Arredondo-Vega et al. 2002); a novel splicing mutation in the WAS gene in two affected brothers with Wiskott–Aldrich syndrome (Abu-Amero et al. 2004b); and a novel SAP gene mutation in a case with X-linked lymphoproliferative disease associated with hypogammaglobulinemia and GH deficiency (Alangari et al. 2006). Children in the Kingdom probably have a higher incidence of polycystic kidney disease, familial juvenile nephronophthisis, congenital urological anomalies, and familial nephrotic syndrome (Mattoo 1998). The genetics of renal diseases, however, is still in its infancy and published work has covered a few disorders: distal renal tubular acidosis and presumably normal hearing in a 13-year-old male with a deletion of 1 bp in codon 376 of the ATP6N1B gene (Smith et al. 2000); Schimke immuno-osseous dysplasia in a patient with SMARCAL1 mutation (Taha et al. 2004); familial hypomagnesemia with hypercalciuria and nephrocalcinosis in two sisters (Al-Elq 2008). In families with nephrogenic diabetes insipidus (NDI), several novel mutations have been identified in both AQP2 (G100R and G180S mutations) and AVPR2 (G122N and contiguous deletion mutations) genes (Carroll et al. 2006).

19


549

A range of other genetic disorders have been observed and reported. Papillon– Lefe`vre syndrome was reported in five unrelated Saudi families with two cathepsin C gene mutations: a novel G300D substitution and a common R272P one (Zhang et al. 2001). Lipoid proteinosis was described in 31 affected individuals from six unrelated consanguineous families. Linkage analysis mapped the disorder to 1q21, and six different homozygous mutations were detected in the ECM1 gene (Hamada et al. 2002). Recently, a homozygous missense mutation (G66C) in fibroblast growth factor 3 (FGF3) was identified in 21 affected individuals from a large extended consanguineous family, phenotypically characterized by autosomal recessive syndromic congenital sensorineural deafness, microtia, and microdontia (Alsmadi et al. 2009).

Novel Syndromes Not unexpectedly, the high incidence of consanguineous marriages in Saudi Arabia has been the reason behind the frequent occurrences of rare and novel autosomal recessive disorders; only a few have been reported in literature though. Here, we briefly review the novel syndromes that have been described in Saudi patients (listed according to date of publication): l

l

l

l

Woodhouse and Sakati (1983) first reported seven individuals from two consanguineous families with a combination of hypogonadism, partial alopecia, diabetes mellitus (DM), mental retardation, and deafness. This autosomal recessive multisystemic disorder was later described in 12 Saudi families (Al-Semari and Bohlega 2007), one of them had been previously reported and three affected members had since developed a neurologic extrapyramidal syndrome with choreoathetoid movements and dystonia. A founder mutation consisting of a single base-pair deletion in a novel gene, C2orf37, was recently identified (Alazami et al. 2008). A report described a child with pancytopenia and several dysmorphic features which have never collectively been described in any of the bone marrow aplasia syndromes (Sackey et al. 1985). Sanjad–Sakati syndrome, an autosomal recessive disorder with congenital hypoparathyroidism, mental retardation, facial dysmorphism, and extreme growth failure, was reported for the first time more than two decades ago (Sanjad et al. 1988, 1991). Linkage analysis in three consanguineous families identified a candidate region on chromosome 1q42–43 (Kelly et al. 2000), and mutated TBCE gene was later found to be the cause of the syndrome (Parvari et al. 2002). A 12-bp deletion was identified in all the 17 Saudi pedigrees studied. An autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive faces was described in a number of

550

l

l

l

l

l


consanguineous families (Al-Mayouf et al. 2000; Al Aqeel et al. 2000). Two family-specific homoallelic MMP2 mutations, R101H and Y244X, were identified (Martignetti et al. 2001). Boyadjiev et al. (2003) described a dysmorphic syndrome in five males and one female in an inbred Saudi family. The craniofacial features included wide open calvarial sutures with large and late-closing anterior fontanels, frontal bossing, hyperpigmentation with capillary hemangioma of the forehead, significant hypertelorism, and a broad and prominent nose. By a genome-wide scan, linkage to chromosome 14q13–q21 was found. Using positional cloning approach, an F382L missense mutation in the SEC23A gene was demonstrated (Boyadjiev et al. 2006). A distinct autosomal recessive syndrome was described in a consanguineous Saudi family in which two of four sibs had the constellation of minor facial anomalies, proportionate intrauterine growth retardation, neonatal nonimmune DM, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys (Taha et al. 2003). Mutations in the GLIS3 gene were later identified in this original family as well as in a second Saudi family (Seneé et al. 2006). A syndrome with horizontal gaze abnormalities in association with deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries and cardiac outflow tract, mental retardation and autism spectrum disorder was described and designated as Bosley–Salih–Alorainy syndrome. Homozygous I75–I76insG truncating mutation in HOXA1 was identified (Tischfield et al. 2005). The spectrum of the phenotype was defined in several other families (Bosley et al. 2007, 2008). Al-Hassnan and Teebi (2007b) reported two sisters, born to consanguineous parents, who had a syndromic form of humeroradial synostosis. Both children had a distinctive facial appearance with a high, broad forehead, high frontal hairline, sparse scalp hair, hypertelorism, epicanthus inversus, depressed nasal bridge, and exotropia, as well as low-set, posteriorly rotated, and malformed ears, and rhizomelic limb shortening. Both girls had a very large anterior fontanel, cranium bifidum occultum, and plagiocephaly. Faqeih et al. (2007) reported four siblings born to first-cousin parents with the constellation of distal renal tubular acidosis, small kidneys, nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial features (prominent cheeks, well-defined philtrum, large bulbous nose, V-shaped upper lip border, full lower lip, open mouth with protruded tongue, and pits on the ear lobule) as a possibly new autosomal recessive syndrome.

Polymorphisms and Common Diseases in Saudi Arabia Several studies have focused on identifying associations between various polymorphisms and common diseases in the Saudi population. Research has concentrated

19


551

on coronary artery disease (CAD), cancer, DM, and to a lesser extent on other conditions.

Coronary Artery Diseases (CADs) Studies have shown no association between CAD and the following polymorphisms: the infrequent band of 3.2-kb of the apolipoprotein A-I/C-III (Johansen et al. 1991); the insertion/deletion sites in the polymorphic region of intron 16 of the angiotensin I-converting enzyme (ACE) gene (Dzimiri et al. 2000); lipoprotein lipase (LPL) polymorphisms (LPL-HindIII and LPL-PvuII) (Abu-Amero et al. 2003b); the W64R polymorphism of the b3-adrenoceptor (b3-AR) gene (Abu-Amero et al. 2005); LPL gene PvuII polymorphism (Cagatay et al. 2007); and the 677C>T and 1298A>C variants of the MTHFR gene (Abu-Amero et al. 2003c). However, another study suggests that the MTHFR C677T variant mildly influences CAD in Saudi individuals (Al-Ali et al. 2005b). On the other hand, CAD was found to be associated with: a variant allele (a C to G substitution in the 30 UTR) of apoprotein-CIII (Hussain et al. 1999); the PlA2 allele resulting from a genetic polymorphism in the glycoprotein IIIa gene (Abu-Amero et al. 2004a); and the null-genotypes of GSTT1 and GSTM1 (AbuAmero et al. 2006a). The E-selectin p.S128R (g.561A>C) polymorphism was associated with angiographic CAD in univariate analysis, but lost its association in multivariate analysis (Abu-Amero et al. 2006b).

Cancer Polymorphisms in five genes (CYP1A1, GSTT1, GSTP1, GSTM1, and NQO1) were characterized in patients with diffuse large B-cell lymphoma (DLBCL). The CYP1A1*2C, GSTT1 null, and GSTP1 TT genotypes demonstrated significant association with DLBCL. None of the other alleles tested proved to be significant indicators (Al-Dayel et al. 2008). Two MTHFR polymorphisms (C677T and A1298C) were found to be possibly associated with susceptibility to develop DLBCL (Siraj et al. 2007). In addition to reported mutations in BRCA1 and BRCA2 in Saudi patients (El-Harith et al. 2002), the frequency of the valine allele at codon 655 of the HER-2 protooncogene, which is associated with increased breast cancer risk, was studied in Saudi women (Ameyaw et al. 2002). The CYP1A1 C4887A genotypes CA, AA and variant allele A were demonstrated to have significant differences and greater risk of developing papillary thyroid cancer in Saudi patients compared to wild type genotype CC. Also, in thyroid cancer GSTT1 null showed higher risk while GSTM1 null showed protective effect (Siraj et al. 2008a). In eight DNA repair genes, RAD52 2259 and RAD52 GLN221GLU were found to be associated with papillary thyroid cancer too (Siraj et al. 2008b).

552


Diabetes Mellitus (DM) A positive association of the E23K variant of KCNJ11 with DM type 2 was found in Saudi individuals (Alsmadi et al. 2008a). To the contrary to what has been found in other populations, there was weak or no association with the rs7903146 and rs12255372 variants of TCF7L2 (Alsmadi et al. 2008b). In a series of 55 Saudi women with abnormal glucose tolerance test during pregnancy, the distribution of HLA antigen frequencies did not differ from a reference group of healthy individuals (Stangenberg et al. 1990). In patients with DM type 2, the risk of acquiring CAD increases significantly in the presence of the 128R mutant allele of the E-selectin gene (Abu-Amero et al. 2007).

Other Diseases Association studies with dyslipidemia was negative for a variant allele (a C to G substitution in the 30 UTR) of apoprotein-CIII (Hussain et al. 1999) but positive for the cholesteryl ester transfer protein TaqI-detectable B polymorphism (Al-Daghri et al. 2003). One study showed significantly higher frequency of Asp-9 residue, but not the Ala-73 residue, of Cw6 and Cw7 alleles of the HLA-C gene in Saudi patients with psoriasis vulgaris (Abanmi et al. 2005). The frequency of various HLA loci with vitiligo suggested that HLA-B7, Bw6, Cw6, Cw7, and DRB4*010101 could be associated with the disease (Abanmi et al. 2006). Several polymorphisms within the promoter region of the human interleukin-10 gene were significantly different in vitiligo patients compared to healthy subjects suggesting an association (Abanmi et al. 2008).

Polymorphisms in the Saudi Population The frequency and distributions of a variety of polymorphisms have been examined and published. In the following section, a summary of these publications is provided: l

Three decades ago, an analysis was performed for EsD, GPT, AcP, ADA, AK, 6-PGD, PGM, C3, Tf, Hp, Gc, Pi, Bf, Hb, and ABO-blood groups, Rh-factor, level of the third component of complement, and immunoglobulins in Saudi Arabia (Goedde et al. 1979). The distribution of eight blood phenotypes (ABO, Rh, MNSs Lutheran, Kell, Duffy, Kidd, and Lewis) was also determined (Abdelaal et al. 1999). The ABO phenotype distribution was similar to African Americans; as was the distribution of the rhesus phenotypes to Caucasians but the MNSs pattern was largely distinct. Heterozygous Kell phenotype, Kk, was much more frequent in Saudis than in either Caucasians, or African Americans.

19

l

l

l

l

l

l

l


553

The Kidd system null allele, JKab was not seen in the studied group. However, increased frequencies of null alleles of the Duff (Fyab) and Lewis (Le(ab)) systems were observed (Abdelaal et al. 1999). In a total of 292 randomly selected subjects belonging to two indigenous Arab and two immigrant tribes from the Western Region, genetic variants of six blood groups, four serum proteins, and five red cell enzyme systems were tested. The distribution of the polymorphic systems was different between indigenous and immigrant tribes, and there was a considerable degree of admixture from the surrounding countries, in particular Africa (Saha et al. 1980). The distribution of human Gm-globulin and Inv-allotypes in Saudi Arabia was also published (Hirth et al. 1979). A study on cord blood samples in Riyadh revealed that the A g T chain or HbF Sardinia was present in 28% with a gene frequency of 0.160. The frequency of two G g-globin genes was 0.0061 and 0.0122, respectively, which is comparable with other ethnic or racial groups (Niazi et al. 1991). The prevalence of a-1-antitrypsin phenotypes was analyzed. The prevalences of PiMM, MS, MZ, SZ, and ZZ of a-1-antitrypsin (a1AT) were 0.8676, 0.0931, 0.0245, 0.0098, and 0.0049, respectively. The gene frequencies of the a1AT variants, PiM, PiS, and PiZ, were 0.9265, 0.0515, and 0.022, respectively (Warsy et al. 1991). Distribution of group-specific component/vitamin-D-binding protein subtypes in Saudi Arabia did not differ significantly from what was found in other population samples from the Middle East (Degheishem et al. 1991). The prevalence of human platelet alloantigens (HPA)-1 polymorphism was found to be similar to that in Caucasians. On the other hand, HPA-4 polymorphism in Saudi individuals was greater than in Caucasians, and more similar to that of Japanese (al-Sheikh et al. 2000). The human neutrophil antigen system-one was found to be highly polymorphic and was similar in its distribution to the Hispanic and Native Americans but different from the Caucasians (Al-Sheikh et al. 2002). Factor V G1691A (FV-Leiden) and prothrombin G20210A single nucleotide polymorphisms were investigated in 149 Saudi healthy subjects. The prevalence of the two variants was 0.0101 and 0.000, respectively. The frequency of the FVLeiden G/A and A/A genotypes were 2.0 and 0.0%, respectively (Almawi et al. 2005). From five different regions of Saudi Arabia, 432 anonymous neonatal blood samples were screened for the lactase persistence/nonpersistence variant C/ T-13910 of the MCM6 gene. One variant, T/G-13915, residing 5 bp upstream of the C/T-13910 variant, was present in 76.9% of the neonatal samples (Imtiaz et al. 2007). This variant as a compound allele, T/G(–13915) within the –13910 enhancer region and a synonymous SNP in the exon 17 of the MCM6 gene T/C (–3712), were found in Saudi individuals. It was suggested that these two major global LP alleles have arisen independently, the latter perhaps in response to camel milk consumption (Enattah et al. 2008). The structure of the mtDNA in Saudi Arabia was elucidated recently (Abu-Amero et al. 2008). The results showed that the Arabian Peninsula has

554


received substantial gene flow from Africa (20%), detected by the presence of L, M1, and U6 lineages, and that an 18% of the Arabian Peninsula lineages have a clear eastern provenance, mainly represented by U lineages; but also by Indian M lineages and rare M links with Central Asia, Indonesia and even Australia. However, the bulk (62%) of the Arabian lineages has a Northern source.

References Abanmi A, Joshi RK, Atukorala DN, Pedersen NB, Khamis OA (1994) Autosomal recessive epidermolysis bullosa simplex. A case report. Br J Dermatol 130(1):115–117 Abanmi A, Al Harthic F, Al Agla R, Khan HA, Tariq M (2005) Study of alanine-73 and aspartate-9 of HLA-C locus in Saudi psoriasis patients, using sequence-specific primers (PCR-SSP). J Biochem Mol Biol 38(3):350–353 Abanmi A, Al Harthi F, Al Baqami R, Al Assaf S, Zouman A, Arfin M, Tariq M (2006) Association of HLA loci alleles and antigens in Saudi patients with vitiligo. Arch Dermatol Res 298(7):347–352 Abanmi A, Al Harthi F, Zouman A, Kudwah A, Jamal MA, Arfin M, Tariq M (2008) Association of interleukin-10 gene promoter polymorphisms in Saudi patients with vitiligo. Dis Markers 24 (1):51–57 Abdelaal MA, Anyaegbu CC, al Sobhi EM, al Baz NM, Hodan K (1999) Blood group phenotype distribution in Saudi Arabs. Afr J Med Med Sci 28(3–4):133–135 Abdelrahman S, Bin-Abbas B, Al-Ashwal A (2000) Wolcott–Rallison syndrome in a Saudi infant. Curr Pediatr Res 4:51–52 Abdullah MA, Al-Hasnan Z, Okamoto E, Abomelha AM (2000) Arthrogryposis, renal dysfunction and cholestasis syndrome. Saudi Med J 21(3):297–299 Abu-Amero KK, Al-Hamed MH, Al-Batniji FS (2003a) Homozygous protein C deficiency with purpura fulminans: report of a new case and a description of a novel mutation. Blood Coagul Fibrinolysis 14(3):303–306 Abu-Amero KK, Wyngaard CA, Al-Boudari OM, Kambouris M, Dzimiri N (2003b) Lack of association of lipoprotein lipase gene polymorphisms with coronary artery disease in the Saudi Arab population. Arch Pathol Lab Med 127(5):597–600 Abu-Amero KK, Wyngaard CA, Dzimiri N (2003c) Prevalence and role of methylenetetrahydrofolate reductase 677 C!T and 1298 A!C polymorphisms in coronary artery disease in Arabs. Arch Pathol Lab Med 127(10):1349–1352 Abu-Amero KK, Wyngaard CA, Dzimiri N (2004a) Association of the platelet glycoprotein receptor IIIa (PlA1/PlA1) genotype with coronary artery disease in Arabs. Blood Coagul Fibrinolysis 15(1):77–79 Abu-Amero KK, Owaidah TM, Al Jefri A, Al-Ghonaium A, Fawaz IM, Al-Hamed MH (2004b) A novel splice site mutation in the WAS gene causes Wiskott–Aldrich syndrome in two siblings of a Saudi family. Blood Coagul Fibrinolysis 15(7):599–603 Abu-Amero KK, Al-Boudari OM, Mohamed GH, Dzimiri N (2005) Beta 3 adrenergic receptor Trp64Arg polymorphism and manifestation of coronary artery disease in Arabs. Hum Biol 77 (6):795–802 Abu-Amero KK, Al-Boudari OM, Mohamed GH, Dzimiri N (2006a) T null and M null genotypes of the glutathione S-transferase gene are risk factor for CAD independent of smoking. BMC Med Genet 7:38 Abu-Amero KK, Al-Boudari OM, Mohamed GH, Dzimiri N (2006b) E-selectin S128R polymorphism and severe coronary artery disease in Arabs. BMC Med Genet 7:52 Abu-Amero KK, Ozand PT, Al-Dhalaan H (2006c) Novel mitochondrial DNA transversion mutation in transfer ribonucleic acid for leucine 2 (CUN) in a patient with the clinical features of MELAS. J Child Neurol 21(11):971–972

19


555

Abu-Amero KK, Al-Mohanna F, Al-Boudari OM, Mohamed GH, Dzimiri N (2007) The interactive role of type 2 diabetes mellitus and E-selectin S128R mutation on susceptibility to coronary heart disease. BMC Med Genet 8:35 Abu-Amero KK, Larruga JM, Cabrera VM, Gonza´lez AM (2008) Mitochondrial DNA structure in the Arabian Peninsula. BMC Evol Biol 8:45 Abu-Amero KK, Dhalaan HA, Zayed ZA, Hellani A, Bosley TM (2009) Five new consanguineous families with horizontal gaze palsy and progressive scoliosis and novel ROBO3 mutations. J Neurol Sci 276(1–2):22–26 Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Crowley WF Jr, Seminara SB (2003) A locus for autosomal recessive idiopathic hypogonadotropic hypogonadism on chromosome 19p13.3. J Clin Endocrinol Metab 88(6):2947–2950 Al Aboud K, Al Hawsawi K, Al Aboud D, Al Githami A (2002) Kindler syndrome in a Saudi kindred. Clin Exp Derm 27:673–676 Al-Alami JR, Tayeh MK, Najib DA, Abu-Rubaiha ZA, Majeed HA, Al-Khateeb MS, El-Shanti HI (2003) Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Med J 24(10):1055–1059 Al-Ali AK, Al-Mustafa ZH, Al-Madan M, Qaw F, Al-Ateeq S (2002) Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in the Eastern Province of Saudi Arabia. Clin Chem Lab Med 40(8):814–816 Al-Ali AK, Al-Ateeq S, Imamwerdi BW, Al-Sowayan S, Al-Madan M, Al-Muhanna F, Bashaweri L, Qaw F (2005a) Molecular bases of beta-thalassemia in the Eastern Province of Saudi Arabia. J Biomed Biotechnol 2005(4):322–325 Al-Ali AK, Al-Muhana FA, Larbi EB, Abdulmohsen MF, Al-Sultan AI, Al-Maden MS, Al-Ateeq SA (2005b) Frequency of methylenetetrahydrofolate reductase C677T polymorphism in patients with cardiovascular disease in Eastern Saudi Arabia. Saudi Med J 26 (12):1886–1888 Alangari A, Abobaker A, Kanegane H, Miyawaki T (2006) X-linked lymphoproliferative disease associated with hypogammaglobulinemia and growth-hormone deficiency. Eur J Pediatr 165 (3):165–167 al Aqeel A, Ozand PT, Gascon G, Nester M, al Nasser M, Brismar J, Blau N, Hughes H, Subramanyan SB, Reynolds CT (1991) Biopterin-dependent hyperphenylalaninemia due to deficiency of 6-pyruvoyl tetrahydropterin synthase. Neurology 41(5):730–737 al Aqeel A, Rashed M, Ozand PT, Brismar J, Gascon GG, al Odaib A, Dabbagh O (1994) 3-Methylglutaconic aciduria: ten new cases with a possible new phenotype. Brain Dev 16:23–32 Al Aqeel A, Al Sewairi W, Edress B, Gorlin RJ, Desnick RJ, Martignetti JA (2000) Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family. Am J Med Genet 93(1):11–18 Al-Aqeel AI, Rashed MS, Ruiter JP, Al-Husseini HF, Al-Amoudi MS, Wanders RJ (2001) Carnitine palmityl transferase I deficiency. Saudi Med J 22(11):1025–1029 Al Aqeel AI, Rashid MS, Ruiter JP, Ijlst L, Wanders RJ (2003) A novel molecular defect of the carnitine acylcarnitine translocase gene in a Saudi patient. Clin Genet 64(2):163–165 Al-Awamy B, Niazi GA, Wilson JB, Huisman TH (1985) Hb Setif or alpha 2 94(G1)Asp–Tyr beta 2 observed in a Saudi Arabian family. Hemoglobin 9(1):87–90 Alazami AM, Al-Mayouf SM, Wyngaard CA, Meyer B (2006) Novel PRG4 mutations underlie CACP in Saudi families. Hum Mutat 27(2):213 Alazami AM, Al-Saif A, Al-Semari A, Bohlega S, Zlitni S, Alzahrani F, Bavi P, Kaya N, Colak D, Khalak H, Baltus A, Peterlin B, Danda S, Bhatia KP, Schneider SA, Sakati N, Walsh CA, Al-Mohanna F, Meyer B, Alkuraya FS (2008) Mutations in c2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am J Hum Genet 83(6):684–691 Al-Daghri NM, Al-Attas O, Patel A, Belyaev ND, Bartlett WA, Jones AF, Kumar S, Bain SC (2003) Association between the cholesteryl ester transfer protein TaqI-detectable B polymorphism and low high-density lipoprotein cholesterol concentration in Saudis. Clin Sci 105 (4):467–472

556


Aldahmesh MA, Abu-Safieh L, Khan AO, Al-Hassnan ZN, Shaheen R, Rajab M, Monies D, Meyer BF, Alkuraya FS (2009a) Allelic heterogeneity in inbred populations: the Saudi experience with Alstro¨m syndrome as an illustrative example. Am J Med Genet A 149A (4):662–665 Aldahmesh MA, Al-Hassnan ZN, Aldosari M, Alkuraya FS (2009b) Neuronal ceroid lipofuscinosis caused by MFSD8 mutations: a common theme emerging. Neurogenetics 10(4):307–311 Al-Dayel F, Al-Rasheed M, Ibrahim M, Bu R, Bavi P, Abubaker J, Al-Jomah N, Mohamed GH, Moorji A, Uddin S, Siraj AK, Al-Kuraya K (2008) Polymorphisms of drug-metabolizing enzymes CYP1A1, GSTT and GSTP contribute to the development of diffuse large B-cell lymphoma risk in the Saudi Arabian population. Leuk Lymphoma 49(1):122–129 Al-Dirbashi OY, Jacob M, Al-Hassnan Z, El-Badaoui F, Rashed MS (2005) Diagnosis of methylmalonic acidemia from dried blood spots by HPLC and intramolecular-excimer fluorescence derivatization. Clin Chem 51(1):235–237 Al-Dirbashi OY, Jacob M, Al-Ahaidib LY, Al-Qahtani K, Rahbeeni Z, Al-Owain M, Rashed MS (2006) Quantification of succinylacetone in urine of hepatorenal tyrosinemia patients by HPLC with fluorescence detection. Clin Chim Acta 365(1–2):243–248 Al-Dirbashi OY, Abu-Amero KK, Alswaid AF, Hoffmann GF, Al-Qahtani K, Rashed MS (2007) LC-MS/MS determination of dibasic amino acids for the diagnosis of cystinuria. Application in a family affected by a novel splice-acceptor site mutation in the SLC7A9 gene. J Inherit Metab Dis 30(4):611 Al-Dirbashi OY, Santa T, Rashed MS, Al-Hassnan Z, Shimozawa N, Chedrawi A, Jacob M, Al-Mokhadab M (2008) Rapid UPLC-MS/MS method for routine analysis of plasma pristanic, phytanic, and very long chain fatty acid markers of peroxisomal disorders. J Lipid Res 49 (8):1855–1862 Al-Elq AH (2008) Familial hypomagnesemia with hypercalciuria and nephrocalcinosis in 2 sisters. Saudi Med J 29(3):447–451 Al-Essa M, Rashed M, Ozand PT (1998a) Tyrosinemia type II: report of the first four cases in Saudi Arabia. Ann Saudi Med 18(5):466–468 Al Essa M, Al-Shamsan L, Rashed MS, Ozand PT (1998a) Alkaptonuria: case report and review of the literature. Ann Saudi Med 18(5):442–444 Al Essa M, Nounou R, Sakati N, Le Quesne G, Joshi S, Archibald A, Ozand PT (1998b) Wolman’s disease: the King Faisal Specialist Hospital and Research Centre experience. Ann Saudi Med 18(2):120–124 Al Essa M, Sakati NA, Dabbagh O, Joshi S, Al Jishi EA, Rashed MS, Powe JE, Ozand PT (1998c) Inborn error of vitamin B12 metabolism: a treatable cause of childhood dementia/paralysis. J Child Neurol 13(5):239–243 Al Essa M, Rashed M, Ozand PT (1998d) Saudi experience with classic homocystinuria. Ann Saudi Med 18(3):230–233 Al Essa M, Rahbeeni Z, Jumaah S, Joshi S, Al Jishi E, Rashed MS, Al Amoudi M, Ozand PT (1998e) Infectious complications of propionic acidemia in Saudi Arabia. Clin Genet 54(1):90–94 Al-Essa M, Bakheet S, Al-Shamsan L, Patay Z, Powe J, Ozand PT (1999a) 18Fluoro2-deoxyglucose (18FDG) PET scan of the brain in type IV 3-methylglutaconic aciduria: clinical and MRI correlations. Brain Dev 21(1):24–29 Al-Essa M, Dhaunsi GS, Rashed M, Ozand PT, Rahbeeni Z (1999b) Zellweger syndrome in Saudi Arabia and its distinct features. Clin Pediatr 38(2):77–86 Al-Essa MA, Al Amir A, Rashed M, Al Jishi E, Abutaleb A, Mobaireek K, Shin YS, Ozand PT (1999c) Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography of the brain, MR spectroscopy, and therapeutic attempts in methylenetetrahydrofolate reductase deficiency. Brain Dev 21(5):345–349 Al-Essa MA, Chaves-Carballo E, Ozand PT (1999d) Hyperpipecolic acidemia: clinical, biochemical, and radiologic observations. Pediatr Neurol 21(5):826–829 Al-Essa MA, Sakati NA, Bakheet SM, Patay ZJ, Dabbagh O, Chaves-Carbello E, Ozand PT (2000a) X-linked adrenoleukodystrophy. The Saudi experience. Saudi Med J 21(1):61–71

19


557

Al-Essa MA, Rashed MS, Bakheet SM, Patay ZJ, Ozand PT (2000b) Glutaric aciduria type II: observations in seven patients with neonatal- and late-onset disease. J Perinatol 20(2):120–128 Al Fadley F, Al Manea W, Nykanen DG, Al Fadley A, Bulbul Z, Al Halees Z (2000) Severe tortuosity and stenosis of the systemic, pulmonary and coronary vessels in 12 patients with similar phenotypic features: a new syndrome? Cardiol Young 10(6):582–589 al-Fawaz IM, al-Mashhadani SA (1995) Congenital dyserythropoietic anaemia type I. Report of two siblings from Saudi Arabia. Acta Haematol 93(1):50–53 al-Gazali LI, Makia S, Azzam A, Hall CM (1995) Wolcott–Rallison syndrome. Clin Dysmorphol 4 (3):227–233 Al-Hassnan ZN, Imtiaz F, Al-Amoudi M, Rahbeeni Z, Al-Sayed M, Al-Owain M, Rashed MS (2006) Identification of the Prevalent MCAD Mutation in the Saudi Population. In: The 6th Meeting of the International Society for Neonatal Screening, 16–19 September 2006, Awaji, Japan Al-Hassnan ZN, Al Budhaim M, Al-Owain M, Lach B, Al-Dhalaan H (2007a) Muscle phosphofructokinase deficiency with neonatal seizures and nonprogressive course. J Child Neurol 22 (1):106–108 Al-Hassnan ZN, Teebi AS (2007b) Craniofacial anomalies, humero-radial synostosis, rhizomelic limb shortness: previously unrecognized autosomal recessive syndrome. Am J Med Genet 143A:521–527 Al-Hassnan ZN, Rashed MS, Al-Dirbashi OY, Patay Z, Rahbeeni Z, Abu-Amero KK (2008) Hyperornithinemia–hyperammonemia–homocitrullinuria syndrome with stroke-like imaging presentation: clinical, biochemical and molecular analysis. J Neurol Sci 264 (1–2):187–194 Al-Hassnan ZN, Al Dhalaan H, Patay Z, Faqeih E, Al-Owain M, Al-Duraihem A, FaiyazUl-Haque M (2009) Sphingolipid activator protein-B deficiency: Report of 9 patients and review of literature. J Child Neurol 24(12):1513–9 Al-Hilali A, Wulff K, Abdel-Razeq H, Saud KA, Al-Gaili F, Herrmann FH (2007) Analysis of the novel factor X gene mutation Glu51Lys in two families with factor X-Riyadh anomaly. Thromb Haemost 97(4):542–545 Al-Hussain H, Zeisberger SM, Huber PR, Giunta C, Steinmann B (2004) Brittle cornea syndrome and its delineation from the kyphoscoliotic type of Ehlers–Danlos syndrome (EDS VI): report on 23 patients and review of the literature. Am J Med Genet 124A:28–34 al-Jarallah AA, Salih MA, al Nasser MN, al Zamil FA, al Gethmi J (1996) Rett syndrome in Saudi Arabia: report of six patients. Ann Trop Paediatr 16(4):347–352 Al-Jishi E, Meyer BF, Rashed MS, Al-Essa M, Al-Hamed MH, Sakati N, Sanjad S, Ozand PT, Kambouris M (1999) Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency. Clin Genet 55(6):444–449 Al-Jumah M, Majumdar R, Al-Rajeh S, Chaves-Carballo E, Salih MM, Awada A, Al-Shahwan S, Al-Uthaim S (2002) Deletion mutations in the dystrophin gene of Saudi patients with Duchenne and Becker muscular dystrophy. Saudi Med J 23(12):1478–1482 Al-Jumah M, Majumdar R, Al-Rajeh S, Awada A, Chaves-Carbello E, Salih M, Al-Shahwan S, Al-Subiey K, Al-Uthaim S (2003) Molecular analysis of the spinal muscular atrophy and neuronal apoptosis inhibitory protein genes in Saudi patients with spinal muscular atrophy. Saudi Med J 24(10):1052–1054 Al Jumah M, Majumdar R, Al Rajeh S, Awada A, Al Zaben A, Al Traif I, Al Jumah AR, Rehana Z (2004) A clinical and genetic study of 56 Saudi Wilson disease patients: identification of Saudispecific mutations. Eur J Neurol 11(2):121–124 Al Jumah M, Majumdar R, Rehana Z, Al Rajeh S, Eyaid W (2007) A pilot study of spinal muscular atrophy screening in Saudi Arabia. J Pediatr Neurol 5(3):221–224 al-Jurayyan NA (1995) Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency in Saudi Arabia: clinical and biochemical characteristics. Acta Paediatr 84(6):651–654 al Kandari H, Katsumata N, Alexander S, Rasoul MA (2006) Homozygous mutation of P450 side-chain cleavage enzyme gene (CYP11A1) in 46, XY patient with adrenal insufficiency,

558


complete sex reversal, and agenesis of corpus callosum. J Clin Endocrinol Metab 91 (8):2821–2826 Allamand V, Sunada Y, Salih MA, Straub V, Ozo CO, Al-Turaiki MH, Akbar M, Kolo T, Colognato H, Zhang X, Sorokin LM, Yurchenco PD, Tryggvason K, Campbell KP (1997) Mild congenital muscular dystrophy in two patients with an internally deleted laminin alpha2-chain. Hum Mol Genet 6(5):747–752 Allanson J, Austin W, Hecht F (1986) Congenital cutis laxa with retardation of growth and motor development: a recessive disorder of connective tissue with male lethality. Clin Genet 29 (2):133–136 Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, Gerrard B, Baird L, Stauffer D, Peiffer A, Rattner A, Smallwood P, Li Y, Anderson KL, Lewis RA, Nathans J, Leppert M, Dean M, Lupski JR (1997) A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 15(3):236–246 Almawi WY, Keleshian SH, Borgi L, Fawaz NA, Abboud N, Mtiraoui N, Mahjoub T (2005) Varied prevalence of factor V G1691A (Leiden) and prothrombin G20210A single nucleotide polymorphisms among Arabs. J Thromb Thrombolysis 20(3):163–168 Al-Mayouf SM, Majeed M, Hugosson C, Bahabri S (2000) New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome. Am J Med Genet 93(1):5–10 Al-Mayouf SM, AlMehaidib A, Bahabri S, Shabib S, Sakati N, Teebi AS (2005) Infantile systemic hyalinosis: a fatal disorder commonly diagnosed among Arabs. Clin Exp Rheumatol 23 (5):717–720 Al-Mutair A, Iqbal MA, Sakati N, Ashwal A (2004) Cytogenetics and etiology of ambiguous genitalia in 120 pediatric patients. Ann Saudi Med 24(5):368–372 al-Rabeeah A, al-Ashwal A, al-Herbish A, al-Jurayyan N, Sakati N, Abobakr A (1995) Persistent hyperinsulinemic hypoglycemia of infancy: experience with 28 cases. J Pediatr Surg 30 (8):1119–1121 Al Rajeh S, el Mouzan MI, Ahlberg A, Ozaksoy D (1988) The syndrome of osteopetrosis, renal acidosis and cerebral calcification in two sisters. Neuropediatrics 19(3):162–165 Al Rajeh S, Majumdar R, Awada A, Adeyokunnu A, Al Jumah M, Al Bunyan M, Snellen A (1998) Molecular analysis of the SMN and NAIP genes in Saudi spinal muscular atrophy patients. J Neurol Sci 158(1):43–46 al Rashed AA, al-Jarallah AA, Salih MA, Kolawole T, al-Jarallah J (1999) Sotos syndrome (cerebral gigantism): a clinical and radiological study of 14 cases from Saudi Arabia. Ann Trop Paediatr 19(2):197–203 Al-Sayed M, Alahmed S, Alsmadi O, Khalil H, Rashed MS, Imtiaz F, Meyer BF (2005) Identification of a common novel mutation in Saudi patients with argininosuccinic aciduria. J Inherit Metab Dis 28(6):877–883 Al-Sayed M, Imtiaz F, Alsmadi OA, Rashed MS, Meyer BF (2006) Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population. BMC Med Genet 7:86 Alsbeih G, Al-Hadyan K, Al-Harbi N (2008) Assessment of carriers’ frequency of a novel MRE11 mutation responsible for the rare ataxia telangiectasia-like disorder. Genet Test 12 (3):387–389 Al-Semari A, Bohlega S (2007) Autosomal-recessive syndrome with alopecia, hypogonadism, progressive extra-pyramidal disorder, white matter disease, sensory neural deafness, diabetes mellitus, and low IGF1. Am J Med Genet 143A:149–160 al-Shamsan L, al-Essa M, al-Mutair A, al-Ashwal A, Sakati N, Ozand PT (1998) Hyperinsulinism and hyperammonaemia. J Inherit Metab Dis 21(6):671–673 al-Sheikh I, Rahi A, al-Khalifa M (2000) Genotyping human platelet alloantigens (HPA 1–5) in Saudis from Eastern Province, Saudi Arabia. East Mediterr Health J 6(1):168–175 Al-Sheikh IH, Al-Khalifa MA, Rahi AS (2002) Frequency of neutrophil alloantigens by polymerase chain reaction. Saudi Med J 23(5):548–551

19


559

Alsmadi OA, Al-Kayal F, Al-Hamed M, Meyer BF (2006) Frequency of common HFE variants in the Saudi population: a high throughput molecular beacon-based study. BMC Med Genet 7:43 Alsmadi O, Al-Rubeaan K, Wakil SM, Imtiaz F, Mohamed G, Al-Saud H, Al-Saud NA, Aldaghri N, Mohammad S, Meyer BF (2008a) Genetic study of Saudi diabetes (GSSD): significant association of the KCNJ11 E23K polymorphism with type 2 diabetes. Diabetes Metab Res Rev 24(2):137–140 Alsmadi O, Al-Rubeaan K, Mohamed G, Alkayal F, Al-Saud H, Al-Saud NA, Al-Daghri N, Mohammad S, Meyer BF (2008b) Weak or no association of TCF7L2 variants with type 2 diabetes risk in an Arab population. BMC Med Genet 9:72 Alsmadi O, Meyer BF, Alkuraya F, Wakil S, Alkayal F, Al-Saud H, Ramzan K, Al-Sayed M (2009) Syndromic congenital sensorineural deafness, microtia and microdontia resulting from a novel homoallelic mutation in fibroblast growth factor 3 (FGF3). Eur J Hum Genet 17(1):14–21 Al-Tahan AY, Divakaran MP, Kambouris M, Bohlega S, Salih M, Ogunniyi A, Al-Ghanmi H (1999) A novel autosomal recessive ‘Huntington’s disease-like’ neurodegenerative disorder in a Saudi family. Saudi Med J 20:85–89 Alzahrani AS, Baitei EY, Zou M, Shi Y (2006a) Clinical case seminar: metastatic follicular thyroid carcinoma arising from congenital goiter as a result of a novel splice donor site mutation in the thyroglobulin gene. J Clin Endocrinol Metab 91(3):740–746 Alzahrani AS, Baitei E, Zou M, Shi Y (2006b) Thiamine transporter mutation: an example of monogenic diabetes mellitus. Eur J Endocrinol 155(6):787–792 Alzahrani AS, Al-Khaldi N, Shi Y, Al-Rijjal RA, Zou M, Baitei EY, Amin T (2008) Diagnosis by serendipity: Cushing syndrome attributable to cortisol-producing adrenal adenoma as the initial manifestation of multiple endocrine neoplasia type 1 due to a rare splicing site MEN1 gene mutation. Endocr Pract 14(5):595–602 Ameyaw MM, Tayeb M, Thornton N, Folayan G, Tariq M, Mobarek A, Evans DA, Ofori-Adjei D, McLead HL (2002) Ethnic variation in the HER-2 codon 655 genetic polymorphism previously associated with breast cancer. J Hum Genet 47(4):172–175 Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, Kim JC, Ross AJ, Eichers ER, Teslovich TM, Mah AK, Johnsen RC, Cavender JC, Lewis RA, Leroux MR, Beales PL, Katsanis N (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome. Nature 425(6958):628–633 Arredondo-Vega FX, Santisteban I, Richard E, Bali P, Koleilat M, Loubser M, Al-Ghonaium A, Al-Helali M, Hershfield MS (2002) Adenosine deaminase deficiency with mosaicism for a “second-site suppressor” of a splicing mutation: decline in revertant T lymphocytes during enzyme replacement therapy. Blood 99(3):1005–1013 Awad M, Al-Ashwal AA, Sakati N, Al-Abbad AA, Bin-Abbas BS (2002) Long-term follow up of carbonic anhydrase II deficiency syndrome. Saudi Med J 23(1):25–29 Badano JL, Ansley SJ, Leitch CC, Lewis RA, Lupski JR, Katsanis N (2003) Identification of a novel Bardet–Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am J Hum Genet 72(3):650–658 Bahabri S, Sakati N, Hugosson C, Hainau B, Al-Balla SR, Al-Mazyed A, Al-Dalaan A (1994) Syndrome of camptodactyly, arthropathy and coxa vara (CAC syndrome). Ann Saudi Med 14 (6):479–482 Bahabri SA, Suwairi WM, Laxer RM, Polinkovsky A, Dalaan AA, Warman ML (1998) The camptodactyly–arthropathy–coxa vara–pericarditis syndrome: clinical features and genetic mapping to human chromosome 1. Arthritis Rheum 41(4):730–735 Banjar H, Kambouris M, Meyer BF, al-Mehaidib A, Mogarri I (1999) Geographic distribution of cystic fibrosis transmembrane regulator gene mutations in Saudi Arabia. Ann Trop Paediatr 19 (1):69–73 Barr DG, Kirk JM, al Howasi M, Wanders RJ, Schutgens RB (1993) Rhizomelic chondrodysplasia punctata with isolated DHAP-AT deficiency. Arch Dis Child 68(3):415–417

560


Bejjani BA, Lewis RA, Tomey KF, Anderson KL, Dueker DK, Jabak M, Astle WF, Otterud B, Leppert M, Lupski JR (1998) Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. Am J Hum Genet 62 (2):325–333 Bejjani BA, Stockton DW, Lewis RA, Tomey KF, Dueker DK, Jabak M, Astle WF, Lupski JR (2000) Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus. Hum Mol Genet 9(3):367–374 Betz RC, Indelman M, Pforr J, Schreiner F, Bauer R, Bergman R, Lentze MJ, No¨then MM, Cichon S, Sprecher E (2007) Identification of mutations in the human hairless gene in two new families with congenital atrichia. Arch Dermatol Res 299(3):157–161 Bhuiyan ZA, Momenah TS, Amin AS, Al-Khadra AS, Alders M, Wilde AA, Mannens MM (2008) An intronic mutation leading to incomplete skipping of exon-2 in KCNQ1 rescues hearing in Jervell and Lange–Nielsen syndrome. Prog Biophys Mol Biol 98(2–3):319–327 Bin-Abbas B, Shabib S, Hainau B, Al-Ashwal A (2001) Wolcott–Rallison syndrome: clinical, radiological and histological findings in a Saudi child. Ann Saudi Med 21(1–2):73–74 Bin-Abbas B, Al-Mulhim A, Al-Ashwal A (2002) Wolcott–Rallison syndrome in two siblings with isolated central hypothyroidism. Am J Med Genet 111(2):187–190 Bin-Abbas BS, Al-Mulhim AN, Sakati NA, Al-Ashwal AA (2003) Persistent hyperinsulinemic hypoglycemia of infancy in 38 children. Saudi Med J 24(8):890–894 Bin-Abbas BS, Sakati NA, Al-Ashwal AA (2004a) Congenital adrenal hyperplasia due to 3 betahydroxysteroid dehydrogenase type II deficiency in 4 Saudi children. Long term follow up. Saudi Med J 25(9):1293–1295 Bin-Abbas BS, Al-Ashwal AA, Al-Alwan IA, Al-Qahtani MH, Al-Mutair AN, Sakati NA (2004b) The syndrome of septo-optic dysplasia in Saudi children. Saudi Med J 25(11):1675–1678 Bo-Abbas Y, Acierno JS Jr, Shagoury JK, Crowley WF Jr, Seminara SB (2003) Autosomal recessive idiopathic hypogonadotropic hypogonadism: genetic analysis excludes mutations in the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes. J Clin Endocrinol Metab 88(6):2730–2737 Bohlega S, Al-Jishi A, Dobson-Stone C, Rampoldi L, Saha P, Murad H, Kareem A, Roberts G, Monaco AP (2003a) Chorea-acanthocytosis: clinical and genetic findings in three families from the Arabian Peninsula. Mov Disord 18(4):403–407 Bohlega S, Lach B, Meyer BF, Al Said Y, Kambouris M, Al Homsi M, Cupler EJ (2003b) Autosomal dominant hyaline body myopathy: clinical variability and pathologic findings. Neurology 61(11):1519–1523 Bohlega S, Abu-Amero SN, Wakil SM, Carroll P, Al-Amr R, Lach B, Al-Sayed Y, Cupler EJ, Meyer BF (2004) Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy. Neurology 62(9):1518–1521 Bohlega S, Al Shubili A, Edris A, Alreshaid A, Alkhairallah T, AlSous MW, Farah S, Abu-Amero KK (2007) CADASIL in Arabs: clinical and genetic findings. BMC Med Genet 8:67 Bolino A, Muglia M, Conforti FL, LeGuern E, Salih MA, Georgiou DM, Christodoulou K, Hausmanowa-Petrusewicz I, Mandich P, Schenone A, Gambardella A, Bono F, Quattrone A, Devoto M, Monaco AP (2000) Charcot–Marie–Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet 25(1):17–19 Bosley TM, Salih MA, Jen JC, Lin DD, Oystreck D, Abu-Amero KK, MacDonald DB, al Zayed Z, al Dhalaan H, Kansu T, Stigsby B, Baloh RW (2005) Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROBO3. Neurology 64(7):1196–1203 Bosley TM, Salih MA, Alorainy IA, Oystreck DT, Nester M, Abu-Amero KK, Tischfield MA, Engle EC (2007) Clinical characterization of the HOXA1 syndrome BSAS variant. Neurology 69(12):1245–1253 Bosley TM, Alorainy IA, Salih MA, Aldhalaan HM, Abu-Amero KK, Oystreck DT, Tischfield MA, Engle EC, Erickson RP (2008) The clinical spectrum of homozygous HOXA1 mutations. Am J Med Genet 146A:1235–1240

19


561

Boyadjiev SA, Justice CM, Eyaid W, McKusick VA, Lachman RS, Chowdry AB, Jabak M, Zwaan J, Wilson AF, Jabs EW (2003) A novel dysmorphic syndrome with open calvarial sutures and sutural cataracts maps to chromosome 14q13–q21. Hum Genet 113(1):1–9 Boyadjiev SA, Fromme JC, Ben J, Chong SS, Nauta C, Hur DJ, Zhang G, Hamamoto S, Schekman R, Ravazzola M, Orci L, Eyaid W (2006) Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi trafficking. Nat Genet 38(10):1192–1197 Brickwood S, Bonthron DT, Al-Gazali LI, Piper K, Hearn T, Wilson DI, Hanley NA (2003) Wolcott–Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3. J Med Genet 40(9):685–689 Brismar J, Brismar G, Gascon G, Ozand P (1990a) Canavan disease: CT and MR imaging of the brain. Am J Neuroradiol 11(4):805–810 Brismar J, Aqeel A, Brismar G, Coates R, Gascon G, Ozand P (1990b) Maple syrup urine disease: findings on CT and MR scans of the brain in 10 infants. Am J Neuroradiol 11(6):1219–1228 Brismar J, Ozand PT (1994) CT and MR of the brain in disorders of the propionate and methylmalonate metabolism. Am J Neuroradiol 15(8):1459–1473 Brismar J, Ozand PT (1995) CT and MR of the brain in glutaric acidemia type I: a review of 59 published cases and a report of 5 new patients. Am J Neuroradiol 16(4):675–683 Bugiani M, Al Shahwan S, Lamantea E, Bizzi A, Bakhsh E, Moroni I, Balestrini MR, Uziel G, Zeviani M (2006) GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy. Neurology 67(2):273–279 Burnichon N, Lacan P, Becchi M, Zanella-Cleon I, Aubry M, Mowafy M, Couprie N, Francina A (2006) A new alpha chain hemoglobin variant: Hb Al-Hammadi Riyadh (alpha75(EF4) Asp!Val (alpha2)). Hemoglobin 30(2):155–164 Cagatay P, Susleyici-Duman B, Ciftci C (2007) Lipoprotein lipase gene PvuII polymorphism serum lipids and risk for coronary artery disease: meta-analysis. Dis Markers 23(3):161–166 Carmignac V, Salih MA, Quijano-Roy S, Marchand S, Al Rayess MM, Mukhtar MM, Urtizberea JA, Labeit S, Guicheney P, Leturcq F, Gautel M, Fardeau M, Campbell KP, Richard I, Estournet B, Ferreiro A (2007) C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann Neurol 61(4):340–351 Carroll P, Al-Mojalli H, Al-Abbad A, Al-Hassoun I, Al-Hamed M, Al-Amr R, Butt AI, Meyer BF (2006) Novel mutations underlying nephrogenic diabetes insipidus in Arab families. Genet Med 8(7):443–447 Chang SS, Grunder S, Hanukoglu A, Ro¨sler A, Mathew PM, Hanukoglu I, Schild L, Lu Y, Shimkets RA, Nelson-Williams C, Rossier BC, Lifton RP (1996) Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet 12(3):248–253 Chen X, Baker BY, Abduljabbar MA, Miller WL (2005) A genetic isolate of congenital lipoid adrenal hyperplasia with atypical clinical findings. J Clin Endocrinol Metab 90(2):835–840 Chishti MA, Bohlega S, Ahmed M, Loualich A, Carroll P, Sato C, St George-Hyslop P, Westaway D, Rogaeva E (2006) T313M PINK1 mutation in an extended highly consanguineous Saudi family with early-onset Parkinson disease. Arch Neurol 63(10):1483–1485 Clayton PT, Leonard JV, Lawson AM, Setchell KD, Andersson S, Egestad B, Sjo¨vall J (1987) Familial giant cell hepatitis associated with synthesis of 3 beta, 7 alpha-dihydroxy-and 3 beta, 7 alpha, 12 alpha-trihydroxy-5-cholenoic acids. J Clin Invest 79(4):1031–1038 Cogan JD, Phillips JA 3rd, Sakati N, Frisch H, Schober E, Milner RD (1993) Heterogeneous growth hormone (GH) gene mutations in familial GH deficiency. J Clin Endocrinol Metab 76 (5):1224–1228 Cook JD, Gascon GG, Haider A, Coates R, Stigsby B, Ozand PT, Banna M (1992) Congenital muscular dystrophy with abnormal radiographic myelin pattern. J Child Neurol 7(Suppl):S51–S63 Dagoneau N, Benoist-Lasselin C, Huber C, Faivre L, Me´garbane´ A, Alswaid A, Dollfus H, Alembik Y, Munnich A, Legeai-Mallet L, Cormier-Daire V (2004) ADAMTS10 mutations in autosomal recessive Weill–Marchesani syndrome. Am J Hum Genet 75(5):801–806

562


Degheishem SM, Sedrani SH, Van Baelen H, Bouillon R, Duhaiman AS (1991) Distribution of group-specific component/vitamin-D-binding protein subtypes in Saudi Arabia. Hum Hered 41 (1):53–56 de Saint Basile G (2007) Inherited hemophagocytic syndromes. In: Ochs HD, Smith CIE, Puck JM (eds) Primary immunodeficiency diseases: a molecular and genetic approach, 2nd edn. Oxford University Press, New York, pp 578–588 de Serres FJ, Blanco I, Fernańdez-Bustillo E (2006) Estimated numbers and prevalence of PI*S and PI*Z deficiency alleles of alpha1-antitrypsin deficiency in Asia. Eur Respir J 28 (6):1091–1099 Dumitrescu AM, Liao XH, Abdullah MS, Lado-Abeal J, Majed FA, Moeller LC, Boran G, Schomburg L, Weiss RE, Refetoff S (2005) Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet 37(11):1247–1252 Dunne MJ, Kane C, Shepherd RM, Sanchez JA, James RF, Johnson PR, Aynsley-Green A, Lu S, Clement JP 4th, Lindley KJ, Seino S, Aguilar-Bryan L (1997) Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 336 (10):703–706 Dzimiri N, Basco C, Moorji A, Meyer BF (2000) Angiotensin-converting enzyme polymorphism and the risk of coronary heart disease in the Saudi male population. Arch Pathol Lab Med 124 (4):531–534 El-Harith EH, Stuhrmann M, Dork T, Eskandarani HA, Schmidtke J (1998) PCR-based analysis of cystic fibrosis mutations specific for Saudi patients. Saudi Med J 19:148–152 El-Harith el-HA, Abdel-Hadi MS, Steinmann D, Dork T (2002) BRCA1 and BRCA2 mutations in breast cancer patients from Saudi Arabia. Saudi Med J 23(6):700–704 El-Harith el-HA, K€uhnau W, Schmidtke J, Gadzicki D, Ahmed M, Krawczak M, Stuhrmann M (2006) Hereditary hemorrhagic telangiectasia is caused by the Q490X mutation of the ACVRL1 gene in a large Arab family: support of homozygous lethality. Eur J Med Genet 49 (4):323–330 El-Hazmi MA, Lehmann H (1980) Human haemoglobins and haemoglobinopathies in Arabia: Hb O Arab in Saudi Arabia. Acta Haematol 63(5):268–273 el-Hazmi MA, Warsy AS (1985) Glutathione reductase deficiency in association with sickle cell and thalassaemia genes in Saudi populations. Hum Hered 35(5):326–332 el-Hazmi MA (1986a) Beta-globin gene polymorphism in the Saudi Arab population. Hum Genet 73(1):31–34 el-Hazmi MA, Al-Swailem AR, Al-Faleh FZ, Warsy AS (1986b) Frequency of glucose6-phosphate dehydrogenase, pyruvate kinase and hexokinase deficiency in the Saudi population. Hum Hered 36(1):45–49 el-Hazmi MA (1987a) Haemoglobinopathies, thalassaemias and enzymopathies in Saudi Arabia: the present status. Acta Haematol 78(2–3):130–134 el-Hazmi MA (1987b) Alpha-thalassemia in Saudi Arabia: deletion pattern. Hum Genet 76 (2):196–198 el-Hazmi MA (1989) Xmn I polymorphism in the gamma-globin gene region among Saudis. Hum Hered 39(1):12–19 el-Hazmi MA, Warsy AS (1990) Frequency of glucose-6-phosphate dehydrogenase variants and deficiency in Arabia. Gene Geogr 4(1):15–19 el-Hazmi MA (1992a) Heterogeneity and variation of clinical and haematological expression of haemoglobin S in Saudi Arabs. Acta Haematol 88(2–3):67–71 el-Hazmi MA, Warsy AS (1992b) Triple alpha-genes (alpha alpha alpha anti3.7) in a patient with sickle cell anaemia. Hum Hered 42(6):360–366 el-Hazmi MA, Bahakim HM, Warsy AS (1992c) DNA polymorphism in the beta-globin gene cluster in Saudi Arabs: relation to severity of sickle cell anaemia. Acta Haematol 88 (2–3):61–66 el-Hazmi MA, al-Swailem AR, Warsy AS, al-Swailem AM, Sulaimani R, al-Meshari AA (1995a) Consanguinity among the Saudi Arabian population. J Med Genet 32:623–626

19


563

el-Hazmi MA, al-Swailem AR, Warsy AS (1995b) Molecular defects in beta-thalassaemias in the population of Saudi Arabia. Hum Hered 45(5):278–285 el-Hazmi MA, Warsy AS (1996) Frequency of sickle cell gene in Arabia. Gene Geogr 10(2): 87–91 el-Hazmi MA, Warsy AS (1999) Appraisal of sickle-cell and thalassaemia genes in Saudi Arabia. East Mediterr Health J 5(6):1147–1153 El-Mouzan MI, Al-Salloum AA, Al-Herbish AS, Qurachi MM, Al-Omar AA (2007) Regional variations in the prevalence of consanguinity in Saudi Arabia. Saudi Med J 28(12):1881–1884 Elseed FA, Karrar ZA (1984) Congenital afibrinogenaemia in a Saudi family: a case report and family study. Acta Haematol 71(6):388–392 Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF, Natah A, Ali A, Natah S, Comas D, Mehdi SQ, Groop L, Vestergaard EM, Imtiaz F, Rashed MS, Meyer B, Troelsen J, Peltonen L (2008) Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. Am J Hum Genet 82(1):57–72 Engle EC, Wang SM, Zwaan JT, Mullaney PB, Jabak MH, Beggs AH (1997) Linkage and homozygosity mapping of a variant of congenital fibrosis of the extraocular muscles to chromosome 11q13.1. Am J Hum Genet 61(Suppl):A30 (abstract) Faivre L, Me´garbane´ A, Alswaid A, Zylberberg L, Aldohayan N, Campos-Xavier B, Bacq D, LegeaiMallet L, Bonaventure J, Munnich A, Cormier-Daire V (2002) Homozygosity mapping of a Weill-Marchesani syndrome locus to chromosome 19p13.3–p13.2. Hum Genet 110(4):366–370 Faiyaz-Ul-Haque M, Faqeih EA, Al-Zaidan H, Al-Shammary A, Zaidi SH (2008) Grebe-type chondrodysplasia: a novel missense mutation in a conserved cysteine of the growth differentiation factor 5. J Bone Miner Metab 26(6):648–652 Faiyaz-Ul-Haque M, Zaidi SH, Al-Sanna N, Alswaid A, Momenah T, Kaya N, Al-Dayel F, Bouhoaigah I, Saliem M, Tsui LC, Teebi AS (2009a) A novel missense and a recurrent mutation in SLC2A10 gene of patients affected with arterial tortuosity syndrome. Atherosclerosis 203(2):466–471 Faiyaz-Ul-Haque M, Al-Owain M, Al-Dayel F, Al-Hassnan Z, Al-Zaidan H, Rahbeeni Z, Al-Sayed M, Balobaid A, Cluntun A, Toulimat M, Abalkhail H, Peltekova I, Zaidi SH (2009b) Novel FBP1 gene mutations in Arab patients with fructose-1, 6-bisphosphatase deficiency. Eur J Pediatr 168(12):1467–71 Fan Y, Esmail MA, Ansley SJ, Blacque OE, Boroevich K, Ross AJ, Moore SJ, Badano JL, May-Simera H, Compton DS, Green JS, Lewis RA, van Haelst MM, Parfrey PS, Baillie DL, Beales PL, Katsanis N, Davidson WS, Leroux MR (2004) Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet–Biedl syndrome. Nat Genet 36 (9):989–993 Faqeih E, Al-Akash SI, Sakati N, Teebi PA (2007) Four siblings with distal renal tubular acidosis and nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial appearance: a possible new autosomal recessive syndrome. Am J Med Genet A 143A(17):1951–1957 Faqeih E, Sakati N, Teebi AS (2008) Meier–Gorlin (ear–patella–short stature) syndrome: growth hormone deficiency and previously unrecognized findings. Am J Med Genet 137A:339–341 Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D, Al-Rumayyan A, Topcu M, Gascon G, Bodell A, Shugart YY, Ruvolo M, Walsh CA (2004) Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 36 (9):1008–1013 Fernet M, Gribaa M, Salih MA, Seidahmed MZ, Hall J, Koenig M (2005) Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder. Hum Mol Genet 14(2):307–318 Ferrari S, Giliani S, Insalaco A, Al-Ghonaium A, Soresina AR, Loubser M, Avanzini MA, Marconi M, Badolato R, Ugazio AG, Levy Y, Catalan N, Durandy A, Tbakhi A, Notarangelo LD, Plebani A (2001) Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci U S A 98(22):12614–12619

564


Gascon GG, Ozand PT, Erwin RE (1992a) GM1 gangliosidosis type 2 in two siblings. J Child Neurol 7(Suppl):S41–S50 Gascon GG, Youssef NG, Subramanyam SB, Ozand PT (1992b) Coincident neuraminidase and aspartoacylase deficiency associated with chromosome 9Q paracentric inversion in a Saudi family. J Child Neurol 7(Suppl):S73–S78 Gissen P, Johnson CA, Morgan NV, Stapelbroek JM, Forshew T, Cooper WN, McKiernan PJ, Klomp LW, Morris AA, Wraith JE, McClean P, Lynch SA, Thompson RJ, Lo B, Quarrell OW, Di Rocco M, Trembath RC, Mandel H, Wali S, Karet FE, Knisely AS, Houwen RH, Kelly DA, Maher ER (2004) Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome. Nat Genet 36(4):400–404 Goedde HW, Benkmann HG, Agarwal DP, Hirth L, Bienzle U, Dietrich M, Hoppe HH, Orlowski J, Kohne E, Kleihauer E (1979) Genetic studies in Saudi Arabia: red cell enzyme, haemoglobin and serum protein polymorphisms. Am J Phys Anthropol 50(2):271–277 Gorden NT, Arts HH, Parisi MA, Coene KL, Letteboer SJ, van Beersum SE, Mans DA, Hikida A, Eckert M, Knutzen D, Alswaid AF, Ozyurek H, Dibooglu S, Otto EA, Liu Y, Davis EE, Hutter CM, Bammler TK, Farin FM, Dorschner M, Topçu M, Zackai EH, Rosenthal P, Owens KN, Katsanis N, Vincent JB, Hildebrandt F, Rubel EW, Raible DW, Knoers NV, Chance PF, Roepman R, Moens CB, Glass IA, Doherty D (2008) CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Am J Hum Genet 83(5):559–571 Gribaa M, Salih M, Anheim M, Lagier-Tourenne C, H’mida D, Drouot N, Mohamed A, Elmalik S, Kabiraj M, Al-Rayess M, Almubarak M, Be´tard C, Goebel H, Koenig M (2007) A new form of childhood onset, autosomal recessive spinocerebellar ataxia and epilepsy is localized at 16q21–q23. Brain 130(Pt 7):1921–1928 Griffith E, Walker S, Martin CA, Vagnarelli P, Stiff T, Vernay B, Al Sanna N, Saggar A, Hamel B, Earnshaw WC, Jeggo PA, Jackson AP, O’Driscoll M (2008) Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat Genet 40 (2):232–236 Gripp KW, Donnai D, Clericuzio CL, McDonald-McGinn DM, Guttenberg M, Zackai EH (1997) Diaphragmatic hernia–exomphalos–hypertelorism syndrome: a new case and further evidence of autosomal recessive inheritance. Am J Med Genet 68(4):441–444 Grody WW, Klein D, Dodson AE, Kern RM, Wissmann PB, Goodman BK, Bassand P, Marescau B, Kang SS, Leonard JV et al (1992) Molecular genetic study of human arginase deficiency. Am J Hum Genet 50(6):1281–1290 Haider N, Salih MA, Al-Rasheed S, Al-Mofada S, Krahn PM, Kabiraj M (1996) Nonketotic hyperglycinemia: a life-threatening disorder in Saudi Newborns. Ann Saudi Med 16 (4):400–404 Hamada T, McLean WH, Ramsay M, Ashton GH, Nanda A, Jenkins T, Edelstein I, South AP, Bleck O, Wessagowit V, Mallipeddi R, Orchard GE, Wan H, Dopping-Hepenstal PJ, Mellerio JE, Whittock NV, Munro CS, van Steensel MA, Steijlen PM, Ni J, Zhang L, Hashimoto T, Eady RA, McGrath JA (2002) Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1). Hum Mol Genet 11(7):833–840 Harfi HA, Brismar J, Hainau B, Sabbah R (1992) Partial albinism, immunodeficiency, and progressive white matter disease: a new primary immunodeficiency. Allergy Proc 13 (6):321–328 Harrison DA, Mullaney PB, Mesfer SA, Awad AH, Dhindsa H (1998) Management of ophthalmic complications of homocystinuria. Ophthalmology 105(10):1886–1890 Hasounah FH, Sejeny SA, Omer JA, Old JM, Oliver RW (1995) Spectrum of beta-thalassaemia mutations in the population of Saudi Arabia. Hum Hered 45(4):231–234 Hellani A, Schuchman EH, Al-Odaib A, Al Aqueel A, Jaroudi K, Ozand P, Coskun S (2004) Preimplantation genetic diagnosis for Niemann–Pick disease type B. Prenat Diagn 24 (12):943–948

19


565

Henriquez H, el Din A, Ozand PT, Subramanyam SB, al Gain SI (1994) Emergency presentations of patients with methylmalonic acidemia, propionic acidemia and branched chain amino acidemia (MSUD). Brain Dev 16(Suppl):86–93 Hirth L, Benkmann HG, Goedde HW (1979) The distribution of human Gm-globulin and Inv-allotypes in populations of Egypt, Saudi-Arabia, Afghanistan and Ecuador. Z Morphol Anthropol 70(2):174–180 Hodgkinson CA, Bohlega S, Abu-Amero SN, Cupler E, Kambouris M, Meyer BF, Bharucha VA (2002) A novel form of autosomal recessive pure hereditary spastic paraplegia maps to chromosome 13q14. Neurology 59(12):1905–1909 Ho¨glund P, Auranen M, Socha J, Popinska K, Nazer H, Rajaram U, Al Sanie A, Al-Ghanim M, Holmberg C, de la Chapelle A, Kere J (1998) Genetic background of congenital chloride diarrhea in high-incidence populations: Finland, Poland, and Saudi Arabia and Kuwait. Am J Hum Genet 63(3):760–768 Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, Martin ND, Walsh CA (2000) Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 26(1):93–96 Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Furga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV, Rezai-Delui H, Legius E, Le Merrer M, Al-Alami J, Bahabri SA, Warman ML (1999) Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 23(1):94–98 Hussain SS, Buraiki J, Dzimiri N, Butt AI, Vencer L, Basco MC, Khan B (1999) Polymorphism in apoprotein-CIII gene and coronary heart disease. Ann Saudi Med 19(3):201–205 Iqbal MA, Sakati N, Nester M, Ozand P (2000) Cytogenetic diagnosis of fragile X syndrome: study of 305 suspected cases in Saudi Arabia. Ann Saudi Med 20(3–4):214–217 Imtiaz F, Savilahti E, Sarnesto A, Trabzuni D, Al-Kahtani K, Kagevi I, Rashed MS, Meyer BF, J€arvel€a I (2007) The T/G 13915 variant upstream of the lactase gene (LCT) is the founder allele of lactase persistence in an urban Saudi population. J Med Genet 44(10):e89 Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, Bernal-Mizrachi E, Mueckler M, Marshall H, Donis-Keller H, Crock P, Rogers D, Mikuni M, Kumashiro H, Higashi K, Sobue G, Oka Y, Permutt MA (1998) A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet 20(2):143–148 Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, R€ ub U, Shattuck D, Salamon G, Kudo LC, Ou J, Lin DD, Salih MA, Kansu T, Al Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger JR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC (2004) Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 304(5676):1509–1513 Johansen K, Dunn B, Tan JC, Kwaasi AA, Skotnicki A, Skotnicki M (1991) Coronary artery disease and apolipoprotein A-I/C-III gene polymorphism: a study of Saudi Arabians. Clin Genet 39(1):1–5 Joshi S, al-Essa MA, Archibald A, Ozand PT (1999) Biotinidase deficiency: a treatable genetic disorder in the Saudi population. East Mediterr Health J 5(6):1213–1217 Kambouris M, Bohlega S, Al-Tahan A, Meyer BF (2000a) Localization of the gene for a novel autosomal recessive neurodegenerative Huntington-like disorder to 4p15.3. Am J Hum Genet 66(2):445–452 Kambouris M, Banjar H, Moggari I, Nazer H, Al-Hamed M, Meyer BF (2000b) Identification of novel mutations in Arabs with cystic fibrosis and their impact on the cystic fibrosis transmembrane regulator mutation detection rate in Arab populations. Eur J Pediatr 159 (5):303–309 Karkashan EM, Joharji HS, Al-Harbi NN (2002) Congenital insensitivity to pain in four related Saudi families. Pediatr Dermatol 19:333–335 Karrar ZA, Elidrissy AT, Al Arabi K, Adam KA (1983) The wrinkly skin syndrome: a report of two siblings from Saudi Arabia. Clin Genet 23(4):308–310

566


Katol J, Takao M, Ideguchi H, Sawada H, Kawashima H, Ono J (2006) Genetic screening for alpha-thalassemia deletional determinants by GapPCR method. Rinsho Byori 54(11): 1095–1100 Katsanis N, Shroyer NF, Lewis RA, Cavender JC, Al-Rajhi AA, Jabak M, Lupski JR (2001) Fundus albipunctatus and retinitis punctata albescens in a pedigree with an R150Q mutation in RLBP1. Clin Genet 59(6):424–429 Katsanis N, Eichers ER, Ansley SJ, Lewis RA, Kayserili H, Hoskins BE, Scambler PJ, Beales PL, Lupski JR (2002) BBS4 is a minor contributor to Bardet–Biedl syndrome and may also participate in triallelic inheritance. Am J Hum Genet 71(1):22–29 Kaya N, Al-Zahrani F, Al-Odaib A, Rahbeeni Z, Al-Hassnan Z, Al-Sharif F, Ozand P, Al-Sayed M (2008a) Identification of Gaucher disease mutations found in Saudi Arabia. Blood Cells Mol Dis 41(2):200–201 Kaya N, Imtiaz F, Colak D, Al-Sayed M, Al-Odaib A, Al-Zahrani F, Al-Mubarak BR, Al-Owain M, Al-Dhalaan H, Chedrawi A, Al-Hassnan Z, Coskun S, Sakati N, Ozand P, Meyer BF (2008b) Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan disease. Genet Med 10(9):675–684 Kelly TE, Blanton S, Saif R, Sanjad SA, Sakati NA (2000) Confirmation of the assignment of the Sanjad–Sakati (congenital hypoparathyroidism) syndrome (OMIM 241410) locus to chromosome 1q42–43. J Med Genet 37(1):63–64 Khan AO, Shamsi FA, Al-Saif A, Kambouris M (2004) A novel missense Norrie disease mutation associated with a severe ocular phenotype. J Pediatr Ophthalmol Strabismus 41(6):361–363 Khan AO, Alam SK, Aldahmesh M, Rajab M, Meyer B (2006a) Familial blepharophimosis-like syndrome with esotropia, uveal coloboma, and short stature. Ophthalmic Genet 27(3):79–82 Khan AO, Aldahmesh M, Meyer B (2006b) Recessive cornea plana in the Kingdom of Saudi Arabia. Ophthalmology 113(10):1773–1778 Khan AO, Aldahmesh MA, Meyer B (2007) Recessive congenital total cataract with microcornea and heterozygote carrier signs caused by a novel missense CRYAA mutation (R54C). Am J Ophthalmol 144(6):949–952 Khan AO, Oystreck DT, Al-Tassan N, Al-Sharif L, Bosley TM (2008) Bilateral synergistic convergence associated with homozygous ROB03 mutation (p.Pro771Leu). Ophthalmology 115(12):2262–2265 Knox-Macaulay HH, Bashawri L, Davies KE (1993) X linked recessive thrombocytopenia. J Med Genet 30(11):968–969 Kozma C, Scribanu N, Gersh E (1996) The microcephaly–lymphoedema syndrome: report of an additional family. Clin Dysmorphol 5(1):49–54 Kulozik AE, Wainscoat JS, Serjeant GR, Kar BC, Al-Awamy B, Essan GJ, Falusi AG, Haque SK, Hilali AM, Kate S et al (1986) Geographical survey of beta S-globin gene haplotypes: evidence for an independent Asian origin of the sickle-cell mutation. Am J Hum Genet 39(2):239–244 Lanes R, Plotnick LP, Bynum TE, Lee PA, Casella JF, Fox CE, Kowarski AA, Migeon CJ (1980) Glucocorticoid and partial mineralocorticoid deficiency associated with achalasia. J Clin Endocrinol Metab 50(2):268–270 Lehmann H, Maranjian G, Mourant AE (1963) Distribution of sickel cell haemoglobin in Saudi Arabia. Nature 198:492–493 Lestringant GG, Berge T (1989) Porokeratosis punctata palmaris et plantaris. A new entity? Arch Dermatol 125(6):816–819 Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque OE, Li L, Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS, Beales PL, Guay-Woodford LM, Yoder BK, Stormo GD, Katsanis N, Dutcher SK (2004) Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117(4):541–552 Lin NU, Malloy PJ, Sakati N, al-Ashwal A, Feldman D (1996) A novel mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor causes hereditary 1,25-dihydroxyvitamin D-resistant rickets. J Clin Endocrinol Metab 81(7):2564–2569

19


567

Mahmoud AA, Yousef GM, Al-Hifzi I, Diamandis EP (2002) Cockayne syndrome in three sisters with varying clinical presentation. Am J Med Genet 111(1):81–85 Majumdar R, Al Jumah M, Al Rajeh S, Fraser M, Al Zaben A, Awada A, Al Traif I, Paterson M (2000) A novel deletion mutation within the carboxyl terminus of the copper-transporting ATPase gene causes Wilson disease. J Neurol Sci 179(S1–2):140–143 Majumdar R, Al Jumah M, Fraser M (2003) 4193delC, a common mutation causing Wilson’s disease in Saudi Arabia: rapid molecular screening of patients and carriers. Mol Pathol 56(5):302–304 Mardini MK, Ghandour M, Sakati NA, Nyhan WL (1978) Johanson–Blizzard syndrome in a large inbred kindred with three involved members. Clin Genet 14(5):247–250 Mallouh A, Sa’di AR, Ahmad MS, Salamah M (1984) Hereditary pyropoikilocytosis: report of two cases from Saudi Arabia. Am J Med Genet 18(3):413–417 Malloy PJ, Xu R, Peng L, Peleg S, Al-Ashwal A, Feldman D (2004) Hereditary 1,25-dihydroxyvitamin D resistant rickets due to a mutation causing multiple defects in vitamin D receptor function. Endocrinology 145(11):5106–5114 Markley KM, Elkhalifa M, Maini A, Hoyer JD (2008) Hb Jeddah (alpha68(E17)Asn!His (alpha1)): a newly recognized alpha chain variant, seen in combination with Hb S (beta6 (A3)Glu!Val), and found in three separate families of middle eastern origin. Hemoglobin 32 (3):297–302 Martignetti JA, Aqeel AA, Sewairi WA, Boumah CE, Kambouris M, Mayouf SA, Sheth KV, Eid WA, Dowling O, Harris J, Glucksman MJ, Bahabri S, Meyer BF, Desnick RJ (2001) Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat Genet 28(3):261–265 Massa V, Fernandez-Vizarra E, Alshahwan S, Bakhsh E, Goffrini P, Ferrero I, Mereghetti P, D’Adamo P, Gasparini P, Zeviani M (2008) Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase. Am J Hum Genet 82(6):1281–1289 Mathew PM, Young JM, Abu-Osba YK, Mulhern BD, Hammoudi S, Hamdan JA, Sa’di AR (1988) Persistent neonatal hyperinsulinism. Clin Pediatr 27(3):148–151 Mattoo TK (1998) Genetically transmitted renal diseases in children: a Saudi perspective. Saudi J Kidney Dis Transpl 9(2):105–109 Mihaylova V, M€uller JS, Vilchez JJ, Salih MA, Kabiraj MM, D’Amico A, Bertini E, Wo¨lfle J, Schreiner F, Kurlemann G, Rasic VM, Siskova D, Colomer J, Herczegfalvi A, Fabriciova K, Weschke B, Scola R, Hoellen F, Schara U, Abicht A, Lochm€ uller H (2008) Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndrome. Brain 131 (Pt 3):747–759 Miller BA, Olivieri N, Salameh M, Ahmed M, Antognetti G, Huisman TH, Nathan DG, Orkin SH (1987) Molecular analysis of the high-hemoglobin-F phenotype in Saudi Arabian sickle cell anemia. N Engl J Med 316(5):244–250 Mitchell GA, Ozand PT, Robert MF, Ashmarina L, Roberts J, Gibson KM, Wanders RJ, Wang S, Chevalier I, Plo¨chl E, Miziorko H (1998) HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q. Am J Hum Genet 62(2):295–300 Morgan JC, Scott DF, Lanclos KD (1996) Two mutations in the locus control region hypersensitivity site-2 (50 HS-2) of haplotype 19 beta s chromosomes alter binding of trans-acting factors. Am J Hematol 51(1):12–18 Mufti MH, Wood SK (1987) Ectrodactyly in sisters and half sisters. J Med Genet 24(4):220–224 Nakano A, Lestringant GG, Paperna T, Bergman R, Gershoni R, Frossard P, Kanaan M, Meneguzzi G, Richard G, Pfendner E, Uitto J, Pulkkinen L, Sprecher E (2002) Junctional epidermolysis bullosa in the Middle East: clinical and genetic studies in a series of consanguineous families. J Am Acad Dermatol 46(4):510–516 Nakano M, Yamada K, Fain J, Sener EC, Selleck CJ, Awad AH, Zwaan J, Mullaney PB, Bosley TM, Engle EC (2001) Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet 29(3):315–320

568


Narchi H (1997) Hyperostosis with hyperphosphatemia: evidence of familial occurrence and association with tumoral calcinosis. Pediatrics 99(5):745–748 Nazer H, Riff E, Sakati N, Mathew R, Majeed-Saidan MA, Harfi H (1989) Cystic fibrosis in Saudi Arabia. Eur J Pediatr 148(4):330–332 Nazer H, Gunasekaran TS, Sakati NA, Nyhan WL (1990) Concurrence of Robinow syndrome and Crigler–Najar syndrome in two offspring of first cousins. Am J Med Genet 37(4):516–518 Niazi GA, Yaish HM, Kutlar F, Huisman TH (1991) Heterogeneity of gamma-globin chain synthesis in Saudi newborns. Int J Hematol 54(5):377–383 Ohlsson A, Stark G, Sakati N (1980) Marble brain disease: recessive osteopetrosis, renal tubular acidosis and cerebral calcification in three Saudi Arabian families. Dev Med Child Neurol 22:72–84 Ohlsson A, Cumming WA, Paul A, Sly WS (1986) Carbonic anhydrase II deficiency syndrome: recessive osteopetrosis with renal tubular acidosis and cerebral calcification. Pediatrics 77:371–381 Ozand PT, Gascon G, al Aqeel A, Roberts G, Dhalla M, Subramanyam SB (1990a) Prevalence of different types of lysosomal storage diseases in Saudi Arabia. J Inherit Metab Dis 13 (6):849–861 Ozand PT, Gascon GG, Dhalla M (1990b) Aspartoacylase deficiency and Canavan disease in Saudi Arabia. Am J Med Genet 35(2):266–268 Ozand PT, Devol EB, Gascon GG (1992a) Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre. J Child Neurol 7(Suppl):S4–S11 Ozand PT, Gascon GG (1992b) Heterogeneity of carboxypeptidase activity in infantile-onset galactosialidosis. J Child Neurol 7(Suppl):S31–S40 Ozand PT, Rashed M, Gascon GG, Youssef NG, Harfi H, Rahbeeni Z, al Garawi S, al Aqeel A (1994a) Unusual presentations of propionic acidemia. Brain Dev 16(Suppl):46–57 Ozand PT, Rashed M, Gascon GG, al Odaib A, Shums A, Nester M, Brismar J (1994b) 3-Ketothiolase deficiency: a review and four new patients with neurologic symptoms. Brain Dev 16(Suppl):38–45 Ozand PT, Nyhan WL, al Aqeel A, Christodoulou J (1994c) Malonic aciduria. Brain Dev 16(1):7–11 Ozand PT, Gascon GG, Al Essa M, Joshi S, Al Jishi E, Bakheet S, Al Watban J, Al-Kawi MZ, Dabbagh O (1998) Biotin-responsive basal ganglia disease: a novel entity. Brain 121 (Pt 7):1267–1279 Parvari R, Hershkovitz E, Grossman N, Gorodischer R, Loeys B, Zecic A, Mortier G, Gregory S, Sharony R, Kambouris M, Sakati N, Meyer BF, Al Aqeel AI, Al Humaidan AK, Al Zanhrani F, Al Swaid A, Al Othman J, Diaz GA, Weiner R, Khan KT, Gordon R, Gelb BD, HRD/ Autosomal Recessive Kenny–Caffey Syndrome Consortium (2002) Mutation of TBCE causes hypoparathyroidism–retardation–dysmorphism and autosomal recessive Kenny–Caffey syndrome. Nat Genet 32(3):448–452 Pasternack SM, von K€ ugelgen I, Aboud KA, Lee YA, R€ uschendorf F, Voss K, Hillmer AM, Molderings GJ, Franz T, Ramirez A, N€ urnberg P, No¨then MM, Betz RC (2008) G proteincoupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nat Genet 40(3):329–334 Pembrey ME, Perrine RP, Wood WG, Weatherall DJ (1980) Sickle beta 0 thalassemia in Eastern Saudi Arabia. Am J Hum Genet 32(1):26–41 Pernasetti F, Milner RD, al Ashwal AA, de Zegher F, Chavez VM, Muller M, Martial JA (1998) Pro239Ser: a novel recessive mutation of the Pit-1 gene in seven Middle Eastern children with growth hormone, prolactin, and thyrotropin deficiency. J Clin Endocrinol Metab 83(6):2079–2083 Phillips JA 3rd, Cogan JD (1994) Genetic basis of endocrine disease. 6. Molecular basis of familial human growth hormone deficiency. J Clin Endocrinol Metab 78(1):11–16 Picard C, Fieschi C, Altare F, Al-Jumaah S, Al-Hajjar S, Feinberg J, Dupuis S, Soudais C, Al-Mohsen IZ, Geńin E, Lammas D, Kumararatne DS, Leclerc T, Rafii A, Frayha H, Murugasu B, Wah LB, Sinniah R, Loubser M, Okamoto E, Al-Ghonaium A, Tufenkeji H, Abel L, Casanova JL (2002) Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Am J Hum Genet 70(2):336–348

19


569

Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, Elbim C, Hitchcock R, Lammas D, Davies G, Al-Ghonaium A, Al-Rayes H, Al-Jumaah S, Al-Hajjar S, Al-Mohsen IZ, Frayha HH, Rucker R, Hawn TR, Aderem A, Tufenkeji H, Haraguchi S, Day NK, Good RA, Gougerot-Pocidalo MA, Ozinsky A, Casanova JL (2003) Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299 (5615):2076–2079 Pomponio RJ, Ozand PT, Al Essa M, Wolf B (2000) Novel mutations in children with profound biotinidase deficiency from Saudi Arabia. J Inherit Metab Dis 23(2):185–187 Prasad RS, Pejaver RK, Hassan A, al Dusari S, Wooldridge MA (1994) Management and followup of harlequin siblings. Br J Dermatol 130(5):650–653 Pressley L, Higgs DR, Clegg JB, Perrine RP, Pembrey ME, Weatherall DJ (1980) A new genetic basis for hemoglobin-H disease. N Engl J Med 303(24):1383–1388 Price Evans DA, Salah KA, Mobrad MA, Mitchell WD, Olin M, Eggertsen G (2007) Cerebrotendinous xanthomatosis in a Saudi Arabian family-genotyping and long-term follow-up. Saudi Med J 28(7):1113–1118 Quadri MI, Islam SI, Nasserullah Z (2000) The effect of alpha-thalassemia on cord blood red cell indices and interaction with sickle cell gene. Ann Saudi Med 20(5–6):367–370 Raef H, Baitei EY, Zou M, Shi Y (2008) Genotype–phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism. Eur J Endocrinol 158(4):577–582 Rahbeeni Z, Ozand PT, Rashed M, Gascon GG, al Nasser M, al Odaib A, Amoudi M, Nester M, al Garawi S, Brismar J (1994) 4-Hydroxybutyric aciduria. Brain Dev 16(Suppl):64–71 Rahbeeni Z, Vaz FM, Al-Hussein K, Bucknall MP, Ruiter J, Wanders RJ, Rashed MS (2002) Identification of two novel mutations in OCTN2 from two Saudi patients with systemic carnitine deficiency. J Inherit Metab Dis 25(5):363–369 Rashed M, Ozand PT, al Aqeel A, Gascon GG (1994) Experience of King Faisal Specialist Hospital and Research Center with Saudi organic acid disorders. Brain Dev 16(Suppl):1–6 Rashed MS, Ozand PT, Bennett MJ, Barnard JJ, Govindaraju DR, Rinaldo P (1995a) Inborn errors of metabolism diagnosed in sudden death cases by acylcarnitine analysis of postmortem bile. Clin Chem 41(8(Pt 1)):1109–1114 Rashed MS, Ozand PT, Bucknall MP, Little D (1995b) Diagnosis of inborn errors of metabolism from blood spots by acylcarnitines and amino acids profiling using automated electrospray tandem mass spectrometry. Pediatr Res 38(3):324–331 Rashed MS, Bucknall MP, Little D, Awad A, Jacob M, Alamoudi M, Alwattar M, Ozand PT (1997) Screening blood spots for inborn errors of metabolism by electrospray tandem mass spectrometry with a microplate batch process and a computer algorithm for automated flagging of abnormal profiles. Clin Chem 43(7):1129–1141 Rashed MS, Rahbeeni Z, Ozand PT (1999a) Screening blood spots for argininosuccinase deficiency by electrospray tandem mass spectrometry. Southeast Asian J Trop Med Public Health 30(Suppl 2):170–173 Rashed MS, Rahbeeni Z, Ozand PT (1999b) Application of electrospray tandem mass spectrometry to neonatal screening. Semin Perinatol 23(2):183–193 Rashed MS, Aboul-Enein HY, AlAmoudi M, Jakob M, Al-Ahaideb LY, Abbad A, Shabib S, Al-Jishi E (2002) Chiral liquid chromatography tandem mass spectrometry in the determination of the configuration of glyceric acid in urine of patients with D-glyceric and L-glyceric acidurias. Biomed Chromatogr 16(3):191–198 Rashed MS, Al-Ahaidib LY, Al-Dirbashi OY, Al Amoudi M, Al-Sayed MM, Rahbeeni Z, Al-Hassnan Z, Al-Dbaas A, Al-Owain M, Ni Luanaigh M (2005) Tandem mass spectrometric assay of succinylacetone in urine for the diagnosis of hepatorenal tyrosinemia. Anal Biochem 339(2):310–317 Reisner SH, Seelenfreund M, Ben-Bassat M (1971) Cutis laxa associated with severe intrauterine growth retardation and congenital dislocation of the hip. Acta Paediatr Scand 60(3):357–360 Ridanp€a€a M, Sistonen P, Rockas S, Rimoin DL, M€akitie O, Kaitila I (2002) Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A!G mutation of the untranslated RMRP. Eur J Hum Genet 10(7):439–447

570


Robinson LK, Jones KL, Culler F, Nyhan WL, Sakati N, Jones KL (1983) The Bo¨rjeson–Forssman–Lehmann syndrome. Am J Med Genet 15(3):457–468 Sackey K, Sakati N, Aur RJ, Shebib S, Sabbah RS, Rifai S (1985) Multiple dysmorphic features and pancytopenia: a new syndrome? Clin Genet 27(6):606–610 Sass JO, Jobard F, Topçu M, Mahfoud A, Werle´ E, Cure S, Al-Sannaa N, Alshahwan SA, Bataillard M, Cimbalistiene L, Grolik C, Kemmerich V, Omran H, Sztriha L, Tabache M, Fischer J (2008) L-2-hydroxyglutaric aciduria: identification of ten novel mutations in the L2HGDH gene. J Inherit Metab Dis (Epub ahead of print) Saha N, Bayoumi RA, El Sheikh FS, Samuel AP, El Fadil I, El Houri IS, Sebai ZA, Sabaa HM (1980) Some blood genetic markers of selected tribes in Western Saudi Arabia. Am J Phys Anthropol 52(4):595–600 Saif GB, Al-Khenaizan S (2007) Netherton syndrome: successful use of topical tacrolimus and pimecrolimus in four siblings. Int J Dermatol 46(3):290–294 Sakati NO, Nyhan WL, Shear CS, Kattan H, Akhtar M, Bay C, Jones KL, Schackner L (1983) Syndrome of cutis laxa, ligamentous laxity, and delayed development. Pediatrics 72:850–856 Salih MA, Mahdi AH, al-Rikabi AC, al-Bunyan M, Roberds SL, Anderson RD, Campbell KP (1996a) Clinical and molecular pathological features of severe childhood autosomal recessive muscular dystrophy in Saudi Arabia. Dev Med Child Neurol 38(3):262–270 Salih MA, Sunada Y, Al-Nasser M, Ozo CO, Al-Turaiki MH, Akbar M, Campbell KP (1996b) Muscular dystrophy associated with beta-dystroglycan deficiency. Ann Neurol 40 (6):925–928 Salih MA, Maisonobe T, Kabiraj M, al Rayess M, al-Turaiki MH, Akbar M, Tahan A, Urtizberea JA, Grid D, Hamadouche T, Guilbot A, Brice A, Leguern E (2000) Autosomal recessive hereditary neuropathy with focally folded myelin sheaths and linked to chromosome 11q23: a distinct and homogeneous entity. Neuromuscul Disord 10(1):10–15 Salih MA, Abdel-Gader AG, Zahraa JN, Al-Rayess MM, Alorainy IA, Hassan HH, Ruitenbeek W, Zeviani M (2006) Stroke due to mitochondrial disorders in Saudi children. Saudi Med J 27 (Suppl 1):S81–S90 Sanjad S, Sakati N, Abu-Osba Y (1988) Congenital hypoparathyroidism with dysmorphic features: a new syndrome. Pediatr Res 23:271A (abstract) Sanjad SA, Sakati NA, Abu-Osba YK, Kaddoura R, Milner RD (1991) A new syndrome of congenital hypoparathyroidism, severe growth failure, and dysmorphic features. Arch Dis Child 66(2):193–196 Sanjad SA, Kaddoura RE, Nazer HM, Akhtar M, Sakati NA (1993) Fanconi’s syndrome with hepatorenal glycogenosis associated with phosphorylase b kinase deficiency. Am J Dis Child 147(9):957–959 Schepers U, Glombitza G, Lemm T, Hoffmann A, Chabas A, Ozand P, Sandhoff K (1996) Molecular analysis of a GM2-activator deficiency in two patients with GM2-gangliosidosis AB variant. Am J Hum Genet 59(5):1048–1056 Seidahmed MZ, Alyamani EA, Rashed MS, Saadallah AA, Abdelbasit OB, Shaheed MM, Rasheed A, Hamid FA, Sabry MA (2005) Total truncation of the molybdopterin/dimerization domains of SUOX protein in an Arab family with isolated sulfite oxidase deficiency. Am J Med Genet A 136(2):205–209 Seliem MA, Mansara KB, Palileo M, Ye X, Zhang Z, Benson DW (2000) Evidence for autosomal recessive inheritance of infantile dilated cardiomyopathy: studies from the Eastern Province of Saudi Arabia. Pediatr Res 48(6):770–775 Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O’Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH (2003) The GPR54 gene as a regulator of puberty. N Engl J Med 349(17):1614–1627 Seneé V, Chelala C, Duchatelet S, Feng D, Blanc H, Cossec JC, Charon C, Nicolino M, Boileau P, Cavener DR, Bougne`res P, Taha D, Julier C (2006) Mutations in GLIS3 are responsible for a

19


571

rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 38 (6):682–687 Shah SS, Al-Rajhi A, Brandt JD, Mannis MJ, Roos B, Sheffield VC, Syed NA, Stone EM, Fingert JH (2008) Mutation in the SLC4A11 gene associated with autosomal recessive congenital hereditary endothelial dystrophy in a large Saudi family. Ophthalmic Genet 29 (1):41–45 Shebib S, Hugosson C, Sakati N, Nyhan WL (1991) Osteodysplastic variant of primordial dwarfism. Am J Med Genet 40(2):146–150 Shen XM, Ohno K, Fukudome T, Tsujino A, Brengman JM, De Vivo DC, Packer RJ, Engel AG (2002) Congenital myasthenic syndrome caused by low-expressor fast-channel AChR delta subunit mutation. Neurology 59(12):1881–1888 Shen J, Eyaid W, Mochida GH, Al-Moayyad F, Bodell A, Woods CG, Walsh CA (2005) ASPM mutations identified in patients with primary microcephaly and seizures. J Med Genet 42 (9):725–729 Simonaro CM, Desnick RJ, McGovern MM, Wasserstein MP, Schuchman EH (2002) The demographics and distribution of type B Niemann–Pick disease: novel mutations lead to new genotype/phenotype correlations. Am J Hum Genet 71(6):1413–1419 Singh B, Jamil A, al-Shahwan SA, Sharif H, al-Deeb SM, Biary N (1993) Choroido-cerebral calcification syndrome with retardation. Neurology 43(11):2387–2389 Siraj AK, Ibrahim M, Al-Rasheed M, Bu R, Bavi P, Jehan Z, Abubaker J, Murad W, Al-Dayel F, Ezzat A, El-Solh H, Uddin S, Al-Kuraya K (2007) Genetic polymorphisms of methylenetetrahydrofolate reductase and promoter methylation of MGMT and FHIT genes in diffuse large B cell lymphoma risk in Middle East. Ann Hematol 86(12):887–895 Siraj AK, Ibrahim M, Al-Rasheed M, Abubaker J, Bu R, Siddiqui SU, Al-Dayel F, Al-Sanea O, Al-Nuaim A, Uddin S, Al-Kuraya K (2008a) Polymorphisms of selected xenobiotic genes contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population. BMC Med Genet 9:61 Siraj AK, Al-Rasheed M, Ibrahim M, Siddiqui K, Al-Dayel F, Al-Sanea O, Uddin S, Al-Kuraya K (2008b) RAD52 polymorphisms contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population. J Endocrinol Invest 31(10):893–899 Smith AN, Skaug J, Choate KA, Nayir A, Bakkaloglu A, Ozen S, Hulton SA, Sanjad SA, Al-Sabban EA, Lifton RP, Scherer SW, Karet FE (2000) Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. Nat Genet 26(1):71–75 Solh H, Da Cunha AM, Giri N, Padmos A, Spence D, Clink H, Ernst P, Sakati N (1995) Bone marrow transplantation for infantile malignant osteopetrosis. J Pediatr Hematol Oncol 17 (4):350–355 Stangenberg M, Agarwal N, Rahman F, Sheth K, al Sedeiry S, De Vol E (1990) Frequency of HLA genes and islet cell antibodies (ICA) and result of postpartum oral glucose tolerance tests (OGTT) in Saudi Arabian women with abnormal OGTT during pregnancy. Diabetes Res 14 (1):9–13 Stangenberg M, Lingman G, Roberts G, Ozand P (1992) Mucopolysaccharidosis VII as cause of fetal hydrops in early pregnancy. Am J Med Genet 44(2):142–144 Stockton DW, Lewis RA, Abboud EB, Al-Rajhi A, Jabak M, Anderson KL, Lupski JR (1998) A novel locus for Leber congenital amaurosis on chromosome 14q24. Hum Genet 103(3):328–333 Stuhrmann M, Bashawri L, Ahmed MA, Al-Awamy BH, K€ uhnau W, Schmidtke J, El-Harith EA (2001) Familial thrombocytosis as a recessive, possibly X-linked trait in an Arab family. Br J Haematol 112(3):616–620 Stuhrmann M, Bukhari IA, El-Harith el-HA (2004) Naxos disease in an Arab family is not caused by the Pk2157del2 mutation. Evidence for exclusion of the plakoglobin gene. Saudi Med J 25 (10):1449–1452 Stuhrmann M, Hennies HC, Bukhari IA, Brakensiek K, N€ urnberg G, Becker C, Huebener J, Miranda MC, Frye-Boukhriss H, Knothe S, Schmidtke J, El-Harith EH (2008) Dyschromatosis

572


universalis hereditaria: evidence for autosomal recessive inheritance and identification of a new locus on chromosome 12q21–q23. Clin Genet 73(6):566–572 Suwairi WM, Bahabri SA, Laxer RM, Polinkovsky A, Warman ML (1997) Autosomal recessive camptodactyly–arthropathy–coxa vara–pericarditis syndrome: clinical features and genetic mapping to chromosome 1q25–31. Am J Hum Genet 61(Suppl):A48 (abstract) Taha D, Barbar M, Kanaan H, Williamson Balfe J (2003) Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome? Am J Med Genet 122A:269–273 Taha D, Boerkoel CF, Balfe JW, Khalifah M, Sloan EA, Barbar M, Haider A, Kanaan H (2004) Fatal lymphoproliferative disorder in a child with Schimke immuno-osseous dysplasia. Am J Med Genet A 131(2):194–199 Taha D, Mullis PE, Ibań˜ez L, de Zegher F (2005) Absent or delayed adrenarche in Pit-1/POU1F1 deficiency. Horm Res 64(4):175–179 Taha D, Al-Harbi N, Al-Sabban E (2008) Hyperglycemia and hypoinsulinemia in patients with Fanconi–Bickel syndrome. J Pediatr Endocrinol Metab 21(6):581–586 Takashima H, Boerkoel CF, John J, Saifi GM, Salih MA, Armstrong D, Mao Y, Quiocho FA, Roa BB, Nakagawa M, Stockton DW, Lupski JR (2002) Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet 32(2):267–272 Tallab TM (1996) Richner–Hanhart syndrome: importance of early diagnosis and early intervention. J Am Acad Dermatol 35(5 Pt 2):857–859 Tanner SM, Li Z, Bisson R, Acar C, Oner C, Oner R, Cetin M, Abdelaal MA, Ismail EA, Lissens W, Krahe R, Broch H, Gr€asbeck R, de la Chapelle A (2004) Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East. Hum Mutat 23(4):327–333 Thakker RV, Farmery MR, Sakati NA, Milner RD (1992) Genetic linkage studies of X-linked hypophosphataemic rickets in a Saudi Arabian family. Clin Endocrinol 37(4):338–343 Thein SL, Wallace RB, Pressley L, Clegg JB, Weatherall DJ, Higgs DR (1988) The polyadenylation site mutation in the alpha-globin gene cluster. Blood 71(2):313–319 Thomas PM, Cote GJ, Hallman DM, Mathew PM (1995a) Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet 56(2):416–421 Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J (1995b) Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268(5209):426–429 Tischfield MA, Bosley TM, Salih MA, Alorainy IA, Sener EC, Nester MJ, Oystreck DT, Chan WM, Andrews C, Erickson RP, Engle EC (2005) Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet 37 (10):1035–1037 van Reeuwijk J, Grewal PK, Salih MA, de Bernabe´ Beltrań-Valero D, McLaughlan JM, Michielse CB, Herrmann R, Hewitt JE, Steinbrecher A, Seidahmed MZ, Shaheed MM, Abomelha A, Brunner HG, van Bokhoven H, Voit T (2007) Intragenic deletion in the LARGE gene causes Walker–Warburg syndrome. Hum Genet 121(6):685–690 Vincent AL, Billingsley G, Buys Y, Levin AV, Priston M, Trope G, Williams-Lyn D, Heón E (2002) Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet 70(2):448–460 Vogt G, Chapgier A, Yang K, Chuzhanova N, Feinberg J, Fieschi C, Boisson-Dupuis S, Alcais A, Filipe-Santos O, Bustamante J, de Beaucoudrey L, Al-Mohsen I, Al-Hajjar S, Al-Ghonaium A, Adimi P, Mirsaeidi M, Khalilzadeh S, Rosenzweig S, de la Calle Martin O, Bauer TR, Puck JM, Ochs HD, Furthner D, Engelhorn C, Belohradsky B, Mansouri D, Holland SM, Schreiber RD, Abel L, Cooper DN, Soudais C, Casanova JL (2005) Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nat Genet 37(7):692–700

19


573

Walne AJ, Vulliamy T, Marrone A, Beswick R, Kirwan M, Masunari Y, Al-Qurashi FH, Aljurf M, Dokal I (2007) Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum Mol Genet 16 (13):1619–1629 Wang SM, Zwaan J, Mullaney PB, Jabak MH, Al-Awad A, Beggs AH, Engle EC (1998) Congenital fibrosis of the extraocular muscles type 2, an inherited exotropic strabismus fixus, maps to distal 11q13. Am J Hum Genet 63(2):517–525 Warsy AS, El-Hazmi MA, Sedrani SH, Kinhal M (1991) Alpha-1-antitrypsin phenotypes in Saudi Arabia: a study in the central province. Ann Saudi Med 11(2):159–162 Warsy AS, el-Hazmi MA (1999) Glutathione reductase deficiency in Saudi Arabia. East Mediterr Health J 5(6):1208–1212 Warsy AS, El-Hazmi MA (2001) G6PD deficiency, distribution and variants in Saudi Arabia: an overview. Ann Saudi Med 21(3–4):174–177 Wojcik J, Berg MA, Esposito N, Geffner ME, Sakati N, Reiter EO, Dower S, Francke U, Postel-Vinay MC, Finidori J (1998) Four contiguous amino acid substitutions, identified in patients with Laron syndrome, differently affect the binding affinity and intracellular trafficking of the growth hormone receptor. J Clin Endocrinol Metab 83(12):4481–4489 Woodhouse NJ, Sakati NA (1983) A syndrome of hypogonadism, alopecia, diabetes mellitus, mental retardation, deafness, and ECG abnormalities. J Med Genet 20(3):216–219 Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T (2001) The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 29 (2):160–165 Zeng WQ, Al-Yamani E, Acierno JS Jr, Slaugenhaupt S, Gillis T, MacDonald ME, Ozand PT, Gusella JF (2005) Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet 77(1):16–26 Zhang Y, Lundgren T, Renvert S, Tatakis DN, Firatli E, Uygur C, Hart PS, Gorry MC, Marks JJ, Hart TC (2001) Evidence of a founder effect for four cathepsin C gene mutations in Papillon–Lefe`vre syndrome patients. J Med Genet 38(2):96–101 Zhang B, Spreafico M, Zheng C, Yang A, Platzer P, Callaghan MU, Avci Z, Ozbek N, Mahlangu J, Haw T, Kaufman RJ, Marchant K, Tuddenham EG, Seligsohn U, Peyvandi F, Ginsburg D (2008) Genotype–phenotype correlation in combined deficiency of factor V and factor VIII. Blood 111(12):5592–5600

URLs OMIM http://www.ncbi.nlm.nih.gov/OMIM PubMed http://www.ncbi.nlm.nih.gov/OMIM The Saudi Central Department of Statistics & Information http://www.cdsi.gov.sa The Saudi Ministry of Heath Health statistics book for the year of 2007. http://www.moh.gov.sa/ statistics/stats2007/2007.html Saudi Geographical Society http://www.saudigs.org

Chapter 20

Genetic Disorders in Sudan Mustafa A.M. Salih

The Country and Population Sudan is Africa’s largest country in surface area (2,505,805 km2). It constitutes more than 8% of the African continent and 1.7% of the world’s total land (Fig. 20.1). It has boundaries with nine countries and extends on its eastern side to the Red Sea, which separates it from Saudi Arabia. The main part of the Nile Valley lies within its boundaries. Connections between the two sides of the Red Sea have been intimate from the dawn of history. Trade routes that passed via the Nile valley were established in ancient times between Arabia and the ports of Abyssinia (current names: Eritrea and Ethiopia), Sudan, and Egypt (MacMichael 1967). Immigration and settlements followed. Following the conquest of Egypt by the Arabs in the eighth century (AD), small groups drifted to Sudan for varied reasons (Hassan 1965b). However, the fall of Dongola (the capital of the Christian kingdom of Nubia), into Muslim hands, by the middle of the fourteenth century opened the door for large successive waves of immigrating Arab nomads who proceeded further to the richer plains of the country. However, western Sudan was affected by settlements of Libyans (Temehu) coming from the western Oasis about 2750 BC and was also influenced by migratory waves from North Africa starting around the fourteenth century (MacMichael 1967). Natural sources of Sudan have made it the focal point for trans-African migrations by humans (Wickens 1970). Sudan’s ethic composition is diverse. The 1955–1956-population census listed 56 separate ethnic groups, further subdivided into 597 subgroups. Of the 115 spoken languages, Arabic is spoken by the majority and forms, as well, the lingua

M.A.M. Salih Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia e-mail: [email protected], [email protected]


575

576

M.A.M. Salih

Fig. 20.1 Map of the Sudan showing geographic locations mentioned

franca of others (Beshir 1980). Generally, the ethnic composition of the Sudanese population can be described as Hamitic in the east, African Nilotes and NiloHamitics in the south, and a mixture of Arab descent in the north, middle, and west. This is reflected in the physical features of the population, which shows a great deal of heterogeneity depending on the degree of Arabic admixture with the aboriginal inhabitants of the land. Among the latter major groups are the Nilotes in the south and the Nuba and Fur in the west of Sudan (Fig. 20.2). While the Fur embraced Islam, the Nuba and Nilotes maintained their cultural identity and were mainly pagans, although many have recently become either Muslims or Christians.

Consanguinity Consanguinity is common in most ethnic groups. However, the Nuba are usually exogamous; marriage within the clan is forbidden (Bayoumi and Saha 1987). Field studies that addressed consanguinity among four tribes living in western Sudan found no incidence of consanguineous marriages among the indigenous Nubian (Nuba) people living within the Nuba Mountains. A high inbreeding

20

Genetic Disorders in Sudan

577

Fig. 20.2 Location of Sudanese tribes and tribal groups where some genetic studies were performed

coefficient (respectively, 0.04167 and 0.036) was recorded among the Baggara tribal group (Arab ancestry) and the Hawazma tribe (part of the Baggara group living adjacent to the Nuba). However, the Fur (aboriginals in Jabal Marra Plateau) had also a high inbreeding coefficient, 0.04450.

Population Genetics The Y chromosome has proved to be crucial in human evolutionary studies (Hammer and Zegura 1996). Binary polymorphisms associated with the nonrecombining region of the human Y chromosome (NRY) preserve the paternal genetic legacy of the human species that has persisted to the present. An international study (Underhill et al. 2000), in collaboration with the Institute of Endemic Diseases, University of Khartoum, explored the haplotype frequencies of 1,062 globally representative individuals. The study showed that the Sudanese and the Ethiopians are distinct from the other Africans and appear to be more associated with populations from the Mediterranean region. This may reflect either repeated genetic contact between Arabia and East Africa during the last 5,000–6,000 years or a Middle Eastern origin with acquisition of African alleles while migrating southwest with agricultural expansion (Cavalli-Sforza et al. 1994). In a comparative population study, Bayoumi et al. 2006 investigated the frequencies of the *I and *D alleles of the angiotensin-converting enzyme (ACE) gene among Sudanese, Somalis, and Arab nationals of the United Arab Emirates (UAE)

578

M.A.M. Salih

and Oman. The ACE gene in humans contains an insertion–deletion polymorphism in its intron 16 and has been widely investigated in different populations owing to its involvement with the rennin–angiotensin system. The allele frequencies of the *I and *D were found to be 0.36 and 0.64, respectively in the 121 Sudanese subjects. A preponderance of the *D allele was observed among the Arab and African populations studied (Sudanese, 0.64; Somalis, 0.73; Emiratis, 0.61; and Omanis, 0.71. The study (Bayoumi et al. 2006) suggested that the lack of significant difference between the groups was probably due to the mixing of gene pools, attributed to the close proximity of UAE and Oman. Another suspected factor was the significant interaction between Omanis and East Africans through trade routes.

Genetic Disorders in Sudan Studies of individual genetic disorders in Sudan were overshadowed by interest in the other major causes of morbidity and mortality, such as endemic diseases, including malaria, schistosomiasis, and leishmaniasis and other health problems related to nutrition. In 1965, a doctoral thesis, “Congenital Diseases in Sudanese Children,” (Hassan 1965a) documented many early reports of genetic disorders in Sudan. In recent years, attention has been directed to red cell genetics and autosomal recessive disorders in general.

Genetic Susceptibility to Infectious Diseases Epidemiological and animal model studies have shown that many apparently nonhereditary diseases, including infectious diseases, develop predominantly in genetically predisposed individuals (Somech et al. 2003).

Malaria Malaria is one of the major causes of death by infectious diseases worldwide and is endemic in more than 90 countries (Greenwood and Mutabingwa 2002). Over the past 50 years, substantial evidence has accumulated to indicate that genetic variants influence response to malaria in humans regarding onset, progression, severity, and ultimate outcome (Fortin et al. 2002). Interaction Between Red Blood Cell Abnormalities and Malaria In areas with high endemicity, innate resistance to falciparum malaria infection appears to have arisen in human populations due to a strong selective pressure (Luzzatto 1979). Inherited defects in the red cell genes had probably evolved as a

20


579

result of this selection and there is considerable evidence for the role played by HbS, G6PD deficiency (G6PD), and thalassemia genes in protecting against falciparum malaria. In this respect, the heterozygote individual is at an advantage over homozygotes for either the normal or the abnormal genes (Gilles et al. 1967; Playfair 1982). In Sudan, Saha and El Sheikh (1987) found a good correlation between the frequencies of HbS and G6PD alleles in eight tribes, suggesting a common ecogenic or selective force for the mutation at the Hb and G6PD loci. This was in agreement with an observed positive association of G6PD with sickle cell and thalassemia genes in the western part of Saudi Arabia (Samuel et al. 1986). In a study in the Sennar region of central Sudan, where Plasmodium falciparum is hyperendemic, erythrocyte traits (HbS and G6PD) were detected in 20% of subjects resistant to falciparum malaria and in only 5% of patients (Bayoumi et al. 1986). The frequency of HbAS heterozygotes was significantly higher among resistant subjects (15%) than among malaria patients (3%) and 3–15 times higher than that (1–5%) of the general population of central Sudan. Bayoumi (1987) suggested that the selective advantage of HbAS individuals is due to the modulation of the immune response in these individuals to P. falciparum malaria. In an endemic area of unstable transmission (a village 20 km south of Gadarif, Fig. 20.1), lymphocytes isolated from healthy individuals with HbAS during the malaria season have been shown to have higher responses to affinity-purified soluble P. falciparum antigens (SPAg) and to purified protein derivative of tuberculin (PPD) compared to lymphocytes isolated from HbAA individuals (Bayoumi et al. 1990; Abu-Zeid et al. 1991). The difference between the two groups was more marked in children than in adults (Abu-Zeid et al. 1991). The lymphoproliferative responses to SPAg of peripheral blood mononuclear cells (PBMC) obtained before and during the malaria season showed two distinct seasonal changes in relation to the Hb phenotype (Theander et al. 1990; Abu-Zeid et al. 1992a). During the malaria season, the lymphoproliferative responses to SPAg were suppressed in HbAA subjects (children and adults) but enhanced in HbAS individuals. No distinct seasonal change in the response to PPD was found in relation to the Hb phenotype. These enhanced responses were explained by better priming of the immune system in carriers of the sickle cell gene. It was suggested that sickling may induce modified expression of parasite antigens, analogous to the recently described modified expression of parasite-induced neoantigens by thalassemia (Luzzi et al. 1991). In a subsequent investigation (Abu-Zeid et al. 1992b), individuals with sickle cell trait who had clinical malaria were found to have lower plasma soluble interleukin-2 (IL-2) receptors and parasite counts compared to normal subjects.

Segregation and Genetic Linkage Analyses An international collaborative study, involving the Department of Biochemistry, Faculty of Medicine, University of Khartoum, and the Malaria Administration of the Sudan Ministry of Health, revealed interesting findings (Roper et al. 1996).

580

M.A.M. Salih

The study was conducted in Daraweesh village in Gadarif state in eastern Sudan, approximately 50 km from the Ethiopian boarder. Malaria transmission is markedly seasonal with cases peaking in October and November in frequently severe outbreaks. A study (Roper et al. 1996) which used nested polymerase chain reaction (PCR) to assay for low level P. falciparum infections that were below the threshold of detection of blood film examination, revealed that many individuals were infected but healthy for most of the year. Longitudinal data, collected from the same village over 11 years, showed distinctly variable level of disease susceptibility (Creasey et al. 2004). Thirty-two percent of the village inhabitants never reported malaria symptoms or required malaria treatment, while others experienced up to eight clinical episodes during the 11 years of observation. It is noteworthy that the people of Daraweesh are descendents of a Fulani group who originated from Burkina Faso and settled in Sudan about a century ago. Of note is that a polymorphism present in the interleukin4 (IL-4) gene showed high frequency in the Fulani of West Africa, and has been associated with elevated antibody levels against malaria antigens (Luoni et al. 2001). In a recent study (Nasr et al. 2007), the FC g receptor IIa (CD32) polymorphism and antibody responses to asexual blood-stage antigens of P. falciparum were explored in 256 Sudanese individuals. These consisted of 115 patients with severe malaria, 85 with mild malaria and 56 malaria-free controls. The study revealed that the Fcg RIIa-R/R131 genotype is associated with the development of severe malaria, while the H/H131 genotype is more likely to be associated with mild malaria. Another finding was that the natural acquisition of immunity against clinical malaria appeared to be more associated with IgG1 and IgG3 antibodies, highlighting their roles in parasite-neutralizing immune mechanisms.

Schistosomiasis Schistosomiasis is the second most important disease worldwide after malaria with an estimated 200 million infected people (Campino et al. 2006; Gryseels et al. 2006). In Sudan, the disease is highly endemic in the Gezira Province which lies between the Blue Nile and the White Nile (in Arabic the word Gezira means Island). Located in this province is the Gezira Scheme, which is the largest single farm in the world under the same irrigation and administration system. The prevalence of Bilharziasis is very high with 68–90% of the population infected by Schistosoma mansoni (Omer et al. 1979; Saeed et al. 2006). Most people living in S. mansoni endemic areas are asymptomatic. However, a few develop periportal fibrosis (PPF) of the liver which is part of the healing process that follows the acute granulomatous reaction around schistosome eggs trapped in hepatic small vessels (Gryseel et al. 2006). Lethal disease due to the hepatic fibrosis occurs in 2–10% of subjects infected by S. mansoni in endemic regions such as the Sudan (Dessein et al. 1999). A series of studies involving researchers from the University of Gezira, University of Khartoum and Al Zaiem Al Azhari University, in collaboration with

20


581

international research centers, focused on the susceptibility to PPF in human S. mansoni infections. These were mainly conducted in Al Taweel, a small village of the Managil area at the southwestern extension of the Gezira Scheme, 300 km south of Khartoum. The study subjects were migrants who settled in the village in the late 1970s, and came from the same region of western Sudan, where Schistosomiasis is not endemic. The population of the village consisted of two tribes: the Tama-Messeria tribe (67%) and Rawashda tribe (33%), who are closely related ethnic groups (Mohamed-Ali et al. 1999). Using ultrasonography at the field, early, moderate and advanced PPF were observed in 58%, 9% and 3%, respectively of Al Taweel village population (Mohamed-Ali et al. 1999). Severe disease (moderate and advanced fibrosis) with portal hypertension affected 6%, occurred mostly in adult men, and was clustered in a few pedigrees. These observations suggested that infection intensity and duration, gender-related factors, and hereditary factors are important in the development of PPF. Combining segregation and linkage analysis, a major locus predisposing subjects infected with S. mansoni to severe hepatic fibrosis was mapped to chromosome 6q22-q23 (Dessein et al. 1991). The locus is closely linked to the IFN – gR1 gene encoding the receptor of the strongly antifibrogenic cytokine interferon-g. This result was subsequently replicated in an Egyptian population (Blanton et al. 2005). Dessein et al. (1999) also demonstrated that levels of infection and hepatic disease owing to S. mansoni are under distinct genetic control. Interferon-g (IFN-g) is a key regulator of the development and function of the immune system and plays a major role in immune defense against infections by various human pathogens. In a study by the same core group of investigators (Henri et al. 2002a), INF-g was found to play a key role in the protection of S. mansoniinfected patients against PPF, whereas tumor necrosis factor-a (TNF-a) may aggravate the disease. They also uncovered three new single nucleotide polymorphisms in the IFN-g genes (Henri et al. 2002b). In a following study (Chevilland et al. 2003), they screened putative polymorphic sites within the IFN-g gene in the populations of two villages, Al Taweela and Umzukra. They found that IFN-g þ 2,109 A/G polymorphism is associated with a higher risk for developing PPF, whereas the IFN-g þ 3,810 G/A polymorphism is associated with less PPF. Eosinophil cationic protein (ECP) is not only a secretary protein of eosinophil granulocytes that efficiently kills the larval stage of S. mansoni but also affects fibroblast function. The prevalence of the ECP gene polymorphism 434 (G > C) was investigated in 297 individuals from an S. mansoni endemic area in Uganda and compared to that of 78 subjects from a nonendemic area in Sudan, as well as a Swedish population (n ¼ 209) (Eriksson et al. 2007). In the Uganda population, there was a significant association between genotypes and prevalence of infection (P ¼ 0.03). The study (Eriksson et al. 2007) suggested that ECP may be important as a component of the immune response against S. mansoni and in the development of PPF. It also suggested genetic selection towards the ECP 434 CC genotype in populations living in S. mansoni endemic areas.

582

M.A.M. Salih

Leishmaniasis Visceral leishmaniasis (VL), which is caused by the protozoa of the Leishmania donovani complex and transmitted by sand flies, is an endemic disease in Sudan and many other tropical countries (Elshafie et al. 2006). Human infections may be asymptomatic (sub-clinical) or may cause a severe visceral disease which is called kala-azar (KA). Post-KA dermal leishmaniasis (PKDL) afflicts patients who have recovered from VL and who are otherwise well. Several studies, that were conducted by the Institute of Endemic Diseases and the Department of Parasitology and Microbiology, Faculty of Medicine, University of Khartoum (in collaboration with international institutes), showed marked differences in the incidence of VL between adjacent villages inhabited by different ethnic groups (Ibrahim et al. 1999). Also, when members of these different populations share the same immediate environment and exposure, certain ethnic groups show a higher risk of developing VL. In one study (Ibrahim et al. 1999), vulnerability to VL was observed in two ethnic groups, namely the Nilotic Baria and Nuba similar to the Nilotic Nuer in the Upper Nile Province in southern Sudan. Other studies (Mohamed et al. 2004) also documented high vulnerability in the Nilosaharan speaking Masalit population who migrated from western Sudan in the early-mid 1980 and settled along the Rahad River in the center of the endemic area in eastern Sudan. Members of the Aringa ethnic group, who migrated from the western Sudan/Chad area and settled in eastern Sudan as agricultural laborers in the 1940s, were also found to have high susceptibility to VL (Bucheton et al. 2003a,b). Utilizing candidate-gene studies in these vulnerable communities, immune system genes have been explored and significant genetic influences were detected. PKDL, which is induced by L. donovani, was found to be influenced by a polymorphism in the IFN-receptor, and polymorphisms in the genes that encode IL-4 (Mohamed et al. 2003; Salih et al. 2007). Natural resistance-associated macrophage protein-1 (NRAMP1), which has initially been implicated in mouse innate susceptibility studies, has been shown to contribute to an increased risk for VL (Bucheton et al. 2003b; Blackwell et al. 2004; Mohamed et al. 2004; El-Safi et al. 2006). Moreover, the findings of the first published genome-wide scan that analyzes susceptibility to human leishmaniasis (Bucheton et al. 2003a) identified a major locus that controls the susceptibility to L. donovani on chromosome 22q12. A second genome-wide scan was undertaken in two villages occupied by the Masalit ethnic group in eastern Sudan, who were also related to the Aringa group (Miller et al. 2007). The cohort included 69 families with 173 affected relatives. Results of the analysis provided evidence for two major susceptibility loci in this ethnic group at 1p22 and 6q27 that were Y chromosome lineage and villagespecific. Contrary to the findings in the related Aringa group (Bucheton et al. 2003a), neither village had evidence for a VL susceptibility gene on 22q12. These findings pointed towards strong lineage-specific genes due to founder effect and consanguinity in these recently immigrant populations.

20


583

Red Cell Genetic Disorders Sickle Cell Disease Sixteen years after the report of Sickle Cell Disease (SCD) from the United States (Herrick, 1910), Archibald (1926) described the first case in Sudan. Since Sudan has been, and is still, affected by mass population movements both within and from outside its borders (El Tay et al. 1988), a comparison with other African countries regarding the prevalence of sickle cell trait may be pertinent. The prevalence was reported to be between 25% and 29% in Nigeria (Molineaux et al. 1979; Adekile et al. 1992), 23.8% in the Lake Victoria region in Kenya (Ojwang et al. 1987), and 14% in Zaire (Nagel and Fleming 1992). In Sudan (Fig. 20.2.) foci of high prevalence were reported from its western and southern regions. A rate of 11.2–30% was detected among the Baggara tribal group that includes Hawazma and Messeria (Vella 1964; Lauder and Ibrahim 1970), and one of up to 18% was found in southern Nilotes and Nilo-Hamitic tribes (Foy et al. 1954). Among tribes that immigrated, from West Africa and settled around the southern part of the Blue Nile, a prevalence of 16% was reported compared to 0–5% among the indigenous population (Ahmed and Baker 1986). The aboriginal tribes of Beja and Nuba (Fig. 20.2) characteristically have zero frequency of hemoglobin S (HbS), whereas studies on aboriginal northern Nilotes (Dinka, Nuer, and Shilluk) have shown variable low frequencies of the sickle cell gene, ranging from 0 to 4% (Foy et al. 1954; Roberts and Lehmann 1955; El Hassan et al. 1968; Omer et al. 1972; Bayoumi and Saha 1987; Saha and El Sheikh 1987). However, the tribal groups residing along the northern part of the Nile (Nubians including Danagla, Shaigia, and Gaalyeen; Fig. 20.2) also have a very low frequency (0.5–1.1%). It is noteworthy that the Nuba Mountains where the Nuba tribes live have been reported to be endemic for malarial infection (Saha and El Sheikh 1987), whereas the Shaigia and Gaalyeen, who are of Arab descent, live in a nonendemic area (Omer 1978). The pattern of clinical manifestations of SCD in Sudan has also been studied. Hassan (1960) described three cases in three families who belonged to the Masalit tribe of western Sudan. Subsequent publications documented the severity of phenotypic expression (Hassan 1965a, 1970). In a group of 25 affected children, a mortality of 20% was recorded and serious complications were noted in others. These included osteomyelitis, hemiplegia, avascular necrosis of the femoral head, and severe anemia leading to congestive heart failure. Bayoumi et al. (1988a) reported on the clinical, hematological and biochemical features of 50 Sudanese patients with SCD. Twenty one patients were children G), codon 6 (–A), IVS-I-6 (T>C), codon 44 (–C), IVS-II-745 (C>G), codon 30 (G>C), 30 (T>G), IVS-I-5 (G>A), codon 5 (–CT), IVS-I-1 (G>A), IVS-II-848 (C>A), IVS-I-2 (T>C), codons 25/26 (þT), codon 8 (–AA), IVS-I-1 (G>T), codon 37 (G>A), and IVS-II-849 (A>C). When the mutation frequencies from the different Tunisian regions were compared the distribution of b-thalassemia alleles differs significantly within each area, Northern Tunisia displays the greatest heterogeneity (Haj Khelil et al. 2004).

a-Thalassemia (OMIM 141800) Compared to the other haemoglobinopathies, a-thalassemia research studies was limited in Tunisia. Hemoglobin screening on newborns has shown a frequency of a-thalassemia trait of 5.48% (Fattoum 2006). Through a screening study conducted on 304 cord blood samples, Zorai et al. (2002) found that the -alpha3.7 deletion was the most common defect (4.5% allele frequency) followed by a polyadenylation (poly A) signal mutation (1.8%), the five nucleotide deletion and the -alpha4.2 deletion (both 0.9%), and no alpha0-thalassemia alleles were found.

Sickle Cell Disease (OMIM 603903) Average frequency of sickle cell disease carriers in Tunisia is 1.89% (Fattoum 2006). The severity pattern of the disease ranges from moderate to severe. This pattern is similar to that of the African type. Ninety-five percent of patients with sickle disease were homozygous for the Benin haplotype (Fattoum et al. 1991).

618

E. Hassen and L. Chouchane

Glucose-6-Phosphate Dehydrogenase (OMIM 305900) Blibech et al. (1989) performed a screening study for glucose-6-phosphate dehydrogenase (G6PD) deficiency on male students originating from several towns in Tunisia. In this study the incidence of the G6PD deficiency was of 1.84%. Blibech et al. (1989) study also showed a marked predominance of the Bþ type (96.2%) compared with the A þ type (1.96%). In a recent study, Daoud et al. (2008) aimed at identifying G6PD mutations in 41 deficient unrelated Tunisian subjects. The most prevalent variant was the G6PD African variant A, which account for 63.63% as allelic frequency. This variant was responsible for severe phenotype leading to haemolytic anemia due to ingestion of fava beans. The presence of this variant in Tunisian population is not surprising since Tunisia is in majority consisting of Africans coming from neighboring regions. The second most prevalent variant is the Mediterranean variant, which was found with an allelic frequency of 11.36%. The third variant detected was the G6PD Aure`s mutation. This mutation was described originally in Algeria (Nafa et al. 1993) and then with less frequency in Saudi Arabia (Niazi et al. 1996) and UAE (Bayoumi et al. 1996). SSCP analysis of mild deficient males, revealed the presence of the association of 1311 CT/93 TC, a newly described silent mutation in the exon 12 associated with the polymorphism in the intron 11 93 TC and tow single intronic base deletion (the first is IVS V 17 (-C) and the second is IVS VIII 43 (-G)) (Daoud et al. 2008). Fanconi Anemia (OMIM 227650) Fanconi anemia (FA) is a rare autosomal recessive and heterogeneous disease with at least eight complementation groups (A–H). In Tunisia a relatively high incidence of FA is observed: 1.4/million/year (Bouchlaka et al. 2003). In order to identify to which complementation group Tunisian patients belong, Bouchlaka et al. (2003), analyzed gene mutations in 39 unrelated families from different regions in Tunisia. Thirty-four families were assigned to the FAA group (94%), whereas one family was probably not linked to FANCA gene or to any known FA gene. For the patients who are assigned to the FAA group, Bouchlaka et al. (2003), identified two homozygous deletions 1693delT and 1751–1754del, which occurred in exon 17 and exon 19, respectively, and two transitions 513G > A in exon 5 and A > G at position 166 (IVS24 + 166A > G) of intron 24. Two new polymorphisms IVS24 – 5G/A, and IVS24–6C/G were also identified in intron 24.

Chromosomal Disorders Down Syndrome (OMIM 190685) To reduce Down syndrome incidence a screening strategy has been established in Tunisia. In a recent retrospective study of a 4-year period, Chelli et al. (2008) found a total prevalence of the Down syndrome of 0.98%. Sixty percent of the cases were

21

Genetic Disorders in Tunisia

619

diagnosed at a prenatal stage and the median gestational age at diagnosis was 21 weeks. In Tunisia legal and religious authorities permit pregnancy termination. After, medical approval parents have the possibility to choose to terminate pregnancy. In Tunisia more than 90% accept termination of pregnancy. (Chaabouni et al. 2001; Chelli et al. 2008).

Turner Syndrome A retrospective analysis of 89 cases of the Turner Syndrome observed during a 6-year period, was performed (Kammoun et al. 2008). Karyotyping was achieved when stature retardation or dysmorphic features or reproduction anomalies were observed. Mosaicism was found in 47%, homogeneous karyotype 45,X was found in 32% and structural anomalies were found in 21%. In the same study a relationship between chromosome anomalies and the clinical expression of Turner Syndrome was established. Total deletion of one chromosome X or imbalanced gene dosage due to structural X anomalies was correlated with short stature and primary amenorrhea. Cases of infertility, recurrent miscarriages and secondary amenorrhea were associated with a mosaic karyotype pattern (45,X/46,XX or 45,X/46,XX/47, XXX ...), with a slight mosaicism in most cases.

Klinefelter’s Syndrome Klinefelter syndrome, also known as the 47, XXY syndrome, is a syndrome where males have an extra X chromosome in most of their cells. A retrospective study was carried out on infertile Tunisian men to determine the prevalence of sex chromosome abnormalities (Abdelmoula et al. 2004). Cytogenetic analysis were performed and among 14 chromosomal abnormalities found, nine were compatible with Klinefelter’s syndrome. Six Klinefelter’s patients showed a nonmosaic 47, XXY and three showed a 47, XXY/46, XY mosaic.

Neuromuscular and Neurodegenerative Disorders Muscular Dystrophies Muscular dystrophies (MDs) constitute a clinically and genetically heterogeneous group of inherited autosomal recessive myopathies. Among Tunisians mutations in the fukutin-related protein gene (FKRP) gene were associated with structural and neurological abnormalities in a subset of patients with a severe congenital form classified as MDC1C (OMIM 606612) (Louhichi et al. 2004). Two homozygous missense FKRP mutations associated with MDC1C and mental retardation were reported in a series of six unrelated Tunisian families (A455D) and in an Algerian patient (V405L) (Louhichi et al. 2004). Moreover, among the Tunisian families a

620


microsatellite close to the FKRP gene was identified, allowing authors to confirm the founder origin of the Tunisian A455D mutation. Mutations in the LAMA2 gene may provoke a primary deficiency in the laminin a2 chain (merosin) resulting in another MD, the MDC1A type (OMIM 607855). Louhichi et al. (2006), identified among two Tunisian consanguineous families with severe MDC1A two homozygous mutations (c.8007del T and c.8244 þ 1G > A) in the LAMA2 gene. An autosomal form of Duchenne-like dystrophy was first described in large Tunisian families (Ben Hamida et al. 1983), affecting both males and females. Later on, this genetic disorder was assigned to chromosome 13q12 (Ben Othmane et al. 1992) and further classified under limb girdle MD type 2 C (OMIM 253700). Mutations in SGCG gene are associated with LMGD2C. A del521T homozygous mutation in exon 6 of the SGCG gene was widely distributed in Tunisian patients (Kefi et al. 2003). Using identified mutations in LAMA2 and SGCG genes among Tunisian families with MDC1A and LGMD2C respectively, Siala et al. (2008) carried out for the first time a molecular prenatal diagnosis and a postnatal follow up. This study included consanguineous families, two affected with MDC1A and one affected with LGMD phenotype. The prenatal diagnosis was successful; however, the postnatal follow up showed a phenotypic intrafamilial variability in two patients with MDC1A form sharing the same mutation in LAMA2 gene.

Spinal Muscular Atrophy (OMIM 253300) Spinal muscular atrophy (SMA) refers to another group of autosomal recessive neuromuscular disorders, which is estimated to be a common disease in Tunisia (Chaabouni-Bouhamed 2008). Spinal muscular atrophy type I (SMA I) is caused by mutation or deletion in the telomeric copy of the SMN gene, known as SMN1. Mrad et al. (2006) examined the deletion of SMN1 and NAIP genes in 60 Tunisian families with the four types of SMA. They showed that exons 7 and 8 of the SMN1 gene were homozygously deleted in 95 and 88%, respectively, while exon 5 of the NAIP gene was homozygously deleted in 58% (77% in ASM I, 27.7% ASM II and 50% in ASM III), with higher deletion prevalence in the more severe SMA cases.

Congenital Myasthenic Syndrome Associated with Acetylcholine Receptor Deficiency (OMIM 608931) Twenty-three families with an early onset form of congenital myasthenic syndrome (CMS) from North African origins (Tunisia, Algeria, Morocco and Libya) were screened for the epsilon1293insG mutation (Richard et al. 2008). The epsilon1293insG mutation was identified in 14 families. Among the later, nine were from Algeria, three from Tunisia, one from Morocco and one from Libya. All these 14 families were consanguineous and included 27 patients who were homozygous

21


621

for the epsilon1293insG mutation. Epsilon1293insG was previously detected in patients originating from the Maghreb including Mauritania, Morocco, Algeria, Tunisia and Libya. Moreover, this mutation has never been reported in the homozygous state in CMS patients of nonMediterranean origin. Thus, in the Richard et al. (2008) study authors suggested that epsilon1293insG is derived from an ancient single founder event in the North African population. The age of the founder event was estimated at approximately 700 years.

Parkinson Disease (OMIM 168600) Parkinson disease (PD) is a complex multifactorial neurodegenerative disease with substantial evidence for genetic risk factors. In the familial cases mutation in at least one of the following genes has been implicated in the PD development: LRRK2 (Leucine-Rich Repeat Kinase 2), PARK2, PARK7, PINK1 (PTENInduced Putative Kinase 1), or SNCA (Synuclein, Alpha). Through a prospective study Gouider-Khouja et al. (2000) described the clinical and genetic characteristics of 88 affected subjects belonging to 21 Tunisian families. A clinically similar feature between familial and sporadic PD cases, apart from younger age at onset, was observed. Moreover, in Tunisia familial PD is genetically heterogenous with an autosomal recessive and autosomal dominant form. The most frequent mutation associated with PD is the Lrrk2 p.G2019S. This mutation was present in 42% of Tunisian families and 2% of US families (Warren et al. 2008). In a recent study Nishioka et al. (2010) compared clinical features of patients with familial PD of unknown etiology and those carrying LRRK2 or PINK1 pathogenic mutations in a Tunisian population with high prevalence of Lrrk2 p.G2019S (32%) and PINK1 (18%) mutation carriers. Clinical data analysis showed that despite similar ages, ages at onset and disease duration, Tunisian patients harboring Lrrk2 p.G2019S have a more severe motor phenotype, a higher rate of dyskinesia and use of dopamine agonists, and less postural tremor than mutation-negative patients. LRRK2 mutation carriers appear to have the most severe clinical phenotype while PINK1 carriers have a longer disease course and the lowest incidence of tremor as initial symptom. LRRK2 and PINK1 carriers have an increased prevalence of resting tremor and dyskinesia compared to those not genetically defined.

Alzheimer Disease (OMIM 104300) In Tunisia, Alzheimer Disease (AD) affects nearly 25,000 people. AD is an irreversible, progressive brain disease. Both, the two AD types, early onset and late-onset forms, have genetic links. Early onset type is a rare form of AD mainly composed of familial cases. Most cases of AD are of the late-onset form. One predisposing genetic risk factor does appear to increase the risk of developing AD, the apolipoprotein E (APOE) gene found on chromosome 19. Smach et al. (2008) conducted a

622


case-control study on 93 AD patients from the central region of Tunisia to study whether genetic polymorphism in ApoE gene is a risk factor for AD Tunisians patients. The ApoE epsilon4 allele increased the risk for AD; odds ratios for heterozygous and homozygous subjects were 3.29 and 9.47, respectively. The same observation was found for French, Italian and Iranian AD patients (Raygani et al. 2005; Piscopo et al. 2006).

Genetic Endocrine Disorders Congenital Adrenal Hyperplasia (OMIM 201910) Approximately 95% of cases of congenital adrenal hyperplasia (CAH) are due to defects in the steroid 21-hydroxylase (CYP21) gene. The mutational spectrum in the Tunisian CAH population was established by Kharrat et al. (2004). The CYP21 gene was analyzed in 51 unrelated patients; at least 31 of them were from consanguineous families. In this study, mutations were detected in over 94% of the chromosomes. The most frequent defect in CYP21 gene was found with a prevalence of 35.3% to be the Q318X mutation in exon 8, followed by large deletions (19.6%), a splice site mutation in intron 2 (17.6%) and I172N mutation in exon 4 (10.8%). Furthermore, novel mutations were detected including R483W, W19X, 2669insC and one small conversion of DNA sequence from exon 5 to exon 8. Investigators also showed a good genotype/phenotype correlation in the case of most mutations. A fifth small 13-bp deletion in exon 1 was found in the CYP21 gene of a Tunisian CAH patient (Kharrat et al. 2005). The patient was homozygous for the deletion that causes a stop codon at amino acid 47 resulting in a nonfunctional enzyme.

Autoimmune Thyroid Diseases Autoimmune thyroid diseases (AITDs), such as Graves’ hyperthyroidism (GD) and Hashimoto’s thyroiditis (HT), are common multifactorial disorders. Some pathogenetic genes are probably shared between these diseases and nonendocrine autoimmune diseases, whereas others are disease specific. Tunisian population studies show that major histocompatibility complex alleles and CTLA4 confer risk for AITDs (Ayadi et al. 2004). A full genome screening in a large Tunisian family affected with thyroid autoimmune disorders including 39 patients affected with GD or HT and 68 related controls, who, belonged to a large consanguinous family composed of more than 200 members. Linkage analysis was performed and a positive Lod score was found for D2S171 marker suggesting the presence of a major AITD susceptibility gene on chromosome 2p21 (Maalej et al. 2001).

21


623

Cystic Fibrosis (OMIM 219700) In Tunisia Cystic Fibrosis (CF) does not seem to be rare. To identify genetic variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, Messaoud et al. (2005) conducted a molecular epidemiological study on 390 cystic fibrosis children belonging to 383 families. In this study 70% of the CF patients were seen carrying CFTR gene’s variations. Seventeen different mutations were identified in the different exons, among them four were newly and exclusively described in the Tunisian population (T665S, 2766del8, F1166C and L1043R). The most frequent mutation was the F508del (50.74%) mutation followed by G542X (7.96%), W1282X (6.66%), N1303K (5.92%), 2766del8 (4.25%), 711 þ 1G > T (4.23%), E1104X (1.85%) and ten rare mutations G85E, D1270N, R74W, R1066C, Y122X, T665S, I148T, V201M, F1166C, L1043R. More recently, among 68 unrelated CF patients, Fredj et al. (2009) detected three novel mutations: I1203V (1.47%), 1811+5A > G (0.74%) and 4268 þ 2T > G (1.47%).

Metabolic and Nutritional Diseases Phenylketonuria (OMIM 261600) Although phenylketonuria (PKU) is a frequent inherited metabolic disorder, epidemiologic and molecular data are lacking in Tunisia. In Tunisia the birth prevalence of PKU would be of 1:9,000 (Chaabouni-Bouhamed 2008). In a recent study conducted on 805 mentally handicapped patients aged between 6 and 46 years, phenylalanine was analyzed using the fluorimetric method. Eleven patients (1.32%) were diagnosed as having PKU (Khemir et al. 2009), this frequency is close to the frequency of 1.6% observed in Kuwaiti mentally handicapped institutions (Teebi et al. 1987).

Insulin-Dependent Diabetes Mellitus (OMIM 222100) Insulin-dependent diabetes mellitus (IDDM) or diabetes type 1 results from an autoimmune selective and irreversible destruction of b-cells of Langerhans. It is one of the most frequent chronic diseases in children, in Tunisia the IDDM incidence is of 6.76–6.95/100,000 (Ben Khalifa et al. 1997). While the etiology is still unclear genetic and environmental factors are suspected. Molecular analysis of HLA-DR subtypes of 18 Tunisian multiplex families with diabetic children showed that two DR subtypes, DR4-DQw8 and DR-Dw25, were significantly more common in the diabetic patients (Jenhani et al. 1990). More recently, Stayoussef et al. (2009) reported an association between HLA-DRB1 and DQB1 alleles and haplotypes in 50 Tunisian patients and identified two susceptibility haplotypes (DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302).

624


Noninsulin-Dependent Diabetes Mellitus (OMIM 125853) Noninsulin-Dependent Diabetes Mellitus (NIDDM) or type 2 diabetes is a major public health problem in Tunisia. Hypertension and obesity were found in respectively 71.3 and 37.6% of diabetic patients (Ben Abdelaziz et al. 2006). Diabetic neuropathy was the most frequent degenerative complication (41.1%) followed by diabetic retinopathy (18.3%). Arfa et al. (2007) reported that familial aggregation of NIDDM was prominent, and among studied subjects, 70% reported at least one relative with diabetes and 34% had at least one parent with diabetes. The calpain-10 (CAPN10) was suggested to be a putative NIDDM susceptibility gene (Horikawa et al. 2000). Kifagi et al. (2008) analyzed the frequency distribution of four CAPN10 polymorphisms (UCSNP-43, UCSNP-19, UCSNP-110 and UCSNP-63) in 222 Tunisian patients. The A allele of UCSNP-43 showed an association with NIDDM and a novel combination of haplotypes (121/221) defined by three polymorphisms (UCNSP-43, -19 and -63) was identified to be associated with an increased risk of NIDDM. Several other associations were described with HSP702 (Zouari Bouassida et al. 2004), glucose transporter 1 (GLUT1) (Makni et al. 2008), methylenetetrahydrofolate reductase (MTHFR) and angiotensin-converting enzyme (ACE) gene polymorphisms (Mehri et al. 2009).

Inflammatory Disorders Familial Mediterranean Fever Gene (OMIM 608107) Familial Mediterranean fever (FMF) is an autosomal recessive inherited disease caused by mutations in MEFV gene. To identify the frequency and distribution of MEFV mutations among Tunisians, Chaabouni et al. (2007) screened eight known MEFV gene mutations in 139 unrelated Tunisian patients. Allele frequencies were for mutations M680l, M694V, E148Q, M694l, V726A, A744S, R761H, l692del and of 32, 27, 18, 13, 5, 3, 1 and 1%, respectively. M680l is the most common mutation, while V726A, the commonest mutation among other Arabs, (Majeed et al. 2005), is, rare in the Tunisian population. Moreover, Belmahi et al. (2006) described the frequencies of the MEFV mutation spectrum among North African Arab patients (85 Algerians, 87 Moroccans, and 37 Tunisians). They found that the M694I mutation is specific to the Arab population from Maghreb and suggested that the M694V mutation arrived at the Maghreb region with migrations from the Middle East.

Systemic Lupus Erythematosus (OMIM 152700) Several association studies have been conducted on Tunisians to identify Systemic Lupus Erythematosus (SLE) susceptibility gene polymorphisms. The

21


625

deoxyribonuclease I (DNASE1) gene seems to contribute in the genetic susceptibility of SLE among Japanese and Spanish patients. Through case-control studies, Chakraborty et al. (2003) first studied the occurrence of the A/T transversion polymorphism in exon 2 at position 172 of the DNASE1 gene, and then Belguith-Maalej et al. (2010) assessed known SNPs genotyping. In both the studies no associations were found with DNASE1 gene polymorphisms. Ayed et al. (2004) assessed the MHC class II (DRB1, DQA1, DQB1) and C4 null allele frequencies in 62 SLE Tunisian patients and 100 controls. In this report, HLA-DRB1*0301, DRB1*1501, C4AQO, HLA-DQA1*0102, DQA1*0501, HLA-DQB1*0201, DQB1*0602 and the C4A null alleles were increased in the SLE patients, while the frequencies of HLA-DRB1*04 and DQB1*03 were decreased. These observations were also noticed in other ethnic groups, suggesting shared susceptibility factors to SLE across ethnic groups.

Dermatological Disorders Xeroderma Pigmentosum (XP) This disease is rare worldwide, but in Tunisia where consanguineous marriage and endogamy are frequent the disease prevalence was estimated to be of 1/10,000 cases per inhabitants (Zghal et al. 2006). XP has eight known complementation groups (XP-A to XP-G and XP-V), seven of which are caused by mutations in genes encoding components of the nucleotide excision repair (NER) pathway. Nishigori et al. (1993) studied the XPA (OMIM 278700) gene alterations in seven Tunisian XPA patients and found that 86% of them had a nonsense mutation in codon 228. To identify the spectrum of XPC (OMIM 278720) gene mutations, Ben Rekaya et al. (2009) examined 20 patients and their family members. All studied patients presented a homozygous deletion of two bases TG, V548AfsX572 XPC mutation that leads to a frame-shift mutation and a premature termination of the encoded protein. Like described previously, in North African (Mahindra et al. 2008), Italian, Turkish (Gozukara et al. 2001) and Ashkenazi–Jewish Israeli patients (Slor et al. 2000) all studied patients correspond to a severe clinical form of XP-C. Furthermore, previous studies of XP-C showed that Moroccan and Algerian (Khan et al. 2006) patients had the V548AfsX572 XPC mutation. Haplotype analysis showed that all available patients from unrelated families shared the same haplotype, suggesting a possible founder effect of the V548A fsX572 XPC mutation.

Dystrophic Epidermolysis Bullosa (RDEB OMIM 226600; DDEB OMIM 131750) Dystrophic Epidermolysis bullosa (DEB) is a clinically and genetically heterogeneous group of dermatological diseases. DEB is a disorder caused by defects in

626


the type VII collagen gene (COL7A1) which encode a fibrous protein that is the main component of the anchoring filaments. Both autosomal dominant (DDEB) and recessive (RDEB) forms were described. Using microsatellite markers, Ouragini et al. (2008) investigated COL7A1 genotyping on 23 Tunisian epidermolysis bullosa consanguineous families. These families were affected by different EB forms: 19 were diagnosed to present the dystrophic form, two the simplex form, one the junctional EB, and one an unclassified form of EB. Haplotype and homozygosity analysis suggest that all families classified clinically as having DEB and the patient who presented himself with an unclassified form of EB are likely linked to the COL7A1 gene, and showed evidence for exclusion for the simplex and junctional cases. Mutational heterogeneity among Tunisian DEB families was also reported and the genetic results correlated with the clinical examination in 94.7% of all studied DEB families. More recently a large DEB multiplex consanguineous family originating from the North of Tunisia was studied (Ouragini et al. 2009). The family included eight affected individuals, three of whom died with a generalized bullous eruption. Screening for the deleterious mutation (c.7178delT) showed that a member with the generalized form was homozygous.

Deafness Nonsyndromic Deafness (OMIM 220290) Nonsyndromic congenital deafness is common in Tunisia, especially in some villages where the prevalence ranges from 2% to 8%. To evaluate the effect of inbred unions on deafness, a study was conducted on 5,020 individuals (160 were deaf) from the northern region of Tunisia (Ben Arab et al. 2004). The highest level of inbreeding was observed in the rural districts. Autosomal recessive genes are responsible for about 80% of the cases of hereditary nonsyndromic deafness. DFNB1 loci is the most important locus for nonsyndromic autosomal recessive deafness, it was originally assigned to chromosome 13q11 by linkage analysis in two large consanguineous Tunisian families with prelingual, profound deafness (Guilford et al. 1994a, b). The 35delG mutation in the GJB2 (connexion 26) gene, which was the first DFNB1 identified mutation, is the single most frequent allele for nonsyndromic recessive deafness in Tunisia and in the world (Ben Arab et al. 2000; Denoyelle et al. 1997). The DFNB2 locus was mapped by a genome search to 11q13.5 in a highly consanguineous family also from Tunisia segregating nonsyndromic, profound deafness (Guilford et al. 1994a). Recently, Tlili et al. (2007) reported the mapping of a novel locus, DFNB63, to chromosome 11q13.3–q13.4 in a large consanguineous Tunisian family.

21


627

Usher Syndrome Type IIA (OMIM 276901) Usher syndrome (USH) is clinically and genetically heterogeneous, and it is categorized into three clinical subtypes. Mutations in USH2 genes can also manifest as atypical USH, as nonsyndromic recessive HI, or as nonsyndromic recessive RP. Ben Rebeh et al. (2008) assessed to localize the USH responsible gene in a consanguineous family originating from the Tunisian center. This consanguineous Tunisian family exhibited no evidence of linkage to any known USH locus. However, Ben Rebeh et al. (2008) suggest that a novel gene implicated in USH2 is likely to reside on 15q.

X-Linked Mental Retardations (OMIM 300419) Among 492 unrelated Tunisian patients suffering from mental retardation (MR) of nonchromosomal origin, familial MR was present in 30% of the cases and consanguinity was prevalent in 59% (Chaabouni-Bouhamed 2008). A new locus was identified in a large Tunisian family with nonspecific X-linked MR, and then the gene was identified as ARX (Bienvenu et al. 2002; Jemaa et al. 1999). To date mutations in the PAK3 gene have been found in four different families of X-linked MR. Rejeb et al. (2008) reported the first PAK3 gene splice mutation identified in a Tunisian family with X-linked MR.

Hereditary Multiple Exostoses Type I (OMIM 133700) Sfar et al. (2009a) investigated the screening of the EXT1 gene mutations among two Tunisian families originating from the middle coast of Tunisia. For each family one distinct mutation was reported, the first in exon 2 was previously described (c.1019G > T) and the second is a novel frame-shift deletion of adenine in exon 1 (c.529_531delA). This newly identified mutation was associated with a wide intrafamilial clinical variability of HME disease ranging from the severe form to subclinical signs.

Predisposition to Cancer Bladder Cancer (OMIM 109800) Bladder cancer is not an inherited disease. Nevertheless, polymorphisms in genes involved in DNA repair or in the detoxification of xenobiotics may play an important role in disease susceptibility. In Tunisia, bladder cancer is the most

628


prevalent cancer of the urogenital tract and the second most frequent cancer affecting men after lung cancer (10.7/100,000 men) (Hsairi et al. 2002). Several case-control studies have been conducted on Tunisians to identify susceptibility genes. Tunisian smokers carrying the GSTM1 null allele are at an approximately 2.2-fold high risk of bladder cancer (Ouerhani et al. 2006). Furthermore, individuals carrying at least one copy of the methionine synthase (MS) variant allele A2756G and heterozygous for MTHFR A1298C polymorphism displayed a 2.33 and 1.8 times increased risk of developing bladder cancer, respectively (Ouerhani et al. 2007). The study of the combined effect of tobacco, MS and MTHFR genotypes in bladder cancer development, has suggested that the inheritance of MTR 2756*G allele (AG or GG genotype) and wild-genotype for MTHFR (MTHFR 677CC) was associated with an increased risk of bladder cancer in both smokers and nonsmoker patients (Ouerhani et al. 2009). However, polymorphisms of the p53 (codon 72) (Mabrouk et al. 2003), the GSTT1 (Ouerhani et al. 2006) and the CYP2D6 (Ouerhani et al. 2008) genes did not appear to influence bladder cancer susceptibility.

Prostate Cancer (OMIM 176807) Prostate cancer (PCa) is the most frequent cancer among men in several industrialized countries. In Tunisia PCa is the fourth more frequent cancer with an incidence rate of 6.1/100,000 men. Like the majority of the cancers, PCa is a multifactorial disorder implying complex interactions among environmental, genetic, and dietary factors. Sfar et al. (2009b, 2006, 2007) assessed the implication of several angiogenic gene polymorphisms effects (individual and combined effects) on PCa susceptibility and progression and demonstrated that angiogenic gene polymorphisms increased markedly the risk of prostate cancer onset and aggressiveness. Indeed, a significant increased risk was associated with the VEGF-634 (GC þ CC) combined genotype and the VEGF-634C allele was associated with high histological grade. However, the VEGF-1154A/-634G haplotype was negatively associated with PCa risk and high tumor grade (Sfar et al. 2006) and no association was observed between the N700S TSP1 polymorphism and PCa risk or severity. Moreover, subjects carrying one copy of the MMP9-1562T allele exhibited a threefold higher risk of developing PCa. Regarding prognostic value, a significant association was found between the occurrence of the MMP9 T allele and the high-grade tumor and the advanced disease (Sfar et al. 2007). Combined effect analysis of the angiogenic gene polymorphisms (VEGF-1154G/A; VEGF-634G/C; MMP9-1562C/T) showed a significant gene-dosage effect for the increasing numbers of potential high-risk genotypes. Compared to referent group (low-risk genotypes), individuals with one (OR ¼ 2.79), two (OR ¼ 4.57) and three highrisk genotypes (OR ¼ 7.11) had increasingly elevated risks of prostate cancer (Sfar et al. 2009b). Cross-classified analysis revealed potential higher order gene– gene interactions between VEGF and TSP1 polymorphisms in increasing the risk of developing an aggressive phenotype disease. Patients carrying three high-risk genotypes showed a 20-fold increased risk of high-grade tumor (Sfar et al. 2009b).

21


629

Breast Cancer (OMIM 114480) In Tunisia like in the countries worldwide, breast cancer is the most frequent cancer among women. Several epidemiological studies about breast cancer have been carried out in Tunisia especially in the national institute of cancer of Salah-Azaiz (ISA). In order to update clinical and epidemiological profile of breast cancer Maalej et al. (2008) census of all new cases of breast cancer were diagnosed in Tunisia during the year 2004. During this period 1,437 new cases of invasive breast cancer were diagnosed. Most of the patients were women, with 1,408 women versus 29 men. The patients mean age was of 51 years and the highest incidence of breast cancer was between 40 and 54 years old. Compared to previous epidemiologic studies (Maalej et al. 1999), an increase in the incidence rate from the age of 40 years which continues until the age of 55 years was observed. Clinical feature revealed that the most frequent tumor stage were T2 in 46.9% cases, then T4 in 24.7% cases (T1 in 12.2% cases, T3 in 11.2% cases). Invasive ductal carcinoma was the most frequent (86.6%) with SBR II grade representing 54.5%. In Western countries, incidence of breast cancer and mortality are higher than in Mediterranean countries. Characteristics of breast cancer in patients from Lebanon, Tunisia and Morocco were more aggressive and patients were 10 years younger at diagnosis (Chalabi et al. 2008). Sixteen differentially expressed genes such as MMP9, VEGF, PHB1, BRCA1, TFAP2C, GJA1 and TFF1 were also found. This study strongly suggests the need to identify specific clinical and genetic features of patients from South Mediterranean countries. In hereditary breast carcinoma, mutations in highly penetrant genes such as BRCA1 or BRCA2 confer a high risk for developing breast carcinoma, though this risk accounts only for about 5–10% of all breast carcinoma cases. As most cases of breast cancer are not inherited (90–95%), it is suggested that the effect of low penetrance cancer susceptibility genes modulated by environmental exposure and lifestyle factors are likely to account for most of the sporadic breast carcinoma cases. In Tunisia, both high and low penetrant genes were studied. Recently, Troudi et al. (2007) published the spectrum of BRCA1 and BRCA2 mutations from 36 Tunisian index cases. Six deleterious mutations were identified four in BRCA1 and two in BRCA2. Among the six distinct mutations identified in this study, only one (c.211dupA) in BRCA1 (exon 5) had not been described previously. Moreover, Troudi et al. (2008) suggested that when breast/ovarian cancer cases are diagnosed in a Tunisian family the molecular analysis should be directed to sequencing the BRCA1 gene and exon 11 region of the BRCA2 gene. Moreover, when a male breast cancer is observed among relatives, the molecular analysis should be directed to sequencing the BRCA2 gene. Uhrhammer et al. (2008) observed a BRCA1 deleterious mutation (c.798–799delTT) in two Algerian families and in two families from Tunisia. These last observations, suggest a North African founder allele, and may be a common genetic profile that would be used as a novel criterion for analysis in the Northern African population. As sporadic cases of breast cancer are frequent in Tunisia, several case-control reports have identified genetic association with cancer risk and/ or aggressiveness (Baccar Harrath et al. 2006; Kharrat et al. 2007; Snoussi et al. 2005). For instance;

630


Khedhaier et al. (2003, 2008) studies assessed the implication of Xenobiotic Metabolizing Enzyme gene polymorphisms (GSTT1, GSTM1, CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) in sporadic breast cancer cases. Khedhaier et al. (2003) showed that the gene deletion of GSTs may predict the early onset of breast carcinoma, the clinical response to chemotherapy and the recurrence-free survival for patients with lymph node-negative breast carcinoma. Moreover, the mEH (C/C) mutant and the NAT2 slow acetylator genotypes were significantly associated with breast carcinoma risk, the CYP2D6 (G/G) wild type was associated with breast carcinoma risk only in postmenopausal patients, and significant differences in overall disease survival with the mEH gene polymorphisms (Khedhaier et al. 2008).

Nasopharyngeal Carcinoma (OMIM 161550) In Tunisia, the incidence of nasopharyngeal carcinoma (NPC) is about 3.5 per 100,000 inhabitants. There are some epidemiological and clinical differences between Asian and North African NPCs. The main difference relates to their age distribution, which is unimodal in China, with one single incidence peak seen at the age of around 50 years old, but bimodal in the Mediterranean area, with a main peak around 50 years (80% of patients) associated with a secondary peak in the range of 10–25 years (20% of patients) (Lombardi et al. 1982). As the incidence is restricted to some ethnic groups or certain geographical regions of the world, numerous etiological environmental factors associated to lifestyle and genetic factors might be responsible for this cancer. In recent years, great progress has been made in genetic research of familial and sporadic NPC cases. In Tunisia published studies were mainly conducted on sporadic cases of NPC. Serological analyses observed positive associations between NPC and HLA class I alleles. Numerous studies based on genetic analysis have indicated that specific human leukocyte antigen (HLA) haplotypes and genes within the HLA complex are associated with NPC (Hassen et al. 2010). Among Tunisians, direct sequencing of the HLA class I genes showed positive associations for HLA-B-18, -B51 and -B57 with NPC risk and allowed the identification a rare haplotype (HLA-B*1402/Cw*0802) in Tunisian patients with NPC (Li et al. 2007). Moreover, Makni et al. (2010) observed positive association for DRB1*03, DRB1*13 and DQB1*02 alleles with NPC. Moreover, nonHLA gene polymorphisms located on chromosome six, nearby or within the HLA class I loci was found to be associated with NPC. Indeed, a panel of positive associations has been described including TAP-1 gene (Hassen et al. 2007), MHC class I chain-related A (MICA) gene belonging to the nonclassical HLA family (Douik et al. 2009) and heat shock protein (HSP) gene located in 6p21.2–p23 (Jalbout et al. 2003). Furthermore, the association between age and NPC onset was demonstrated for several genes, such as HLA-class I, TAP-1, IL-18 promoter, IL-10 and IFN-g genes polymorphisms (Li et al. 2007; Farhat et al. 2008a, b; Hassen et al. 2007).

21


631

Colorectal Cancer (OMIM 114500) In Tunisia, Colorectal cancer (CRC) represents the first digestive cancer with an incidence of 7.4 new cases per 100,000 inhabitants per year. CRC is a multifactorial disease that involves environmental and genetic factors. CRC cases can present sporadic or more rarely hereditary form. Genetic studies on Tunisian cases of CRC are weak. The Bougatef et al. (2009) study conducted on Tunisian sporadic cases showed significant association between the I1307K, E1317Q and D1822V variants of the Adenomatous polyposis coli gene (APC) and CRC risk. Hereditary nonpolyposis CRC (HNPCC; OMIM 120435) is the most frequent cause of inherited CRC. It is caused by constitutional mutations in the DNA mismatch repair (MMR) genes. In a family with six patients diagnosed with a colorectal or an endometrial cancer at an early age, MMR gene analysis revealed the presence of a large deletion in MLH1 removing exon 6. This germline MLH1 rearrangement was associated to a severe phenotype (Aissi-Ben Moussa et al. 2009).

Conclusion After listing the above-described genetic disorders among Tunisians, it is clear that these diseases constitute a major national health problem. Some disorders occur in high frequencies causing suffering or handicaps leading most of the time to premature death. To limit the damages caused by genetic disorder in Tunisia, a better knowledge on the local risk factors are required. In fact, more data on the epidemiological and biological feature of each disease will allow the implementation of efficient prevention strategies. Epidemiological studies will permit to select a target population at high risk of disease incidence and genetic defects census will be useful for genetic counseling. In Tunisia, although insufficient, published reports on genetic disorders are markedly increasing. Seventy-two percent of the reports were published between 1997 and 2009. Some of these studies reported very useful data on specific mutational spectrum of some monogenic diseases in Tunisia. In Tunisia, there are national centers and laboratories that offer genetic counseling services. Unfortunately, this genetic service is only localized in the greatest urban region of Tunisia and needs to be expanded to cover a larger part of the Tunisian territory.

References Abdelmoula NB, Amouri A, Portnoi MF, Saad A, Boudawara T, Mhiri MN, Bahloul A, Rebai T (2004) Cytogenetics and fluorescence in situ hybridization assessment of sex-chromosome mosaicism in Klinefelter’s syndrome. Ann Genet 47:163–175 Aissi-Ben Moussa S, Moussa A, Lovecchio T, Kourda N, Najjar T, Ben Jilani S, El Gaaied A, Porchet N, Manai M, Buisine MP (2009) Identification and characterization of a novel MLH1

632


genomic rearrangement as the cause of HNPCC in a Tunisian family: evidence for a homologous Alu-mediated recombination. Fam Cancer 8:119–126 Al-Abdulkareem AA, Ballal SG (1998) Consanguineous marriage in an urban area of Saudi Arabia: rates and adverse health effects on the offspring. J Community Health 23:75–83 Al-Gazali LI, Bener A, Abdulrazzaq YM, Micallef R, al-Khayat AI, Gaber T (1997) Consanguineous marriages in the United Arab Emirates. J Biosoc Sci 29:491–497 Arfa I, Abid A, Malouche D, Ben Alaya N, Azegue TR, Mannai I, Zorgati MM, Ben Rayana MC, Ben Ammar S, Blousa-Chabchoub S, Ben Romdhane H, Zouari B, Dellagi MK, Abdelhak S (2007) Familial aggregation and excess maternal transmission of type 2 diabetes in Tunisia. Postgrad Med J 83:348–351 Ayadi H, Hadj Kacem H, Rebai A, Farid NR (2004) The genetics of autoimmune thyroid disease. Trends Endocrinol Metab 15:234–239 Ayed K, Gorgi Y, Ayed-Jendoubi S, Bardi R (2004) The involvement of HLA -DRB1*, DQA1*, DQB1* and complement C4A loci in diagnosing systemic lupus erythematosus among Tunisians. Ann Saudi Med 24:31–35 Baccar Harrath A, Yacoubi Loueslati B, Troudi W, Hmida S, Sedkaoui S, Dridi A, Jridi A, Ben Ayed F, Ben Rhomdhane K, Ben Ammar Elgaaied A (2006) HLA class II polymorphism: protective or risk factors to breast cancer in Tunisia? Pathol Oncol Res 12:79–81 Bayoumi RA, Nur-E-Kamal MS, Tadayyon M, Mohamed KK, Mahboob BH, Qureshi MM, Lakhani MS, Awaad MO, Kaeda J, Vulliamy TJ, Luzzatto L (1996) Molecular characterization of erythrocyte glucose-6-phosphate dehydrogenase deficiency in Al-Ain District, United Arab Emirates. Hum Hered 46:136–141 Belguith-Maalej S, Hadj-Kacem H, Kaddour N, Bahloul Z, Ayadi H (2010) DNase1 exon2 analysis in Tunisian patients with rheumatoid arthritis, systemic lupus erythematosus and Sjo¨gren syndrome and healthy subjects. Rheumatol Int 30:69–74 Belmahi L, Sefiani A, Fouveau C, Feingold J, Delpech M, Grateau G, Dode´ C (2006) Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever. C R Biol 329:71–74 Ben Abdelaziz A, Drissi L, Tlili H, Gaha K, Soltane I, Amrani R, Ghannemr H (2006) Epidemiologic and clinical features of patients with type 2 diabetes mellitus in primary care facilities (Sousse, Tunisie). Tunis Med 84:415–422 Ben Arab S, Hmani M, Denoyelle F, Boulila-Elgaied A, Chardenoux S, Hachicha S, Petit C, Ayadi H (2000) Mutations of GJB2 in three geographic isolates from northern Tunisia: evidence for genetic heterogeneity within isolates. Clin Genet 57:439–443 Ben Arab S, Masmoudi S, Beltaief N, Hachicha S, Ayadi H (2004) Consanguinity and endogamy in Northern Tunisia and its impact on non-syndromic deafness. Genet Epidemiol 27:74–79 Ben Hamida M, Attia N, Chaabouni H, Fardeau M (1983) Autosomal recessice severe, proximal myopathy in children, common in Tunisia. Rev Neurol 139:289–297 Ben Hamida C, Doerflinger N, Belal S, Linder C, Reutenauer L, Dib C, Gyapay G, Vignal A, Le Paslier D, Cohen D et al (1993) Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nat Genet 5:195–200 Ben Khalifa F, Mekaouar A, Taktak S, Hamhoum M, Jebara H, Kodia A, Zouari B, Chakroun M (1997) A five-year study of the incidence of insulin-dependent diabetesmellitus in young Tunisians (preliminary results). Diabetes Metab 23:395–401 Ben Othmane K, Ben Hamida M, Pericak-Vance MA, Ben Hamida C, Blel S, Carter SC, Am B, Petruhkin K, Gilliam TC, Ad R, Hentati F, Vance JM (1992) Linkage of Tunisian autosomal recessive Duchenne-like muscular dystrophy to the pericentromeric region of chromosome 13q. Nat Genet 2:315–317 Ben Rebeh I, Benzina Z, Dhouib H, Hadjamor I, Amyere M, Ayadi L, Turki K, Hammami B, Kmiha N, Kammoun H, Hakim B, Charfedine I, Vikkula M, Ghorbel A, Ayadi H, Masmoudi S (2008) Identification of candidate regions for a novel Usher syndrome type II locus. Mol Vis 14:1719–1726

21


633

Ben Rekaya M, Messaoud O, Talmoudi F, Nouira S, Ouragini H, Amouri A, Boussen H, Boubaker S, Mokni M, Mokthar I, Abdelhak S, Zghal M (2009) High frequency of the V548A fs X572 XPC mutation in Tunisia: implication for molecular diagnosis. J Hum Genet 54:426–429 Bener A, Hussain R (2006) Consanguineous unions and child health in the State of Qatar. Paediatr Perinat Epidemiol 20:372–378 Bienvenu T, Poirier K, Friocourt G, Bahi N, Beaumont D, Fauchereau F, Benjemaa L, Zemni R, Vinet MC, Francis F, Couvert P, Gomot M, Moraine C, Van Bokhoven H, Kalscheuer V, Frints S, Gecz J, Ohzaki K, Chaabouni H, Desportes V, Fryns JP, Beldjord C, Chelly J (2002) ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Hum Mol Genet 11:981–991 Blibech R, Gharbi Y, Mrad A, Zahra H, Mahjoub T, Belhaj A, Laatiri Z, Kastally R, Rosa R (1989) Incidence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Tunisian populations. Nouv Rev Fr Hematol 31:189–191 Bouchlaka C, Abdelhak S, Amouri A, Ben Abid H, Hadiji S, Frikha M, Ben Othman T, Amri F, Ayadi H, Hachicha M, Rebaı¨ A, Saad A, Dellagi K, Tunisian Fanconi Anemia Study Group (2003) Fanconi anemia in Tunisia: high prevalence of group A and identification of new FANCA mutations. J Hum Genet 48:352–361 Bougatef K, Marrakchi R, Ouerhani S, Sassi R, Moussa A, Kourda N, Blondeau Lahely Y, Najjar T, Ben Jilani S, Soubrier F, Ben Ammar Elgaaied A (2009) No evidence of the APC D1822V missense variant’s pathogenicity in Tunisian patients with sporadic colorectal cancer. Pathol Biol 57:67–71 Chaabouni H, Chaabouni M, Maazoul F, M’Rad R, Jemaa LB, Smaoui N, Terras K, Kammoun H, Belghith N, Ridene H, Oueslati B, Zouari F (2001) Prenatal diagnosis of chromosome disorders in Tunisian population. Ann Genet 44:99–104 Chaabouni HB, Ksantini M, M’rad R, Kharrat M, Chaabouni M, Maazoul F, Bahloul Z, Ben Jemaa L, Ben Moussa F, Ben Chaabane T, Mrad S, Touitou I, Smaoui N (2007) MEFV mutations in Tunisian patients suffering from familial Mediterranean fever. Semin Arthritis Rheum 36:397–401 Chaabouni-Bouhamed H (2008) Tunisia: communities and community genetics. Community Genet 11:313–323 Chakraborty P, Hadj Kacem H, Makni-Karray K, Jarraya F, Hachicha J, Ayadi H (2003) The A/T mutation in exon 2 of the DNASE1 gene is not present in Tunisian patients with systemic lupus erythematosus or in healthy subjects. Arthritis Rheum 48:3297–3298 Chalabi N, Bernard-Gallon DJ, Bignon YJ, Breast Med Consortium, Kwiatkowski F, Agier M, Vidal V, Laplace-Chabaud V, Sylvain-Vidal V, Bertholet V, De Longueville F, Lacroix M, Leclercq G, Remacle J, Sibille C, Zammateo N, Ben Jaafar N, Sefiani A, Ouldim K, Me´garbane´ K, Jalkh N, Mahfoudh W, Troudi W, Ben Ammar-El Gaıëd A, Chouchane L (2008) Comparative clinical and transcriptomal profiles of breast cancer between French and South Mediterranean patients show minor but significative biological differences. Cancer Genomics Proteomics 5:253–261 Chalbi N, Zakaria D (1998) Models of family, endogamy and consanguinity in Tunis. Essais de mesure Famille et population 1:39–59 Chelli D, Dimassi K, Chaabouni M, Ben Saad M, Mssaed H, Bchir F, Zouaoui B, Sfar E, Gaigi S, Chelli H, Chanoufi B (2008) Prenatal diagnosis of trisomy 21: the Tunisian experience. Sante 18:199–203 Chibani J, Vidaud M, Duquesnoy P, Berge´-Lefranc JL, Pirastu M, Ellouze F, Rosa J, Goossens M (1988) The peculiar spectrum of b-thalassemia genes in Tunisia. Hum Genet 78:190–192 Chouk I, Daoud BB, Mellouli F, Bejaoui M, Ge´rard N, Dellagi K, Abbes S (2004) Contribution to the description of the beta-thalassemia spectrum in Tunisia and the origin of mutation diversity. Hemoglobin 28:189–195 Daoud BB, Mosbehi I, Pre´hu C, Chaouachi D, Hafsia R, Abbes S (2008) Molecular characterization of erythrocyte glucose-6-phosphate dehydrogenasedeficiency in Tunisia. Pathol Biol 56:260–267

634


Denoyelle F, Weil D, Maw MA, Wilcox SA, Lench NJ, Allen-Powell DR, Osborn AH, Dahl HH, Middleton A, Houseman MJ, Dode´ C, Marlin S, Boulila-El Gaıëd A, Grati M, Ayadi H, BenArab S, Bitoun P, Lina-Granade G, Godet J, Mustapha M, Loiselet J, El-Zir E, Aubois A, Joannard A, Petit C (1997) Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet 6:2173–2177 Douik H, Ben Chaaben A, Attia Romdhane N, Romdhane HB, Mamoghli T, Fortier C, Boukouaci W, Harzallah L, Ghanem A, Gritli S, Makni M, Charron D, Krishnamoorthy R, Guemira F, Tamouza R (2009) Association of MICA-129 polymorphism with nasopharyngeal cancer risk in a Tunisian population. Hum Immunol 70:45–48 Farhat K, Hassen E, Bouzgarrou N, Gabbouj S, Bouaouina N, Chouchane L (2008a) Functional IL-18 promoter gene polymorphisms in Tunisian nasopharyngeal carcinoma patients. Cytokine 43:132–137 Farhat K, Hassen E, Gabbouj S, Bouaouina N, Chouchane L (2008b) Interleukin-10 and interferon-gamma gene polymorphisms in patients with nasopharyngeal carcinoma. Int J Immunogenet 35:197–205 Fattoum S (2006) Hemoglobinopathies in Tunisia. An updated review of the epidemiologic and molecular data. Tunis Med 84:687–696 Fattoum S, Guemira F, Oner C, Oner R, Li HW, Kutlar F, Huisman TH (1991) Beta-thalassemia, HB S-beta-thalassemia and sickle cell anemia among Tunisians. Hemoglobin 15:11–21 Fredj SH, Messaoud T, Templin C, Des Georges M, Fattoum S, Claustres M (2009) Cystic fibrosis transmembrane conductance regulator mutation spectrum in patients with cystic fibrosis in Tunisia. Genet Test Mol Biomarkers 13:577–581 Gouider-Khouja N, Belal S, Hamida MB, Hentati F (2000) Clinical and genetic study of familial Parkinson’s disease in Tunisia. Neurology 54:1603–1609 Gozukara EM, Khan SG, Metin A, Emmert S, Busch DB, Shahlavi T, Coleman DM, Miller M, Chinsomboon N, Stefanini M, Kraemer KH (2001) A stop codon in xeroderma pigmentosum group C families in Turkey and Italy: molecular genetic evidence for a common ancestor. J Invest Dermatol 117:197–204 Guilford P, Ayadi H, Blanchard S, Chaib H, Le Paslier D, Weissenbach J, Drira M, Petit C (1994a) A human gene responsible for neurosensory, non-syndromic recessive deafness is a candidate homologue of the mouse sh-1 gene. Hum Mol Genet 3:989–993 Guilford P, Ben Arab S, Blanchard S, Levilliers J, Weissenbach J, Belkahia A, Petit C (1994b) A non-syndrome form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nat Genet 6:24–28 Haj Khelil A, Laradi S, Miled A, Omar Tadmouri G, Ben Chibani J, Perrin P (2004) Clinical and molecular aspects of haemoglobinopathies in Tunisia. Clin Chim Acta 340:127–137 Hamamy H, Jamhawi L, Al-Darawsheh J, Ajlouni K (2005) Consanguineous marriages in Jordan: why is the rate changing with time? Clin Genet 67:511–516 Hassen E, Farhat K, Gabbouj S, Jalbout M, Bouaouina N, Chouchane L (2007) TAP1 gene polymorphisms and nasopharyngeal carcinoma risk in a Tunisian population. Cancer Genet Cytogenet 175:41–46 Hassen E, Ghandri N, Bouaouina N, Chouchane L (2010) The human leukocyte antigen class I genes in nasopharyngeal carcinoma risk. Mol Biol Rep 37:119–126 Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26:163–175 Hsairi M, Fakhfakh R, Ben Abdallah M, Jlidi R, Sellami A, Zheni S, Hmissa S, Achour N, Nacef T (2002) Assessment of cancer incidence in Tunisia 1993–1997. Tunis Med 80:57–64 Jalbout M, Bouaouina N, Gargouri J, Corbex M, Ben Ahmed S, Chouchane L (2003) Polymorphism of the stress protein HSP70-2 gene is associated with thesusceptibility to the nasopharyngeal carcinoma. Cancer Lett 193:75–81 Jemaa LB, des Portes V, Zemni R, Mrad R, Maazoul F, Beldjord C, Chaabouni H, Chelly J (1999) Refined 2.7 centimorgan locus in Xp21.3–22.1 for a nonspecific X-linked mental retardation gene (MRX54). Am J Med Genet 85:276–282

21


635

Jenhani F, Bardi R, Ayed K, Chammakhi S, Jeddi M, Labonne MP, Gebuhrer L, Betuel H (1990) Extended HLA haplotypes in multiplex families with insulin dependent diabetes mellitus in Tunisian population: HLA serological typing and RFLP analysis. Dis Markers 8:327–331 Kammoun I, Chaabouni M, Trabelsi M, Ouertani I, Kraoua L, Chelly I, M’rad R, Ben Jemaa L, Maaˆzoul F, Chaabouni H (2008) Ann Endocrinol (Paris) 69:440–445 Kefi M, Amouri R, Driss A, Ben Hamida C, Ben Hamida M, Kunkel LM, Hentati F (2003) Phenotype and sarcoglycan expression in Tunisian LGMD 2C patients sharing the same del521T mutation. Neuromuscul Disord 13:779–787 Kerkeni E, Monastiri K, Saket B, Guediche MN, Ben Cheikh H (2007) Interplay of socioeconomic factors, consanguinity, fertility, and offspring mortality in Monastir, Tunisia. Croat Med J 48:701–707 Khan SG, Oh KS, Shahlavi T, Ueda T, Busch DB, Inui H, Emmert S, Imoto K, Muniz-Medina V, Baker CC, DiGiovanna JJ, Schmidt D, Khadavi A, Metin A, Gozukara E, Slor H, Sarasin A, Kraemer KH (2006) Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients. Carcinogenesis 27:84–94 Kharrat M, Tardy V, M’Rad R, Maazoul F, Jemaa LB, Refaı¨ M, Morel Y, Chaabouni H (2004) Molecular genetic analysis of Tunisian patients with a classic form of 21-hydroxylase deficiency: identification of four novel mutations and high prevalence of Q318X mutation. J Clin Endocrinol Metab 89:368–374 Kharrat M, Tardy V, M’rad R, Maazoul F, Morel Y, Chaabouni H (2005) A novel 13-bp deletion in exon 1 of CYP21 gene causing severe congenital adrenal hyperplasia. Diagn Mol Pathol 14:250–252 Kharrat N, Al’Fadhli S, Rebai M, Aifa MS, Kallel I, Khabir A, Sellami-Boudawara T, Frikha M, Rebai A (2007) (AC) dinucleotide repeat polymorphism in intron 1 of human EGFR shows ethnic specificities and high evidence for association with breast cancer. Int J Biol Markers 22:258–264 Khedhaier A, Remadi S, Corbex M, Ahmed SB, Bouaouina N, Mestiri S, Azaiez R, Helal AN, Chouchane L (2003) Glutathione S-transferases (GSTT1 and GSTM1) gene deletions in Tunisians: susceptibility and prognostic implications in breast carcinoma. Br J Cancer 89:1502–1507 Khedhaier A, Hassen E, Bouaouina N, Gabbouj S, Ahmed SB, Chouchane L (2008) Implication of Xenobiotic Metabolizing Enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) polymorphisms in breast carcinoma. BMC Cancer 18:109 Khemir S, Tebib N, Nasrallah F, Ben Nour F, Mizouni H, Elasmi M, Sanhaji H, Jemaa R, Feki M, Ben Dridi MF, Mebazaa A, Kaabachi N (2009) Phenylketonuria in Tunisian institutions for the mentally handicapped. Arch Dis Child 94:647–648 Khlat M (1988) Consanguineous marriage and reproduction in Beirut, Lebanon. Am J Hum Genet 43:188–196 Kifagi C, Makni K, Mnif F, Boudawara M, Hamza N, Rekik N, Abid M, Rebaı¨ A, Granier C, Jarraya F, Ayadi H (2008) Association of calpain-10 polymorphisms with type 2 diabetes in the Tunisian population. Diabetes Metab 34:273–278 Lambert JC, Pasquier F, Cottel D, Frigard B, Amouyel P, Chartier-Harlin MC (1998) A new polymorphism in the APOE promoter associated with risk of developing Alzheimer’s disease. Hum Mol Genet 7:533–540 Li X, Ghandri N, Piancatelli D, Adams S, Chen D, Robbins FM, Wang E, Monaco A, Selleri S, Bouaouina N, Stroncek D, Adorno D, Chouchane L, Marincola FM (2007) Associations between HLA class I alleles and the prevalence of nasopharyngeal carcinoma (NPC) among Tunisians. J Transl Med 5:22 Lombardi F, Gasparini M, Gianni C, De Marie M, Molinari R, Pilotti S (1982) Nasopharyngeal carcinoma in childhood. Med Pediatr Oncol 10:243–250 Louhichi N, Triki C, Quijano-Roy S, Richard P, Makri S, Me´ziou M, Estournet B, Mrad S, Romero NB, Ayadi H, Guicheney P, Fakhfakh F (2004) New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families. Neurogenetics 5:27–34

636


Louhichi N, Richard P, Triki CH, Meziou M, Ayadi H, Guicheney P, Fakhfakh F (2006) Novel mutations in LAMA2 gene responsible for a severe phenotype of congenital muscular dystrophy in two Tunisian families. Arch Inst Pasteur Tunis 83:19–23 Maalej M, Frikha H, Ben Salem S, Daoud J, Bouaouina N, Ben Abdallah M, Ben Romdhane K (1999) Le cancer du sein en Tunisie: e´tude clinique et e´pide´miologique. Bull Cancer 86:302–306 Maalej A, Makni H, Ayadi F, Bellassoued M, Jouida J, Bouguacha N, Abid M, Ayadi H (2001) A full genome screening in a large Tunisian family affected with thyroid autoimmune disorders. Genes Immun 2:71–75 Maalej M, Hentati D, Messai T, Kochbati L, El May A, Mrad K, Romdhane KB, Ben Abdallah M, Zouari B (2008) Breast cancer in Tunisia in 2004: a comparative clinical and epidemiological study. Bull Cancer 95:5–9 Mabrouk I, Baccouche S, El-Abed R, Mokdad-Gargouri R, Mosbah A, Saı¨d S, Daoud J, Frikha M, Jlidi R, Gargouri A (2003) No evidence of correlation between p53 codon 72 polymorphism and risk of bladder or breast carcinoma in Tunisian patients. Ann N Y Acad Sci 1010:764–770 Mahindra P, DiGiovanna JJ, Tamura D, Brahim JS, Hornyak TJ, Stern JB, Lee CC, Khan SG, Brooks BP, Smith JA, Driscoll BP, Montemarano AD, Sugarman K, Kraemer KH (2008) Skin cancers, blindness, and anterior tongue mass in African brothers. J Am Acad Dermatol 59:881–886 Majeed HA, El-Khateeb M, El-Shanti H, Rabaiha ZA, Tayeh M, Najib D (2005) The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum 34:813–818 Makni H, Daoud J, Ben Salah H, Mahfoudh N, Haddar O, Karray H, Boudawara T, Ghorbel A, Khabir A, Frikha M (2010) HLA association with nasopharyngeal carcinoma in southern Tunisia. Mol Biol Rep PMID:19714482 (in press) Makni K, Mnif F, Boudawara M, Hamza N, Rekik N, Abid M, Rebaı¨ A, Jarraya F, Granier C, Ayadi H (2008) Association of glucose transporter 1 polymorphisms with type 2 diabetes in the Tunisian population. Diabetes Metab Res Rev 24:544–548 Mehri S, Koubaa N, Nakbi A, Hammami S, Chaaba R, Mahjoub S, Zouari B, Abid M, Arab SB, Baudin B, Hammami M (2009) Relationship between genetic polymorphisms of angiotensinconverting enzyme and methylenetetrahydrofolate reductase as risk factors for type 2 diabetes in Tunisian patients. Clin Biochem 43:259–266 Messaoud T, Bel Haj Fredj S, Bibi A, Elion J, Fe´rec C, Fattoum S (2005) Molecular epidemiology of cystic fibrosis in Tunisia. Ann Biol Clin 63:627–630 Mrad R, Dorboz I, Ben Jemaa L, Maazoul F, Trabelsi M, Chaabouni M, Mlaiki B, Miladi N, Hentati F, Chaabouni H (2006) Molecular analysis of the SMN1 and NAIP genes in 60 Tunisian spinal muscular atrophy patients. Tunis Med 84:465–469 Nafa K, Reghis A, Osmani N, Baghli L, Benabadji M, Kaplan JC, Vulliamy TJ, Luzzatto L (1993) G6PD Aures: a new mutation (48 Ile>Thr) causing mild G6PD deficiency is associated with favism. Hum Mol Genet 2:81–82 Niazi GA, Adeyokunnu A, Westwood B, Beutler E (1996) Neonatal jaundice in Saudi newborns with G6PD Aures. Ann Trop Paediatr 16:33–37 Nishigori C, Zghal M, Yagi T, Imamura S, Komoun MR, Takebe H (1993) High prevalence of the point mutation in exon 6 of the xeroderma pigmentosum group A-complementing (XPAC) gene in xeroderma pigmentosum group A patients in Tunisia. Am J Hum Genet 53:1001–1006 Nishioka K, Kefi M, Jasinska-Myga B, Wider C, Vilarino-Guell C, Ross OA, Heckman MG, Middleton LT, Ishihara-Paul L, Gibson RA, Amouri R, Yahmed SB, Sassi SB, Zouari M, Euch GE, Farrer MJ, Hentati F (2010) A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson disease. J Neurol Neurosurg Psychiatry PubMed PMID: 19726410 (in press) Ouerhani S, Tebourski F, Slama MR, Marrakchi R, Rabeh M, Hassine LB, Ayed M, Elgaaıëd AB (2006) The role of glutathione transferases M1 and T1 in individual susceptibility to bladder cancer in a Tunisian population. Ann Hum Biol 33:529–535

21


637

Ouerhani S, Oliveira E, Marrakchi R, Ben Slama MR, Sfaxi M, Ayed M, Chebil M, Amorim A, El Gaaied AB, Prata MJ (2007) Methylenetetrahydrofolate reductase and methionine synthase polymorphisms and risk of bladder cancer in a Tunisian population. Cancer Genet Cytogenet 176:48–53 Ouerhani S, Marrakchi R, Bouhaha R, Ben Slama MR, Sfaxi M, Ayed M, Chebil M, El Gaaied AB (2008) The role of CYP2D6*4 variant in bladder cancer susceptibility in Tunisian patients. Bull Cancer 95:1–4 Ouerhani S, Rouissi K, Marrakchi R, Ben Slama MR, Sfaxi M, Chebil M, ElGaaied AB (2009) Combined effect of NAT2, MTR and MTHFR genotypes and tobacco on bladder cancer susceptibility in Tunisian population. Cancer Detect Prev 32:395–402 Ouragini H, Cherif F, Daoud W, Kassar S, Charfeddine C, Rebaı¨ A, Boubaker S, Ben OsmanDhahri A, Abdelhak S (2008) Haplotypic classification of dystrophic epidermolysis bullosa in Tunisian consanguineous families: implication for diagnosis. Arch Dermatol Res 300:365–370 Ouragini H, Cherif F, Kassar S, Floriddia G, Pascucci M, Daoud W, Osman-Dhahri AB, Boubaker S, Castiglia D, Abdelhak S (2009) Dystrophic epidermolysis bullosa phenotypes in a large consanguineous Tunisian family. J Dermatol Sci 54:114–120 Piscopo P, Manfredi A, Malvezzi-Campeggi L, Crestini A, Spadoni O, Cherchi R, Deiana E, Piras MR, Confaloni A (2006) Genetic study of Sardinian patients with Alzheimer’s disease. Neurosci Lett 398:124–128 Raygani AV, Zahrai M, Raygani AV, Doosti M, Javadi E, Rezaei M, Pourmotabbed T (2005) Association between apolipoprotein E polymorphism and Alzheimer disease in Tehran, Iran. Neurosci Lett 375:1–6 Rejeb I, Saillour Y, Castelnau L, Julien C, Bienvenu T, Taga P, Chaabouni H, Chelly J, Ben Jemaa L, Bahi-Buisson N (2008) A novel splice mutation in PAK3 gene underlying mental retardation with neuropsychiatric features. Eur J Hum Genet 16:1358–1363 Richard P, Gaudon K, Haddad H, Ammar AB, Genin E, Bauche´ S, Paturneau-Jouas M, M€ uller JS, Lochm€uller H, Grid D, Hamri A, Nouioua S, Tazir M, Mayer M, Desnuelle C, Barois A, Chabrol B, Pouget J, Koenig J, Gouider-Khouja N, Hentati F, Eymard B, Hantaı¨ D (2008) The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa. Neurology 71:1967–1972 Riou S, El Younsi C, Chaabouni H (1989) Consanguinite´ dans la population du nord de la Tunisie. Tunis Med 67:167–172 Sfar S, Hassen E, Saad H, Mosbah F, Chouchane L (2006) Association of VEGF genetic polymorphisms with prostate carcinoma risk and clinical outcome. Cytokine 35:21–28 Sfar S, Saad H, Mosbah F, Gabbouj S, Chouchane L (2007) TSP1 and MMP9 genetic variants in sporadic prostate cancer. Cancer Genet Cytogenet 172:38–44 Sfar S, Abid A, Mahfoudh W, Ouragini H, Ouechtati F, Abdelhak S, Chouchane L (2009a) Genetic analysis of hereditary multiple exostoses in Tunisian families: a novel frame-shift mutation in the EXT1 gene. Mol Biol Rep 36:661–667 Sfar S, Saad H, Mosbah F, Chouchane L (2009b) Combined effects of the angiogenic genes polymorphisms on prostate cancer susceptibility and aggressiveness. Mol Biol Rep 36:37–45 Siala O, Kammoun Feki F, Louhichi N, Hadj Salem I, Gribaa M, Elghzel H, Saad A, Triki C, Fakhfakh F (2008) Molecular prenatal diagnosis of muscular dystrophies in Tunisia and postnatal follow-up role. Genet Test 12:581–586 Slor H, Batko S, Khan SG, Sobe T, Emmert S, Khadavi A, Frumkin A, Busch DB, Albert RB, Kraemer KH (2000) Clinical, cellular, and molecular features of an Israeli xeroderma pigmentosum family with a frameshift mutation in the XPC gene: sun protection prolongs life. J Invest Dermatol 115:974–980 Smach MA, Charfeddine B, Lammouchi T, Harrabi I, Ben Othman L, Dridi H, Bennamou S, Limem K (2008) CSF beta-amyloid 1-42 and tau in Tunisian patients with Alzheimer’s disease: the effect of APOE epsilon4 allele. Neurosci Lett 440:145–149 Snoussi K, Strosberg AD, Bouaouina N, Ben Ahmed S, Chouchane L (2005) Genetic variation in pro-inflammatory cytokines (interleukin-1beta, interleukin-1alpha and interleukin-6)

638


associated with the aggressive forms, survival, and relapse prediction of breast carcinoma. Eur Cytokine Netw 16:253–260 Stayoussef M, Benmansour J, Al-Jenaidi FA, Nemr R, Ali ME, Mahjoub T, Almawi WY (2009) Influence of common and specific HLA-DRB1/DQB1 haplotypes on genetic susceptibilities of three distinct Arab populations to type 1 diabetes. Clin Vaccine Immunol 16: 136–138 Teebi AS, Al-Awadi SA, Farag TI, Naguib KK, el-Khalifa MY (1987) Phenylketonuria in Kuwait and Arab countries. Eur J Pediatr 146:59–60 Tlili A, Masmoudi S, Dhouib H, Bouaziz S, Rebeh IB, Chouchen J, Turki K, Benzina Z, Charfedine I, Drira M, Ayadi H (2007) Localization of a novel autosomal recessive nonsyndromic hearing impairment locus DFNB63 to chromosome 11q13.3-q13.4. Ann Hum Genet 71:271–275 Troudi W, Uhrhammer N, Sibille C, Dahan C, Mahfoudh W, Bouchlaka Souissi C, Jalabert T, Chouchane L, Bignon YJ, Ben Ayed F, Ben Ammar Elgaaied A (2007) Contribution of the BRCA1 and BRCA2 mutations to breast cancer in Tunisia. J Hum Genet 52:915–920 Troudi W, Uhrhammer N, Romdhane KB, Sibille C, Amor MB, Khodjet El Khil H, Jalabert T, Mahfoudh W, Chouchane L, Ayed FB, Bignon YJ, Elgaaied AB (2008) Complete mutation screening and haplotype characterization of BRCA1 gene in Tunisian patients with familial breast cancer. Cancer Biomark 4:11–8 Uhrhammer N, Abdelouahab A, Lafarge L, Feillel V, Ben Dib A, Bignon YJ (2008) BRCA1 mutations in Algerian breast cancer patients: high frequency in young, sporadic cases. Int J Med Sci 5:197–202 Warren L, Gibson R, Ishihara L, Elango R, Xue Z, Akkari A, Ragone L, Pahwa R, Jankovic J, Nance M, Freeman A, Watts RL, Hentati F (2008) A founding LRRK2 haplotype shared by Tunisian, US, European and Middle Eastern families with Parkinson’s disease. Parkinsonism Relat Disord 14:77–80 Zghal M, Fazaa B, Kamoun MR (2006) Xeroderma pigmentosum. EMC (Elsevier SAS, Paris). Dermatologie 10:98–660 Zorai A, Harteveld CL, Bakir A, Van Delft P, Falfoul A, Dellagi K, Abbes S, Giordano PC (2002) Molecular spectrum of alpha-thalassemia in Tunisia: epidemiology and detection at birth. Hemoglobin 26:353–362 Zouari Bouassida K, Chouchane L, Jellouli K, Che´rif S, Haddad S, Gabbouj S, Danguir J (2004) Polymorphism of stress protein HSP70-2 gene in Tunisians: susceptibility implications in type 2 diabetes and obesity. Diabetes Metab 30:175–180

Chapter 22

Genetic Disorders in the United Arab Emirates Lihadh Al-Gazali and Bassam R. Ali

The Country and Population The United Arab Emirates (UAE) was founded in 1971 as a federation of seven emirates on the Arabian Gulf. It is bounded by Qatar on the northwest, Saudi Arabia on the west and southwest, Oman on the east and northeast, and the Arabian Gulf on the north. It occupies an area of 83,600 km2 and Abu Dhabi is the capital of the state. Six of the emirates lie on the southern shore of the Arabian Gulf and present a continuous coastline stretching some 600 km. The six emirates in geographical order from west to east are Abu Dhabi (which comprises 87% of the entire area of the UAE), Dubai, Sharjah, Ajman, Um Al-Quween, and Ras Al Khaimah. Fujairah is the only emirate without a coastline on the Arabian Gulf; it lies entirely on the Gulf of Oman. The UAE population was 1,043,225 in 1980 according to the 1980 population census. Since then, the population almost doubled every 10 years to reach 2,011,400 in 1992 and 3,750,000 in 2002. Currently, the population is estimated to be 5.3 million. The growth rate varied considerably from year to year with an annual growth of 5.9%. About 30% of the growth was due to natural increase and the rest due to inflow of expatriates (Alwash and Abbas 1999).

Population History The ancestors of this tribal population have not always lived in this region. They took possession of this land during successive waves of population movement, which brought Arab tribes from Yemen by way of Oman as well as by way of L. Al-Gazali (*) Department of Paediatrics, Faculty of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates e-mail: [email protected]


639

640

L. Al-Gazali and B.R. Ali

Central and Northern Arabia. They would have found people already settled in the economically viable locations, and there were probably some nomadic groups here as well, combining herding, hunting, and fishing (Heard-Bay 1999). There is in fact archaeological evidence of fairly well to do communities who lived in the area as far as 5,000 years ago. The descendants of this original population were probably absorbed, although some were for a long time identifiable as separate communities particularly in the mountains of Oman (Heard-Bay 1976). The local society was and is still tribal in nature. This implies that every individual in the society belongs to one of the 70 tribes which can now be identified in the UAE. This also means that traditionally his or her existence was largely regulated by the tribal community. Through the tribe and its hierarchy, the individual had protection, and the system also served as a strong defense for small, weak groups on their own in the desert. The tribe also provides economic security for individuals and within the family, and tribal unit tasks as well as resources are shared. The traditional tribal system even makes a young man’s choice of his bride largely unnecessary because he had in any case a first option for the daughter of his paternal uncle (Heard-Bay 1999). Most marriages were between close relatives to guarantee the continuity of the economic unity of the family (Heard-Bay 1976). Thus before the advent of oil, the entire population formed one homogenous society. Significant intermixing has probably only occurred with adjacent Arabs of the peninsula and with Persians and East Africans of the Omani Empire territories. Persian intermixing resulted from the alternating Arab and Persian domination of both coasts of the Arabian Gulf (Abdulla 1978). The slave traffic from Africa resulted in many blacks later being absorbed into the local community (Ramahi 1973). There has also been continuous exodus of Baluchis to Oman and the UAE. These people originate from Baluchistan which is across the Strait of Hormuz and are now in Iran, Afghanistan, and Pakistan. These people have a history that goes back over 2,000 years. In fact, attention has been drawn to the earliest inhabitants of Baluchistan, who moved across the gulf to Arabia after being defeated by Iranian Gedrasians sometime before Alexander’s conquest (Quaife et al. 1994). Although many of the Baluchis are now UAE nationals, they remain isolated with high level of inbreeding. Many do not speak Arabic and do not send their female children to school and therefore form very isolated communities.

Current Population Currently after several decades of immigration by foreign experts and laborers, the UAE society as a whole is anything but homogenous. It consists of, in addition to the original local population, a mixture of immigrants from Oman, Yemen, other Middle Eastern countries, North Africa, Iran, India, Pakistan, Bangladesh, Baluchistan, and Europe. Intermarriages with these immigrants are limited but increasing, although the majority of the Bedouins still form tribal communities which are

22

Genetic Disorders in the United Arab Emirates

641

quite isolated. Belonging to a well respected local tribe or an influential family is still of prime importance in today’s local society. Because of the large number of expatriates, the population pyramid in the UAE shows a unique composition. It has a normal base during childhood, and then the pyramid broadens in the age group 20–50 years (mainly males) constituting about 42.8% of the whole population. This feature is mainly due to the influx of young expatriate male workers. The pyramid gets narrower as the age exceeds 50 years constituting less than 2% of the population above 60 years (Alwash and Abbas 1999). The local population is also characterized by a consistently high fertility rate which is considered desirable by the government and various measures are in place to encourage fertility among the national population. The government does not support the provision of contraception, but there are no major limits on access to birth control options except abortion which is illegal (Annual Report Ministry of Health 1993). The family size is therefore large with an average of five children per family. Women continue to reproduce well after the age of 40 years and men well into their 60s. There has been steady decline in the death rate among nationals for all age groups, which is reflected in longer life expectancy, currently estimated at 74 years for males and 76 years for females. There has also been a significant decline in mortality among infants and children under 5 years of age which reached 8.19/ 1,000 and 10.5/1,000, respectively, in 2,000. With the decreasing incidence of child and infant mortality, congenital and hereditary diseases are receiving increased attention especially as such problems have been recorded as the fourth leading cause of death in the country during the last decade (Annual Report, Ministry of Health 2000).

Consanguinity The rate of consanguineous marriages in the UAE is high, estimated at 50.5% and the average coefficient of inbreeding up to second cousin is 0.0222 (Al-Gazali et al. 1997). The commonest type of consanguineous marriages is first cousin (26%). Furthermore, type 1 (paternal) first cousin constitutes 17% of all marriages and 64% of first cousin marriages. This is similar to that in other Arab countries and reflects the cultural practice among the Arab families of consulting with paternal uncles before accepting the marriage of a girl from a non-consanguineous partner (Al-Gazali et al. 1997). Other types of consanguineous marriages include double first cousin (3.5%), first cousin once removed (3.1%) and second cousin (3%) (Al-Gazali et al. 1997). There are also families with very complex consanguinity with very high coefficient of inbreeding particularly among the Bedouins and other isolates like Baluchis and Yemenis. The custom of consanguineous marriage is due to cultural and historical, rather than religious reasons. Such marriages are considered to be more stable and economically beneficial, through the maintenance of family fortune within the

642


family structure. This tradition is deeply rooted in the Arab culture and therefore is very difficult to change and is in fact, increasing rather than decreasing (Al-Gazali et al. 1997). The reason for this trend is not known, but a recent study assessing the attitude of the population toward consanguinity showed that the majority of people in this country still prefer this type of marriage for themselves and their children (Al-Gazali 2005).

Genetic Services In spite of the high frequency of genetic disorders in the UAE, genetic services are still fragmented and not very well established. Currently genetic services are provided by three centers. The first one is the Genetic and Thalassemia Center which is based in Dubai and was established by the Dubai Department of Health in 1989. This center provides services for thalassemia patients from all over the UAE. It is supported by cytogenetic, molecular, and biochemical diagnostic laboratories. The second one is based in Al-Ain in the Faculty of Medicine and Health Sciences (FMHS). It was established in 1990 and also provides service for patients from all Emirates. It is supported by a small cytogenetics laboratory and a developing molecular genetics laboratory. The third service is located in Abu Dhabi and it is under the Maternity and Child Health Department of the Ministry of Health. It was established in 1999 and the service is provided through two genetic clinics located in two primary health care centers supported by a cytogenetics laboratory. Genetic counseling in the three genetic centers is provided by clinical geneticists (three in total) who are not supported by genetic counselors, health visitors, or social workers. Premarital genetic counseling, mainly for thalassemia and sickle cell anemia, is also offered at the two primary health care centers in Abu Dhabi where the genetic clinics are run. Premarital testing for these disorders is currently compulsory. However, there are no options available for carriers as prenatal diagnosis is still not widely available and abortion is still not legal in this country. National screening for phenylketonuria (since 1995) and congenital hypothyroidisim (since 1998) is provided by the Maternity and Child Health Department. Sickle cell anemia screening at birth was added in 2001 in Abu Dhabi Emirate and implemented at the national level in 2005. Congenital adrenal hyperplasia screening program was initiated in 2005 in Abu Dhabi and implemented at the national level in 2007. The Maternity and Child Health Department also run a national registry for congenital abnormalities which was established in 2000, and a national registry for genetic diseases which was established in 2002. In addition, a registry for birth defects covering Al Ain Medical District was established in 1995 by members at the FMHS which subsequently became a member of the International Clearing House for Birth Defects (ICBD).

22


643

Prenatal diagnosis service in general is not well established in the UAE as abortion is still not legal in this country. Antenatal diagnosis of fetal anomalies by ultrasonography is offered in Al Ain and Dubai and amniocentesis is also done in some cases in these centers. Chorionic villus sampling is not currently available but it is being developed in Al Ain. However, as there are no options available for couples, the benefits of prenatal diagnosis in the UAE remain questionable. A genetic interest group “Genetic and Development Research Priority Group” was formed at the FMHS in 2002. The mission of the group is to provide the highest quality patient care, research into genetic diseases, and education of both professionals and the public. In addition, the newly formed National Research Foundation will fund a research center of excellence in “Genes and Diseases” based at FMHS. In 2003, a new initiative by Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences resulted in the establishment of the “Center for Arab Genomic Studies” in Dubai. The main objectives of this center are (1) to raise public awareness on the importance of genetic diseases in the Arab world, (2) to identify disease causing genes in the Arab population, (3) to develop a database of genetic diseases prevalent in the Arab world, (4) to prevent genetic diseases by providing comprehensive genetic services, and (5) to develop a center of excellence in Dubai for genetic research and clinical services in the Arab world. This project is still in its early stages of implementation but a database of genetics diseases in Arab populations has been established and is available to the public. The government is committed to provide children with special needs and handicapped individuals the education and care they require and therefore several centers for this purpose have been established in the country. However, apart from the Thalassemia and the Down Syndrome Associations there are no patients or parents associations or support groups in this country, and this issue needs to be addressed.

Genetic Disorders in the UAE Genetic diseases are an important cause of morbidity and mortality in the UAE. According to the Ministry of Health Annual Report 2002, birth defects are the fourth cause of death in the UAE. In addition, the UAE is currently ranked 6th out of 193 countries in terms of prevalence of birth defects, mainly as a result of genetic causes (Christianson et al. 2006). More than 270 genetic diseases have been reported in the UAE population with about 60% of those diseases being autosomal recessive (Fig. 22.1). The epidemiology of genetic disorders in the UAE is especially complicated as many families and tribal groups have descended from a limited number of main ancestors and the disease genes present reflect the sample carried by the founding members. Therefore, some conditions are confined to specific villages, families, and tribal groups. This has lead to the fact that some groups have unusual burden of genetic diseases while others are free of genetic diseases. On the other hand, there

644


Fig. 22.1 Number and classification of genetic disorders reported in UAE population. Data compiled from CTGA database of the Center for Arab Genomic Studies (www.cags.org.ae). Accessed on 24/02/2009

are certain disorders which are common throughout the UAE like the thalassemias and hemoglobinopathies and G6PD deficiency. In addition, different congenital malformations caused by recessive genes and several metabolic disorders are also common across the UAE.

b-Thalassemia b-Thalassemia constitutes a major health problem in the UAE. There are no accurate data regarding the exact b-thalassemia frequency in the country; nevertheless, between 1989 and 2003, more than 850 patients have been registered at the Dubai Genetic and Thalssemia Center (Baysal 2005). However, DNA based data indicate this number to be much higher when other emirates are taken into account. Previous surveys showed that the UAE exhibits one of the highest carrier frequency of b-thalassemia in the Gulf region with defective allele frequency of 8.3% (Baysal 2001). Mutation analysis among UAE nationals and expatriate b-thalassemia patients demonstrated that the UAE is the most heterogeneous b-thalassemia population in the world with more than 50 different mutations reported to date (Baysal 2005 and personal cummunication). The most common mutation in the UAE is IVS-1-5 (G > C) which is known to exist at very high frequencies in the Indian subcontinent

22


645

Table 22.1 The 11 most common b-thalasaemia mutations with their Gene Frequency in the UAE Mutation Gene frequency (%) IVS-1-5(G>C) 44.5 25 bp del 8.6 Cd 8/9 (+G) 3.0 IVS-11-1 (G>A) 2.8 Cd 39 C>T 2.2 Cd 8 (-AA) 2.2 Hb D-Punjab 2.2 Cd 30 (G>C) 2.1 Cd 5 (CT) 2.1 IVS-1-6(T>C) 1.5 88 (C>A) 1.1 Addapted from Baysal et al. (2007)

and among populations surrounding India but not among the Middle East Arabs. It is very likely that IVS-1-5 (G > C) allele was introduced to the Arabian Peninsula by gene migration from Baluchistan (Quaife et al. 1994). Its low frequency in Kuwait and high frequency in the UAE and Oman favor the speculation that the gene was introduced into the Arabian Peninsula across the Strait of Hormuz. This navigational route still constitutes a major trade link between the Indian Subcontinent and the Gulf states (Baysal 2005). One of the most striking features of b-thalassemia distribution in the UAE is the diversity of mutations. Table 22.1 shows the 11 most common mutations and their frequencies. It is apparent from molecular studies of b-thalassemia in the UAE that gene flow and heterogeneity of b-thalassemia mutations represent complex anthropological influence from the East Mediterranean, Asia, India, Sub-Sahara and East Africa, supporting the the hypothesis that the diversity of b-thalassemia mutations may reflect historical events and gene migration in the region (Baysal 2005).

Sickle Cell Disease (SCD) and Other Haemoglobinopathies The frequency of sickle cell disease (SCD) carriers in the UAE is 0.014 which is much lower than that found in Oman (0.06) (White et al. 1993). The overall picture of SCD disease in the UAE is that of mild to moderate severity similar to that observed in Eastern Saudi Arabia (Awad and Bayoumi 1993). However, there are also reports of severe SCD similar to the African type (White et al. 1993; Kamel 1979). Haplotype studies showed that 68% of the SCD patients in the UAE were homozygous for the Saudi Arabian/Indian haplotype (31/31), whereas only 8% were homozygous for the Bantu haplotype (20/20) which signifies the African influence. No homozygous Benin (19/19) was observed (Baysal 2005). This is in contrast to the haplotypes of patients of Omani origin where 34% had the 19/19

646


type, 24% had 20/20, and 22% had 31/31 type indicating the East African influence on the Arabian Peninsula (Baysal 2005). Haplotype 31 was associated with elevated mean HbF levels, as compared to the other two haplotypes. This resulted in less severe clinical symptoms and a majority of the patients with this haplotype did not require blood transfusion at all. Most of the sickle cell patients had concomitant a-thalassemia, which in turn reduced the severity of their disease. El-Kalla and Baysal (1998) identified eight different b-thalassemia mutations in heterozygous condition with the HbS allele. Seven of these eight mutations were beta-zero (b ) and their coexistence with the sickle gene manifested severe clinical symptoms. It was concluded that the SCD phenotypes are genetically complex and multifactorial and that epistatic factors influence the severity of the disease to a large extent.Other Hb variants seen in the UAE include Hb D-Punjab, Hb C, Hb E, and HbO-Arab, Hb Al Ain, Abu Dhabi (White et al. 1986; Abbes et al. 1992).

a-Thalassemia The frequency of a-thalassemia in the UAE is one of the highest in the world (El-Kalla and Baysal 1998). Almost half (49%) of those screened for an a-globin gene defect were positive (El-Kalla and Baysal 1998). Molecular characterization showed that the gene frequency of the alpha 3.7 was 0.2847 and that of alpha 4.2 was 0.0072. In addition, four non-deletional a-thalassemia mutations were found, alpha PA-1, alpha PA - 2, HbCS, and alpha 5ntdel with gene frequencies of 0.0036, 0.0012, 0.0024, and 0.0072, respectively (El-Kalla and Baysal 1998). Clinically most of the compound heterozygotes due to deletional and non-deletional a-thalassemia–2 were categorized phenotypically as very mild HbH disease (El-Kalla and Baysal 1998). Bart’s hydrops fetalis (/) and non-mutational HbH (/alpha) to our knowledge have not been seen in the UAE, which is also the case for other Gulf countries (El-Kalla and Baysal 1998).

G6PD Deficiency The frequency of G6PD deficiency in men in the UAE ranges from 11 to 15% (Bayoumi et al. 1996; Abdulrazzaq et al. 1999) while in females it is 5% (Bayoumi et al. 1996). This level is lower than that reported from neighboring Gulf countries such as Bahrain 21% (Mohammed et al. 1992) and Oman 27% (White et al. 1993); however, variable frequencies within different ethnic groups were found with UAE nationals and Yemenis at low frequency of 3–6% while Baluchis had a high frequency of 28–45% (Bayoumi et al. 1996). Among the non deficient subjects, the major normal phenotype was Gd B phenotype (Bayoumi et al. 1996). Of 18 deficient subjects, 14 had the B type mobility of G6PD Mediterranean and four had the A type mobility of G6PD.

22


647

The Mediterranean mutation (563 C>T, 188 Ser>Phe) was found to be the most common mutation causing G6PD deficiency in the UAE. Other mutations detected include the African mutation 202 G>A, 68Val>Met and G6PD-Aures (143 T>C, 48 lle>Thr) (Bayoumi et al. 1996).

Cystic Fibrosis (CF) (MIM 219700) Several cases of CF from the UAE have been identified since its first report in the UAE (Benson et al. 1987; Abdul Aziz et al. 1991; Frossard et al. 1999a, b; Dawson and Frossard 1994). Twenty three patients with CF were investigated at the molecular level. Two mutations were found, del F508 and S549R (T>G) accounting for 46 out of 52 (88%) alleles and characterizing 95% (18 out of 19) of the affected families. All patients were homozygous for either of the two mutations (Frossard et al. 1999a, b). Both these mutations identified have been shown to affect the processing of the CFTR protein, leading to its degradation, and therefore, resulting in very severe forms of the disease. In addition, all patients of Bedouin origin (16) were homozygous for S549R (T>G) and all patients of Baluchi origin (7) were homozygous for del F508 (Frossard et al. 1999a). The authors also screened 400 asymptomatic UAE nationals for these mutations to establish the carrier frequency of these two mutations. The carrier frequency of S549R (T>G) was 1:100 and for del F508 was 1:200. From these figures, the carrier frequency of any CF mutation was estimated to be 1:63 and the frequency of affected CF subjects in the emirates population was 1:15,876. This figure was thought to be a conservative estimate (Frossard et al. 1999b). The clinical severities associated with the two cystic fibrosis (CF) mutations S549R (T>G) and deltaF508 were also compared (Dawson and Frossard 2000). Clinical and biochemical variables of CF were compared in two age- and sexmatched groups of CF children in the United Arab Emirates. The clinical severities of mutations S549R (T>G) and deltaF508 were very similar, with very low Shwachman scores and high sweat chloride levels indicating that patients homozygous for either of these mutations have a severe clinical presentation and illness, and are indistinguishable on clinical grounds. It was also suggested that the founding chromosomes for the S549R (T>G) may have originated in Bedouins of eastern Arabia (Dawson and Frossard 2000). Saleheen and Frossard (2006) reported an Emirati CF patient homozygous for the 3120þ1 G>A mutation.

Deafness Non-syndromic autosomal recessive deafness is common in the UAE. A genetic etiological survey of children attending classes for the deaf in the UAE, in whom a known acquired cause for their deafness had been excluded, showed that overall

648


there was a high prevalence of AR deafness (92%) in the study group with autosomal dominant deafness constituting 7% and sporadic deafness 1% (Al-Gazali 1998). Non-syndromic deafness was present in 81% of cases and most of those (98%) had autosomal recessive type. The frequency of connexin 26 mutation is not known in the UAE; however, two genes were mapped in two consanguineous families and a novel mutation in the otoferlin gene was found in another family from the UAE (Campbell et al. 1997; Pulleyn et al. 2000; Houseman et al. 2001).

Malformation Syndromes Several studies on the pattern of congenital anomalies in the UAE population have shown increased frequency of rare recessive syndromes or disorders (Al-Gazali et al. 1995a, 1999a, 2003a; Al-Talabani et al. 1998). It has also been shown that malformation syndromes are an important cause of morbidity and mortality in this community. For example a study to determine the causes of neonatal death in Al-Ain Medical District found that lethal malformations were the second cause of death, being responsible for 70% of deaths in normal-weight infants and almost half of these malformations were multiple anomalies that were due to specific autosomal recessive syndromes (Dawodu et al. 2000). Some of these syndromes are common throughout the population while others cluster in certain communities and some are restricted to one or two families. In addition, there are several new or previously not described syndromes. Examples of these syndromes include the following:

Bardet–Biedl Syndrome (MIM 209900) This autosomal recessive syndrome is known to be common in the Arab Bedouins (Teebi 1994). Several families from the UAE with this syndrome were evaluated. All affected children had polydactyly, retinitis pigmentosa, and obesity. In two families, the affected female children presented with hydrometrocolpos in the neonatal period. The molecular basis of this syndrome has not been established in the UAE.

Cohen Syndrome (MIM 216550) Seven children from three families with Cohen syndrome were evaluated. All presented with microcephaly with mental retardation and the typical facial appearance. Molecular study in two of these families revealed two different mutations in the COH1 gene [homozygous c.6530_6732del (deletion axon 37), (p.Val2245fsX16), homozygous mutation in axon 9 c.1225G > T (p.Glu409X)] (Taban et al. 2007).

22


649

Donnai–Barrow Syndrome (MIM 222448) This autosomal recessive disorder is characterized by congenital diaphragmatic hernia, agenesis of corpus callosum, craniofacial dysmorphology, high myopia, sensorineural hearing loss, and developmental delay. This disorder was diagnosed in one large consanguineous family of Yemini origin and UAE nationality. There were five affected children in two branches. Molecular study revealed a homozygous mutation in LRP2 (Megalin) (7564T > C) (Kantarci et al. 2007).

Sanjad–Sakati Syndrome (MIM 241410) This autosomal recessive syndrome is characterized by severe failure to thrive, developmental delay, dysmorphic features, and hypoparathyroidism. It is known to be common in the Arabs and is caused by mutations in the TBCE gene. Seven children from six families all from the UAE were seen with this syndrome. However, no molecular studies were done on these children (Al-Gazali and Dawodu 1997; Al-Gazali unpublished data).

Hennekam Syndrome (MIM 235510) This is an autosomal recessive syndrome characterized by lymphangiectasia, severe peripheral lymphedema, facial anomalies, seizures, mild growth retardation, and variable mental retardation (Hennekam et al. 1989). Six children from five different families (four published) with this syndrome were evaluated. All had flat mid face with hypertelorism but only two of them had dysplastic ear with atretic ear canal. (Al-Gazali et al. 2003b, unpublished data). Intestinal lymphangectasia was present in five of the six patients. Three of the six had mild-borderline mental retardation and one had moderate retardation. (Al-Gazali et al. 2003b, unpublished data).

Fraser Syndrome (MIM 219000) In a family of UAE origin in which the parents were first cousins, five children out of a total of six had features of Fraser syndrome. All of them either died immediately after birth or were stillborn. All had cryptophthalmos, renal agenesis,

650


syndactyly, and abnormalities of the genitalia. Genetic study revealed a homozygous mutation in FRAS1 gene (c.9524A>C; p.3175Y>S) (van Haelst et al. 2008).

Mowat–Wilson Syndrome (MIM 235730) Mutation analysis of homeo box 1 B in a child with this syndrome ( Hirschsprung disease, distinct facial appearance, microcephaly, agenesis of corpus callosum, and mental retardation) revealed a de novo 7 bp deletion (1773 delTGGCCCC) resulting in a termination codon at aminoacid residue 604 (604X) in exon 8 (Sztriha et al. 2003).

Down Syndrome The birth prevalence of Down syndrome in Al-Ain medical district varied from 14.84 in 10,000 in 1996 to 26.30 in 10,000 in 2001 (Al-Gazali 2005). This increase is probably due to better ascertainment. Another study from Dubai found a birth prevalence of 22 per 10,000 in the national and expatriate population and 31 per 10,000 in the national population (Murthy et al. 2007). The mean maternal age of UAE national mothers was 33.48 8.08 with 41.66% of the mothers being in the advanced maternal age group (>35 years). The prevalence of the translocation and mosaic type of Down syndrome was very low (Murthy et al. 2007).

Brain Malformation Syndromes Brain malformation syndromes are common in the UAE. A prospective study of the pattern of CNS anomalies in 9,610 births in Al-Ain Medical District showed that 42% of the babies with congenital anomalies of the CNS had syndromic type of anomalies and 92% of these syndromes were inherited as autosomal recessive. Examples of such syndromes include microlissencephaly, micrencephaly and pontocerebellar hypoplasia with arthrogryposis, agyria-pachygyria, complex brain malformation with dense bones, and microcephaly caused by peroxismal defect (Al-Gazali et al. 1999a). Other recessively inherited brain malformation syndromes seen in the UAE include Walker–Warburg syndrome, eye-brain-muscle syndrome, AR cerebellar hypoplasia with cerebral gyral simplification, AR Dandy –Walker malformation, and bilateral frontal polymicrogyria (Guerrini et al. 2000). In a review of 25 patients with a spectrum of hindbrain malformations, Sztriha and Johansen (2005) found that 11 patients from six families had malformation of the hindbrain and midbrain with molar tooth sign (ten from five families had typical Joubert syndrome), five patients showed severe supratentorial anomalies in addition to hindbrain malformations, five patients had ponto-cerebellar or cerebellar hypoplasia with anterior horn cell disease in the

22


651

spinal cord, and four patients showed malformations affecting predominantly the hindbrain without substantial involvement of other systems. Sztriha et al. (2004) reviewed the MRI findings and the clinical features of 14 children with the combination of microcephaly and abnormal gyral pattern. Seven patients showed features of simplified gyral pattern with relatively preserved posterior fossa structure, two had a cortical malformation in the agyria-pachgyria spectrum with agenesis of corpus callosum and cerebellar hypoplasia in one of them, two had polymicrogyria and leukoencephalopathy and cortical dysplasia, one had callosal and pontocerebellar dysplasia, and another had a simplified gyral pattern with severe cerebellar hypoplasia. In a child with X-linked recessive CRASH syndrome (corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, and hydrocephalus) Sztriha et al. (2000) identified a novel missense mutation in LICAM gene (c.604G>T; p.D202Y). The following are examples of brain malformation syndromes seen frequently in the UAE:

Joubert Syndrome (MIM 213300) Joubert syndrome is an autosomal recessive disorder characterized by congenital cerebellar ataxia, hypotonia, oculomotor apraxia, and mental retardation. The neuroradiological hallmark of the disorder is a malformation of the midbrain–hindbrain junction known as the “molar tooth sign” consisting of cerebellar vermis hypoplasia or dysplasia, thick horizontally-oriented superior cerebellar peduncles, and abnormally deep interpeduncular fossa. This syndrome is seen frequently in the UAE. The birth prevalence in the UAE is estimated to be 1 in 5,000 (Al-Gazali et al. 1999a). Thirty eight cases from 15 families with Joubert syndrome were evaluated. Using homozygosity mapping, several genes and mutations were identified in some of these families. Gene AHI 1 CEP290 INPP5E

Exon 8 41 7 9

Mutation c.787dupC (p.Q263fs) c.5668G>T (p.G1890X) c.1534C>T (p.R512W) c.1543C>T (p.R515W) c.1688G>A (p.R563H)

Origin Palestinian UAE UAE (Omani origin) UAE (Omani origin) UAE (Omani origin)

References Dixon-Salazar et al. (2004) Valente et al. (2006) Biels et al. (2009)

Meckel Syndrome (MIM 249000) Another commonly seen syndrome is Meckel syndrome. This autosomal recessive syndrome has a birth prevalence of 1/5,000 in the UAE (Al-Gazali et al. 1999a) and is known to be common in Bedouins in Kuwait and in Palestinian Arabs (Teebi 1997). One family, originally from Oman, was studied at the molecular level and was found to have a homozygous mutation in mecklin (MKS3) gene (383384delAC, p.H128fsX140 (Smith et al. 2006).

652


AR Microcephaly (MIM 608716) This type of microcephaly is common in the UAE but no prevalence figures are available. Molecular study in one consanguineous family with eight affected children in two branches showed a mutation in ASPM gene (c.9751delA) (AlGazali unpublished data). One of the affected children in this family died of acute myeloid leukemia. Genetic study in another UAE family in which two affected children had severe microcephaly, and one of them had in addition, persistent vitreous and retinal detachment, revealed a homozygous mutation in ASPM gene (c.3067T>G) (Al-Gazali unpublished data). Seckel syndrome was diagnosed in two inbred UAE families. Three children were affected in the first family and two children in the second family. These children had severe microcephaly with receding forehead, bilateral radial dislocation, and short stature (Al-Gazali unpublished data).

Osteochondrodysplasias Osteochondrodysplasias are relatively common in the UAE. In a study of 38,084 births in Al Ain medical district, 36 cases of skeletal dysplasias were found (9.46 in 10,000) (Al-Gazali et al. 2003a). There was high prevalence of dysplasias caused by autosomal recessive genes (4.7/10,000 births) and new dominant mutations (2.62/ 10,000). Some of the dysplasias seen frequently in the UAE include the following:

Stuve–Wiedemann Syndrome (MIM 601559) This rare autosomal recessive syndrome is relatively common in the UAE (AlGazali et al. 1996a, 2003c). The syndrome is characterized by camptomelia, camptodactyly with pursing of the mouth on stimulation. The course of the disorder is complicated by hyperthermia, feeding and swallowing difficulties leading to frequent aspirations, and respiratory problems. Most children die in the first year of life. However, if they survive, they develop progressive spinal deformity associated with insensitivity to pain leading to self mutilating behavior and corneal scarring (Al-Gazali et al. 2003a, c). Thirty five cases from 21 families have been evaluated. Most of these families originated from Oman and Yemen. Molecular study revealed a founder mutation in the leukemia inhibitory factor receptor gene (LIFR) [c.653_654 insT at exon 6] in these families (Dagoneau et al. 2004; Al-Gazali unpublished data).

22


653

Microcephalic Osteodysplastic Primordial Dwarfism Type II (MIM 210720) This disorder is seen in the UAE most commonly in families of Omani and Pakistani origin. Six children from six families have been evaluated. Using homozygosity mapping, the gene and mutations were identified in some of these families. Two mutations in pericentrin gene were identified in some of these families c.5767C > T (p.R1923X), c.1336C > T (p.Q446X) (Rauch et al. 2008).

Fibrochondrogenesis (MIM 228520) This disorder was found to be relatively common in the UAE with a birth prevalence of 1.05/10,000 births (Al-Gazali et al. 2003a). This disorder was thought to be lethal in the neonatal period. However, two out of the eight children evaluated in the UAE have survived, one is 3 years old and the other is 18 months old at the time of writing. Both have severe short stature and developmental delay.

Raine syndrome (MIM 279775) Raine syndrome is a lethal bone dysplasia characterized by generalized osteosclerosis with periosteal new bone formation and distinctive facies (Al-Gazali et al. 2003d). Four consanguineous families with several affected children were seen in Al-Ain. (Al-Gazali et al. 2003d, unpublished data) Molecular study in one of these families revealed a mutation in FAM20C gene (c.915-3C > G) (Simpson et al. 2007).

Dygve–Melchior–Clausen Syndrome (MIM 304950) This disorder was diagnosed in two families living in the UAE. One family was of Lebanese origin and the other one of Palestenian origin. Both had the typical clinical and radiological features. Molecular study showed a homozygous mutation in dymeclin gene (IVS II 1252-1G > A at exon 12 in one of these families (El Ghouzzi et al. 2003).

654


Ellis-van-Creveld (MIM 225500) and Jeune Syndromes (MIM 208500) Ellis-van-creveld syndrome is seen frequently in the UAE. Five families with this syndrome were studied at the clinical and molecular level. Molecular study revealed a homozygous mutation in exon 13 of EVC1 Q605X in one family, a homozygous deletion (c.981delG) in exon (8) of EVC2 in the second, and splice site homozygous change (IVS13-1G > T) in intron 13 of EVC2 gene in the third (Ali et al. in preperation). Two families with Jeune syndrome were evaluated. In one family, the child died in utero while the second family had two affected children, and both had the typical clinical and radiological features, but one was mildly affected and is doing well at the age of 13 years with no renal and retinal complication while the other child had a stormy neonatal course requiring management in the ICU but is doing well currently at the age of 7 years.

Larsen (MIM245600) and Desbuquois (MIM 251450) Syndromes Autosomal recessive Larsen syndrome was diagnosed in an inbred UAE family (Topley et al. 1994). Both children had severe intrauterine growth retardation, genu recruvatum, and multiple joint dislocations with limited extension of both elbows. In 1996, Al-Gazali et al reported a consanguineous Arab Bedouin family with Desbuquois syndrome. Affected members of the family had typical Desbuquois syndrome features including a midface hypoplasia and joint laxity. This was probably the first report on Desbuquois syndrome in Arab Bedouins. Using homozygosity mapping, the gene responsible for Desbuquois syndrome was mapped to chromosome 17q25.3 with a possible genetic homogeneity of the clinical subtype with hand anomalies (Faivre et al. 2003). Another consanguineous family from the UAE with one child affected with Desbuquois syndrome without hand anomalies was also seen (Al-Gazali unpublished data).

Acromesomelic Dysplasia Two families with acromesomelic dysplasia, Maroteaux type (MIM 602875), were evaluated. One was originally from Oman and had two affected sibs. One of the affected had in addition cervical spina bifida and died in the first few months of life. Molecular study in this family showed c.2869C > T change leading to p.R957C missense mutation in NRP2 gene (Bartels et al. 2004).

22


655

Another family had Langer mesomelic dysplasis (MIM 249700) which was confirmed by molecular study showing homozygous deletion encompassing CA SHOX, GA SHOX, and CT SHOX (Al-Gazali unpublished data).

Limb/Pelvis/Hypoplasia/Aplasia Syndrome (MIM 276820) One family, originally Syrian Bedouins, had three children in two branches with the typical phenotype of this syndrome. This included ectrodactyly of the right hand with nail dysplasia, contractures at the right elbow joint, and no elbow joint on the left with left arm ending in an appendage which looked like a deformed finger with dysplastic nail; lower limbs were absent and replaced by a stick like appendage more severe on the right side. The second child had no elbow joints bilaterally and complete absence of the lower limbs. Molecular study in this family revealed a homozygous missense mutation in exon 4 in Wnt7 gene c.1179C > T leading to substitution of arginine for cysteine (Woods et al. 2006).

Wollcott–Rallison Syndrome (MIM 226980) Al-Gazali et al. 1995b reported an Omani family with two children affected with this syndrome. Molecular study revealed a homozygous mutation in E1F2Ak3 gene (IVS14+1G>A (Brickwood et al. 2003).

Miscellaneous Bone Dysplasias Other bone dysplasia seen in the UAE include short-rib-polydactyly type III, Schneckenbecken dysplasia, osteopetrosis, micromelic dwarfism (Al-Gazali et al. 2003a), OSMED (Al-Gazali and Lytle 1994), spondylometaepiphyseal dysplasia, abnormal calcification type (Al-Gazali et al. 1996b), omodysplasia (Al-Gazali and Abo saad 1995), chondrodysplasia puctata, thanatophoric dysplasia, and achondroplasia. In addition, several new forms of bone dysplasia were also described from the UAE (Al-Gazali et al. 2003a, 2001, Al-Gazali et al. 1996c).

Neurometabolic Disorders Inborn errors of metabolism comprise a wide range of autosomal recessive disorders which show defects in metabolism of carbohydrates, amino acids, organic acids, and fatty acids. Although the incidence of each of the inborn errors of metabolism is relatively low, the overall number of inborn errors of metabolism is rather high, affecting more than 2% of all live newborns. Reports from the Gulf

656


region indicate that metabolic diseases constitute a significant cause of neonatal and infant death and mental retardation. Most of the work in the Gulf region has been generated from Saudi Arabia, where 15 common metabolic diseases have been identified through a universal screening program (Afifi and Abdul-Jabbar 2007). The prevalence of this group of genetic diseases in UAE populations is believed to be high, but the molecular causes are not well established. A recent retrospective study on metabolic disorders at Al-Wasl Hospital in Dubai conducted by the Centre for Arab Genomic Studies Work Group (Al-Ali et al. 2006) between 1995 and 2004 and an audit by Al-Wasl Hospital indicated the presence of at least 30 metabolic disorders including phenylketonuria (PKU), homocystinuria, propionicacidemia, maple syrup urine disease (MSUD), kabbe disease, and galactosemia. In addition, Tawam Hospital (Tawam Hospital web site) indicates the presence of PKU, MSUD, b-ketothiolase, tyrosinaemia (Type2), isovaleric acidaemia, methylmalonic aciduria, homocystinuria, arginosuccinic, aciduria, and galactosaemia. It is clear that the most common metabolic disorder in the UAE is PKU with incidence of 1:20050 (Al-Hosani et al. 2003). The molecular basis and epidemiology of most inborn errors of metabolism disorders are not well established for Emirati population. Abdulrazzaq et al. (2009) screened 2,981 school children for homogentisic acid and identified a family with high levels of this metabolite indicating alkaptonuria. Molecular studies revealed a homozygous single nucleotide deletion at c.342 delA in exon 3 leading to a frame-shift at amino acid position 58 in all affected children (Abdulrazzaq et al. 2009). In the second study, a homozygous single nucleotide deletion in ARG1 gene in three affected siblings with arginase deficiency was identified and the carrier status of other members of the family was established (Herticant et al. 2009). Molecular study on three children from UAE (2 sibs and 1 unrelated child) with infantile GM1-gangliosidosis showed two novel mutations. The first one was a homozygous missense mutation in exon 4 of GLB1 gene, c.451G > T, and the second mutation was a splicing mutation in intron 8, c.914þ4A > G (Georgiou et al. 2004). Mevalonic aciduria was described in two very low birthweight sibs with unspecific clinical signs and recurrent septicaemia. Both were homozygous for a T > C transition at nucleotide 104 of mevalonate kinase gene (L35S) (Raupp et al. 2004). Hamdan et al. 2008 reported a 35 week part -of-twin neonate with Pompe disease. There was a history of an older sib who died with the same condition. Mutation analysis of GAA gene revealed homozygosity for c.1327-2A (GAA intr 8) (Hamdan et al. 2008).

Genodermatosis Ehlers–Danlos Syndrome VIA (EDSVIA) (MIM 225400) Ehlers–Danlos Syndrome Type VIA is an inherited connective tissue disorder characterized by severe muscular hypotonia and kyphoscoloisis at birth, joint hypermobility, and skin fragility. It is caused by a deficiency of collagen lysyl

22


657

hydroxylase deficiency due to mutations in PLOD1 gene. Sixteen children from 12 Bedouin UAE families were identified as having this disorder. Some of them were diagnosed initially as Nevo syndrome. However, molecular study showed that in fact Nevo syndrome and EDSVIA are allelic. A founder mutation In the PLOD1 gene was found in these families (p.R319X nonsense mutation) (Giunta et al. 2005 and Al-Gazali unpublished data).

Epidermolysis Bullosa Epidermolysis bullosa is a group of inherited disorders of the skin and characterized by blistering of the skin and mucous membranes even with minor trauma. The disease is traditionally classified into three groups: (1) epidermolysis bullosa simplex results from separation of the skin above the basement membrane, (2) junctional epidermolysis bullosa (MIM 226700) is manifested by blister formation within the basement membrane, and (3) in dystrophic epidermolysis bullosa (MIM 226600), blisters appear below the basement membrane. Two major clinical variants of junctional epidermolysis bullosa subtype have been reported, namely, the Herlitz and the moderately severe non-Herlitz junctional epidermolysis bullosa. The Herlitz type is associated with extensive skin and mucosal blistering, nail dystrophy, exuberant granulation tissue, enamel defects, and a high perinatal mortality resulting from overwhelming infections and respiratory complications. The non-Herlitz type on the other hand is characterized by localized to generalized blistering, nail dystrophy, scarring alopecia, and mucosal involvement. The different types of epidermolysis bullosa are seen frequently in the UAE. In their seminal study, Al-Talabani et al. (1998) observed two cases of generalized atrophic benign epidermolysis bullosa in consanguineous families from the UAE. They also reported the recurrence of this condition in other members of the family. Non-Herlitz junctional epidermolysis bullosa was identified in a consanguineous family originating from the UAE (Nakano et al. 2002). The affected child turned out to be heterozygote for two mutations, Q1083X and 1296insA, in the LAMB3 gene. Interestingly, both the grandmothers of the child originated from Palestine. Several families with pyloric atresia-junctional epidermolysis bullosa (MIM226730) were seen in the UAE (Lestringant et al. 1992; Al-Gazali unpublished data). Molecular study in one of these families showed missense mutation (S47L) in ITAG6 gene resulting in rapid decay of alpha 6 integrin (Allegra et al. 2003a, b). In a consanguineous UAE family, two children were affected with epidermolysis bullosa-muscular dystrophy, and one of them died at the age of 4 months. The children presented with blistering in the neonatal period involving the limbs and face and were severely hypotonic with increased CPK (Al-Gazali unpublished data).

658


Atopic Dermatitis Atopic dermatitis is an allergic hypersensitivity inflammation reaction affecting skin. In some patients, the condition may also be associated with allergic rhinitis, food allergy, urticaria, and/or increased IgE production. Lestringant et al. (1996) described three patients from the UAE with an association of lichen nitidus and atopic dermatitis.

Congenital Ichthyosis and Related Conditions Congenital ichthyosis is a clinically and genetically heterogeneous group of disorders of keratinization characterized by a significant and incapacitating scaling of the skin. Most forms are congenital and display different modes of inheritance. Al-Talabani et al. (1998) observed one case of autosomal recessive lamellar ichthyosis in a consanguineous family from the UAE out of 24,233 consecutive live and stillbirths at Corniche hospital in Abu Dhabi. Lestringant et al. (1998) reported five UAE sibs from a consanguineous family with normal stature, diffuse congenital ichthyosis, generalized and diffuse non-scarring hypotrichosis, and marked hypohidrosis. On the dorsum of the wrists and around the elbows and knees there was a zone where ichthyosis progressively transformed into follicular atrophoderma. The ichthyosis was present at birth; there were no collodion babies. Steroid sulfatase activity was normal and this excluded the possibility of an X-linked recessive ichthyosis and the authors concluded that this family may suffer from a previously described autosomal recessive genodermatosis. Molecular study in the family revealed a homozygous splice site mutation (c.2269þ1G > A) in the gene suppression of tumorigenicity-14 (ST14) (Alef et al. 2009).

Waardenburg–Shah Syndrome (MIM 277580) Waardenburg–Shah syndrome is divided into four distinct types on the basis or absence of dystopia canthorum: (1) type I with dystopia canthorum, (2) type II without dystopia canthorum, (3) type III without dystopia canthorum but with a one-sided ptosis, and (4) type 4, patients presenting with aganglionosis in association with hypopigmentation. Abdulrazzaq (1989) reported a full term baby boy with Waardenburg’s syndrome in the UAE of Omani origin with long segment Hirschsprung’s disease, who was born to a non-consanguineous Omani family. Two male siblings who died during the neonatal period had long segment Hirschsprung’s disease.

22


659

Erythrokeratodermia Variabilis (MIM 133200) Erythrokeratodermia variabilis is a rare genetic disorder that is inherited through an autosomal dominant gene with variable expressivity. Erythrokeratodermia variabilis is characterized by two distinct morphologic features: erythematous patches and hyperkeratotic plaques. In 2004, Galadari and Galadari described a 4-year-old girl with a history of erythematous skin lesions on her face, extremities, forearms, and joints that started a few months after birth and the condition progressed over a period of time. There was no family history of a similar problem, although her older brother showed marginal hair loss without any skin lesions. The hair showed normal appearance, but there was no hair growth on the margins of the scalp. No molecular data are available about this family.

Mal de Meleda Disease (MIM 248300) Mal de Meleda is a rare autosomal recessive disorder characterized by diffuse transgressive palmoplantar keratoderma, keratotic skin lesions, perioral erythema, brachydactyly, and nail abnormalities. Hyperkeratosis soon appears after birth and progresses with age and extends from the palms and soles onto the dorsal surface of the hands and feet, elbows, and knees without involvement of other organs. Lestringant et al. (1992, 1997) reported families from the UAE with Mal de Meleda with unusual features including prominent knuckle pads, peculiar finger-nail anomalies, and pseudo-ainhum on both fifth fingers. Patients of one of the families were the product of consanguineous marriages. Four years later, Lestringant et al. (2001) examined five patients and reported that the patients had diffuse erythrodermic PPK and transgressive erythrodermic keratosis, often with scaly borders, plaques of erythrodermic keratosis on the knees, and red nails with preserved lunula; none had hyperhidrosis. The MDM interval on chromsome 8q was excluded by homozygosity mapping in all three families. Lestringant et al. (2001) concluded that the MDM phenotype is due to at least two different genotypes. When the oldest patient was aged 23, keratoderma palmoplantaris was grayish, diffuse and waxy, and smooth and reported mutations affecting the initiation codon in SLURP-1 gene (Ecckl et al. 2003).

Restrictive dermatopathy (MIM 275210) Restrictive dermatopathy (RD) is a severe neonatal skin syndrome characterized by intrauterine growth retardation, taut translucent and easily eroded skin, and multiple joint ankylosis. Affected children usually die shortly after birth. RD is usually caused by homozygous or compound heterozygous mutations in ZMPSTE24 that

660


are predicted to cause loss of function of the encoded zinc metalloproteinase STE24. Two distantly related families from the UAE were reported to have two children with RD. The diagnosis was confirmed by skin biopsy. Both died at the age of 2 months. In both patients, a homozygous splice site mutation c.627+1G > C in ZMPSTE24 was identified. Accumulation of prelamin A could be detected at the nuclear envelope of the patient’s blood lymphocyte (Sander et al. 2008).

X-Linked Dyskeratosis Congenita (MIM 305000) This is a rare multisystem disorder characterized by lesions in the skin and appendages. Pulmonary manifestation is another rare feature. It is caused by mutations in DKC1 gene on Xq28.Two sibs originally from Egypt were studied at the molecular level and were found to have a novel missense mutation 5C > T (A > V) in exon 1 of the DKC1 (Dyskerin) gene (Safa et al. 2001).

Neuromuscular Disorders Spinal Muscular Atrophy, Type I (MIM 253300) In their study, Al-Talabani et al. (1998) reported three cases of type I spinal muscular atrophy born to first cousin couples from the UAE. No molecular data are available about this condition in UAE populations. Four children with congenital spinal muscular atrophy were identified during a 2 year prospective study of congenital malformations in the UAE (Al-Gazali et al. 1995a, b). All presented with arthrogryposis multiplex at birth. Similarly, in a prospective study on the pattern of CNS anomalies in the UAE, Al-Gazali et al. (1999a, b) found 1 affected child in 9,610 births. No molecular studies were performed on these children.

Muscular Dystrophy, Congenital, 1B (MIM 604801) Congenital muscular dystrophy 1B represents a heterogeneous group of conditions characterized by proximal girdle weakness, generalized muscle hypertrophy, and rigidity of the spine and contractures of the tendo Achilles. Muntoni et al. (1998) described a form of autosomal recessive congenital muscular dystrophy characterized by proximal muscle weakness, generalized muscle hypertrophy, rigidity of the spine, and contractures of the Achilles tendons in children from a UAE consanguineous family. Severe diaphragmatic involvement was responsible for the early respiratory failure in children. Serum creatine kinase levels were grossly elevated,

22


661

and muscle biopsy samples showed dystrophic changes. Biochemical data from muscle indicated that affected individuals have laminin alpha-2 deficiency (LAMA2). However, linkage analysis excluded the LAMA2 gene locus on 6q22-q23. Further genome-wide linkage studies by Brockington et al. (2000) performed on the same family found a homozygous region on 1q42, spanning 6–15 cM in two affected children. The two affected sisters died as a result of respiratory complications at the ages of 4 and 7 years.

Myotonic Dystrophy 1 (MIM 160900) Myotonic dystrophy 1 is the most common dominant inherited neuromuscular disease in adults, with incidence rates of about 1 in 7,400 live births. The disorder shows a very wide range of presentations and progressions. The adult onset form typically presents with distal dystrophy and myotonia after 20 years of age and progress leading to significant disability. Characteristic facial changes are also common including low-set ears, a hatchet chin, and drooping of the lips and ptosis. Severe cases of adult-onset myotonic dystrophy may also show presenile cataracts, testicular atrophy, diabetes, kidney failure, and early frontal balding in males. Anwar et al. (1986) reported a 35 year old Emirati man with dystrophia myotonica and characteristic appearance of a long and haggard face with bilateral partial ptosis, atrophy of the temporalis and masseter muscles, atrophy of the sternomastoids, and premature frontal baldness. Tests in this patient revealed increased insertional activities with frequent fibrillations, myotonic discharges, primary gonadal failure, typical diabetic curve, and marked testicular atrophy. In a UAE family, a mother was affected with myotonic dystrophy confirmed by molecular study. She had five children with congenital myotonic dystrophy. All presented with severe hypotonia and arthrogryposis multiplex. Two died in the neonatal period and the other three are alive at the age of 15, 12, and 10 years. All are severely retarded (Al-Gazali unpublished data).

Neurogenetic Disorders Other than Neurodegenerative Disorders Congenital Insensitivity to Pain Sixteen children from six families with congenital insensitivity to pain were evaluated. One was of Palestinian origin, one of Baluchi origin, and the rest were UAE Bedouins. All had self mutilating behavior with repeated infections, fractures, and joint dislocations. Some presented with hyperthermia in the first few weeks of life because of the lack of sweating. In one family, the children had normal

662


intelligence, in one there was severe developmental delay, and the rest had mild-moderate delay. Molecular study showed a mutation in the NGFB gene in one of these families. In another UAE family, one affected child with congenital insensitivity to pain associated with anhydrosis (Sztriha et al. 2001) was found to have homozygosity for 30 splice site mutation G > C in the first position of intron 4 (IVS4-1G > C) of NTRK1 gene (Mardy et al. 1999). In addition, the child had C > A transversion at nucleotide 337 in exon 2, which causes an Arg > Ser substitution at aminoacid 85. The authors suggested that the phenotype in this child is probably caused by these double mutations although the IVS4-1G > C is likely to be the main cause considering the effect of exon skipping or alternative splicing (Mardy et al. 1999).

AR Spastic Paraplegia with Thin Corpus Callosum This condition was diagnosed in one large consanguineous family with six affected children in two branches and two small families with two affected in one and one affected in the other. Homozygosity mapping in the large family localized the gene to chromosome 8p12-p11.21 between marker D8S1820 and D8S532 with a LOD Score of 7.071, but candidate gene analysis was negative so far (Al-Yahyaee et al. 2006).

Crisponi Syndrome (MIM 601378) This rare autosomal recessive disorder is characterized by congenital muscular contraction of facial muscles, with trismus in response to stimuli, dysmorphic features with bilateral camptodactyly, major feeding and respiratory difficulties, and hyperthermia leading to death in the first few months of life. It overlaps with Stuve–Wiedemann syndrome (SWS) but there is no congenital lower limb bowing which is characteristic in SWS. Three families were seen with this syndrome and molecular study in one family showed a homozygous mutation in cytokine related factor CRLF1 (c.527þ5G>A) (Dagoneau et al. 2007).

Progeriod Syndromes Several syndromes leading to premature aging have been diagnosed in the UAE.

22


663

Generalized Lipodystrophy of Seip (MIM 269700) Four families, each with one affected child with this disorder, were evaluated. All had the typical features except one child who presented at birth with lipodystrophy and had high serum lipids. Molecular study in three families revealed mutations in AGPAT2 in two families (CG 8100, del 158G homozygous [H52sx59]) and a mutation in BSCL2 gene (658 del GTATC [F105fsx111] (Agarwal et al. 2003; Al-Gazali unpublished data).

Neonatal Progeria (Wiedemann-Rautenstrauch Syndrome) (MIM 264090) Four children from two families with this condition were seen. One family with one affected child was originally from Yemen. The child presented at birth with growth retardation (weight, height, and head circumference were all below 3rd centile), aged facial appearance, prominent scalp veins with wide sutures and fontanelle, scaphocephaly with triangular face, small eyes with sparse eyebrows and eyelashes, curved profile of the nose, small pointed chin and contractures at the elbow joints, and large hands and feet with generalized deficient subcutaneous fat. Serum cholesterol and triglycerides were elevated (Al-Gazali unpublished data). The other family was originally from Lebanon and had three affected children. All had the typical features presenting from birth. The eldest is 22 years old now and is probably one of the few patients with this syndrome who survived till adulthood (Al-Gazali unpublished data). Mutation analysis in both LMNA gene and ZMPSTE24 gene were negative (Ali unpublished data).

SHORT Syndrome (MIM 269880) This syndrome is characterized by short stature, hyperextensibility of the joints, hernias, ocular depression, Rieger anomaly, and teething delay. In a UAE family four children and their father had features suggestive of this syndrome. The parents were first cousins once removed and the parents of the father were distantly related. One sister of the father had similar phenotype. All affected had failure to thrive since birth with dysmorphic features which included old looking appearance of the face, large eyes which were deep set, pinched nose and small mouth, and prominent forehead and ears. The teeth were small and there was reduced subcutaneous fat all over the body. Ophthalmological examination was normal. There was no Rieger anomaly. It is likely that this syndrome is inherited as autosomal recessive disorder in this family. However, autosomal dominant inheritance cannot be ruled out (Al-Gazali unpublished data).

664


Gerodermia Osteodysplastica (GO) (MIM 231070) Go is an autosomal recessive disorder characterized by lax wrinkled skin, joint laxity, and a typical face with a prematurely aged appearance. Skeletal signs include severe osteoporosis leading to frequent fractures, malar and mandibular hypoplasia, and a variable degree of growth retardation. Four families from the UAE (1 Palestinian, 1 Syrian, 1 UAE of Bahraini origin, 1 from Qatar) with a phenotype overlapping GO and the wrinkly skin syndrome characterized by congenital skin wrinkling, most pronounced on the dorsum of the hands and feet, triangular face with a progeroid appearance with hypoplasia of the jaw resulting in a prominent chin, and generalized connective tissue weakness with fingers contractures (Al-Gazali et al. 2001, Revesade et al. 2009). SCYL1B1 mutations were excluded in these families. Genetic studies on these families identified four different mutations in the PYCR1 gene c.617_633þdel, c.797þ2_797þ 5del (p.Lys215_Asp139del), c.535G > A(p.Ala179Thr), c.616G > A (p.Gly206Arg) (Revesade et al. 2009).

Leprechaunism and Leprechaunism-like Syndromes (MIM 246200) In a Yemeni family living in the UAE, five out of eight children were affected with a syndrome very similar to leprechaunism but a milder phenotype was evaluated (Al-Gazali et al. 1993). All the affected individuals are still alive in their 20s. Molecular study revealed a new mutation in the insulin receptor gene (Ile119Met) (Hone et al. 1994). Two other families of UAE origin had two affected children each with classical leprechaunism.

Setleis Syndrome (MIM 227260) This syndrome is characterized by distinctive bitemporal scar-like depression resembling forceps marks, lateral deficiency of the eyebrows, double row eyelashes, and of course, aged facial appearance. An inbred family from the UAE had two children and an uncle from the father side affected with this syndrome (Al-Gazali and Al Talabani 1996). Molecular study in this family identified a nonsense mutation in the TWIST1 gene (p.Q119X) (Desnick et al. 2004).

Genetic Disorders of the Kidneys Congenital nephrosis is seen frequently in the UAE. Molecular study in three families with congenital nephrosis showed a homozygous mutation in exon 9 of NPHS1 gene (c.1134G > A, p.W378X) in one family and a homozygous missense

22


665

mutation in exon 6 of NPHS2 gene (p.V260E) in the other two families (Al-Gazali unpublished data). Abou-Chaaban et al. (1997) studied the pattern of pediatric renal diseases among children in the Dubai Emirate during the period from 1991 to 1996. In this period, a total of 712 pediatric patients, including 230 nationals of the United Arab Emirates, were seen with various renal problems. Of a total of 13 patients with congenital nephrotic syndrome, three were nationals from the United Arab Emirates. These patients either expired, within the first two weeks of life, or were on conservative treatment awaiting cadaveric donor renal transplantation. Abou-Chaaban et al. (1997) noted that consanguineous parents were a striking feature among their patients with congenital nephritic syndrome. In a family originally from Pakistan with childhood onset glomerular kidney disease and ocular abnormalities affecting seven children, a compound heterozygosity for two novel mutations in LAMB2 gene was found (p.Q1728X, p.DV79) (Matejas et al. 2006). Proximal renal tubular acidosis associated with ocular abnormalities was diagnosed in a family originally of Jordanian Bedouin origin. Molecular study showed a homozygous mutation in NBC1 gene (R881C) (Horita et al. 2005). Two families with renal tubular acidosis associated with deafness were seen but no molecular studies were performed.

Genetic Disorders of the Eyes Several genetic disorders affecting the eyes have been identified in the UAE. Examples include retinitis pigmentosa with and without mental retardation, congenital glaucoma and cataract, and congenital Leber’s amourosis. In one UAE family in which the parents were first cousins, three out of seven children were diagnosed with osteoporosis-pseudoglioma syndrome presenting with blindness at birth and developing fractures during childhood. Autosomal recessive anophthalmia/microphthalmia is also seen frequently in the UAE. Al-Gazali et al. (1994b) reported on a child of consanguineous parents with microphthalmia and distal limb abnormalities. The authors suggested that the features in this child represent a milder manifestation of ophthalmo-acromelic syndrome. No molecular studies have been done so far to identify the genes involved in all of these disorders. In a consanguineous UAE family, two sibs were affected with Goldmann syndrome (MIM 268100). Both had poor vision and night blindness since early childhood. Ophthalmoscopy showed macular and peripheral retinoschisis as well as clumps of pigment and subretinal changes along the temporal vascular arcades and in the mid-peripheral fundus (Chavala et al. 2005). Molecular study revealed a homozygous mutation in exon 6 of the NR2E3 gene (c.932G > A, p.Arg311Gln) (Chavala et al. 2005). Two families from the UAE were diagnosed with achromatopsia (MIM 262300) which is also known as rod monochromacy or total color blindness (Ahuja et al 2008). This is an autosomal

666


recessive disorder with an incidence of less than 1in 30,000. It presents in infancy with poor vision, pendular nystagmus, severe sensitivity to light, and complete lack of color perception (Ahuja et al. 2008). Two mutations in the CNGA3 gene were found in these families (c.847C > T p.Arg283Trp and c.1190G > T p.Gly397Val (Ahuja et al. 2008). In the first family, one branch was homozygous for p.Gly397Val mutation and the second branch was compound heterozygous for p.Gly397Val and p.Arg283Trp while the second family was homozygous for p.Arg283Trp mutation (Ahuja et al. 2008).

Miscellaneous Genetic Disorders In a family originally from Oman, one child was diagnosed with infantile systemic hyalinosis (MIM 2364900). This is an autosomal recessive disorder in which the main clinical symptoms include painful joint contractures, generally thickened skin with livid-red hyper pigmentation over bony prominence, fleshy nodules in the perianal region, gingival hypertrophy, and increased susceptibility to bone fractures and infections. The child presented with joint contractures, restlessness, and pain on handling. He had livid-red macular lesions over bony prominences. Genetic study revealed homozygous mutation in the CMG2 gene (p.L45P) (Al-Gazali unpublished data). In an inbred UAE family, four children were diagnosed as having combined immune deficiency microcephaly of Cemunnous/XLF type (Al-Gazali unpublished data). Multiple pterygium syndrome (MIM 265000) was diagnosed in one UAE national family originally from Pakistan. Two children were affected. Both presented with joint contractures at birth and developed pterygia with time. Both had expressionless face and had normal intelligence. Genetic study revealed a homozygous mutation in the embryonal acetylcholine receptor subunit (CHRNG) (IVS4-9T > C) (Morgan et al. 2006). Autosomal recessive Russell-silver syndrome was seen in nine children from two inbred UAE families originally from Oman. Features included Intrauterine Growth Retardation (IUGR), triangular face, large eyes, depressed nasal bridge, short neck, short thorax with pectus excavatum, asymmetric length of limbs, clinodactyly, and normal intelligence. There was poor response to growth hormone therapy (Al-Gazali unpublished data). Examples of other genetic disorders reported or seen in the genetic clinic include ataxia telengectasia, Chediac-Higashi syndrom, Cornelia de Lange syndrome, Noonan syndrome, neurofibromatosis, tuberous sclerosis, Crouzon and Saethre-Chotzen syndrome, Cockayne syndrome, Beckwith-wiedemann syndrome, Coffin-Seris syndrome, hypophosphatasia, Williams syndrome, Prader-Willi and Angelman syndrome, Bruck syndrome, Holt-Oram syndrome, split hand/foot malformation with long bone deficiency (Naveed et al. 2007), and Sotos syndrome (Table 22.2).

CHIME-like syndrome (MIM 612379) Catechoaminergic polymorphic ventricular tachycardia Peters plus like syndrome

Bifid nose, renal and rectal Malformation (MIM 608980) Bamforth-like syndrome

Macrocephaly-multiple epiphyseal dysplasia (MIM607131)

Retinopathy, aplastic anemia, CNS abnormalities with IUGR (MIM 268130) Agyria-pacygyria with agenesis of corpus callosum Al-Gazali syndrome (MIM 609465)

þ þ þ

UAE

Sudanese

Syrian

þ

Palestinian

þ þ

Palestinian Omani

7p14-p22

FREM1 c.2721delG (p.V907fs)

Ch.15q26

þ

Sudanese

þ

þ

Palestinian

Egypt

?

Gene and mutation

Sudanese

Table 22.2 New genetic disorders diagnosed in the UAE Disorder Ethnic origin Consanguinity

Anterior segments anomalies of eye, growth retardation, endocrine abnormalities

Choanal atresia,athelia/ hypothelia and thyroid gland anomalies Ichthyoisis, ocular coloboma, brain malformation Sudden death

Macrocephaly with absence of corpus callosum and multiple epiphyseal dysplasia Nasal defect with renal agenesis and rectal atresia

Anterior segment anomalies of the eye with clefting and skeletal abnormalities

Same as in title

Manifestation

Genetic Disorders in the United Arab Emirates (continued)

Al-Gazali et al. 2009

Bhuiyan et al. 2007


Al-Gazali et al. (2002a, b)

Al-Gazali et al. 2002a, Alazami et al. 2009

Al-Gazali and Bakalinova (1998), Bayoumi et al. (2001)

Al-Gazali et al. 1994a, 1999b

Sztriha et al. 1998

Revesz et al. (1992)

References

22 667

Manifestation

As in title

As in title

þ

þ

þ

UAE

UAE of Omani origin

Sudanese

Micrencephaly with simplified gyral pattern with abnormal myelination and arthrogryposis Optic nerve coloboma and renal anomalies associated with arthrogryposis multiplex Congenital bowing associated with camptodactyly and agenesis of corpus callosum

þ

UAE (Baluchi origin)

TORCH-like syndrome

þ

þ

Flat face with joint dislocation and congenital heart disease Macrocephaly, webbed neck, CHD, distinctive face Scalp defect, abnormal ear and hypoplastic nipple with developmental delay Developmental delay, brain calciffication and destruction, cataract, CHD. Brain malformation , microcephaly and arthrogryposis

Gene and mutation

þ

Consanguinity

UAE

UAE (Iranian origin) UAE

Ethnic origin

Scalp-ear-nipple like syndrome

Noonan-like

Larsen-like

Table 22.2 (continued) Disorder

Al-Gazali et al. (2000b)

Al-Gazali et al. (2000a)

Sztriha et al. 1999

Al-Gazali et al. (1999c), unpublished data


Al-Gazali et al. (1996a, b, c)

Baasanjav et al. 2009

References

668 L. Al-Gazali and B.R. Ali

22


669

Future Directions It is clear that genetic disorders have a great impact on morbidity and mortality in the UAE creating a burden on the health system and financial resources. Despite the progress in genetics research and the establishment of several prevention programs for genetic diseases in this country, genetic disorders continue to be a big problem in this country and genetic counseling has not been very effective in the control of these disorders. This is probably due to the cultural and religious beliefs of the community, the unchanging traditional practice of consanguineous marriages, and most importantly to the lack of options available to carrier couples. For any prevention program to be effective, options need to be made available for the community. This point need to be addressed and the current legal and religious attitudes in this country need to be discussed and reviewed. In addition, effective genetic counseling requires an appropriate infrastructure with adequate genetic diagnostic facilities. For a small population like that of the UAE, there should be one national center to deal with referred cases, implement research projects, and develop expertise in disorders which are prevalent in this community. The center should also provide specialist training for clinical genetics, molecular genetics, and cytogenetics in addition to training genetic counselors. The newly established “Genes and Disease Research Center” in the FMHS is a step in the right direction. The government should also promote the development of education programs and materials for the community and encourage collaboration with non-government organizations with emphasis on patients and parents organizations ensuring the care for individuals with handicap or chronic illness and their integration into society. In addition, more research on the molecular causes of single-gene disorders should be prioritized in view of the immediate impact of such findings on diagnosis and prevention approaches.

References Abbes S, Rad A, Fitzgerald P, Dormer P, Blouquit Y, Kister J, Galacteros F, Wajeman H (1992) HB Al Ain Abu Dhabi [a 18(A16)Gly!Asp]: A new haemoglobin variant discovered in an Emirati family. Haemoglobin 16:355–362 Abdul Aziz S, Salem F, Gohary A (1991) Cystic fibrosis in the United Arab Emirates. Emerg Med J 9:202–204 Abdulla MM (1978) The United Arab Emirates: a modern history. Harper and Row, New York, pp 221–243 Abdulrazzaq YM (1989) Waardenburg’s syndrome with long segment Hirschsprung’s disease in an Omani family. Emirates Med J 7:26–29 Abdulrazzaq YM, Micallef R, Qureshi MM, Dawodu A, Ahmed I, Khidr A, Bastaki SMA, Al-Kayat AI, Bayoumi RA (1999) Diversity in expression of glucose-6-phosphate dehydrogenase deficieny in females. Clin Genet 55:13–19 Abdulrazzaq YM, Ibrahim A, Al-Khayat AI, Nagelkerke N, Ali BR (2009) R58fs Mutation in the HGD Gene in a Family with Alkaptonuria in the UAE. Ann Hum Genet 73:125–130

670


Abou-Chaaban M, Al Murbatty B, Abdul Majid M (1997) Spectrum of pediatric renal diseases in Dubai. Saudi J Kidney Dis Transpl 8:310–313 Afifi AM, Abdul-Jabbar MA (2007) Saudi newborn screening. A national public health program: needs, costs, and challenges. Saudi Med J 28:1167–1170 Agarwal A, Simha V, Arioglu Oral E, Gordon P, O’Rahilly S, Zaidi Z, Gurakan F, Arslanian SA, Klar A, Ricker A, White NH, Bindl L, Herbst K, Kennel K, Patel S, Al-Gazali L, Garg A (2003) Pheotypic and Genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab 88:4840–4847 Ahuja Y, Kohl S, Traboulsi EI (2008) CNGA3 mutations in two United Arab Emirates families with achromatopsia. Mol Vis 14:1293–1297 Alazami AM, Shaheen R, Alzahrani F, Snape K, Saggar A, Brinkmann B, Bavi P, Al-Gazali LI, Alkuraya FS (2009) FREM1 mutations cause bifid nose, renal agenesis and anorectal malformations syndrome. Am J Hum Genet 85:414–418 Al Talabani J, Shubbar AI, Mustafa KE (1998) Major congenital malformations in United Arab Emirates (UAE): need for genetic counselling. Ann Hum Genet 62(Pt 5):411–418 Al-Ali MT, Al-Hashmi H, Mohammed N, Ahmed Z (2006) New perspectives in inborn errors of metabolism: the Dubai experience. In Genetic Disorders in Arab World-Bahrain, Centre for Arab Genomic Studies Work Group Alef T, Torres S, Hausser I, Metze D, Tursen U, Lestringant GG, Hennies HC (2009) Ichthyosis, follicular atrophoderma and hypotrichosis caused by mutations in ST14 is associated with impaired profilaggrin processing. J Invest dermatol 129:862–869 Al-Gazali LI (1998) A genetic aetiological survey of severe childhood deafness in the United Arab Emirates. J Trop Paed 44:157–160 Al-Gazali LI (2005) Attitudes towards genetic counseling in the United Arab Emirates. Community Genet 8:48–51 Al-Gazali LI, Abo Saad F (1995) Autosomal Recessive Omodysplasia. Clin Dysmorphol 4: 52–57 Al-Gazali LI, Al Talabani J (1996) Setleis Syndrome: Autosomal Recessive or Autosomal Dominant Inheritance. Clin Dysmorphol 5:249–254 Al-Gazali LI, Dawodu A (1997) The syndrome of hypoparathyroidism growth retardation, developmental delay and distinctive facies. Clin Dysmorphol 6:233–237 Al-Gazali LI, Bakalinova D (1998) Autosomal recessive syndrome of macrocephaly multiple epiphyseal dysplasia and distinctive facial appearance. Clin Dysmorphol 7:177–184 Al-Gazali LI, Khalil M, Devadas K (1993) A Syndrome of Insulin Resistance Resembling Leprechaunism in Five Sibs of Consanguineous Parents. J Med Genet 30:470–475 Al-Gazali LI, Lytle W (1994) Otospondylomega epiphyseal dysplasia (OSMED) report of three sibs and review of the literature. Clin Dysmorphol 3:46–54 Al-Gazali LI, Al-Talabani J, Mosawi A, Lytle W (1994a) Anterior segment anomalies of the eye, clefting and skeletal abnormalities Michls syndrome or new syndrome? Clin Dysmorphol 3:238–244 Al-Gazali LI, Sabarinathan K, Khidir A (1994b) Micropthalmia and distal limb abnormalities. Clin Dysmorphol 3:258–262 Al-Gazali LI, Dawodu AH, Sabarinathan K, Varghese M (1995a) The profile of congenital abnormalities in UAE population. J Med Genet 32:7–13 Al-Gazali LI, Makia S, Azzam A, Hall C (1995b) Walcott-Rallison Syndrome. Clin Dysmorphol 4:227–234 Al-Gazali L, Varghese M, Varady E, Al Talabani J, Scorer J, Bakalinoval D (1996a) Neonatal Schwartz-Jampel syndrome: a common AR syndrome in the UAE population. J Med genet 33:203–211 Al-Gazali LI, Bakalinova D, Sztriha L (1996b) Spondylo Metaepiphyseal Dysplasia Abnormal Calcification type. Clin Dysmorphol 5:197–206 Al-Gazeli LI, Aziz SA, Bakalinova D (1996c) Desbuquois syndrome in an Arab Bedouin family. Clin Genet 50(4):255–259

22


671

Al-Gazali LI, Aziz SAA, Salem F (1996d) A syndrome of short stature, mental retardation, facial dysmorphism, short webbed neck, skin changes and congenital heart disease. Clin Dysmorphol 5:321–327 Al-Gazali LI, Bener A, Abdulrazzaq YM, Micallef R, Al-Kayat AI, Gaber T (1997) Consanguineous marriages in the United Arab Emirates. J Biosoc Sci 29:491–497 Al-Gazali LI, Sztriha L, Dawodu A, Varady E, Bakir M, Khadir A, Johansen J (1999) Complex consanguinity associated with short rib polydactyly syndrome III and congenital infection like syndrome: a diagnostic problem in dysmorphic syndromes. J Med Genet 36:461–466 Al-Gazali LI, Sztriha L, Dawodu A, Bakir M, Varghese M, Varady E, Scorer J, Abdulrazzaq YM, Bener A, Padmanabhan R (1999a) Pattern of central nervous system anomalies in a population with a high rate of consanguineous mattiages. Clin Genet 55:95–102 Al-Gazali LI, Bakir M, Sedaghatian MN, Nath R, Hass D (1999b) Anterior segment anomalies of the eye with multiple skeletal anomalies and early lethality: confirmation of an autosomal recessive syndrome. Clin Dysmorphol 8:81–92 Al-Gazali LI, Dawodu A. The syndrome of hypoparathyroidism growth retardation, developmental delay and distinctive facies. (1997) Clin Dysmorphol 6 :233–237 Al-Gazali LI, Bakir M, Hamid MY, Haas D, Amirlak I, Rushdi R (2000a) A new syndrome of optic nerve colobomas and renal abnormalities associated with arthrogryposis multiplex. Clin Dysmorphol 9:183–189 Al-Gazali LI, Bakir M, Hamid MY, Nath R, Haas D (2000b) Congenital bowing of the long bones associated with camptodactyly and agenesis of corpus callosum. Clin Dysmorphol 9:93–99 Al-Gazali LI, Sztriha L, Sakaff F, Hass D (2001) Gerodermia Osteodysplatica and wrinkly skin syndrome: are they the same. Am J Med Genet 101:213–220 Al-Gazali LI, Bakir M, Hamud OA, Gerami S (2002a) An autosomal recessive syndrome of nasal anomalies associated with renal and ano-rectal malformations. Clin Dysmorphol 11:33–38 Al-Gazali LI, Hamid Z, Hertecant J, Bakir M, Nath KA (2002b) An autosomal recessive syndrome of choanal atresia, athelia/hypothelia and thyroid gland anomalies overlapping Bamforth’s syndrome ANOTHER syndrome and methimazole emberyopathy. Clin Dysmorphol 11:79–85 Al-Gazali LI, Bakir M, Hamid Z, Varady E, Varghese M, Haas D, Bener A, Padmanabhan R, Abdulrazzaq YM, Dawodu A (2003a) Birth prevalence and pattern of osteochondrodysplasias in an inbred high risk population. Birth Defects Res (Part A) 125:125–132 Al-Gazali LI, Hertecant J, Ahmed R, Khan NA, Padmanabhan R (2003b) Further delineation of Hennekam syndrome. Clin Dysmorphol 12:227–232 Al-Gazali LI, Ravenscroft A, Feng A, Shubber A, Al-Saqqaf A, Haas D (2003c) Stuve-Wiedemann syndrome in children surviving infancy: clinical and radiological features. Clin Dysmorphol 12:1–8 Al-Gazali L, Jehier K, Nazin B, Abtin F, Haas D, Sadagahatian R (2003d) Further delineation of Raine syndrome. Clin Dysmorpholo 12:89–94 Al-Gazali LI, Alwash R, Abdulrazzaq YM (2005) United Arab Emirates: Communities and Community Genetics. Community Genet 8:186–196 Al-Gazali L, Nath R, Iram D, Al Malik H (2007) Hpotonia, developmental delay and features of scalp-ear-nipple syndrome in an inbred Arab kindred. Clin Dysmorphol 16:105–107 Al-Gazali L, Hertecant J, Algawi K, El Teraifi H (2008) A new autosomal recessive syndrome of ocular colobomas. Ichhthyosis, brain malformations and endocrine abnormalities in an inbred emirati family. Am J Med Genet A 146A:813–819 Al-Gazali L, Shather B, Kaplan W, Algawi K, Ali B (2009) Anterior segment anomalies of the eye, growth retardation associated with hypoplastic pituitary gland and endocrine abnormalities: Jung syndrome or new syndrome? Am J Med Genet 149:251–256 Al-Hosani H, Salah M, Saade D, Osman H, Al-Zahid J (2003) United Arab Emirates National Newborn Screening Programme: an evaluation 1998-2000. East Mediterr Health J 9:324–332 Allegra M, Gagnoux-Palacios GY, Roques S, Lestringant G, Ortonne J, Meneguzzi G (2003a) Rapid decay of alpha 6 integrin caused by a mis-sense mutation in the propeller domain results in severe junctional epidermolysis bullosa with pyloric atresia. J Invest Dermatol 121:1336–1346

672


Allegra M, Gagnoux-Palacios GY, Roques S, Lestringent G, Otonne J, Meneguzzi G (2003b) Rapid decay of alpha 6 integrin caused by a mis-sense mutation in the propeller domain results in severe junctional epidermolysis bullosa with pyloric atresia. J Invest Dermatol 121:1336–1346 Alwash R, Abbas A (1999) Public Health practice in UAE. Public Health Med 1:113–117 Al-Yahyaee S, Al-Gazali LI, Al-Barwany H, Al-Kindi M, Chand P, Khoul R, Poovathor J, Guru Raj A, Sztriha L, Parrado A, Ott J, De Jonghe P, Van Broeckhoven C, Timmerman V, Bayoumi RA (2006) A novel locus for autosomal recessive hereditary paraplegia with thin corpus callosum and epilepsy. Neurology 66:1230–1234 Anwar S, Afify H, Hussein A (1986) Dystrophia myotonica presenting as infertility. Emirates Med J 4:137–139 Awad M, Bayoumi R (1993) Sickle cell disease in adult Bedouins of Al Ain District, UAE. Emerg Med J 11:21–24 Baasanjav S, Al-Gazali L, Hashiguchi T, Mizumoto S, Fischer B, Horn D, Seelow D, Ali BR, Aziz SA, Langer R, Becker C, Nurnberg G, Cantagrel V, Gleeson JG, Linder TH, Nurnberg P, Sugahara K, Mundlos S, Hoffmann K (2009) Faulty initiation step (GIcAT-I) of proteoglycan synthesis causes joint dislocations, facial abnormalities and congenital heart defect, a distinct disease that overlaps with Larsen syndrome, multiple hereditary exostosis, Ehlers-Danlos syndrome and progeria (submitted) Bartels CF, Bukulmez H, Padayatti P, Rhee DK, Ravenswaaiji-Arts CV, Pauli RM, Mundlos S, Chitayat D, Shih L, Al-Gazali LI, Kant S, Cole T, Morton J, Cormier-Daire V, Faivre L, Lees M, KirkJ MGR, Akker FVD, Warman ML (2004) Human skeletal growth is regulated by transmembrane natriuretic peptide receptor NPR-B. Am J Hum Genet 75:27–34 Bayoumi RA, Nur-E-Kamal MSA, Tadayyon M, Mohamed KKA, Mahboob BH, Qureshi MM, Lakhani MG, Ausiad MO, Kaeda J, VullamyTJ LL (1996) Molecular characterization of erythrocyte glucose –6-phosphate dehydrogenase deficiency in Al Ain District, United Arab Emirates. Hum Hered 46:136–141 Bayoumi R, Saar K, Nurnberg G, Reis A, Nur-E-Kamal M, Al-Gazali LI (2001) Localization of a gene for an autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia (MED) and distinctive facies to chromosome 15q26. J Med Genet 38:369–373 Baysal E (2001) Hemoglobinopathies in the United Arab Emirates. Hemoglobin 25:247–253 Baysal E (2005) Molecular heterogeneity of b thalassemia in the United Arab Emirates. Community Genet 8:35–39 Baysal E, Yousef I, Zeinali M, Abdulla H, Essa M, Taleb M (2007) Molecular basis oh haemoglobinopathies in the UAE: implication for prenatal diagnosis and prevention programmes. Emerg Med J 25:7–21 Benson PF, Fahmy NA, Vaswani K, Semrin A (1987) Cystic Fibrosis in the United Arab Emirates. A Case report. Emerg Med J 5:156–157 Bhuiyan ZA, Hamdan M, Shamsi E, Postma AV, Mannens MM, Wilde A, Al-Gazali L (2007) A novel early onset lethal form of catecholaminergic polymorphic ventricular tachycardia maps to chromosome 7p14-p22. J Cardiovasc Electrophysiol 8:1060–1066 Biels SL, Silhavy JL, Brancati F, Kisseleva MV, Al-Gazali L, Sztriha L, Bayoumi RA, Zaki M, Rosti O, Kayserili H, Scott LC, Field SJ, Dallapiccola B, Majerus PW, Valente EM, Gleeson JG (2009) Mutations in the inositol polyphosphate-5-phosphatase E gene link phosphatidyl inositol signaling to the ciliopathies. Nat Genet 41:1032–1036 Brickwood S, Bonthron DT, Al-Gazali LI, Piper K, Hearn D, Wolson DI, Hanley NA (2003) Wolcott-Rallison syndrome: pathogenic insight into neonatal diabetes from new mutation and expression studies of ELF2Ak3. J Med Genet 40:685–689 Brockington M, Sewry CA, Herrmann R, Naom I, Dearlove A, Rhodes M, Topaloglu H, Dubowitz V, Voit T, Muntoni F (2000) Assignment of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42. Am J Hum Genet 66:428–435 Campbell DA, McHale DP, Brown KA, Moynihan LM, Houseman M, Karbani G, Parry G, Janjua AH, Newton V, Al-Gazali LI, Markham AF, Lench NJ, Mueller RF (1997) A new locus for non-syndromal autosomal recessive sensorineural hearing loss (DFNB16) maps to human chromosome 15q21-q22. J Med Genet 34:1015–1017

22


673

Chavala SH, Sari A, Lewis H, Pauer GJT, Simpson E, Hagstrom SA, Traboulsi EIT (2005) An Arg311GIN NR2E3 mutation in a family with classic Goldmann-Favre syndrome. Invest Ophthalmol Vis Sci 46: E-abstract 1824 Christianson A, Modell B, Howson C (2006) March of Dimes global report on birth defects: the hidden toll of dying and disabled children. White Plains, NY: March of Dimes Birth Defects Foundation Dagoneau N, Scheffer D, Huber C, Al-Gazali LI, Di Rocco M, Godard A, Marrinovic J, Raas-Rothschild A, Sigaudy S, Unger S, Nicole S, Fontaine B, Taupin J, Moreau J, Superti-Furga A, Le Merrer M, Bonaventure J, Munnich A, Legeai-Mallet L, Cormier-Daire V (2004) Null Leukemia Inhibitory Factor Receptor (LIFR) mutations in Stuve-Wiedemann/ Schwartz-Jampel 2 syndrome. Am J Hum Genet 74:298–305 Dagoneau N, Bellais S, Blanchet P, Srda P, Al-Gazali L, Di Rocco M, Huber C, Goff L, Munnich A, Cormier-Daire V (2007) Mutations in Ctytokine-Like Factor 1 (CRLF1) account for both Crisponi and Cold Induced Sweating syndromes. Am J Hum Genet 80:966–970 Dawodu A, Vardy E, Varghese M, Al-Gazali LI (2000) Neonatal audit in the United Arab Emirates: a country with rapidly developing economy. East Mediterr Health J 6:55–64 Dawson K, Frossard P (1994) Cystic Fibrosis in the UAE: Clinical presentation. Emerg Med J 12:245–247 Dawson KP, Frossard PM (2000) The geographic distribution of cystic fibrosis mutations gives clues about population origins. Eur J Paediatr 159:496–499 Desnick RJ, Tukel T, Diaz N, Al-Gazali LI, Marion RW, Clark RD, Cadilla C (2004) Homozygous nonsense mutations in TWIST2 gene cause Setleis syndrome. Am Hum Genet Meeting, Toornto Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, Scott LC, Gururaj A, Al-Gazali L, Al-Tawari AA, Kayserili H, Sztriha L, Gleeson GG (2004) Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet 75:979–987 Ecckl KM, Stevens HP, Lestringant G, Westenberger-Treumann M, Traupe H, Hinz B, Frossard PM, Stadler R, Leigh IM, Nurnberg P, Reis A, Hennies HC (2003) Mal de Meleda caused by mutations in the gene for SLURP-1 in patients from Germany, Turkey, Palestine, and the United Arab Emirates. Hum Genet 112:50–56 El Ghouzzi V, Dagoneau N, Kinning E, Thauvin-Robinet C, Chemaitilly W, Prost-Squarcioni C, Al-Gazali L, Verloes A, Le Merrer M, Munnich A, Trembath R, Cormier-Daire V (2003) Mutations in a novel gene Dymeclin (FLJ20071) are responsible for Dyggve-Melchoir-Clausen Syndrome. Hum Mol Genet 12:357–364 El-Kalla S, Baysal E (1998) Alpha thalassemia in the United Arab Emirates. Acta Haematol 100:49–53 Faivre L, Le Merrer M, Al-Gazali LI, Ausems MG, Bitoun P, Bacq D, Maroteaux P, Munnich A, Cormier-Daire V (2003) Homozygosity mapping of a Desbuquois dysplasia locus to chromosome 17q25.3. J Med Genet 40:282–284 Frossard P, Hertecant J, Bossard Y, Dawson KP (1999a) Genotype-phenotype correlations in Cystic Fibrosis: clinical severity of mutation S549R (T>G). Eur Respir J 13:100–102 Frossard P, Lestringant G, Girodon E, Goossens M, Dawson KP (1999b) Determination of the prevalence of Cystic Fibrosis in the United Arab Emirates by genetic carrier screening. Clin Genet 55:496–497 Galadari I, Galadari H (2004) Case study: erythrokeratodermia variabilis. Skin med 3:231–232 Georgiou T, Drousiotou A, Campos Y, Caciotti A, Sztriha L, Gururaj A, Ozand P, Zammarchi E, Morrone A, D’Azzo A (2004) Four novel mutations in patients from the middle east with infantile form of GM1-gangliosidosis. Hum Mutat 24:352 Giunta C, Randolph A, Al-Gazali LI, Brunner HG, Kraenzlin ME, Steinmann B (2005) The Nevo syndrome is allelic to the kyphoscoliotic type of Ehlers-Danlos syndrome VIA (EDS VIA)expansion of the phenotype. Am J Med Genet 133A:158–164 Guerrini R, Barkovich AJ, Sztriha L, Dobyns WB (2000) Bilateral frontal polymicrogyria: a newly recognized brain malformation syndrome. Neurology 54:909–913

674


Hamdan MA, Almalik MH, Mirghani HM (2008) Early administration of enzyme replacement therapy for Pompe disease: short term follow up results. J Inherit Metab Dis [Epub ahead of print] Heard-Bay F (1976) The people of the UAE. Em Nat Hist Group (Abu Dhabi) 5:11–15 Heard-Bay F (1999) The Tribal society of the UAE and its traditional economy. In: Edit Gareeb E, Al Abed I (eds) Perspectives on the UAE. Trident Press Ltd, London, pp 254–272 Hennekam RCM, Geerdink RA, Hamel BCJ, Hennekam FAM, Kraus P, Rammeloo JA (1989) Autosomal recessive intestinal lymphangiectasia and lymphedema with facial anomalies and mental retardation. Am J Med Genet 34:593–600 Herticant J, Al-Gazali L, John A, Karuvantevida NS, and Ali BR (2009) A novel mutation in ARG1 gene is responsible for arginase deficiency in an Asian family. Saudi Med J 12:160–163 Hone J, Acillin D, Al-Gazali LI, Lestringant G, Orban T, Taylor SI (1994) Homozygosity for a new mutation Ile 119 – met in the insulin receptor gene in 5 siblings with familial insulin resistance. J Med Genet 9:715–717 Horita S, Yamada H, Inatomi J, Moriyama N, Sekine T, Igarashi T, Endo Y, Dasouki M, Ekim M, Al-Gazali L, Shimadzu M, Seki G, Fujita T (2005) Functional analysis of NBC1 mutants associated with proximal renal tubular acidosis and ocular abnormalities. J Am Soc Nephrol 16:2270–2278 Houseman MJ, Jackson AP, Al-Gazali LI, Badin RA, Roberts E, Mueller RF (2001) A novel mutation in a family with non-syndromic sensorineural hearing loss that disrupt the newly characterized OTOF long isoform. J Med Genet 38:E25 Kamel K (1979) Heterogeneity of sickle cell anaemia in Arabs: review of cases with various amounts of fetal haemoglobin. J Med Genet 16:428–430 Kantarci S, Al-Gazali L, Hill R, Donnai D, Black G, Bieth E, Chassaing N, Lacombe D, Devriendt K, Teebi A, Loscertales M, Robson C, MacLaughlin DT, Noonan K, Russell M, Walsh C, Donahoe PK, Pober B (2007) Mutations in megalin, a multiligand receptor, cause DonnaiBarrow syndrome and facio-oculo-acoustic-renal syndromes. Nat Genet 39:957–959 Lestringant GG, Hadi SM, Qayed KI, Blayney BJ (1992) Mal de Meleda: recessive transgressive palmoplantar keratoderma with three unusual facultative features. Dermatology 184:78–82 Lestringant GG, Frossard PM, Adeghate E, Qayed KI (1997) Mal de Meleda: a report of four cases from the United Arab Emirates. Pediatr Dermatol 14:186–191 Lestringant GG, Kuster W, Frossard PM, Happle R (1998) Congenital ichthyosis, follicular atrophoderma, hypotrichosis, and hypohidrosis: a new genodermatosis? Am J Med Genet 75:186–189 Lestringant GG, Frossard PM, Eckl KM, Reis A, Hennies HC (2001) Genetic and clinical heterogeneity in transgressive palmoplantar keratoderma. J Invest Dermatol 116:825–827 Lestringant GG, Piletta P, Feldmann R, Galadari I, Frossard PM, Saurat JH (1996) Coexistence of atopic dermatitis and lichen nitidus in three patients. Dermatology 192(2):171–173 Mardy S, Miru Y, Endo F, Mastsuda I, Sztriha L, Frossard P, Moosa A, Imail EAR, Macaya A, Andria G, Toscano E, Gibson W, Graham GE, Indo Y (1999) Congenital insensitivity to pain with anhydrosis: novel mutations in the TRKA (NTRK1) gene encoding a high affinity receptor for nerve growth factor. Am J Hum Genet 64:1570–1579 Marsh SE, Leeflang EP, Woods CG, Guru Raj A, Al-Gazali LI, Sztriha L, Gleeson JG (2003) Linkage analysis in families with Joubert syndrome plus oculo-renal involvement identifies the CORS2 locus on chromosome 11p12-q13.3. Am J Hum Genet 73:656–662 Matejas V, Al-Gazali L, Amirlak I, Zenker M (2006) A syndrome comprising childhood-onset glomerular kidney disease, cataract, anterior chamber abnormalities, and progressive loss of vision is caused by mutated LAMB2. NDT Nephrol Dial Transplant 21:3283–3286 Ministry of Health, United Arab Emirates (1993). Annual Report Ministry of Health, United Arab Emirates (2000). Annual Report Mohammed AM, Al-Hilli F, Nadkarni KV, Bhagwat GP, Bapat JP (1992) Hemoglobinopathies and glucose – 6 – phosphate dehydrogenase deficiency in hospital births in Bahrain. Ann Saudi Med 12:536–539

22


675

Morgan N, Brueton L, Cox P, Greally M, Tolmi J, Pasha S, Aligianis IA, van Bokhoven H, Marton T, Al-Gazali L, Morton JEV, Oley C, Johnson CA, Trembath RC, Brunner HG, Maher ER (2006) Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and escobar variants of multiple pterygium syndromes. Am J Hum Genet 79:390–392 Muntoni F, Taylor J, Sewry CA, Naom I, Dubowitz V (1998) An early onset muscular dystrophy with diaphragmatic involvement, early respiratory failure and secondary alpha2 laminin deficiency unlinked to the LAMA2 locus on 6q22. Eur J Paediatr Neurol 2:19–26 Murthy SK, Malhortra AK, Mani S, Shara ME, Al-Rowaished EE, Naveed S, Alkhayat AI, Alali MT (2007) Incidence of Down syndrome in Dubai, UAE. Med Princ Pract 16:25–28 Nakano A, Lestringant G, Paperna T, Bergman R, Greshoni R, Frossard P, Kanaan M, Meneguzzi G, Pulkkinen L, Sprecher E (2002) Junctional epidermolysis bullosa in the Middle East: clinical and genetic studies in a series of consanguineous families. J Am Acad Dermatol 46:510–516 Naveed M, Nath SK, Gaines M, Al-Ali MT, Al-Khaja N, Hutchings D, Golla J, Deutsch S, Bottani A, Antonarakis SE, Ratnamala U, Radhakrishna U (2007) Genome wide linkage scan for split-hand/foot malformation with long-bone deficiency in a large Arab family identifies two novel susceptibility loci on chromosomes 1q42.2-q43 and 6q14.1. Am J Hum Genet 80:105–111 Pulleyn LJ, Jackson AP, Roberts E, Carridice A, Muxworthy C, Houseman M, Al-Gazali LI, Lench NJ, Markham AF, Mueller RF (2000) A new locus for autosomal recessive nonsyndromal sensorineural hearing impairment (DFNB27) on chromosome 2q23-q31. Eur J Hum Genet 8:991–993 Quaife R, Al-Gazali LI, Abbes S, Fitzgerald P, Old J (1994) Spectrum of B thalassemia mutations in the UAE national population. J Med Genet 34:59–61 Ramahi SA (1973) Economic and political evolution in the Arabian Gulf States. Carlton Press, New York, pp 42,45,57,81,203 Rauch A, Theil CT, Schindler D, Wick U, Crow YJ, Ekici AB, van Essen AJ, Goecke TO, Al-Gazali L, Chrzanowska KH, Zweier C, Brunner HG, Becker K, Curry CJ, Dallapiccola B, Devriendt K, Dorfler A, Kinning E, Megarbane A, Meinecke P, Semple RK, Spranger S, Toutain A, Trembath RC, VoB E, Wilson L, Hennekam R, de Zegher F, Dorr HG, Reis A (2008) Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science 319:816–819 Raupp P, Varady E, Duran M, Wanders RJ, Waterham HR, Houten SM (2004) Novel genotype of mevalonic aciduria with fatalities in premature siblings. Arch Dis Child Fetal Neonatal Ed 89 (1):F90–F91 Revesade B, Escandle-Beillard N, Dimopoulou A, Fischer B, Chng SC, Li Y, Shboul M, Tham PY, Kayserili H, Al-Gazali L, Shahwan M, Brancati F, Lee H, O’Connor B, Schmidt-von Kegler M, Merriman B, Nelson SF, Masri A, Guerra D, Ferrari P, Nando A, Rajab A, Markie D, Gray M, Nelson J, Grix A, Sommer A, Savarirayan R, Janecke AR, Steichen E, Sillence D, HauBer I, Budde B, Nunberg P, Seeman P, Zambruno G, Dallapiccola B, Schuelke M, Robertson S, Hamamy H, Wollink B, Maldergem LV, Mundlos S, Kornak U (2009) Mutations in the PYCR1 gene cause Cutis Laxa with progeroid features. Nat Genet 41(9):1016–1021 Revesz T, Fletcher S, Al-Gazali LI, DeBuse P (1992) Bilateral retinopathy aplastic anaemia and central nervous system abnormalities. Possibly a new syndrome. J Med Genet 29:673–675 Safa WF, Lestringant GG, Frossard PM (2001) X-linked dyskeratosis congenital:restrictive pulmonary disease and a novel mutation. Thorax 56:891–894 Saleheen D, Frossard PM (2006) 3120+1 G!A: a rare variant in Emirati CF patients. J Coll Physicians Surg Pak 16:139–140 Sander CS, Salman N, van Geel M, Broers JL, Al-Rahmani A, Chedid F, Hausser I, Oji V, Al Nuaimi K, Berger TG, Verstraeten VL (2008) A newly identified splice site mutation in ZMPSTE24 causes dermatopathy in the Middle East. Br J Dermatol 159:961–967 Simpson MA, Hsu R, Keir LS, Hao J, Sivapalan G, Ernst LM, Zackai EH, Al-Gazali LI, Hulskamp G, Kingston HM, Prescott TE, Ion A, Patton MA, Murday V, George A, Crsby AH (2007)

676


Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development. Am J Hum Genet 81:906–912 Smith UM, Tee JT, Consugar M, Tee LJ, McKee BM, Maina E, Whelan S, Morgan NV, Gissen P, Goranson E, Aligianis IA, Lilliquist S, Ward CJ, Pasha S, Sharif SM, Batman PA, Bennett CP, Woods CG, McKeown C, Bucourt M, Miller CA, Punyashthiti R, Cox P, AlGazali L, Trembath RC, Torres VE, Kelly DA, Attie-Bitach T, Maher ER, Gattone VH, Harris PC, Johnson CA (2006) Meckelin (MKS3), a novel transmembrane protein is mutated in MeckelGruber syndrome and the wpk rat. Nat Genet 38:191–196 Sztriha L, Al-Gazali LI, Dawodu A, Bakir M, Chandran P (1998) Agyria-Pachygria, a genesis of the corpus callosum and crebellar hypoplasia: Autosomal recessive inheritance with neonatal death. Neurology 50:1466–1469 Sztriha L, Al-Gazali LI, Varady E, Goebel H, Nork M (1999) Autosomal recessive Micrencephaly with simplified gyral pattern, abnormal myelination and arthrogryposis. Neuropediat 30:141–145 Sztriha L, Frossard P, Hofstra RM, Verlind E, Nork M (2000) Novel missense mutation in the L1 gene in a child with corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis and hydrocephalus. J Child Neurol 15:239–243 Sztriha L, Lestringant GG, Hertecant J, Frossard PM, Masouye I (2001) Congenital insensitivity to pain with anhydrosis. Pediatr Neurol 25:63–66 Sztriha L, Espinosa-Parrilla Y, Gururaj A, Amiel J, Gerami S, Johansen JG (2003) Frameshift mutation of the zinc finger homeo box 1 gene in syndromic corpus callosum agenesis (MowatWilson syndrome). Neuropediatrics 34:322–325 Sztriha L, Daodu A, Gururaj A, Johansen JG (2004) Microcephaly associated with abnormal gyral pattern. Neuropediatrics 35:346–352 Sztriha L, Johansen JG (2005) Spectrum of malformations of the hindbrain (cerebellum, pons, and medulla) in a cohort of children with high rate of parental consanguinity. Am J Med Genet 135:134–141 Taban M, Memoracion-Peralta DSA, Wang H, Al-Gazali L, Traboulsi EI (2007) Cohen syndrome: report of nine cases and review of the literature with emphasis on ophthalmic features. J AAPOS 11:431–437 Teebi AS (1994) Autosomal recessive disorders among Arabs: an overview from Kuwait. J Med Genet 31:224–233 Topley JM, Varady E, Lestringant GG (1994) Larsen syndrome in siblings with consanguineous parents. Clin Dysmorphol 3(3):263–265 Valente EM, Silhavy JL, Brancati F, Marsh SE, Barrano G, Krishnaswami SR, Castori M, Boltshauser BL, Al-Gazali L, Fazzi E, Bellaccchio E, Signorini S, Bertini E, Dallapiccola B, Gleeson JG (2006) Mutations in the CEP290 gene, encoding a putative centosomal protein, cause pleotropic forms of Joubert Syndrome. Nat Genet 38:623–625 van Haelst MM, Maiburg M, Baujat G, Jadeja SMonti E, Bland E, Pearce K, Fraser Syndrome Collaboration Group, Hennekam RC, Scambler PJ (2008) Molecular study of 33 families with Fraser syndrome new data and mutation review. Am J Med Genet 146A:2252–2257 White JM, Byrne M, Richards R, Buchanan T, Katsoulis E, Weerasingh K (1986) Red cell genetic abnormalities in Peninsular Arabs: sickle haemoglobin, G6PD deficiency, and alpha and beta thalassaemia. J Med Genet 23:245–251 White JM, Christie BS, Nam D, Daar S, Higg DR (1993) Frequency and clinical significance of erythrocyte genetic abnormalities in Omanis. J Med Genet 30:396–400 Woods CG, Person S, Sherridan E, Roberts E, Springell K, Scott S, Stern R, Cox J, Karbani G, Malik S, Toombes C, Kumar D, Al-Gazali L, Mundlos S (2006) Mutations in WNT7A cause a range of limb malformations including Furhman-syndrome and Al Awadi/Raas Rothchild/ Schnzil phocomelia syndrome. Am J Hum Genet 79:402–409

Chapter 23

Genetic Disorders Among Jews from Arab Countries Efrat Dagan and Ruth Gershoni-Baruch

History of Jews from Arab Countries The Jewish Diaspora dates back to the Assyrian and Babylonian conquests in the Levant and is portrayed by complex migratory trajectories over the ensuing millennia. Considerable conversion of autochthonic populations to Judaism, which took place during ancient times, has been offset by numerous expulsions and forced conversion of Jews to Christianity and Islam, resulting in a drastic reduction of large Jewish populations and even extermination of Jewish-ethnic communities (Khaibar (Hedjaz) in the seventh century C.E.). Some Jewish societies in Arab countries remained virtually isolated for over 1,000 years (e.g., in Yemen) whereas others were enriched by the influx of Jews from outside the Arab world. A major change includes the settling of a large number of exiled Spanish and Portuguese Jews in the Mediterranean countries at the end of the fifteenth century. Later, up into the twentieth century, cross-migration of Jews expanded some pre-existing Jewish communities in Arab countries, for example, Turkish, Kurdish, and Iranian Jews who joined the ancient Babylonian community and European Jews (Ashkenazi Jews) who settled in Libya and in Egypt. In the last 100 years, Jews originating from Arab countries, namely, the Arabian peninsula, Mesopotamia, the Levant or North Africa have emigrated to Europe, USA, and Israel (Goodman et al. 1989; Behar et al. 2008). The greater part settled in Israel and constitutes the non-Ashkenazi Jewish population, of about three million, comprising among other North African, Iraqi, Iranian, Yemenite, and Iberian Exile Jewish communities. (http://www.cbs.gov.il/ishuvim/demographic_report.pdf).

R. Gershoni-Baruch (*) Institute of Human Genetics, RAMBAM Health Care Campus and the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Institute of Technology, Haifa, Israel email: [email protected]


677

678

E. Dagon and R. Gershoni-Baruch

This chapter seeks to provide information on the profile of genetic diseases that characterize Jewish communities from Arab countries. The genetic data presented are mainly supplied by studies from Israel. Diseases will be referenced and identified both by their commonly used names and by their numbers in McKusick’s catalogs (MIM) (http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim).

Pan Ethnic Diseases The diseases described in this subsection are found at high frequencies in Jews from Arab Countries.

Familial Mediterranean Fever (FMF, MIM 249100) Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by dramatic episodes of fever and serosal inflammation. It affects primarily people of Mediterranean extraction, mostly Sepharadic Jews, Armenians, Arabs, and Turks. The disease is characterized by painful, recurrent, self-limited attacks of fever with sterile peritonitis, pleurisy, and/or synovitis. Most patients (90%) begin to suffer before 20 years of age, and 60% before 10 years of age (Sohar et al. 1967). Some patients develop systemic amyloidosis (Pras et al. 1982). FMF is mainly attributed to five founder mutations (M680I, M694V, M694I, V726A, E148Q) in the MEFV gene. Mutation M694V is frequent in North African Jews (carrier rate 11%) while mutation V726A is prevalent among all patients other than North African Jews (carrier rate 7%). It has been assumed that these mutations originated in Israel some 2,000 years ago, and the convergence of intragenic SNP haplotypes for both the M694V and the V726A chromosomes, bearing different microsatellite haplotypes, indicates an ancient founder effect at the origin of a large fraction of FMF cases from the Mediterranean basin (French FMF consortium 1997; International FMF consortium 1997; Gershoni-Baruch et al. 2001).

Cystic Fibrosis (CF, MIM 219700) Cystic fibrosis (CF) is an autosomal recessive disease that affects the exocrine glands of the lungs, liver, pancreas, and intestines and cause progressive disability due to multisystem failure. CF is attributed to mutations in the CF transmembrane conductance regulator (CFTR). The product of this gene is a chloride ion channel important in creating sweat, digestive juices, and mucus. The incidence of CF and the frequency of disease-causing mutations vary among different ethnic and geographic populations. Among Ashkenazi Jews, the frequency of CF is 1:3,300,

23

Genetic Disorders Among Jews from Arab Countries

679

similar to the frequency observed in Caucasian populations. Among non-Ashkenazi Jews, the disease occurs at a frequency of 1:2,700 among Jews from Libya, but is rare in Jews from Yemen (1:8,800), Morocco (1:15,000), Iraq (1:32,000), and Iran (1:39,000). In each Jewish ethnic group, the disease is caused by a different repertoire of mutations. About 20 mutations have been identified in non-Ashkenazi Jews enabling the identification of 90% of the CF chromosomes in this subpopulation. With this in mind, carrier screening of healthy individuals has become feasible for Jews originating from Arab countries and is currently undertaken by the ministry of health (Kerem et al. 1995; Quint et al. 2005).

Fragile X (MIM 309550) Fragile X syndrome is the second most common inherited form of mental retardation, and the carrier frequency in the general population is approximately 1 in 250 females (Rousseau et al. 1995). Fragile-X syndrome is caused by the expansion, in excess of 200 repeats (full mutation expansion) of a trinucleotide element, (CGG)n, located in the 50 untranslated region of the FMR1 gene at Xq27. Normal individuals have a range of approximately 5 to 54 repeats. Carriers of premutations (intermediate alleles in the range of 55–200 repeats) are at risk of bearing children with fragile X syndrome as such alleles can undergo expansion to the full mutation on transmission from mother to offspring. Full mutation expansions are generally accompanied by silencing of the FMR1 gene, with attendant lack of FMR1 protein synthesis, leading to fragile X syndrome. In Jews of Tunisian descent, fragile X syndrome is more prevalent than in the general population and has been attributed to a founder effect of a rare haplotype, consisting of FMR1 CGG repeats which are completely devoid of AGG interruptions that normally serve to stabilize the repeats and prevent their expansion (Falik-Zaccai et al. 1997; Toledano-Alhadef et al. 2001).

Non syndromic Deafness (MIM 121011) The DFNB1 locus, which is located on chromosome 13q11-12, was the first deafness recessive locus to be discovered. DFNB1 was initially identified by linkage analysis in a large Tunisian family exhibiting recessive hearing loss (Ben Arab et al. 1990). Disruptions at this locus are mainly attributed to mutations in the GJB2 gene, responsible for up to 50% of all cases of autosomal recessive nonsyndromic hearing impairment, with prelingual onset in most populations (Kelsell et al. 1997). GJB2 is a small gene that encodes the gap junction protein connexin 26 which is involved in potassium (k+) homeostasis in the cochlea of the inner ear. One mutation, 35delG (also referred to as 30delG), accounts for the majority of mutant alleles and its prevalence among all ethnic groups amounts to 1:30 (Sobe et al. 2000).

680


Spinal Muscular Atrophy (SMA, MIM 253300) Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by progressive muscle weakness. It is caused by a mutation in the survival motor neuron gene 1 (SMN1). SMA has a carrier frequency of 1:33–1:60 in most populations (Basel-Vanagaite et al. 2008). A multicentric study in Israel has derived a carrier prevalence of 1:50 in the various ethnic groups (unpublished data).

Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD, MIM 305900) Glucose-6-phosphate dehydrogenase deficiency (G6PD) is the most common human enzyme deficiency, with an estimated 400 million people affected, worldwide. The highest prevalence rates were reported in malaria-endemic areas. G6PD is an X-linked trait almost entirely attributable to a single widespread mutation, G6PD Mediterranean. G6PD deficiency renders erythrocytes susceptible to hemolysis under conditions of oxidative stress. Although most affected individuals are asymptomatic, exposure to oxidative stressors (drugs or infection) can elicit acute hemolysis. The ingestion of fava beans induces an oxidative stress leading to acute hemolysis (Mason et al. 2007).

Thalassemias (MIM 141800, 141850, 141900) Thalassemias are inherited autosomal recessive blood diseases that result from reduced synthesis of one of the globin chains that make up hemoglobin and constitute the most common single-gene disorder in the world. The most common types in clinical practice are those that affect either a or b chain synthesis. A selective advantage for survival in individuals with the thalassemia trait, in regions where malaria is endemic, reflects the balance between the premature death of homozygotes and the increased fitness of heterozygotes. Two active a genes, located on each chromosome 16, give a-thalassemia the unique feature of gene duplication contrasted to only one active b-globin gene on chromosome 11.

Alpha Thalassemia (MIM 141800, 141850) Alpha thalassemia is rare and is more common in Southeast Asia. Absent of one or two a genes define silent carriers with two or three, of the four genes, active. The patients are hematologically healthy, except for mild anemia and occasional low

23


681

RBC indices. In contrast, HbH disease (a-thalassemia intermedia) which results from the deletion or inactivation of three a-globin genes features mild to moderate anemia, splenomegaly, icterus, and abnormal RBC indices. Alpha-thalassemia major, attributed to complete deletion of the a gene cluster on both copies of chromosome 16, leads to the severe form of a-thalassemia, which is usually incompatible with life and causes hydrops fetalis. Other than deletions of the a-globin genes, a-thalassemia has been occasionally ascribed to missense or frameshift mutations (identified in a family of Turkish Jewish extraction and in a Kurdish family) (Oron-Karni et al. 2000).

b-Thalassemia (MIM 141900) Beta-thalassemia is due to reduced production of b chains and the formation of abnormal hemoglobin molecules. Excessive a chains, unable to form Hb tetramers, precipitate in the RBC precursors and interact with the membrane (causing significant damage). For clinical purposes, b thalassemia is divided into thalassemia major (Cooley anemia or transfusion dependent), thalassemia intermedia (of intermediate severity), and thalassemia minor (asymptomatic). Clinical symptoms include anemia, massive splenomegaly, bone deformities and growth retardation. Beta-thalassemia is caused by a repertoire of mutations in the b-globin gene that mirror migration events that occurred in the past millennium. Most of the encountered mutations are single-base changes, small deletions, or insertions of 1–2 bases. Beta-thalassemia alleles include the common Mediterranean type and other founder mutations originating in Jews from Kurdistan and Samaritans. Only one mutant allele-nonsense codon 37- appears to be indigenous to Israel. Among Kurds, Iraqis, and Yemenites, a variability of unique mutations including both deletions and point mutations were reported (Filon et al. 1994; Rund et al. 1997).

Usher Syndrome Type IIA (USH2A MIM 276901) Usher syndrome Type 2 (USH2) is a recessively inherited disorder, characterized by early onset, moderate-to-severe sensorineural hearing loss and vision impairment due to retinitis pigmentosa. The majority of USH2 cases are caused by mutations in the USH2A gene, encoding for usherin, an extracellular matrix protein, which plays an important role in the development and maintenance of neurosensory cells in both retina and cochlea. To date, over 70 pathogenic mutations of USH2A have been reported in individuals of various ethnicities. Many of these mutations are rare private mutations segregating in single families. USH2 which is occasionally diagnosed in Jewish patients of non-Ashkenazi descent is mainly due to four USH2A mutations (239–240insGTAC, 1000C > T, 2209C > T, and 12067-2A > G) accounting for 64% of mutant alleles underlying USH2 in non-Ashkenazi Jews (Auslender et al. 2008).

682


Iraq, Kurdistan and Iran Jewish settlements were established in Mesopotamia following the deportation of Israelites and Judeans by the Assyrians and Babylonians (722 B.C. and 586 B.C., respectively) and have been the leading cultural center of the Jewry world; probably, constituting the majority of living Jews. The number of their descendants at present is estimated to be 260,000. An isolated Jewish community with different linguistic, cultural, and genetics characteristics lived among the Kurds in northern Iraq and together with Kurdish Jews of south-eastern Turkey and western Iran, constitute a distinct community. Iranian Jewry comprises an ancient community with a very high degree of inbreeding. Although the community remained relatively isolated, it had strong ties with Babylonian Jewry in Iraq (Zlotogora 1995).

Beta-Thalassemia (MIM, 141900) and G6PD Deficiency (MIM 305900) Jews of Kurdistan have a high incidence of b-thalassaemia and G6PD deficiency. Beta-thalassaemia, in this population, shows an unusual mutational diversity; more than a dozen different mutations were identified, two of which account for over 50% of chromosomes studied. Four mutations are unique to Kurdish Jews and have not been discovered in any other population. A fifth was found outside Kurdish Jews, in an Iranian from Khuzistan, a region bordering Kurdistan. Two-thirds of the mutant Kurdish chromosomes carry the mutations unique to Kurdish Jews. Haplotype analysis suggests that thalassemia in central Kurdistan (Northern Iraq) has evolved primarily from multiple mutational events. In Turkish Kurdistan, the primary mechanism is genetic admixture with the local population. In Iranian Kurdistan, a founder effect appears to be partly responsible (Rund et al. 1991). G6PD in this inbred population reaches the highest known incidence in the world, and affects about 70% of males, mostly, attributable to a single widespread mutation, G6PD Mediterranean. Among the Jewish populations in Shiraz and southern Iran, the most common mutation causing G6PD deficiency is G6PD Mediterranean (563 C > T). Occasional mutations include 1376 (G > T) and G6PD A- (Oppenheim et al. 1988, 1993; Karimi et al. 2008).

Factor XI Deficiency (PTA, MIM 264900) Factor XI deficiency is a rare disease; patients with the severe form of the disease are usually at risk of excessive bleeding after surgery and injury, particularly when trauma involves tissues rich in fibrinolytic activity. The disease is found predominantly in Ashkenazi Jews, in whom two different mutations were observed. One of

23


683

them (type II mutation) was detected in four unrelated Iraqi Jewish families raising the possibility that the mutation was present in Jews already 2.5 millennia ago. The allele frequency among Iraqi Jewish patients was found to be 0.0167 (0.03%) (Shpilberg et al. 1995).

Glanzmann’s Thrombasthenia (MIM 273800) Glanzmann thrombasthenia (GT) is a rare bleeding disorder resulting from mutations in either glycoprotein (GP) IIb or GPIIIa genes. The disease is relatively frequent in Iraqi Jews and is caused by two different in GPIIIA mutations originating from two distinct founders. The most frequent mutation causing GT in Iraqi Jews (IJ-1) is an 11-bp deletion in exon 13 of the GP IIIa gene, resulting in the elimination of the disulfide bond and a premature termination codon. The second mutation is an 11.2-kb deletion between intron 9 and exon 13 of the GP IIIa gene. The mutant DNA is transcribed into mRNA in which exons 10 through 13 are absent. The allele frequencies of these mutations are 0.0043 and A, respectively (Quint et al. 2005). Data collected from genetic centers in Israel, derived after screening 2,499 healthy Iraqi Jewish individuals, revealed a carrier frequency of 1:68.5, 1:435, and 0, for the 31211G > A, Y1092X, and 2751 þ 1insT mutations, respectively (Reish et al. 2009).

Hereditary Breast-Ovarian Cancer (MIM 113705, 600185) The BRCA1 and BRCA2 genes were isolated in the 90s of the twentieth century (Miki et al. 1994; Tavtigian et al. 1996). Mutations in these two genes impose a lifetime risk for breast and/or ovarian cancer of 60–80% and 20–40%, respectively. In Ashkenazi Jews, three predominant founder mutations, with a combined frequency of 2–3% in the healthy population, were detected in 20% of breast cancer patients and 40% of ovarian cancer patients (Simchoni et al. 2006). Of these, the 185delAG in BRCA1 was identified in Iraqi Jews, with a carrier frequency of 0.5% (Sher et al. 1996). Another mutation in BRCA1, Tyr987X, occurs in less than 0.5% of healthy Iraqi, Kurdish, and Iranian Jews (Shiri-Sverdlov et al. 2001).

Congenital Myasthenia Syndrome (CMS, MIM 608931) Congenital myasthenic syndromes (CMS) are genetic disorders of the neuromuscular junction and can be classified, by the site of the transmission defect, as presynaptic, synaptic, or postsynaptic. In 14 Jewish patients from 10 families of either Iraqi or Iranian origin, congenital myasthenia associated with facial malformations, including an elongated face,

23


685

mandibular prognathism, malocclusion, and a high-arched palate was described. Muscle weakness was restricted predominantly to facial and masticatory muscles. The course was mild and nonprogressive. Despite the early onset, half the patients had been diagnosed between the ages of 18 and 42 years (Goldhammer et al. 1990). Patients of Jewish Iraqi or Iranian origin harbor the -38A!G mutation in the RAPSN gene which encodes rapsyn, a 43 kDa postsynaptic peripheral membrane protein that clusters the nicotinic acetylcholine receptor at the motor endplate. Haplotype analysis shows that -38A!G arises from a common founder (Ohno et al. 2003). Otherwise, two novel E-box mutations in the RAPSN promoter region in eight other congenital myasthenic syndrome patients were found.

Corticosterone Methyloxydase Deficiency Type II (CMO-II, MIM 610600) CMO type II deficiency is an autosomal recessive disorder caused by a defect in the terminal step of aldosterone biosynthesis and characterized by a typical salt-wasting syndrome, increased 18-hydroxycorticosterone and impaired aldosterone biosynthesis. Patients present with manifestations of mineralocorticoid deficiency during the first weeks of life. CMO-II deficiency is frequent among Jews from Iran (1 in 4,000 births). All individuals affected were double homozygotes for two missense mutations in CYP11B2. The first, in exon 3, codon 181, CGG (arginine) to TGG (tryptophane) is a mutation that completely abolishes both CMO-I and II activities, whereas the second, in exon 7, codon 386, from GTG (valine) to GCG (alanine) is a more conservative substitution that produces only a minimal reduction in CMO-I activity. All individuals affected with CMO-II deficiency were homozygous for both mutations, whereas asymptomatic subjects who were homozygous for R181W alone or homozygous for V386A alone were asymptomatic. These findings confirm that P450XIB2 is a major enzyme mediating oxidation at position 18 in the adrenal and suggest that a small amount of residual activity undetectable in vitro assays is sufficient to synthesize normal amounts of aldosterone (Ro¨sler and White 1993; Leshinsky-Silver et al. 2006).

Dubin–Johnson Syndrome (DJS, MIM 237500) Dubin–Johnson syndrome (DJS) is a rare autosomal recessive disorder in the excretion of conjugated bilirubin by hepatocytes. It is characterized by chronic jaundice and hyperbilirubinemia, alteration in coproporphyrin metabolism, and intracellular deposition of a dark melanin-like pigment giving the liver a typical black cast. The disorder is caused by mutations in MRP2 gene and is relatively frequent among Iranian and Moroccan Jews. DJS is caused by two founder

686


mutations, I1173F and R1150H, in the MRP2 gene, specific for Iranian and Moroccan Jewish patients, respectively. The estimated age of the I1173F mutation is approximately 1,500 years (Mor-Cohen et al. 2007).

Factor VII Deficiency (FVII, MIM 227500) Factor VII is part of the initiating complex of the extrinsic coagulation pathway. Laboratory diagnosis is easy, given that FVII deficiency is the only congenital bleeding disorder characterized by isolated prolonged prothrombin time. Clinical manifestations are heterogeneous, ranging from severe life-threatening hemorrhages, such as cerebral, gastrointestinal, and joint hemorrhages, to miscellaneous minor bleeding. Factor VII (FVII) deficiency is a rare autosomal recessive disorder caused by mutations in FVII gene. The disorder is relatively frequent among Iranian and Moroccan Jews. FVII deficiency in both populations is caused by a founder A244V mutation in the FVII gene. The estimated age of the A244V mutation is approximately 2,600 years (Mor-Cohen et al. 2007).

Achromatopsia II (MIM 216900) Achromatopsia belong to a genetically and phenotypically heterogeneous group of retinal degenerations. This rare disorder, that primarily affects the cone photoreceptor system, is caused by mutations in several genes, CNGA3, CNGB3, and GNAT2. As infants, the patients have nystagmus, which decreases later. Photophobia and restricted vision in ordinary light were described. Vision in dim light is relatively better. The disease was identified among Iraqi, Iranian, and Moroccan Jews (Zlotogora 1995; Kohl et al. 2005).

Colobomatous Microphthalmia (MIM 610092) Colobomatous microphthalmia is a common ocular malformation with a heterogeneous phenotype, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Most cases are isolated and have an autosomal dominant inheritance pattern (MIM 605738). A few cases with autosomal recessive transmission have been described in multiple relatives of five families of Jewish Iranian descent. In these families, a mutation in CHX10 gene on 14q24.3 chromosome was described. A relatively high incidence of this recessive allele is found in this community (Zlotogora et al. 1994).

23


687

Polyglandular Syndrome (PGA I, MIM 240300) Polyglandular Syndrome is mainly characterized by hypoparathyroidism, candidiasis, and adrenal insufficiency (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome-APCED). Nineteen families of Iranian Jewish descent, manifesting PGA I with hypoparathyroidism, rarely candidiasis and no keratopathy, were described. The inheritance is autosomal recessive. The prevalence among Iranian Jews was estimated to be between 1:6,500 and 1:9,000. Among Iranian Jews, the disease is due to a mutation Y85C in exon 2 of the APECED-related autoimmune regulator (AIRE) gene (Zlotogora and Shapiro 1992).

Inclusion Body Myopathy 2 (IBM2, MIM 600737) A progressive proximal and distal muscle weakness and wasting of the upper and lower limbs resulting in severe incapacitation within 10–20 years characterize the disorder. Disease onset is usually after 20 years of age and before the middle of the fourth decade of life. It was first described in Jews of Iranian descent (Argov and Yarom 1984) and later in Jews originating from other Middle Eastern countries, as well as in non-Jews. Homozygosity for the GNE M712T mutation was identified in 129 Middle Eastern patients with IBM2 from 55 families. Eleven patients with atypical features and five unaffected individuals from five different IBM2 families (including two who were 50 and 68 years old) were homozygous for the mutation. The families included Middle Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin. This founder mutation is approximately 1,300 years old and is not limited to patients of Jewish descent (Argov et al. 2003).

The Near East Jews from Syria, Lebanon, and Egypt emigrated to Israel after World War II. The composition of these communities was tinted by immigrant Jews from the west (Spain and Maghreb), the east (Iraq), and the north (Turkey and Europe). Consequently, these communities are not characterized by a significant frequency of genetic conditions. Yet, FMF and G6PD are relatively common in these communities as well.

Yemen The number of Yemenite Jews is estimated at 180,000, both from North and from South Yemen (Aden and Habban, Hadramaut). There were two major centers of population for Jews in southern Arabia besides the Jews of Northern Yemen, one in

688


Aden and the other in Hadramaut. The Jews of Aden lived in and around the city, and flourished during the British protectorate. The Jews of Hadramaut lived a much more isolated life, and the community was not known to the outside world until the early 1900s. In the early twentieth century, they numbered about 50,000; they currently number only a few hundred individuals and reside largely in Sa’dah and Rada’a. The greater part of both communities were airlifted to Israel after the declaration of the state, in 1948 (Operation Magic Carpet). The distribution of various polymorphic genes in the Yemenite community reveals a special genetic identity, defined by African marker genes with adaptive advantage (Weingarten 1992).

Thalassemia (HBA2, MIM 141850) A deletion that involves the two a-globin genes is found in Yemenites. The deletion was found in four unrelated Israeli patients with HbH disease, all originating in Yemen, and has been designated – YEM (Shalmon et al. 1994, 1996; Oron-Karni et al. 1997; Tamary et al. 1998).

Phenylketonuria (PKU, MIM 261600) Hyperphenylalaninemia (HPA) is a group of diseases characterized by persistent elevation of phenylalanine levels in tissues and biological fluids. The most frequent form is phenylalanine hydroxylase deficiency (PAH), causing phenylketonuria (PKU). PKU is an autosomal recessive inborn error of metabolism. The disease is very rare among Ashkenazi Jews and relatively frequent among Jews from Yemen, the Caucasian Mountains, Bukhara, and Tunisia. The mutation responsible for the high frequency among Yemenite Jews is deletion of exon3 in the PAH gene (Bercovich et al. 2008).

Metachromatic Leukodystrophy (MLD, MIM 250100) Late infantile metachromatic leukodystrophy (MLD) is a neurodegenerative disease, most commonly caused by the deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Late infantile MLD is frequent (1/75 live birth) in a small isolated Jewish community which lived in Habban. Three mutations were detected, of which the P377L allele is predominant both in Habbanite and Yemenite Jews, denoting a common ancestor for most MLD carriers in this community. The origin

23


689

and the means by which the mutation spread between the two communities remain unknown (Zlotogora et al. 1995).

Chronic Familial Neutropenia (Benign FL, MIM 162700) Benign autosomal dominant hereditary leukopenia–neutropenia has been reported in several ethnic groups, including Yemenite and Ethiopian Jews, Blacks of South African extraction, West Indians, and Arab Jordanians. The subjects with benign familial neutropenia were shown not to have an increased incidence of infections, and their response to infection does not differ from subjects with normal white blood cell counts. The suggested mechanism of this type of neutropenia is a defect in the release of mature WBC from the bone marrow to the peripheral circulation. Screening of 780 Yemenite Jewish individuals revealed 16 with neutropenia and 80 of 104 of their relatives had neutropenia (Berrebi et al. 1987; Shoenfeld et al. 1988).

Peroxidase and Phospholipid Deficiency in Eosinophils (MIM 261500) Autosomal recessive inheritance of an anomaly of eosinophils characterized by nuclear hypersegmentation, hypogranulation, and negative peroxidase and phospholipid staining was described in Yemenite Jews in Israel (Joshua et al. 1970).

Hereditary Breast-Ovarian Cancer (MIM 113705, 600185) In Jews from Yemen a founder mutation, 8765delAG, was found in the BRCA2 gene with a population frequency of 0.7% (Lerer et al. 1998). Haplotype analysis revealed that this mutation has an independent origin in geographically and ethnically distinct populations, acting as a founder mutation in Yemen (Manning et al. 2001). Mutations in BRCA2 gene predominantly predispose to breast and/or ovarian cancer. More information on these genes appears in the section on Iraq.

Myotonic Dystrophy I (MIM 160900) Myotonic dystrophy (DM) is an autosomal dominant disorder characterized mainly by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and ECG changes. The genetic defect in DM1 results from an amplified trinucleotide

690


repeat in the 30 untranslated region of a protein kinase gene. Disease severity varies with the number of repeats: normal individuals have 5–30 repeats, mildly affected persons have 50–80 repeats, and severely affected individuals have 2,000 or more copies. Amplification is frequently observed after parent-to-child transmission, but extreme amplifications are not transmitted through the male line. This mechanism causes genetic anticipation and the occurrence of the severe congenital form almost exclusively in the offspring of affected women. In a comprehensive epidemiologic survey among Jews living in Israel, an average prevalence of DM of 15.7 per 100,000 (1 case in 6,369) was found with intercommunity variations. Ashkenazi Jews had the lowest rate (1 case in 17,544) compared to Sephardic and Yemenites Jews (1 in 5,000 and 1 in 2,114 cases, respectively). The intragenic haplotype of the DM alleles is the same as that of DM patients in many populations worldwide (including Ashkenazi Jews); however, 2 markers closely linked to DM, D19S207, and D19S112, were in linkage disequilibrium with the DM mutation in patients of Yemenite and Moroccan extractions. This observation indicated a common ancestral origin for the DM premutation as a consequence of a founder premutation in these non-Ashkenazi Jewish communities (Segel et al. 2003).

Retinitis Pigmentosa (RP, MIM 608381) Retinitis pigmentosa (RP) is the most common form of hereditary retinal degeneration, with a worldwide prevalence of 1 in 4,000. RP actually encompasses a heterogeneous group of retinal dystrophies characterized by night blindness followed by visual field loss, often resulting in severe visual impairment. A related form of retinal dystrophy is cone–rod degeneration (CRD). Besides being clinically heterogeneous, both RP and CRD are genetically heterogeneous. In most patients, the disease is limited to the eye (nonsyndromic RP/CRD), suggesting that the genes involved encode largely eye- and retina-specific products. A novel homozygous splice-site mutation, 238 þ 1G > A in CERKL gene on chromosome 2q31.3.3 was found in a Yemenite Jewish family. Further investigation revealed a carrier frequency of 4.4% in this population. The 238 þ 1G > A underlies approximately one-third of autosomal recessive retinal degeneration cases in the Yemenite Jewish population (Auslender et al. 2007).

Cystic Fibrosis (CF, MIM 219700) CF in Yemenite Jews is due to a founder mutation, namely, mutation I1234V in the CFTR gene with a carrier frequency of 1:45 (Kerem et al. 1995; Quint et al. 2005).

23


691

Rare Diseases FMF and G6PD deficiency are relatively rare in Yemenite Jews compared to Jews born in other Arab countries (Weingarten 1992). The mutation underlying FMF in Yemenite Jews remains unknown.

North African Jews Jews from Libya, Tunisia, Algeria, and Morocco are designated North African Jews and/or Sephardic and/or non-Ashkenazi Jews. This population is noted for its high frequency of mutations, in MEFV, causing FMF (Gershoni-Baruch et al. 2001) and low frequency of G6PD deficiency. The different disorders associated with each subgroup will be referenced below.

Familial Mediterranean Fever (FMF, MIM 249100) As described earlier in this chapter, North African and Iraqi Jews are the two largest ethnic Jewish communities enduring FMF in Israel. North African Jews have a more severe disease manifested by earlier age of onset, increase in frequency and severity of joint involvement, higher incidence of erysipelas-like erythema, and higher doses of colchicine required to control symptoms (Pras et al. 1998). M694V and E148Q are the most prevalent mutation in this population with a carrier frequency of 1:5 (Gershoni-Baruch et al. 2001).

Glycogen Storage Disease III (GSD, MIM 232400) Glycogen storage disease type III (GSD III) is an autosomal recessive disease caused by the deficiency of glycogen-debranching enzyme. The overall incidence of the disease is about 1:100,000 life births in the USA; however, it is unusually frequent among North African Jews in Israel (prevalence 1:5,400, carrier prevalence 1:35). All North African Jewish GSD III patients examined have both liver and muscle involvement. While all patients showed the characteristic features related to the liver enzyme deficiency, the peripheral muscular impairment varied from minimal to severe, with neuromuscular involvement. A single mutation in the AGL gene, the deletion of T at position 4,455 (4,455delT) in homozygous form, was found in this patient population. The mutation appears to be ethnic-specific (Parvari et al. 1997).

692


Libya Libyan Jews retain genetic signatures distinguishable from those of the other populations. This finding is in agreement with some historical records on the relative isolation of this community. The lowest differentiation involving Libyan Jews is with Moroccan Jewry which may reflect shared ancestral Iberian Jewish or Berber contribution to these population, or gene flow between them (Rosenberg et al. 2001).

Creutzfeldt–Jakob Disease (CJD, MIM 123400) Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder. Various mutations in the prion protein (PrP) gene are associated with the disease. Among Libyan Jews, CJD is a familial disease with an incidence of about 100 times higher than in the worldwide population. After age adjustment, the mean annual incidence rate per million was 43 among Libyan-born and 0.9 in other populations. Among Jews born in Egypt and Tunisia, countries neighboring Libya, the adjusted rates were higher than in the other Israeli Jewish communities (3.5 and 2.3 per million, respectively). CJD in the Libyan community segregates with a point mutation at codon 200 of the PrP gene which causes the substitution of lysine for glutamate. Homozygous patients have the same disease pattern and age of onset as heterozygous patients, which argues that CJD associated with the codon 200 lysine mutation, is a true dominant disorder. Among Libyan Jews, there was no association between incidence rate of CJD and age at immigration, that is, duration of exposure to a hypothetical infectious factor in Libya (Zilber et al. 1991; Gabizon et al. 1994; Rosenmann et al. 1998; Frenkel et al. 1999).

Cystinuria (MIM 220100) Cystinuria is an autosomal recessive disease characterized by the development of kidney stones. The disease is caused by a defect in a renal tubular amino acid transporter resulting in impaired reabsorption of cystine and the dibasic amino acids, lysine, arginine, and ornithine. Mutations in SLC3A1 cause type I disease, while mutations in SLC7A9 are associated with non-type I disease with similar clinical manifestations. In Israel, cystinuria is especially common among Libyan Jews who suffer from non-type I disease with an estimated prevalence of 1:2,500. A founder mutation, V170M in the SLC7A9 gene, with a carrier rate of 1:25 was found in Libyan Jews and account for the disease in most of the patients (Sidi et al. 2003).

23


693

Muscular Dystrophy Type 2B (Limb-Girdle MD (LGMD), MIM 253601) LGMD is an autosomal recessive heterogeneous disease. LGMD2B is caused by mutations in the dysferlin gene. In Jews of Libyan origin, LGMD2B, attributed to mutation 1624delG in the dysferlin gene, is prevalent with a carrier frequency of approximately 5% and disease prevalence of at least 1 per 1,300 adults. In 29 patients from 12 families, homozygosity for the same mutation was found. However, clinical features were heterogeneous even within the same family; in half of the patients, onset was in the distal muscles of the legs while in others onset was in the proximal muscles of the legs, similar to other forms of limb-girdle dystrophies. Progression is slow regardless of age of onset, patients remaining ambulatory until at least 33 years. The variable features in this ethnic cluster contribute to the definition of the clinical spectrum of dysferlinopathies in general. The cause of the observed heterogeneity remains unclear (Argov et al. 2000).

Cystic Fibrosis (CF, MIM 219700) CF is common in Libyan Jews with a carrier frequency of 1:25. In this population, CF is due to two mutations, namely, mutations F508 and 405 þ 1G!A. (Kerem et al. 1995; Quint et al. 2005).

Tunisia Between 1945 and 1970, around 100,000 Jews emigrated from Tunisia, mainly to Israel and France. This community is an Ancient Jewish congregation that lived in the region, including a small isolate on the island of Jerba whose tradition claims for continuous existence since the sixth century B.C.

Phenylketonuria (PKU, MIM 261600) and Hyperphenylalaninemia (MIM 612349) Among Tunisian Jews, the L48S mutation causing PKU was found (Bercovich et al. 2008). In Jews from Morocco and Tunisia, a missense mutation, TCASer!CCAPro, at codon 349 in exon 10 of the phenylalanine hydroxylase gene was detected. A homozygote for this mutation showed the most severe (“classical”) type of PKU, while compound heterozygotes showed two other types of HPA – “atypical” PKU and “high benign” HPA – illustrating the interplay between different mutations that

694


gives rise to various HPAs (Weinstein et al. 1993). Further information on the disease can be seen under Yemenite Jews.

Brittle Cornea Syndrome (BCS, MIM 229200) Brittle cornea syndrome (BCS) is characterized by blue sclera and hyperextensible joints. In Israel, five families of Tunisian Jewish origin characterized by red hair in all affected individuals were identified (Zlotogora et al. 1990). Linkage to chromosome 16q24 surrounding the hair color gene, MC1R, has been shown (Abu et al. 2006). The gene 2NF469 and the causing mutations were subsequently identified (Abu et al. 2008).

Cystic Fibrosis (CF, MIM 219700) The estimated carrier rate of CF among Tunisian Jews is 1:60. In this population, CF is due to four mutations, namely, mutations 405 þ 1G!A, F508, W1282X and 3849 þ 10KbC!T, in descending order of prevalence (Kerem et al. 1995; Quint et al. 2005).

Algeria Following the independence of Algeria in 1962, about 130,000 Jews emigrated, mainly to France. In Israel, there are about 30,000 Algerian Jews. Like in other Maghreb communities, FMF is common in this ethnic community. Other genetic diseases are described in individual families.

Morocco The largest community of Jews from Arab countries emigrated from Morocco (750,000). Most of them live in Israel and the rest in France and elsewhere. Twenty thousand came from Iberia and maintained a separated and isolated community. This group is different from the classic Moroccan Jewry and has a higher frequency of G6PD deficiency.

Oculocutaneous Albinism (MIM 203100) Oculocutaneous albinism is a genetically heterogeneous congenital disorder characterized by decreased or absent pigmentation in the hair, skin, and eyes. Albinism is characterized by specific ocular changes resulting from reduced amounts of

23


695

melanin in the developing eye; the abnormalities in the eye and optic system being specific and pathognomonic. Aside from decreased pigment in the iris and retina, optic changes include decreased visual acuity, misrouting of the optic nerves at the chiasm, and nystagmus. Among Moroccan Jews with type IA (i.e., tyrosinasenegative) OCA, a highly predominant mutant allele of the tyrosinase (TYR) gene, with a carrier frequency of 1:40, harboring a missense substitution, Gly47Asp (G47D), was identified. This mutation occurs on the same haplotype as in patients from the Canary Islands and Puerto Rico, suggesting that the G47D mutation in these ethnically distinct populations may stem from a common origin (GershoniBaruch et al. 1994).

Ataxia Telangiectasia (AT, MIM 208900) The ATM gene is responsible for the autosomal recessive disorder ataxia-telangiectasia (AT), characterized by cerebellar degeneration, immunodeficiency, and cancer predisposition. A wide variety of AT mutations, most of which are unique to single families, were identified in various ethnic groups, precluding carrier screening with mutation-specific assays. However, a single mutation, 103C!T, was observed in 32/33 defective ATM alleles in Jewish AT families of North African origin, from various regions of Morocco and Tunisia. This mutation results in a stop codon at position 35 of the ATM protein. The carrier frequency of this mutation in Jews from Morocco and Tunis is about 1% (Gilad et al. 1996).

Tay Sachs (TSD, MIM 272800) Classical Tay-Sachs disease (TSD) is characterized by the onset in infancy of developmental arrest, followed by paralysis, dementia, and blindness, with death in the second or third year of life. The disease is one of the four lysosomal storage diseases prevalent among Ashkenazim; TSD, Gaucher disease type I, NiemannPick disease, and mucolipodosis type IV. TSD is caused by mutations in the alpha subunit of the hexosaminidase A gene (HEXA). Moroccan Jewry is the only nonAshkenazi Jewish community in which TSD is not extremely rare with an estimated frequency of 1 in 140. Seven mutations were found in Moroccan Jews, three of which (deltaF 304/305, R170Q, IVS-2A!G) were more frequently observed and not described in Ashkenazi Jews (Kaufman et al. 1997).

Adrenal Hyperplasia IV (MIM 202010) Congenital adrenal hyperplasia due to 11-b-hydroxylase deficiency is an autosomal recessive disorder of corticosteroid biosynthesis resulting in androgen excess,

696


virilization, and hypertension. The defect causes decreased synthesis of cortisol and corticosterone in the zona fasciculata of the adrenal gland, resulting in accumulation of the precursor’s 11-deoxycortisol and 11-deoxycorticosterone; the latter is a potent salt-retaining mineralocorticoid that leads to arterial hypertension. In Jews of Moroccan descent, the prevalence of steroid 11-b-hydroxylase deficiency (11-OHD) is relatively high, with a carrier rate estimated at approximately 1 in 40. A single mutation in the CYP11B1 gene (encoding 11beta-hydroxylase), R448H, accounts for the disease in this population. However, screening of more than 200 Moroccan Jews revealed an allele frequency lower than was assumed previously (Paperna et al. 2005).

Fanconi Anemia A (MIM 607139) Fanconi anemia (FA) is an autosomal recessive disorder affecting all bone marrow elements and associated with cardiac, renal, and limb malformations, as well as dermal pigmentary changes. FA is a genetically heterogeneous disease with at least eight complementation groups (A–H). In the non-Ashkenazi population in Israel, four ethnic-specific mutations were identified in FA group A (FANCA): two “Moroccan mutations,” the 2172–2173insG (exon 24) and the 4275delT (exon 43); a “Tunisian mutation” 890–893del (exon 10); and an “Indian mutation” 2574C > G (S858R). The tetranucleotide CCTG motif, previously identified as a mutation hotspot in FANCA and other human genes, was found in the vicinity of 2172–2173insG and 890–893del. The four mutations account for the majority (88%) of the FANCA alleles in the Israeli Jewish non-Ashkenazi FA population. Two “Indian mutation” carriers were identified among 53 Indian Jews. All carriers within each ethnic group had the same haplotype, suggesting a common founder for each mutation (Tamary et al. 2000).

Phenylketonuria and Hyperphenylalaninemia (MIM 612349) In Jews from Morocco and Tunisia, a missense mutation, TCASer!CCAPro, at codon 349 in exon 10 of the phenylalanine hydroxylase gene was detected (Weinstein et al. 1993). Further information can be found under Yemen and Tunisia.

Cerebrotendinous Xanthomatosis (CTX, MIM 213700) Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive inherited lipid-storage disease characterized clinically by progressive neurologic dysfunction (cerebellar ataxia beginning after puberty, systemic spinal cord involvement and a

23


697

pseudobulbar phase leading to death), premature atherosclerosis, and cataracts. Large deposits of cholesterol and cholestanol are found in virtually every tissue, particularly the Achilles tendons, brain, and lungs. Plasma cholesterol concentrations are low-normal in CTX patients. In Moroccan Jews, the estimated carrier rate is 1 in 108 (Berginer and Abeliovich 1981). The defect in cerebrotendinous xanthomatosis was shown to reside in the CYP27A1 gene (Cali et al. 1991). Two mutations were identified, deletion of a thymidine in exon 4 and a G-to-A transition at the 30 splice acceptor site of intron 4, in patients of four families (three families were consanguineous and the fourth was nonconsanguineous) (Leitersdorf et al. 1993).

Dubin–Johnson Syndrome (DJS, MIM 237500) As described earlier (under Iraq and Iranian Jewry), DJS is a rare autosomal recessive disease caused by mutations in MRP2 gene. It is relatively frequent among Iranian and Moroccan Jews. DJS is caused by two founder mutations, I1173F and R1150H, specific for Iranian and Moroccan Jewish patients, respectively (Mor-Cohen et al. 2007).

Factor VII Deficiency (FVII, MIM 227500) Factor VII is part of the initiating complex of the extrinsic coagulation pathway. Factor VII (FVII) deficiency is rare autosomal recessive disorder caused by mutations in FVII gene. The disorder is relatively frequent among Iranian and Moroccan Jews. FVII deficiency in both populations is caused by a founder A244V mutation in the FVII gene. The estimated age of the A244V mutation is approximately 2,600 years (Mor-Cohen et al. 2007).

Muscular Dystrophy I (MIM 253600) In Jews living in Israel, the average prevalence of myotonic dystrophy (DM) is 15.7/10.000 (1:6,369); Ashkenazi Jews have the lowest rate, 5.7/100.000 (1 case in 17,544) compared to the rate in Sephardic Jews 20/10(5) (1:5,000) and Yemenite Jews 47.3/100.000 (1:2,114). The difference in the incidence of DM was attributed to a higher mutation rate in non-Ashkenazi Jews compared to the rate in Ashkenazi Jews. Markers in linkage disequilibrium with the DM mutation in patients of Yemenite and Moroccan extractions and not in the Ashkenazi patients indicate that the difference in the prevalence of DM among the Jewish communities is a consequence of founder premutations in the non-Ashkenazi Jewish communities (Segel et al. 2003).

698


Concluding Remarks This review portrays the genetic disease profile of the major Jewish communities that have emigrated to Israel from Arab countries. On the basis of population screening and family studies, information regarding clinical manifestation, disease, and mutation frequency is provided. In most cases, these frequencies reflect the relative genetic isolation of Jewish communities from each other and from their respective Arab host populations. In addition to the relatively common diseases mentioned here, rare conditions that have been documented in few families are also mentioned. Accumulating data in molecular genetics indicate that hereditary diseases are marked by clinical and genetic heterogeneity. In Israel, population screening programs have been set to identify carriers of genetic diseases. Mutation detection has become affordable to couples at risk. On the basis of disease severity and mutation frequencies within the various communities, genetic diagnosis is recommended aiming at health promotion and disease prevention. It must be stressed, however, that this synopsis is by no means exhaustive, partially because we have probably failed to retrieve all the relevant data from the medical literature.

References Abu A, Frydman M, Marek D, Pras E, Stolovitch C, Aviram-Goldring A, Rienstein S, Reznik-Wolf H, Pras E (2006) Mapping of a gene causing brittle cornea syndrome in Tunisian Jews to 16q24. Invest Ophthalmol Vis Sci 47:5283–5287 Abu A, Frydman M, Marek D, Pras E, Nir U, Reznik-Wolf H, Pras E (2008) Deleterious mutations in the zinc-finger u69 gene cause brittle cornea syndrome. Am J Hum Genet 82:1217–1227 Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O (2001) Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet 69:1218–1224 Argov Z, Yarom R (1984) “Rimmed vacuole myopathy” sparing the quadriceps: A unique disorder in Iranian Jews. J Neurol Sci 64:33–43 Argov Z, Sadeh M, Mazor K, Soffer D, Kahana E, Eisenberg I, Mitrani-Rosenbaum S, Richard I, Beckmann J, Keers S, Bashir R, Bushby K, Rosenmann H (2000) Muscular dystrophy due to dysferlin deficiency in Libyan Jews: Clinical and genetic features. Brain 123:1229–1237 Argov Z, Eisenberg I, Grabov-Nardini G, Sadeh M, Wirguin I, Soffer D, Mitrani-Rosenbaum S (2003) Hereditary inclusion body myopathy: the Middle Eastern genetic cluster. Neurology 60:1519–1523 Auslender N, Sharon D, Abbasi AH, Garzozi HJ, Banin E, Ben-Yosef T (2007) A common founder mutation of CERKL underlies autosomal recessive retinal degeneration with early macular involvement among Yemenite Jews. Invest Ophthalmol Vis Sci 48:5431–5438 Auslender N, Bandah D, Rizel L, Behar DM, Shohat M, Banin E, Allon-Shalev S, Sharony R, Sharon D, Ben-Yosef T (2008) Four USH2A founder mutations underlie the majority of Usher syndrome type 2 cases among non-Ashkenazi Jews. Genet Test 12:289–294 Basel-Vanagaite L, Taub E, Drasinover V, Magal N, Brudner A, Zlotogora J, Shohat M (2008) Genetic carrier screening for spinal muscular atrophy and spinal muscular atrophy with respiratory distress 1 in an isolated population in Israel. Genet Test 12:53–56

23


699

Behar DM, Metspalu E, Kivisild T, Rosset S, Tzur S, Hadid Y, Yudkovsky G, Rosengarten D, Pereira L, Amorim A, Kutuev I, Gurwitz D, Bonne-Tamir B, Villems R, Skorecki K (2008) Counting the founders: the matrilineal genetic ancestry of the Jewish Diaspora. PLoS One 3:e2062 Ben Arab S, Bonaı¨ti-Pellie´ C, Belkahia A (1990) An epidemiological and genetic study of congenital profound deafness in Tunisia (governorate of Nabeul). J Med Genet 27:29–33 Bercovich D, Elimelech A, Yardeni T, Korem S, Zlotogora J, Gal N, Goldstein N, Vilensky B, Segev R, Avraham S, Loewenthal R, Schwartz G, Anikster Y (2008) A mutation analysis of the phenylalanine hydroxylase (PAH) gene in the Israeli population. Ann Hum Genet 72:305–309 Berginer VM, Abeliovich D (1981) Genetics of cerebrotendinous xanthomatosis (CTX): an autosomal recessive trait with high gene frequency in Sephardim of Moroccan origin. Am J Med Genet 10:151–157 Berrebi A, Melamed Y, Van Dam U (1987) Leukopenia in Ethiopian Jews. N Engl J Med 316:549 Cali JJ, Hsieh C-L, Francke U, Russell DW (1991) Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem 266: 7779–7783 Falik-Zaccai TC, Shachak E, Yalon M, Lis Z, Borochowitz Z, Macpherson JN, Nelson DL, Eichler EE (1997) Predisposition to the fragile X syndrome in Jews of Tunisian descent is due to the absence of AGG interruptions on a rare Mediterranean haplotype. Am J Hum Genet 60:103–112 Filon D, Oron V, Krichevski S, Shaag A, Shaag Y, Warren TC, Goldfarb A, Shneor Y, Koren A, Aker M et al (1994) Diversity of beta-globin mutations in Israeli ethnic groups reflects recent historic events. Am J Hum Genet 54:836–843 Fink N, Mouallem M (2006) Costeff syndrome: a syndrome that was described in Israel and the responsible gene discovered by an Israeli doctor. Harefuah 145:402–403, 472 French FMF Consortium (1997) A candidate gene for familial Mediterranean fever. Nat Genet 17:25–31 Frenkel YR, Ben-Israel J, Korczyn AD, Chapman J (1999) Penetrance and phenotypic expression of a mutation linked to Creutzfeldt-Jakob disease in the elderly. Dement Geriatr Cogn Disord 10:47–50 Gabizon R, Rosenman H, Meiner Z, Kahana I, Kahana E, Shugart Y, Ott J, Prusiner SB (1994) Mutation in codon 200 and polymorphism in codon 129 of the prion protein gene in Libyan Jews with Creutzfeldt-Jakob disease. Philos Trans R Soc Lond B Biol Sci 343:385–390 Gershoni-Baruch R, Rosenmann A, Droetto S, Holmes S, Tripathi RK, Spritz RA (1994) Mutations of the tyrosinase gene in patients with oculocutaneous albinism from various ethnic groups in Israel. Am J Hum Genet 54:586–594 Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R (2001) Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet 9:634–637 Gilad S, Bar-Shira A, Harnik R, Shkedy D, Ziv Y, Khosravi R, Brown K, Vanagaite L, Xu G, Frydman M, Lavin MF, Hill D, Tagle DA, Shiloh Y (1996) Ataxia-telangiectasia: founder effect among north African Jews. Hum Mol Genet 5:2033–2037 Goldhammer Y, Blatt I, Sadeh M, Goodman RM (1990) Congenital myasthenia associated with facial malformations in Iraqi and Iranian Jews. A new genetic syndrome. Brain 113:1291–1306 Goodman RM, Bonne-Tamir B, Adam A, Voss R, Bach G, Shiloh Y, Katznelson MB, Barkai G, Goldman B, Padeh B et al (1989) Medical genetics in Israel. J Med Genet 26:179–189 International FMF Consortium (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90:797–807 Joshua H, Spitzer A, Presentey B (1970) The incidence of peroxidase and phospholipid deficiency in eosinophilic granulocytes among various Jewish groups in Israel. Am J Hum Genet 22:574–578 Karimi M, Yavarian M, Afrasiabi A, Dehbozorgian J, Rachmilewitz E (2008) Prevalence of betathalassemia trait and glucose-6-phosphate dehydrogenase deficiency in Iranian Jews. Arch Med Res 39:212–214

700


Kaufman M, Grinshpun-Cohen J, Karpati M, Peleg L, Goldman B, Akstein E, Adam A, Navon R (1997) Tay-Sachs disease and HEXA mutations among Moroccan Jews. Hum Mutat 10:295–300 Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM (1997) Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 387:80–83 Kerem E, Kalman YM, Yahav Y, Shoshani T, Abeliovich D, Szeinberg A, Rivlin J, Blau H, Tal A, Ben-Tur L et al (1995) Highly variable incidence of cystic fibrosis and different mutation distribution among different Jewish ethnic groups in Israel. Hum Genet 96:193–197 Kohl S, Varsanyi B, Antunes GA, Baumann B, Hoyng CB, J€agle H, Rosenberg T, Kellner U, Lorenz B, Salati R, Jurklies B, Farkas A, Andreasson S, Weleber RG, Jacobson SG, Rudolph G, Castellan C, Dollfus H, Legius E, Anastasi M, Bitoun P, Lev D, Sieving PA, Munier FL, Zrenner E, Sharpe LT, Cremers FP, Wissinger B (2005) CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Eur J Hum Genet 13:302–308 Laron Z (2008) Insulin-like growth factor-I treatment of children with Laron syndrome (primary growth hormone insensitivity). Pediatr Endocrinol Rev 5:766–771 Leitersdorf E, Reshef A, Meiner V, Levitzki R, Schwartz SP, Dann EJ, Berkman N, Cali JJ, Klapholz L, Berginer VM (1993) Frameshift and splice-junction mutations in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis in Jews of Moroccan origin. J Clin Invest 91:2488–2496 Lerer I, Wang T, Peretz T, Sagi M, Kaduri L, Orr-Urtreger A, Stadler J, Gutman H, Abeliovich D (1998) The 8765delAG mutation in BRCA2 is common among Jews of Yemenite extraction. Am J Hum Genet 63:272–274 Leshinsky-Silver E, Landau Z, Unlubay S, Bistrizer T, Zung A, Tenenbaum-Rakover Y, Devries L, Lev D, Hanukoglu A (2006) Congenital hyperreninemic hypoaldosteronism in Israel: sequence analysis of CYP11B2 gene. Horm Res 66:73–78 Manning AP, Abelovich D, Ghadirian P, Lambert JA, Frappier D, Provencher D, Robidoux A, Peretz T, Narod SA, Mes-Masson AM, Foulkes WD, Wang T, Morgan K, Fujiwara TM, Tonin PN (2001) Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families. Hum Hered 52:116–120 Mason PJ, Bautista JM, Gilsanz F (2007) G6PD deficiency: the genotype-phenotype association. Blood Rev 21:267–283 Medlej-Hashim M, Loiselet J, Lefranc G, Me´garbane´ A (2004) Familial Mediterranean Fever (FMF): [from diagnosis to treatment]. Sante 14:261–266 Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71 Mor-Cohen R, Zivelin A, Fromovich-Amit Y, Kovalski V, Rosenberg N, Seligsohn U (2007) Age estimates of ancestral mutations causing factor VII deficiency and Dubin–Johnson syndrome in Iranian and Moroccan Jews are consistent with ancient Jewish migrations. Blood Coagul Fibrinolysis 18:139–144 Ohno K, Sadeh M, Blatt I, Brengman JM, Engel AG (2003) E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. Hum Mol Genet 12:739–748 Oppenheim A, Cohen S, Goldfarb A, Katzhendler J, Deutsch J, Rachmilewitz EA (1988) Detection of specific beta-globin mutations in Kurdish Jews with beta-thalassemia. Hemoglobin 12:31–38 Oppenheim A, Jury CL, Rund D, Vulliamy TJ, Luzzatto L (1993) G6PD Mediterranean accounts for the high prevalence of G6PD deficiency in Kurdish Jews. Hum Genet 91:293–294 Oron-Karni V, Filon D, Rund D, Oppenheim A (1997) A novel mechanism generating short deletion/insertions following slippage is suggested by a mutation in the human alpha2-globin gene. Hum Mol Genet 6:881–885 Oron-Karni V, Filon D, Shifrin Y, Fried E, Pogrebijsky G, Oppenheim A, Rund D (2000) Diversity of alpha-globin mutations and clinical presentation of alpha-thalassemia in Israel. Am J Hematol 65:196–203

23


701

Paperna T, Gershoni-Baruch R, Badarneh K, Kasinetz L, Hochberg Z (2005) Mutations in CYP11B1 and congenital adrenal hyperplasia in Moroccan Jews. J Clin Endocrinol Metab 90:5463–5465 Parvari R, Moses S, Shen J, Hershkovitz E, Lerner A, Chen YT (1997) A single-base deletion in the 30 -coding region of glycogen-debranching enzyme is prevalent in glycogen storage disease type IIIA in a population of North African Jewish patients. Eur J Hum Genet 5:266–270 Pras M, Bronshpigel N, Zemer D, Gafni J (1982) Variable incidence of amyloidosis in familial Mediterranean fever among different ethnic groups. Johns Hopkins Med J 150:22–26 Pras E, Livneh A, Balow JE Jr, Pras E, Kastner DL, Pras M, Langevitz P (1998) Clinical differences between North African and Iraqi Jews with familial Mediterranean fever. Am J Med Genet 75:216–219 Quint A, Lerer I, Sagi M, Abeliovich D (2005) Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening. Am J Med Genet A 136:246–248 Reish O, Borochowitz ZU, Adir V, Shohat M, Karpati M, Shtorch A, Orr-Urtreger A, Yaron Y, Shalev S, Fares F, Gershoni-Baruch R, Falik-Zaccai TC, Chapman-Shimshoni D (2009) Dynamic modification strategy of the Israeli carrier screening protocol: inclusion of the Oriental Jewish Group to the cystic fibrosis panel. Genet Med 11:101–103 Rosenberg N, Yatuv R, Orion Y, Zivelin A, Dardik R, Peretz H, Seligsohn U (1997) Glanzmann thrombasthenia caused by an 11.2-kb deletion in the glycoprotein IIIa (beta3) is a second mutation in Iraqi Jews that stemmed from a distinct founder. Blood 89:3654–3662 Rosenberg NA, Woolf E, Pritchard JK, Schaap T, Gefel D, Shpirer I, Lavi U, Bonne-Tamir B, Hillel J, Feldman MW (2001) Distinctive genetic signatures in the Libyan Jews. Proc Natl Acad Sci USA 98:858–863 Rosenmann H, Vardi J, Finkelstein Y, Chapman J, Gabizon R (1998) Identification in Israel of 2 Jewish Creutzfeld-Jakob disease patients with a 178 mutation at their PrP gene. Acta Neurol Scand 97:184–187 Ro¨sler A, White PC (1993) Mutations in human 11 beta-hydroxylase genes: 11 beta-hydroxylase deficiency in Jews of Morocco and corticosterone methyl-oxidase II deficiency in Jews of Iran. J Steroid Biochem Mol Biol 45:99–106 Rousseau F, Rouillard P, Morel ML, Khandjian EW, Morgan K (1995) Prevalence of carriers of premutation-size alleles of the FMRI gene–and implications for the population genetics of the fragile X syndrome. Am J Hum Genet 57:1006–1018 Rund D, Cohen T, Filon D, Dowling CE, Warren TC, Barak I, Rachmilewitz E, Kazazian HH Jr, Oppenheim A (1991) Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan. Proc Natl Acad Sci USA 88:310–314 Rund D, Oron-Karni V, Filon D, Goldfarb A, Rachmilewitz E, Oppenheim A (1997) Genetic analysis of beta-thalassemia intermedia in Israel: diversity of mechanisms and unpredictability of phenotype. Am J Hematol 54:16–22 Segel R, Silverstein S, Lerer I, Kahana E, Meir R, Sagi M, Zilber N, Korczyn AD, Shapira Y, Argov Z, Abeliovich D (2003) Prevalence of myotonic dystrophy in Israeli Jewish communities: inter-community variation and founder permutations. Am J Med Genet A 119A:273–278 Shalmon L, Kirschmann C, Zaizov R (1994) A new deletional alpha-thalassemia detected in Yemenites with hemoglobin H disease. Am J Hematol 45:201–204 Shalmon L, Kirschmann C, Zaizov R (1996) Alpha-thalassemia genes in Israel: deletional and nondeletional mutations in patients of various origins. Hum Hered 46:15–19 Sher C, Sharabini-Gargir L, Shohat M (1996) Breast cancer and BRCA1 mutations. N Engl J Med 334:1199 Shevah O, Borrelli P, Rubinstein M, Laron Z (2003) Identification of two novel mutations in the human growth hormone receptor gene. J Endocrinol Invest 26:604–608 Shinar Y, Kuchuk I, Menasherow S, Kolet M, Lidar M, Langevitz P, Livneh A (2007) Unique spectrum of MEFV mutations in Iranian Jewish FMF patients–clinical and demographic significance. Rheumatology 46:1718–1722

702


Shiri-Sverdlov R, Gershoni-Baruch R, Ichezkel-Hirsch G, Gotlieb WH, Bruchim Bar-Sade R, Chetrit A, Rizel S, Modan B, Friedman E (2001) The Tyr978X BRCA1 mutation in nonAshkenazi Jews: occurrence in high-risk families, general population and unselected ovarian cancer patients. Commun Genet 4:50–55 Shoenfeld Y, Alkan ML, Asaly A, Carmeli Y, Katz M (1988) Benign familial leukopenia and neutropenia in different ethnic groups. Eur J Haematol 41:273–277 Shpilberg O, Peretz H, Zivelin A, Yatuv R, Chetrit A, Kulka T, Stern C, Weiss E, Seligsohn U (1995) One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews. Blood 85:429–432 Sidi R, Levy-Nissenbaum E, Kreiss I, Pras E (2003) Clinical manifestations in Israeli cystinuria patients and molecular assessment of carrier rates in Libyan Jewish controls. Isr Med Assoc J 5:439–442 Simchoni S, Friedman E, Kaufman B, Gershoni-Baruch R, Orr-Urtreger A, Kedar-Barnes I, ShiriSverdlov R, Dagan E, Tsabari S, Shohat M, Catane R, King MC, Lahad A, Levy-Lahad E (2006) Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc Natl Acad Sci USA 103:3770–3774 Sobe T, Vreugde S, Shahin H, Berlin M, Davis N, Kanaan M, Yaron Y, Orr-Urtreger A, Frydman M, Shohat M, Avraham KB (2000) The prevalence and expression of inherited connexin 26 mutations associated with nonsyndromic hearing loss in the Israeli population. Hum Genet 106:50–57 Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 43:227–253 Tamary H, Klinger G, Shalmon L, Kirschmann H, Koren A, Bennet M, Zaizov R (1998) The diverse molecular basis and mild clinical picture of HbH disease in Israel. Ann N Y Acad Sci 850:432–435 Tamary H, Bar-Yam R, Shalmon L, Rachavi G, Krostichevsky M, Elhasid R, Barak Y, Kapelushnik J, Yaniv I, Auerbach AD, Zaizov R (2000) Fanconi anaemia group A (FANCA) mutations in Israeli non-Ashkenazi Jewish patients. Br J Haematol 111:338–343 Tavtigian SV, Simard J, Rommens J et al (1996) The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 12:333–337 Toledano-Alhadef H, Basel-Vanagaite L, Magal N, Davidov B, Ehrlich S, Drasinover V, Taub E, Halpern GJ, Ginott N, Shohat M (2001) Fragile-X carrier screening and the prevalence of premutation and full-mutation carriers in Israel. Am J Hum Genet 69:351–360 Weingarten MA (1992) Changing health and changing culture: the Yemenite Jews in Israel. Praeger, London, pp 20–23 Weinstein M, Eisensmith RC, Abadie V, Avigad S, Lyonnet S, Schwartz G, Munnich A, Woo SLC, Shiloh Y (1993) A missense mutation, S349P, completely inactivates phenylalanine hydroxylase in North African Jews with phenylketonuria. Hum Genet 90:645–649 Yatuv R, Rosenberg N, Zivelin A, Peretz H, Dardik R, Trakhtenbrot L, Seligsohn U (2001) Identification of a region in glycoprotein IIIa involved in subunit association with glycoprotein IIb: further lessons from Iraqi-Jewish Glanzmann thrombasthenia. Blood 98:1063–1069 Zilber N, Kahana E, Abraham M (1991) The Libyan Creutzfeldt-Jakob disease focus in Israel: an epidemiologic evaluation. Neurology 41:1385–1389 Zlotogora J (1995) Hereditary disorders among Iranian Jews. Am J Med Genet 58:32–37 Zlotogora J, Shapiro MS (1992) Polyglandular autoimmune syndrome type I among Iranian Jews. J Med Genet 29:824–826 Zlotogora J, BenEzra D, Cohen T, Cohen E (1990) Syndrome of brittle cornea, blue sclera, and joint hyperextensibility. Am J Med Genet 36:269–272 Zlotogora J, Legum C, Raz J, Merin S, BenEzra D (1994) Autosomal recessive colobomatous microphthalmia. Am J Med Genet 49:261–262 Zlotogora J, Bach G, Bo¨senberg C, Barak Y, von Figura K, Gieselmann V (1995) Molecular basis of late infantile metachromatic leukodystrophy in the Habbanite Jews. Hum Mutat 5:137–143

Part V Cultural and Religious Attitudes Towards Genetic Issues

Chapter 24

Prevention and Care of Genetic Disorders: An Islamic Perspective Aida I. AL Aqeel

Islam and Ethics Islam is the continuum and the culmination of, not an alternative to, the sister Abrahamic faiths of Judaism and Christianity. In the Quran, they are links of the one chain of God’s message to humanity. The Quran, which Muslims believe is God’s very word, says: The same religion He enjoined on you as the one He enjoined on Noah, and this We reveal unto you and that We enjoined upon Abraham, Moses and Jesus, that you should uphold the faith and break-not your unity therein (The Holy Quran 42:13). This commonality we respect, although we are aware that on further comparison it is natural to find differences and distinct schools of thought between the faiths, and even within one faith. Islam is the predominant religion in the developing world; however, it is not an “Arab” religion. In fact, out of the 1.6 billion Muslims in the world,

Genetic Disorders Among Arab Populations

Addictive Disorders in Medical Populations

Dysgenics: Genetic Deterioration in Modern Populations

Genetic Aberrancies and Neurodegenerative Disorders

Genetic Diagnosis of Endocrine Disorders

Handbook of Genetic Communicative Disorders

Genetic Skin Disorders, Second Edition

Gale Encyclopedia of Genetic Disorders

Genetic Basis for Respiratory Control Disorders

Advances in the Study of Genetic Disorders

The Gale Encyclopedia of Genetic Disorders

The Gale Encyclopedia of Genetic Disorders

The Gale Encyclopedia of Genetic Disorders

Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment (Milunsky, Genetic Disorders and the Fetus)

Genetic Basis for Respiratory Control Disorders

Genetic Basis for Respiratory Control Disorders

Community Control of Genetic and Congenital Disorders

The Gale Encyclopedia of Genetic Disorders

Arab

Arab

Genetic Disorders of Endocrine Neoplasia (Frontiers of Hormone Research)

The Gale encyclopedia of genetic disorders M-Z

Life Span Development in Genetic Disorders: Behavioral and Neurobiological Aspects

Genes, Brain and Development: The Neurocognition of Genetic Disorders

Life Span Development in Genetic Disorders: Behavioral and Neurobiological Aspects

The Gale Encyclopedia of Genetic Disorders (Volume 2, M-Z)

Gale Encyclopedia of Genetic Disorders, Two Volume Set. M-Z

Genetic Disorders Sourcebook, Fourth Edition (Health Reference Series)

Gale Encyclopedia of Genetic Disorders 2 Vol-set, 3rd Edition

Genetics for Pediatricians: The Molecular Genetic Basis of Pediatric Disorders

Gale Encyclopedia of Genetic Disorders, Two Volume Set. A-L

Genetic Disorders Among Arab Populations

Addictive Disorders in Medical Populations

Dysgenics: Genetic Deterioration in Modern Populations

Genetic Aberrancies and Neurodegenerative Disorders

Genetic Diagnosis of Endocrine Disorders

Handbook of Genetic Communicative Disorders

Genetic Skin Disorders, Second Edition

Gale Encyclopedia of Genetic Disorders

Genetic Basis for Respiratory Control Disorders

Advances in the Study of Genetic Disorders

The Gale Encyclopedia of Genetic Disorders

The Gale Encyclopedia of Genetic Disorders

The Gale Encyclopedia of Genetic Disorders

Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment (Milunsky, Genetic Disorders and the Fetus)

Genetic Basis for Respiratory Control Disorders

Genetic Basis for Respiratory Control Disorders

Community Control of Genetic and Congenital Disorders

The Gale Encyclopedia of Genetic Disorders

Arab

Arab

Genetic Disorders of Endocrine Neoplasia (Frontiers of Hormone Research)

The Gale encyclopedia of genetic disorders M-Z

Life Span Development in Genetic Disorders: Behavioral and Neurobiological Aspects

Genes, Brain and Development: The Neurocognition of Genetic Disorders

Life Span Development in Genetic Disorders: Behavioral and Neurobiological Aspects

The Gale Encyclopedia of Genetic Disorders (Volume 2, M-Z)

Gale Encyclopedia of Genetic Disorders, Two Volume Set. M-Z

Genetic Disorders Sourcebook, Fourth Edition (Health Reference Series)

Gale Encyclopedia of Genetic Disorders 2 Vol-set, 3rd Edition

Genetics for Pediatricians: The Molecular Genetic Basis of Pediatric Disorders

Gale Encyclopedia of Genetic Disorders, Two Volume Set. A-L

Recommend Documents