Genetics for Ophthalmologists: The Molecular Genetic Basis of Ophthalmic Disorders

Genetics for Ophthalmologists The Remedica Genetics for… Series Genetics for Cardiologists Genetics for Dermatologist...

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Genetics for Ophthalmologists

The Remedica Genetics for… Series Genetics for Cardiologists Genetics for Dermatologists Genetics for Hematologists Genetics for Oncologists Genetics for Ophthalmologists Genetics for Orthopedic Surgeons Genetics for Pulmonologists Genetics for Rheumatologists

Published by the REMEDICA Group REMEDICA Publishing Ltd, 32–38 Osnaburgh Street, London, NW1 3ND, UK REMEDICA Inc, Tri-State International Center, Building 25, Suite 150, Lincolnshire, IL 60069, USA E-mail: [email protected] www.remedica.com Publisher: Andrew Ward In-house editors: Tamsin White & Eilidh Jamieson Design: REGRAPHICA, London, UK © 2002 REMEDICA Publishing Limited All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher. ISBN 1 901346 20 X British Library Cataloguing-in Publication Data A catalogue record for this book is available from the British Library

Genetics for Ophthalmologists The molecular genetic basis of ophthalmic disorders Graeme CM Black Wellcome Senior Clinical Fellow, Academic Units of Ophthalmology and Clinical Genetics Manchester University, Manchester, UK Honorary Consultant in Genetics and Ophthalmology, Central Manchester and Manchester Children's University Hospitals NHS Trust, Manchester, UK

Series editor: Eli Hatchwell Investigator, Cold Spring Harbor Laboratory

Introduction to Genetics for… series Medicine is changing. The revolution in molecular genetics has fundamentally altered our notions of disease etiology and classification, and promises novel therapeutic interventions. Standard diagnostic approaches to disease focused entirely on clinical features and relatively crude clinical diagnostic tests. Little account was traditionally taken of possible familial influences in disease. The rapidity of the genetics revolution has left many physicians behind, particularly those whose medical education largely preceded its birth. Even for those who might have been aware of molecular genetics and its possible impact, the field was often viewed as highly specialist and not necessarily relevant to everyday clinical practice. Furthermore, while genetic disorders were viewed as representing a small minority of the total clinical load, it is now becoming clear that the opposite is true: few clinical conditions are totally without some genetic influence. The physician will soon need to be as familiar with genetic testing as he/she is with routine hematology and biochemistry analysis. While rapid and routine testing in molecular genetics is still an evolving field, in many situations such tests are already routine and represent essential adjuncts to clinical diagnosis (a good example is cystic fibrosis). This series of monographs is intended to bring specialists up to date in molecular genetics, both generally and also in very specific ways that are relevant to the given specialty. The aims are generally two-fold: (i)

to set the relevant specialty in the context of the new genetics in general and more specifically

(ii)

to allow the specialist, with little experience of genetics or its nomenclature, an entry into the world of genetic testing as it pertains to his/her specialty


These monographs are not intended as comprehensive accounts of each specialty — such reference texts are already available. Emphasis has been placed on those disorders with a strong genetic etiology and, in particular, those for which diagnostic testing is available. The glossary is designed as a general introduction to molecular genetics and its language. The revolution in genetics has been paralleled in recent years by the information revolution. The two complement each other, and the World Wide Web is a rich source of information about genetics. The following sites are highly recommended as sources of information: 1.

PubMed. Free on-line database of medical literature. http://www.ncbi.nlm.nih.gov/PubMed/

2.

NCBI. Main entry to genome databases and other information about the human genome project. http://www.ncbi.nlm.nih.gov/

3.

OMIM. On line inheritance in Man. The On-line version of McKusick’s catalogue of Mendelian Disorders. Excellent links to PubMed and other databases. http://www.ncbi.nlm.nih.gov/omim/

4.

Mutation database, Cardiff. http://www.uwcm.ac.uk/uwcm/mg/hgmd0.html

5.

Retnet. A listing of cloned and/or mapped genes causing retinal diseases. http://www.sph.uth.tmc.edu/Retnet/disease.htm

Eli Hatchwell Cold Spring Harbor Laboratory

Introduction

Preface A decade ago, it was unimaginable that the entire genomic sequence would be completed within a few years. The identification and mapping of our genes has already led to a better understanding of their expression and function. Over this period a vast number of genes underlying monogenic ophthalmic disorders have been identified and our understanding of disorders affecting every part of the eye has been enhanced immeasurably. As genetic testing technologies become more readily available and accessible as an aid to both diagnosis and management, the impact on the practice of ophthalmology will be profound. As a result, an understanding of its power and capabilities has become essential. A working knowledge of the practice of genetics has become relevant and should no longer be regarded as a quaint academic pursuit. Furthermore, its importance should not be underestimated: in pediatric ophthalmology, around half (probably more) of the cases of childhood blindness have a genetic cause, while inherited factors contribute to the blinding effects of adult-onset diseases such as diabetes, glaucoma and age-related macular degeneration. As is clear from the clinical sections, awareness of extraocular manifestations is crucial to the diagnosis and correct management of many of the conditions in this book. Therefore, ophthalmologists must think broadly when approaching their genetic patients: without consideration of cardiac complications, the management of ectopia lentis in Marfan syndrome will not meet all of that patient’s needs. The same is true of the need for sun protection in albinism, or tumor surveillance in those with von Hippel Lindau disease. Fortunately, encyclopedic knowledge is not required. As with any branch of clinical medicine there are generalized principles in the approach to, and management of, inherited disorders whose understanding enables both the generalist and the subspecialist to deal in a standardized – and reliable – fashion with the often Genetics for Ophthalmologists

complex problems that are posed by genetic disease. The purpose of this book is to present current knowledge of a range of inherited ocular disorders in a concise, approachable format to enable the clinician to gather easily a working knowledge of the clinical manifestations and molecular features of each disorder. It is primarily aimed at the ophthalmologist but it will also be useful to trainees at all levels as well as clinical geneticists and molecular scientists who share an interest in genetic ophthalmology. Genetic testing An increasing number of genes are being cloned that are responsible for inherited ophthalmic conditions. While it is assumed – especially by patients and their families – that gene identification is followed closely and inevitably by routinely available genetic testing, this has been shown repeatedly not to be the case. The time lag leads to a significant gulf between the expectations of patients and the abilities of the clinician to fulfil them. There are a number of factors to consider: • Screening for mutations in most genes is a labor-intensive and time-consuming process that requires analysis of the whole gene. Exceptions to this are TIMP3 (Sorsby dystrophy) and BIGH3 (stromal corneal dystrophies) where the range of mutations is limited. Therefore, in the majority of cases screening may take a number of months. • In conditions where a broad range of genes may cause an identical phenotype (e.g. retinitis pigmentosa) there is no way to ascertain which gene is responsible; this makes screening impractical in a clinical setting, using current techniques. • Mutation detection procedures are not 100% sensitive. Many methods of identifying mutations within a gene are ~70% successful. Therefore, in many cases molecular analysis will not produce a ‘definitive’ result. Where mutation screening is appropriate, blood samples are usually only taken from an affected member of the family: mutation

Preface

screening of an unaffected family member is only of use once a mutation is found. Therefore, in a proportion of families that are seen, mutation screening is not available because a sample cannot be obtained from an affected member of the family. A negative result in an unaffected person may mean that a mutation is not present, or for technical reasons a mutation has not been detected, or that a mutation may be present in another gene. Genetic testing has come to mean mutation testing in the eyes of many. However, it should not be forgotten that chromosome analysis (karyotyping) is an important tool which, when used selectively in the correct circumstances, is critical to the management and diagnosis of many genetic conditions (see ‘karyotype’ in the glossary). Predictive testing Examining relatives in the clinic can be a valuable adjunct to diagnosis. This is true for both static, developmental disorders (congenital cataract, coloboma) and progressive disorders (retinal dystrophies). However, when faced with expectant, as yet unaffected, relatives or children what should the clinician do? Within genetic centers, protocols are in place for predictive testing (either through examination or genetic testing) in families with adult-onset genetic disorders. These are based on protocols for testing in families with Huntington disease. They include discussion of the risks associated with mutations, the implications to the wider family of a mutation result and a discussion of how patients may cope with a ‘bad’ news result that confirms a high risk of developing symptoms. Patients are advised to seek financial advice, as the situation with regard to access to results for insurance companies is currently uncertain. Within the ophthalmic setting there has been little consideration of the potential impact of presymptomatic genetic diagnosis – either through examination or genetic testing. It should be remembered that the aim of testing must be to improve diagnosis and management, and to facilitate counselling of patients and their families. Clearly, if such a test disadvantages patients then it fails to meet these aims.


Therefore, consideration needs to be given to the clinical need for genetic testing, and patients and their relatives need to understand the pros and cons of such a process. When approaching asymptomatic at-risk relatives it may be useful to ask these questions prior to examining or drawing blood: • Is there a clinical need in proceeding with presymptomatic diagnosis? • Does it need to be done now? (What is done can never be undone.) • Are there disadvantages to presymptomatic diagnosis (psychological, employment, financial)? • Does the patient really want to know? Genetic counselling The aim of genetic counselling is to inform patients and their families about how and why a condition affects them now and in the future, and to explain its reproductive implications. This is not simply a question of defining risks and explaining inheritance patterns. Fundamental to any counselling process is accurate clinical diagnosis and, within a genetic ophthalmic clinic, the clinician must be prepared to modify or even to change a previous diagnosis. Such a process takes time and an appropriate clinical setting is required such as a clinical genetic or joint genetic-ophthalmic clinic. Such a consultation will then allow accurate history/family history taking, examination (often of multiple family members), discussion, explanation and answering patients’ questions. Finally, when approaching genetic counselling, the expectations of the patient must be considered. It is important to understand what they are seeking and why they may be unsatisfied at the end of the process. Through the power of the internet, as well as the many excellent patient organizations, those with inherited ocular disorders are often well informed about their conditions – perhaps more

Preface

up-to-date than their physicians! While information is often what they require, either by way of confirmation or reassurance, two specific themes recur. Firstly, patients will often want genetic testing to define the risks to offspring. Sadly, current techniques often make this either impossible or unlikely to be successful. Secondly, and perhaps more importantly, patients are often keen to seek novel treatments that will either prevent or restore loss of sight. The latter is strongly fuelled by frenetic media coverage and leads to unrealistic expectations. In any counselling setting it is important to feel comfortable giving bad news. It is in no-one’s interest to be unrealistically optimistic about future prospects. Total pessimism is similarly unhelpful. Therefore, ‘cautious realism’ in explaining that hope for the future may not, in fact, be translated into practical help for the present is often important in helping families come to terms with the reality of a situation and in enabling them to begin to prepare for the future.


What the experts say Recent advances in molecular biology have impacted on all areas of clinical medicine including ophthalmology. Molecular genetic diagnosis is now possible for many inherited eye disorders and the identification of the genetic mutations causing eye disease has greatly improved our understanding of disease mechanisms. A new era of novel molecular targeted therapy beckons. All ophthalmologists will need to keep abreast of advances in this rapidly changing field. This excellent book, written by Dr Graeme Black, an international authority in the field of genetic eye disease, gives a wonderfully clear and concise summary of the many eye disorders that have a genetic basis. The text covers both isolated eye disease and multi-system disorders with an ocular component. The chapters follow a very clear structure detailing the clinical findings, age of onset, molecular genetics and diagnosis and this makes for great ease of use. The illustrations also serve to aid diagnosis. There is a very useful glossary at the end of the book that gives a clear explanation of genetic terminology with which the ophthalmologist may not be familiar. I can thoroughly recommend this excellent book; it will appeal not only to clinical ophthalmologists but to other specialists such as clinical geneticists and paediatricians. It is the ideal book to keep close at hand in the consulting room. AT Moore, Professor of Ophthalmology, Institute of Ophthalmology and Moorfields Eye Hospital, London, UK Advances in the molecular genetics of ophthalmology are revolutionizing the specialty. However, clinicians find it difficult to access or utilize this new genetic information. This book provides a solution. It does a spectacular job of presenting an authoritative, up to date summary of molecular ophthalmology. The clear style and excellent illustrations demystify the molecular genetics of ophthalmology. It will be an excellent reference book for any health care practitioner who wishes to incorporate molecular genetics into the management of his or her patients. It is easy to read and I wholeheartedly recommend it both as an educational and reference tool. Andrew Lotery, MD FRCOphth, Assistant Professor of Ophthalmology, University of Iowa Hospitals & Clinics, USA Genetics for Ophthalmologists

Genetics for Ophthalmologists is a comprehensive reference tool for the General Ophthalmologist to the Ophthalmic Geneticist. Hereditary eye diseases and syndromes are grouped ‘anatomically’ as a comprehensive catalog. Each disorder has a succinct synopsis of clinical features, illustrations, inheritance and information on the genes, mutations and presumed mechanism of action. Most importantly perspective on the utility and availability of genetic testing are given for each condition as well as a general opening section discussing issues relating to predictive testing and counselling. The extensive glossary gives a clear explanation of many terms used in genetics. Genetics for Ophthalmologists is an essential reference resource for every eye department. David Mackey, MD FRANZCO Centre for Eye Research, Australia Graeme Black has performed an extensive review of the ophthalmic genetic literature and provided a masterpiece that has been long awaited by those with an interest in the genetics of eye disease. Until now it has been extremely difficult for the clinician to find this information without spending hours at the computer searching for relevant publications. This book provides a comprehensive coverage of inherited eye diseases starting at the cornea and working back towards the optic nerve. The format is easy to follow with useful summaries of the clinical and diagnostic criteria for each condition. Information about inheritance patterns, penetrance, the effect of mutations and whether genetic screening is currently possible will be invaluable to all those involved in counselling families. There is also a very helpful Glossary for those less used to genetic terminology. Clinical Geneticists and Ophthalmologists alike will find this an indispensable tool in their clinics and every medical library should have a copy. Despite the fast pace of genetics I feel sure this book will remain a valuable text for many years to come. Amanda Churchill, PhD MBChB FRCOphth Consultant Senior Lecturer in Ophthalmology, University of Bristol, UK Genetics for Ophthalmologists

Acknowledgements I am extremely grateful to my colleagues – in particular Robyn Jamieson, Alan Ridgway and Jill Clayton-Smith – for taking the time to review the manuscript and for making corrections and helpful suggestions. I would also like to thank those listed below for supplying the following illustrations: Amanda Churchill (pp 78), Jill Clayton-Smith (pp 53–4, 252), Dian Donnai (pp 80, 153, 173–4, 178, 180), Susie Downes (pp 98, 127), Gareth Evans (pp 249, 255), John Grigg (pp188, 196), Chris Lloyd (pp 31, 46, 52, 58, 237, 220), David McLeod (pp 172,181), Francis Munier (pp 12, 31), Alan Ridgway (pp 10, 17, 23), Fiona Spencer (pp 61, 70), Andrew Webster (pp 90).

Contents Corneal disease Lens Glaucoma Inherited retinal disease Vitreoretinal disorders Optic nerve Defects of pigmentation Metabolic disorders Conditions associated with increased risk of malignancy Defects of ocular/adnexal development Glossary Abbreviations Index


1 27 57 81 169 187 201 213 241 267 279 333 341


1 1. Corneal disease

Abnormalities of corneal shape Cornea plana 5 Corneal dystrophies Epithelial Gelatinous drop-like corneal dystrophy 7 Meesmann corneal dystrophy 8 BIGH3-Related Bowman’s layer dystrophy type I 10 Bowman’s layer dystrophy type II 12 Granular corneal dystrophy 14 Lattice corneal dystrophy type I 18 Stromal Lattice corneal dystrophy type II 20 Macular corneal dystrophy 23 Endothelial Fuchs' endothelial corneal dystrophy 25

Introduction A wide range of inherited conditions, both ocular and multisystemic, are associated with abnormalities of corneal development, shape, clarity or integrity. Corneal size

Mean corneal diameter is around 10 mm at birth reaching a maximum of 12.5 mm at 2 years. Abnormalities of corneal size include microcornea (diameter 13 mm). Microcornea is often associated with other ocular abnormalities including microphthalmos (q.v.), coloboma or cataract. Isolated megalocornea, in the absence of other ocular abnormalities, is an uncommon, X-linked recessive condition of benign prognosis. It is often initially diagnosed as congenital glaucoma but may easily be distinguished by a high endothelial cell count.

Corneal shape

Cornea plana is associated with non-progressive reduced corneal curvatures. Increased corneal curvature is seen particularly in corneal ectasias, a subgroup of the corneal dystrophies. Of these, keratoconus is the most common. Isolated keratoconus affects 1:2–5000 of the population and has a well-recognized genetic predisposition, although the genetic etiology remains undefined. A small number of cases have been shown to carry mutations in the ocular transcription factor VSX1. The systemic associations include Down syndrome, Ehlers-Danlos syndrome and Leber congenital amaurosis.

Anterior segment dysgenesis

Corneal abnormalities are a feature of many forms of the developmental anterior segment disorders. In Peters anomaly, a severe developmental abnormality, corneal opacification (often central) is associated with a defect in Descemet's membrane often with adhesions between the cornea, the lens and/or iris. Hereditary forms are recognized including defects of PAX6, PITX2, CYP1B1 and MAF. Aniridia may be associated with abnormal peripheral corneal vascularization, which is often progressive and may be troublesome in later life.

2


Corneal dystrophies

The corneal dystrophies have been defined as inherited, bilateral, slowly progressive disorders that alter corneal function in the absence of inflammation and systemic sequelae. In most cases this definition holds true, although exceptions can be found including unilateral cases, those of rapid progression and those with systemic associations. Traditionally, corneal dystrophies have been subdivided according to the anatomical site at which the presumed defect is located, i.e. anterior, stromal and posterior, or endothelial dystrophies, with a remaining group of ectatic dystrophies. Such morphological classification becomes increasingly cumbersome as the genetic bases for these disorders are defined. It is now evident that a remarkable number of supposedly distinct dystrophies share a common molecular etiology (see Table 1). While a morphological classification remains valid, this may prompt its re-evaluation.

Inborn errors of metabolism

A number of metabolic disorders are associated with corneal manifestations. These include Wilson disease or hepatolenticular degeneration (Kayser-Fleischer ring), Fabry disease (vortex keratopathy), mucopolysaccharidoses (corneal clouding) and cystinosis (crystal deposition). The following section includes a relatively small number of corneal dystrophies and isolated corneal developmental abnormalities for which the precise molecular defect has been defined. The chromosomal location is known for a number of other, similar conditions (see Table 2) and it is likely that this group will expand in the near future as the genes that underlie other corneal dystrophies are discovered.

Corneal disease

3

Table 1. Mutation of the common BIGH3-related dystrophies. Condition Reis-Bucklers Thiel-Behnke Granular Avellino Lattice type I

Exon 4 12 12 4 4

Mutation R124L R555Q R555W R124H R124C

Table 2. Inheritance pattern and chromosomal localization of the inherited corneal dystrophies. Condition Meesmann Lisch Cogan (Map-Dot Fingerprint) Gelatinous drop-like Reis-Bucklers Thiel-Behnke Thiel-Behnke Granular Avellino Macular Lattice type I Lattice type II Lattice type IIIa Schnyder crystalline Fuchs Posterior polymorphous Congenital hereditary endothelial Congenital hereditary endothelial

4

MIM 122100 121820 204870 121900 121900 602082 121900 121900 217800 122200 105120 122200 121800 136800 122000 121700 217700

Inheritance AD XL AD AR AD AD AD AD AD AR AD AD AD AD AD AD AD AR

Chromosome 12q, 17q Xq22.3 1p31 5q31 5q31 10q24 5q31 5q31 16q22 5q31 9q34 5q31 1p34.1–p36 20p11.2–q11.2 20cen 20p13

Gene K3, K12 M1S1 BIGH3 BIGH3 BIGH3 BIGH3 CHST6 BIGH3 Gelsolin BIGH3 VSX1 -


Cornea plana (also known as: CNA1; CNA2) MIM

217300; 603288 (KERA)

Clinical features

Both dominant and recessive forms are described, with the latter being the more severe. Anterior segment abnormalities include extreme hypermetropia (+10 D or more), a hazy corneal limbus with stromal opacities and marked arcus juvenilis. The cornea is thin with an indistinct sclerocorneal boundary. The two forms are distinguished by a round thickened central opacity, approximately 5 mm in width, which is seen in most recessive cases but not those of dominant inheritance. Iris malformations and iridocorneal adhesions are more prevalent in the recessive form. Mild microphthalmia may be present in the recessive form.

Age of onset

Congenital

Epidemiology

Rare in the UK. Although prevalence is uncertain, the condition has been described in autosomal dominant form in Cuba and autosomal recessive form in Finland (carrier frequency estimated at 1:126 in north-east Finland).

Inheritance

Autosomal dominant; autosomal recessive

Chromosomal location

12q21.3–q22 (autosomal recessive). Linkage analysis of a dominant form in a Cuban kindred confirmed linkage to the region of 12q implicated in recessive cornea plana. Finnish families with a dominant form of cornea plana do not link to 12q, suggesting two distinct dominant forms.

Gene

Keratocan (KERA) (recessive form)

Corneal disease

5

Mutational spectrum

Mutations have been found in the recessive form of cornea plana. One nonsense mutation and a missense mutation within the highly conserved leucine-rich repeat (LRR) have been described.

Effect of mutation

Keratan sulfate proteoglycans (KSPGs) are members of the small leucine-rich proteoglycan (SLRP) family. KSPGs, particularly keratocan, lumican and mimecan, are important to the transparency of the cornea. Keratocan is expressed early in neural crest development and later in corneal stromal cells. The missense mutation described results in an asparagine to serine substitution, affecting the most highly conserved amino acid in the LRR motif throughout the SLRP family.

Diagnosis

6

Clinical examination

Cornea plana

Gelatinous drop-like corneal dystrophy (also known as: GLDL; primary subepithelial corneal amyloidosis) MIM

204870; 137290 (M1S1)

Clinical features

Amyloid accumulation beneath the epithelium produces whitish deposits that are said to resemble a mulberry. These accumulations lead to photophobia, discomfort and reduced visual acuity. Histologically the amyloid deposits are seen above Bowman’s layer and within the epithelium as well as within the stroma.

Age of onset

Amyloid begins to accumulate in the cornea during the first two decades of life.

Epidemiology

1:300,000 (Japan). Rare but not unknown outside Japan.

Inheritance

Autosomal recessive


1p31

Gene

Membrane component, chromosome 1, surface marker 1 (M1S1)

Mutational spectrum

Four nonsense mutations described in a Japanese cohort of patients.

Effect of mutation

Protein truncating mutations result in the production of a shortened amyloidogenic protein that accumulates within the tissues of the anterior cornea. The function of the protein is unknown.

Diagnosis

GLDL is a clinical diagnosis. Genetic testing is not widely available and does not alter clinical management. Molecular analysis of patients with ‘gelatino-lattice’ dystrophy—in which there are overlapping features of type I lattice dystrophy and GLDL—has revealed a mutation in BIGH3 (R124C, see lattice dystrophy) but none in M1S1. It is likely that this does not represent GLDL.

Corneal disease

7

Meesmann corneal dystrophy (also known as: juvenile familial corneal dystrophy) MIM

122100; 148043 (KRT3); 601687 (KRT12)

Clinical features

Meesmann dystrophy is an epithelial corneal dystrophy. Slit-lamp examination reveals multiple intra-epithelial microcysts and symmetrical, sharply demarcated, intra-epithelial opacities of uniform size that resemble vesicles. Fragility of the corneal epithelium leads to recurrent erosions, often by the end of the first or during the second decade. Patients describe photophobia and lacrimation particularly during acute episodes but reduction in vision is generally relatively mild. However, frequent recurrent erosions and extreme sensitivity to minor trauma (such as intolerance of contact lenses) ultimately leads to superficial corneal scarring and reduced visual acuity. This may be severe enough to warrant keratoplasty.

Epithelial microcysts in Meesman dystrophy.

Age of onset

Signs of the disease are present early in life and may well be congenital. However, symptoms may be delayed into the second or third decades.

Inheritance

Autosomal dominant

8

Meesmann corneal dystrophy


17q12 (KRT3); 12q13 (KRT12)

Gene

Cornea-specific keratins: keratin 3 (KRT3) and keratin 12 (KRT12).

Mutational spectrum

Missense mutations within the helix-initiation or helix-termination motifs of KRT3 or KRT12. The majority have been described in KRT12, within the helix-initiation region.

Effect of mutation

Mutations act in a dominant negative manner leading to defective epithelial cytoskeletal function and epithelial fragility. Ultrastructural examination reveals cytoplasmic densities, which are likely to represent tonofilament clumping as seen in other dominant keratin disorders. Keratin proteins are structurally important intermediate filaments found in epithelia. The family of proteins is divided into type I (acidic, K9–K21) and type II (neutral or basic, K1–K8) and their expression is tissue-specific. Keratins 3 and 12 are coexpressed (paired) to form a heterodimer which is specific to the corneal epithelium. Several inherited epidermal diseases, such as epidermolysis bullosa simplex, are caused by keratin mutations. Each protein contains a helical domain flanked by a helix-initiation motif and a helixtermination motif. These are highly conserved and thought to play important roles in filament assembly and stability; they are recognized as a mutation hotspot.

Diagnosis

Corneal disease

Diagnosis is usually clear from history and slit-lamp examination. Mutation analysis is available on a research basis only, and does not alter clinical management.

9

Bowman’s layer dystrophy type I (also known as: type I – CDBI; Reis-Bucklers corneal dystrophy/geographic granular dystrophy) MIM

121900; 601692 (TGFBI)

Clinical features

Accurate differentiation of the subforms of Bowman’s layer corneal dystrophy has been a cause of controversy and it is for these groups that genetic characterization has been particularly helpful. Bilateral geographic subepithelial opacities begin in the first decade. These are initially irregular and asymmetric but eventually become widespread and uniform. Recurrent erosions begin during the first 5 years of life. Visual reduction is severe and leads to surgery during the second to third decades.

CDB type 1. Geographic opacification which is not homogenous is seen beneath the Bowman’s layer.

Age of onset

10

CDB1 presents with recurrent erosions in the first decade of life.

Bowman’s layer dystrophy type I


5q31

Gene

Beta-Ig-H3/transforming growth factor, beta-induced (BIGH3/TGFB1).

Mutational spectrum

There is a tight genotype-phenotype correlation amongst mutations in the BIGH3 gene (see granular dystrophy). CDBI is caused by an R124L mutation in exon 4. A single Sardinian family has been described with Reis-Bucklers dystrophy, a trinucleotide deletion of exon 12 (∆F540).

Effect of mutation

The R124L mutation is thought to cause abnormal folding of the BIGH3 protein (see granular dystrophy).

Diagnosis

Slit-lamp examination may be sufficient for diagnosis, aided by histopathological examination of the diseased cornea after surgery. In CDBI there is accumulation of Masson trichrome positive material above Bowman's layer, but may also be present in the anterior stroma. The material is characterized by rod-shaped bodies on electron microscopy and has led to the condition being called ‘superficial granular dystrophy’. Since the different mutations causing the Bowman’s layer dystrophies have clear phenotypic effects, confirmation of the diagnosis by molecular testing may aid prediction of prognosis and speed of progression.

Corneal disease

11

Bowman’s layer dystrophy type II (also known as: Type II – CDBII; Thiel-Behnke corneal dystrophy/honeycomb corneal dystrophy) MIM

602082 (type II)

Clinical features

CDBII usually presents with frequent recurrent erosions within the first years of life. Bilateral superficial opacification in a honeycomb pattern develops during early adult life but visual acuity is less severely affected than in CDBI.

CDB type II or honeycomb dystrophy. Irregular, honeycombed opacification is seen at the level of the Bowman’s layer.

Age of onset

CDBII presents with recurrent erosions in the first decade of life.


5q31 (BIGH3) 10q24 (see below)

Mutational spectrum

As mentioned previously, there is a tight genotype-phenotype correlation amongst mutations in the BIGH3 gene (see granular dystrophy).

12

Bowman’s layer dystrophy type II

CDBII is caused by an R555Q mutation in exon 12. Confusion is added by the description of a family with a superficial corneal dystrophy (also called Thiel-Behnke dystrophy or CDBII) which is linked to chromosome 10q24 and is not caused by mutations in the BIGH3 gene. This suggests further, poorly delineated, heterogeneity amongst the superficial Bowman’s layer dystrophies. Effect of mutation

Mutations are thought to cause abnormal folding of the BIGH3 protein (see granular dystrophy).

Diagnosis

Slit-lamp examination may be sufficient for diagnosis. Histopathological examination of the diseased cornea after surgery will facilitate diagnosis. In CDBII, the Bowman’s layer is replaced by a fibrous, paucicellular layer of variable thickness between the epithelium and stroma. On electron microscopy this material demonstrates the presence of short, twisted ‘curly fibers’. Since the different mutations causing Bowman’s layer dystrophies have clear phenotypic effects, confirmation of the diagnosis by molecular testing may aid prediction of prognosis and speed of progression.

Corneal disease

13

Granular corneal dystrophy (also known as: Groenouw type I corneal dystrophy; CDGG1; Avellino-type corneal dystrophy) MIM

121900; 601692 (TGFBI)

Clinical features

Granular corneal dystrophy is characterized by the progressive development of discrete, grayish-white opacities within the central anterior corneal stroma. The condition is bilateral and symmetrical and the intervening stroma remains clear. The number of opacities increases with time and their position within the stroma deepens but the limbal region of the cornea is spared. Two main forms of granular dystrophy exist. Classical granular dystrophy Visual acuity often deteriorates during the third decade. Such a decline continues to a point where penetrating keratoplasty is required, often during the fifth decade of life. Corneal erosions are described in the condition but do not represent a major symptom. While penetrating keratoplasty is effective in improving vision the condition recurs, presumably as a result of deposition of granular material into the graft from the recipient’s epithelium. Histopathological examination of the diseased cornea after surgery reveals anterior stromal opacities which stain red with the Masson trichrome stain.

Granular corneal dystrophy.

14

Granular corneal dystrophy

Granular corneal dystrophy host corneal button stained with Masson trichrome to demonstrate red granular deposits within stroma.

Atypical granular dystrophy The atypical form has ring-shaped or snowflake-like granular deposits that are fewer in number than in the classical form. Grafting is seldom required as visual acuity is affected to a considerably lesser degree. This form of granular dystrophy, also known as Avellino dystrophy, was first described in a family from a small town in Italy. This is the prevalent form of granular dystrophy in SE Asia and Japan and has now been described in many different parts of the world.

Atypical granular (Avellino) dystrophy.

Corneal disease

15

Age of onset

In classical granular dystrophy, symptoms of photophobia are seen within the first decade with visual acuity remaining good during childhood. In the atypical form, symptoms may not present until the third decade.

Mutational spectrum

Mutations in the BIGH3 gene show very strong genotype-phenotype correlation. The classical form of granular corneal dystrophy is caused by an arginine to tryptophan substitution of amino acid 555 (R555W). Atypical, or Avellino, dystrophy is caused by an arginine to histidine substitution of residue 124 (R124H). A third mutation (R124S) has also been described in a late-onset form of granular dystrophy. The arginine residues at positions 124 and 555 are important in the development of a number of corneal dystrophies.

Effect of mutation

Both mutations are thought to cause abnormal folding of the BIGH3 protein which results in abnormal aggregates or deposits of the protein within the cornea. The BIGH3 protein is an extracellular matrix molecule, which is induced by TGFb. The protein is widely expressed and, in the cornea, is produced by the epithelium and stromal keratocytes. It is thought to be important in the wound-healing response although its exact function in the cornea is not yet defined. The granular deposits are identical in both forms of granular dystrophy (R555W and R124H). However, deposition of amyloid material, as observed in lattice corneal dystrophy, is seen in some cases of atypical granular dystrophy.

16

Granular corneal dystrophy

Atypical granular dystrophy – a teenage girl with severe granular-like corneal dystrophy. She is homozygous for the R124H mutation. Recurrences within the grafts were frequent and severe.

Diagnosis

Slit-lamp examination may be sufficient for diagnosis. Since the different mutations have clear phenotypic effects, confirmation of the diagnosis by molecular testing may aid the prediction of prognosis. While granular dystrophy is autosomal dominant, the condition is strictly semi-dominant: homozygous patients within consanguineous families (i.e. those with two affected parents) show a severe and early-onset form of the disease which shows rapid progression and marked, early visual loss. In these cases the disorder recurs rapidly within grafted tissue (see above).

Corneal disease

17

Lattice corneal dystrophy type I (also known as: LCD; lattice corneal dystrophy, type III/IIIa [LCDIII]) MIM

122200; 601692 (TGFBI)

Clinical features

LCD is characterized by the development of anterior stromal opacities. In LCDI these are gray, linear and fine, situated mainly within the central cornea. The intervening cornea remains clear initially but becomes progressively hazy. As in granular dystrophy, the opacities do not extend to the limbus. Erosions may begin early, even in childhood, while visual acuity is usually normal until early adulthood. Grafting is usually required from the third decade. Recurrence within the graft can lead to further visual deterioration. The histologic findings are of congophilic deposits that have the characteristics of amyloid protein. In some forms of autosomal dominant LCD, termed lattice corneal dystrophy type IIIa, the onset of symptoms is delayed until the fifth/sixth decade when there is visual deterioration and development of recurrent erosions. Examination demonstrates the appearance of sparse, thick rope-like lattice lines which are often asymmetrical unlike those of LCDI. Histological examination is indistinguishable.

Isolated LCD type I. Fine linear opacities are seen within the stroma.

18

Lattice corneal dystrophy type I

LCD type IIIa. Stromal lattice lines are said to be thicker in late onset forms of isolated LCD.

Age of onset

First decade of life in LCDI; fourth/fifth decades in LCDIIIa.

Mutational spectrum

To date, all analyzed forms of early-onset LCD (LCDI) have been caused by a single mutation (R124C) within exon 4 of the BIGH3 gene. Amongst later-onset forms of isolated lattice dystrophy a broader range of missense mutations exist, usually in the later exons of the gene. This explains at least some of the clinical, interfamilial heterogeneity seen amongst patients with isolated lattice dystrophy. BIGH3 mutations underlying dominant, late-onset forms of LCD have not been found to have any geographic or racial bias.

Effect of mutation

As with the other BIGH3-related dystrophies it is hypothesized that there is abnormal folding of BIGH3 which has amyloidogenic potential and aggregates within the cornea. Amyloid deposits in corneas from patients with lattice dystrophy have been shown on immunohistochemical analysis to co-localize with BIGH3.

Diagnosis

Slit-lamp examination and histologic examination of corneal buttons. Mutation analysis can facilitate the determination of prognosis.

Corneal disease

19

Lattice corneal dystrophy type II (also known as: amyloidosis V; Finnish-type amyloidosis; Meretoja-type amyloidosis) MIM

105120; 137350 (Gelsolin)

Clinical features

This is one of the inherited systemic amyloidoses and is characterized by corneal lattice dystrophy and cranial neuropathy.

Lattice corneal dystrophy type II. Dermal amyloid accumulation gives skin a waxy appearance. The skin is lax with fullness of lips and brow. Note that nostrils are held open with a nasal prong.

Ocular Slit-lamp examination demonstrates bilateral lattice corneal opacification. Recurrent erosions are not a feature of the disorder and visual deterioration develops later in life. Progressive corneal anesthesia is common and may lead to neuropathic ulceration as well as compromising the success of penetrating keratoplasty. Glaucoma, presumably secondary to amyloid accumulation in the trabecular meshwork, is a recognized complication. 20

Lattice corneal dystrophy type II

Dermal Amyloid accumulation gives the face a waxy appearance with a full brow and lower lip, and laxity similar to cutis laxa. The fullness of the lower lip leads to drooling, slurred speech and even an inability to eat, while the nostrils may become occluded. Neurological Abnormalities are common. Cranial neuropathy (especially of the facial nerve), peripheral polyneuropathy (mainly affecting vibration and touch senses) and minor autonomic dysfunction are frequent. Facial paralysis is progressive although extraocular muscles are not affected and there is no ptosis. Amyloid deposition is widespread and can also cause cardiac and renal symptomatology. Age of onset

Slit-lamp examination may reveal subtle lattice lines from the fourth decade onwards. At this stage mild neurological abnormalities, such as corneal hypoesthesia and facial paresis, may be detected. There may then be evidence of dermal changes in the face, particularly in the brow and lower lip.

Inheritance

Autosomal dominant


9q34

Gene

Gelsolin

Mutational spectrum

Two missense mutations of residue 187 (Asp187Asn and Asp187Tyr).

Effect of mutation

Gelsolin is part of the extracellular actin-scavenger system which prevents the toxic effects of actin release into the extracellular space during necrosis. It is required by those cell types involved in mediating responses to stress and apoptosis. If transfected into mammalian cultured cells, the pathogenic substitutions result in the secretion of an aberrant polypeptide which contains an amyloidforming sequence.

Corneal disease

21

Diagnosis

22

Amyloidosis V is one of the differential diagnoses of late-onset lattice dystrophy. Although it is of higher frequency in Finland, the diagnosis should not be dismissed in other parts of the world. Patients should be screened for potential complications: from an ophthalmic viewpoint screening for glaucoma should be instituted.

Lattice corneal dystrophy type II

Macular corneal dystrophy (also known as: MCDC; Groenouw type II corneal dystrophy) MIM

217800; 605294 (CHST6)

Clinical features

Macular corneal dystrophy is characterized by a diffuse corneal stromal clouding and reduction of corneal thickness by about one-third. The opacity is initially superficial but deepens with time and results in progressive visual deterioration. Recurrent erosions do not occur. Unlike the granular and lattice dystrophies, corneal clouding does not spare the limbal region. On examination there are ill-defined grayish-white stromal opacities between which the intervening stroma is hazy. After penetrating keratoplasty, histological examination of corneal buttons shows staining of abnormal deposits with alcian blue demonstrating the presence of lakes of glycosaminoglycans within the stromal matrix.

Macular corneal dystrophy. Stromal deposits cause corneal clouding without discrete opacities. A. Opacification reaches the limbus.

B. Recurrence within the grafts is rare.

Age of onset

Corneal opacities may be present from the first decade of life. Visual deterioration is variable and penetrating keratoplasty is usually indicated from the third and fourth decades. Recurrence in the graft is exceptional and is not sight-threatening.

Inheritance

Autosomal recessive

Corneal disease

23


16q22

Gene

Carbohydrate sulfotransferase 6 (CHST6), also known as corneal N-acetylglucosamine-6-sulfotransferase.

Mutational spectrum

Type I MCDC is characterized by absent sulfated keratan sulfate in serum. Inactivating mutations of CHST6, including missense frameshift and deletion mutations, are described. Type II MCDC is characterized by the presence of sulfated keratan sulfate, in serum. Large rearrangements in the 5´ region upstream of CHST6 have been defined.

Effect of mutation

CHST6 is thought to be important in the production of sulfated keratan sulfate, which is essential for the maintenance of corneal clarity. It is hypothesized that mutations in type I MCDC result in the inactivation of CHST6. In type II MCDC, loss of tissue-specific regulatory elements are thought to abolish CHST6 expression in the cornea.

Diagnosis

MCDC is diagnosed clinically. Genetic testing is available on a research basis only but does not generally alter clinical management; delineation of type I or type II MCDC is not important clinically or for genetic counselling.

24

Macular corneal dystrophy

Fuchs’ endothelial corneal dystrophy (also known as: FECD)

Including: Posterior polymorphous dystrophy (PPCD) MIM

136800 (FECD); 122000 (PPCD)

Clinical features

FECD is one of the most common indications for corneal transplantation (up to 19%) in developed countries. Symptoms of painful visual loss result from corneal decompensation. The development in the central cornea of focal wart-like guttae arising from Descemet’s membrane, which is thickened by abnormal collagenous deposition. There is reduced endothelial function and cell density as well as cellular pleomorphism. PPCD is characterized by formation of blister-like lesions within the corneal endothelium or by regions of endothelial basement membrane thickening with associated corneal edema. There is replacement of the normal amitotic endothelial cells by epitheliallike cells that possess abundant intermediate filaments, desmosomes and microvilli. The endothelium becomes multilayered and the abnormally proliferating cells may extend outwards from the cornea over the trabecular meshwork to cause glaucoma. In this regard PPCD resembles iridocorneal endothelial (ICE) syndrome.

Age of onset

In FECD signs may be present from the 4th decade of life onwards. PPCD although variable in both penetrance and expressivity usually presents earlier and may be symptomatic from childhood.

Inheritance

FECD is usually sporadic although this may be a reflection of its late onset. Highly penetrant dominant forms are described. PPCD is inherited in an autosomal dominant manner.


FECD: 1p34.3–p32 (COL8A2) PPCD: 20p11.2–q11.2 (VSX1)

Corneal disease

25

Gene

Collagen type VIII, alpha 2 (COL8A2)

Mutational spectrum

Missense substitutions of the X position of the Gly-X-Y triplet of the collagenous triple helical domain of the α2 chain of type VIII collagen have been described in families with early-onset and classical Fuchs’ dystrophy as well as in PPCD. Mutations were found in 100 in each eye) of small, irregularly shaped, off-white, radially arrayed, peripheral cortical lens opacities. Often there are areas (‘clock hours’) with a relatively high density of opacities, whilst other areas are relatively spared. The opacities are more common in the anterior cortex. There may also be visually significant posterior polar lens opacities. Ocular examination may help to identify these phenomena.

46

Lowe oculocerebrorenal syndrome

Extraocular Hypotonia is present at or soon after birth, and motor development is delayed. Hypermobile joints are also common with about 50% of affected boys developing scoliosis. Short stature is common. Intellectual impairment varies widely; around 50% of individuals are severely delayed and 25% are in the mild to moderate range of mental retardation. Seizures occur in about 50% of patients. Day-to-day functioning is often impaired by characteristic behavior patterns. Boys have a characteristic facial appearance with frontal bossing, a hypotonic appearance and sunken eyes. Renal tubular dysfunction usually becomes apparent by 1 year of age and progresses to renal failure (a major cause of premature death) from about 10 years. As a result, vitamin D resistant rickets is common. Age of onset

Congenital

Inheritance

X-linked recessive


Xq26.1

Gene

OCRL1

Mutational spectrum

A large number of mutations have been described. Nonsense/ premature terminations form around 50% of mutations. Around 70% of missense mutations are found within conserved residues of exon 15.

Effect of mutation

It is likely that most mutations lead to loss of function. The OCRL1 gene encodes a polypeptide that is similar to human inositol polyphosphate 5-phosphatase, a ubiquitously expressed enzyme which is localized in the Golgi apparatus. The enzyme converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate. Abnormalities of inositol metabolism/transport have been implicated in the pathogenesis of cataracts in galactosemia and diabetes mellitus.

Lens

47

Diagnosis

Although the condition may be suspected on clinical grounds and supported by abnormal urine amino acids, definitive diagnosis can now be confirmed by testing for the presence of phosphatidylinositol 4,5-bisphosphate 5-phosphatase in fibroblasts. Detection of enzyme activity in amniocytes allows for prenatal diagnosis. Mutation testing may supplement biochemical analysis but is generally only available on a research basis. While most of the counselling issues regarding Lowe syndrome are likely to be dealt with by clinical geneticists, the ophthalmologist may be directly involved with carrier detection. In experienced hands this is highly sensitive, although the lens opacities are not in themselves pathognomonic of the condition.

48

Lowe oculocerebrorenal syndrome

Myotonic dystrophy (also known as: DM; dystrophia myotonica 1) MIM

160900

Clinical features

Ocular Cataract is the cardinal ocular feature of DM. Due to the variable nature of the condition as it passes from generation to generation (genetic anticipation, see below), cataract in older patients may be the presenting feature in a family. The characteristic feature is the ‘Christmas tree’ cataract in which there are multiple refractile colored opacities throughout the lens. These may be progressive and become associated with cortical or posterior subcapsular lens opacification. While retinal findings have been described in DM, including macular pigmentary disturbance and mild ERG changes, these are seldom visually significant. As the disease progresses muscle weakness can lead to ophthalmoplegia. Extraocular In the classical form, patients develop muscle weakness (particularly distal) and wasting. The typical impassive (myotonic) faces are due to facial muscle weakness, and are associated with frontal balding and ptosis. Myotonia (inability to relax muscles voluntarily, particularly in the cold) may interfere with daily activities such as using tools and household equipment. Smooth muscle involvement may produce dysphagia and gastrointestinal symptoms. DM seldom progresses to the point where the patient is confined to a wheelchair. Cardiac conduction abnormalities and cardiomyopathy are common and are a significant cause of early mortality. Affected females risk giving birth to children with congenital DM. Such infants may present before birth with polyhydramnios and reduced fetal movement. After birth the main features are severe generalized weakness, hypotonia and respiratory compromise.

Lens

49

In these children, mortality from respiratory failure is high but surviving infants experience gradual improvements in motor function. Mental retardation is present in 50–60% of such patients. Age of onset

The age of onset for classical myotonic dystrophy is typically in the second to third decades, although there may be subtle features evident in childhood.

Epidemiology

An approximate prevalence of 1:20,000 is estimated worldwide.

Inheritance

Autosomal dominant. The condition shows anticipation (increase in severity of disease symptoms and/or a decrease in age of onset of the relevant phenotype). When passed on by a female, the abnormal DM gene expansion may enlarge further since it is unstably transmitted through female meiosis. Since larger alleles have a more severe phenotypic effect, DM is likely to show increased severity as it passes through the generations. Data concerning the likelihood that an affected mother will have an offspring with a particular size CTG repeat or phenotype are useful in recurrence risk counselling.


19q13

Gene

Dystrophia myotonica protein kinase (DMPK)

Mutational spectrum

Within the non-coding portion of the gene there is a CTG trinucleotide repeat region (i.e. CTGCTGCTG……CTG). In normal individuals there are 5–37 CTG trinucleotides arranged in tandem. Expansions of 50–150 copies are seen in those with mild DM. Those with classical DM carry one allele with around 100–1000 copies, while those with congenital DM carry >1000.

Effect of mutation

DMPK is an intracellular protein found within heart and skeletal muscle in structures associated with intercellular conduction and impulse transmission. The effects of the CTG repeat are uncertain; it may be that the CTG repeat causes abnormal DMPK mRNA

50

Myotonic dystrophy

processing. In addition, the expansion may alter expression of genes close to DMPK. For example the SIX5 gene, which is nearby on chromosome 19, causes cataracts in the mouse when disrupted— it has been hypothesized that alteration of SIX5 expression may cause the cataracts in DM. Diagnosis

When cataract secondary to DM is suspected clinically, neurological investigation is indicated. Molecular analysis will enable detection of an abnormal repeat expansion. Since DM is, in its classical form, an adult-onset and progressive condition, the advent of genetic testing carries with it the potential hazards of presymptomatic diagnosis. In general this should not be undertaken by those unfamiliar with the recognized protocols for dealing with such circumstances. Surgery carries additional hazards in DM patients; some patients experience respiratory depression in response to benzodiazepines, opiates and barbiturates. Myotonia may be increased by depolarizing agents.

Lens

51

Marfan syndrome (including isolated ectopia lentis) (also known as: MFS1) MIM

154700; 129600 (isolated ectopia lentis); 134797 (fibrillin 1)

Clinical features

MFS1 is a multisystemic connective tissue disorder characterized in particular by skeletal, cardiac and ophthalmic manifestations. A positive diagnosis requires the presence of sufficient major features of the disorder in at least two categories (family history, cardiac, ocular, skeletal, pulmonary or spinal).

Lens subluxation in Marfan syndrome.

Ocular The major ophthalmic feature of MFS1 is displacement of the crystalline lens. Congenital upwards subluxation is common although this may be in any direction. Pupillary displacement may occur and occasionally zonules may be defective segmentally and seen only on pupil dilatation. Patients are often myopic resulting from alteration of lens shape, increased axial length and/or relative corneal flattening. Those with higher axial lengths and/or lens dislocation are at increased risk of retinal detachment. An autosomal dominant form of ectopia lentis has been described in which patients do not show the cardiac manifestations of MFS1, although there may be mild skeletal signs of the condition (e.g. arachnodactyly).

52

Marfan syndrome (including isolated ectopia lentis)

Extraocular MFS1 can affect a wide range of organ systems. Patients are generally tall, thin and often describe an inability to increase weight. A wide range of skeletal features are associated with MFS1. These include increased height with disproportionately long limbs (arm span = [>1.05] x height; the upper to lower segment ratio is reduced), arachnodactyly, pectus abnormality, pes planus, significant scoliosis, reduced elbow extension, and a narrow, highly arched palate. While these skeletal features are strong indicators of the disorder, many are also common among the normal population and sufficient features must be present to differentiate true MFS1 from those with a ‘Marfanoid habitus’.

Arachnodactyly.

Lens

53

Marfanoid habitus.

Lumbar striae.

The major complication of MFS1 is aortic root dilatation leading to aortic dissection or development of a thoracic aortic aneurysm. Mitral valve prolapse and regurgitation are also common. Patients with MFS1 may have a history of spontaneous pneumothorax. These result from apical pulmonary blebs. Patients with MFS1 often have striae (‘stretch marks’) which can be extremely prominent over the lumbar region and reflect both rapid growth and skin fragility. On MRI of the lumbosacral spine, dural ectasia is a common finding that represents a major criterion of high specificity and sensitivity. Family history

A family history of MFS1 or of a fibrillin gene defect are both important positive indicators that diagnostic criteria in first-degree relatives indicates true Marfan syndrome.

Epidemiology

Marfan syndrome has an incidence of 1:15,000–25,000 births

Age of onset

Lens luxation is of early-onset and patients may present with reduced vision during childhood. Infrequently, children with de novo fibrillin mutations may be born with ‘congenital Marfan syndrome’, in which they have loose skin, cardiac malformations and pulmonary emphysema. Skeletal features of MFS1 develop as the child grows.

54


Inheritance

Autosomal dominant with highly variable expression.


15q21.1

Gene

Fibrillin 1 (FBN1)

Mutational spectrum

A broad range of mutations throughout the FBN1 gene have been described. The majority are family-specific and are missense changes. There is little genotype-phenotype correlation. Mutations in exons 59–65 may be more likely to be associated with a mild phenotype than those in earlier exons, but this is not a sufficiently close relationship to be clinically useful. Mutations in neonatal MFS1 cluster around exons 24–32.

Effect of mutation

The FBN1 gene is large (~110 kb) and comprises 65 exons, which makes mutation testing highly labor-intensive. The gene encodes a 2871 amino acid protein that contains 47 tandem EGF domains, suggesting a role in protein-protein and cell-cell interactions. Fibrillin is a large ubiquitously distributed connective tissue glycoprotein, which is the major component of extracellular microfibrils. Elastic fibers are complex structures that comprise elastin, 10–12 nm microfibrils, lysyl oxidase and proteoglycans. The microfibrils consist of several proteins, one of which is fibrillin. Microfibrils associated with amorphous elastin are found in skin, lung, kidney, blood vessels, cartilage and tendons. In addition, they are found without elastin in the ciliary zonules. Microfibril function is poorly defined but it is suggested that they act as scaffolding for elastic fibers as well as potentially anchoring them to cells.

Diagnosis

Lens

MFS1 can lead to reduced life-expectancy from progressive aortic root dilatation, dissection or rupture, or valvular regurgitation which impairs cardiac function. Progression of the cardiac complications can be slowed in response to medical treatment (reducing blood pressure, slowing heart rate) and through avoidance of excessive physical activity. These should be monitored during high-risk periods such as pregnancy. 55

MFS1 shows a high degree of inter and intrafamilial variability in clinical expression. Furthermore, a number of conditions mimic MFS1 including MASS phenotype (Mitral valve prolapse, mild Aortic root dilatation, Skin involvement (striae) and Skeletal findings). As a result it is often difficult to make a positive diagnosis of MFS1 or to exclude the condition. There have been several attempts to classify the clinical findings of Marfan syndrome but none are entirely satisfactory (e.g. revised or ‘Ghent’ criteria: De Paepe, 1996). Molecular genetic analysis is not available on a routine basis, but may supplement clinical investigation. Mutation testing is unsuccessful in the majority of borderline cases and may only define a mutation in 70% of definite familial cases. A definitive diagnosis will commonly rely upon careful clinical examination (skeletal, ophthalmic and cardiovascular) and targeted investigation (e.g. ECG, CXR and MRI of the spine).

56


3 3. Glaucoma

Primary glaucomas Primary congenital glaucoma 58 Juvenile primary open angle glaucoma 61 Primary open angle glaucoma 63 Secondary glaucomas Aniridia 65 Anterior segment mesenchymal dysgenesis 68 Glaucoma-related pigment dispersion syndrome 70 Iridogoniodysgenesis 72 Nail-patella syndrome 74 Rieger syndrome 77 Rubinstein-Taybi syndrome 79

Primary congenital glaucoma (also known as: GLC3; primary congenital glaucoma; buphthalmos) Including: Peters' anomaly. MIM

601771 (CYP1B1)

Clinical features

Primary infantile glaucoma is not associated with extraocular manifestations or other ocular abnormalities. It is thought to be due to abnormal development of the drainage angle of the anterior chamber. Symptoms are of corneal enlargement or clouding, excessive tearing, photophobia or general malaise. The condition is usually bilateral although asymmetry is common.

Congenital glaucoma with corneal enlargement.

Congenital glaucoma with splits in Descemet membrane.

Age of onset

Onset is at birth or soon afterwards. Over 80% are symptomatic by 3 months of age.

Epidemiology

Incidence of 1:10,000

Inheritance

Autosomal recessive

58

Primary congenital glaucoma

Chromosomal location MIM Locus Gene Chromosome 231300 GLC3A CYP1B1 2p22–p21 600975 GLC3B 1p36.2–p36.1 GLC3C* Unknown * Around 60% of families with more than one affected individual demonstrate linkage to GLC3A. Around 50% of the non-GLC3A families are also not linked to GLC3B; linkage to a third specific region is undefined. Gene

Cytochrome P450B1 (CYP1B1)

Mutational spectrum

A large number of mutations has been described including protein truncating mutations, as well as missense mutations, of the conserved domains of the protein. Studies of an inbred population in Saudi Arabia, where primary infantile glaucoma is common, suggest that mutations in CYP1B1 show reduced penetrance and expressivity. A defect in CYP1B1 has been demonstrated in a single patient with bilateral congenital glaucoma and bilateral Peters’ anomaly. The individual carried two CYP1B1 mutations (compound heterozygote), one nonsense (protein truncating) and the other was likely to abolish translation. This finding underlies the phenotypic heterogeneity of individuals carrying mutations in this gene.

Effect of mutation

CYP1B1 is a member of the cytochrome P450 multigene superfamily, whose role is the physiological inactivation of both endogenous and exogenous substrates. CYP1B1 is the first of these enzymes identified to be involved in a developmental process and its role in ocular development remains unclear. Both protein truncation mutations and missense mutations in the heme-binding region have been described; it is thought that both may result in reduced heme binding, which is critical for the functioning of cytochrome P450 molecules.

Glaucoma

59

Diagnosis

60

Clinical. Mutation testing is available on a research basis only. Younger siblings of children with primary congenital glaucoma should be examined soon after birth for evidence of glaucoma.

Primary congenital glaucoma

Juvenile primary open angle glaucoma (also known as: open angle glaucoma type 1a [GLC1A]; juvenile-onset primary open angle glaucoma [JOAG]) MIM

137750; 601652 (myocilin)

Clinical features

Early onset POAG. Individuals do not develop buphthalmos and have normal anterior segment examination. Intraocular pressure may be high—often over 50 mmHg. Patients are often myopic and invariably require filtration surgery.

Grossly cupped disc in POAG.

Age of onset

JOAG typically affects children in their teenage years. Mean age at diagnosis in one study was 18 years, although onset from the age of 3 years is described.

Inheritance

Autosomal dominant with high penetrance (80–100% by age 20 years). One family with autosomal recessive JOAG has been described (see below).


Glaucoma

1q24.3–q25.2 Some families with juvenile POAG do not map to this region.

61

Gene

Myocilin (MYOC); alternative name: trabecular meshwork-induced glucocorticoid response protein gene (TIGR).

Mutational spectrum

JOAG – autosomal dominant MYOC is a widely expressed gene that encodes a 504-amino acid protein. The gene contains three exons. Exon 3 encodes a conserved C-terminal homologous to frog olfactomedin, an extracellular matrix glycoprotein of the olfactory epithelium. Mutations have been described in a number of families with JOAG–these are generally missense mutations within the conserved exon 3 domain. JOAG – autosomal recessive Recessive families with JOAG associated with homozygous proteinterminating MYOC mutations have been reported. These are associated with loss of function of MYOC. Adult-onset POAG The impact of MYOC mutation on more common forms of adultonset POAG has been extensively investigated. One study examined 1700 individuals from five populations and found MYOC mutations in 3–4% of adult POAG individuals. One mutation, Gln368Ter, is common and accounts for ~1.5% of all POAG.

Effect of mutation

Myocilin was originally shown to be upregulated by the administration of corticosteroids to the trabecular meshwork. Its function is not known. Mutations in juvenile forms of POAG may act in a dominant negative fashion. In one extensive Canadian kindred, several individuals who were homozygous for a highly penetrant dominant mutation did not develop glaucoma; it is presumed that the mutant protein is functional and, when homozygous, does not have a dominant negative effect.

Diagnosis

62

Clinical. Mutation testing in families with JOAG is available on a research basis. Testing for MYOC mutations in adult POAG is not currently undertaken due to the low frequency of mutations. Juvenile primary open angle glaucoma

Primary open angle glaucoma (also known as: POAG) MIM

See below

Clinical features

POAG is a common, highly variable condition of complex etiology that causes a characteristic optic neuropathy, progressive disc cupping and arcuate field loss. It is likely to be caused by a number of interacting factors, both genetic and environmental. Raised intraocular pressure is a major risk factor but not an absolute requirement for diagnosis. Family history is another major risk factor which justifies the screening of first-degree relatives. 1 in 10 first degree relatives of affected individuals are themselves affected. Like many complex disorders (e.g. heart disease, schizophrenia or obesity), our understanding of the pathogenesis of POAG is surprisingly rudimentary. POAG has a number of uncommon Mendelian subforms which are amenable to analysis using current techniques. Our understanding of the more common forms of POAG may be improved by characterizing the genes underlying these single gene disorders. In the table below, chromosomal locations are listed for different forms of open angle glaucoma. Genes have been found to underlie juvenile POAG and nail-patella syndrome at the GLC1A, GLC1E and NPS loci, respectively. The others have been defined by linkage analyses in single families or, in one case (GLC1B), by pooling small families. These are statistical methodologies for localizing putative chromosomal positions. Within single families it is generally assumed that a single gene defect affects all members of a family; this assumption renders these techniques prone to error as it is not possible to differentiate clinically identical, genetically distinct ‘phenocopies’ affecting different individuals of a family. Final proof of their true relevance will follow confirmation of linkage in other families or discovery of a causative gene at a given location.

Glaucoma

63

Age of onset

Adulthood

Epidemiology

POAG is the second most common adult-onset cause of blindness in the developed world. It affects around 2% of the adult population.

Inheritance

The mode of inheritance of the common forms of POAG is complex. The Mendelian forms are autosomal dominant.

Chromosomal location MIM Locus Gene 137750 GLC1A MYOC 137760 GLC1B 601682 GLC1C 602429 GLC1D 602432 GLC1E* 603383 GLC1F 161200 NPS (q.v.) LMX1B * Family had normal tension glaucoma.

Chromosome 1q24.3–q25.2 2cen–q13 3q21–q24 8q23 10p14–p15 7q35–q36 9q34.1

Method of localization Gene Pooled families Single family Single family Single family Single family Gene

Genes

Myocilin (MYOC; see juvenile POAG) and LIM homeo box transcription factor 1, beta (LMX1B; see nail-patella syndrome).

Mutational spectrum

Unknown

Effect of mutation

Unknown

Diagnosis

Genetic testing is not yet available for POAG.

64

Primary open angle glaucoma

Aniridia MIM

106210

Total aniridia. Note ‘frill’ of iris remnant and cataract.

Partial aniridia; in some patients this may resemble an ‘atypical’ coloboma.

Clinical features

There is usually total absence of iris tissue. Partial or segmental aniridia may manifest as ‘atypical colobomata’. There may be segmental iris hypoplasia. There is often intrafamilial variability in severity and complications. The condition affects numerous ocular structures. Peripheral corneal vascularization associated with stem cell failure leads to a progressive keratitis and ocular surface abnormalities that may be problematic in later life. Abnormal development of the anterior segment/trabeculum/angle structures poses a significant life-time risk of developmental glaucoma in 20–50% of cases. Cataract, in particular anterior polar cataracts, may occur.

Glaucoma

65

In the posterior segment, foveal hypoplasia is a major contributor to reduced vision. There may be associated optic nerve hypoplasia. Posterior segment abnormalities commonly lead to the development of nystagmus. Age of onset

Congenital

Inheritance

Aniridia is usually autosomal dominant. Sporadic cases are well documented and in these cases a deletion may encompass adjacent loci including the WT1 gene, which underlies Wilms’ tumor.


11p13

Gene

Paired box gene 6 (PAX6)

Mutational spectrum

Around 140 mutations have now been described throughout the gene (Human PAX6 Allelic variant database; http://www.hgu.mrc.ac.uk/Softdata/PAX6/). Missense mutations are under-represented. A wide variety of ocular phenotypes are associated with PAX6 mutations; apart from ‘simple’ aniridia these include Peters’ anomaly, autosomal dominant keratitis, autosomal dominant cataract and isolated foveal hypoplasia. One compound heterozygote has been reported. The infant had severe craniofacial and central nervous system defects and no eyes. The head was small with large ears; the brain was small with abnormal cerebral hemispheres and a partially absent corpus callosum. The infant died after 8 days.

Effect of mutation

66

The majority of mutations lead to premature termination of the PAX6 protein and are thought to act by means of haploinsufficiency.

Aniridia

Diagnosis

In the absence of a family history, aniridia may be due to a deletion of 11p13, which could include neighboring genes. Of these, WT1, when absent, may predispose to Wilms’ tumors. One such contiguous gene syndrome is the WAGR syndrome (Wilms’ tumor, Aniridia, Genitourinary abnormalities and mental Retardation). Among individuals with a presumed de novo mutation, chromosomal analysis and FISH should be used to exclude a WT1 deletion. In classical cases, in particular those with a family history, the diagnosis is often simple. However, variant cases with partial aniridia or atypical colobomata (in particular those not affecting the inferior iris) or with other forms of anterior segment dysgenesis may be suspected in the presence of nystagmus and/or foveal hypoplasia, which is almost invariant among individuals with PAX6 mutations. Mutation testing is available through diagnostic laboratories. However, in most cases this is not of major clinical significance. Prenatal diagnosis has been undertaken.

Glaucoma

67

Anterior segment mesenchymal dysgenesis (also known as: ASMD; anterior segment ocular dysgenesis [ASOD]) MIM

107250; 602669 (PITX3); 601094 (FOXE3)

Clinical features

As discussed under iridogoniodysgenesis (q.v.), isolated anterior segment dysgenesis forms a heterogeneous group. ASMD is a generic term describing the broad range of anterior dysgenesis phenotypes. The term suggests a potential pathogenic mechanism common to different forms of anterior segment dysgenesis. Axenfeld, Rieger and Peters’ anomalies may occur in the same family—this suggests that these clinical distinctions do not necessarily reflect underlying differences in etiology.

Age of onset

A developmental disorder which is present at birth. Secondary developmental glaucoma commonly develops during childhood.

Inheritance

Isolated anterior segment dysgenesis is often autosomal dominant. However, affected sib-pairs and affected children within consanguineous marriages suggest that autosomal recessive forms exist.


10q25 (paired-like homeodomain transcription factor 3 [PITX3]) 1p32 (forkhead box E3 [FOXE3])

Gene

PITX3; FOXE3. Other families with dominant forms of the disease do not have defects in these genes. This suggests that other genes cause a similar phenotype.

Mutational spectrum

PITX3: a single premature protein truncation mutation was observed in one family with ASMD. There was a variable phenotype including Peters’ and Axenfeld anomalies as well as cataract. The protein truncation mutation removes a highly conserved C-terminal domain, thought to be involved in protein-protein interaction. Similar, presumed haploinsufficiency mutations in PITX2 (q.v. Rieger

68

Anterior segment mesenchymal dysgenesis

syndrome) have been described. PITX2 and PITX3 are highly homologous homeodomain-containing proteins that are critical to ocular development. One missense mutation was observed in a family with bilateral congenital cataract. FOXE3: A mutation has been defined in a single family with anterior segment ocular dysgenesis and cataracts. A frameshift mutation resulted in an abnormal terminal amino acid sequence with the addition of 111 amino acids. Effect of mutation

PITX3 is a developmental transcription factor expressed in the developing lens placode and through all stages of lenticular development. In addition, the gene is expressed in the midbrain, tongue and mesenchymal structures around the sternum, vertebrae and head muscles. A spontaneous mouse mutant aphakia, in which mice have small eyes with no lens, has a deletion mutation of the murine homolog, Pitx3. FOXE3 is a transcription factor that is critical during lens development. It is regulated by other modulators of ocular development such as PAX6. During development, FOXE3 is expressed in developing lens tissues from the start of lens placode induction and becomes turned off after lens fiber cell differentiation.

Diagnosis

Glaucoma

Clinical examination. Children who are at risk need regular follow-up to monitor the potential development of glaucoma.

69

Glaucoma-related pigment dispersion syndrome (also known as: GPDS1; pigment dispersion syndrome; pigmentary glaucoma) MIM

1

600510

2

3

Clinical features

70

Pigment dispersion syndrome is an early-onset form of open angle glaucoma. There is pigment loss from the iris epithelium leading to slit-shaped defects visible on transillumination (1). Pigment is deposited throughout the anterior segment, onto the lens, lens zonules, iris, trabecular meshwork (2) and corneal endothelium, where it forms Krukenberg spindles (3). Pigment loss is thought to occur from physical abrasion between the iris and the lens zonules. Initially, increased pressure may result directly from pigment accumulation (for example, there may be an increase in pressure after exercise). Ultimately, this pigment is phagocytosed, leading to trabecular meshwork damage.

Glaucoma-related pigment dispersion syndrome

The disorder is said to be more common in myopes and males, although autosomal dominant inheritance has been demonstrated. Pigment dispersion is a strong risk factor for glaucoma but does not always lead to glaucomatous damage. Age of onset

Usually affects individuals under the age of 40 years.

Inheritance

Autosomal dominant. The occurrence of many sporadic individuals suggests that there may be reduced penetrance.


7q35–q36

Gene

The gene underlying GPDS has not been defined.

Effect of mutation

Unknown

Diagnosis

Clinical, including examination of first-degree relatives. Gene identification may aid screening of family members.

Glaucoma

71

Iridogoniodysgenesis type I (also known as: IRID1; iridogoniodysgenesis anomaly [IGDA]; familial iridogoniodysplasia) MIM

601631; 601090 (FOXC1)

Clinical features

Autosomal dominant IGDA is characterized by iris hypoplasia and goniodysgenesis. The major risk is of childhood-onset developmental glaucoma. The phenotype is highly variable and may include Axenfeld anomaly, Rieger syndrome and iris hypoplasia. In general, there are no extraocular manifestations.

Age of onset

This is a developmental disorder which is present at birth. Developmental glaucoma is common during childhood.

Inheritance

Isolated anterior segment dysgenesis/iridogoniodysgenesis is often autosomal dominant. However, affected sib-pairs and affected children within consanguineous marriages suggest that autosomal recessive forms exist.


6p25

Gene

Forkhead box C1 (FOXC1) (alternative names: FREAC3/FKHL7). There are other known dominant families that are not caused by defects in this locus; this suggests that other genes cause a similar phenotype.

Mutational spectrum

Nonsense mutations that result in premature protein truncation and missense mutations within the forkhead transcription domain have been described. The range of phenotypes shows intrafamilial variability. One family with Rieger syndrome with extraocular manifestations has been shown to carry a FOXC1 mutation. Affected patients with a duplication of 6p25 have been described. This is not visible microscopically but results in the presence of three functional copies of FOXC1. This suggests that increased, as well as decreased, dosage of FOXC1 can cause anterior segment abnormalities.

72

Iridogoniodysgenesis type I

Effect of mutation

FOXC1 is a transcription factor that regulates the expression of genes critical to ocular anterior segment development. The mutations currently described result in haploinsufficiency. Those within the forkhead transcription domain abolish the ability of the protein to bind to specific DNA sequences.

Diagnosis

Clinical examination. At-risk children need to be maintained under regular follow-up as the risk of developmental glaucoma is high (>50% in many proven dominant families). Genetic testing, while possible, has few clinical benefits, although exclusion of a mutation among the children of proven gene-carriers gives confidence that an individual carries no risk of developmental glaucoma.

Glaucoma

73

Nail-patella syndrome (also known as: NPS; onychoosteodysplasia) MIM

161200; 602575 (LMX1B)

Clinical features

Ocular Primary open angle glaucoma is common. Ophthalmic follow-up is therefore suggested for all patients. Extraocular Hypoplasia or aplasia of the patellae is a cardinal feature, leading to instability of the knee and recurrent patellar dislocation. Generalized joint laxity is also described. On x-ray examination there may be iliac horns on the pelvis. Patients may have reduced extension and/or supination/pronation of the elbow due to radial head dysplasia/dislocation. The nails of the hand are dystrophic and small. They split easily and have triangular lunules at the base. Around a quarter of patients develop renal disease, which may manifest at any age. About 5% may develop renal failure. Renal symptoms include proteinuria, nephrotic syndrome and glomerulonephritis. Thickening of the glomerular basement membrane may be observed on renal biopsy.

Age of onset

Congenital

Epidemiology

2:100,000

Inheritance

Autosomal dominant


9q34.1

Gene

LIM homeobox transcription factor 1beta (LMX1B)

74

Nail-patella syndrome

Lester sign. Patients with NPS have a characteristic ‘clover-leaf’ iris.

Patellar aplasia.

Nail dystrophy.

Mutational spectrum

A broad range of mutations have been described. Premature protein termination mutations are common. Missense mutations, when present, are often within important, conserved residues of both the LIM and homeodomains.

Effect of mutation

Haploinsufficiency. There is no genotype-phenotype correlation. Functional studies have shown that missense mutations disrupt sequence-specific DNA binding. LMX1B is a conserved transcription factor. LIM-homeodomain proteins are characterized by the presence of two tandem cysteine/histidine-rich, zinc-binding LIM domains. LMX1B has been shown to be important in dorsoventral limb patterning. Expression patterns also show it to be important in renal and ocular development.

Glaucoma

75

Diagnosis

76

Clinical. While DNA diagnosis is now possible this is largely of academic interest. Prenatal diagnosis is rarely an issue as this can only detect the presence of a mutation rather than predict its severity. NPS is highly variable and ocular complications are rarely present early in life: families should be aware of the risks and ongoing screening made available to them.

Nail-patella syndrome

Rieger syndrome (also known as: iridogoniodysgenesis with somatic anomalies; iridogoniodysgenesis type II; autosomal dominant iris hypoplasia) MIM

180500 (type I); 601499 (type II)

Clinical features

Ocular Rieger syndrome is characterized by anterior segment dysgenesis associated with goniodysgenesis, posterior embryotoxon and anterior synechiae. Variable iris hypoplasia is often associated with corectopia and/or polycoria. In Rieger syndrome, the ocular manifestations are variable and may include iris hypoplasia, Axenfeld anomaly or Peters’ anomaly, and anterior polar cataract. Foveal hypoplasia is not seen and, in the absence of media opacity, vision may be normal. However, the risk of developmental glaucoma is extremely high (perhaps 75%).

(R) Rieger anomaly and (L) Peters’ anomaly from a patient with a mutation in PITX2.

Extraocular The most common extraocular manifestation is abnormal dental development, which can vary from peg-shaped incisors, widely spaced teeth or missing teeth to total anodontia. Redundant umbilical skin is also commonly seen. Other extraocular manifestations include cleft palate, anterior-placed anus and anal atresia.

Glaucoma

77

Dental hypoplasia/aplasia.

Redundant umbilical skin.

Age of onset

Congenital

Inheritance

Autosomal dominant


4p25 (type I); 13p13 (type II)

Gene

Paired-like homeodomain transcription factor 2 (PITX2). Bicoid-related homeobox-containing gene (type I). The gene for type II is unknown.

Mutational spectrum

Splice-site mutations, missense mutations (in particular within the homeodomain) and nonsense mutations are all described. Many patients (~50%) have no proven genetic abnormality.

Effect of mutation

It is likely that most mutations result in functional haploinsufficiency. All families with PITX2 mutations have evidence of some systemic abnormalities (in particular dental/umbilical abnormalities).

Diagnosis

Systemic features suggest the presence of a PITX2 mutation that may be tested on a research basis. Visual impairment will be seen in those with significant media opacities (e.g. Peters’ anomaly) or resulting from the complications of developmental glaucoma. The high risk of glaucoma requires life-long screening.

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Rieger syndrome

Rubinstein-Taybi syndrome (also known as: RSTS) MIM

180849; 600140 (CREBBP)

Clinical features

Rubinstein-Taybi syndrome is a rare cause of mental handicap associated with characteristic facial dysmorphism, broad thumbs and toes. Ocular The ocular manifestations of RSTS are under-recognized but wideranging. There may be congenital or early-onset glaucoma due to goniodysgenesis with high iris insertions. Congenital cataract of variable severity is also described. Retinal dystrophy is a frequent and important finding (>70%), which becomes more common with age. Retinal examination and ERG investigation demonstrate cone and cone-rod dystrophy. Extraocular Developmental delay is often severe with a mean IQ of around 50. Children are generally shorter than average, with relative microcephaly. Facial features are characteristic with down-slanting palpebral fissures, long beaked nose and unusual thickened ears. Thumbs and big toes are broad with spatulate distal phalanges.

Age of onset

Congenital

Inheritance

Most cases are sporadic


16p13.3

Gene

CREB-binding protein (CREBBP)

Glaucoma

79

(L) Characteristic facial features include a long beaked nose with prominent columella. (R) Spadulate distal phalanx of the thumb in Rubinstein-Taybi syndrome.

Mutational spectrum

A microdeletion of 16p13.3 is estimated to cause around 10–15% of RSTS. Mutations of CREBBP have been described; the majority result in protein truncation.

Effect of mutation

It is likely that loss of function of one copy of CREBBP leads to RSTS. CREBBP is a transcriptional co-activator that binds to the transcription factor CREB. The exact functions of CREB (and hence of CREBBP) are not fully understood.

Diagnosis

Children with RSTS have significant handicaps. Screening for ocular abnormalities and recognizing multisensory handicap are important in their long-term care. When suspected clinically, FISH analysis may detect a 16p13.3 microdeletion. Mutation analysis is available on a research basis only.

80

Rubinstein-Taybi syndrome

4 4. Inherited retinal disease

Cone dystrophies

Progressive rod-cone dystrophies

Achromatopsia 82

Retinitis pigmentosa 122

Blue cone monochromatic color blindness 84

Autosomal dominant retinitis pigmentosa 125

Progressive cone dystrophy 86

Peripherin/RDS 127

Macular dystrophies 88 Doyne familial honeycombed choroiditis 90 Pseudoxanthoma elasticum 92

Rhodopsin 130 Autosomal recessive retinitis pigmentosa 132 Retinitis pigmentosa, PPRPE type 135

Sorsby pseudoinflammatory fundus dystrophy 96

Digenic retinitis pigmentosa 137

Stargardt disease 98

X-linked retinitis pigmentosa 138

Vitelliform macular dystrophy 104 Miscellaneous retinal dystrophies Choroideremia 107 Cone-rod dystrophy 110

Stationary night blindness Congenital stationary night blindness 141 Fundus albipunctatus 144 Oguchi disease 145

Enhanced S-cone syndrome 112

Syndromic retinal dystrophies

Leber congenital amaurosis 114

Alström syndrome 147

Retinitis punctata albescens 120

Bardet-Biedl syndrome 149 Cockayne syndrome 153 Cohen syndrome 156 Joubert syndrome 158 Mitochondrial disease and retinopathy 159 Usher syndrome 163

Achromatopsia (also known as: ACHM2; ACHM3; rod monochromatism) MIM

216900 (ACHM2); 262300 (ACHM3)

Clinical features

Achromatopsia or rod monochromatism is a stationary cone disorder characterized by an absence of normally functioning cones. Patients present with congenital nystagmus at birth or early in life. They are photophobic and describe vision that is better in dim light. Achromats have normal retinal examination. There is complete color blindness and visual acuity of around 6/60. ERG shows an absence of cone responses, in the presence of normal rod responses. Some patients with partial achromatopsia retain better visual acuity with residual cone function.

Epidemiology

Achromatopsia is estimated to affect around 1:30,000 in the USA.

Age of onset

Congenital

Inheritance

Autosomal recessive


2q11 (ACHM2); 8q21–q22 (ACHM3)

Gene

ACHM2: cyclic nucleotide-gated cation channel, alpha subunit (CNGA3) ACHM3: cyclic nucleotide-gated cation channel, beta subunit (CNGB3)

Mutational spectrum

82

CNGA3: missense mutations (including frameshift and protein truncating mutations) have been described in highly conserved amino acids. It is likely that the missense mutations result in improper folding or inability to integrate the protein into the plasma membrane. CNGA3 mutations have also been described in a small number of patients with evidence of severe progressive cone dystrophy.

Achromatopsia

CNGB3: missense, frameshift and protein truncation mutations have all been described. Homozygous null mutations cause an identical phenotype to missense mutations. Effect of mutation

It is likely that all mutations result in loss of function. Cyclic nucleotide-gated channels are important in vertebrate sensory systems. CNGA3 and CNGB3 encode the a- and b-subunits of a single cyclic nucleotide-gated channel that is located in the photoreceptor plasma membrane. The cone cGMP-gated cation channel is an a/b-2 heteromeric tetramer required for development of the light-evoked responses of cones. The proteins contain six transmembrane domains and a hydrophilic pore structure. Loss of function would result in an inability to respond to cGMP, and elimination of the dark current resulting in a situation akin to permanent light exposure.

Diagnosis

Inherited retinal disease

Mutation screening is available on a research basis only.

83

Blue cone monochromatic color blindness (also known as: CBBM; blue cone monochromatism) MIM

303700

Clinical features

Blue cone monochromats have only functional rods and short wavelength (blue) cones. Patients have severely reduced central vision and photophobia, abnormal color discrimination and nystagmus. Retinal examination is normal. ERG examination reveals normal scotopic and photopic responses demonstrating absence of cone responses to white and red light. There is preservation of blue cone function, which allows discrimination of yellow objects on a blue field.

Age of onset

Congenital

Epidemiology

Rare, less than 1:100,000

Inheritance

X-linked recessive


Xq28

Gene

Red cone pigment, including protanopia (MIM 303900). Green cone pigment, including deuteranopia (MIM 303800).

Mutational spectrum

The red and green pigment genes are carried on the X chromosome at Xq28. They lie in a head-to-tail tandem array, which predisposes to homologous recombination and rearrangement of the region. This mechanism gives rise to over 90% of the red and green cone color vision variations. In the normal state, each X chromosome carries one red pigment gene and one or more green pigment genes. Blue cone monochromatism results from a number of conformations of the red/green pigment arrays including:

84

Blue cone monochromatic color blindness

• deletion of locus control region. Deletion of a region that lies upstream of the red pigment transcription start site. This region is essential for normal transcription of both red and green pigment genes. This mechanism accounts for 40% of families. • point mutations inactivating X chromosome pigment genes. In the majority of individuals in this group, homologous recombination reduces the pigment gene array to a single gene. A second mutational event then inactivates this gene. Both missense and nonsense changes are described, but the mutation of cysteine to arginine at codon 203 is the most common. Effect of mutation

Absence of functional red and green cones. In general, this is a static condition although some patients have a late-onset, slowly progressive, central retinal dystrophy. This suggests that normal genes are required for long-term maintenance of cones.

Diagnosis

CBBM, when suspected clinically, may be confirmed by ERG testing. There is often a clear history consistent with X-linked inheritance. In some cases, female carriers are said to have abnormal cone responses on ERG testing.


85

Progressive cone dystrophy (also known as: retinal cone dystrophy; cone dystrophy 3; COD3) MIM

602093

Clinical features

The cone dystrophies are heterogeneous disorders, which may be progressive or non-progressive (achromatopsia). The progressive cone dystrophies are characterized by reduced central visual function (reduced VA, altered color vision, photophobia) and abnormal conemediated ERGs. Fundoscopy reveals pigment disturbance at the macula in the early stages of the disease or a typical bull’s eye appearance. There is progression over time with the development of atrophic macular scarring, although this is variable in degree.

48-year old male with progressive cone dystrophy.

Age of onset

Variable. Some individuals with cone dystrophies have early-onset disease (in the first decade of life), while others develop symptoms in early adulthood. Patients in one family with COD3 showed symptoms in adulthood.

Inheritance

Autosomal dominant; X-linked recessive. Many cases are sporadic.


6p21–6cen (RDS peripherin) – see section on RDS peripherin/ADRP. 6p21.1 (COD3); Xp11.4 (linkage); Xq27 (linkage).

86

Progressive cone dystrophy

Gene

RDS/peripherin (RDS) Guanylate cyclase activator 1A (GUCA1A); MIM 600364 Cyclic nucleotide-gated cation channel, alpha subunit (CNGA3)

Mutational spectrum

A small number of families with missense changes in RDS (e.g. serine-27-phenylalanine) have been described with progressive cone dystrophy (see section on RDS). A single missense mutation (Y99C) has been described in GUCA1A.

Effect of mutation

GUCA1A is a calcium-binding protein expressed exclusively in photoreceptors, particularly cones. In photoreceptors, cGMP is synthesized by RetGC, which is activated by GUCA1A at low levels of intracellular Ca2+ (i.e. light-adapted photoreceptors) and inhibited at high Ca2+ levels. At all physiological Ca2+ concentrations, the mutant GUCA1A results in RetGC activation, which leads to constitutive cGMP synthesis. Elevated cGMP alters Ca2+/Na+ flux and this is thought to result in progressive retinal damage.

Diagnosis


Many patients with a childhood-onset cone dystrophy pattern develop rod dysfunction (i.e. cone-rod dystrophy). The genetic basis of the most progressive cone dystrophies remains undefined and genetic testing is not yet available.

87

Macular dystrophies Age-related macular degeneration (ARMD) is the most common cause of blindness in the developed world and genetic factors are extremely important in its pathogenesis. One avenue towards identifying such factors is through the analysis of the early-onset, monogenic macular dystrophies, and a large number of their genetic localizations have now been identified (see Table 5.1). More recently this has included the identification of loci (e.g. ARMD1 on chromosome 1q25–q31: MIM 603075) that underlie phenocopies of ARMD. Several genes underlying the Mendelian macular dystrophies have now been characterized including Stargardt and Best disease (ABCA4, VMD2), Doyne honeycomb dystrophy and Sorsby fundus dystrophy (EFEMP1, TIMP3). These are discussed in the following sections. In addition, mutations in the RDS gene, which was identified as the causative gene in some forms of adRP, are associated with a range of macular phenotypes including adult vitelliform and butterfly-shaped dystrophies as well as one form of central areolar choroidal dystrophy (see section on RDS). Finally, certain maternally inherited mitochondrial mutations have now been shown to cause abnormal macular function (see mitochondrial section). Common forms of ARMD There has been considerable work investigating the role of the genes underlying the Mendelian macular dystrophies as etiological factors in common forms of ARMD. Currently, there is no convincing evidence that implicates EFEMP1, TIMP3 or VMD2. ABCA4 The situation with regard to ABCA4 is more confusing. The ABCA4 gene and the protein it encodes vary significantly from person to person (i.e. there is a high level of polymorphism). It is therefore difficult to define whether or not changes that are relatively common within a population significantly alter the predisposition to ARMD, a condition that is also common. While many studies have found little

88

Macular dystrophies

evidence to support the hypothesis, some have found that certain missense mutations may be associated with ARMD. It is also suggested that some people who are heterozygous for mutations in the gene (the parents and siblings of Stargardt disease patients) may have a higher predisposition to ARMD. The significance of this is uncertain. Current evidence suggests that the ABCA4 gene is not a major contributing factor to a large proportion of ARMD cases. Table 5.1 Disorder

Gene

Chromosome

Inheritance

MIM

Age-related macular degeneration

-

1q25–q31

AD

603075

Stargardt disease

ABCA4

1p21–p22

AR

248200

Doyne honeycomb dystrophy

EFEMP1

2p16–p21

AD

126600

STGD4

-

4p

AD

603786

Adult vitelliform dystrophy

RDS

6p21.2-cen

AD

179605

Butterfly-shaped dystrophy

RDS

6p21.2-cen

AD

179605

Central areolar choroidal dystrophy

RDS

6p21.2-cen

AD

179605

Best disease

VMD2

11q13

AD

153700

Pseudoxanthoma elasticum

ABCC6

16p13.1

AD/AR

177850

Stargardt disease (3)

ELOVL4

6q14

AD

600110

North Carolina macular dystrophy

-

6q14–q16.3

AD

136550

Central areolar choroidal dystrophy

-

17p13–p12

AD

215500

Sorsby fundus dystrophy

TIMP3

22q12.1–q13.2

AD

136900


89

Doyne familial honeycombed choroiditis (also known as: Doyne honeycomb retinal dystrophy; DHRD; Doyne honeycomb degeneration of retina; Malattia Leventinese [MLVT]; autosomal dominant radial drusen) MIM

126600

Clinical features

Characteristically, drusen involving the posterior pole, macula and optic disc (including nasal to the disc) appear in early adult life. The drusen are frequently distributed in a radial pattern and may progress to form a ‘honeycomb’. In younger individuals there may be hard drusen at the macula. The syndromes described by Doyne in England and by Vogt in Switzerland (malattia leventinese) represent the same condition.

A 55-year-old patient with a dominant family history of early central visual loss and acuities of 6/24 in each eye. Notice the juxta-papillary lesions characteristic of this disorder.

Age of onset

90

While there are occasional reports of patients with early-onset visual loss, the majority of patients will not develop symptoms until adult life. Advanced disease is associated with severe visual loss and posterior pole atrophy. Increasing age is not invariably associated with severe visual loss.

Doyne familial honeycombed choroiditis

Inheritance

True autosomal dominant. One individual who is homozygous for the characteristic mutation has been shown to have a retinal phenotype identical to heterozygotes of similar age.


2p16–21

Gene

EGF-containing fibrillin-like extracellular matrix protein 1 (EFEMP1)

Mutational spectrum

A single missense mutation (arginine to tryptophan substitution of residue 345) has been found in all families.

Effect of mutation

The exact role of this extracellular molecule in retinal function is unclear. As a result it is not yet known why defects lead to DHRD.


91

Pseudoxanthoma elasticum (also known as: PXE; Grönblad-Strandberg syndrome) MIM

264800 (autosomal recessive); 177850 (autosomal dominant); 603234 (ABCC6)

Clinical features

PXE is characterized by yellowish papular plaques in the skin of the flexures (pseudoxanthomata) associated with angioid streaks of the retina.

Angioid streaks.

Ocular About 50% of those with angioid streaks are said to have PXE, although this may be an underestimate. They are irregular broad gray lines, often present around the papilla, and represent breaks in the elastic lamina of Bruch’s membrane. They are not present at birth and age of onset varies; they can be identified in some PXE patients before the age of 10 years. The most common early retinal feature is a ‘peau d’orange’ appearance, a mottled fundus that classically precedes the appearance of streaks and is often seen in the mid-periphery. Other retinal changes include ‘salmon patches’ and yellow/white dot-like foci, both of which represent resolving hemorrhage. Optic nerve head drusen have been associated with PXE. The major complication of angioid streaks is the development of subretinal neovascular membranes. As a result, sequential and dramatic loss of central vision is common in middle age. 92


Pseudoxanthoma elasticum. Angioid streaks in 40-year-old female with no family history who described recent alteration of vision (bottom). Fluorescein angiography revealed a small sub-retinal neovascular membrane (top).

Pseudoxanthomata in the antecubital fossa in a teenage girl with PXE.


93

Dermatological Pseudoxanthomata are yellowish papules or plaques that are seen on the flexural aspects including the neck, axillae, antecubital fossa and groin. Although asymptomatic, they may have poor cosmetic consequences. The skin in these areas may become lax with time, and surgery, attempted for cosmetic reasons, may heal poorly. Gastrointestinal Gastric hemorrhage is a recognized complication. Although the exact prevalence is uncertain, a 10% lifetime risk of hemorrhage is quoted. An increased frequency of GI bleeds during pregnancy has also been reported. Cardiovascular Mitral valve prolapse, hypertension, ischemic heart disease and peripheral vascular disease have all been associated with PXE. Their exact prevalence is uncertain. Age of onset

While ocular manifestations (e.g. peau d’orange) may be present in childhood, angioid streaks develop later. Subretinal neovascular membranes (SRNVMs) generally develop during adulthood.

Epidemiology

Incidence has been estimated at 1:25,000–50,000.

Inheritance

Among those cases with a family history, the majority are consistent with autosomal recessive inheritance. However, autosomal dominant kindreds may be seen. A large number of cases are sporadic.


16p13.1

Gene

ATP-binding cassette, subfamily C, member 6 (ABCC6); alternative name: multidrug resistance protein 6 (MRP6).

94


Mutational spectrum

Among autosomal recessive pedigrees, homozygous mutations including deletions, frameshifts, splice-site and missense mutations have all been described. These include a recurrent R1141X mutation which generates a stop codon and is shown to result in loss of ABCC6 expression. Both frameshift and missense mutations have been described in presumed dominant families. These also include the R1141X mutation, which has therefore been shown to be associated with PXE phenotypes in both the heterozygous and homozygous state. The majority of sporadic individuals have been found to have heterozygous mutations although some are recessive. There is, as yet, no clear-cut genotype/phenotype correlation.

Effect of mutation

ABCC6 is a member of the ATP-binding cassette transmembrane transporter family (like ABCA4, see Stargardt disease), and is involved in drug-resistance, especially relating to cancer chemotherapy. ABCC6 is expressed highly in the kidney and liver where its function is unknown. It is suggested that altered ABCC6 function may result in the defective transport of compounds that are essential for extracellular matrix turnover or deposition.

Diagnosis

PXE is diagnosed on clinical grounds. Mutation analysis is not yet widely available. In addition to PXE, angioid streaks are seen in sickle cell anemia, thalassemia, Paget disease of bone and beta alipoproteinemia. All patients with angioid streaks should be examined for evidence of PXE. Patients with apparently isolated angioid streaks should be monitored to exclude the possibility of PXE, which may become more apparent with time. Patients should be aware of the risks of SRNVM and are advised to seek specialist help if there is any change or distortion of vision, or altered performance on an Amsler grid test. While GI and cardiovascular complications are recognized, they are not common.


95

Sorsby pseudoinflammatory fundus dystrophy (also known as: SFD) MIM

136900; 188826 (TIMP3)

Clinical features

SFD is characterized by loss of central vision due to subretinal neovascular membrane (SRNVM) formation in middle life. The eyes are affected sequentially leading to severe and sudden loss of vision in virtually all affected individuals. Examination prior to the development of SRNVM demonstrates pigmentary disturbance, fine drusen-like deposits and atrophic lesions at the macula. The peripheral retina is affected and patients may also describe nyctalopia, which may precede the maculopathy. This may be accompanied by peripheral visual field loss, decrease in dark adaptation, and subnormal scotopic and photopic ERGs. There is progressive peripheral chorioretinal atrophy and a generalized retinal dystrophy may develop with bone spicule pigmentation, vascular attenuation and choroidal atrophy.

A 45-year-old female with family history of Sorsby fundus dystrophy, proven on TIMP3 mutation analysis. Vision is normal. Note the distribution of drusen around the arcades.

Age of onset

Major symptoms result from development/hemorrhage of SRNVM. This occurs in the fourth and fifth decades.

Inheritance

Autosomal dominant. Reports of recessive inheritance have been shown to be incorrect.

96

Sorsby pseudoinflammatory fundus dystrophy


22q12.1–q13.2

Gene

Tissue inhibitor of metalloproteinase 3 (TIMP3)

Mutational spectrum

Only six mutations in this gene have been described to date, five of which are missense mutations introducing a novel cysteine residue into the C-terminal domain. Of these mutations, one (a serine to cysteine substitution of residue 181) has been found in the majority of UK families tested to date. This suggests a stronger founder effect in British families.

Effect of mutation

Gain of function/dominant negative effect. All mutations give rise to a protein that has characteristics of the normally functioning protein but which forms stable dimers. These are thought to accumulate in the retina, giving rise to an increase in TIMP3 activity within the retina, which ultimately causes the disease process. Increased TIMP3 expression has been observed in other retinal dystrophies and it is suggested that TIMP3 overexpression may be a secondary step in the progression of other degenerative retinopathies.

Diagnosis

In suspected SFD patients, genetic analysis is quick and highly reliable. However, while proving an aid to diagnosis, DNA testing does not alter the management of the condition. SFD is a highly penetrant autosomal dominant condition associated with sudden and severe loss of vision. Counselling of at-risk individuals is highly complex. Both clinical examination and genetic testing can identify those who are carriers of causative mutations. For many, the knowledge of future visual disability is an enormous burden. As some may live to regret presymptomatic diagnosis, genetic testing and examination of unaffected relatives should be undertaken with caution and with the support of those familiar with presymptomatic testing protocols for other late-onset inherited conditions.


97

Stargardt disease: autosomal recessive (also known as: STGD; fundus flavimaculatus) Including: age-related macular degeneration; RP19; CORD3 MIM

248200; 601691 (ABCA4)

Macular atrophy in autosomal recessive Stargardt disease.

Clinical features

STGD is one of the most common early-onset forms of macular degeneration. The course of the disease is rapidly progressive and the final visual outcome is poor. The condition causes progressive loss of central vision, but, in general, patients have good preservation of peripheral/night vision even in the final stages of the disorder. Visual loss continues over a period of several years, progressing to, and stabilizing at, around 6/36–3/60. Many patients with STGD are registered blind. Throughout the posterior pole there are round, linear or pisiform lesions—the characteristic retinal flecks—which may extend to the equator. Fundus flavimaculatus (in which such retinal flecks are more widespread) and STGD form part of a spectrum of flecked-

98

Stargardt disease: autosomal recessive

retina disorders. The retinal flecks represent lipofuscin-containing deposits which accumulate in the RPE layer. The deposition of lipofuscin gives rise to the ‘dark choroid’ sign on fluorescein angiography due to masking of the underlying choroidal vasculature. Electrophysiology is relatively uninformative. ERGs are normal early in the disease but show reduction in the later stages. EOGs may be normal or slightly depressed. With time, the retinal flecks may reduce or disappear. There is progressive and generalized atrophy of the RPE and choroidal vascular atrophy leading to widespread macular/RPE atrophy and the development of a ‘beaten-bronze’ appearance at the macula. Age of onset

Patients are usually diagnosed before the age of 20 years. Loss of central vision may begin from around 6 years of age. However, sometimes symptoms do not appear until adulthood.

Epidemiology

STGD is one of the most common causes of macular degeneration in children, with a frequency of around 1:10,000.

Inheritance

Autosomal recessive


1p21–p22.1

Gene

ATP-binding cassette, subfamily A, number 4 (ABCA4); alternative name: ATP-binding cassette transporter, retina-specific (ABCR).

Mutational spectrum

Mutations of this gene show a broad range of phenotypic heterogeneity. STGD and fundus flavimaculatus A wide variety of disease-causing mutations have been described in STGD. Using current techniques, mutations are found in around 60% of cases. While both protein truncating and missense mutations may cause STGD, the majority are missense mutations affecting amino acids that are conserved between species and are thought to be necessary for protein function.


99

RP19 Mutations in ABCA4 have also been discovered in families with arRP. The age of onset of nyctalopia is around 8 years, followed by a decrease in visual acuity, starting at 14 years of age. It is hypothesized that more severe mutations (abolition of function) give rise to RP rather than STDG. CORD3 ABCA4 mutations have been shown to be an important cause of autosomal recessive CRD. ARMD The role of ABCA4 in the etiology of classical ARMD remains controversial. Effect of mutation

While the major expression of ABCA4 is confined to rods, immunofluorescence microscopy and Western blot analysis suggest that the protein is present in cones as well. It is uncertain whether the pathogenic effects relate to direct cone-mediated damage or a more widespread effect. In the rod, ABCA4 is found on the disc membrane of the retinal outer segments. ABCA4 knockout mice show delayed dark adaptation, increased levels of all-trans-retinaldehyde following light exposure and lipofuscin deposition. Biochemical data suggest that ABCA4 facilitates transmembrane transport. Abnormal ABCA4 is hypothesized to lead to accumulation of an opsin/all-transretinaldehyde complex in discs.

Diagnosis

100

Ophthalmic examination and electrophysiological assessment are often sufficient for diagnosis. STGD1 is often diagnosed in a child after parents have decided to have more offspring and carries a 25% a priori risk to siblings. A small number of dominant phenocopies are described, although these are rare.

Stargardt disease: autosomal recessive

ABCA4 is a 6819 bp gene encoding a 2273-amino acid protein. It contains 51 exons ranging in size from 33–266 bp. Analysis of such a gene is an enormous task, and one that is not yet available outside the research sphere.


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Stargardt disease: autosomal dominant (also known as: STGD; fundus flavimaculatus) MIM

600110 (STGD3); 603786 (STGD4)

Clinical features

STGD is one of the most common early-onset forms of macular degeneration. As discussed in the previous section, the condition is generally autosomal recessive. However, a number of phenocopies are recognized that are inherited in a dominant manner. Amongst the dominant forms at least two have been shown to link to regions distinct from chromosome 1, ABCA4 locus that causes the typical recessive form of STGD. The form linked to chromosome 6 (STGD3) shows reduced central vision (onset is in the first and second decades) progressing to a final visual acuity in the range of 3/60 or less. Patients have a well circumscribed atrophic lesion of the choriocapillaris and RPE at the macula with surrounding flecks. As with ‘typical’ STGD, the ERG is well preserved early on although there may be mild reduction in later life. Fluorescein angiography demonstrates absence of the ‘dark choroid’ sign that is seen in typical, recessive STGD.

Stargardt disease.

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Stargardt disease: autosomal dominant

Age of onset

First or second decades

Epidemiology

The dominant forms of STGD are rare

Inheritance

Autosomal dominant


6cen–q14 (STGD3) 4p (STGD4)

Gene

Elongation of very long-chain fatty acids-like gene 4 (ELOVL4; MIM 605512).

Mutational spectrum

To date, a single 5 bp deletion has been described in five families; four families had AD STGD while the fifth family had ‘autosomal dominant macular atrophy’.

Effect of mutation

The mutation described results in a frameshift and premature protein termination. ELOVL4 is a member of a family of genes important in fatty acid elongation. The gene is highly expressed in the photoreceptors and shows low expression in the brain.

Diagnosis

STGD is generally a recessive condition and the majority of individuals have been found to carry mutations in the ABCA4 gene on chromosome 1. Ophthalmic examination and electrophysiological assessment are usually sufficient for diagnosis. Among the few proven dominant families the ‘dark choroid’ sign seen on fluorescein angiography was not found. However, the single family with a dominant form of STGD linked to chromosome 4 does show the ‘dark choroid’ sign. As a result this cannot be used as a reliable indicator of inheritance pattern. Currently, genetic testing of the Stargardt genes is on a research basis only.


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Vitelliform macular dystrophy (also known as: VMD2; Best macular dystrophy; Best disease) MIM

153700

(L) ‘Egg yolk’ lesion early in disease progression. At this stage central visual acuity remains good. (R) Scarring of macular region. This 40-year-old has a visual acuity of 6/18.

Clinical features

In the initial stages, a bright yellow cyst forms under the RPE beneath the macula. This classical lesion is the round or oval, yellow ‘egg yolk’ (vitelliform) lesion at the macula. Characteristically, fundoscopic changes precede visual impairment and, despite the presence of the cyst, visual acuity may remain normal or near normal (between 6/9 and 6/18) for many years. Peripheral vision is generally unaffected. In many individuals, the cyst eventually ruptures (vitelliruptive stage) leading to visual loss from macular/RPE atrophy. At this stage there may be deterioration of central vision. Amongst the inherited macular dystrophies, clinical outcome in VMD2 is relatively optimistic. Many patients retain a binocular visual acuity of 6/18 or better, at a late stage of the disease course. Significant asymmetry is often noted. While older patients tend to have worse visual acuities, many retain useful central vision in one eye with a visual acuity of about 6/12 in the better eye. There is marked intrafamilial variability in macular pathology (even amongst families with different mutations within the VMD2 gene).

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Vitelliform macular dystrophy

Diagnosis is confirmed by electrophysiology. There is a grossly reduced EOG (reduced light-induced rise A wave) on scotopic ERG. This ‘positive wave ERG’ pattern is often seen amongst dominant forms of CSNB.

Male patient with X-linked CSNB and moderate myopia. There are few retinal findings apart from the peripapillary atrophic changes of myopia.

Age of onset

Birth

Genes

Gene

Gene name

MIM

CACNA1F

Calcium channel alpha-1 subunit

300110

NYX

Nyctalopin

300278

GNAT1

Alpha subunit of rod transducin

139330

RHO

Rhodopsin

180380

PDE6B

Beta subunit, rod cGMP phosphodiesterase

180072

Mutational spectrum The genetic mutations that lead to stationary forms of night and effects of mutations blindness have a variety of pathogenic mechanisms. X-linked CSNB A variety of mutations in CACNA1F are described including missense, frameshift and nonsense mutations. They are predicted to result in loss 142

Congenital stationary night blindness

of function. CACNA1F encodes a voltage-gated calcium channel that is retina-specific. It is thought that the mutations result in an alteration of Ca2+-mediated neurotransmitter release from photoreceptors in response to light. There are at least two forms of X-linked CSNB, and mutations in CACNA1F are associated with the incomplete form. NYX, which encodes a leucine rich extracellular matrix proteoglycan, nyctalopin, has been shown to be mutated in the complete form of X-linked CSNB. Frameshift, missense and whole exon deletions have all been defined. The 481 amino acid protein is expressed within the kidney and retina. Within the retina it is expressed in the inner segment, inner and outer nuclear layers and in the ganglion cells. Leucine-rich repeats are generally involved in protein-protein interactions and, while the function of the protein is not known, other members of this family of molecules are implicated in cell growth, adhesion and migration. Autosomal dominant CSNB Dominant negative RHO mutations associated with CSNB are found in residues that lie within a similar region of the folded rhodopsin molecule. They result in constitutive, light-independent activation of transducin, and hence of the phototransduction cascade (see page 130, rhodopsin adRP). A specific missense mutation (His258Arg) in the b subunit of phosphodiesterase (PDE) also causes CSNB (the majority of mutations in this gene cause autosomal recessive RP). This mutation is found near to the N-terminal portion of the protein and is thought to alter the inactivation of PDE in dark-adapted conditions. Reduced inactivation of PDE results in constitutive activation of phototransduction. The single missense mutation of GNAT1 alters a conserved residue. Transducin is the second component of the phototransduction cascade, which in turn binds to the third protein, PDE. The mutant transducin does not bind to the inhibitory g subunit of PDE suggesting that this does not cause CSNB via activation of the phototransduction cascade, but acts via a different pathogenic mechanism.


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Diagnosis

When suspected clinically, diagnosis of CSNB is generally supported by electrodiagnosis. At the current time, the degree of heterogeneity precludes molecular analysis, which is not widely available.

Fundus albipunctatus MIM

136880; 601617 (RDH5)

Clinical features

In fundus albipunctatus, congenital night blindness is present with well-preserved, or normal, visual acuity. Fundus examination reveals white dots scattered throughout the retina. There is no RPE degeneration and no progression with time. ERG testing is characteristic of CSNB with reduction on the B wave of the scotopic ERG. However, this returns to normal with prolonged dark adaptation (up to 3 h).

Fundus albipunctatus. 20-year-old Asian female with non-progressive night blindness.

Age of onset

Birth

Inheritance pattern

Autosomal recessive


12q13–q14

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Fundus albipunctatus

Gene

Retinol dehydrogenase 5 (RDH5)

Mutational spectrum

Both missense and frameshift mutations have been described in RDH5.

Effects of mutations

Several molecules that are important in the visual cycle regenerating retinol dehydrogenase 5 have been implicated in retinal degeneration. RDH5 is expressed in the RPE and catalyzes the conversion of 11-cis retinol to 11-cis retinal. RDH5 mutations have been shown severely to reduce its activity. It is thought that reduced enzyme levels lead to reduced production of 11-cis retinal, which in turn leads to abnormally slow regeneration of cone and rod photopigments. Ultimately, photopigments do regenerate, which may explain the normalization of the ERG after prolonged dark adaptation, and may result from residual enzyme activity.

Diagnosis

When suspected clinically, diagnosis of fundus albipunctatus, as opposed to retinitis punctata albescens, is supported by electrodiagnosis. Mutation testing is only available on a research basis at the current time.

Oguchi disease MIM

258100; 181031 (SAG); 180381 (RHOK)

Clinical features

Oguchi disease is a form of congenital stationary night blindness (CSNB) rarely seen outside Japan. In the light-adapted state, the retina has a greenish hue that returns to normal after dark adaptation. ERG testing reveals a CSNB negative waveform pattern. Unlike fundus albipunctatus, this does not improve with dark adaptation.

Age of onset

Birth

Inheritance pattern

Autosomal recessive


145


2q37.1 (SAG) 13q34 (RHOK)

Gene

S-antigen (SAG); alternative name: arrestin. Rhodopsin kinase (RHOK)

Mutational spectrum and effect of mutations

Rhodopsin kinase and arrestin act together to deactivate rhodopsin after stimulation by light. RHOK phosphorylates rhodopsin at specific residues. This modified form of rhodopsin is then complexed by arrestin. Null mutations in both result in the same clinical phenotype. Loss of function mutations (deletion, missense and frameshift) are described in RHOK, and protein truncation mutations in arrestin. Mutations would, therefore, result in reduced deactivation of rhodopsin.

Diagnosis

Oguchi disease is rare ouside Japan.

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Oguchi disease

Alström syndrome (also known as: ALMS1) MIM

203800

Clinical features

ALMS1 is an under-diagnosed multisystemic condition associated with obesity, diabetes, retinal degeneration and acanthosis nigricans. Unlike Bardet-Biedl syndrome, polydactyly is not present and intelligence is often normal. Ocular Children with ALMS1 develop an early-onset severe cone-rod dystrophy. Nystagmus is often present and children are photophobic. The ERG is usually extinguished when tested but, if present, shows better preservation of rod responses. Patients may progress to having no light perception by the end of the second decade. Fundoscopy reveals vessel attenuation early in the course of the disease with disc pallor. Bull’s eye maculopathy or bone corpuscular pigmentation is rare. Extraocular The majority of children are found to have dilated cardiomyopathy, which is a common cause of death in infancy. Children are overweight and often develop hearing loss before 10 years of age. Children may have acanthosis nigricans. Diabetes and progressive renal dysfunction may develop in adult life.

Age of onset

Birth

Inheritance

Autosomal recessive


2p13

Gene

ALMS1


147

Mutational spectrum

Frameshift and nonsense mutations have been described.

Effect of mutation

The ALSM1 protein is an uncharacterized protein encoded by a ubiquitously expressed gene of 23 exons. The protein is large (4169 amino acids) and contains a tandem repeat encoding 47 amino acids.

Diagnosis

Diagnosis is on clinical grounds and may be supported by ophthalmic investigation. An autosomal recessive condition, recurrence risks are 25% for further children. Currently, DNA diagnosis is not available.

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Alström syndrome

Bardet-Biedl syndrome (also known as: BBS) MIM

604896 (MKKS)

Clinical features

BBS is an autosomal recessive condition associated with postaxial polydactyly, obesity, mental retardation and retinal degeneration. The condition is highly variable, which occasionally leads to delays in diagnosis.

Severe retinal dystrophy in Bardet-Biedl syndrome with vessel attenuation and disc pallor. There were also classical bone-spicule changes in the periphery.

Large atrophic lesion of the macula in a 47-year-old male with BBS.


149

Ocular Retinal dystrophy in BBS is an extremely common, perhaps invariant, finding. Visual deterioration is of early onset—often within the first 5 years of life. Presenting features include nyctalopia, nystagmus and photophobia. Reduced visual acuity is often an early feature and a large number of patients are myopic. On examination there is usually evidence of widespread retinal changes. Macular changes, which range from mild pigmentary disturbance and bull’s eye maculopathy to gross atrophic lesions, are seen in the majority of patients. ERG measurements are often unrecordable.

Brachydactyly in BBS.

Nubbin of postaxial polydactyly.

Polydactyly in BBS – this adult patient had early surgery to remove extra digit from this foot.

150

Bardet-Biedl syndrome

Extraocular Postaxial polydactyly is variable; in one study around two-thirds to three-quarters of patients had obvious polydactyly. However, others will have a skin tag, while brachydactyly is also seen. Obesity is common but is only apparent from around the age of 2–3 years. Developmental delay (particularly in fine and gross motor skills) is noted in around a third of patients. Learning difficulties are not invariable and about a quarter of patients will stay in mainstream schooling with supplementary help. Genitourinary malformations are common. Most males will have small external genitalia, while female structural genital abnormalities (including uterus duplex, septate vagina, vaginal atresia and congenital hydrometrocolpos) are described. Severely reduced renal function leading to early chronic renal failure is a common cause of premature death. Age at onset

In one study the average age at diagnosis was about 9 years. However, polydactyly is present at birth, obesity within the first 2–3 years, and visual problems noticed at around 5 years of age.

Inheritance

Autosomal recessive

Chromosomal location and genes

Disorder BBS1 BBS2 BBS3 BBS4 BBS5 BBS6

Mutation spectrum and

BBS2

effect of mutations

A widely expressed, 17 exon gene of unknown function. The gene has no known homology to genes of known function, and has no known functional relationship to other genes that cause BBS. Both

Gene BBS2 BBS4 MKKS

Chromosome 11q13 16q21 3p13–p12 15q22.3–q23 2q31 20p12

MIM 209901 209900 600151 600374 603650 604896

nonsense and missense mutations have been identified. It has been estimated that this is the second most common form of BBS accounting for around 9% of cases. Inherited retinal disease

151

BBS4 A widely expressed, 16 exon gene of unknown function. The gene is homologous to O-linked N-acetylglucosamine (O-GlcNAc) transeferase (OGT) which is thought to be involved with insulin resistance in humans and may play a role in diabetes mellitus. Both nonsense and splice-site mutations have been identified in consanguineous BBS families. BBS4 mutations are thought to account for around 1% of BBS. MKKS (McKusick-Kaufman Syndrome gene) Recessive mutations have been found in the MKKS gene in BBS as well as McKusick-Kaufman syndrome (MKKS). The gene has been estimated to cause around 4% of BBS. MKKS is a rare autosomal recessive condition characterized by hydrometrocolpos, postaxial polydactyly and congenital heart disease. It has been suspected, prior to gene identification, that this condition may overlap with BBS because a number of girls with postaxial polydactyly and structural genital abnormalities (including uterus duplex, septate vagina, vaginal atresia and congenital hydrometrocolpos) had later developed mental deficiency, obesity and retinal dystrophy. In BBS, the majority of mutations defined have been frameshifts, suggesting that the phenotype results from loss of function mutations in both alleles. Missense mutations are present in families with MKKS suggesting that the phenotype is seen amongst patients in whom there is retention of some protein function. The MKKS gene encodes a putative chaperonin protein that is responsible for the folding of a wide range of proteins. The exact role of the protein is not defined. Diagnosis

152

BBS is a clinical diagnosis that is often delayed. However, DNA testing is not yet available to facilitate the diagnosis.


Cockayne syndrome (also known as: CKN)

Clinical features

Cockayne syndrome is a rare recessive disorder resulting from defective DNA repair. Ocular Poor vision, often associated with nystagmus is of diverse etiology. Corneal damage is secondary to reduced tear production, as well as lagophthalmos. Early-onset or congenital cataracts are common. In addition, there is a progressive retinal dystrophy associated with peripheral retinal pigmentation, optic atrophy and arteriolar attenuation. Extraocular Children with CKN have a characteristic facial appearance with a beaked nose and sunken eyes. Progressive leukodystrophy is associated with increasing microcephaly and calcification of basal


153

ganglia. There is extreme failure to thrive associated with poor weight gain and loss of adipose tissue. Children have skeletal deformities including kyphosis and contractures (e.g. of the hip and fingers). Neurosensory hearing loss is common and may be the presenting feature. Extreme skin photosensitivity, reflecting defective DNA repair, may be noticeable even through glass. There is progressive deterioration and in severe cases children may die during the first decade of life. They seldom survive beyond the end of the second decade. Age at onset

Cataracts may be noted at birth. Some patients will feed poorly from early in life, but weight gain is often reasonable for the first few months before progressive emaciation and developmental delay become evident during the first year. The majority of patients present at around the age of 3 years with neurosensory deafness, failure to thrive and developmental delay.

Chromosomal location and genes

Gene ERCC8 ERCC6

Mutational spectrum

While there is variability in the severity of CKN, the phenotypes associated with mutations in the two genes are indistinguishable; 80% have mutations in ERCC6, the majority being frameshift and nonsense mutations. Recessive mutations in ERCC8 include nonsense and deletion mutations.

Effect of mutations

ERCC8 encodes a 396 amino acid protein containing WD40 repeats. ERCC6 encodes a 1493 amino acid protein with helicase motifs. Mutations in either gene affect transcription-coupled repair (TCR), the mechanism by which damaged DNA in RNA polymerase II transcribed genes is preferentially repaired. CKN cells fail to breakdown RNA polymerase II after UV exposure and to remove the transcription complex which is stalled at sites of DNA damage.

154

Chromosome Locus 5q11.2 CKN1 10q11 CKN2

MIM 216400 133540

Cockayne syndrome

Diagnosis


CKN can usually be diagnosed after clinical investigation. Currently, supplemental molecular and genetic tests are available on a research basis only. Cultured fibroblasts show increased sensitivity to UV light; there is decreased survival and reduced levels of DNA/RNA synthesis several hours after irradiation. UV sensitivity tests have been used for both postnatal and prenatal diagnosis. Mutation testing is available on a research basis only.

155

Cohen syndrome (also known as: COH1) MIM

216550

Clinical features

Cohen syndrome is an uncommon multisystemic condition associated with developmental delay, a characteristic dysmorphic appearance and retinal degeneration. The condition is under-recognized leading to delays in diagnosis. Ocular Children with Cohen syndrome often develop early-onset myopia that may be severe. The classical manifestation is an early-onset retinal dystrophy. There is reduced acuity, night blindness and restriction of visual fields suggesting widespread degeneration. Bull’s eye maculopathy is common. Patients are often registered as partially sighted/blind in their teenage years. Less common associations include keratoconus, lens dislocation and retinal coloboma. Extraocular Children have a characteristic facial appearance with a short philtrum (revealing apparently large upper incisors), a beaked nose and a snarling smile. There is mild microcephaly associated with moderate to severe developmental delay. Children have childhoodonset truncal obesity and elongated hands and feet with tapering digits. Patients have a neutropenia that is generally benign although frequent gum infections have been described.

Age of onset

Birth. Myopia is noted in the first 2–3 years and visual symptoms are common in the first decade.

Inheritance

Autosomal recessive

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Cohen syndrome

Long, tapering fingers.


8q22–q23

Gene

Unknown

Diagnosis

Diagnosis is on clinical grounds and may be supported by ophthalmic and hematological investigation. Being an autosomal recessive condition, recurrence risks are 25% for further children. Currently, DNA diagnosis is not available and, although linkage has been defined, genetic testing is likely to await gene identification.

Characteristic facial appearance with short philtrum and prominent incisors. Despite truncal obesity, the extremities remain slender.


157

Joubert syndrome (also known as: JBTS1; cerebelloparenchymal disorder IV (CPD IV); cerebellar vermis agenesis; Joubert-Boltshauser syndrome) MIM

213300

Clinical features

JBTS1 is a rare autosomal recessive syndrome with a variable phenotype. There is complete or partial cerebellar vermian agenesis. During the neonatal period, characteristic breathing difficulties include episodic tachypnea and apnea. Children are hypotonic and development is significantly delayed. Associated abnormalities include renal cystic disease (50% in those receiving external beam radiation. In addition there is a low risk of pinealomas which have a poor prognosis. A small number of patients carry large chromosomal deletions encompassing the RB1 gene and the genes surrounding it on 13q (see figure). The deletions may cause clinical manifestations due to loss of these genes—a contiguous gene syndrome—including developmental delay and facial dysmorphism.

Conditions associated with increased risk of malignancy

257

A

B

Retinoblastoma in first trimester fetus with multiple abnormalities. A visible deletion of chromosome 13q was seen on karyotype analysis. A. The fetus has a small jaw, low set ears, short, broad neck and short thumbs. B. Swelling of the right eye was noted. Macroscopic and histopathological analysis revealed a large retinoblastoma.

Age of onset

Mean age of onset for bilateral cases is 15 months and for unilateral cases 24 months.

Epidemiology

Incidence of 4:1,000,000, or about 1:23,000 live births.

Inheritance

Autosomal dominant. Penetrance is >99% for most mutations that abolish RB1 function. However, in some families penetrance is reduced to around 40%. Around 10% of individuals have a positive family history, most of these developing bilateral multifocal tumors. Approximately 30% of patients have no family history but develop bilateral tumors; they are assumed to have new germline mutations. The remaining 60% develop unilateral tumors wherein the majority result from somatic mutations arising after the production of the zygote.

258

Retinoblastoma


13q14.1–q14.2

Gene

Retinoblastoma (RB1)

Mutational spectrum

RB1 is a large gene containing 27 exons covering over 180 kb of genomic DNA. While major deletions are reported, the majority of mutations are single base changes. All forms of mutation have been described including protein truncating mutations, splice-site mutations and missense changes. The majority of mutations (80–85%) result in premature termination.

Effect of mutation

RB1 is a tumor suppressor gene that expresses a nuclear protein involved in cell cycle regulation and transition from G1–S phase. RB1 acts to inhibit cellular transcription factors and tRNA/rRNA gene transcription. Mutations in RB1 that cause low penetrance forms of retinoblastoma have been shown to retain some function.

Diagnosis and counselling issues

Clinical. Using sensitive screening techniques around 80–90% of mutations can be found in patients with germline mutations. Genetic testing is now widely available. Ongoing screening of both affected children and unaffected siblings is a major cause of anxiety. However, mutation testing may be useful in reducing the need for examination under anesthetic and repeated fundoscopy in unaffected siblings who are not mutation carriers. A major area of concern is the possibility that the proband or one of his or her parents has a germline mutation that may be passed on to other family members. Family history and mutation analyses can be used to help determine these risks. In unilateral cases, negative screening of blood does not exclude the possibility of mosaicism as both affected and unaffected germ cells may exist and can be passed on to offspring. Molecular genetic testing of tumor DNA may aid the search for mutations. If two disease causing mutations are identified in a tumor, peripheral blood from relatives can then be screened for these mutations.


259

Family history

Tumor type

Probability of germline mutation

Risk to offspring

Risk to siblings

Positive

Bilateral retinoblastoma

100%

50%

-

Negative

Bilateral retinoblastoma

95%

Assumed to be 50%

Around 3–5% (due to germline mosaicism)

Negative

Multifocal, unilateral retinoblastoma

Uncertain

Difficult to determine

Difficult to determine

Negative

Unifocal, unilateral retinoblastoma

5–10%

2–5%

1%

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Retinoblastoma

Tuberous sclerosis complex (also known as: TSC; tuberous sclerosis) MIM

191100 (TSC1); 191092 (TSC2)

Clinical features

TSC is a highly variable autosomal dominant disorder in which affected individuals have a high risk of seizures and renal disease, both of which are significant causes of premature mortality. Ocular These are usually asymptomatic. The classical lesions are retinal astrocytic hamartomas, ‘mulberry tumors’, or small intraretinal translucent patches. In addition, achromic patches analogous to the hypopigmented skin lesions are present. One or more of these lesions may be present in up to 75% of patients. CNS Tumors include subependymal glial nodules and giant cell astrocytomas as well as cortical and subcortical tubers. Over 80% of patients diagnosed with TSC have seizures, and at least 50% have developmental delay. Renal Benign angiomyolipomas occur in at least 70% of patients and can cause hemorrhage or replacement of renal tissue. Some patients have a combined phenotype with features of TSC and PKD and in these patients cystic disease may lead to renal failure. Skin Facial angiofibromas (adenoma sebaceum), periungual fibromas, hypomelanotic macules and shagreen patches are all observed.


261

A

B

C A & B. Astrocytic hamartomata of disc. C. Hypopigmented patches in tuberous sclerosis.

262

Tuberous sclerosis complex

Cardiac Cardiac rhabdomyoma Other Minor manifestations include multiple dental pits, hamartomatous rectal polyps, bone cysts and gingival fibromas. Age of onset

Signs of the disorder may be present from birth, although it is generally diagnosed during childhood.

Epidemiology

The prevalence of TSC is suggested to be as high as 1:5800 births.

Inheritance

Autosomal dominant. About 70% of all cases are new mutations.


9q34 (TSC1); 16p13 (TSC2)

Gene

Tuberous sclerosis complex 1 and 2 (TSC1, TSC2)

Mutational spectrum

More than 300 mutations have been described in TSC1. None are missense mutations. Of over 250 mutations described in TSC2, around 75% are gene rearrangements, splice mutations and nonsense mutations, 25% are missense mutations.

Effect of mutation

Both TSC1 and TSC2 are thought to act as tumor suppressor genes. The two genes have been shown to form heterodimers and are believed to regulate cell cycle and cell proliferation.

Diagnosis

Clinical. The role of the ophthalmologist is to aid diagnosis by recognition of retinal lesions. While mutation testing for both TSC1 and TSC2 is now available, this will only identify mutations in 60–80% of cases.


263

von Hippel-Lindau syndrome (also known as: VHL) MIM

193300

Clinical features

Ocular About 70% of patients have retinal hemangioblastomas, which are often the presenting feature of the disorder. Hemangioblastomas are vascular tumors associated with feeder and draining vessels and are mainly located in the temporal periphery of the retina, although they may also be found at the posterior pole and optic disc. The angiomas are usually asymptomatic when small. As they enlarge they may cause exudation, hemorrhage and retinal detachment. Laser photoablation or cryotherapy of early retinal angiomas results in regression. Optic disc tumors are not amenable to treatment. The average number of retinal angiomas per patient is two (there may be up to 15); this number does not increase with age. Extraocular CNS hemangioblastomas are the classic lesion of VHL. Around 80% develop in the cerebellar hemispheres, the remaining 20% in the spinal cord. Multiple renal cysts are common. In addition, clear-cell renal carcinoma occurs in >40% of patients. Pheochromocytoma, either symptomatic or asymptomatic, may be seen within the adrenal glands or elsewhere. Multiple pancreatic cysts are frequent, and occasionally pancreatic tumors develop. Tumors of the endolymphatic sac of the membranous labyrinth are rare but may cause early deafness. Epididymal cystadenomas are relatively common in males with VHL syndrome but rarely cause problems.

Age of onset

264

Symptoms are rare before the age of 5 years. Annual screening should begin from around the age of 5 years because photoablation can successfully treat retinal lesions and preserve vision.

von Hippel-Lindau syndrome

Epidemiology

Prevalence in the UK has been estimated to be approximately 1:50,000.

Inheritance

Autosomal dominant


3p25–p26

Gene

von Hippel-Lindau (VHL)

Mutational spectrum

Mutations are found in almost all patients. Around one-third are caused by partial or whole gene deletion, the remainder result from point mutations. A wide range of mutations including truncating, splice-site and missense mutations have been described. There is significant genotype-phenotype correlation for mutations in the VHL gene: truncating and null mutations generally cause VHL without pheochromocytoma, while patients with pheochromocytoma generally have a missense mutation.

Effect of mutation

The VHL protein (pVHL) is involved in the regulation of hypoxicallyinduced vascular endothelial growth factor (VEGF) and glucose transporter-1 (GLUT-1). It is also involved in the degradation of hypoxia-inducible factor-1 (HIF-1). HIF-1 usually controls factors promoting the formation of blood vessels. If pVHL is abnormal, the degradation of HIF-1 does not take place resulting in abnormal proliferation of blood vessels. This could account for the vascular tumors seen in VHL. Further work is ongoing to fully understand the interactions of pVHL with other proteins and to understand the genotype/phenotype correlation. The VHL gene is a tumor suppressor gene requiring biallelic loss for tumorigenesis, however, the presence of a genotype-phenotype correlation suggests that some missense mutations retain aspects of protein activity.

Diagnosis

Patients with retinal angiomas should be investigated for the presence of other characteristic lesions. DNA testing is available through molecular diagnostic laboratories.


265

266

10 10. Defects of ocular/adnexal development

Alacrima 268 Blepharophimosis, ptosis and epicanthus inversus 270 Congenital fibrosis of extraocular muscles 272 Isolated microphthalmos 274

Alacrima (also known as: achalasia-addisonianism-alacrima syndrome (AAAS); triple-A syndrome; Allgrove syndrome) MIM

231550; 605378 (Aladin)

Clinical features

AAAS is a variable condition in which patients may have some, but not all, of the features. Ocular features Congenital alacrima is present in most patients and leads to significant ocular discomfort. Autonomic disturbance may lead to anisocoria. The pupil is hypersensitive to topical parasympathomimetics. Optic atrophy is described in a small number of patients. Extraocular manifestations Adrenal insufficiency is usually diagnosed in the first years of life. Symptoms relating to recurrent hypoglycemia generally begin between the ages of 1–8 years. This is often associated with hyperpigmentation of the skin. Adrenal insufficiency responds to steroid replacement. A number of patients also have evidence of mineralocorticoid deficiency. Achalasia of the esophageal cardia is present in the majority of patients and is diagnosed between the ages of 2–20 years, often before cortisol deficiency is noted. When diagnosed, the majority of patients require surgical intervention. Neurological manifestations are highly variable but include evidence of upper and lower motor neuron dysfunction, ataxia, sensory impairment, as well as autonomic dysfunction. There may be lateonset progressive neurological symptoms including cerebellar ataxia and mild dementia.

268

Alacrima

Age of onset

While a diagnosis of AAAS is often delayed, features of the condition are usually present in the first years of life.

Inheritance

Autosomal recessive


12q13

Gene

Achalasia-addisonianism-alacrima syndrome gene (AAAS)

Mutational spectrum

The majority of mutations described are frameshift and truncating mutations that result in premature protein truncation. However, a number of missense mutations have also been described.

Effect of mutation

The AAAS gene encodes a 546 amino acid protein (Aladin), which contains so-called WD-repeats. While it is expressed in all tissues, there is high expression in the adrenal gland, gastrointestinal structures, pituitary and cerebellum. WD-proteins form a b-propeller structure which facilitates protein-protein interactions. The exact function of the protein, or the identity of the proteins with which it interacts, is unknown. However, the presence of a peroxisomal targeting signal suggests a peroxisomal function.

Diagnosis

Diagnosis of AAAS may be delayed, and the ophthalmic features are often valuable in facilitating this process. Mutation testing is available on a research basis only.

Defects of ocular/adnexal development

269

Blepharophimosis, ptosis and epicanthus inversus (also known as: BPES) MIM

110100; 605597 (FOXL2)

Clinical features

Ocular BPES is associated with abnormal development of the eyelid structures.

BPES: Note upward insertion of inner canthus of lower lid.

Blepharophimosis leads to horizontal shortening of the palpebral fissure; in BPES this is 2–2.2 cm as compared with a normal adult horizontal length of 2.5–3 cm. Ptosis results from reduced horizontal fissure length as well as from abnormal levator function. This leads to a chin-up head-tilt and arching of the eyebrows. Epicanthus inversus is characterized by a small fold of skin, running upwards from the medial aspect of the lower lid, which appears to override the medial insertion of the upper lid. There is often telecanthus (lateral displacement of the inner canthi). Occasionally, individuals with BPES have been described with ocular malformations such as anophthalmos and microphthalmos. Extraocular Female infertility is common in some families with BPES, and has been termed ‘type I BPES’. There are differing degrees of ovarian failure, from streak gonads to ovaries of essentially normal appearance but with irregular or infrequent menstruation associated with abnormal hormonal function. Type II describes isolated BPES.

270

Blepharophimosis, ptosis and epicanthus inversus

Age of onset

Congenital

Inheritance

Autosomal dominant. There is a high number of sporadic cases. Infertility is sex-limited (i.e. only in females) but may be passed on by males.


3q23

Gene

Forkhead transcription factor (FOXL2)

Mutational spectrum

In patients with type I BPES, there are premature protein termination mutations. These are likely to result in loss of function of the FOXL2 transcription factor. In patients with type II BPES, intragenic duplications result in expansion of a 14-residue polyalanine amino acid domain. This may result in reduction, rather than abolition of protein function. Several patients with translocations through 3q23 have been described. The translocations lie within several hundred kb of FOXL2.

Effect of mutation

FOXL2 is a transcription factor whose expression is highly tissuespecific. During development, expression is confined to the periocular mesenchyme—the developing eyelid structures. In the adult, expression is confined to the ovary.

Diagnosis

Distinction between types I and II is important in order to counsel females regarding the possible risks of infertility, in particular amongst those with de novo mutations and no family history. The gene has only recently been described, therefore mutation testing is only on a research basis.


271

Congenital fibrosis of extraocular muscles (also known as: CFEOM; FEOM1; FEOM2) MIM

135700 (FEOM1); 602078 (FEOM2)

Clinical features

Affected individuals are born with non-progressive restriction of ocular movement. The disorder is characterized by anchoring of the eyes in downgaze with ptosis and a chin-up head-tilt. There is restrictive ophthalmoplegia with the globes frozen, often in extreme abduction, with little or no ability to adduct, elevate or depress them. In addition to fibrosis of the extraocular muscles and Tenon’s capsule, adhesions between muscles, Tenon’s and the globe are seen. It is thought that CFEOM is caused by abnormal development of oculomotor subnuclei resulting in anomalous innervation of the extraocular musculature.

CFEOM: In these individuals, from the same family, the eyes are held in a depressed position, in abduction. There is absent levator function. Vision is normal in both cases.

Age of onset

Congenital

Inheritance

Autosomal dominant (FEOM1); autosomal recessive (FEOM2).

272

Congenital fibrosis of extraocular muscles


12p11.2–q11.2 (FEOM1); 11q13.2 (FEOM2).

Gene

Drosophila aristaless homeobox gene homolog (ARIX); MIM 602753 (FEOM2).

Mutational spectrum

In autosomal recessive FEOM, both splice-site mutations and a missense mutation of a conserved amino acid have been described.

Effect of mutation

Unknown

Diagnosis

It is likely that the splice mutations would result in the production of an unstable transcript or truncated, non-functional proteins. ARIX encodes a homeodomain-containing transcription factor that is required for generation and preservation of adrenergic neurons and brainstem motor neurons. It is thought to be important for the development of the cranial nerve nuclei.


273

Isolated microphthalmos (nanophthalmos and anophthalmos) Microphthalmia is not a single clinical entity. It may be associated with a large number of single gene disorders as well as developmental abnormalities of broad etiology, including chromosomal abnormalities, maternal infection, maternal toxin ingestion (e.g. anti-epileptic drugs or alcohol) and fetal disruptions. Environmental influences have also been suggested. MIM

142993 (CHX10)

A

B

C

A. Colobomatous microphthalmia. B & C. Right sided microcornea in a patient with branchio-oculo-facial syndrome has bilateral chorioretinal colobomata. Note the hemangioma.

274

Isolated microphthalmos (nanophthalmos and anophthalmos)

Clinical features

Microphthalmia is defined as an axial length of 200

XLR

309548

Friedreich’s ataxia (FRDA)

frataxin 9q13

GAA

intron

1 7-22

-

200- >900

AR

229300

Huntington’s disease (HD)

huntingtin 4p16.3

CAG

ORF

6-34

-

36-180

AD

143100

Dentatorubal-pallidoluysian atrophy (DRPLA)

atrophin 12p12

CAG

ORF

7-25

-

49-88

AD

125370

Spinal and bulbar muscular atrophy (SBMA – Kennedy syndrome)

androgen receptor CAG Xq11-12

ORF

11-24

-

40-62

XLR

313200

Spinocerebellar ataxia type 1 (SCA1)

ataxin-1 6p23

CAG

ORF

6-39

-

39-83

AD

164400


ataxin-2 12q24

CAG

ORF

15-29

-

34-59

AD

183090


ataxin-3 14q24.3-q31

CAG

ORF

13-36

-

55-84

AD

109150


PQ calcium channel 19p13

CAG

ORF

4-16

-

21-30

AD

183086


ataxin-7 3p21.1-p12

CAG

ORF

4-35

28-35

34- >300

AD

164500


SCA8 13q21

CTG

3’UTR

6-37

-

~107-2501

AD

603680


SCA10 22q13-qter

ATTCT

intron 9

10-22

-

500-4,500

AD

603516


PP2R2B 5q31-33

CAG

5’UTR

7-28

-

66-78

AD

604326

Myotonic dystrophy (DM)

DMPK 19q13.3

CTG

3’UTR

5-37

~50-180

~200- >2,000

AD

160900

1Longer alleles exist but are not associated with disease. AD: autosomal dominant; AR: autosomal recessive; ORF: open reading frame (coding region); 3’ UTR: 3’ untranslated region (downstream of gene); 5’ UTR: 5’ untranslated region (upstream of gene); XLR: X-linked recessive.

Polyacrylamide gel electrophoresis Allows resolution of proteins or DNA molecules differing in size by only 1 base pair. Pulsed field gel electrophoresis (Also performed using agarose) refers to a specialist technique that allows resolution of much larger DNA molecules, in some cases up to a few Mb in size.

294


Empirical recurrence risk – recurrence risk

Based on observation, rather than detailed knowledge of, e.g., modes of inheritance or environmental factors.

Endonuclease

An enzyme that cleaves DNA at an internal site (see also restriction enzyme).

Euchromatin

Chromatin that stains lightly with trypsin G banding and contains active/potentially active genes.

Euploidy

Having a normal chromosome complement.

Exon

Coding part of a gene. Historically, it was believed that all of a DNA sequence is mirrored exactly on the messenger RNA (mRNA) molecule (except for the presence of uracil in mRNA compared to thymine in DNA). It was a surprise to discover that this is generally not the case. The genomic sequence of a gene has two components: exons and introns. The exons are found in both the genomic sequence and the mRNA, whereas the introns are found only in the genomic sequence. The mRNA for dystrophin, an X-linked gene associated with Duchenne muscular dystrophy (DMD), is 14,000 base pairs long but the genomic sequence is spread over a distance of 1.5 million base pairs, because of the presence of very long intronic sequences. After the genomic sequence is initially transcribed to RNA, a complex system ensures specific removal of introns. This system is known as splicing.

Expressivity

Glossary

Degree of expression of a disease. In some disorders, individuals carrying the same mutation may manifest wide variability in severity of the disorder. Autosomal dominant disorders are often associated with variable expressivity, a good example being Marfan’s syndrome. Variable expressivity is to be differentiated from incomplete penetrance, an all or none phenomenon that refers to the complete absence of a phenotype in some obligate carriers.

295

C

A

T

G

T

T

T

T

C

C

C

C

C

A

C

C

C

A

PITX2 sequence

Mutant (protein)

ATG Met

TTT Phe

TCC Ser

CCC Pro

ACC Thr

CAA Gln

Normal (protein)

ATG Met

TTT Phe

TCC Ser

CCA Pro

CCC Pro

AAC Asn

Figure 8. Frameshift mutation. This example shows a sequence of PITX2 in a patient with Rieger’s syndrome, an autosomal dominant condition. The sequence graph shows only the abnormal sequence. The arrow indicates the insertion of a single cytosine (C) residue. When translated the triplet code is now out of frame by one base pair. This totally alters the translated protein’s amino acid sequence. This leads to a premature stop codon later in the protein and results in Rieger’s syndrome.

F Familial

Any trait that has a higher frequency in relatives of an affected individual than the general population.

FISH

Fluorescence in situ hybridization (see In situ hybridization).

Founder effect

The high frequency of a mutant allele in a population as a result of its presence in a founder (ancestor). Founder effects are particularly noticeable in relative genetic isolates, such as the Finnish or Amish.

Frameshift mutation

Deletion/insertion of a DNA sequence that is not an exact multiple of 3 base pairs. The result is an alteration of the reading frame of the gene such that all sequence that lies beyond the mutation is effectively nonsense (see Figure 8). A premature stop codon is usually encountered shortly after the frameshift.

296


G Gamete (germ cell)

The mature male or female reproductive cells, which contain a haploid set of chromosomes.

Gene

An ordered, specific sequence of nucleotides that controls the transmission and expression of one or more traits by specifying the sequence and structure of a particular protein or RNA molecule. Mendel defined a gene as the basic physical and functional unit of all heredity.

Gene expression

The process of converting a gene’s coded information into the existing, operating structures in the cell.

Gene mapping

Determines the relative positions of genes on a DNA molecule and plots the genetic distance in linkage units (centiMorgans) or physical distance (base pairs) between them.

Genetic code

Relationship between the sequence of bases in a nucleic acid and the order of amino acids in the polypeptide synthesized from it (see Table 2). A sequence of three nucleic acid bases (a triplet) acts as a codeword (codon) for one amino acid or instruction (start/stop).

Genetic counselling

Information/advice given to families with, or at risk of, genetic disease. Genetic counselling is a complex discipline that requires accurate diagnostic approaches, up-to-date knowledge of the genetics of the condition, an insight into the beliefs/anxieties/wishes of the individual seeking advice, intelligent risk estimation and, above all, skill in communicating relevant information to individuals from a wide variety of educational backgrounds. Genetic counselling is most often carried out by trained medical geneticists or, in some countries, specialist genetic counsellors or nurses.

Genetic heterogeneity

Association of a specific phenotype with mutations at different loci. The broader the phenotypic criteria, the greater the heterogeneity

Glossary

297

1st

1st

1st

1st

T

C

A

G

2nd

2nd

2nd

T

C

A

2nd G

TTT Phe [F]

TCT Ser [S]

TAT Tyr [Y]

TGT Cys [C]

T

TTC Phe [F]

TCC Ser [S]

TAC Tyr [Y]

TGC Cys [C]

C

TTA Leu [L]

TCA Ser [S]

TAA Ter [end]

TGA Ter [end]

A

TTG Leu [L]

TCG Ser [S]

TAG Ter [end]

TGG Trp [W]

G

CTT Leu [L]

CCT Pro [P]

CAT His [H]

CGT Arg [R]

T

CTC Leu [L]

CCC Pro [P]

CAC His [H]

CGC Arg [R]

C

CTA Leu [L]

CCA Pro [P]

CAA Gln [Q]

CGA Arg [R]

A

CTG Leu [L]

CCG Pro [P]

CAG Gln [Q]

CGG Arg [R]

G

ATT Ile [I]

ACT Thr [T]

AAT Asn [N]

AGT Ser [S]

T

ATC Ile [I]

ACC Thr [T]

AAC Asn [N]

AGC Ser [S]

C A

ATA Ile [I]

ACA Thr [T]

AAA Lys [K]

AGA Arg [R]

ATG Met [M]

ACG Thr [T]

AAG Lys [K]

AGG Arg [R]

G

GTT Val [V]

GCT Ala [A]

GAT Asp [D]

GGT Gly [G]

T

GTC Val [V]

GCC Ala [A]

GAC Asp [D]

GGC Gly [G]

C

GTA Val [V]

GCA Ala [A]

GAA Glu [E]

GGA Gly [G]

A

GTG Val [V]

GCG Ala [A]

GAG Glu [E]

GGG Gly [G]

G

3rd

3rd

3rd

3rd

Table 2. The genetic code. To locate a particular codon (e.g. TAG, marked in bold) locate the first base (T) in the left hand column, then the second base (A) by looking at the top row, and finally the third (G) in the right hand column (TAG is a stop codon). Note the redundancy of the genetic code—for example, three different codons specify a stop signal, and threonine (Thr) is specified by any of ACT, ACC, ACA and ACG.

(e.g. mental retardation). However, even very specific phenotypes may be genetically heterogeneous. Tuberous sclerosis is a good example: this autosomal dominant condition is now known to be associated (in different individuals) with mutations either in the TSC1 gene at 9q34 or the TSC2 gene at 16p13.3. There is no obvious distinction between the clinical phenotypes associated with these two genes. Genetic heterogeneity should not be confused with allelic heterogeneity, which refers to the presence of different mutations at the same locus. Genetic locus

A specific location on a chromosome.

Genetic map

A map of genetic landmarks deduced from linkage (recombination) analysis. Aims to determine the linear order of a set of genetic markers along a chromosome. Genetic maps differ significantly from physical maps, in that recombination frequencies are not identical across different genomic regions, resulting occasionally in large discrepancies.

298


Genetic marker

A gene that has an easily identifiable phenotype so that one can distinguish between those cells or individuals that do or do not have the gene. Such a gene can also be used as a probe to mark cell nuclei or chromosomes, so that they can be isolated easily or identified from other nuclei or chromosomes later.

Genetic screening

Population analysis designed to ascertain individuals at risk of either suffering or transmitting a genetic disease.

Genetically lethal

Prevents reproduction of the individual, either because the condition causes death prior to reproductive age, or because social factors make it highly unlikely (although not impossible) that the individual concerned will reproduce.

Genome

The complete DNA sequence of an individual, including the sex chromosomes and mitochondrial DNA. The genome of humans is estimated to have a complexity of 3.3 x 109 base pairs (per haploid genome).

Genomic

Pertaining to the genome. Genomic DNA differs from complementary DNA in that it contains non-coding as well as coding DNA.

Genotype

Genetic constitution of an individual, distinct from expressed features (phenotype).

Germ line

Germ cells (those cells that produce haploid gametes) and the cells from which they arise. The germ line is formed very early in embryonic development. Germ line mutations are those present constitutionally in an individual (i.e. in all cells of the body) as opposed to somatic mutations, which affect only a proportion of cells.

Giemsa banding

Light/dark bar code obtained by staining chromosomes with Giemsa stain. Results in a unique bar code for each chromosome.

Guanine (G)

One of the bases making up DNA and RNA (pairs with cytosine).

Glossary

299

H Haploid

The chromosome number of a normal gamete, containing one each of every individual chromosome (23 in humans).

Haploinsufficiency

The presence of one active copy of a gene/region is insufficient to compensate for the absence of the other copy. Most genes are not ‘haploinsufficient’—50% reduction of gene activity does not lead to an abnormal phenotype. However, for some genes, most often those involved in early development, reduction to 50% often correlates with an abnormal phenotype. Haploinsufficiency is an important component of most contiguous gene disorders (e.g. in Williams syndrome, heterozygous deletion of a number of genes results in the mutant phenotype, despite the presence of normal copies of all affected genes).

Hemizygous

Having only one copy of a gene or DNA sequence in diploid cells. Males are hemizygous for most genes on the sex chromosomes, as they possess only one X chromosome and one Y chromosome (the exceptions being those genes with counterparts on both sex chromosomes). Deletions on autosomes produce hemizygosity in both males and females.

Heterochromatin

Contains few active genes, but is rich in highly repeated simple sequence DNA, sometimes known as satellite DNA. Heterochromatin refers to inactive regions of the genome, as opposed to euchromatin, which refers to active, gene expressing regions. Heterochromatin stains darkly with Giemsa.

Heterozygous

Presence of two different alleles at a given locus.

Histones

Simple proteins bound to DNA in chromosomes. They help to maintain chromatin structure and play an important role in regulating gene expression.

300


Holandric

Pattern of inheritance displayed by mutations in genes located only on the Y chromosome. Such mutations are transmitted only from father to son.

Homologue or homologous gene

Two or more genes whose sequences manifest significant similarity because of a close evolutionary relationship. May be between species (orthologues) or within a species (paralogues).

Homologous chromosomes

Chromosomes that pair during meiosis. These chromosomes contain the same linear gene sequences as one another and derive from one parent.

Homology

Similarity in DNA or protein sequences between individuals of the same species or among different species.

Homozygous

Presence of identical alleles at a given locus.

Human gene therapy

The study of approaches to treatment of human genetic disease, using the methods of modern molecular genetics. Many trials are underway studying a variety of disorders including cystic fibrosis. Some disorders are likely to be more treatable than others—it is probably going to be easier to replace defective or absent gene sequences rather than deal with genes whose aberrant expression results in an actively toxic effect.

Human genome project

Worldwide collaboration aimed at obtaining a complete sequence of the human genome. Most sequencing has been carried out in the USA, although the Sanger Centre in Cambridge, UK has sequenced one third of the genome, and centers in Japan and Europe have also contributed significantly. The first draft of the human genome was released in the summer of 2000 to much acclaim. The finished sequence may not be available until 2003. Celera, a privately funded venture, headed by Dr Craig Ventner, also published its first draft at the same time.

Glossary

301

Hybridization

Pairing of complementary strands of nucleic acid. Also known as re-annealing. May refer to re-annealing of DNA in solution, on a membrane (Southern blotting) or on a DNA microarray. May also be used to refer to fusion of two somatic cells, resulting in a hybrid that contains genetic information from both donors.

I Imprinting

A general term used to describe the phenomenon whereby a DNA sequence (coding or otherwise) carries a signal or imprint that indicates its parent of origin. For most DNA sequences, no distinction can be made between those arising paternally and those arising maternally (apart from subtle sequence variations); for imprinted sequences this is not the case. The mechanistic basis of imprinting is almost always methylation—for certain genes, the copy that has been inherited from the father is methylated, while the maternal copy is not. The situation may be reversed for other imprinted genes. Note that imprinting of a gene refers to the general phenomenon, not which parental copy is methylated (and, therefore, usually inactive). Thus, formally speaking, it is incorrect to say that a gene undergoes paternal imprinting. It is correct to say that the gene undergoes imprinting and that the inactive (methylated) copy is always the paternal one. However, in common genetics parlance, paternal imprinting is usually understood to mean the same thing.

In situ hybridization

Annealing of DNA sequences to immobilized chromosomes/cells/ tissues. Historically done using radioactively labeled probes, this is currently most often performed with fluorescently tagged molecules (fluorescent in situ hybridization – FISH, see Figure 9). ISH/FISH allows for the rapid detection of a DNA sequence within the genome.

Incomplete penetrance

Complete absence of expression of the abnormal phenotype in a proportion of individuals known to be obligate carriers. To be distinguished from variable expressivity, in which the phenotype always manifests in obligate carriers but with widely varying degrees of severity.

302


Figure 9. Fluorescence in situ hybridization. FISH analysis of a patient with a complex syndrome, using a clone containing DNA from the region 8q24.3. In addition to that clone, a control from 8pter was used. The 8pter clone has yielded a signal on both homologues of chromosome 8, while the ‘test’ clone from 8q24.3 has yielded a signal on only one homologue, demonstrating a (heterozygous) deletion in that region.

Index case – proband

The individual through which a family medically comes to light. For example, the index case may be a baby with Down syndrome. Can be termed propositus (if male) or proposita (if female).

Insertion

Interruption of a chromosomal sequence as a result of insertion of material from elsewhere in the genome (either a different chromosome, or elsewhere from the same chromosome). Such insertions may result in abnormal phenotypes either because of direct interruption of a gene (uncommon), or because of the resulting imbalance (i.e. increased dosage) when the chromosomes that contain the normal counterparts of the inserted sequence are also present.

Intron

A non-coding DNA sequence that ‘interrupts’ the protein-coding sequences of a gene; intron sequences are transcribed into messenger RNA (mRNA) but are cut out before the mRNA is translated into a protein (this process is known as splicing). Introns may contain sequences involved in regulating expression of a gene. Unlike the

Glossary

303

exon, the intron is the nucleotide sequence in a gene that is not represented in the amino acid sequence of the final gene product. Inversion

A structural abnormality of a chromosome in which a segment is reversed, as compared to the normal orientation of the segment. An inversion may result in the reversal of a segment that lies entirely on one chromosome arm (paracentric) or one that spans (i.e. contains) the centromere (pericentric). While individuals who possess an inversion are likely to be genetically balanced (and therefore usually phenotypically normal), they are at increased risk of producing unbalanced offspring because of problems at meiosis with pairing of the inversion chromosome with its normal homologue. Both deletions and duplications may result, with concomitant congenital abnormalities related to genomic imbalance, or miscarriage if the imbalance is lethal.

K Karyotype

A photomicrograph of an individual’s chromosomes arranged in a standard format showing the number, size, and shape of each chromosome type, and any abnormalities of chromosome number or morphology (see Figure 10).

Kilobase (kb)

1000 base pairs of DNA.

Knudson hypothesis

See tumor suppressor gene

L Linkage

304

Co-inheritance of DNA sequences/phenotypes as a result of physical proximity on a chromosome. Before the advent of molecular genetics, linkage was often studied with regard to proteins, enzymes or cellular characteristics. An early study demonstrated linkage between the Duffy blood group and a form of autosomal dominant congenital cataract (both are now known to reside at 1q21.1). Phenotypes may Genetics for Ophthalmologists

Figure 10. Schematic of a normal human (male) karyotype. (ISCN 550 ideogram produced by the MRC Human Genetics Unit, Edinburgh, reproduced with permission.)

also be linked in this manner (i.e. families manifesting two distinct Mendelian disorders). During the recombination phase of meiosis, genetic material is exchanged (equally) between two homologous chromosomes. Genes/ DNA sequences that are located physically close to each other are unlikely to be separated during recombination. Sequences that lie far apart on the same chromosome are more likely to be separated. For sequences that reside on different chromosomes, segregation will always be random, so that there will be a 50% chance of 2 markers being co-inherited. Linkage analysis

Glossary

An algorithm designed to map (i.e. physically locate) an unknown gene (associated with the phenotype of interest) to a chromosomal 305

region. Linkage analysis has been the mainstay of diseaseassociated gene identification for some years. The general availability of large numbers of DNA markers that are variable in the population (polymorphisms), and which therefore permit allele discrimination, has made linkage analysis a relatively rapid and dependable approach (see Figure 11). However, the method relies on the ascertainment of large families manifesting Mendelian disorders. Relatively little phenotypic heterogeneity is tolerated, as a single misassigned individual (believed to be unaffected despite being a gene carrier) in a pedigree may completely invalidate the results. Genetic heterogeneity is another problem, not within families (usually) but between families. Thus, conditions that result in identical phenotypes despite being associated with mutations within different genes (e.g. tuberous sclerosis) are often hard to study. Linkage analysis typically follows a standard algorithm: 1. Large families with a given disorder are ascertained. Detailed clinical evaluation results in assignment of affected vs. unaffected individuals. 2. Large numbers of polymorphic DNA markers that span the genome are analyzed in all individuals (affected and unaffected). 3. The results are analyzed statistically, in the hope that one of the markers used will have demonstrably been co-inherited with the phenotype in question more often than would be predicted by chance. The LOD score (logarithm of the odds) gives an indication of the likelihood of the result being significant (and not having occurred simply as a result of chance co-inheritance of the given marker with the condition). Linkage disequilibrium

306

Association of particular DNA sequences with each other, more often than is likely by chance alone (see Figure 12). Of particular relevance to inbred populations (e.g. Finland), where specific disease mutations are found to reside in close proximity to specific variants of DNA markers, as a result of the founder effect. Genetics for Ophthalmologists

5kb 2kb

2kb

5kb 2kb

5kb 2kb

5kb 2kb

2kb

5kb 2kb

2kb

2kb

2kb

In the example above, note that the (affected) mother has a 5 kb band in addition to a 2 kb band. All the unaffected individuals have the small band only, all those who are affected have the large band. The unaffected individuals must have the mother’s 2 kb fragment rather than her 5 kb fragment, and the affected individuals must have inherited the 5 kb band from the mother (as the father does not have one)—note that those individuals who only show the 2 kb band still have two alleles (one from each parent), they are just the same size and so cannot be differentiated. Thus, it appears that the 5 kb band is segregating with the disorder. The results in a family such as this are suggestive but further similar results in other families would be required for a sufficiently high LOD score.

X

2kb

X

3kb

X

Probe

The probe recognizes a DNA sequence adjacent to a restriction site (see arrow) that is polymorphic (present on some chromosomes but not others). When such a site is present, the DNA is cleaved at that point and the probe detects a 2 kb fragment. When absent, the DNA is not cleaved and the probe detects a fragment of size (2 + 3) kb = 5 kb. X refers to the points at which the restriction enzyme will cleave the DNA. The recognition sequence for most restriction enzymes is very stringent—change in just one nucleotide will result in failure of cleavage. Most RFLPs result from the presence of a single nucleotide polymorphism that has altered the restriction site. Figure 11. Schematic demonstrating the use of restriction fragment length polymorphisms (RFLPs) in linkage analysis.

Linkage map

A map of genetic markers as determined by genetic analysis (i.e. recombination analysis). May differ markedly from a map determined by actual physical relationships of genetic markers, because of the variability of recombination.

Locus

The position of a gene/DNA sequence on the genetic map. Allelic genes/sequences are situated at identical loci in homologous chromosomes.

Glossary

307

Marker A

Marker B

–

+

–

–

+

+

+

–

Mutant allele

Many generations

+

–

–

–

Mutant allele

Mutant allele

A gene is physically very close to marker B and further from marker A. Markers A and B, both on the same chromosome, can exist in one of two forms : +/-. Thus there are 4 possible haplotypes, as shown. If the founder mutation in the gene occurred as shown, then it is likely that even after many generations the mutant allele will segregate with the – form of marker B, as recombination is unlikely to have occurred between the two. However, since marker A is further away, the gene will now often segregate with the – form of marker A, which was not present on the original chromosome. The likelihood of recombination between the gene and marker A will depend on the physical distance between them, and on rates of recombination. It is possible that the gene would show a lesser but still significant degree of linkage disequilibrium with marker A. Figure 12. Schematic demonstrating the concept of linkage disequilibrium.

Locus heterogeneity

Mutations at different loci cause similar phenotypes.

LOD (Logarithm of the Odds) score

A statistical test of linkage. Used to determine whether a result is likely to have occurred by chance or to truly reflect linkage. The LOD score is the logarithm (base 10) of the likelihood that the linkage is meaningful. A LOD score of 3 implies that there is only a 1:1000 chance that the results have occurred by chance (i.e. the result would be likely to occur once by chance in 1000 simultaneous

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studies addressing the same question). This is taken as proof of linkage (see Figure 11). Lyonisation

The inactivation of n-1 X chromosomes on a random basis in an individual with n X chromosomes. Named after Mary Lyon, this mechanism ensures dosage compensation of genes encoded by the X chromosome. X chromosome inactivation does not occur in normal males who possess only one X chromosome but does occur in one of the two X chromosomes of normal females. In males who possess more than one X chromosome (i.e. XXY, XXXY, etc.), the rule is the same and only one X chromosome remains active. X-inactivation occurs in early embryonic development and is random in each cell. The inactivation pattern in each cell is faithfully maintained in all daughter cells. Therefore, females are genetic mosaics, in that they possess two populations of cells with respect to the X chromosome: one population has one X active, while in the other population the other X is active. This is relevant to the expression of X-linked disease in females.

M Meiosis

The process of cell division by which male and female gametes (germ cells) are produced. Meiosis has two main roles. The first is recombination (during meiosis I). The second is reduction division. Human beings have 46 chromosomes, and each is conceived as a result of the union of two germ cells; therefore, it is reasonable to suppose that each germ cell will contain only 23 chromosomes (i.e. the haploid number). If not, then the first generation would have 92 chromosomes, the second 184, etc. Thus, at meiosis I, the number of chromosomes is reduced from 46 to 23.

Mendelian inheritance

Refers to a particular pattern of inheritance, obeying simple rules: each somatic cell contains 2 genes for every characteristic and each pair of genes divides independently of all other pairs at meiosis.

Glossary

309

Mendelian Inheritance in Man (MIM/OMIM)

A catalogue of human Mendelian disorders, initiated in book form by Dr Victor McKusick of Johns Hopkins Hospital in Baltimore, USA. The original catalogue (produced in the mid-1960s) listed approximately 1500 conditions. By December 1998, this number had risen to 10,000, at the time of writing (November 2001) the figure had reached 13,118. With the advent of the Internet, MIM is now available as an online resource, free of charge (OMIM – Online Mendelian Inheritance in Man). The URL for this site is: http://www.ncbi.nlm.nih.gov/omim/. The online version is updated regularly, far faster than is possible for the print version, therefore, new gene discoveries are quickly assimilated into the database. OMIM lists disorders according to their mode of inheritance: 1 - - - - (100000- ) Autosomal dominant (entries created before May 15, 1994) 2 - - - - (200000- ) Autosomal recessive (entries created before May 15, 1994) 3 - - - - (300000- ) X-linked loci or phenotypes 4 - - - - (400000- ) Y-linked loci or phenotypes 5 - - - - (500000- ) Mitochondrial loci or phenotypes 6 - - - - (600000- ) Autosomal loci/phenotypes (entries created after May 15, 1994). Full explanations of the best way to search the catalogue are available at the home page for OMIM.

Messenger RNA (mRNA)

The template for protein synthesis, carries genetic information from the nucleus to the ribosomes where the code is translated into protein. Genetic information flows: DNA → RNA → protein.

Methylation

See DNA methylation

Microdeletion

Structural chromosome abnormality involving the loss of a segment that is not detectable using conventional (even high resolution)

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cytogenetic analysis. Microdeletions usually involve 1–3 Mb of sequence (the resolution of cytogenetic analysis rarely is better than 10 Mb). Most microdeletions are heterozygous, although some individuals/families have been described with homozygous microdeletions. See also contiguous gene syndrome. Microduplication

Structural chromosome abnormality involving the gain of a segment that may involve long sequences (commonly 1–3 Mb), which are, nevertheless, undetectable using conventional cytogenetic analysis. Patients with microduplications have 3 copies of all sequences within the duplicated segment, as compared to 2 copies in normal individuals. See also contiguous gene syndrome.

Microsatellites

DNA sequences composed of short tandem repeats (STRs), such as di- and trinucleotide repeats, distributed widely throughout the genome with varying numbers of copies of the repeating units. Microsatellites are very valuable as genetic markers for mapping human genes.

Missense mutation

Single base substitution resulting in a codon that specifies a different amino acid than the wild-type.

Mitochondrial disease/disorder

Ambiguous term referring to disorders resulting from abnormalities of mitochondrial function. Two separate possibilities should be considered. 1. Mutations in the mitochondrial genome (see Figure 13). Such disorders will manifest an inheritance pattern that mirrors the manner in which mitochondria are inherited. Therefore, a mother will transmit a mitochondrial mutation to all her offspring (all of whom will be affected, albeit to a variable degree). A father will not transmit the disorder to any of his offspring. 2. Mutations in nuclear encoded genes that adversely affect mitochondrial function. The mitochondrial genome does not code for all the genes required for its maintenance, many are encoded in the

Glossary

311

Figure 13. Mitochondrial inheritance. This pedigree relates to mutations in the mitochondrial genome.

nuclear genome. However, the inheritance patterns will differ markedly from the category described in the first option, and will be indistinguishable from standard Mendelian disorders. Each mitochondrion possesses between 2–10 copies of its genome, and there are approximately 100 mitochondria in each cell. Therefore, each cell possesses 200–1000 copies of the mitochondrial genome. Heteroplasmy refers to the variability in sequence of this large number of genomes—even individuals with mitochondrial genome mutations are likely to have wild-type alleles. Variability in the proportion of molecules that are wild-type may have some bearing on the clinical variability often seen in such disorders. Mitochondrial DNA

The DNA in the circular chromosome of mitochondria. Mitochondrial DNA is present in multiple copies per cell and mutates more rapidly than genomic (nuclear) DNA.

Mitosis

Cell division occurring in somatic cells, resulting in two daughter cells that are genetically identical to the parent cell.

Monogenic trait

Causally associated with a single gene (see Mendelian trait).

Monosomy

Absence of one of a pair of chromosomes.

Monozygotic

Arising from a single zygote or fertilized egg. Monozygotic twins are genetically identical.

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Mosaicism or mosaic

Refers to the presence of two or more distinct cell lines, all derived from the same zygote. Such cell lines differ from each other as a result of DNA content/sequence. Mosaicism arises when the genetic alteration occurs post-fertilization (post-zygotic). The important features that need to be considered in mosaicism are: The proportion of cells that are ‘abnormal’. In general, the greater the proportion of cells that are abnormal, the greater the severity of the associated phenotype. The specific tissues that contain high levels of the abnormal cell line(s). This variable will clearly also be relevant to the manifestation of any phenotype. An individual may have a mutation bearing cell line in a tissue where the mutation is largely irrelevant to the normal functioning of that tissue, with a concomitant reduction in phenotypic sequelae. Mosaicism may be functional, as in normal females who are mosaic for activity of the two X chromosomes (see Lyonisation). Mosaicism may occasionally be observed directly. X-linked skin disorders, such as incontinentia pigmenti, often manifest mosaic changes in the skin of a female, such that abnormal skin is observed alternately with normal skin, often in streaks (Blaschko’s lines), which delineate developmental histories of cells.

Multifactorial inheritance

A type of hereditary pattern resulting from a complex interplay of genetic and environmental factors.

Mutation

Any heritable change in DNA sequence.

N Non-disjunction

Glossary

Failure of two homologous chromosomes to pull apart during meiosis I, or two chromatids of a chromosome to separate in meiosis II or mitosis. The result is that both are transmitted to one daughter cell, while the other daughter cell receives neither.

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Non-dynamic (stable) mutations

Stably inherited mutations, in contradistinction to dynamic mutations, which display variability from generation to generation. Includes all types of stable mutation (single base substitution, small deletions/ insertions, microduplications and microdeletions).

Non-penetrance

Failure of expression of a phenotype in the presence of the relevant genotype.

Nonsense mutation

A single base substitution resulting in the creation of a stop codon (see Figure 14).

Northern blot

Hybridization of a radio-labeled RNA/DNA probe to an immobilized RNA sequence. So called in order to differentiate it from Southern blotting which was described first. Neither has any relationship to points on the compass. Southern blotting was named after its inventor Ed Southern (currently Professor of Biochemistry at Oxford University, UK).

Nucleotide

A basic unit of DNA or RNA consisting of a nitrogenous base— adenine, guanine, thymine or cytosine in DNA, and adenine, guanine, uracil or cytosine in RNA. A nucleotide is composed of a phosphate molecule, and a sugar molecule—deoxyribose in DNA and ribose in RNA. Many thousands or millions of nucleotides link to form a DNA or RNA molecule.

O Obligate carrier

See obligate heterozygote

Obligate heterozygote (obligate carrier)

An individual who, on the basis of pedigree analysis, must carry the mutant allele.

Oncogene

A gene that, when over expressed, causes neoplasia. In contrast to tumor suppressor genes, which result in tumorigenesis when their activity is reduced.

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G G

A C T

G T C

C T C

T G A

G

Collagen IIa1 sequence

Mutant (protein)

ACT Thr

GTC Val

CTC Leu

TGA STOP

Normal (protein)

ACT Thr

GTC Val

CTC Leu

TGC Cys

Figure 14. Nonsense mutation. This example shows a sequence graph of collagen II (alpha 1) in a patient with Stickler syndrome, an autosomal dominant condition. The sequence is of genomic DNA and shows both normal and abnormal sequences (the patient is heterozygous for the mutation). The base marked with an arrow has been changed from C to A. When translated the codon is changed from TGC (cysteine) to TGA (stop). The premature stop codon in the collagen gene results in Stickler syndrome.

P p

Short arm of a chromosome (from the French petit) (see Figure 4).

Palindromic sequence

A DNA sequence that contains the same 5’ to 3’ sequence on both strands. Most restriction enzymes recognize palindromic sequences. An example is 5’ – AGATCT – 3’, which would read 3’ – TCTAGA – 5’ on the complementary strand. This is the recognition site of BglII.

Pedigree

A schematic for a family indicating relationships to the proband and how a particular disease or trait has been inherited (see Figure 15).

Penetrance

An all-or-none phenomenon related to the proportion of individuals with the relevant genotype for a disease who actually manifest

Glossary

315

4

Male, female - unaffected

Abortion/stillbirth

Sex not known

Twins

Male, female - affected

Monozygotic twins

4 unaffected females

Heterozygote (AR)

Deceased, affected female

Heterozygote (X-linked)

Consanguineous marriage

Propositus/proband

Figure 15. Symbols commonly used in pedigree drawing.

the phenotype. Note the difference between penetrance and variable expressivity. Phenotype

Observed disease/abnormality/trait. An all-embracing term that does not necessarily imply pathology. A particular phenotype may be the result of genotype, the environment or both.

Physical map

A map of the locations of identifiable landmarks on DNA, such as specific DNA sequences or genes, where distance is measured in base pairs. For any genome, the highest resolution map is the complete nucleotide sequence of the chromosomes. A physical map should be distinguished from a genetic map, which depends on recombination frequencies.

Plasmid

Found largely in bacterial and protozoan cells, plasmids are autonomously replicating, extrachromosomal, circular DNA molecules that are distinct from the normal bacterial genome and are often used as vectors in recombinant DNA technologies. They

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are not essential for cell survival under non-selective conditions, but can be incorporated into the genome and are transferred between cells if they encode a protein that would enhance survival under selective conditions (e.g. an enzyme that breaks down a specific antibiotic). Pleiotropy

Diverse effects of a single gene on many organ systems (e.g. the mutation in Marfan’s syndrome results in lens dislocation, aortic root dilatation and other pathologies).

Ploidy

The number of sets of chromosomes in a cell. Human cells may be haploid (23 chromosomes, as in mature sperm or ova), diploid (46 chromosomes, seen in normal somatic cells) or triploid (69 chromosomes, seen in abnormal somatic cells, which results in severe congenital abnormalities).

Point mutation

Single base substitution.

Polygenic disease

Disease (or trait) that results from the simultaneous interaction of multiple gene mutations, each of which contributes to the eventual phenotype. Generally, each mutation in isolation is likely to have a relatively minor effect on the phenotype. Such disorders are not inherited in a Mendelian fashion. Examples include hypertension, obesity and diabetes.

Polymerase chain reaction (PCR)

A molecular technique for amplifying DNA sequences in vitro (see Figure 16). The DNA to be copied is denatured to its single strand form and two synthetic oligonucleotide primers are annealed to complementary regions of the target DNA in the presence of excess deoxynucleotides and a heat-stable DNA polymerase. The power of PCR lies in the exponential nature of amplification, which results from repeated cycling of the ‘copying’ process. Thus, a single molecule will be copied in the first cycle, resulting in 2 molecules. In the second cycle, each of these will also be copied, resulting in 4 copies. In theory, after n cycles, there will be 2n molecules for

Glossary

317

3'

5'

5'

3' 95°C

DENATURATION

3'

5' P1

P2

1st Cycle

5'

3'

3'

5'

5'

3'

3'

5'

5'

3'

2nd Cycle

P2

P1

Genomic doublestranded DNA Temperature is lowered to ~50°C to permit annealing of primers to their complementary DNA sequence Temperature is elevated to the optimal heat (~72°C) for the thermophilic polymerase, resulting in primer extension

Denaturation and annealing of primers

3'

Figure 16. Schematic illustrating the technique of polymerase chain reaction (PCR).

each starting molecule. In practice, this theoretical limit is rarely reached, mainly for technical reasons. PCR has become a standard technique in molecular biology research as well as routine diagnostics. Polymorphism

May be applied to phenotype or genotype. The presence in a population of two or more distinct variants, such that the frequency of the rarest is at least 1% (more than can be explained by recurrent mutation alone). A genetic locus is polymorphic if its sequence exists in at least two forms in the population.

Premutation

Any DNA mutation that has little, if any, phenotypic consequence but predisposes future generations to the development of full mutations with phenotypic sequelae. Particularly relevant in the analysis of diseases associated with dynamic mutations.

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Proband (propositus) – index case

The first individual to present with a disorder through which a pedigree can be ascertained.

Probe

General term for a molecule used to make a measurement. In molecular genetics, a probe is a piece of DNA or RNA that is labeled and used to detect its complementary sequence (e.g. Southern blotting).

Promoter region

The non-coding sequence upstream (5’) of a gene where RNA polymerase binds. Gene expression is controlled by the promoter region both in terms of level and tissue specificity.

Protease

An enzyme that digests other proteins by cleaving them into small fragments; proteases may have broad specificity or only cleave a particular site on a protein or set of proteins.

Protease inhibitor

A chemical that can inhibit the activity of a protease. Most proteases have a corresponding specific protease inhibitor.

Proto-oncogene

A misleading term that refers to genes that are usually involved in signaling and cell development, and are often expressed in actively dividing cells. Certain mutations in such genes may result in malignant transformation, with the mutated genes being described as oncogenes. The term proto-oncogene is misleading because it implies that such genes were selected for by evolution in order that, upon mutation, cancers would result because of oncogenic activation. A similar problem arises with the term tumor suppressor gene.

Pseudogene

Near copies of true genes. Pseudogenes share sequence homology with true genes but are inactive as a result of multiple mutations over a long period of time.

Purine

A nitrogen-containing, double-ring, basic compound occurring in nucleic acids. The purines in DNA and RNA are adenine and guanine.

Glossary

319

Pyrimidine

A nitrogen-containing, single-ring, basic compound that occurs in nucleic acids. The pyrimidines in DNA are cytosine and thymine, and cytosine and uracil in RNA.

Q q

Long arm of a chromosome (see Figure 4).

R Re-annealing

see hybridization

Recessive (traits, diseases)

Manifest only in homozygotes. For the X chromosome, recessivity applies to males who carry only one (mutant) allele. Females who carry X-linked mutations are generally heterozygotes and, barring unfortunate X-inactivation, do not manifest X-linked recessive phenotypes.

Reciprocal translocation The exchange of material between two non-homologous chromosomes. Recombination

The creation of new combinations of linked genes as a result of crossing over at meiosis (see Figure 6).

Recurrence risk

The chance that a genetic disease, already present in a member of a family, will recur in that family and affect another individual.

Restriction enzyme

Endonuclease that cleaves double-stranded (ds) DNA at specific sequences. For example, the enzyme BglII recognizes the sequence AGATCT, and cleaves after the first A on both strands. Most restriction endonucleases recognize sequences that are palindromic— the complementary sequence to AGATCT, read in the same orientation, is also AGATCT. The term ‘restriction’ refers to the function of these enzymes in nature. The organism that synthesizes a given restriction

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enzyme (e.g. BglII) does so in order to ‘kill’ foreign DNA— ‘restricting’ the potential of foreign DNA that has become integrated to adversely affect the cell. The organism protects its own DNA from the restriction enzyme by simultaneously synthesizing a specific methylase that recognizes the same sequence and modifies one of the bases, such that the restriction enzyme is no longer able to cleave. Thus, for every restriction enzyme, it is likely that a corresponding methylase exists, although in practice only a relatively small number of these have been isolated. Restriction fragment length polymorphism (RFLP)

A restriction fragment is the length of DNA generated when DNA is cleaved by a restriction enzyme. Restriction fragment length varies when a mutation occurs within a restriction enzyme sequence. Most commonly the polymorphism is a single base substitution but it may also be a variation in length of a DNA sequence due to variable number tandem repeats (VNTRs). The analysis of the fragment lengths after DNA is cut by restriction enzymes is a valuable tool for establishing familial relationships and is often used in forensic analysis of blood, hair or semen (see Figure 11).

Restriction map

A DNA sequence map, indicating the position of restriction sites.

Reverse genetics

Identification of the causative gene for a disorder, based purely on molecular genetic techniques, when no knowledge of the function of the gene exists (the case for most genetic disorders).

Reverse transcriptase

Catalyses the synthesis of DNA from a single-stranded RNA template. Contradicted the central dogma of genetics (DNA → RNA → protein) and earned its discoverers the Nobel Prize in 1975.

RNA (ribonucleic acid)

Glossary

RNA molecules differ from DNA molecules in that they contain a ribose sugar instead of deoxyribose. There are a variety of types of RNA (including messenger RNA, transfer RNA and ribosomal RNA) and they work together to transfer information from DNA to the protein-forming units of the cell.

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Robertsonian translocation

A translocation between two acrocentric chromosomes, resulting from centric fusion. The short arms and satellites (chromosome segments separated from the main body of the chromosome by a constriction and containing highly repetitive DNA) are lost.

S Second hit hypothesis

See tumor suppressor gene

Sex chromosomes

Refers to the X and Y chromosomes. All normal individuals possess 46 chromosomes, of which 44 are autosomes and 2 are sex chromosomes. An individual’s sex is determined by his/her complement of sex chromosomes. Essentially, the presence of a Y chromosome results in the male phenotype. Males have an X and a Y chromosome, while females possess two X chromosomes. The Y chromosome is small and contains relatively few genes, concerned almost exclusively with sex determination and/or sperm formation. By contrast, the X chromosome is a large chromosome that possesses many hundreds of genes.

Sex-limited trait

A trait/disorder that is almost exclusively limited to one sex and often results from mutations in autosomal genes. A good example of a sexlimited trait is breast cancer. While males are affected by breast cancer, it is much less common (~1%) than in women. Females are more prone to breast cancer than males not only because they possess significantly more breast tissue but also because their hormonal milieu is significantly different. In many cases, early onset bilateral breast cancer is associated with mutations either in BRCA1 or BRCA2, both autosomal genes. An example of a sex-limited trait in males is male pattern baldness, which is extremely rare in pre-menopausal women. The inheritance of male pattern baldness is consistent with autosomal dominant, not sex-linked dominant, inheritance.

Sex-linked dominant

See X-linked dominant

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Sex-linked recessive

See X-linked recessive

Sibship

All the sibs in a family.

Silent mutation

One that has no (apparent) phenotypic effect.

Single gene disorder

A disorder resulting from a mutation on one gene.

Somatic cell

Any cell of a multicellular organism not involved in the production of gametes.

Southern blot

Hybridization with a radio-labeled RNA/DNA probe to an immobilized DNA sequence (see Figure 17). Named after Ed Southern (currently Professor of Biochemistry at Oxford University, UK), the technique has spawned the nomenclature for other types of blot (Northern blots for RNA and Western blots for proteins).

Figure 17. Southern blotting.

Glossary

323

Splicing

Removal of introns from precursor RNA to produce messenger RNA. The process involves recognition of intron-exon junctions and specific removal of intronic sequences, coupled with re-connection of the two strands of DNA that formerly flanked the intron.

Start codon

The AUG codon of messenger RNA recognized by the ribosome to begin protein production.

Stop codon

The codons UAA, UGA, or UAG on messenger RNA (mRNA) (see Table 2). Since no transfer RNA molecules exist that possess anticodons to these sequences, they cannot be translated. When they occur in frame on an mRNA molecule, protein synthesis stops and the ribosome releases the mRNA and the protein.

T Telomere

End of a chromosome. The telomere is a specialized structure involved in replicating and stabilizing linear DNA molecules.

Teratogen

Any external agent/factor that increases the probability of congenital malformations. A teratogen may be a drug, whether prescribed or illicit, or an environmental effect, such as high temperature. The classical example is thalidomide, a drug originally prescribed for morning sickness, which resulted in very high rates of congenital malformation in exposed fetuses (especially limb defects).

Termination codon

See stop codon

Thymine (T)

One of the bases making up DNA and RNA (pairs with adenine).

Transcription

Synthesis of single-stranded RNA from a double-stranded DNA template (see Figure 18).

Transfer RNA (tRNA)

An RNA molecule that possesses an anticodon sequence (complementary to the codon in mRNA) and the amino acid which

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RNA polymerase

CTC

Sense strand

DNA 3' CUC GAG

Antisense strand

5' RNA

Figure 18. Schematic demonstrating the process of transcription. The sense strand has the sequence CTC (coding for leucine). RNA is generated by pairing with the antisense strand, which has the sequence GAG (the complement of CTC). The RNA produced is the complement of GAG, CUC (essentially the same as CTC, uracil replaces thymine in RNA).

that codon specifies. When the ribosome ‘reads’ the mRNA codon, the tRNA with the corresponding anticodon and amino acid is recruited for protein synthesis. The tRNA ‘gives up’ its amino acid to the production of the protein. Translation

Glossary

Protein synthesis directed by a specific messenger RNA (mRNA), (see Figure 19). The information in mature mRNA is converted at the ribosome into the linear arrangement of amino acids that constitutes a protein. The mRNA consists of a series of trinucleotide sequences, known as codons. The start codon is AUG, which specifies that methionine should be inserted. For each codon, except for the stop codons that specify the end of translation, a transfer RNA (tRNA) molecule exists that possesses an anticodon sequence (complementary to the codon in mRNA) and the amino acid which that codon specifies. The process of translation results in the sequential addition of amino acids to the growing polypeptide chain. When translation is complete, the protein is released from the ribosome/mRNA complex and may then undergo post-translational modification, in addition to folding into its final, active, conformational shape. 325

Growing polypeptide chain

LEU tRNA with anticodon GAG, charged with Leucine

Amino (NH2) terminus of protein

GAG CUCGUC 5'

3' mRNA

Ribosome

Ribosome moves to next codon

Figure 19. Schematic of the process of translation. Messenger RNA (mRNA) is translated at the ribosome into a growing polypeptide chain. For each codon, there is a transfer RNA molecule with the anticodon and the appropriate amino acid. Here, the amino acid leucine is shown being added to the polypeptide. The next codon is GUC, specifying valine. Translation happens in a 5’ to 3’ direction along the mRNA molecule. When the stop codon is reached, the polypeptide chain is released from the ribosome.

Translocation

Exchange of chromosomal material between 2 or more nonhomologous chromosomes. Translocations may be balanced or unbalanced. Unbalanced translocations are those that are observed in association with either a loss of genetic material, a gain, or both. As with other causes of genomic imbalance, there are usually phenotypic consequences, in particular mental retardation. Balanced translocations are usually associated with a normal phenotype but increase the risk of genomic imbalance in offspring, with expected consequences (either severe phenotypes or lethality). Translocations are described by incorporating information about the chromosomes involved (usually but not always two) and the positions on the chromosomes at which the breaks have occurred. Thus t(11;X)(p13;q27.3) refers to an apparently balanced translocation involving chromosome 11 and X, in which the break on 11 is at 11p13 and the break on the X is at Xq27.3

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Triplet repeats

Tandem repeats in DNA that comprise many copies of a basic trinucleotide sequence. Of particular relevance to disorders associated with dynamic mutations, such as Huntington’s chorea (HC). HC is associated with a pathological expansion of a CAG repeat within the coding region of the huntingtin gene. This repeat codes for a tract of polyglutamines in the resultant protein, and it is believed that the increase in length of the polyglutamine tract in affected individuals is toxic to cells, resulting in specific neuronal damage.

Trisomy

Possessing three copies of a particular chromosome instead of two.

Tumor suppressor genes

Genes that act to inhibit/control unrestrained growth as part of normal development. The terminology is misleading, implying that these genes function to inhibit tumor formation. The classical tumor suppressor gene is the Rb gene, which is inactivated in retinoblastoma. Unlike oncogenes, where a mutation at one allele is sufficient for malignant transformation in a cell (since mutations in oncogenes result in increased activity, which is unmitigated by the normal allele), both copies of a tumor suppressor gene must be inactivated in a cell for malignant transformation to proceed. Therefore, at the cellular level, tumor suppressor genes behave recessively. However, at the organismal level they behave as dominants, and an individual who possesses a mutation in only one Rb allele still has an extremely high probability of developing bilateral retinoblastomas. The explanation for this phenomenon was first put forward by Knudson and has come to be known as the Knudson hypothesis (also known as the second hit hypothesis). An individual who has a germ-line mutation in one Rb allele (and the same argument may be applied to any tumor suppressor gene) will have the mutation in every cell in his/her body. It is believed that the rate of spontaneous somatic mutation (defined functionally, in terms of loss of function of that gene by whatever mechanism) is of the order of one in a million per gene per cell division. Given that there are many more than one million retinal cells in each eye, and many cell divisions involved in retinal development, the chance that the second (wild-type) Rb

Glossary

327

allele will suffer a somatic mutation is extremely high. In a cell that has acquired a ‘second hit’, there will now be no functional copies of the Rb gene, as the other allele is already mutated (germ-line mutation). Such a cell will have completely lost its ability to control cell growth and will eventually manifest as a retinoblastoma. The same mechanism occurs in many other tumors, the tissue affected being related to the tissue specificity of expression of the relevant tumor suppressor gene.

U Unequal crossing over

Occurs between similar sequences on chromosomes that are not properly aligned. It is common where specific repeats are found and is the basis of many microdeletion/microduplication syndromes (see Figure 20).

Uniparental disomy (UPD)

In the vast majority of individuals, each chromosome of a pair is derived from a different parent. However, UPD occurs when an offspring receives both copies of a particular chromosome from only one of its parents. UPD of some chromosomes results in recognizable phenotypes whereas for other chromosomes there do not appear to be any phenotypic sequelae. One example of UPD is Prader-Willi syndrome (PWS), which can occur if an individual inherits both copies of chromosome 15 from their mother.

Uniparental heterodisomy

Uniparental disomy in which the two homologues inherited from the same parent are not identical. If the parent has chromosomes A,B the child will also have A,B.

Uniparental isodisomy

Uniparental disomy in which the two homologues inherited from the same parent are identical (i.e. duplicates). So, if the parent has chromosomes A,B then the child will have either A,A or B,B.

Uracil (U)

A nitrogenous base found in RNA but not in DNA, uracil is capable of forming a base pair with adenine.

328


A1

B1

A2

B2

C1

Repeats 1 and 2 represent identical repeated sequences in different positions on the chromosome. These are likely to have no function.

C2 Equal (normal) recombination at meiosis

A1

B1

A2

A1 A2

B1

B2

C2

Product 1 Duplication of region B and all genes within it A2

C2

B2 C1 Meiotic exchange (crossing over)

C1 Unequal (abnormal) recombination at meiosis B2

B1

C1

Product 2 Deletion of region B and all genes within it A1

C2

Figure 20. Schematic demonstrating (i) normal homologous recombination and (ii) homologous unequal recombination, resulting in a deletion and a duplication chromosome.

V Variable expressivity

Variable expression of a phenotype: not all-or-none (as is the case with penetrance). Individuals with identical mutations may manifest variable severity of symptoms, or symptoms that appear in one organ and not in another.

Variable number of Certain DNA sequences possess tandem arrays of repeated tandem repeats (VNTR) sequences. Generally, the longer the array (i.e. the greater the number of copies of a given repeat), the more unstable the sequence, with a consequent wide variability between alleles (both within an individual and between individuals). Because of their variability, VNTRs are extremely useful for genetic studies as they allow for different alleles to be distinguished.

Glossary

329

W Western blot

Like a Southern or Northern blot but for proteins, using a labeled antibody as a probe.

X X-autosome translocation Translocation between the X chromosome and an autosome. X chromosome

See sex chromosomes

X-chromosome inactivation

See Lyonisation

X-linked

Relating to the X chromosome/associated with genes on the X chromosome.

X-linked recessive (XLR) X-linked disorder in which the phenotype is manifest in homozygous/hemizygous individuals (see Figures 21a and 21b). In practice, it is hemizygous males that are affected by X-linked recessive disorders, such as Duchenne’s muscular dystrophy (DMD). Females are rarely affected by XLR disorders, although a number of mechanisms have been described that predispose females to being affected, despite being heterozygous. X-linked dominant (XLD)

X-linked disorder that manifests in the heterozygote. XLD disorders result in manifestation of the phenotype in females and males (see Figure 22). However, because males are hemizygous, they are more severely affected as a rule. In some cases, the XLD disorder results in male lethality.

Y Y chromosome

330

See sex chromosomes


Figure 21a. X-linked recessive inheritance – A. Most X-linked disorders manifest recessively, in that heterozygous females (carriers) are unaffected and males, who are hemizygous (possess only one X chromosome) are affected. In this example, a carrier mother has transmitted the disorder to three of her sons. One of her daughters is also a carrier. On average, 50% of the male offspring of a carrier mother will be affected (having inherited the mutated X chromosome), and 50% will be unaffected. Similarly, 50% of daughters will be carriers and 50% will not be carriers. None of the female offspring will be affected but the carriers will carry the same risks to their offspring as their mother. The classical example of this type of inheritance is Duchenne’s muscular dystrophy.

Figure 21b. X-linked recessive inheritance – B. In this example the father is affected. Because all his sons must have inherited their Y chromosome from him and their X chromosome from their normal mother, none will be affected. Since all his daughters must have inherited his X chromosome, all will be carriers but none affected. For this type of inheritance, it is clearly necessary that males reach reproductive age and are fertile—this is not the case with Duchenne’s muscular dystrophy, which is usually fatal by the teenage years in boys. Emery-Dreifuss muscular dystrophy is a good example of this form of inheritance, as males are likely to live long enough to reproduce.

Figure 22. X-linked dominant inheritance. In X-linked dominant inheritance, the heterozygous female and hemizygous male are affected, however, the males are usually more severely affected than the females. In many cases, X-linked dominant disorders are lethal in males, resulting either in miscarriage or neonatal/infantile death. On average, 50% of all males of an affected mother will inherit the gene and be severely affected; 50% of males will be completely normal. Fifty percent of female offspring will have the same phenotype as their affected mother and the other 50% will be normal and carry no extra risk for their offspring. An example of this type of inheritance is incontinentia pigmenti, a disorder that is almost always lethal in males (males are usually lost during pregnancy).

Glossary

331

Z Zippering

A process by which complementary DNA strands that have annealed over a short length undergo rapid full annealing along their whole length. DNA annealing is believed to occur in 2 main stages. A chance encounter of two strands that are complementary results in a short region of double stranded DNA, which if perfectly matched, stabilizes the two single strands so that further re-annealing of their specific sequences proceeds extremely rapidly. The initial stage is known as nucleation, while the second stage is called zippering.

Zygote

Diploid cell resulting from the union of male and female haploid gametes.

332


12 12. Abbreviations

334

AAAS

achalasia-addisonianism-alacrima syndrome

ABCC6

ATP-binding cassette, subfamily C, member 6

ABCR

ATP-binding cassette transporter, retina-specific

ACHM

achromatopsia

AD

autosomal dominant

adRP

autosomal dominant retinitis pigmentosa

AIPL1

arylhydrocarbon-interacting receptor protein-like 1

ALMS1

Alström syndrome

AP3B1

adaptin beta-3a

APC

adenomatous polyposis of the colon

AQPO

aquaporin O

AR

autosomal recessive

ARCC

autosomal recessive congenital cataracts

ARMD

age-related macular degeneration

arRP

autosomal recessive retinitis pigmentosa

ASMD

anterior segment mesenchymal dysgenesis

ASOD

anterior segment ocular dysgenesis

BBS


BCNS

basal cell nevus syndrome

BIGH3

beta-Ig-H3

BPES

blepharophimosis, ptosis and epicanthus inversus

CAL

café-au-lait

CBS

cystathionine beta synthase

CFEOM

congenital fibrosis of extraocular muscles

CHM

choroideremia

CHRPE

congenital hypertrophic lesions of the retinal pigment epithelium


Abbreviations

CHS1

Chediak-Higashi syndrome

CHST6

carbohydrate sulfotransferase 6

CKN

Cockayne syndrome

CLN3

ceroid lipofuscinosis type 3

CNGA3

cyclic nucleotide-gated cation channel, alpha subunit

CNGB3

cyclic nucleotide-gated cation channel, beta subunit

CNS

central nervous system

COD3

cone dystrophy 3

COH1

Cohen syndrome

COL8A2

collagen type VIII, alpha 2

CPD IV

cerebelloparenchymal disorder IV

CRALBP

cellular retinaldehyde-binding protein

CRD

cone-rod dystrophy

CREBBP

CREB-binding protein

CRYBA1

αB1 crystallin

CRYBB2

βB2 crystalin

CRYG3

γ3 crystallin

CRYGD

γD crystallin

CSNB

congenital stationary night blindness

CTNS

cystinosin

CVS

chorionic villus sampling

CX

connexin

CXR

chest x-ray

CYP1B1

cytochrome P450B1

DHRD

Doyne honeycomb retinal dystrophy

DMPK

dystrophia myotonica protein kinase

DNA

deoxyribonucleic acid

335

336

DOA

dominant optic atrophy

ECG

electrocardiogram

EFEMP1

EGF-containing fibrillin-like extracellular matrix protein 1

EGF

epidermal growth factor

ELOVL4

elongation of very long-chain fatty acids-like gene 4

EOG

electro-oculogram

ERG

electroretinogram

ES

embryonic stem

ESCS

enhanced S-cone syndrome

EVR1

exudative vitreoretinopathy 1

FAP

familial adenomatous polyposis

FBN1

fibrillin 1

FECD

Fuchs’ endothelial corneal dystrophy

FEOM

fibrosis of extraocular muscles

FEVR

familial exudative vitreoretinopathy

FOXC1

forkhead box C1

FOXE3

forkhead box E3

FOXL2

forkhead transcription factor

FTL

ferritin light chain

GALK

galactokinase

GALT

galactosidase galactose-1-phosphate uridyltransferase

GI

gastrointestinal

GLUT-1

glucose transporter-1

GPCR

G protein-coupled receptor

GPDS

glaucoma-related pigment dispersion syndrome

GRT

giant retinal tears

GUCA1A

guanylate cyclase activator 1A


Abbreviations

GUCY2D

guanylate cyclase 2D

HESX1

homeobox gene expressed in ES cells

HEXA

hexosaminidase A

HEXB

hexosaminidase B

HIF-1

hypoxia-inducible factor-1

HPS

Hermansky-Pudlak syndrome

ICE

iridocorneal endothelial

IGDA

iridogoniodysgenesis anomaly

IP2

incontinentia pigmenti type II

IRE

iron responsive element

IRID1

iridogoniodysgenesis type I

IRP

iron responsive protein

JBTS

Joubert syndrome

KRT12

keratin 12

KRT3

keratin 3

kDa

kilo Dalton

KERA

keratocan

KNO

Knobloch syndrome

KSPG

keratan sulfate proteoglycans

KSS

Kearns-Sayre syndrome

LCA

Leber congenital amaurosis

LCD

lattice corneal dystrophy

LHON

leber hereditary optic neuropathy

LMX1B

LIM homeo box transcription factor 1, beta

LRR

leucine-rich repeat

LYST

lysosomal trafficking regulator

MASS

Mitral valve prolapse, mild Aortic root dilatation, Skin involvement striae and Skeletal findings

337

338

MELAS

mitochondrial encephalopathy, lactic acidosis and stroke

MFS

Marfan syndrome

MIM

Mendelian inheritance in man

MIP

major intrinsic protein

MKKS

McKusick-Kaufman Syndrome

MLVT

malattia leventinese

MPS

mucopolysaccharidoses

MRI

magnetic resonance imaging

MRP6

multidrug resistance protein 6

mtDNA

mitochondrial DNA

MYO7A

myosin VIIa

MYOC

myocilin

NARP

neuropathy, ataxia and retinitis pigmentosa

NBCCS

nevoid basal cell carcinoma syndrome

NEMO

NFκB essential modulator

NF1

neurofibromatosis type I

NF2

neurofibromatosis type II

NHS

Nance-Horan syndrome

NPS

nail-patella syndrome

NR2E3

nuclear receptor subfamily 2, group E, member 3

OA1

ocular albinism type 1

OAT

ornithine aminotransferase

OCA

oculocutaneous albinism

ONCR

optic nerve coloboma with renal disease

ONH

optic nerve hypoplasia

OPA1

optic atrophy 1

P

pink-eye gene,

PAX2

paired box gene 2 Genetics for Ophthalmologists

PAX6

paired box gene 6

PHYH

phytanoyl-CoA hydroxylase

PKD

polycystic kidney disease

PITX2

paired-like homeodomain transcription factor 2

PITX3

paired-like homeodomain transcription factor 3

POAG

primary open angle glaucoma

PPCD

posterior polymorphous dystrophy

PPRPE

preserved para-arteriolar retinal pigment

PTCH

patched gene

pVHL

VHL protein

PXE

pseudoxanthoma elasticum

Rab-GGTase Rab geranylgeranyl transferase

Abbreviations

RB

retinoblastoma

RDH5

retinol dehydrogenase 5

RDS

retinal degeneration slow

REP-1

Rab escort protein 1

RHO

rhodopsin

RHOK

rhodopsin kinase

RLBP1

retinaldehyde-binding protein 1

RNA

ribonucleic acid

ROM1

rod outer segment protein 1

RP

retinitis pigmentosa

RPA

retinitis punctata albescens

RPE65

retinal pigment epithelium-specific protein, 65 kDa

RPX

Rathke pouch homeobox

RRD

rhegmatogenous retinal detachment

rRNA

ribosomal ribonucleic acid

RS1

X-linked retinoschisis 339

340

RSTS

Rubinstein-Taybi syndrome

SAG

S-antigen

SCH

schwannomin

SFD

Sorsby pseudoinflammatory fundus dystrophy

SLRP

small leucine-rich proteoglycan

SOD

septo-optic dysplasia

SRNVM

subretinal neovascular membrane

STGD

Stargardt disease

STL

Stickler syndrome

TGFBI

transforming growth factor, beta-induced

TGF-β

transforming growth factor beta

TIGR

trabecular meshwork-induced glucocorticoid response

TIMP3

tissue inhibitor of metalloproteinase 3

tRNA

transfer RNA

TRP1

tyrosine-related protein 1

TSC

tuberous sclerosis complex

TYR

tyrosinase

UBO

unidentified bright object

VA

visual acuity

VEGF

vascular endothelial growth factor

VHL

von Hippel-Lindau syndrome

VMD

vitelliform macular dystrophy

WAGR

Wilms’ tumor, Aniridia, Genitourinary abnormalities and mental Retardation

WBC

white blood cell

WFS

Wolfram syndrome

XLRP

X-linked retinitis pigmentosa


13 13. Index

ABCA4 (ATP-binding cassette, subfamily A, member 4) 88–9, 99–101, 110, 134 ABCC6 (ATP-binding cassette, subfamily C, member 6) 89, 94 N-acetylgalactosamine-4-sulfatase (ARSB) 236 achalasia–addisonianism–alacrima (AAAS) syndrome 268–9 achromatopsia 82–3 aculeiform cataract 32–3 adaptin beta-3a (AP3B1) 209–10 adenomatous polyposis of colon 244–6 adnexal developmental defects 267–77 age-related macular degeneration (ARMD) 88–9 AIPL1 (arylhydrocarbon-interacting receptor protein-like 1) 115, 118 alacrima 268–9 albinism (OCA) 202–6, 211–2 Allgrove syndrome 268–9 alpha subunit of rod transducin (GNAT1) 142 Alström syndrome 147–8 amyloidosis Finnish-type/Meretoja-type 20–2 lattice corneal dystrophy, type I 18–9 primary subepithelial 7 amyloidosis V 20–2 Anderson–Fabry disease 215–6 aniridia 65–7 anophthalmos 274–5 anterior polar cataract 34 anterior segment ocular (mesenchymal) dysgenesis (ASOD) 68–9 AP3B1 (adaptin beta-3a) 209 APC (adenomatous polyposis of colon) 244–6 aquaporin O (AQPO) 41 arachnodactyly 53 ARMD (age-related macular degeneration) 88 arrestin (SAG S-antigen) 134 ARSB (N-acetylgalactosamine-4-sulfatase) 236 arthro-ophthalmopathy, progressive 180–4 arylhydrocarbon-interacting receptor protein-like 1 (AIPL1) 118 ATP-binding cassette, subfamily A, member 4 (ABCA4) 88–9, 99–100, 134 ATP-binding cassette, subfamily C, member 6 (ABCC6) 89, 94 Avellino-type corneal dystrophy 14–7 Axenfeld anomalies 68, 72, 77 Bardet–Biedl syndrome 149–52 basal cell nevus syndrome 247–50 Batten disease 231–3 BBS2, BBS4 151–2 Best macular dystrophy 104–6 beta-Ig-H3/transforming growth factor (BIGH/TGFB1) 10–9 bicoid-related homeobox-containing gene 78 BIGH3-related dystrophies 4 10–9

342


Blaschko’s lines 173 blepharophimosis, ptosis and epicanthus inversus 270–1 Bloch–Sulzberger syndrome 172–4 blue cone monochromatic color blindness 84–5 Bowman’s layer dystrophy type I 10–1 type II 12–3 buphthalmos 58–60 cadherin-like gene CDH23 166 calcium channel alpha-1 subunit (CACNA1F) 142 carbohydrate sulfotransferase-6 (CHST6) 24 cataract 28–44 aculeiform 32–3 autosomal dominant (ADCC) 29 autosomal recessive (ARCC) 30 cerulean (blue-dot) 36–7 congenital zonular with sutural opacities 38 Coppock-like 39–40 embryonic nuclear 39–40 hyperferritinemia–cataract syndrome 45 Lowe (oculocerebrorenal) syndrome 46–8 myotonic dystrophy 49–51 polymorphic and lamellar 41 posterior polar 42 syndromic 45–51 X-linked with Hutchinsonian teeth 35 Lowe syndrome 46–8 zonular pulverulent 43–4 cataract–dental syndrome 35 CBBM (blue cone monochromatic color blindness) 84–5 CEH10 homeodomain-containing homolog (CHX10) 276 cellular retinaldehyde-binding protein 1 (CRBP1) 120 central areolar choroidal dystrophy (CACD) 127–9 cerebellar vermis agenesis 158 cerebelloparenchymal disorder IV (CPDIV) 158 ceroid lipofuscinosis type-3 231–3 CFEOM (congenital fibrosis of extraocular muscles) 272–3 Chediak–Higashi syndrome 207–8 choroid, and retina, gyrate atrophy 226–7 choroidal dystrophy, central areolar 127–9 choroidal sclerosis (choroideremia) 107–9 choroiditis, Doyne honeycomb retinal dystrophy 90–1 CHRPEs, retinal pigment epithelium 244 CHX10 (CEH10 homeodomain-containing homolog) 276 CLN3 (ceroid lipofuscinosis type-3) 231–3 CNGA1 134

Index

343

Cockayne syndrome 153–5 COD(3) 86–7 Cohen syndrome 156–7 collagens type II,alpha1 (COL2A1) 183 type VIII,alpha2 (COL8A2) 26 type XI,alpha1 (COL11A1) 183 type XVIII,alpha1 (COL18A1) 175 coloboma with renal disease (ONCR) 194–5 color blindness, blue cone monochromatic 84–5 cone dystrophies 82–7 cone–rod dystrophy 110–1 cone–rod homeobox (CRX) 119 connexins (CX) 43–4 Coppock-like cataract 39–40 CORD1–9 110 CORD3 (Stargardt disease) 98–101 cornea plana 5–6 corneal amyloidosis, primary subepithelial 7 corneal dystrophies 3–26 CDBI 10–1 CDBII 12–3 chromosomal localization 4 Fuchs’ endothelial 25–6 Granular 14–7 Groenouw type I 14–7 Groenouw type II 23–4 honeycomb 12–3 inheritance pattern 4 lattice 18–22 corneal shape abnormalities 2–6 CRD (cone-rod dystrophy) 110–1 CREB-binding protein (CREBPP) 79–80 Criswick–Schepens syndrome 170–1 crumbs homolog 1 (CRB1) 134, 135 CRX 126 crystallins (CRY) 29, 30 alphaA (CRYAA) 276 alphaB (CRYAB) 42 betaA1 (CRYBA1) 36 betaB2 (CRYBB2) 36, 39, 276 gamma (CRYG) 40 gammaD (CRYGD) 32 CSNB1–3 141 cyclic nucleotide-gated cation channel alpha subunit (CNGA3) 82 beta subunit (CNGB3) 82 cystathionine beta-synthase (CBS) 228–30

344


cystinosin (CTNS) 237–8 cytochrome P450B1 (CYP1B1) 2, 59 de Morsier syndrome 196–8 deafness 199–200 diabetes mellitus, diabetes insipidus, optic atrophy and deafness (DIDMOAD) 199–200 digenic retinitis pigmentosa 137 dominant optic atrophy, type-1 188–9 Doyne honeycomb retinal dystrophy (choroiditis) 90–1 Drosophila homologs crumbs 1 (CRB1) 134, 135 patched (PTCH) 250 drusen, radial 90–1 dystrophia myotonica protein kinase (DMPK) 49–51 ectopia lentis 52–6 EGF-containing fibrillin-like extracellular matrix protein-1 (EFEMP1) 89, 91 elongation of VLC fatty acids-like gene 4 (ELOVL4) 89, 103 embryonic nuclear cataract 39–40 endothelial 25–6 enhanced S–cone syndrome 112–3 epicanthus inversus 270–1 ERCC6, ERCC8 154 exudative vitreoretinopathy EVR1 170–1 X-linked (EVR2) 177–9 Fabry disease 215–6 familial adenomatous polyposis (FAP) 244–6 familial iridogoniodysplasia 72–3 FECD (Fuchs’ endothelial corneal dystrophy) 25–6 ferritin light chain (FLC) 45 fibrillin 1 (FBN1) 55 fibrillin-like extracellular matrix protein-1 (EFEMP1) 89, 91 fibrosis of extraocular muscles (FEOM1, FEOM2) 272–3 fifth phakomatosis 247–50 Finnish-type amyloidosis 20–2 forkhead box C1 (FOXC1) 72 forkhead box E3 (FOXE3) 68 forkhead transcription factor (FOXL2) 271 Franceschetti sign 114 Fuchs’ endothelial corneal dystrophy 25–6 fundus albipunctatus 144–5 fundus flavimaculatus 98–101, 102–3 galactose-1-phosphate uridyltransferase (GALT) deficiency 219–21 galactosemia 219–21 cataract 47

Index

345

galactokinase deficiency 217–8 galactosidase alpha (GLA) 216 galactosidase beta (GLB1) 236 GALNS (galactosamine-6-sulfate sulfatase) 236 Gardner syndrome 244–6 gelatinous drop-like corneal dystrophy 7 gelsolin 21 geographic granular dystrophy 10–1 glaucoma 57–80 primary 58–64 congenital glaucoma 58–60 juvenile open angle 61–2 open angle glaucoma 63–4 secondary 65–80 glaucoma-related pigment dispersion syndrome 70–1 GM2 gangliosidosis type I 222–5 type II 222–5 GNAT1 (alpha subunit of rod transducin) 142 Goldmann–Favre syndrome 112 Gorlin–Golz syndrome 247–50 granular corneal dystrophy 14–7 granular dystrophy, geographic 10–1 green cone pigment, including deuteranopia 84 Groenouw corneal dystrophy type I 14–7 type II 23–4 Grönblad–Strandberg syndrome 92–5 GTPases, Rab escort proteins 108 guanylate cyclase 2D (GUCY2D) 116 activator 1A (GUCAA1A) 7 gyrate atrophy of choroid and retina 226–7 harmonin 165 heparan sulfate proteoglycans 76 Hermansky–Pudlak syndrome 209–10 hexosaminidase A/B deficiency, HEXA, HEXB 222–5 von Hippel–Lindau syndrome 264–5 homeobox gene expressed in ES cells (HESX1) 197 homocystinuria 228–30 honeycomb corneal dystrophy 12–3 honeycomb degeneration of retina 90–1 HPS 209–10 Hunter syndrome 234–6 Hurler syndrome 234–6 Hutchinsonian teeth, X-linked cataract 35 hyperferritinemia–cataract syndrome 45

346


IDS (iduronate sulfatase) 236 IDUA (alpha-L-iduronidase) 236 incontinentia pigmenti type II (IP2) 172–4 infantile nephropathic cystinosis 237–8 inherited retinal disease 81–167 iridogoniodysgenesis 72–3, 77–8 anomaly (IGDA) 72–3 with somatic anomalies 77–8 type I 72–3 type II 77–8 iris hypoplasia 77–8 isolated ectopia lentis 52–6 isolated microphthalmos 274–5 Joubert–Bolthauser syndrome 158 juvenile familial corneal dystrophy 8–9 juvenile neuronal ceroid lipofuscinosis, type-3 231–3 juvenile optic atrophy 188–9 juvenile-onset primary open angle glaucoma (JOAG) 61–2 Kearns–Sayre syndrome 160 keratan sulfate, carbohydrate sulfotransferase-6 (CHST6) 24 keratan sulfate proteoglycans (KSPGs) 6 keratocan (KERA 5) 276 Kjer-type optic atrophy 188–9 Knobloch syndrome 175–6 Krukenberg spindles 70 lattice corneal dystrophy type I 18–9 type II 20–2 Leber congenital amaurosis (LCA) 114–9 Leber hereditary optic atrophy/neuropathy 190–3 lens, anatomy 29 lens disorders 27–56 lens subluxation 53–6 homocystinuria 228–30 Lester sign 75 LIM homeobox transcription factor 1beta (LMX1B) 74 LIM2 30 Lowe (oculocerebrorenal) syndrome 46–8 LRAT 134 lysosomal trafficking regulator (LYST) 207 McKusick–Kaufman syndrome 152 macular corneal dystrophy 23–4 macular dystrophies 88–106 macular pattern dystrophy, deafness and diabetes 161

Index

347

MAF 2, 276 major intrinsic protein of lens fiber membrane (MIP) 41 Malattia Leventinese (MLVT) 90–1 malignancy (increased risk) 241–65 Knudson’s two-hit hypothesis 242 Marfan syndrome 52–6 Maroteux–Lamy syndrome 234–6 MASS phenotype 56 MCDC (macular corneal dystrophy 23–4 Meesmann corneal dystrophy 8–9 membrane component, chr-1, surface marker-1 (M1S1) 7 Meretoja-type amyloidosis 20–2 merlin 255 MERTK 134 mesenchymal dysgenesis, anterior segment 68–9 metabolic disorders 213–40 MFS1 (Marfan syndrome) 52–6 microphthalmos, isolated 274–5 mitochondrial disease and retinopathy 159–62 mitochondrial genes, LHON 190–3 MKKS (McKusick–Kaufman syndrome) 152 Morquio syndrome 234–6 de Morsier syndrome 196–8 mucopolysaccharidoses 234–6 multidrug resistance protein 6 (MRP6) 94 myocilin (MYOC) 62–4 myosin VIIa 165 myotonic dystrophy 49–51 nail dystrophy 174 nail–patella syndrome 74–6 Nance–Horan sydrome (NHS) 35 nanophthalmos 274–5 NARP (neuropathy, ataxia and retinitis pigmentosa) 162 NDP (Norrie disease) 177–9 nephropathic cystinosis 237–8 Nettleship–Falls type ocular albinism 211–2 neurofibromatosis type I 251–3 type II 254–6 neurofibromin (NF1) 253 neuronal ceroid lipofuscinosis, juvenile type-3 231–3 neuropathy, ataxia and retinitis pigmentosa 162 nevoid basal cell carcinoma syndrome (NBCCS) 247–50 NFκB essential modulator (NEMO) 174 night blindness 141–4 Norrie disease 177–9 NRL 126

348


nuclear receptor subfamily 2, group E, member 3 (NR2E3) 112 nyctalopin (NYX) 142 OA1, X-linked albinism 211–2 OAT (ornithine aminotransferase) 226–7 occipital encephalocoele 175–6 OCRL (oculocerebrorenal syndrome) 46–8 ocular albinism, type-1 211–2 ocular/adnexal developmental defects 267–7 oculocerebrorenal syndrome 46–8 oculocutaneous albinism 202–6 Oguchi disease 145–6 onychoosteodysplasia 74–6 OPA1 (optic atrophy type 1) 188–9 open-angle glaucoma type 1a (GLCIA) 61–2 optic atrophy 187–200 DIDMOAD 199–200 optic nerve coloboma with renal disease (ONCR) 194–5 ornithine aminotransferase (OAT) deficiency 226–7 paired box gene 2 (PAX2) 192 paired box gene 6 (PAX6) 66 paired-like homeodomain transcription factors (PITX2) 78 (PITX3) 68 patched homolog (PTCH) 250 patellar aplasia 74–6 PCDH15 166 PDE6A 134 PDE6B 134, 142 peripherin/RDS-related RP 87, 127–9 Peters’ anomaly 68, 77 phytanoyl-CoA hydroxylase (PHYH) 240 pigment dispersion syndrome (pigmentary glaucoma) 70–1 pigmentation defects 201–12 red and green cone pigment 84 pink-eye (P) gene 205 polymorphic and lamellar cataract 41 posterior polar cataract 42 posterior polymorphous dystrophy (PPCD) 25–6 primary subepithelial corneal amyloidosis 7 progressive arthro-ophthalmopathy 180–4 progressive cone dystrophy 86–7, 127 progressive rod–cone dystrophies 122–40 PROML1 134 PRPC8 126 pseudoxanthoma elasticum (PXE) 92–5 ptosis and epicanthus inversus 270–1

Index

349

Rab escort protein 1 (REP-1) 108 radial drusen 90–1 Rathke pouch homeobox (RPX) 197 RB1 (retinoblastoma) 257–60 RBP4 134 RDH5 (retinol dehydrogenase 5) 143 RDS/peripherin (RDS) 87, 89, 126, 129 von Recklinghausen disease 251–3 red cone pigment, including protanopia 84 Refsum disease 239–40 Reis–Buckler’s corneal dystrophy 10–1 renal–coloboma syndrome 194–5 RetGC1 116 retina, and choroid, gyrate atrophy 226–7 retinal degeneration slow (RDS) 87, 89, 126, 129 retinal detachment 175–6 retinal dystrophies 81–167 cone 82–7 macular 88–106 miscellaneous 107–21 mitochondrial diseases 159–62 progressive rod–cone 122–40 stationary night blindness 141–4 syndromic 147–67 retinal pigment epithelium, congenital hypertrophic lesions (CHRPEs) 244 retinal pigment epithelium-specific protein (RPE65) 117, 134 retinaldehyde-binding protein 1 (RBP1) 120 retinitis pigmentosa 122–40 autosomal dominant 125–6 genes 125–6 autosomal recessive 132–6 genes 134 digenic 137 peripherin/RDS 127–9 PPRPE type 135–6 rhodopsin-related 130–1 stationary night blindness 141–6 type-12 (RP12) 135–6 X-linked 138–40 genes 139 retinitis punctata albescens 120–1, 127 retinoblastoma 257–60 retinol dehydrogenase 5 (RDH5) 143 retinoschisis, X-linked 185–6 RGR 134 RHO (rhodopsin-related RP) 130–1, 142 RHOK (rhodopsin kinase) 146 Rieger anomalies 68, 72

350


Rieger syndrome 72, 77–8 RLBP1 134 rod, see also cone–rod rod monochromatism 82–3 rod outer segment protein 1 (ROM1) 137 rod transducin, alpha subunit (GNAT1) 142 ROM/RDS 126, 137 RP1 126 RP2 139 RPA (retinitis punctata albescens) 120–1 RPE65 (retinal pigment epithelium-specific protein) 117–8, 134 RPGR 139 RPGRIP1 (RPGR-interacting protein) 118 RPX (Rathke pouch homeobox) 197 RSI X-linked retinoschisis 185–6 Rubinstein–Taybi syndrome 79–80 SAG (S-antigen) 134 Sandhoff disease (hexosaminidase B deficiency) 222–5 SCH (schwannomin) 255 Scheie syndrome 234–6 septo–optic dysplasia 196–8 SFD (Sorsby pseudoinflammatory fundus dystrophy) 96–7 SIX5 51 small leucine-rich proteoglycans (SLRPs) 6 Sorsby pseudoinflammatory fundus dystrophy 96–7 Stargardt disease 98–103 autosomal dominant 102–3 autosomal recessive 98–101 stationary night blindness 141–6 Stickler syndrome 180–4 stromal 21–4 subretinal neovascular membranes (SRNVMs) 94 Tay–Sachs disease (hexosaminidase A deficiency) 222–5 Thiel–Behnke corneal dystrophy 12–3 tissue inhibitor of metalloproteinase 3 (TIMP3) 89, 97 trabecular meshwork-induced glucocorticoid response (TIGR) 62 trinucleotide repeat (CTG) regions 50 triple-A syndrome 268–9 tuberous sclerosis complex (TSC1, TSC2) 261–3 TULP1 134 tumor predisposition 242–3 tumor suppressor genes Knudson’s two-hit hypothesis 242 RB1 (retinoblastoma) 257–60 tyrosinase (TYR), OCA1 202–6 tyrosine-related protein (TYP1), OCA3 205–6

Index

351

Usher syndrome 163–7 USH2A/usherin 134, 164 USH genes 164 VHL (von Hippel–Lindau) 264–5 vitelliform dystrophy (RDS-related) 127–8 vitelliform macular dystrophy (VMD2) 104–6 vitreoretinal disorders 169–86 VMD2 89,104–6 Vogt–Spielmeyer (Batten) disease 231–3 von Hippel–Lindau syndrome 264–5 von Recklinghausen disease 251–3 VSX1 2, 4, 25 WAGR (Wilms’ tumor, aniridia, genitourinary defects and retardation) 67 WFS1 (wolframin) 199–200 Wolfram syndrome 199–200 X-linked disorders anophthalmos 274–5 cataract with Hutchinsonian teeth 35 familial exudative vitreoretinopathy (EVR2) 177–9 Hunter syndrome 234–6 ocular albinism 211–2 retinitis pigmentosa 138–40 retinoschisis 185–6 zonular cataract, with sutural opacities 38 zonular pulverulent cataract 43–4

352


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