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NIEUROLOGICAL DISEASE AND THERAPY Series Editor
WILLIAM C. KOLLER Department of Neurolog...
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andbook of Ataxia Disorders
NIEUROLOGICAL DISEASE AND THERAPY Series Editor
WILLIAM C. KOLLER Department of Neurology University of Kansas Medical Center Kansas City, Kansas
1. Handbook of Parkinson's Disease,edited by William C. Koller 2. Medical Therapy of Acute Stroke,edited by Mark Fisher 3.FamilialAlzheimer'sDisease:MolecularGeneticsandClinicalPerspectives, edited by Gary D. Miner, Ralph W. Richter, John P. Blass, Jimmie L. Valentine,and Linda A. Winte~-Miner 4. Alzheimer's Disease: Treatment and Long-Term Management, edited by Jefrey L. Cummings and Bruce L. ille er 5. Therapy of Parkinson's Disease, edited by William C. Koller and George Paulson 6. Handbook of Sleep Disorders, edited by MichaelJ. Thorpy 7. Epilepsy and Sudden Death, edited by Claire M. Lathers and Paul L. Schmeder 8. Handbook of Multiple Sclerosis,edited by Stuart D. Cook 9. Memory Disorders: Research and Clinical Practice, edited by Takehiko Yanagiham and Ronald C. Petersen 10. The Medical Treatment of Epilepsy, edited by Stanley R. Resor, Jr., and Henn Kutt 1l.Cognitive Disorders: Pathophysiology and Treatment, edited by Leon J. Thal, WalterH. Moos, and Elkan R. Gamzu 12.Handbook of AmyotrophicLateralSclerosis, edited by Richard Alan Smith 13.Handbook of Parkinson'sDisease:SecondEdition,RevisedandExpanded, edited by William C. Koller 14. Handbook of Pediatric Epilepsy, edited by Jerome V. ~ u r p h yand Fereydoun Dehkharghaffi 15.Handbook of Tourette'sSyndromeandRelatedTicandBehavioral Disorders, edited by Roger Kurfan 16. Handbook of Cerebellar Diseases,edited by Richard Lechtenberg 17. Handbook of Cerebrovascular Diseases,edited by Harold P. Adams, Jr. 18. ParkinsonianSyndromes, editedbyMatthewB. Stern and William C. Koller 19. Handbook of Head and Spine Trauma, edited byJonathan Greenberg 20. Brain Tumors: A Comprehensive Text, edited by Robert A. Momntz and John W. Walsh 21. Monoamine Oxidase Inhibitors in Neurological Diseases, edited by Abmham Lieberman, C. Wamn Olanow, Moussa B. H. Youdim, and Keith 77pton
22. Handbook of Dementing Illnesses,edited by JohnC. Morris 23. Handbook of Myasthenia Gravis and Myasthenic Syndromes, edited by Robert P. Lisak 24. Handbook of Neurorehabilitation,edifed by David C. Good and James R. Couch, Jr. edited by Joseph JankovicandMark 25. TherapywithBotulinumToxin, Hallett 26. Principles of Neurotoxicology,edited by Louis W. Chang 27. Handbook of Neurovirology,edited by Robert R. McKendall and William G. Stroop 28. Handbook of Neuro-Urology, edited by DavidN. Rushton 29. Handbook of Neuroepidemiology,edifed by Philip B. Gorelick and ~ i l t o n Alter 30. Handbook of Tremor Disorders, edited by Leslie J. findley and William C. Koller 31. Neuro-Ophthalmological Disorders: Diagnostic Work-up and Management, edited by RonaldJ. Tusa and Steven A. Newman edited by Richard L. Doty 32. Handbook of Olfaction and Gustation, 33. Handbook of Neurological Speech and Language Disorders, edited by Howard S. Kirshner 34. TherapyofParkinson'sDisease:SecondEdition,RevisedandExpanded, edited byWilliam C. Koller and George Paulson edited by Barney S. 35. EvaluationandManagementofGaitDisorders, Spivack 36. Handbook of Neurotoxicology,edited by Louis W. Chang and Robert S. Dyer edited by Ronald G. Wiley 37. Neurological Complications of Cancer, 38. Handbook of Autonomic Nervous System Dysfunction, edited by Amos D. Korczyn 39. Handbook of Dystonia,edited by Joseph King Ching Tsuiand Donald B. Calne edited by Jonas H.€//enberg, William C. 40. Etiology of Parkinson's Disease, Koller, and J. WilliamLangston 41, Practical Neurology of the Elderly, edited by Jacob l. Sage and Margery H. Mark 42. Handbook of Muscle Disease,edited by Russell J. M. Lane 43. Handbook of Multiple Sclerosis: Second Edition, Revised and Expanded, edited by Stuart D. Cook 44. CentralNervousSystemInfectiousDiseasesandTherapy, edited by Karen L. Roos 45 SubarachnoidHemorrhage:ClinicalManagement, edited by Takehiko Yanagihara, David G. Piepgras,and John L. D. Atkinson edited byRichardLechtenbergand 46. NeurologyPracticeGuidelines, Henry S. Schutta edited by Gordon L. 47. Spinal Cord Diseases: Diagnosis and Treatment, €ngler, Jonathan Cole,and W. Louis Merton 48. Management of Acute Stroke, edited by Ashfaq Shuaib and Lany B. Goldstein (I
49. Sleep Disorders and Neurological Disease, edifed by Antonio Culebms 50. Handbook of Ataxia Disorders,edifed by Thomas K/oc~gefhe~ Additional Volumes in Preparation
Axonal Regeneration in the Central Nervous System,edited by Nicholas A. lngoglia and MarionMumy TheAutonomicNervousSystem Goldsfein
in StressandDisease,
David S.
of axia
edited by as Klockgether University of Bonn Bonn, Germany
MARCEL
MARCEL DEKKER, INC. D E K K E R
NEWYORK BASEL
ISBN: 0-8247-0381-2
This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http:Nwww.dekker.com
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Series
Our basic knowledge of neurological disease, and thusof treatment options, has increased tremendously in recent years. This is particularly true for spinocerebellar ataxias, for which enomous advances have been made. Clearly, the discoveries identifying the genetic basics of cerebellar disease have changed many clinical concepts regarding ataxic disorders. These disorders now are easier to diagnose and classify becauseof recent geneticjdiscoveries. Treatmentof cerebellar disorders remains difficult, however. It is hoped that new knowledge regarding pathogenesis will lead to adequate treatment. Handbook of AtaxiaDisorders, edited by Dr. ThomasKlockgether, addresses both basic and clinical science regarding the cerebellar disorders. This all clinicians andwill help allprofessionals who see book will prove valuable for these patients. Handbook of Ataxia Disorders is indeed comprehensive and will answer any queries regarding cerebellar disorders. William C. Koller
iii
This Page Intentionally Left Blank
Preface
In 1863, Nikolaus Friedreich described a distinctive familial syndrome characterized by progressive ataxia, with onset during puberty, caused by degeneration of spinal fiber tracts. Friedreich’s observation was the beginningof a long tradition of clinical and neuropathological work on degenerative diseases of the cerebellum and spinal cord associated with progressive ataxia. This work provided extensiveknowledge of thebewilderingphenotypicalvariety of degenerative ataxia, Nevertheless, for more than a century, investigators in the fieldof ataxia remained widely ignorant of the underlying mechanisms causing the disorders with which they were dealing. This situation dramatically changed with the advent of modern molecular genetics. By using the positional-cloning approach, moleculargeneticistssucceeded in identifying more than ten gene mutations leading to hereditary ataxia. At present, efforts are underway to elucidate the cellular mechanismsby which these mutations cause degeneration of the cerebellum and spinal cord. The recent molecular genetic discoveries completely changed our clinical attitude toward ataxia. Laboratory tests have become a powerful diagnostic tool that supplement clinical examination and the established diagnostic procedures. As a result of the identification of molecular causes of ataxia, discussions on its proper classification have fortunately ceased. On the other hand, the novel mutations define disease entities that have not been previously recognized. Clinicians are beginning to establish the relationship between the underlying genotype and the resulting clinical phenotype. Unfortunately, the improved knowledge of the etiology of ataxia disorders has not yet led to effective therapies, although there are some notable exceptions. Thus, patients, relatives, and physicians often
vi
Preface
remain confronted with diseases that may cause severe disability, personal suffering, and premature death. The radical changes in our thinking about ataxia caused by the molecular discoveries prompted us to compile this book. Primarily, it should serve as a practical guide to the diagnosis and managementof the various ataxic disorders. We hope that it will help clinicians keep pace with the rapidly expanding knowledge of the molecular genetics and pathogenesis of ataxia. This book will also be useful for neuropathologists, geneticists, and neuroscientists who seek comprehensive information about clinical and genetical aspects of ataxia. The book is organized in terms of the various distinctive ataxic disorders. We have attempted to give a comprehensive view of all relevant aspects of each disorder, including epidemiology, molecular pathogenesis, neuropathology, clinical features, ancillary tests, and management. As a general introduction to the topic, the discussionof the individual disordersis preceded by chapters that deal with the anatomy of the spinocerebellar system, its normal function, the history of ataxia research, and the clinical approach to the ataxic patient. Thomas Hockgether
ontents
Series Introduction Preface Contributors
WilliamC.Koller
..I)
111
V
xi
Introduction 1. Functional Architecture of the Cerebellar System Fahad Sultan, Martin Mock, and Peter Thier
1
2. Normal Functions of the Cerebellum Helge Topka
53
3. History of Ataxia Research
77
Jose' Berciano, Julio Pascual, and Jose' M. Polo
4.
Clinical Approach to Ataxic Patients Thomas Hockgether
101
Developmental Disorders 5. Cerebellar Malformations Vt'ncent 7: Ramaekers
115
vii
viii
Contents
Autosomal Recessive Ataxias 6. Friedreich’s Ataxia
151
Michel Koenig and Alexandra Diirr 7. Ataxia-Telangiectasia Nada Jabado, Patrick Concannon, and Richard A. Gatti 8 . Early-Onset Cerebellar Ataxia with Retained Tendon Reflexes
163
191
Alessandro Filla and Giuseppe De Michele 9. Abetalipoproteinernia
205
Alfried Kohlschutter
10. Ataxia with Isolated Vitamin E Deficiency Michel Koenig
223
13
235
*
Heredopathia Atactica Polyneuritiformis: Refsurn’s Disease Frederick B. Gibberd and Anthony S. Wierzbicki
12. Cerebrotendinous Xanthomatosis
257
Vardiella Meiner and Eran Leitersdorf 13. Ataxias Associated with Rare Metabolic Disorders Eugen Boltshauser
27 1
14. Infantile-Onset Spinocerebellar Ataxia Tuula Lonnqvist, Anders Paetau, Helena Pihko, and Kaisu Nikali
293
15. Autosomal Recessive Spastic Ataxia (Charlevoix-Saguenay) Jean-Pierre Bouchard, Andrea Richtec Serge B. Melangan, Jean Mathieu, and Jean Michaud
311
Mitochondrial Disorders 16. Ataxia in Mitochondrial Disorders Heinz Reichrnann
325
Autosomal Dominant Ataxias 17. Spinocerebellar Ataxia Type 1 Harry 7: Orr and Thomas Klockgether
343
ix
Contents 18. Spinocerebellar Ataxia Type 2 Katrin Biirk and Johannes Dichgans
363
19. Spinocerebellar Ataxia Type 3 Ludger Schols, Henry Paulson, and Olaf Riess
385
20.
Spinocerebellar Ataxia Type 4 Ying-Hui Fu, Michael Abele, and Louis J. PtaZek
425
21.
Spinocerebellar Ataxia Type 5 Lawrence J.Schut, John W Day, H. Brent Clark, Michael D. Koob, and Laura P. W Ranum
435
22.
Episodic Ataxia Type 2 and Spinocerebellar Ataxia Type 6 Robert W Baloh and Joanna C. Jen
447
23.
Spinocerebellar Ataxia Type 7 Giovanni Stevanin, Alexandra Diirv; and Alexis Brice
469
24. Episodic Ataxia Type 1 Ewout R. Brunt 25.
Spinocerebellar Ataxia Type 10 Stefan-M. Pulst
487
5 17
Transmissible Spongiforrn Encephalopathies 26.
Ataxia in the Transmissible Spongiform Encephalopathies Lev G. Goldfarb, Cathrin M. Biitejisch, and Paul Brown
523
Nonhereditary Ataxias 27.
to
Idiopathic Cerebellar Degeneration: Multiple System Atrophy 545 Jorg B. Schulz and Johannes Dichgans
28. Alcoholic Cerebellar Degeneration (Including Ataxias That Are Due 571 Toxic Causes) Dagmar Timmann-Braun and Hans-Christoph Diener
Degeneration Cerebellar Paraneoplastic 29. Josep 0. Dalmau and Jerome B. Posner
607
Contents
X
30.
Ataxia CausedbyAcquiredVitamin Deficiency or Metabolic Disorders Peter Thier
633
3 1. Cerebellar Encephalitis Marios Hadjivassiliou and Richard A. Griinewald
649
32.
667
Index
Ataxia Dueto Physical Causes Michael Abele
677
Contributors
MichaelAbele,M.D.
Department of Neurology, University of Bonn, Bonn,
Germany
Robert W. Baloh,M.D.
Professor,Departments of NeurologyandSurgery (Head and Neck), UCLA School of Medicine, Los Angeles, California
JosC Berciano, Ph.D. Professor and Chair, Department of Neurology, University Hospital “Marquits de Valdecilla,” Santander, Spain
Eugen Boltshauser, M.D. Professor, Department of Pediatric Neurology, Children’s University Hospital, Zurich, Switzerland
Jean-PierreBouchard,M.D.,F.R.C.P.(C)
Professor of Medicine(Neurology), Department of Neurological Sciences, Centre HospitalierAffiliit Universitaire de Quitbec, Pavillon Enfant-Jitsus, Qukbec City, Quitbec, Canada
Alexis Brice, M.D. Professor, Neurogenetics Group, INSERM U289, Hiipital de la Salpgtrikre, Paris, France
PaulBrown,M.D.
NationalInstitute of NeurologicalDisordersandStroke, National Institutes of Health, Bethesda, Maryland
Ewout R. Brunt, M.D. Department of Neurology, University Hospital Groningen, Groningen, The Netherlands xi
xii
Contributors
Katrin Biirk, M.D. Department of Neurology, University of Tubingen, Tubingen, Germany
Cathrin M. Biitefisch, M.D. Medical Neurology Branch, National Institute of NeurologicalDisordersandStroke,NationalInstitutes of Health,Bethesda, Maryland
H. Brent Clark, M.D., Ph.D. Professor, Laboratory Medicine/Pathology and Neurology, University of Minnesota, Minneapolis, Minnesota
PatrickConcannon,Ph.D.
Director,MolecularGeneticsProgram,Virginia Mason Research Center, Seattle, Washington
Josep 0. Dalmau, M.D., Ph.D. Kettering Cancer Center, and New York
Department of Neurology, Memorial SloanCornel1 University Medical College, New York,
John W. Day, M.D., Ph.D. Associate Professor, Department of Neurology and the Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota
Guiseppe De Michele, M,D. Assistant Professor, Department of Neurological Sciences, Federico I1 University, Naples, Italy Johannes Dichgans, M.D.
Professor, Department, of Neurology, University of Tubingen, Tubingen, Germany
Hans-Christoph Diener, M.D. Chairman and Professor, Department of Neurology, University of Essen, Essen, Germany Alexandra Durr, M.D., Ph.D.
Genetique Medicale, HBpital de la Salp&i&re,
Paris, France
Alessandro Filla, M.D. Associate Professor, Department of Neurological Sciences, Federico 11 University, Naples, Italy Ying-Hui Fu, Ph.D. Research Associate Professor, Departments of Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah
Richard A. Gatti, M.D. Professor, Department of Pathology, UCLA School of Medicine, Los Angeles, California
Contributors
xiii
Frederick B. Gibberd, M.D., F.R.C.P. (London)
Consultant Neurologist, Department of Neurology, Chelsea and Westminster Hospital, London, England
Lev G. Goldfarb, M.D., Ph.D.
Office of the Clinical Director, National Institute of NeurologicalDisordersandStroke,NationalInstitutes of Health, Bethesda, Maryland
Richard A. Grunewald, D.Phi1. Consultant Neurologist, Department of Neurology, Royal Hallamshire Hospital, Sheffield, England Marios Hadjivassiliou,M.D. Consultant Neurologist, Department of Neurology, Royal Hallamshire Hospital, Sheffield, England
NadaJabado,M.D.
Department of Biochemistry,McGillUniversity,Mon-
trkal, Canada
Joanna C. Jen,M.D.,Ph.D.
Assistant Professor, Department of Neurology, UCLA School of Medicine, Los Angeles, California
ThomasKloclcgether,M.D.
Professor, Department of Neurology, University
of Bonn, Bonn, Germany
Michel Koenig, M.D., PhD. Professor, Institut de Gknktique et de Biologie Mol6culaire et Cellulaire, University Louis Pasteur, Strasbourg, France
AlfriedKohlschiitter,M.D.
Professor of Pediatrics,Klinikfur Jugendmedizin, University of Hamburg, Hamburg, Germany
Ender- und
Michael D. Koob, Ph.D. Assistant Professor, Departmentof Neurology, and the Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota Eran Leitersdorf, M.D. Head, Center for Research, Prevention and Treatment of Atherosclerosis,Department Jerusalem, Israel
of Medicine,HadassahUniversityHospita
TuulaLonnqvist,M.D.
Specialist, Department of Child Neurology, Hospital for Children and Adolescents, University of Helsinki, Finland
Jean Mathieu, M.D., M.Sc., F.R.C.P.(C) Neurologist, Department of Neurology, Complexe Hospitalier de la Sagamie, Chicoutimi, Qukbec, Canada
VardiellaMeiner,M.D.
Department of Human Genetics, Hadassah Medical Organization, Hadassah University Hospital, Jerusalem, Israel
xiv
Contributors
Serge B. Melanqon, M.D. Honorary Professor, Department of Pediatrics, Hapita1 Sainte-Justine, Universite de Montreal, Montreal, Quebec, Canada Jean Michaud, MD., F.R.C.P. Chair, Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada
Martin Mock, Ph.D. Research Fellow, Section on Sensorimotor Research, Department of Neurology, University of Tubingen, Tubingen, Germany
KaisuNikali
Department of HumanMolecularGenetics,NationalPublic Health Institute, Helsinki, Finland
Harry T.Orr, Ph. D, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
Anders Paetau
Department of Pathology, Helsinki University Central Hospital and Haartman Institute, University of Helsinki, Helsinki, Finland
Julio Pascual, Ph.D., M.D. Staff Neurologist, Department of Neurology, University Hospital “Marques de Valdecilla,” Santander, Spain
Henry Paulson, M.D., Ph.D.
Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa
Helena Pihko, MD., Ph.D. Senior Lecturer, Department of Child Neurology, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
JosC M. Polo, Ph.D.
Department of Neurology, University Hospital “Marques de Valdecilla,” Santander, Spain
Jerome B. Posner, M.D. Department of Neurology, Memorial Sloan-Kettering Cancer Center, and Cornell University Medical College, New York, New York
Louis PtaEek, M.D. Associate Investigator, Howard Hughes Medical Institute, Departments of Neurology and Human Genetics, University of Utah, Salt Lake City, Utah
Stefan-M. Pulst, M.D. Warschaw Chair and Director, Division of Neurology, of Medicine, UCLA Schoolof MediCedars-Sinai Medical Center, and Professor cine, Los Angeles, California
Contributors
xv
Vincent T. Ramaekers, M.D., Ph.D.
Pediatric Neurologist, Division of Pediatric Neurology, Departmentof Pediatrics, University Hospital Aachen, Aachen, Germany
Laura P.W. Ranum, Ph.D. Associate Professor, Departmentof Genetics, Cell Biology and Development, and the Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota Heinz Reichmann, M.D., Ph.D. Professor, Department of Neurology, University of Dresden, Dresden, Germany
Andrea Richter, Ph.D, de Genetique Medicale, treal, Quebec, Canada
Assistant Professor, Department of Pediatrics, Service HGpital Sainte-Justine, Universite de Montreal, Mon-
Olaf Riess, M.D. Professor, Department of Medical Genetics, Children’s Hospital, University of Rostock, Rostock, Germany LudgerSchols,M.D.
Department of Neurology,RuhrUniversity,St.Josef Hospital, Bochum, Germany
Jorg B. SchUlz, M.D.
Department of Neurology, University of Tubingen, TU-
bingen, Germany
LawrenceJ.Schut,M.D.
Department of Neurology, CentraCare, St. Cloud,
Minnesota
Giovanni Stevanin, Ph.D.
Neurogenetics Group, INSERM U289,
HGpital de
la Salpgtrikre, Paris, France
Fahad Sultan, M.D. Research Fellow, Section on Sensorimotor Research, Department of Neurology, University of Tubingen, Tubingen, Germany
Peter Thier, M.D.
Professor, Section on Sensorimotor Research, Department of Neurology, University of Tubingen, Tubingen, Germany
DagmarTimmann-Braun,M.D.
Professor,Department of Neurology,Uni-
versity of Essen, Essen, Germany
HelgeTopka,M.D.,Ph.D. AssistantProfessor,Department University of Tubingen, Tubingen, Germany
of Neurology,
Anthony S. Wierzbicki, B.M., B.Chir., D.Phi1. Senior Lecturer, Chemical Pathology, St. Thomas’s Hospital, London, England
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Handbook of Ataxia Disorders
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Functional Architecture of the Cerebellar System Fahad Sultan, Martin Mock, and Peter Thier University of Tiibingen, Tiibingen, Germany
INTRODUCTION I.
2
11. CEREBELLAR CORTEX: CELL TYPES AND FIBERS A. The Purkinje Cell Layer: The Output Units B. The Granular Layer and the Mossy Fibers: The Input Layer C. Functional Interpretation of the Cerebellar Architecture D.Long-TermDepression
4 5 10 11 12
111. DEVELOPMENT OF THE CEREBELLUM of Cerebellar Neurons A. Origin and Migration B.NeuronalDifferentiation C. Development of Mossy and Climbing Fibers D.MolecularCompartmentsintheCerebellum
13 13 14 15 15
IV. THESOURCESOFMOSSYFIBERS A. The PontineNuclei B. The NucleusReticularisTegmentiPontis C.OtherBrainStemPrecerebellarNuclei D. The SpinocerebellarTracts
16 17 21 22 23
V.
THE SOURCE OF CLIMBING FIBER AFFERENTS: THE INFERIOR OLIVE A. GrossMorphology B.FineStructure C. PhysiologicalProperties D.FunctionalImplications
25 25 26 28 30 1
Sultan et al.
2 VI. THE DEEP CEREBELLAR NUCLEI A. GrossMorphology B.FineStructureandPhysiologicalProperties C. How Is the Cortical Output Mapped onto the DCN? REFERENCES
1.
31 31 31 32 33
INTRODUCTION
Although the volumeof the cerebellum is only one-seventh that of the cerebrum, the t ern cerebellum i.e., the small brain, is misleading, because it is small only in volume.On the other hand, the surface of the cerebellar cortex is about the size of one hemisphere of cerebral cortex and the anteroposterior length of the flattened cerebellar cortex of humans, with 2 m, is even seven times that of the cerebral cortex. Finally, also the numberof neurons in both corticesis of the same order of magnitude (10"')).All these comparisons suggest that the complexity and importance of the functional roleof the cerebellar cortex matches thatof the cerebral cortex. The cerebellum consists of a cortex and nuclei that are embedded in the depth of the cerebellaranlage. The heavily folded cerebellar cortex is grouped in to lobules that are separated by fissures that in part reach down deep into the cerebellum (Fig, 1A, B). The deepest fissure, the fissura prima, delineates an anterior from a posterior lobe. Another important fissure, the fissura posterior lateralis separates the posterior lobe from the flocculus and nodulus, two lobes that are situated at the caudal end of the cerebellar cortex (see Fig. 1B). The total cerebellar anlage is located dorsal to the fourth ventricle and is connected by the three
Figure 1 (A)A myelin-stained mediosagittal section of the human cerebellum with the of the mammalian cerebella. (From Bolk, names of lobulesas used in comparative studies 1906.) (B) A drawing of the dorsal view of the human cerebellum with the folial pattern of the different lobules. (Modified from Riley, 1928.) (C) Surface extension of the unfolded human cerebellum. The drawing was obtained by connecting the ends of the most prominent folia. The scaleon the left corresponds to l m. (From Sultan and Braitenberg, 1993.) (D, E) Two schematic representation of the unfolded folial chain are shown with the singular anterior folial chain that divids into three chains more posteriorly: the caudal vermis and the two hemispheres with the paraflocculus and the flocculus. (P modified from Braitenberg and Atwood, 1958; E from Bolk, 1906.)
Architecture of the Cerebellar System
3
A
E3 Lingula I
C
e
n
t
r
a
l lob
ramedian lobule
I Nodulus occulus dorsalis L. paraflocculus ventralis
C
L. anterior
D
Cerebellar hemiwheres
L. simplex
L. ansiformis (Crus I)
Velum medulare anterior
~~~~~~l~~
E L. ansiformis (Crus 11)
L. anterior L. simplex
Lob. paramed. Lob. paraflocc. dors. Lob. paraflocc. ventralis
caudal vermis
Sultan et al.
4
cerebellar peduncles, with the brain stem at the level of the pons and the medulla oblongata. A rough parasagittal subdivision of the cerebellar cortex is apparent in most mammals: medial (vermis), intermediate, and lateral (hemispheres). Comhauplan validforall parativeanatomicalstudieshavesuggestedageneral mammalian cerebella. We can think of the cerebellar cortex as a surface that is based on a single, rostrocaudally oriented chain of folia in its anterior part, which then divides into three separate, parallel chains in its posterior part (see Fig.1D and E). Of these latter three chains, the medial one corresponds to the posterior vermis and the two lateral chains form the posterior parts of the hemispheres (see Fig. IC). Two different principles of further compartmentalization have been proposed: a horizontal lobular (Bolk, 1906) and a parasagittal subdivision (Jansen and Brodal, 194.0). The former is based on the presenceof deep fissures that delineate the lobi and are present from an early developmental stage on (Bolk, 1906). The latter scheme builds on the highly anisotropic organization of both afferent and efferent connections of the cerebellum and parcels into parasagittally oriented slices.The question of whether these subdivisions have implications for function has as yet not been answered conclusively.
H.
CEREBELLAR CORTEX: CELL TYPES AND FIBERS
The cerebellar cortex has three distinct layers: the outermost molecular layer, the Purkinje cell layer, and the innermost granular layer, which borders on the white matter (see Fig. 1A). The cerebellar cortex has four major typesof cells that exhibit distinct differences: the Purkinje cells, the interneurons of the molecular layer (stellate and basket cells), granule cells, and Golgi cells. All of these cells, with the exceptionof the granule cells, are inhibitory. The excitatory granule cells contact only inhibitory neurons: namely, the inhibitory interneurons of the molecular layer and the Purkinje cells, but never other granule cells. Probably the most striking featureof the architectureof cerebellar cortex is the highly regular, lattice-like arrangement of the many axons and dendrites in the molecular layer, which is reflected by several of the cell types mentioned. Axons run either in a laterolateral or in an anteroposterior direction. The former are about 100 times more numerous than the latter and are almost exclusively parallel fibers, the branches of granule cell axons. Axons, which stay inside the cerebellar cortex, have a length of about 5 mm in the laterolateral direction and0.3 mm in the anteroposterior direction. In other words, unlike intrinsic axons in the cerebral cortex, those in cerebellar cortex are short, local, and confined to two orthogonal orientations, which greatly reduces the spreadof information from a given point in the cerebellar cortex.
Architecture of the System Cerebellar
A.
5
The Purkinje Cell Layer: The Output Units
Purkinje cells are the only output elements of the cerebellar cortex. Their number in humans has been estimated to be on the order of 15-30 million (Mayhew, 1991; Braitenberg and Atwood, 1958; Andersen et al., 1992) Purkinje cells are part in the cerebellar nuGABAergic (It0 et al., 1964) and terminate for the most clei and in the vestibular nuclei (Brodal, 1981), depending on their location in the cerebellum.Purkinjecellaxonssendcollateralstoperikarya of neighboring Purkinje cells, but also to those of basket cells (Lemkey-Johnston and Larramendi,1968). The dendritic tree of Purkinje cells is peculiar in several ways. First its ge3) andinhumansoccupiesaspace of ometryisnearlyplanar(Figs.2and 3SOX 350X 30p m (Braitenberg and Atwood, 1958). Second, the dendritic tree of the Purkinje cell is the seat of an incredibly large number of synapses. For instance, rat Purkinje cells accommodate 160,000 synapses (Napper and Harvey, 1988) that are mostly localized on dendritic spines. This is the largest number of synapses seen on any neuron in the mammalian brain. The number of synapses of human Purkinje cells has not been counted; however, there is reason to assume that their number is even higher. Most of the synapses on Purkinje cells are made by parallel fibers (Harvey and Napper, 1991), originating from cerebellar granule cells (see later discussion) and are classified as excitatory both on electronmicroscopic (Gray, 1961)andelectrophysiologicalgrounds(Ecclesetal.,1966a). These fibers stem from aT-like bifurcation of the granule cells’ axons ascending part and both segments, the ascending branch as well as the parallel fibers proper contact Purkinje cells. However, there are important differences between the two segments of the granule cell axon, which may be functionally relevant (Bower and Woolston, 1983;LlinBs, 1982). The total number of the synapses on the parallel fibers is much larger than those on the ascending branch (Sultan and Rotter, 1994; Napper and Harvey, 1988), Nevertheless, the perpendicular course of the parallel fiber relative to the plane of the Purkinje cell dendritic tree keeps the number of synapses maintained on a given Purkinje cell much smaller than the number of synapses established by the ascending branch, neighboring a given Purkinje cell for a large part of its length. Hence, a few ascending fibersmay be sufficient to excite a Purkinje cell (Bower and Woolston, 1983), whereas on the other hand, conjoint activity in larger bundles of parallel fiber system may be needed (Braitenberg et al., 1997). A second, much smaller group of synapses with Purkinje cells are maintained by the climbing Jibers, exclusively originating from the inferior olive (see following). The climbing fiber divides into several branches, which follow and wind around dendritic branches of the Purkinje cell, and overall, about300-500 excitatory synapses (Hillman, 1969) are established with dendritic spines of a given cell (Silver et al., 1998). The massive synaptic connectionof a single climb-
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Architecture of the System Cerebellar
7
ing fiber manifests itself in the induction of a distinct action potential, the camplex spike, a multiphasic potential,fired at very low frequenciesby Purkinje cells which is clearly distinct from the ordinarysimple spike (Thach, 1972), the latter evoked by excitation through the granular cell-parallel fiber input. It is commonly held that the specific nature of the complex spike is due to the especially strong anatomical relation between each Purkinje cell and the associated climbing fiber in combination with a particular selection of membrane channels that are under the influenceof the climbing fiber (Knopfel et al., 1991). Although the excitatoryparallelfibersutilizethetransmitterglutamate(Hockbergeretal., 1987; Somogyi et al., 1986; Stone, 1979), the major transmitter of climbing fibersseemsto be aspartate(Heinemannetal.,1984),althoughglutamateor N-acetylaspartylglutamate(Renno et al., 1997) may also be involved. Irrespective of the transmitter substance released, the postsynaptic receptor seems to be an non-N-methyl-D-aspartic acid (NMDA) glutamate receptorof the a-amino-3hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA) kind (Baude et al., 1994; Hausser and Roth, 1997). While there is little dispute about the fact that the dominating type of glutamate receptors in adult Purkinje cells is of the nonNMDA kind, there is evidence for NMDA receptors playing an important role in juvenile Purkinje cells. Several studies have shown by in situ hybridization of mRNA that the NMDA receptor subunit 1 is present in Purkinje cells of young animals (Watanabe et al., 1994; Masu et al., 1993). NMDA currents begin to be expressed in thefirst postnatal week and then decline to adult levels after the third postnatal week (Crepe1 and Audinat, 1991). A speculative function of NMDA receptorinthedevelopingcerebellummightbetoguaranteethesurvival of Purkinje cells during a time period when only few parallel fiber inputs are present (Yuzaki et al., 1996). This idea has been prompted by the correlation between the buildup of parallel fiber synapses and the decrease in NMDA sensitivity(Crepe1
Figure 2 Microphotographs of rapid Golgi-stained sections of different elements of the mammalian cerebellar cortex. (A)A tangential section (parallel to the pia) through the molecular layer of aMacaca rnuZZata monkey. Several Purkinje cell dendritic trees (white asterisks) can be seen under a perspective (compare Fig.orientation) that shows them 3 for as narrow strips and in parallel to each other, whereas several parallel fibers (arrows) course the dendritic trees at right angles. Between the Purkinje cells two molecular interneurons are visible at right angles to the parallel fibers (arrowheads). (B) This micrograph shows several granule cells from the rat cerebellum scattered throughout the granule layer. The granule cell somata (asterisks) have a diameter of about 5-7 pm. Some granule cells in focus are seen emitting several dendritic processes (arrows) that terminate in a claw-like bifurcation, by which they contact the mossy fiber rosettes. (C) A mossy fiber rosette with its typical “mossy” appearance which stems from the numerous granule cell dendritic “claws” that contact the mossy fibers at this synaptic specialisation. Scale bar: A:50 pm, C : 10 pm.
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Sagittal side Figure 3 A semidiagramatic three-dimensional representationof parts of two folia of the cerebellar cortex with the main neuronal elements. The granular layer is indicated by gray shading. The planar build of the Purkinje cells is revealed by showing them both in sagittal and transversal view. The two types of molecular interneurons, the stellate and basket cells, are shown as flat structures in the transverse1 view. The boxright sumon the marizes the numbers of the major anatomical elements per square meter for the rat cerebellum. Abbreviations: Cf, climbing fiber; IIml, inhibitory interneurons of the molecular layer; G, granule cells; GC, Golgi cells; Mf, mossy fibers; Pc, Purkinje cells; pf, parallel fibers. (Modified from Hlimori and Szentligothai, 1966.)
and Audinat, 1991). It receives further support from the fact that the staggerer mutant mouse, in which parallel fibers do not establish functional synaptic contacts with Purkinje cells, Purkinje cells keep their sensitivity to NMDA until adulthood (Dupont et al., 1984). In addition to the AMPA receptor a second type of ionotropicglutamatereceptor,theGluR62 is presentonPurkinjecells (Mishina et al., 1993). Although during development this receptor is expressed both on distal and on partsof the dendritic tree, in contact with both the parallel fibers and the climbing fibers, in the adult the GluR62 receptor is confined to the fine distal dendrites (Landsend et al., 1997). This receptor has been implicated in several important functions: establishmentof the correct numberof parallel fiber synapses (Kurihara et al., 1997), reduction of the number of climbing fibers, and finally the inductionof long-term potentiation(discussed later) (Kashiwabuchi et al., 1995). Besides the ionotropic AMPA and GluR82 receptors there are also
Architecture of the System Cerebellar
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metabotropic glutamate receptors of the subtype mGluRl expressed in Purkinje cells (Blackstone et al., 1989). These receptors are coupled to phospholipase by C the Gq family of guanine nucleotide-binding proteins to produce diacylglycerol and to activate protein kinase C and the inositol 1,4,5-trisphospbate (for review see Exton, 1996).The metabolic glutamate receptorsmGluRl is an important element in one of several pathways by which long-term potentiation can be induced in the cerebellum (see later). Purkinje cells also display inhibitory, y-aminobutyric acid-A (GABAJergic synapses, both on the dendritic tree and on the soma. Most of them are contacted by two kinds of inhibitory interneurons, the stellate cells and the basket cells, which differ in the termination site of their synapses on the dendritic tree. Basket cells with their terminations surround the perikaryon and the initial segment of the Purkinje cell axon, whereas stellate cells tend to terminate on the dendritic tree. They are otherwisevery similar in terms of the length and geometric distribution of their axons in the cortical plane (Sultan and Bower, 1998), the shape of their own dendritic trees, and in their synaptic relations (Pouzat and Kondo, 1996; Rakic, 1972). Both types of inhibitory interneurons are excited through the same mossyfiber-granule cell-parallel fiber channel that also serves the Purkinje cell, with the difference that parallel fibers contact the dendrites of inhibitory interThe number of inhibitory neurons directly; thoseof Purkinje cells through spines. l00 times lowerthan than of excitatory synsynapses on Purkinje cells is roughly apses (Sultan and Bower, 1998).The inhibitory synapses seem to be able to compensate their low numbers by inducing much stronger conductance changes, allowing them to counterbalance the huge parallel fiber input (Llano et al., 1991a). The Purkinje cells are probably the biophysically best-investigated cells in the vertebrate nervous system (e.g., Midtgaard et al., 1993; Llano et al., 1991b; Konnerth et al., 1990; Gahwiler and Llano, 1989; Hounsgaard and Midtgaard, 1988; LlinBs and Sugimori, 1980a,b). Recent electrophysiological and computer simulation studies have revealed a wealthof data that have furthered our understanding of the integrational capabilities of Purkinje cells, as well as other cerebellar neurons (Rapp et al., 1994; De Schutter and Bower, 1994a,b). The Purkinje cell disposes of somatic voltage-gated channels for sodium and potassium for the initiation of fast somatic action potentials. Probably the same sodium channels, albeit with different levels of phosphorylation induced peak current reduction (Colbert and Johnston, 1998), are also present at lower densities in the cell’s dendrite and soma outside the action-potential-generating axon hillock, where they contribute to the high, resting firing of rate the Purkinje cell (LlinBs and Sugimori, 1980a,b). High-threshold calcium channels of the P-type variety are found on the dendrites of Purkinje cells (Llinis et al., 1989). They are capable of generating calcium-mediated depolarization plateau potentials as well as dendritic calcium spikes (Llinis and Sugimori, 1980a,b). These channels are primarily activated by climbing fiber input and are responsible for the generation of complex spikes
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(Konnerth et al., 1992) . However, it has been shown that parallel fiber input is also capable of activating these channels (Tank et al., 1988). Calcium channels consist of an a,-subunit. which serves as the pore and the voltage sensor (McCleskey, 1994). The A variant of this subunit (a,,-subunit) is highly expressed in both Purkinje cells and in granule cells, and alternative splicing of the gene encoding for this subunit results in channels with distinct kinetic, pharmacological. and modulatory properties, such as the P- or the Q-type (Bourinet et al.. 1999). Mutations in the a,,-subunit underly two types of ataxias, the familial episodic ataxia type 2 and the spinocerebellar ataxia type 6 (see Chapter 22), as well as familial hemiplegic migraine and certain forms of epilepsy (see Ophoff et al.. 1998 for review). P-type cuirents account for more than 90% of the calcium currents in adult Purkinje cells. The low-threshold T-type calcium channel seems to be more pronounced in immature Purkinje cells and probably plays a stronger role in developmental processes than in the mature Purkinje cell (Mouginot and Gahwiler, 1995). Purkinje cells dispose of intricate systems to control the intracellular calcium concentration. Besides considerable amounts of the calcium-binding proteins calbindin D28k and parvalbumin. also present in other neurons, the protein calsequestrin is uniquely found in Purkinje cells (Takei et al., 1992). These and several additional calcium-binding and clearance systems are supplemented by receptors. such as the ryanodine receptor, controlling the internal release of calcium (Fierro and Llano, 1996). The functional relevance of these sophisticated calcium-regulating system can be seen in the calbindin (calbindin D28K) null mutant, which shows marked impairments in motor coordination (Airaksinen et al., 1997). One of the functional hallmarks of Purkinje cells is their tendency to discharge at high frequencies, even if no obvious stimulus that might drive the cell is available (Thach, 1970, 1972: Harvey et al., 1977; Fortier et al., 1989). Purlclnje cells also fire at high rates in vitro when no excitatory afferents are available to drive the cell. This suggests that the high-discharge rates reflect a rich provision of Purkinje cells with voltage-gated ion channels and the persistent sodium channel (Usowicz et al., 1992; Gahwiler and Llano, 1989). which weigh in for the constant depolarization. B. The Granular Layer and the Mossy Fibers: The Input Layer The granular layer consists of three distinct anatomical elements: the granule cells, the Golgi cells, and the mossy fibers, the latter originating from various precerebellar nuclei in the brain stem as well as from the spinal cord (see later). The granule cells (see Fig. 2B) are the most numerous cell type in the brain. Recent estimates of their number in humans amount to 10" cells, which equals 79%
Architecture of the Cerebellar System
11
of all neurons in the central nervous system (Andersen et al., 1992, Pakkenberg and Gundersen, 1997). Golgi cells and mossy fibers are much less numerous and are about equal in numbers to Purkinje cells (30X lo6). The granule cells are probably the most uniform cells in the central nervous system. Their three to five small dendrites radiate unbifurcated a distance from the cells body where they end in five to eight claw-like terminals to contact the mossy fibers. The radial arrangement of the dendrite is believed by many to ensure that the cells do not contact the same mossy fiber twice (Eccles et al., 1967). The mossy fiber is characterized by two main features. First, its peculiar synaptic specialization, the rosette (see Fig. 3) is the site of hundreds of synapses clustered spatially (Jakab and Himori, 1988). The rosette and the approximately 50 granule cell claw-like terminal dendrites that contact a rosette (Jakab and Himori, 1988) are referred to as the glomerulum. The second characteristic of the mossy fibers is the large divergence of mossy fiber-to-granule cell contacts. Because there are about 5,000 times more granule cells than mossy fibers (Tomasch, 1969; Andersen et al., 1992) and because four mossy fibers converge onto one granule cell (Eccles et al., 1967), we have to expect that a single mossy fiber must contact about 20,000 granule cells. It is assumed that this dual mossy fiber characteristic (i.e., large divergence and large number of spatially clustered synapses in the rosettes) is an organizational principle that ensures both a maximal number of different mossy fibers will be present in any one cerebellar folium and that one mossy fiber input in a given folium is restricted to a given spatial location (Brodal and Bjaalie, 1997; Sultan et al., 1992). Both aspects support the tidal wave theory of cerebellar function discussed later (for further details see Braitenberg et al., 1997). Mossy fibers convey a wide spectrum of sensory and nonsensory signals to the cerebellum. Early work on mossy fibers mediating somatosensory information, based on surface-evoked potentials by Snider (Snider and Stowell, 1942), suggested a somatotopic pattern of cutaneous somatosensory projections to cerebellar cortex. However, later analysis involving more subtle micromapping pointed to a much more complex “fractured” representation of the body surface, characterized by the fact that neighboring patches of cerebellar cortex may represent non adjoining parts of the body surface and that a given part of the body surface may project to multiple patches on the cerebellum (Welker, 1987; Shambes et al., 1978). It is still a matter of debate, how this mosaic relates to the parasagittal organization of the climbing fiber system (see later; Bower and Woolston, 1983).
C.
Functional Interpretation of the Cerebellar Architecture
The anisotropic structure of the cerebellar cortex, sketched in the foregoing, led Braitenberg and Atwood (1958) to suggest that cerebellar cortex might serve as
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a timing device. The early version of this model held that the slow transmission (about 0.3 d s ) along individual parallel fibers would yield temporal delays appropriate to generate the temporal pattern needed to coordinate a group of muscles involved in a given niovement. Unfortunately, the parallel fiber length available would permit delays in the range of tens of milliseconds only that would be too short for movements, which mostly extend over hundreds of milliseconds. In a more recent version of the timing theoiv (Braitenberg, 1967; Braitenberg et al., 1997). Purkinje cells are supposed to detect synchronous activity in their parallel fiber input (the so-called tidal wave) arising from a precise temporal input pattern (differences between consecutive inputs in the range of a few milliseconds) through the mossy fibers and the granule cells. Although other studies have lent support to the existence of such precise temporal patterns in the cerebral cortex (Abeles et al., 1993), how the Purkinje cells and the deep cerebellar nuclei cells might read out and transfer the signals mediated by the tidal wave is still a matter of ongoing research.
D. Long-Term Depression Each cerebellar Purkinje cell receives two types of excitatory inputs, one from parallel fibers, the other from a climbing fiber. When these two types of inputs are activated conjunctively, a long-lasting depression of parallel fiber-to-Pukinje cell transmission results (Ito and Kano, 1982). This modification of synaptic efficacy, long-term depression (LTD), complements long-term potentiation (LTD), the other form of activity-dependent synaptic plasticity in the brain. The two are thought to be the major mechanisms underlying certain types of learning and memory, and LTD has been suggested to be the mechanism underlying motor learning, a putative cerebellar functions first suggested by the influential theories on cerebellar function by Marr and Albus (Marr, 1969; Albus, 1971; see Chap. 2). LTD is hypothesized to be a postsynaptic phenomenon, reflecting a desensitization of Purkinje cell AMPA receptors, which sense the parallel fiber transmitter (Kano and Kato, 1987). This desensitizaton seems to result from a phosphorylation of these receptors, induced by a cascade that, among others, involves the release of nitric oxide from activated climbing fibers, a consecutive increase in cGMP levels, and activation of several enzymes, such as phospholipase A2, protein kinase C, and tyrosine kinases (Shibuki and Okada, 1991; Daniel et al., 1998). In line with the view that cerebellar LTD is the basis of motor learning is the observation that niGluR1 niutant mice show deficient LTD as well as an impaired conditioned eyeblink response, a specific example of motor learning. On the other hand, the same mutants do not show any disturbance of their cerebellar anatomy or deficiencies of synaptic transmission from parallel or climbing fibers to Purkinje cells (Aiba et a]., 1994). The interpretation of LTD in the context of motor learning has been challenged for several reasons. First, it has been disputed whether the cerebellar cor-
Architecture of the System Cerebellar
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tex itself is indeed essential for storing learned behavior (Bloedel et al., 1991). Second, the Mm-Albus theory requires that the parallelfiber signal (equivalent to the conditioning stimulus) preceeds the climibing fiber signal (the unconditioned stimulus). However,LTD has been best evoked in the reverse order (Karachot et al., 1994). Third, all experiments, revealing LTD, have been carried out under highly unnatural conditions; namely, in the absence of normal levels of inhibition, achieved by the application of GABA, receptor blockers, such as bicuculline, to the preparation (It0 and Kano, 1982). In view of the aforementioned reservations, De Schutter (1995) has proposed that LTD might be autoinduced by parallel fiber input, rather than by climbing fiber activity. Rather than serving motor learning, LTD, according to this author, helps prevent overstimulation of Purkinje cells by parallel fiber input.
111.
DEVELOPMENT OF THECEREBELLUM
The cerebellar cortex is a brain region that is exceptionally well-suited for studies trying to reveal the developmentof central nervous structures. This is due to the few and morphologically well-defined classesof cells present in the cerebellum, which makes them easy to identify and to discern any maldevelopment in their appearance as well as the crystal-like arrangement of some of the neurons and the intrinsic fibers that allows one to observe any deviation from the normal structure with ease. This is why major developmental concepts, such as the notion that neuron generation follows a precisely timed schedule, were first formalized for the cerebellum (Rakic, 1972; Bayer and Altman, 198’7).
A.
Origin and Migration of Cerebellar Neurons
All cerebellar neurons originate from the neuroepithelium that surrounds the latcereral recess of the fourth ventricle in the pons and medulla and is termed the ebellar anlage. The first cerebellar neurons born in the rat at E13-15 are those that later form the deep cerebellar nuclei (Altman and Bayer, 1985b) (see later). The future Purkinje cells follow them shortly in the rat at E14-El5. They stay in externalgranular a cortical transition zone in the cerebellar anlage, until the layer (or externalgerminal layer, according to Bayer and Altman) appears at E17. They then start to proliferate, covering the cerebellar anlage (Altman and Bayer, 1985a). In the human cerebellum, the Purkinje cellsof the cerebellar anlage segregate into five to eight parasagittally oriented clusters (Maat, 1981). In the rat the cells of the external germinal layer start to proliferate (P4-7), giving rise to the many granule cells; ultimately covering the whole cerebellar anlage. Cell proliferation in the external granular layer ends at P19, and the granule cells descend to theirfinal position in the internal granular layer from P12 P21-30. to It is stillunclearwhether basket and stellate cells actually emerge from the
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Purkinje cell part of the cerebellar anlage (Napieralski and Eisenman, 1993), or from the external granular layer (Altman and Bayer, 1978).
B. NeuronalDifferentiation The pattern of neuronal differentiation in the cerebellar cortex has been extensively studied since the days of Ramcin y Cajal (1909). Granule cell diflerentiation starts alreadyin the external granular layer. The granule cells form twohorizontally oriented growth cones that grow in opposite directions laterolaterally, later becoming the parallel fibers. At this stage (P12), the granule cells start their descent to the future internal granular layer, first approaching the Purkinje cells, then bypassing them,and finally stopping below in the internal granule cell layer proper. This downward migration of the granule cells is guided by the radiallyarranged Bergmann glia fibers as well as by other radially arranged neuronal processes, such as Purkinje cell dendrites (Hager et al., 1995). During the migration, the early axonal processesof the granule cell turn into T-like a structure, consisting of the precursors of the parallel fibers. They stay in the external granular layer, which transforms into the molecular layer, and are connected to the descending soma by an unpaired and radially oriented axonal segment that extends to become the later ascending partof the granule cell axon. The close aligrnent of theascendingaxonestablishedduringthedescent of thegranulecellsis thought to be important for ensuring multiple synaptic connections with Purkinje cells. Unlike the granule cells, the Purkinje cells stay in place while their dendritic trees and axons differentiate. First dendriticand axonal processes are seen at P3-7, shortly after the Purkinje cell precursor cells have moved to cover the cerebellar anlage and the differentation of processes ends at P 3 0 4 5 (Altman, 1972; Takacs and Hdmori, 1994), in time with the final differentiation of the parallel fibers. Cerebelladeficient in granule cellsand parallel fibers, either as a consequence of the weaver mutation or x-ray irradiation, surprisingly develop (Dumesnilbousez and Sotelo, 1992; Lannoo et al., 1991) postsynaptic spines, despite the lack of their presynaptic parallel fibers (Rakicand Sidman, 1973). Although these observations suggest that intrinsic factors do contribute to the differentaof basket, stellate,and tion, the workof Altman (1976) emphasized a crucial role granule cells for shaping the Purkinje cell dendrites. The study was based on x-ray irradiationapplied at differentdevelopmentalstages, and theresults showed that basket and stellate cells are crucial for establishing the correct orientation of the primary and secondary dendrites, respectively, whereas the parallel fibers are critical for the correct maturation and arrangement of the tertiary spiny branchlets. These and other studies (Hillman et al., 1988) imply that the striking geometric orientationof the Purkinje cell dendrites is shaped by the parallel fibers.
Architecture of the Cerebellar System
C.Development
15
of Mossy and Climbing Fibers
The two major afferents of the cerebellum grow and differentiate at different stages, The climbing fibers are the first to establish contacts with the Purkinje cells, Mossyjibers, on the other hand, reach their at birth in mice (Mason et al., 1990). respective targets, the granule cells, not earlier than postnatal6-15, daysprobably a direct consequenceof the fact that their targets, the granule cells do not start to migrate into the internal granular layer before P5. After having reached the internal granular layer, mossy fibers establish a surplusof synaptic contacts with granule cells. In a subsequent stage, which continues late into adult life (until P40), these synaptic contacts are pruned, with the consequence that the overall number of mossy fiber-granule cell synapses again decreases(HAmori and Somogyi, 1983). Interestingly, about postnatal day5, when the granule cells begin to descend and are not yet available in the internal granule cells layer, mossy fiber can be seen in transient contact with Purkinje cells. Conversely, climbing fibers transiently exhibit the rosette-like synaptic specialization typical of mossy fibers in the vicinity of the descending granule cells (Mason and Gregory, 1984). Climbing jibers find their Purkinje cell targets, at least in part, guided by chemical attractors expressed transiently during development by Purkinje cells (Wassef et al., 1992a, b).At an early age (i.e., before P14 in the mouse) Purkinje cells are innervatedby multiple climbing fibers that then begin to regress to leave a given Purkinje cell in contact with a single climbing fiber (Dupont and Crkpel, 1979). This process of climbing fiber elimination is impaired in mutant mice lacking protein kinase Cy(PKCy) (Kano et al., 1995), in mutants lacking the metabotropicglutamatereceptor1(Kanoetal.,1997)andintheGluR62 receptor-deficient mutant (Kashiwabuchi et al., 1995). Because the molecules affected in these mutations are all thought to be involved in long-term depression of the parallel fiber synapse, it seems that the normal, adult pattern of climbing fiber innervation depends on the involvementof climbing fibers in the processes underlying long-term depression.
D.MolecularCompartments
in the Cerebellum
The expression of a number of molecules displayed by Purkinje cells show a characteristic, highly anisotropic dependence on location in cerebellar cortex (see HerrupandKuemerle,1997).Typically,theexpressionstaysconstant if one moves parallel to the rostrocaudal parasagittal axis, whereas it changes periodically if one moves orthogonally to that axis, thereby defining parallel cortical stripes or ribbons of about lmm in diameter. Generally, seven of these parasagittal compartments can be delineated on each side, and they seem to coincide with the compartmentalizations exhibited by the corticonuclear and the olivonuclear projections. The molecules exhibiting these spatial patterns have different func-
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tions: they are either proteins or glycolipids, and include, for instance, the cGMPL7 dependent kinase (Wassef and Sotelo, 1984) and the Purkinje cell marker (Oberdick et al., 1990). Although the markers mentioned so far are expressed C [marks zebrin 11-positive only during development, others, such as aldolase Purkinje cells (Hawkes andHemp, 1995)], and the complementary P-path(9-0acetylgangliosides (Lecferc et al., 1992; for a review see Herrup and Kuemerle, 1997) are also present in the adult cerebellum. The zebrins are probably the best studied of these pattern-forming markers. Zebrin stripes are presenta in wide variety of animals, ranging from fish to mammals, the only clear exception so far being the lamprey (Lannoo and Hawkes, 1997), which is believed to have the most primitive Cerebellum (AriSns Kappers et al., 1960). Unfortunately, studies on the molecular compartmentalization of the human cerebellum are rare, and the few carried out on the adult brain that are available have failed to bring up evidence for molecular compartmentalization [for instance, with the Purkinje cellspecific antibody Q113 (Plioplys et al., 1985), which delineates parasagittal compartments in the rat (Hawkes and Leclerc, 1987)]. At any rate, thereis evidence for parasagittal Purkinje cell compartmentalization in the human cerebellum in early stages of development (Maat, 1981). The pattern of parasagittal ribbonsis supplemented by an orthogonal, organizational principle, based on two borders that delineate the anterior lobe from theposteriorlobeandtheposteriorlobefromtheflocculonodular 1obe.The Purkinje cells in these three different anteroposterior compartments seem to orignate from distinct precursor cells in the primordial cerebellar anlage (Herrup and Kuemerle, 1997) and can be differentiated through either the presence of the or the genes Wnt-7b for the boundary between the anterior and the posterior lobe genes En-2 and L7:Zac7 for the boundary between the posterior and the flocculonodular lobe. Several “cerebellar” mouse mutants show patternsof cerebellar degeneration that reflect the parasagittal or anteroposterior compartmentalization of cerebellar cortex. For instance, in the Purkinje cell degeneration (PCD), the nervous and the tambaleante mutants, the surviving Purkinje cells lie in parasagittal bands with interspersed bands of degenerated cells (Wassef et al., 1987). On the other hand, both the meander tail (Ross et al., 1990) and the leaner mutants (Herrup andWilczynski,1982)havedegenerationsaffectingtheanteriorlobemore strongly, a pattern that is reminscentof the one in “alcoholic” cerebellar atrophy (see Chapter 28).
IV. THE SOURCES OF MOSSY FIBERS The term precerebellar nuclei is used to capture those cell groups in the brain stem sending axons to the cerebellum. All of these axons, with the exception of
Architecture of the System Cerebellar
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those originating from the inferior olive, end as mossy fibers. The precerebellar nuclei comprise the inferior olive, dealt with in a separate section of this chapter, the pontine nuclei (PN), the reticular tegmental nucleusof the pons (nucleus reticularis tegmenti pontis;NRTP), the lateral reticular nucleus (LRN), located lateral to the inferior olive, and several minor nuclei.
A. ThePontineNuclei 1. Connectivityand intrinsic Organization The pontine nuclei (PN) are the largest of the precerebellar nuclei (Brodal, 1981). The neurons of the PN surround the fibersof the cerebral peduncle on theirway through the pons. Based on their location relative to the fiber bundles of the cerebral peduncle and subtle cytoarchitectural criteria, medial, ventral, lateral, dorsal, and peduncular parts have been distinguished (Sunderland, 1940; Nyby and Jansen, 1951; Schmahmann and Pandya, 1991). Because these boundaries are vague and ill-defined, the popular parcelling into various nuclei (e.g., the dorsolateral PN, the dorsomedial PN) should be understood as a useful topographical characterization, rather than as a description of distinct nuclei. Differencesin the function of different partsof the PN are largely, if not exclusively, determinedby differences in connectivity, which rarely reflect the boundaries between these nuclei. Although the input to thePN is derived from a numberof places, by far the most important sourceis layer 5 of the cerebral cortex. Neurons projecting to the PN are found in nonhuman primates in a rather compact region, bordered by the cingulate sulcus medially, the lateral fissure laterally, the superior temporal sulcus caudally, and the more rostral parts of frontal cortex rostrally (Sunderland, 1940; Nyby and Jansen, 1951; Jansen and Brodal, 1958; Brodal, 1978; Wiesendanger et al., 1979; Glickstein et al., 1980, 1985; Hartmann-von Monakow et al., 1981; Vilensky and Van Hoesen,1981;Fries,1990;Leichnetzetal.,1984; Schmahmann and Pandya, 1993, 1997). As a ruleof thumb, all parts of cerebral cortex. involved in motor behavior and spatial orientation seem to maintain strong connections to the PN (Glickstein et al., 1985). That more than half of cerebral cortex of primates projects to thePN explains the enormous sizeof the cerebrocorticopontine fiber bundle that has been estimated to involve2 X 20 million fibers in humans, a number that exceeds that of the number of corticospinal or pyramidaltractfibers by afactor of 20 (Tomasch,1969). The fibers of the cerebrocorticopontine projection descend with those of the cerebrocorticospinal tract in the internal capsule and the cerebral peduncle and end almost inclusively on the ipsilateral side. Axons originating from a small cortical region end in multiple, widely scattered and rather sharply demarcated pontine lamellae which take the appearanceof disparate patches with a diameter of several hundred micrometers on frontal sections through the PN (Nyby and Jansen, 1951; Brodal, 1978;
ai.
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Wiesendangeretal.,1979; Hartmann-von Monakowet al., 1981; May and Anderson, 1986; Schwarz and Thier, 1995). Different cortical regions seem to project to different setsof lamellae, even if the cortical areas or regions regarded have related functions: rat (Schwarz and Thier, 1995; Schwarz and Mock, unpublished observation); and monkey (Thier, Cavada, and Ilg, unpublished observation; see, however, Brodal and Bjaalie, 1997 afor different view). Corticopontine axons seem to make rather selective contact with individual pontine projection neurons. These pontine projection neurons tend to keep their dendrites within a given patch subserved by a given cortical region, thereby avoiding making contact with axon terminals in neighboring patches receiving input from other parts of cortex (Schwarz and Thier, 1995). Divergence and a lack of significant convergence of efferents from different cortical areas seems to be one of the hallmarks of the corticopontine projection.The second oneis the abandonmentof the simple topographic rules governing the sensory and motor representations in cortex (Schwarz and Thier; 1995).The essence of these simple cortical topographies is continuity: neighboring points on the sensory or motor surface are mapped onto neighboring points of the cortical area at stake. The larger the distance on the sensory or motor surface, the larger will be the distance between the corresponding two cortical representations. On the other hand, the representation of these surfaces in the PN is clearly noncontinuous.If one injects two locations in a sensory cortical area with two different anterograde tracers, one finds complex patterns of overlap and nonoverlap of the corticopontine axon terminal fields in the PN, rather than obtaining nonoverlapping terminal fields, of which the distance in the PN would reflect the distance of the two corresponding points on the sensory surface. We have argued elsewhere that the featuresof the corticpontine projections outlined might be the basis of the elaboration of the so-called fractured topography (see Sec. II. B) (Schwarz and Thier, 1995, 1999). The large majority of all pontine afferents originate from the cortex. The remainder emanates from a number of subcortical nuclei, such as the ventral nucleus of the lateral geniculate body (Graybiel, 1974), the inferior and superior colliculi(Casagradeetal.,1972;Hartingetal.,1973;BeneventoandFallon, 1975; Kawamura, 1975; Harting, 1977; Glickstein etal., 1980), several pretectal nuclei (Weber and Harting, 1980), the mamillary nuclei (Aas and Brodal, 1989), of the raphe nuclei several hypothalamic nuclei (Aas and Brodal, 1988), parts (Mihailoff et al., 1989), and the zona incerta (Mihailoff, 1995). The latter two are important as sources of fibers mediating GABAergic inhibition and serotoninergic modulation, respectively. Another interesting sourceof pontine afferents are the deep cerebellar nuclei (Angaut, 1970; Brodal et al., 1972; Batton et al., 1977; Chan-Palay, 1977; Asanuma et al., 1983; Gerritts et al., 1984). Most of the cerebellofugal fibers leave the cerebellum through the superior cerebellar peduncle and make exclusively excitatory, most probably glutamatergic synapses
Architecture of the System Cerebellar
19
inthePN(SchwarzandSchmitz,1997).Considerablespeciesdifferencesin the size of the cerebellofugal nucleopontine tract and its termination in the PN have been reported in the literature, and it has been suggested that there may actually be a phylogenetic trend to reduce this tract (Gerrits et al., 1984). Nevertheless, in nonhuman primates, projections from the fastigial nucleus as well as the dentate nucleus have been demonstrated. These afferents terminate in the dorsal parts of the pontine nuclei (Batton et al., 1977; Asanuma et al., 1983; Chan-Palay, 1977). Most PN neurons are large-projection neurons, the axons of which end as cerebellar mossy fibers with collaterals sent to the deep cerebellar nuclei (Hoddevik, 1975; Eller and Chan-Palay, 1976; Hoddevik et al., 1977; McCrea et al., 1977; Brodal andWalberg, 1977; Ruggiero et al., 1977; Hoddevik, 1978; Brodal, 1979, 1980a,b, 1982; Rosina et al., 1980; Gerrits and Voogd, 1987; Shinoda et al., 1992; Mihailoff, 1993). The size and the significance of this collateral pathway to the deep cerebellar nuclei has been a subject of some controversy, which lasts until the present day. Assuming that both the collateral pathway to the DCN as well as the projection back from the DCN to the PN are substantial in primates, (i.e., the obvious question to ask Do is: the two projections establish a closed loop do the same cells that send axon collaterals the the DCN receive feedback from the DCN neurons contacted)? In addition to the large and rather homogeneous group of PN projection neurons, there exists a less numerous groupof paucidendritic neurons exhibiting many of the morphological featuresof intrinsic neurons, the axonsof which stay within the boundaries of the PN (Cooper and Fox, 1976; Thier and Koehler, 1987). These neurons, which are found in significant numbers only in the PN of primates, are most likely GABAergic (Thier and Koehler, 1987). Althoughnonprimates show few if any of these neurons (Border and Mihailoff, 1985; Brodal et al., 1988; Mock et al., 1999), nevertheless, they contain a dense plexus of GABAergic fibers, largely originating from the zona incerta (Mihailoff, 1995), which is most likely responsible for the strong GAB&-mediated inhibition seen in the PN of rats (see later). Pontine projection neurons send their axons to their targets in the cerebellum by the pontine brachium, mostly after having crossed the midline at the level of the PN. Convergence seems to be the dominating organization principle underlying this projection with small regions in the cerebellar cortex receiving input from widespread parts of the PN (Hoddevik, 1975; Hodeevik et al., 1977; Brodaland Walberg, 1977;Brodal,1979,1980a,b,1982;ThielertandThier, 1993).Large-scaledivergence,characterized by the temination of fibersin widely segregated parts of the respective target structure, the dominant theme in the corticopontine projection, is also an important featureof the pontocerebellar projection (Rosina et al., 1980; Brodal, 1982, Brodal and Bjaalie, 1997).
Sultan et al.
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2.
Physiology and Behavior
a.MembraneProperties
andSynaptic Mechanisms. For many yearsknowledge about the membrane physiology of PN neurons and the synaptic transmission onto them was largely confined to sporadic intracellular recordings performed in vivo (Allen et al., 1969, 1970, 1971, 1975a,b; Sasaki etal., 1970; Tsukahara and Bando,1970).Recently,however,substantialprogressinunderstandingthe single-cell electrophysiology of PN neurons has been made by intracellular recordings conducted in brain slice preparationsof the rat brain stem (Schwarz et al., 1997; Mocket al., 1997). These in vitro recordings demonstrated that PN neurons are endowed with an abundant set of ionic conductances and postsynaptic transmitter receptors. On the one hand, PN neurons possess two different conductances responsible for all-or-none potentials: the fast-inactivating sodium conductance, and a high-threshold Ca2+ conductance underlying theNa+ action poCa2' spike, respectively. On the other hand, graded tentials and the high-threshold potential responses are based on a persistent sodium conductance as well as on several different potassium conductances. The latter group is composedof Ca2+dependent and Ca2+-independent K' conductances underlying two kinds of afterhyperpolarizations, a fast inward-rectifying conductance, anda delayed outwardrectifyingconductance. PN cells,however,lackionicconductancesenabling intrinsically generated rhythmic firing. Therefore, they are absolutely nonspontaneously active at rest in the slice preparation. Intracellular stimulationssuwith prathreshold depolarizing current pulses evoke regular trains of action potentials that show substantial firing rate adaptation. The regular firing pattern, however, switches to an irregular one with intercalated periods of irregular subthreshold membrane potential fluctuations during persistent depolarizations. Synaptic transmission ontoPN neurons is both excitatory and inhibitory: excitation is mediated byAMPA- and NMDA-type glutamate receptors, whereas inhibition is solely transmitted by GABA, receptors. The excitatory synaptic transmission is subject to a robust frequency-dependent short-term plasticity preferring frequencies of about 20-50 Hz. Taken together, the basic properties of PN neurons closely resemble those of cerebrocortical reguZar-spiking neurons and are very different from any of the neurons of the cerebellum or the inferior olive. Functionally,as well as clinically, itis important that the PN receive input from brain stem nuclei known to modulate the membrane propertiesof many neurons in other brain regions (Mihailoff et al., 1989). A recent attempt, undertaken to evaluate the modulatory effectof serotoninergic input onto PN neurons, showed that bath application of serotonin consistently increased the excitability of PN neurons in vitro, but decreased the synaptic transmission onto them (Mock et al., 1998). b. In vivo Observations. Most of whatwe know todayaboutthefunctional role of the primate pontine nuclei is based on work on eye movements (Suzuki
Architecture System Cerebellar of the
21
and Keller, 1984; Mustari et al., 1988; May et al., 1988; Thier and Erickson, 1992a,b; Thier et al., 1988, 1989, 1991, 1993, 1994; Dicke et al., 2000). Converging evidence from electrophysiological studies of the PN of awake, behaving monkeys, from experimental lesionsof the pontine nuclei in monkeys, and from the study of “natural” lesions of the human PN have suggested that the dorsolateral partof the PN, the so-called dorsolateral pontine nucleus (DLPN), is a major element in a cerebropontocerebellar pathway for smooth-pursuit eye movements. The cerebellum, in turn, has been thought to hook up to the eye movements effectors in the brain stem by way of the caudal fastigial nucleus. The view that emergedfromthisearlywork,therefore,suggestedtwoparallelpathways through the brain stem, a pathway for saccades, build on several phylogenetically old structures in the brain stem tegmentum, such as the superior colliculus and theparamedianpontinereticularformation,andasecond,phylogenetically younger pathway for smooth-pursuit through the dorsolateral pontine nucleus. Recently, it became clear that this concept of separate brain stem pathways for saccades and smooth-pursuit is hardly tenable, given that the dorsal pontine nuclei seem to house not only smooth-pursuit-related neurons, but also a large number of saccade-related neurons (Dicke et al., 1999a). Moreover, unlike eye movement-related neurons in cerebral cortex, which respond either to saccades or to smooth-pursuit, manyof those in the PN can be driven by both types of targetdirected eye movements (Dicke and Thier, 1999).
S. TheNucteusReticularisTegrnentiPontis The nucleus reticularis tegmenti pontis(NRTP) is located dorsal to the PN, from which it is separatedby the fibersof the medial lemniscus. Its neurons share crucial morphological features with projection neurons in the neighboring dorsal PN, which, from a morphological viewpoint, are as close to the NRTP as to the ventral PN (Schwarz and Thier, 1996). Similar to the PN, the NRTP receives cerebral afferents and projects to the cerebellum through the middle cerebellar peduncles, The projection to the cerebellum is bilateral, with an emphasis on the contralateral side. In primates, the cerebral input is mainly derived from the ipsilateral primary sensory and motor cortices (Brodal and Brodal, 197 1; Brodal, 1980a) with some evidence for additional input from frontal as well as parietal cortex (Leichnetz et al., 1984). In quantitative terms, more important than this cerebral input is the input from the contralateral deep cerebellar nuclei through the superior peduncle (Brodal et al., 1972;Chan-Palay, 1977; Noda et al., 1990; Mihailoff, 1993). The afferents originate from the dentate nucleus and the interpositus nucleus with a more modest contribution from the fastigial nucleus. Other sources of input are the contralateral vestibular nuclei and the superior colliculus (Huerta and Harting, 1984).The fibers from the NRTP mostly projectto the cerebellar vermis, especially to lobules VI and VII, and the flocculus (Hoddevik,
22
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1978; Brodal, 1980b;Yamada and Noda, 1987; Thielert and Thier, 1993). In other words, the projection from theNRTP emphasizes parts of the cerebellum which, in turn, project to the fastigial nucleus, rather than to those projecting to the dentate and interpositus nucleus, from which most of the NRTP afferents are derived. The main NRTP targets in the cerebellum, lobuliVI and VI1 and the flocculus, are involved in the organization of eye movements. It is, therefore,not too surprising that the physiological work on the NRTP has focused on oculomotor functions and has indeed provided rich evidence for contributions to saccades, smooth-pursuit, and vergence eye movements (Crandall and Keller, 1985; Van Opstaletal.,1996;Gamlinetal.,1995; Yamada etal.,1996). The work by Yamada et al. suggests that the NRTP is divided functionally into a rostral, smooth-pursuit-related portion and a caudal, saccade-related segment.
C, OtherBrainsternPrecerebeilarNuclei The lateral reticular nucleus is a precerebellar nucleus mediating spinal as well as cortical signals to the cerebellum. It is located lateral to the inferior olive. It projects to the cerebellum through the inferior cerebellar peduncle, mainly to the anterior lobe and the paramedian lobule (Kunzle, 1975), with some fibers to all deep cerebellar nuclei (Matsushita and Ikeda, 1976; McCrea et al., 1977;ChanPalay 1977). The main afferent input is from the spinal cord, conveying bilateral hindlimb and forelimb information, relayed ainsomatotopic pattern to the lateral reticular nucleus and through this nucleus on corresponding areas of the anterior al., 1974). Additional input is derived lobe (Corvaja et al., 1977; Clendenin et fromprimarysomatosensorycortex(Kuypers,1958a,b),thecontralateralred nucleus (Edwards, 1972; Corvaja et al., 1977), the ipsilateral vestibular nucleus (Ladpli and Brodal, 1968), the superior colliculus (Kawamura et al., 1974), and the fastigial nucleus (Batton et al., 1977; Corvaja et al., 1977). The paramedian reticular nucleus is a small nucleus located in the medial medulla at the level of the hypoglossal nucleus, the major targetof which is the cerebellum. Afferents originate, among other, from the spinal cord (Mehler et al., 1960) and from somatosensory cortex (Sousa-Pinto, 1970). Other sources of cerebellar afferents are the perihypoglossal nuclei. They surroundthehypoglossalnucleusandconsist of theintercalatenucleus,the nucleus of Roller, and the largest of the group, the nucleus prepositus hypoglossi. These nuclei are noteworthy as centers involved in the integration of information relevant for the organization of eye movements. They project to the anterior lobe, to the posterior vermis, the uvula, the nodulus, the flocculus, the fastigial nucleus, and the interpositi nuclei (Frankfurter et al., 1977; Ruggiero et al., 1977; Alley et al., 1975; Kotchabhakdi et al., 1978) and, in addition, to several motor and premotor brain stem centers for eye movements (Graybiel and Hartwieg, 1974).
Architecture Cerebellar of the
System
23
An important sourceof eye-movement-related information for the cerebellum is the paramedian pontine reticular formation, a premotor center for saccades, located in the midline brain stem tegmentumbetween oculomotor nuclei, which projects to lobuli VI and VI1 and, in turn, receives input from the caudal fastigial nucleus (Yamada and Noda, 1987; Thielert and Thier, 1993). Finally, among the minor projections to the cerebellum, the ones originating from the locus coeruleus, the raphe nuclei are noteworthy as sources of norKerr and adrenergic and serotoninergic input to the cerebellum (Dietrichs, 1988; and the Bishop, 1991). Cholinergic fibers to the uvula, the nodulus, the flocculus, ventral flocculus emanate from the medial vestibular nucleusand the prepositus hypglossi ( B m a c k et al., 1992a,b).
D. TheSpinocerebellarTracts Besides the vestibular system, the spinocerebellar tracts provide the only direct i n f o ~ a t i o nfrom the periphery to the cerebellum. They convey signals from various peripheral proprio-, extero-, and enteroceptors. The afferents from the peripheral receptors contact neurons located on different levels within the spinal cord, including the dorsal column nuclei which, in turn, project as mossy fibers to the cerebellar cortex and deep cerebellar nuclei through the inferior or superior cerebellar peduncles (Yoss, 1952a,b). Basedon the location of the cells of origin, the spinocerebellar system has traditionally been subdivided into five distinct tracts: the dorsal spinocerebellar tract (DSCT), the ventral spinocerebellar tract (VSCT),therostralspinocerebellartract(RSCT),thecuenocerebellartract (CCT), and a tract arising from the central cervical nucleus (CCN). The DSCT arises from neurons within Clarke's column located in thoracic to upper lumbar segments (T1-L2 in humans) and ascends uncrossed within the dorsal part of the lateral funiculus (Boehme, 1968; Loewy, 1970; Yoss, 1952a). The VSCT most probably originates from the so-called spinal border cells in L3-L6 (Burke et al., 1971). It crosses at segmental levels, ascendsin the ventrolateral funiculus, and recrosses within the cerebellum (Yoss, 1952b;Matsushita,andOkado,1981). Cells giving rise to the RSCT havebeen identified within the cervical segments C4-C8 (Matsushita and Hosoya, 1979). Their axons ascend uncrossed within the lateral funiculus (Oscarssonand Uddenberg, 1964, 1965; Oscarsson, 1965). CCT neurons are located within the mainand the external cuneate nuclei (Cooke et al., 1971a,b; Jansen and Brodal, 1954; Grant, 1962;'Holmqvist etal., 1963). Finally, the crossed fibersof the CCN originatein Cl-C4 (Wiksten, 1979). They allcarry large-caliber, myelinated axons, with conduction. velocities ranging between 30 and 125 m/s (Burke et al., 1971; Lundbergand Oscarsson, 1960; Oscarsson and Uddenberg, 1964, 1965). Some observations suggest the existence of even more spinocerebellar tracts (see Oscarsson, 1973).
24
Sultan et al.
The spinocerebellar tracts differ in various anatomical and functional criteria, such as the location of their receptive fields, receptive field size, or the properties of the peripheral receptor served: the DSCT and theVSCT, represent the hindlimbs and lower trunk, whereas the RSCT and the CCT represent the forelimbs and upper trunk (Holmqvist et al., 1963; Oscarsson and Uddenberg, 1964). The neurons of the CCN receive input from the neck and the vestibular system (Hirai et al., 1978). DSCT andCCT neurons have small receptive fields. They are often innervated by afferents from single muscles or small groups of muscles acting synergistically ata single joint,or by skin areas as small as1 cm2 (Holmqvist et al., 1956; Jansen et al., 1969; Lundberg and Oscarsson, 1960). The direct excitatory synaptic transmission to these neuronsvery is prominent and effective (Kuno and Miyahara, 1968; Lundberg, 1964; Oscarsson, 1965; Jansen et al., 1966, 1969; Rkthelyi, 1970), their firing frequency is high (up to 500 spikes per second; Eccles et al., 1961), and shows a linear relation to the membrane depolarization (Eide et al., 1969a,b). Thus, they are able to faithfully transmit peripheral input to the cerebellum. Finally, DSCT as well asCCT terminate ipsilaterally in restricted areas of the anterior lobe, the pyramis, and the paramedian lobe (Ekerot and Larson, 1972; Grant, 1962; Korlin and Larson, 1970; Somana and Walberg, 1980). On the other hand, the receptive fieldsof VSCT and RSCT neurons are often larger, and they receive much more polysynaptic inhibitory inputs on the segmental level (Lundberg and Weight, 197 1;Oscarsson and Uddenberg, 1964, 1965; Oscarsson, 1965). Furthermore, both VSCT and RSCT neurons are influencedby descending inhibitory and excitatory fibers carried by rubrospinal, reticulospinal, vestibulospinal, and corticospinal tracts (Baldissera and Roberts, 1975; Baldissera and ten Bruggencate, 1976; Lundberg and Weight, 1971). The VSCT as well as the RSCT are characterized by a bilateral termination within the anterior lobe of the cerebellum (Matsushita and Okado, 1981). From many of these properties, Lundberg (197 1) proposed that the VSCT is concerned with monitoring the synaptic transmission within the poolof interneurons of individual segments. In other words, the VSCT would contribute mainly to signal the internal state of lower motor centers, rather than transmitting peripheral information in the strict sense.A similar function might be subserved by the RSCT, as suggested by the many similarities between this tract and the VSCT. In contrast, the DSCT and CCT seem to be more suited to convey information about mechanical stimuli, muscle length, tension, and velocity, or, as has been suggested recently, about the position of limb segments in relation to the limb axisor entire limbs in relation to the body axis (Bosco et al., 1996). Because of the converging input from neck muscles and the vestibular system,a comparable function, namely the signalingof head position and movements in relation to gravity and the body, has been suggested for the tract arising from the CCN (Ito, 1984). Table 1 summarizes the major features of the spinocerebellar tracts discussed.
Architecture of the Cerebellar System
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V. THE SOURCE OF CLIMBING FIBER AFFERENTS: THE INFERIOR OLIVE The inferior olive (IO) is unique among the precerebellar nuclei because it is the only sourceof climbing fibers (Szentigothai and Rajkovits, 1959; Desclin, 1974). This singular anatomical status is supplementedby several outstanding morphological and physiological featuresof IO neurons, suggesting a key roleof the IO within the cerebellar circuitry.
A.
GrossMorphology
The IO, located bilaterally at the ventromedial edge of the caudal partof the medulla oblongata, is composedof three main (principal olive, dorsal accessory01ive, and medial accessory olive) and several small (ventrolateral outgrowth, dmsal cap of Kooy, beta-nucleus, and dorsomedial cell column) subnuclei @rod& 1940; Kooy, 1917; Whitworth and Haines, 1986). All but a few IO neurons are projection neurons that send their axons exclusively to the contralateral cerebellum, contacting Purkinje cell dendrites as well as deep cerebellar nuclei (DCN) neurons by means of climbing fiber collaterals (Bloedel and Courville, 1981; Courville et al., 1977; Groenewegen, 1979; Voogd and Bigare, 1980; Anderson and Armstrong, 1987). Individual climbing fibers frequently branch at the level of the cerebellar cortex and innervate10-15 Purkinje cells (Escobar et al., 1968; Mlonyeni, 1973; Moatamed, 1966). The most salient feature of the interconnections between the IO and the cerebellum is that they form topographically organized, reciprocal loops. Climbing fibers from distinct groups of IO neurons, organized in so-called lamellae, terminate on Purkinje cells arranged in parasagittal zones, corresponding to the zones defined by the molecular markers discussed earlier. The axons of these Purkinje cells contact deep cerebellar nuclei (DCN) neurons that receive collateral input from the same IO lamellae. Finally, these DCN neurons project backto the IO neurons locatedin the corresponding lamellae (Ruigrok, 1997). A second, more indirect feedback from the deep cerebellar nucleiinvolvesvariousm6sodiencephalicnuclei(nucleus of Darkschewitsch, parvocellular part of red nucleus, and nucleusof Bechterew (Onodera, 1984). In addition to afferents from the deep cerebellar nuclei or from brain stem nuclei under their control, the IO receives afferent fibers from a varietyof others parts of the central nervous system: Spinal input reaches the IO by collaterals of spinocerebellar fibers. The trigeminal and vestibular nuclei complexes, the lateral and paramedian reticular nuclei, the perihypoglossal nucleus, and neurons widely distributed throughout the reticular formation form the group of medullary inputs. Subcerebral visual information is relayed to the IO by way of the superior colliculus, the pretectal nuclei, and the nucleiof the accessory optic tract. Direct cerebral input to the1 0 arises mainly from motor cortex, but additional cerebral
al.
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Table 1 Major Features of the Spirocerebellar Tracts
Receptive
lain origin Main Tract DSCT Clarke’s column; TI-L2 From muscles, joints, skin Small of hindlimbs and lower trunk
VSCT ‘Spinal border cells’; From muscles, joints, Large skin of trunk lower and hindlimbs L3-L6
CCT Main and external cuneate From muscles, joints, skin Small of trunk upper and forelimbs nuclei
RSCT Dorsal horn C4-C8, in From muscles, joints, skin lamina VI in C2-T1, 1aminaVII in C6-Tl Cl-C4CCN
of
Large
forelimbs and upper trunk Neck muscles and vestibular system
?
information is provided by indirect connections involving midbrain structures, the reticular formation, and the superior colliculus.
6 . FineStructure The IO consists mainly of projection neurons with medium-sized, spherical somata (diameter: 15-30 pm) and contains less than 0.1% interneurons (Nelson and Mugnaini, 1988; Walberg and Ottersen, 1989). The projection neurons may be classified by means of the morphology of their dendritic trees:The prevailing type is characterized by highly branched dendrites that frequently turn back toward the soma, whereas the second type has elongated, sparsely branched dendrites covering a much larger dendriticfield (Ruigrok andVoogd, 1990; Scheibel
Architecture of the System Cerebellar
27
Conduction
umed nvelocity termination MainCourse Restricted areas in the anterior lobe, pyramis, paramedian lobe; ipsilateral Widespread areas in the anterior lobe; bilateral
30-100
?
Lateral funiculus; uncrossed
Restricted areas in the anterior lobe, pyramis, paramedian lobe; ipsilateral Widespread areas in the anterior lobe; bilateral
Crossed
Lobuli I and I1
?
Dorsal part of lateral funiculus; uncrossed Ventrolateral funiculus; crosses at segmental level, recrosses within the cerebellum ?
m/s
90-125 m/s
95 d s
Transmission of sensory input from the hindlimbs and lower trunk to the cerebellum Signaling internal state of lower motor centers in lower spinal segments
Transmission of sensory input from the forelimbs and upper trunk to the cerebellum Signaling internal state of lower motor centers in upper spinal segments Signaling head position and movements in relation to gravity and body
andScheibel,1955).Bothtypes of dendriticarborsbearnumerousdendritic spines with remarkably long necks, which are key elements in the formation of the characteristic olivary neuropil (de Zeeuw et al., 1990b; Gwyn et al., 1977; Ruigrok et al., 1990). Commonly, five to six dendritic spines, originating from different neurons, are clustered forming the core of a so-called glomerulus. Most, IO participate in the formation of the glomerular if not all, spines within the cores. These cores are surrounded by several axonal terminals and glial sheaths (de Zeeuw et al., 1990a, b).The most important feature of the olivary glomeruli is that the spines located in their cores form an exceptionally high numberof gap junctions, the basis of an extensive electrotonic coupling of olivary neurons (de Zeeuw et al., 1989, 1990a; Sotelo et al., 1974). The number of neurons coupled by gap junctions has been estimatedby intracellular injection of Lucifer Yellow,
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Sultan et al.
a fluorescent dye able to permeate through gap junctions. Using this approach, it IO neurons are coupled in slices of guinea has been demonstrated that six to eight pig olivary glomeruli (Benardo and Forster, 1986). An even higher degree of coupling has been suggested basedon the analysis of synchonous activity of IO neurons in vivo. After pharmacologically enhancing rhythmical firing and reducing GABA-induced uncoupling (with harmaline and picrotoxin), it was proposed that hundredsof IO neurons couldbe coupled (de Zeeuw et al., 1996, Lang et al., 1996; LlinBs and Volkind, 1973).Estimates of thenumber of gapjunctions amount to 500-1000 for the total number of gap junctions formed by an indiIO neurons (de vidual IO neuron and to 10-20 gap junctions shared by two Zeeuw et al., 1997). A second characteristic featureof the dendritic structureof IO neurons may play a crucial role in the control of the electrotonic coupling. Close to the glomeruli, olivary dendrites show numerous varicosities that contain membranous cisternae, the lamellar bodies. Their density correlates with the of level cerebellar input as well as with the level of synchronous activity within the IO. Therefore, they may serve to control the turnover and assembly of gap junctions (de Zeeuw et al., 1995, 1997). The morphology of synaptic input to 1 0 neurons has been best studied for the direct cerebellar backprojection and the indirect loop through the mesodiencephalic nuclei. Terminals derived from DCN axons are GABAergic, have pleiomorphicvesicles,and form symmetricalsynapses.Incontrast,thesynapses made by theindirectloopareexcitatory,asymmetrical,andcontainround vesicles (de Zeeuw et al., 1988). About 50% of the synapses are made on dendrites inside the glomeruli.The remaining terminals predominantly contact nonglomerular dendrites, with only very few contacts formed on somata and axons. The most outstanding feature of the synaptic inputs to IO neurons is that every individual spine is contacted by excitatory as well as inhibitory terminals (de Zeeuw et al., 1989, 1990a,b,c). As will be discussed in the following, both inputs serve to translate increased activity in the DCN into a reduction of the amount of electronic coupling between IO cells.
C. PhysiologicalProperties Early electrophysiological studies of the IO carried out in vivo demonstrated some of the important properties of this structure. First, IO neurons fire at remarkably low frequenciesof 1-10 Hz (Armstrong etal., 1968). Second, they tend to show oscillatory firing, which may occur spontaneously (Armstrong et al., 1968), or be inducedby drugs such as the alkaloid harmaline (de Montigny and Lamarre, 1973; LlinBs and Volkind, 1973). The latter studies showed that harmaline induces a 10-Hz tremor that closely resembles physiological tremor. Third, olivaryneuronscharacteristicallyexhibitprolongedactionpotentials(Crill, 1970; Armstrong et al., 1968). Finally, IO neurons are electrotonically coupled
Architecture of the System Cerebellar
29
&lings et al., 1974). Since then, work on the IO has followed two different lines. o n the one hand, the intrinsic properties of IO neurons have been studied in slice of activity in Io neurons preparations of the IO. On the other hand, the influence on Purkinje cells and DCN neurons has been investigated in intact animals and in an isolated brain stem-cerebellar preparation. By intra- and extracellularly recording from IO neurons in slice preparations, LJin6s and Yarom (1981a,b) were able to characterize a set of ionic conductances and their subcellular distribution in olivary neurons. These conductances generate a sequenceof activation and inactivation, enablingIO neurons to fire rhythmically. The sequence starts with a fast,Na'-based, somatic action POtential followed by a prolonged (10-15 ms) plateau potential. The latter is elicited by Ca2+ influx through voltage-sensitive, noninactivating channels, with a high-activation threshold, located on the dendrites. A consequence of the influx of Ca2' is the activation of a Ca2'-activated K' conductance that not only abruptly terrninates the plateau potential, but also generates a massive and long250 ms). The AHP is most prominent lasting after-hyperpolarization (AHP; up to in dendrites. During this AHP the membrane potential is virtually clamped to the K' equilibrium potential and the membrane is completely inexcitable. The important, final step to generate rhythmic behavior is to depolarize the membrane again to elicit theNa+ spike. Llinhs andYarom proposed that this is achievedby a second, somatic Ca2' conductance that is inactive at rest, but deinactivates on hyperpolarization. Thus, after inactivation of the Ca2+-activatedK' conductance the low-threshold Ca2' conductance drives the membrane potential back to the threshold for the Na' spike. Recently, l3al and McCormick (1997) were able to demonstrate that a second hyperpol~zation-activatedchannel for Na' and K' ions (known as I,; McCormick and Pape, 1990) contributes to the redepolarization of IO neurons. The frequency of rhythmic firing inIO neurons critically depends on the durationof the AHP that, in turn, is correlated with the Ca2' influx during the high-threshold Ca2' plateau. Llin6s and Yarom (1986) also described Ca2'-based, subthreshold membrane potential oscillations (4-6 Hz, 5-10 mV amplitude) that occurred spontaneously in a fraction of IO neurons. Occasionally, the subthreshold oscillations generated somatic or dendritic spikes that always occurred during the depolarizing phase. Even more important was their finding that the subthreshold oscillations were similar in amplitude, frequency, and phase in pairs of simultaneously impaled IO neurons. This indicates that ensembles of IO neurons synchronize throughgapjunctions.Interestingly,intracellularcurrentapplicationtoindividual IO neurons did not alter the oscillatory rhythm, whereas gross extracellular stimulation, influencing large portions of coupled IO neurons, were able to transiently quench the subthreshold oscillations, alter the rhythm, or eventually, initiate oscillations in a previously nonoscillating ensemble. Does the olivocerebellar systep translate the rhythmic activity in the olivary neuronal network into rhythmic activity within the cerebellum? This ques-
al.
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tion has been addressed using anovel in vitro system, consistingof the brain stem and the cerebellum of guinea pigs, which was perfused through the arterial system (Llinriis et al., 1981; Llinriis and Miihlethaler, 1988). Stimulation of the IOevoked short-latency excitatory postsynaptic potentials (EPSPs) DCN in neurons followed by delayed inhibitory postsynaptic potentials (IPSPs). This sequence is explained by the direct excitatory input to DCN neurons by climbing fiber collaterals (Bloedel and Courville, 1981; Courville etal., 1977) and the direct excitatory climbing fiber input to Purkinje cells (Eccles et al., 1966b) that,in turn, directly inhibit DCN neurons. Addition of harmaline to the perfusate, which elicits EPSP-IPSP serhythmic firing in IO neurons, resulted in rhythmic IPSPs or quences in DCN neurons. The IPSPs were often large enough to generate rhythmic rebound firing in the DCN. Dissection of the inferior cerebellar peduncle, which carries the climbingfiber, impeded the rhythmic synaptic activity in DCN neurons, proving their olivary origin. What is the spatial pattern of cerebellar Purkinje cells controlled by ensembles of synchronously active IO neurons? Llinris and co-workers (Bowerand Llinriis, 1982; Llinriis and Sasaki, 1989; Sasaki and Llinriis, 1985; Sasaki et al., 1989; Yamamoto et a1.,1986) have tried to address this questionby recording simultaneously from multiple Purkinje cells in vivo. By using cross-correlation analysis, they were able to show that neighboring Purkinje cells tend to fire complex spikes synchronously.A tremendous increasein the number and spatial distribution of synchronously active Purkinje cells was observed after blocking the effects of CABAergic axon terminals in the IO (Lang et al., 1989) or, alternatively, by destroying the DCN (Llinriis, 1991), the likely sourceof these GABAergic fibers. These findings suggest that the function of the inhibitory feedback projection to the DCN is to restrict the extent of electrotonic coupling in the IO. Unlike the roleof the inhibitory input to the glomerular spines, the ofrole the excitatory input, mainly derived from the indirect projection from the DCNby the mesencephalic nuclei, isnot yet completely clear. It has been proposed that the indirect feedback might be synergistic to the direct feedback, by enhancing the effects of the inhibitory synapses on the glomerular spines (de Zeeuw et al., 1998). In summary, the sizeof neuronal ensembles within the IO being synchronously active at any given instant in time is likely to be dynamically controlled by inhibition, directly derived from the DCN, and excitation, indirectly derived from the DCN, through the mesodiencephalic nuclei.
D. FunctionalImplications On the basis of the outstanding morphologicaland physiological propertiesof the IO, two theories about its functional significance have been proposed: the comparator hypothesis and the timing hypothesis. The comparatorhypothesis, first proposed by Oscarsson(1969,1980), assumes that 1 0 neurons calculate an error signal by comparing motor com-
Architecture of the System Cerebellar
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mands with feedback information from the spinal cord about the actual motor performance. In contrast to the comparator hypothesis, according to the timing hypothesis, proposed by LlinBs (1974), the IO is not concerned with the correction of inaccurate motor performance, but serves as a timing device that provides appropriate timing of motor commands. It is based on the specific properties of the IO described in the foregoing; that is, the abilityof IO neurons to fire rhythmically, the dynamically controlled electrotonic couplingof IO neurons, and the correlation of movement initiation and performance with synchronous olivary activity. Readers interested in a more detailed description of these hypotheses are referred to de Zeeuw et al. (1998).
VI.
THEDEEPCEREBELLARNUCLEI
A.
GrossMorphology
The cerebellar cortex output converges onto the deep cerebellar nuclei (DCN), the efferents of which mediate the cerebellar influence on the red nucleus, the thalamus, the reticular formation, the vestibular nuclei, and other brain stem centers. The DCN can be delineated into several mediolaterally arranged nuclei that have different input-output and cytological characteristics. In all mammal cerebella, four subgroups can be delineated with some effort. From medial we encounter first a nucleus medialis, then the nucleus interpositus anterior and posterior, and most laterally, the nucleus lateralis. The nucleus medialis is probably equivalent to the fastigial nucleusin humans, whereas the anterior and posterior interpositus nucleus resemble the nucleus emboliform and globose, respectively. The nucleus dentate in humans is equivalent to the nucleus lateralis in other animals. The border between the fastigial nucleus and the globose nucleus is not well defined, whereas the latter is well isolated through fiber bundles from the emboliform and the dentate nuclei.The shape of the human dentate resembles a “crumbeld purse” (Chan-Palay, 1977) with its opening directed ventromedially and rostrally.The human dentate is one of the few folded nucleiof the brain, the other one being the pars principalisof the inferior olive, which interestingly, has strong connections with the dentate nucleus. It is not clear why these two nuclei are folded. Atany rate, this feature seems to be confined to humans and the great apes, whereas otherm a m a l s with large cerebella, such as the cetaceans, exhibit more globular nuclei.
B. FineStructureandPhysiologicalProperties There are about5 X lo6 neurons in the DCN of the human cerebellum (Andersen et al., 1992). In the rat, the species in which DCN have been studied most exten-
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sively, these neurons can be parsed into several distinct populations based on soma size, their dendritic morphology, the neurotransmitter used, and the areas targeted (Voogd, 1995). All DCN contain GABAergic and glutamatergic cells (Batini et al., 1992).The glutamatergic neurons constitute a rather homogeneous population of large projection neurons that send their axons to the ventrolateral thalamus (Sakai et al., 1996), the red nucleus (Kennedy et al., 1986), the pontine nuclei (Schwarz and Schmitz, 1997), the vestibular nuclei (Walberg et al., 1962), and various other brain stem nuclei.The GABAergic cells can be separated into at least two distinct groups, the larger one projects to the inferior olive (Angaut and^ Sotelo, 1987), whereas the neurons of the smaller group most probably do not project to targets outside the DCN. For unknown reasons, a substantial portion of GABAergic neurons in the DNC seem to coexpress the inhibitory transmitter glycine (Chen and Hillman, 1993). In several species, such as rats and monkeys, the lateral nucleus shows differences in cell size, depending on location in the nucleus, which allows one to differentiate a ventromedial parvocellularandadorsolateralmagnocellularportion(Korneliussen,1968). The latter projects to the ventrolateral thalamus, whereas the former projects to the principal part of the inferior olive (Angaut and Sotelo, 1987). In the human dentate the magnocellular part lies ventromedially and the parvocellular portion caudolaterally. There is also a differentiation into a macrogyric part, which lies rostrolaterally, and a microgyric part, which lies dorsomedially, with the latter having larger cells (Demole, 1927). Compared with the rich information available on the electrophysiolgical properties of Purkinje cells, comparatively littleis known about the electrophysiological features of DCN neurons. What is known is reminiscent of some of the essential features of Purkinje cells. For instance, similar to Purkinje cells, DCN neurons have a high spontaneous discharge rate, which is on the order of 40-50 spikes per second in the monkey (Harvey et al., 1979). This inclination to fire despite the presenceof substantial, inhibitory Purkinje cell input reflects the provision of DCN neurons with strong depolarizing conductances in the form of deactivating and nondeactivating voltage-gated sodium channels,T-type as well as L-type channel calcium channels, and hyperpolarization-activated mixed cation channels (IH) (Llinhs and Muhlethaler, 1988; Jahnsen, 1986; Czubayko et al., 2000) *
C. How
Is the Cortical Output Mapped onto the
DCN?
As suggested by the fact that the number of Purkinje cells exceeds the number of DCN neurons by far, the projection from the cerebellar cortex to the DCN is characterized by a high degreeof convergence of Purkinje cells on DCN neurons. The ratios characterizing the number of Purkinje cells converging onto individual DCN neurons seem to vary somewhat between species, with estimates ranging
Architecture of the System Cerebellar
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between 3 :1 and 6 :1 in humans (Mayhew, 1991; Andersen et al., 1992),8 :1 to 16: 1 in the macaque monkey (Lange, 1975; Smoljaninov, 1966; Could and Rakic, 1981), 26: 1 in the cat (Palkovits et al., 1971, 1977) and 6-15 in rodents (Korbo et al., 1993; Armstrong and Schild, 1970; Caddy and Biscoe, 19’79). Although some of the differences may reflect different methods, it is close at hand to interpret the low amount of convergence in the human cerebellocorticonuclear projection as reflecting an increase in the sizeof the DCN as compared with the size of cerebellar cortex.
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Schwarz C, Thier P (1995). Modular organization of the pontine nuclei in rats: dendritic fields of identified pontine projection neurons respect bordersof cortical afferent fields. J Neurosci 15:3475-3489. Schwarz C, Thier P (1996). Morphology of projection neurons in the the pontine nuclei and nucleus reticularis tegmenti pontis of the rat. J Comp Neurol 376:403-419. Schwarz C, Thier P (1999). Binding of signals relevant for action. Towards a hypothesis of the functional roleof the pontine nuclei. Trends Neurosci 22:443-45 1. Schwarz C, Mock M, Thier P (1997). Electrophysiological properties of neurons in the rat pontine nuclei in vitro. I. Membrane conductances. J Neurophysiol 78:33233337. Scott T (1963). A unique patternof localization in the cerebellum. Nature 200:793. Shambes GM, Beerman DH, WelkerW1 (1978). Multiple tactile areas in cerebellar cortex: another patchy cutaneous projection to granule cell columns in the rat. Brain Res156:123-128. Shibuki K, Okada D (1991). Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. Nature 349:326-328. Shinoda Y, Sugiuchi U; Futami T, Izawa R (1992). Axon collaterals of mossy fibers from the pontine nucleus in the cerebellar dentate nucleus.J Neurophysiol 67:547-560. Silver RA, Momiyama A, Cull CS (1 998). of Locus frequency-dependent depression identified with multiple-probability fluctuation analysis at rat climbing fibre-Purkinje cell synapses. J Physiol 510:881-902. Smoljaninov VV (1966). Einige Besonderheiten im Bau der Kleinhirnrinde. In: Strukturelle und Funktionelle Modelle Einiger Biologischer Systeme. UdSSR: Verl Acad Wiss. Snider RS, Stowell A (1942). Receiving areas of the tactile, auditory and visual systems in the cerebellum. J Neurophysiol 7:331-357. Somana R, Walberg F (1980). A re-examination of the cerebellar projections from the gracile, main and external cuneate nuclei in the cat. Brain Res 186:33-42. Somogyi P, Halasy K, Ottersen OP, Sornogyi J, Storm-Mathisen J (1986). Quantification of immunogold labeling reveals enrichment of glutamate in mossy and parallel fiber terminals in cat cerebellum. Neuroscience 19: 1045-1050. Sotelo C, Llin6s R, Baker B (1974). Structural of study inferior olivary nucleusof the cat: morphological correlates of electrotonic coupling. J Neurophysiol 37:541-559. Sousa-Pinto A (1970). The cortical projection onto the paramedian reticular and perihypoglossal nuclei (nucleus praepositus hypoglossi, nucleus intercalatus and nucleus of Roller)ofthemedullaoblongatainthecat.Anexperimentalstudy.BrainRes 18177-91. Stone TW (1979). Glutamate as the neurotransmitter of Cerebellar granule cells in the rat: electrophysiological evidence. Br JPhmacol 66:291-296. Sultan F, Bower JM (1998). Golgi study of the cerebellar basket and stellate cells in the rat: a principal component analysis. J Comp Neurol 393:353-373. Sultan F, Braitenberg V (1993). Shapes and sizes of different mammalian cerebella. A study in quantitative comparative neuroanatomy. J Hirnforsch 34:79-92. Sultan F, Rotter S (1994). Distribution of the parallel fiber swelling’s in the cat’s cerebel-
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Tsukahara N, Bando T (1970). Red nuclear and interposate nuclear excitation of pontine nuclear cells. Brain Res 19:295-298. Usowicz MM, Sugimori M, Cherksey B, LlinAs R (1992). P-type calcium channels in thesomataanddendrites of adultcerebellarPurkinjecells.Neuron9: 11851199. Van Opstal J, Hepp K, SuzukiY, Henn V (1996). Roleof monkey nucleus reticularis tegmenti pontis in the stabilization of listing’s plane. J Neurosci 16:7284-7296. Vilensky JA, Van Hoesen GW (1981). Corticopontine projections from the cingulate cortex in the rhesus monkey. Brain Res 205:391-395. Voogd J (1995). Cerebellum. In: G Paxinos, ed. The Rat Nervous System. San Diego: Academic Press, pp 309-352. Voogd J, Bigart5 F (1980). Topographic distributionof olivary and corticonuclear fibers in the cerebellum. A review. In: J Courville, C de Montigny, Y Lamarre, eds. The Inferior Olivary Nucleus. New York: Raven Press, pp 207-235. Walberg F, Ottersen OP (1989). Demonstration of GABA immunoreactive cells in the inferior olive of baboons (Papio papio and P q i o anubis). Neurosci Lett 101:149155. Walberg F, Pompeiano 0, Brodal A, Jansen J (1962). The fastigiovestibular projection in the cat. An experimental study with silver impregnation methods. J Comp Neurol 11 8:49-76. Wassef M, Sotelo C (1984). Asynchrony in the expression of guanosine 3’:5’-phosphatedependent protein kinase by clusters of Purkinje cells during the perinatal development of rat cerebellum. Neurosci 13: 121 7-1241. Wassef M, Sotelo C, Cholley B, Brehier A, Thomasset M (1987). Cerebellar mutations affecting the postnatal survival of Purkinje-cells in the mouse disclose a longitudinal pattern of differentially sensitive cells. Dev Biol 124:379-389. Wassef M, Cholley B, Heizmann CW, Sotelo C (1992a). Development of the olivocerebellar projection in the rat.11. Matching of the developmental compartmentations of the cerebellum and inferior olive through the projection map. J Cornp Neurol 323:537-550. Wassef M, Chedotal A, Cholley B, Thomasset M, Heizmann CW, Sotelo C (1992b). Development of the olivocerebellar projection in the I.rat. Transient biochemical compartmentation of the inferior olive. J Comp Neurol 323:519-536. Watanabe M, Mishina M, Inoue Y (1994). Distinct spatiotemporal distributions of the N-methyl-D-aspartate receptor channel subunit rnRNAs in the mouse cervical cord. J Comp Neurol 345:314-319. Weber JT, Harting JK (1980). The efferent projections of the pretectal complex: an autoradiographic and horseradish peroxidase analysis. Brain Res 194: 1-28. Welker W (1987). Comparative study of cerebellar somatosensory representations. The importance of micromapping and natural stimulation. In: M Glickstein, C Yeo, J Stein, eds. Cerebellum and Neuronal Plasticity. New York: Plenum Press, pp 109118. Whitworth RH Jr, Haines DE (1986). On the question of nomenclature of homologous subdivisions of the inferior olivary complex. Arch Ita1 Biol 124:271-317. Wiesendanger R, WiesendangerM, Ruegg DG (1979). An anatomical investigation of the
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Normal Functions of the C~rebell~m Helge Topka University of Tubingen, Tdbingen, Germany
INTRODUCTION
I.
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11. CONTROL OF EYE MOVEMENTS
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111. CEREBELLAR CONTROL OF VOLUNTARY MOVEMENT
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IV. V. VI.
CEREBELLAR TREMORS
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CEREBELLUM AND MOTOR LEARNING
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BASIC OPERATION OF CEREBELLAR CIRCUITRY TEMPORAL OR SENSORY SEQUENCES?
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VII. COGNITIVE FUNCTIONS VIII.
1.
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CEREBELLAR CONTRIBUTION TO SPEECH
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REFERENCES
67
INTRODUCTION
Staggering gait, dysarthric speech, and imprecise, clumsy limb movements, in addition to oculomotor problems represent clinical hallmarks of cerebellar dysfunction that are easily recognized by the clinician. However, despite the ease with which cerebellar dysfunction may be diagnosed, the exact normal function 53
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of the cerebellum and the pathophysiological basis of cerebellar clinical signs and symptoms have yet tobe determined. Recent studies, however, have yielded considerable insight into the mechanisms by which cerebellar pathways control voluntary movement and participate in motor adaptation and learning, in the processing of language, and in the processing of sensory afferent information. Moreover, several lines of evidence suggest that cerebellar structures may also contribute to cognitive functions. Anatomically, the cerebellum may be divided in three lobes, the anterior lobe, the posterior lobe, and the flocculonodular lobe. Despite this anatomical distinction, the microarchitectureof the essential cerebellar cortical circuitry consisting of two afferent pathways, mossy fibers, originating from pontine nuclei; and parallel fibers, originating from granular cells and the only output neurons, the Purkinje cells, is remarkably homogeneous across different cerebellar subdivisions. Differences in the function of cerebellar subdivisions are thought to arise from different afferent and efferent pathways projecting to each of the subdivision (l-3),a phenomenon that bas been referred toas functional compartmentalization (4). Lesions of the lateral cerebellar hemispheres and the dentate nucleus cause disorders of voluntary movement, chiefly limb movements; postural ataxia results from lesions of the anterior lobe; and oculomotor symptoms are associated with lesions of the cerebellar flocculus and the fastigial nuclei.
F EYE ~ O V E ~ E N T ~ Cerebellar pathways are involved in control of both saccadic and smooth-pursuit eye movements. The most common oculomotor signs of cerebellar dysfunction are gaze-evoked or gaze-paretic nystagmus and ocular dysmetria, mainly over(5-7). Gaze-evokednystagmusresults shootduringsaccadiceyemovements from an inability to voluntarily hold eccentric gaze and may occur both with lateral or vertical conjugated gaze. Smooth-pursuit eye movements are interrupted by saccades. Ocular dysmetria is thought to originate from deficient modulation of saccadic eye movements in the face of cerebellar dysfunction. In addition, optokinetic kinetic nystagmus, physiologically evoked when watchinga target that rapidly moves in one direction in healthy subjects,may be disturbed, in that patients with cerebellar disorders may exhibit either exaggerated or dampened excursions of the eyes with such a stimulus. It is widely accepted that cerebellar pathways play an important role in (8). Deficient controlof modulating the gainof the vestibulo-ocular reflex (VOR) the VOR gain in patients with cerebellar disorders causes another prominent symptom of cerebellar oculomotor, dysfunction which an is enhanced gainof the vestibulo-ocular reflex and,inparticular, a decreasedabilitytosuppressthe vestibulo-ocular reflex during fixationof a target while rotating the patient along
Normal ~ u n ~ t i o of n sthe Cerebellum
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a longitudinal axis. In most patients with cerebellar disorders, the severity of symptoms correlates well and consistently with the amount of atrophy of the flocculus and the dorsal vermis (6,7).
At this point, it is widely accepted that a major roleof cerebellar pathways is in the execution of voluntary movement. Current views on cerebellar functions in controlling movement largely stem from observations in human cerebellar disorders or findings in animal experiments. Historically, various terms have been used to describe the clinical consequences of cerebellar damage to voluntary movement. The term ataxia literally means disordered movement. Other terms that have been used to describe specific aspects of disordered voluntary movement in cerebellar disorders, include dysmetria, dyssynergia, or dysdiadochokinesis. The difficulties cerebellar patients exhibit when asked to perform rapid alternating movements have been termed dysdiadocho~inesis.The term dysmetria refers to the disturbance of limb placement which leads to the inaccuracy of willed movement. In contrast, dyssynergia refers to the disordered coordination of different muscles or muscle groups that is associated with cerebellar dysfunction (9). The observation that patients with cerebellar disorders tend to move one joint at a time, rather than moving multiple joints of one limb simultaneously, has decomposition of movereceived particular attention and has been referred to as ment. These apparent difficulties in coordinating movements of adjacent joints, despite normal maximal muscle strength and absence of disordered sensation, have prompted a long-lasting controversy over the specific ofrole the cerebellum in motor control. Whereas Hughlings Jackson (10) and others (11) felt that all motor difficulties observed in cerebellar disordersmay be explained by elernentary motor deficits that affect a single joint, Flourens (12) and Babinski (13) argued that a major role of the cerebellum in controlling movements was to orchestrate movements of adjacent joints to provide for coordinated movement of a limb. Thach (14), in his comprehensive work, reviewed pertinent neuroanatomical and neurophysiological data and suggested that, indeed, the architecturesof cerebellar cortex and outflow pathways are compatible with the notionof a specific role of the cerebelllum in coordination per se. In particular, length and spatial layout of cerebellar cortical parallel fibers in relation to a roughly somatotopic representation of the body within the cerebellar nuclei has prompted the notion that interactions between parallel fibers and cerebellar output nucleimay represent an ideal neuroanatomical substrate for cerebellar interjoint coordination.Earlyphysiologicalstudieshavelargelyusedsimplesingle-jointmovements to study cerebellar motor deficits and, hence, experimental evidence that bears on the issueof cerebellar interjoint coordination has been gathered only re-
56
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cently. Gordon Holmes was the first to provide quantitative measurements of (15,16). When studyinggrasping voluntarymovementsincerebellarataxia movements in patients with unilateral cerebellar lesions, he noted some 200-ms delay in movement initiation, a decrease in phasic muscle strength, and a prolongation of the time required to produce maximal muscular force in the arm ipsilateral to the lesion. Numerous subsequent studies have studied rapid single-joint movements as a modelof a simple movement and analyzed movement kinematics as well as the pattern of electromyographic (EMG) activity associated with themovement.Because of theirshortdurations,theserapidmovementsare thought to beexecuted, or at least initiated, without feedback and, therefore, have been termed ballistic movements. In healthy subjects, ballistic movements are characterized by short-reaction or motor-preparation times, high peak velocities, and a nearly symmetrical and bell-shaped velocity profile. A characteristic threephasic patternof EMG activity that consistof an initial agonist burst, an overlapping burst in the antagonist, and a subsequent second agonist burst (17) is associated with rapid ballistic movements. In patients with cerebellar dysfunction, attempted ballistic movements exhibit a numberof abnormalities. Movements are dysmetric, frequently overshooting the target (Fig. 1). Movement dysmetria is thought to be related to asymmetries in the velocity profiles. Although peak movement velocities may be normal, peak acceleration frequently is reduced and the velocity profile is asymmetrical, in that amplitudesof peak deceleration may increase relative to the amplitudeof peak deceleration (18,19), or the accelerative phase of the movement may be prolonged compared with the duration of the decelerative phase (20). Similarly, the EMG pattern of muscle activation that subserve single-joint movements is disordered in patients. The onset of the initial agonist burst is delayed, and the rise of EMG activity occurs more gradually (19,21,22), giving rise to decreased acceleration. Corresponding to the dysmetria of the movement, the onset of antagonistic EMG activity is delayed, causing a delay in braking the movement. Several studies suggest that cerebellar output to the cerebral cortex provides a facilitatory influence on motor cortical areas (23-26) during preparation and execution of voluntary movements. Although single-joint studies have identified a number of elementary deficits that are associated with cerebellar dysfunction,isitonly recently that studies have addressed the role of the cerebellum in controlling multijoint movements. Becker and colleagues (27) studied the coordination of upper arm, lower arm, and hand during a throwing movement in patients with cerebellar disorders and in healthy subjects. In their study, the patient’s movements were less accurate; however, several movement variables that were thought to reflect coordination between limb segments, such as the timingof muscle activation in proximal and of elbow and hand movements, were nomal. distal muscles or the relative timing Inadditiontoanalyzingthekinematic(i.e.,thespatial-temporalpatterns of
57
Normal Functions of the Cerebellum Normal Subject
Cerebellar Patient
Extensor carpi radialis m.
Flexor carpi radialis m.
Figure 1 Kinematics and electromyographic (EMG) patterns of rapid wrist extension movements (30")in a healthy subject anda patient with cerebellar degenerative disorder: (Upper panel) Wrist angular position as measured with a rnanipulandurn. Three trials are superimposed. The patient exhibits dysmetric movements overshooting the target. Movement termination is abnormal showing terminal oscillations. (Lower panel) Electrornyographic pattern of muscle activation during the movement. Depicted are traces from a single movement. The patients' movementis characterized by a more gradual rise in agonist EMG activity and a delay in activating the antagonist muscle.
movements), more recently researchers have employed inverse dynamics techniques that permit analysis of dynamic movement variables, such as the forces that drive movements about a given joint in a quantitative fashion (28-30). These studies have provided for some insight into the nature of specific control problems that have to be resolved by the central nervous system when performing multijointmovements.Mostimportantly,thesestudieshaveemphasizedthat movement of a joint is caused not only by direct activation of muscles that span this joint, but also, results from complex interactions between forces that are generated by local muscular activation and external forces, such as gravitational forces or passive reaction forces that arise from movements of adjacent joints. The concept that voluntary activationof a muscle has to be adjustedto cornpensate for the physical consequencesof the movement was first proposedby Bernstein (31). Bernstein hypothesized that the role of the central nervous system in
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controlling multijoint movements is to provide for muscular activation that takes external forces into account, takes advantage of them if external forces support the goal of the movement, or compensates for them if they oppose the goalof the movement. With inverse dynamics techniques, the contribution of these external forces that act ona joint during a movement can be determined quantitatively. In addition, forces that drive movements of a joint can be parsed into forces that originate from gravitation, muscular activation, or passive joint interactions, owing to the physics of a multijoint movement. Froma theoretical pointof view, the most important component of dynamic movement variables, which is related to the coordinationof multiple jointsof a limb, are passive joint interactions or passive reaction forces. For coordinated movement to occur, passive reaction forces occurring during a movement have to be accurately assessed and monitored by the central nervous system and, because muscular activation represents the only dynamic movement variable that is actively controlled by the nervous system, muscle activation at the joint involved has to be adapted accordingly. Therefore, when studying the pathophysiologyof cerebellar dyscoordination of movement, the mechanisms by which the central nervous system deals with passive interaction forces have received close attention. Indirect evidence for deficient controlof passive interaction forces during limb movements in cerebellar ataxia has been derived from kinematic studies of multijoint arm movements. These studies (32,33) revealed that kinematic movement abnormalities, such as hypermetriaof elbow and shoulder movements and, as a consequence, an increased hand path and an abnormal degree of hand trajectory curvature, as well as decreased hand acceleration were most prominent when patients performed fast movements, but were only minor when patients moved at slow and moderate speeds. The observation of velocity-dependent deficits in cerebellar ataxia is thought to originate from an impairment in generating noma1 coordination between appropriate levels of muscle torques to support shoulder and elbow joints. Recent studies have also directly investigated the role (28) of passive interaction forces in cerebellar limb ataxia. Bastian and colleagues performed a kinetic analysis of torques generated at each joint during slowaccurate-andfast-accurate-reachingmovements.Inparticularduringfastreaching movements, patients with cerebellar disorders produced abnormal torque profiles, compared with healthy subjects, with inappropriate levels of shoulder muscle torque and elbow muscle torques that did not vary appropriately with the dynamic interaction torques that occurred at the elbow. Kinematic characteristics of cerebellar limb ataxia, therefore, are thought to result from an abnormal influence of dynamic joint interactions and reflect a critical role of cerebellar pathways in generating muscle torques that predict and of the compensate for interaction torques that originate from other moving joints same limb.
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At this point, the exact mechanisms that lead to an abnormal control of inof inadequate muscuteraction torques are unknown. In principle, the generation lartorques may resultfrom an impairmentingeneratingsufficientlevels of torques, or froman inaccurate assessment and predictionof the mechanical consequences of movements of one limb segment on adjacent joints. Recent studies suggest that the critical role of the cerebellum in generating normal levels of phasic muscle forces known from single-joint studies may, to a large extent, also contribute to the dyscoordination of fast multijoint movements (30,34). Quantitative analysis of muscular forces during vertical multijoint pointing movements reveal that cerebellar hypermetric movements are associated with smaller peak of torque change at elbow and shoulder joints. muscular torques and smaller rates The patients’ deficitin generating appropriate levelsof muscular force are prominent during two different phases of the pointing movement. Peak muscular forces at the elbow are reduced during the initial phase of the movement when simultaneous shoulder joint flexion generated an extensor influence on the elbow joint. When attempting to terminate the movement, gravitational and dynamic interaction forces cause overshooting extension at the elbow joint. Interestingly, the timing of shoulder and elbow joint muscle torques that is characterized by a large degree of synchronicity (35) in normal subjects is preserved in cerebellar patients, despite severe kinematic abnormalities of ataxic movements (30). Thisfinding,amongothers(27,36),ischallenginganearlierinfluential hypothesis that suggested that a major role of the olivocerebellar system is in providing accurate-timing measurements for the central nervous system(37-40) (fordiscussion of thetiminghypothesisseelaterdiscussion).Althoughthis controversy has yet to be resolved, deficits in generating normal phasic muscular forces that compensate for dynamic interaction forces acting on remote partsof the body may well explain earlier findings of deficient coordination of various muscle groups involved in stabilizingof normal posture during execution of focal voluntary motor tasks. In standing human subjects, movements of the upper limbs are preceded, accompanied, and followed by muscular activation in postural muscles of the trunk and the legs that have to be adapted to compensate for dynamic interaction forces that potentially jeopardize stable posture (41). Several studies have compared muscle activation patterns during motor preparation in healthy subjects and in patients with cerebellar disorders (42-44). These a disordered sestudies demonstrated that cerebellar ataxia is associated with quence of preparatory and voluntary muscle activation inadequate to cope with the dynamic consequences of a focal movement of the arm on the stability of posture. Subsequent studies on postural control in cerebellar patients suggest that the disability in generating normal preparatory muscle activation may reflect a more fundamental deficit in generating responses of normal magnitudes based
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on a task-specific predictive central set, instead of an impairment in using velocityfeedbackororganizingthetemporalsequence of multijointpostural coordination (45).
IV. The relation between the dysmetria, dyscoordination of voluntary movement, and another clinical sign of cerebellar dysfunction-cerebellar kinetic or intention tremor-is not fully understood. Cerebellar tremor is characterized by oscillations of a limb that purely or dominantly occur during termination of a voluntary movementorduringmaintainedposture(46).Tremorfrequencies may vary somewhat depending on the part of the body that is involved. Truncal tremor in 4 Hz, the lower limbs as observed in anterior lobe damage varies between 3 and tremors of the upper limbs may show frequencies between 3 and 8 Hz (postural tremor) and 5 and 8 Hz (kinetic tremor). The tremors may occur bilateral or unilateral. Sensory influences strongly affect cerebellar tremor, indicating that the tremor is generated within central motor loops (47). Both animal experiments (48-50), as well as observations in humans (3,51,52), suggest that the tremors that occur when approaching the target are related to lesions in cerebellar outflow pathways consisting of the dentate nucleus and its projections to the red nucleus and the thalamus. Hore and Flament (18,53) argued that cerebellar postural and terminal tremors may reflect essential involvement of cerebellar pathways in stabilizing a limb during maintained posture or after brisk voluntary movements. To counteract terminal tremor, the central nervous system generates bursts of muscle activity that do not seem to be stretch-reflex-driven, but seem to be preprogrammed in advance. Cooling of the cerebellar nuclei disrupts the timing of the corrective bursts in bothEMC recordings from muscles and from the cortex. With the corrective bursts being absent, positional corrections of the limb become As opposed driven by spinal and transcortical (long-loop) reflex activity (18,53). to cerebellar-controlled preprogrammed or anticipated activity, transcortical reflex activity is essentially relying on feedback loops, therefore, introducing delays in responses and, consequently, a mismatch between movement phase and corrective muscle activity. Because of these delays in the feedback loop, transcortical reflex activity may sometimes even reinforce the oscillations, rather than dampening them. In human cerebellar disease, stretch reflexes themselves are often abnormal, exhibiting delays and an abnormal increasein magnitude (54,55). Recent physiological studies in normal subjects provide some additional support for this hypothesis. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex evokes terminal and postural tremors in healthy subjects of 4-7 Hz, that are phenotypically very similar to the tremors associated with cerebellar disorders and thatdo not depend on the frequencyof the stimulation (56).
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In analogy to patients with cerebellar disorders, rTMS seems to induce tremor by enhancing the activity of transcortical reflex loops.
V.
CEREBELLUMANDMOTORLEARNING
Interpreting the basic neuronal circuitryof the cerebellar cortex with two inputs to the only cerebellar output neurons, the Purkinje cells, one originating from the inferior olive through climbing fibers and the other from pontine nuclei through mossy fibers,Marr (57) and Albus (58) suggested that the cerebellar cortical network provides the ideal neuronal substrate to implement adaptive and learning capabilities to the central nervous system. Experimental evidence for a “teacher of climbing fiber inputs (57) was first givenby Ito (59), who demonstrated that coincident or“c~njunctive’~ stimulation of vestibular afferents (mossy fibers) and inputs from the inferior olive (climbing fibers) resulted in adaptation of Purkinje cell responses to mossy fiber input. Conceivably, gain adaptation of simple reflexes, such as the vestibulo-ocular reflex (60), or the acquisition and retention of the classically conditioned eye blink responses (for detailed review see Refs. 61 and 62) involve these adaptive mechanisms. In particular, classic conditioning of the eyeblink response, which is analogous to the nictitating membrane response in rabbits, has served as a model of simple associative motor learning in a large numberof studies. Several linesof evidence from these studies seem to support the notion of cerebellar involvement in motor adaptation or motor learning processes (62,63). Cerebellar cortical lesions may either abolish (64,65) the acquisition of the conditioned response in classic conditioning paradigms or slow its acquisition (66), in particular, the interpositus nucleus seems to play a critical role in classic conditioning, as lesions of this cerebellar nucleus abolish conditioned responses of the nictitating membrane response in rabbits (67-70). Similar to animal studies, deficits in the acquisition of the classically conditioned eyeblink response have also been observed in patients with cerebellar disorders (71,712). Although the acquisition of novel associations between conditioned and unconditioned stimuli is impaired in patients with cerebellar disorders, the expression of conditioned responses that were acquired before onset of the cerebellar disease is preserved, suggesting that cerebellar pathways are important for the acquisitionof novel associations; however, they do not seem tobe the site of storage of naturally acquired conditioned responses (73). Cerebellar involvement in general may be considered widely accepted; however, there is a long-standing controversy over whether cerebellar pathways are essential for this type of simple motor learning, or whether cerebellar circuitry plays a mere supportive role. In support of the latter view are findings in animal experiments demonstrating that conditioningmay occur, to some extent, also in decerebellate and decerebrate animals (74), and that reversible inactivation of the anterior in-
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terpositus nucleus with lidocaine does not necessarily block the acquisition of the conditioned response (75). Along these lines, the siteof plasticity in the adaptation of the vestibulo-ocular reflex has been localized to the target nuclei of the vestibulocerebellum (flocculus) in the brain stem, rather than to the cerebellar cortex (76,77). Deficits similar to the one observed in gain adaptation of the vestibuloocular reflex have been demonstrated in humans in a variety of different forms of simple motor adaptation learning or conditioning, such as visuomotor adaptation when wearing prisms (78,79), classic conditioningof the flexor reflex (80), habituation of the acoustic startle response (81), the adaptation of postural reflexes (82), or the adaptation of limb movements to novel loads in both monkey (83,84) and humans (85). Although there is a large body of evidence documenting cerebellar involvement in simple formsof adaptation learning, only recently studieshaveexploredthepossibilitythatcerebellarcircuitryisinvolvedin motor-learning processes in a broader sense. Neuroimaging studies measuring cerebral blood flow in various brain regions during learning of simple motor tasks (86), a complicatedfinger sequence (87), or learning a novel movement trajectory (88) demonstrated that practice and acquisition of a novel motor task regularly is accompanied by changes in regional blood flow, among other brain areas, in the cerebellum. Sanes and colleagues reported an impairment in learning a limb movement trajectory in a mirror-reversed task in patients with cerebellar degeneration (89). Several recent studies suggest, however, that cerebellar dysfunction in humansmay prevent normal ratesof learning in a complex motor task (90), but does not seem to degrade the ability in patients to achieve normal levels of improvement after a prolonged period of practice (90,91).These observations have led to the concept that cerebellar circuitrymay be involved chiefly in the adaptation component of limb movements, butmay not be critical for other aspects of motor skill learning, such as generating the appropriate kinematic plan (92). Such a conceptmay also be helpful in explaining the relation between motor deficits seen with cerebellar damage and deficits in motor learning. Coordinating movements about multiple joints, in particularwhen encountering changing environmental conditions, requires adaptive capabilities. Thus, a major role of the cerebellum in controlling movementsmay be to combine simple elements of movement into more complex synergies and provide for adaptive capabilities that provide for appropriate responses under different task conditions (14).
VI.
BASIC O~ERATIONOF CEREBELLAR C~RCU~TRY TE~~ORA OR L SENSORY SEQUENCES?
The deficits in providing normal phasic muscle activation appropriate to compensate for “parasitic” forces that accompany almost any normal human move-
Normal F~nctionsof the Cerebellum
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ment have led to the concept that cerebellar pathways are essentially dealing with by Braitenberg earlier, the physics of movement, a term that has been introduced based on theoretical considerations (93). The observation that sensory deafferentation results in deficits controlling movement dynamics that are partially reminiscent of cerebellar dysfunction (94,95), but affect different phases of the movement, has prompted the notion that cerebellar pathways may be part of a threestage control system consistingof anticipatory mechanisms, error correction, and mechanisms of postural control (96). In such a scheme, the cerebellummay contribute by holding an internal model or representation of the biomechanic properties of the body that is continuously updated and recalibrated by afferent sensory information (96,97). In addition, there may exist a functional partitioning within cerebellar pathways that link anticipatory activation to lateral aspects of the cerebellar hemisphere, including the dentate nucleus and monitoring of ongoing movement execution, as well as error correction to the intermediate cerebellum including the interpositus nuclei (98). Although there is little doubt that lesions to differentof parts the cerebellum may cause distinct syndromes, relative to the extent and the specifics of motor deficits associated with the lesion (4), the major anatomical hallmark of the cerebellar architecture is its remarkable homogeneity across different sections of the a numcerebellum. This anatomical homogeneity and its regularity has prompted ber of hypotheses that attempted to identify a single operation within cerebellar pathways common to all sections of the cerebellum. One influential hypothesis suggested that the regularity of cerebellar microarchitecture may point to a role of cerebellar circuitry in detecting temporal sequences (37-39,99). To date, the role of the cerebellum asa central time-keeperis still controversial. A large body of evidence supports the idea that cerebellar pathwaysplay an important role in as the timing between antagonistic controlling temporal movement variables such muscles during rapid single-joint movements (19,21), the relative timing between activation of postural muscles and limb muscles during motor preparation and exof two distinct stimuli, ecution (43),or the acquisitionof a novel temporal relation as is required in classic conditioning (71). In addition, cerebellar pathways may be involved notonly in controlling temporal variables of movement execution, but also may be relevant for time perception (99-101). On the other hand, attempts to directly localize clock functions to neurons in the inferior olive or cerebellar cortex have failed(36). One major problem witha cerebellar timing function has always been in the quantitative anatomy of cerebellar cortex. In mammals, the avof maximally erage lengthof cerebellar cortical parallel fibers allows for detection 10 ms, whereas even rapid movements require temporal controlof at least some 200 ms. To resolve this issue, Braitenberg and colleagues proposed that several sets of parallel fibersmay be involved in processing temporal information in tidal waves that may last up to 200 ms (102). However, this model does not seem to as teleosts, the total cerebellar width of which be applicable to other species, such
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does not allow for detection of time differencesof more than 5ms (103,104). Others have emphasized that in principle, the specific geometry of the cerebellar microarchitecture is not necessary to implement temporal sequence detection in a neuronal system (105) and that network models for aspects of timing suggest that simulated neurons may not display any clear timing function individually or exof cerebellar corplicitly (106,107). Instead, the dramatic orthogonal organization tex was interpreted to represent the neuronal machinery for detection of sensory sequences, rather than temporal sequences (108,109). During recent years, the concept that a major role of the cerebellum may be to predict the sensory consequences of motor acts, rather than processingof primary motor sequences, has receivedsubstantialsupportfromvarioussources.Recentfunctional-imaging studies have demonstrated that the lateral cerebellar output nucleus is highly activated during a passive and active sensory discrimination task whether not or the task involves movement (110).Along these lines, other studies have shown perceptual deficits in patients with cerebellar disorders during preparation and execution of limb movements (loo), processing of visual information ( l l l ) , as well as during processing of speech stimuli (112). Basedon the framework of cerebellar involvement in the processingof sensory information (113-115), in particular in assessing sensory consequences of motor acts, Paulin (116, 117) suggested that one major function of the cerebellum may be in constructing neural representations of moving systems, including the body, its parts, and objects in the environment. Conceivably, cerebellar circuitry acts as a “stable estimator” (118) involved in constructing internal estimates of the physical variables that characterize movements of the body and provides for a regulating circuit that optimizes the pro cess of estimation and predictionof the sensory consequencesof movement. Although additional experimental evidence is required to confirm such a theoryof cerebellar function, the concept of the cerebellum monitoring internally and externally generated movements of the body or its parts in sensory space seems very helpful in explaining the various seemingly different functions of the cerebellum in controlling eye, limb, and body movements, motor adaptation processes, and potentially also cognitive processes.
Vll.
COGNITIVEFUNCTIONS
Although the essential role of cerebellar circuitry in controlling movement is widely accepted, recent studies seem to suggest that cerebellar pathways may also play some role in cognitive processes. Several lines of evidence suggest that cerebellar contributionis not limited to controlling the execution of a movement. For example, compared with healthy subjects, patients with cerebellar degenerationexhibitprolongedmovementtimesnotonlywhenactuallyexecutinga movement, but also exhibit increased movement times when simulating similar
Normal Functions of the Cerebellum
65
movements mentally (119). Similarly, functional-imaging studies seem to provide some support for this hypothesis, demonstrating that cerebellar pathways, in particular the dentate nucleus, are more intensely activated when subjects attempted to solve a pegboard puzzle compared with a situation in which subjects performed simple movements of the pegs (120). Although these observations emphasize a potential role of the cerebellum in nonmotor tasks, the exact nature and the extent of cerebellar involvement in cognitiveprocessesisstillcontroversial. To date,severalneuropsychological studies have been performed in patients with cerebellar disorders without providing a conclusive picture. Mild general cognitive retardation may occur in children with congenital cerebellar atrophy without supratentorial changes (121); however, most researchers agree that neither degenerative diseases nor focal cerebellar lesions in adults are necessarily associated with general intellectual impairment,suchasdementia,unlessextracerebellarinvolvementoccurs.Several studies suggest that patients with cerebellar disorders may present with selective cognitive dysfunction, such as deficits in temporal processing, in frontal lobe function, visuospatial processing, or nonmotor-skill learning (122). Deficits in visuospatial processing have been reported in a small series of patients both with chronic unilateral left-sided cerebellar lesions (123) and in a patient with a cerebellar degenerative disorder (124) without elucidating the exact nature of visuospatial impairments. These impairments seem to be very selective because selective visual attention, visual spatial attention, and mental rotation of geometric designs is not necessarily impaired in patients with degenerative disorders (125). Thus, further studies are necessary to clarify this issue. Similarly, studies that bear on the issue of a potential roleof the cerebellum in nonmotor-associative learning are still inconclusive. Whereas patients with cerebellar degenerative disorders have been reported to be impaired in learning the association between pairsof colors and numerals, compared with healthy subjects (126), other studies found impairment in skill acquisition only in patients with degeneration of both cerebellar and brain stem pathways, but no impairment if the pathology was restricted to the cerebellum (127). Other cognitive impairments in patients with cerebellar disorders include deficits in cognitive planning of strategies, as studied with the Tower of Hanoi test (128), or deficits in decision making that seem to be independent of motor impairment (129). Earlier reports of deficits in verbal and nonverbal intelligence, verbal associative learning in single patients with a cerebellar degenerative disorder (124), have not been confirmed in other studies demonstrating normal cognitive functions in language skills, word fluency, response time, memory, or visuomotor procedural learning (128). One theory suggests that a key role of the cerebellummay be in shifting selective attention between sensory modalities emphasizing the multitude of anatomical connections between the pulvinar, the superior colliculus, as well as parietal and frontal cortices (130). Some support for this hypotheses stems from
66
Topka
functional magnetic resonance studies in healthy subjects suggesting that attention and motor performance selectively activate distinct areasof the cerebellum (1 31).On the other hand, electrophysiological studies investigating event-related potentials in healthy subjects and in patients with damage to the lateral cerebellum failed to detect differences between groups that were specific for an impairment of visuospatial attention shift in the patients (132). Direct anatomical evidence that bears on the issue of potential cerebellar cognitive functions is still limited. Retrograde transneuronal tracer studies have identifiedsubcorticalneuronsinrestrictedregions of thecerebellardentate nucleus and the internal pallidum that project through the thalamus toof areas the primate prefrontal cortex, which are thought to be involved in spatial working memory (1 33). Indirect evidenceof projections between the prefrontal cortex and cerebellar circuitry stems from studies that demonstrated the existence of projections connecting the prefrontal cortex and pontine nuclei which, in turn, give rise to one of the two cerebellar inputs, the mossy fibers (134) (for a detailed review see Chapter 1). Some indirect support of a linkage between cognitive functions, as well as behavior and cerebellar circuitry originates from studies investigating the neuroanatomical basis of autism, a developmental disorder characterized by the lack of social maturation despite relatively preserved motor functions. In autism, children have difficulties in forming emotional bonds with parents or other individuals and exhibit severely reduced responses to external verbal stimuli. Several lines of evidence link the presence of autistic features with disorders of the cerebellum.In. Joubert’s syndrome, autism coincides with agenesis of the cerebellar vermis (135). Abnormalities of cerebellar vermian lobules VI and VII, both hypoplasia and hyperplasia, have been identified in patients with infantile autism using magnetic resonance imaging (136). However, the specificity of this finding has been questioned because other imaging studies werenot able to confirm size differences of the cerebellar vermis in autistic individuals compared with healthy subjects (137); rather, they detected more differences in the size of the midbrain and medulla oblongata than in the cerebellar vermis in autistic children (138) or detected similar hypoplasiaof the cerebellar vermis in individuals without clinical signs of autism (139).
In addition to controlling eye and limb movements, cerebellar pathways are involved in speech production. Cerebellar dysfunction is associated with dysarthric speech,resultingfromaslowingdown of articulatorymovements,increased variability of pitch and loudness (“scanning speech”), articulatory impreciseness (14.0,141), and imperfect syllable timing (142). Abnormal kinematics of ataxicbreathingmovementsduringspeech may contributetocerebellardysarthria
Normal Functions of the Cerebellum
67
(143). Several studies suggest that cerebellar involvement in speech production may be localized to a small region of the paravermal aspect of the superior cerebellar hemispheres (140,141,144). Initial reportsof an exclusive left-sided cerebellar representation of speech functions (140,144) have been questioned becausecerebellardysarthriahasalsobeenobservedinpatientswithdamage limited to the right cerebellar hemisphere (141).If cerebellar circuitry also contributes to cognitive aspects of speech generation, such as grammatism, is still controversial. In single patients, right-sided cerebellar infarction was reported to beassociatedwithagrammatismwithoutothercognitiveimpairments(145); however, recent functional imaging in healthy subjects suggest, rather, that cerebellar activation is related more to the articulatory level of speech production than to cognitive operations (146). Perhaps even more obscure than the linkage between autism and the cerebela synlum is the relation between dysfunction of cerebellar pathways and mutism, drome that describes complete inhibition of verbal capabilities ina patient whose perceptual capabilities are otherwise fully intact. Mutism is a rare disorder. Most frequently, the syndrome follows surgical resection of intrinsic posterior fossa tumors, cerebellar hemorrhages, or after trauma, in both children (147) and adults (148). Mutism cannot be attributed to severe brain stem dysfunction, for cranial nerves and long-tract functions consistently remain intact (149). Since recovery from mutism is frequently associated with dysarthria, some authors have hypothesized that mutism may reflect a very severe form of dysarthria associated with acute dysfunction of the pathways connecting the brain stem and the cerebellum (147,150). Although mutism is frequently associated with cerebellar pathology, the syndrome doesnot seem to be specific for the disruption of afferent or efferent cerebellar pathways,as similar syndromes have also been observed in obstructive of the periaqueductal gray hydrocephalus (15l),right parietal lesion (152), lesions (153), with bilateral lesions of the internal globus pallidum (154,155), or with brain ischemia involving bilaterally the anterior cerebral artery (156).
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99. Ivry RB, Keele SW. Timing functions of the cerebellum. J Cogn Neurosci 1989; 1:136-152. 100. Diener HC, Hore J, Ivry R, Dichgans J. Cerebellar dysfunction of movement and perception. Can J Neurol Sci 1993; 20(suppl 3):S62-69 101. Jueptner M, Rijntjes M, Weiller C, Faiss JH, Timmann D, Mueller SP, Diener HC. Localization of a cerebellar timing process usingPET. Neurology 1995; 45:15401545. 102. Braitenberg V, Heck D, Sultan F. The detection and generation of sequences as a key to cerebellar function: experiments and theory. Behav Brain Sei 1997; 20:229245 103. Meek J. Comparative aspectsof cerebellar organization. From mormyrids to mammals. Eur J Morpho1 1992; 30:37-51. 104. Meek J. Why run parallel fibers parallel? Teleostean Purkinje cells as possible coincidence detectors, in a timing device subserving spatial coding of temporal differences. Neuroscience 1992; 48:249-283. 105. AbbottLF,BlumKI.Functionalsignificanceoflong-termpotentiationfor sequence learning and prediction. Cereb Cortex 1996; 6:406"416. 106. Miall RC, Weir DJ, Wolpert DM, Stein JF.Is the cerebellum a Smith Predictor? J Mot Behav 1993; 25:203-216. 107. Miall RC. The storage of time intervals using oscillating neurons. Neural Comput 1989;11359-371. 108. Miall RC. Sequences of sensory predictions. Behav Brain Sci 1997; 20:258-259. 109. Bower JM. Control of sensory data acquisition. Int Rev Neurobiol 1997; 41:489513. J, Li J, FoxPT. Cerebellum implicatedin 110. Gao JH, Parsons LM, Bower JM, Xiong sensory acquisition and discrimination rather than motor control. Science 1996; 272:545-547. 111. Nawrot M, Rizzo M. Motion perception deficits from midline cerebellar lesionsin human. Vision Res 1995; 35:723-73 l. 112. Ackermann H, Graber S, Herterich I, Daum I. Cerebellar contributions to the perception of temporal cues within the speech and non-speech domain. Brain Lang 1999; 67~228-241. 113. Nitschke MF, Hahn C, Melchert UH, Handels H, Wessel K. Activation of the cerebellum by sensory finger stimulation and by finger opposition movements. A functional magnetic resonance imaging study. J Neuroimaging 1998;8:127-1 31, 114. Blakemore SJ, Wolpert DM, Frith CD. Central cancellation of self-produced tickle sensation. Nat Neurosci 1998; 1:635-640. 115. Tesche CD, Karhu J. Somatosensory evoked magnetic fields arising from sources in the human cerebellum. Brain Res 1997; 744:23-3 1. 116. Paulin MG. The roleof the cerebellum in motor control and perception. Brain Behav Evol 1993; 41:39-50. 117. Paulin MG. Neural representations of moving systems. Int Rev Neurobiol 1997; 41~515-533. 118. Darlot C. The cerebellumas a predictor of neural messages-I. The stable estimator hypothesis. Neuroscience 1993; 56:617-646.
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119. Kagerer FA, BrachaV,Wunderlich DA, Stelmach GE, Bloedel JR. Ataxia reflected in the simulated movements of patients with cerebellar lesions. Exp Brain Res 1998;121:125-134. 120. Kim SG, Ugurbil K, Strick PL. Activation of a cerebellar output nucleus during cognitive processing. Science 1994; 265:949-95 1. 121. Guzzetta F, Mercuri E, BonannoS, Longo M, Spano M. Autosomal recessive congenitalcerebellaratrophy.Aclinicalandneuropsychologicalstudy.BrainDev 1993; 15:439445. 122. Daum I, AckermannH.Neuropsychologicalabnormalitiesincerebellarsyndromes-fact or fiction? Int Rev Neurobiol 1997; 41 :455-47 1. 123. WalleschCW, Horn A.Long-termeffectsofcerebellarpathologyoncognitive functions. Brain Cogn 1990; 14:19-25. 124. Akshoomoff NA, Courchesne E, Press GA, Iragui V.Contribution of the cerebellum to neuropsychological functioning: evidence from a case of cerebellar degenerative disorder. Neuropsychologia 1992; 30:3 15-328, 125. Dimitrov M,Grafman J, Kosseff P, WachsJ, Alway D, HigginsJ, Litvan I, Lou JS, Hallett M. Preserved cognitive processes in cerebellar degeneration. Behav Brain Res 1996; 79:131-135. 126. Drepper J, Timmann D, Kolb FP, Diener HC. Non-motor associative learning in patients with isolated degenerative cerebellar disease. Brain 1999; 122:87-97. 127. Daum I,Ackermann H, SchugensMM, Reimold C, Dichgans J, Birbaumer N. The cerebellum and cognitive functions in humans. Behav Neurosci 1993; 107:411-419. 128. Grafman J, Litvan I, Massaquoi S, Stewart M, Sirigu A, Hallett M. Cognitive planning deficit in patients with cerebellar atrophy. Neurology 1992; 42:1493-1496. 129. Canavan AG, Sprengelmeyer R, Diener HC, Homberg V.Conditional associative learningisimpairedincerebellardiseaseinhumans.BehavNeurosci1994; 108:475-485. 130. Akshoomoff NA, Courchesne E. A new role for the cerebellum in cognitive operations. Behav Neurosci 1992; 106:731-738. 131. Allen G, Buxton RB, Wong EC, Courchesne E. Attentional activation of the cerebellum independent of motor involvement. Science 1997; 275: 1940-1 943. 132. Yamaguchi S, Tsuchiya H, Kobayashi S. Visuospatial attention shift and motor responses in cerebellar disorders. J Cogn Neurosci 1998; 10:95-107. 133. Middleton FA, Strick PL. Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science 1994; 266458461. 134. Schm~mannJD, Pandya DN. Prefrontal cortex projections to the basilar pons in rhesusmonkey:implicationsforthecerebellarcontributiontohigherfunction. Neurosci Lett 1995; 199:175-178. Autistic features in Joubert syndrome: a genetic 135. Holroyd S, Reiss AL, Bryan disorder with agenesis of the cerebellar vermis. Biol Psychiatry 1991; 29:287-294. 136. Courchesne E, Saitoh0, Yeung CR, Press GA, Lincoln AJ, Haas RH, Schreibman L. Abnormality of cerebellar vermian lobulesVI and VI1 in patients with infantile autism: identification of hypoplastic and hyperplastic subgroups with MR imaging. AJR Am J Roentgen01 1994; 162:123-1 30. 137. Piven J, Nehme E, Simon J, Barta P, Pearlson G, Folstein SE. Magnetic resonance R N ,
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imaging in autism: measurement of the cerebellum, pons, and fourth ventricle. Biol Psychiatry 1992; 31:491-504. Hashimoto T, Tayama M, Miyazaki M, Murakawa K, Kuroda Y. [MRI measurements of the brain stem and cerebellum in high functioning autistic children]. No To Hattatsu 1994; 26:3-8. Schaefer GB, Thompson JN, Bodensteiner JB, McConnell JM, Kimberling WJ, Gay CT, Dutton WD, Hutchings DC, Gray SB. Hypoplasia of the cerebellar vermis in neurogenetic syndromes. Ann Neurol 1996; 39:382-285. Lechtenberg R, GilmanS. Speech disorders in cerebellar disease. Ann Neurol 1978; 3:285-290 Ackermann H, Vogel M, Petersen D, Poremba M. Speech deficits in ischaemic cerebellar lesions. J Neurol 1992; 239:223-227. AckermannH,Hertrich I. Speechrateandrhythmincerebellardysarthria:an acoustic analysis of syllabic timing. Folia Phoniatr Logop 1994; 46:70-78. Murdoch BE, Chenery HJ, Stokes PD, Hardcastle WJ. Respiratory kinematics in speakers with cerebellar disease. J Speech Hear Res 1991; 34:768-780. Amarenco P, Chevrie MC, RoulletE, Bousser MG. Paravermal infarct and isolated cerebellar dysarthria.Ann Neurol 1991;30:211-2 13. Silveri MC, Leggio MC, Molinari M. The cerebellum contributes to linguistic production: a case of agrammatic speech following a right cerebellar lesion. Neurology 1994; 44:2047-2050. Ackermann H, Wildgruber D, Daum I, Grodd W. Does the cerebellum contribute to cognitive aspectsof speech production? A functional magnetic resonance imaging (fMRI) study in humans. Neurosci Lett 1998; 247:187-190. Van Calenbergh F, Van de Laar A, Plets C, Goffin J, CasaerP. Transient cerebellar mutism after posterior fossa surgery in children. Neurosurgery 1995; 37:894-898. D’Avanzo R, Scuotto A, Natale M, Scotto P, Cioffi FA. Transient “cerebellar” mutism in lesions of the mesencephalic-cerebellar region. Acta Neurol (Napoli) 1993; 151289-296. Turgut M. Transient “cerebellar” mutism. Childs Nerv Syst 1998; 14:161-166. Dietze DD, Mickle JP. Cerebellar mutism after posterior fossa surgery. Pediatr Neurosurg1990;16:25-31. Abekura M. Akinetic mutism and magnetic resonance imaging in obstructive hydrocephalus. Case illustration. J Neurosurg 1998; 88:161. Chaudhuri JR, Anand J, Shivshadcar N, Jaykumar PN, Suvarna A, Murali T, Taly AB. Right parietal infarction with concomitant mutism. Acta Neurol Scand 1999; 99:77-79. Esposito A, Demeurisse G, Alberti B, Fabbro F. Complete mutism after midbrain periaqueductal gray lesion. Neuroreport 1999; 10:681-685. Mega MS, Cohenour RC. Akinetic mutism: disconnection of frontal-subcortical circuits. Neuropsychiatry Neuropsychol Behav Neurol 1997; 10:254-259. Ure J, Faccio E, Videla H, Caccuri R, Giudice F, Ollari J, Diez M. Akinetic mutism: a report of three cases. Acta Neurol Scand 1998; 98:439-444. Minagar A, David NJ. Bilateral infarction in the territory of the anterior cerebral arteries. Neurology 1999; 52:886-888.
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History of Ataxia Research Jose Berciano, Julio Pascual, and JoseM. Polo
University Hospital “Marques de Valdecilla,Santander, Spain I’
I.ORIGINANDMEANING
OF ATAXIA
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11. CLASSIC CLINICOPATHOLOGICAL FORMS OF ATAXIA A.Friedreich’ S Ataxia B.HereditarySpasticParaplegia C.OlivopontocerebellarAtaxia D. CorticalCerebellarAtrophy E. Marie’sCerebellarAtaxia F. Cerebellar Ataxia and Myoclonus (Ramsay Hunt Syndrome) G. SpinopontineAtrophy
79 79 79 81 83 83
111. CLASSIFICATION OF THE ATAXIAS A. PathologicalClassification of theAtaxias B.ClinicogeneticClassification
88 88 89
REmRENCES
1.
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ORIGIN AND MEANING O F ATAXIA
The semantics of the term ataxia was masterfully analyzed in the seminal paper by Bell and Carmichel (1). Therefore, we have quoted several passages from it for this first paragraph. The term ataxia-literally meaning, irregularity, confusion or disorderliness-was, in this sense, in use from the days of Hippocrates or 77
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before;thusHippocrates (Precepts, XIV) saysthat ataxia-that is,irregularity-in a disease signifies that it will be a long one. Byfield in 1615, writing on angels, says: “we arenot to thinke there is any ataxie among those glorious creatures.” As late as 1853 Mayne’sLexicon described ataxia as a term for irregularity, want of order, as occurring in the progressof diseases or in the natural functions, thus emphasizing its application to medical states in general, but making no reference to a particular application to the nervous system. Althaus, in his textbook on nervous diseases in 1877, refers to the fact that as old as thatoftabes,for italsooriginatedwith thetermataxiais Hippocrates, and it has likewise entirely changed its meaning in the course of time. Some authors have applied it to chorea, others to fevers, others to variousnervousdisorders.Atpresent,however,weunderstandbyataxy, not a disease itself, but merely a symptom to which various disorders may giveriseandwhichessentiallyconsistsof a wantof coordination of voluntary movements and a tendency on the part of the patient to lose his balance, but without actual loss of power, and apart from tremor, chorea or paralysis.
Any further change in the use of the word has consisted in the increasing tendency to apply it to designate a particular disease, of which it is a prominent symptom, rather than to confine it to the descriptionof the symptom, thus locomotor ataxia, Friedreich’s ataxia, cerebellar ataxia, and hereditary ataxia occur frequently throughout medical literature of today (cf.Ref. 1). It is worth noting that Bell and Carmichel’s paper was the pointof reference for including the hereditary spastic paraplegia (HSP) within the ataxias(2) despite that this disorder does not usually include ataxia as an outstanding semeiology. The reason for such inclusion was twofold: first, in some ataxia pedigrees theremay be patients with almostpurepyramidalsigns;andsecond,theneedfordistinguishingcases with absence of deep tendon reflexes (characteristicof Friedreich’s ataxia [FA]) from those with present or exaggerated deep reflexes (characteristic of spastic ataxia or HSP). As outlined in the foregoing, the history of the contemporaneous concept of ataxia starts from the original descriptionsof main degenerative ataxic disorders. On this basis, there emerged several attempts at classification giving rise to nosological confusion around the complex topic of ataxias. Wishing to clarify this question we have divided this paper into two parts: the first is dedicated to reviewing the original descriptionsof classic clinicopathological entities following their chronological orderof publication (FA, HSP, olivopontocerebellar atrophy [OPCA], Marie’s ataxia, cortical cerebellar atrophy [CCA], Ramsay Hunt syndrome, and spinopontine atrophy), and the second to the the different proposals of classification up to the present division based on recent molecular genetic discoveries.
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II. CLASSIC ~LI~ICOPATHOLOGICAL FORMS OF ATAXIA A.
Friedreich’sAtaxia
Inaseries of five paperspublishedbetween1863and1877,Friedreichdescribedadistinctiveclinicalsyndromeinninepatients(sevenmaleandtwo female) belonging to five sibships (3-7). The age of onset was near puberty. Established clinical picture consisted of progressive gait and limb ataxia and dysarthria.Othersymptomsandsignsinthecourse of thediseaseincluded nystagmus, areflexia (cases 11, VI, VII, and IX examined after 1875), sensory loss,muscleweakness,skoliosis,diabetes,andtachycardia.Autopsyinfour cases showed a uniform pathological picture consisting of degeneration of posterior funiculus, posterior spinal roots, Clarke’s columns, and spinal lateral funiculus. Furthermore, Friedreich described cardiomyopathy in three cases. The proposal that the disorder he reported was a distinct entity, called hereditary 1868 Charcot considered ataxia, initially met with considerable opposition. In (8). In 1876 Friedreich that Friedreich’s patients suffered from multiple sclerosis wrote (6): It is incomprehensive that anyone can still speakof disseminated sclerosis when I have given the resultsof 3 detailed studies.I am pleased to know that some French pathologists (Bourdon and Topinard) have recognized my cases as examples of authentic noncomplicated ataxia . . .and I hope that Charcot, in the vast field of observation which he commands, will sooner or later find a case analogous to those I have described. Ironically, Charcot recognized hereditary ataxia2 years after Friedreich’s death, which occurred in 1882 (see Refs. 2’8). Nicolaus Friedreich not only introduced the concept of hereditary ataxia, but was also the first author to precisely describe a clinicopathological study of a form of spinocerebellar degeneration. Becauseof this, Brousse’s proposal (see Ref. 8 ) to apply thetermFriedreich’sataxiatohereditaryataxiawassoon accepted.
B. HereditarySpasticParaplegia In a series of four successive papers (9-12) Striimpell described two families with a uniform clinical picture characterizedby vertical transmission (at least in family Polster) and progressive lower limb spasmodic pseudoparalysis; that is, predominance of dynamic spasticity over pyramidal weakness and at-rest hypertonia (Fig. l), a clinical finding later on recognized as a semeiological characteristic of HSP (13-15). Onset of symptoms occurred between 34 and 56 years of age. Two autopsy studies revealed degeneration of pyramidal tracts, posterior columns, and spinocerebellar tracts.
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A
f Figure 1 (A)Pedigree of Polster family elaborated from Striimpell data (From Refs.11 and 12). (B) Characteristic spastic posture (Case Johann Polster; From Ref. 13.)
In short,Adolf Striirnpell reported a clinicopathological entity. Despite this in the literature, there has been a tendency to call the syndrome by the eponym “Striimpell-Lorrain” disease (16,17).This merits abrief c o m e n t . Lorrain’s thesis (18) can be divided into three parts. The first is a general review addressing of personal the questionof what a familial disorder is.The second is a description observations, including four sporadic cases (no. I, 11, 111, and XXI) and two familial cases (caseXXII, corresponding to a doubtful spastic paraplegia, and case XXVIII, suffering from familial spastic ataxia); furthermore in this second part 20 publications. In the third Lorrain carried out a literature review encompassing of HSP,translating the part of his doctoral thesis Lorrain describes the pathology case of F Gaum reported by Striimpell and presenting histological features of a personal sporadic case. Lorrain concluded that familial diseases have numerous transitional forms, and thatHSP and hereditary spasmodic tabes are synonymous disease designations. It is obvious that Striimpell defined a hereditary disorder characterizedby pure spastic paraplegia, now known as “pure” HSP (14), with a uniform neuropathological framework. Lorrain carried out a literature review reporting a heterogeneous personal series; in fact, noneof his patients could retrospectively be
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included within “pure”HSP. For historical reasons and to avoid semantic confussion, the eponym “Striimpell disease” should be used to designate “pure” HSP, and such an eponym should not be used to designate other “complicated” forms of the disease.
C. OlivopontocerebellarAtrophy The term OPCA was introduced by Dejerine and Thomas, in 1900, to designate (19). Nine the pathological framework in a sporadic case with progressive ataxia years before, however, Menzel had reported a family with a complex clinical picture characterized by progressive ataxia, spasmodic dysphonia, rigidity in the lower limbs, dysphagia, and dystonic posture of the neck (20). Onset of symptoms was at about 30 years of age. There were four affected members over two generations. Autopsy revealed olivopontocerebellar lesions together with degeneration of posterior and Clarke’s columns, pyramidal and spinocerebellar tracts, and substantia nigra. Menzel found “very flattened and reduced subthalamic nuclei,” but unfortunately he did not give any microscopic description of these structures; demonstrationof luysian atrophy would have beenof great interest in view of the dystonic postures of the patient. Be that as it may, this family is a good example of autosomal dominant cerebellar ataxia (ADCA) typeI in Harding’S classification (see later discussion). DejerineandThomas(19)describedasporadiccasewithprogressive ataxic gait, dysarthria, impassive face, hypertonia, hyporreflexia, and urinary incontinence beginning at the age of 53. Autopsy 2 years later showedan advanced degeneration of the basis pontis, inferior olives, middle cerebellar peduncles, and to a lesser degree, inferior cerebellar peduncles. There was severe atrophy of Purkinje cells, more marked in the cerebellar hemispheres than in the vermis. Neither the basal ganglia nor substantia nigra are mentioned. According to the authors, OPCA is a nonfamilial disease that should be included among primary cerebellar degenerative disorders. Berciano(2 1,22) revised the pathological material of this case (“Vais D.V.” Dejerine Laboratory, Paris), available preparations stained with the Weigert-Pal or carmin methods being as follows: seven transverse sections of the spinal cord, six transverse sections of the brain-stem and cerebellum through medulla, pons, andisthmus rombencephali, and one horizontal sectionof the basal ganglia through the anterior commisure. While confirming the reported olivopontocerebellar lesions (Fig.2) and the absenceof apparent lesions of the putamen, it was not possible to establish whether or not the substantia nigra was degenerated. This finding would have been of great interest because the patient had had an incipient parkinsonism. (23), The early reportsof Dejerine and Thomas (19) and later Loew’s thesis developed under the tutelageof Dejerine himself, considered OPCA to be atypical when there was a hereditary factor (as in the aforementioned family reported
82
et
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al.
Figure 2 Olivopontocerebellar lesions in the case reported by Dejerine and Thomas. Pathological material belongs to Dejerine Laboratory (Facultyof Medicine, Paris). Both transverse sections are stained with the Weigert-Pal method. (A) This section through medulla and cerebellum shows demyelination of the cerebellar white matter and olivocerebellar fibers.(B) This section through the upper half of the pons shows demyelination of middle cerebellar peduncles. (From Ref. 19.)
by Menzel), lesions extending beyond of olivopontocerebellar framework, or a clinical presentation not limited to cerebellar symptoms. However, the concept of atypical OPCA fell into disuse with the recognition of familial OPCA(24,25) and of the many lesions that frequently accompany olivopontine degeneration (26). Already outlined in the original caseof Dejerine and Thomas (see foregoing), extrapyramidal rigidity and nigrostriatal lesions are outstanding featuresof OPCA (21,22,27-29). From a clinicopathological studyof two cases, Guillain et
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al. (30,31)proposed the hypothesis of a cerebellar origin for extrapyramidal rigidity in OPCA. This hypothesis was prevalent until 1933,when Scherer addressed the question of pathophysiology of rigidity in OPCA starting from the clinicopathological study of four sporadic OPCA cases. Two patients had severe parkinsonism masking cerebellar symptoms. Pathologically both cases displayed marked degenerationof the striatum and nigra and non-fully developed olivopontocerebellar lesions. Cerebellar ataxia was the outstanding symptomatologyin the other two, their pathological study showing severe OPCA and incipient striatonigral atrophy. Scherer stated that severity of parkinsonism in OPCA correlated not with the degree of cerebellar degeneration but with that of the striatum and nigra. Furthermore, Scherer compared striatal degeneration in his patients with that previously reported in Huntington’s disease and considered, leaving aside the question of hereditary factor, that both diseases should be included under the same nosological umbrella. Indisputably, with these superb papers Scherer not only ruled out the erroneous concept of cerebellar parkinsonism in OPCA, but gave the first accurate description of striatonigral degeneration (32,33).
D. CorticalCerebellarAtrophy Holmes, in 1907, described a family with an autosomal recessive disorder giving rise to cerebellar ataxia and hypogonadism (34). The sibship included four affected members (three male and one female), with onset of symptoms in the fourth decadeof life. Autopsy studyof one case showed cerebello-olivary degeneration. Greenfield (35) erroneously classified this family together with autosomal d o ~ n a n pure t CCA, Since then the eponym “Holmes type” has been used to designate familial cerebello-olivary (or CCA) without any reference to hypogonadism. A sporadic and idiopathic form of the disease was later reported (36).
E. Marie’sCerebellarAtaxia The basic clinicopathological hallmark of familial ataxias and paraplegias was outlined at the beginning of this century. Meanwhile, a series of cases not conforming to thoseso far described was appearing in the literature. Ladame, in 1890, when reviewing 165 cases of the so-called FA from published reports, found that (8). Under many were “incomplete, doubtful or absolutely atypical to Friedreich” such circumstances, Pierre Marie (37) drew attention to four families (38-41) with a clinical picture different from that described by Friedreich. The age of onset was later, the tendon reflexes were increased, was thereophthalmoplegia or visual loss, and neither kyphoscoliosis nor foot deformity was observed. By this time two autopsy studies (38,39) had shown a pathology restricted to the cerebellum (Table 1).As the term “hereditary ataxia” was vacant after the acceptation of Friedreich’s disease, Marie proposed to apply that term for families with ataxia and normo-
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Table 1 Marie’sAtaxia:OriginalNeuropathologicalFindings Spinal cord Gray
owers FleschigPosterior Case tractscolumns (Ref.)Author no. I 2
horns
Fraser (39) Nonne (38), case A. Stub Nonne (40), case F. Stub Meyer (43), case VI Barker (44), case XVIII Barker (44), case XX Switalski (43, case FranqoisW Thomas and Roux (46), case Amelie H Rydel (47), case Louis H Guillain et a1 (48), case Chass
2a 3 3a
3b
4 4a
4b 4c
-
columns
-
-
-
+ + + ++ +++
+++
++ +
+++ +++ +++ +++ ++
++ +
+++ +
+++ +++
+ + +/-
+++ +++
+++ ++S
-
+++
+++
-
+I-+
NM
Cases 3 to 3a belong to Sanger Brown pedigree (41) and cases 4 to 4c to Klippel and Durante (40) pedigree. (+ +), severe lesion; (++), moderate lesion;(C), mild lesion; (+/-), doubtful lesion; ( ) , no lesion detectable; (NM), not mentioned.
+
or hypereflexia, adding the epithet “c6r6belleuse” on the basis of pathological findings in the two mentioned autopsy studies. Eight further autopsy studies in not only three of these four families (Table 1) showed extensive lesions involving the cerebellum, but also the spinal cordand brain-stem (49). In spite of this, the term hereditary cerebellar ataxia (Marie’s ataxia) was soon accepted(50), and it is occasionallyin use nowadays(50-53). Heterogeneity of Marie9sataxia was severely criticized by Holmes (54), who considered it a convenient pigeon-hole in which to group together cases of obscure nature with some symptoms in common, and it may have been of service in drawing attention to such cases till it was possible to clarify them accurately; but neither clinical nor pathological experience justifies its retention as a descriptive title of a form of disease. Holmes considered that the majority of cases of progressive cerebellar disease belongs to the classof OPCA and more rarely to cerebello-olivaryatrophy, thus
85
History of Ataxia Research
Brainstem-cerebellum
Inferior white Cerebellar Griseum cerebellar olivary attercortexpontis peduncles nuclei NM
NM
NM
-
-
NM
-
-
NM
+ + -
NM
___
___
+
-
-
__
__
__
-
___
__
__
-
-
++
+
-
NM rootsdorsal ___ and ventral Spinal
-
-
+ +
-
++
+l-
NM ___
+ +
(+)
nerve Optic (++); spinal ventral and dorsal roots (+)
Spinal ventral and dorsal roots (+) Cerebellar dentate nuclei(+ +) __ Fastigi (+ +)dentate and (+ +) nuclei Spinal ventral and dorsal roots (+);optic nerve (++) -roots dorsal and ventral Spinal (+)
+
NM roots ventral Spinal
+
superior and
+
(+ +)
nucleiDentate cerebellar peduncles(+++); substantia nigra (+)
outlining the pathological classification of ataxias (see Sec. 111. A). In spite of these severe criticisms, some credit is due to Marie for recognizing that there were cases of hereditary ataxia distinct from FA (2).
F. CerebellarAtaxiaandMyoclonus (Ramsay Hunt Syndrome) The nosology of Ramsay Hunt is so complex that it is timely to remember the statement by Radermecker (55): “If there is one disease in the neurological literature which is difficult to define and demarcate, it is the cerebellar dyssynergia of Ramsay Hunt.” Starting from the clinical features of three patients aged between28 and 4’7 years, Ramsay Hunt (56) created the term dyssynergia cerebellaris progressiva (DCP) to designate a syndrome characterized by volitional tremor, hypermetria, dysmetria,adiadokokinesis,dyssinergia,hypotonia,andintermittentasthenia. There was also gait ataxia although in all three cases appendicular ataxia was predominant. Ages of onset ranged from 23 to 40 years. Ramsay Hunt indicated that the semeiology observed was that expected when there is aofloss cerebellar
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controlovervoluntarymovements;therefore he proposedthatthedisorder should be considered of cerebellar origin. The gradual progression and chronic clinical course led him to suggest a progressive degeneration of certain special cerebellar structures. A few years later, however, autopsyof case l revealed the characteristic lesions of Wilson’s disease, especially involving striatum, pons, and cerebellum. This gave place to the following comment: I isolatedsomeyearsago as Therefore,thesmallclinicalgroupwhich chronic progressive cerebellar tremor (dyssynergia cerebellaris progressiva) may be modified as a result of subsequent pathologic study. In one group, dyssynergia cerebellaris myoclonica, the cerebellar tremor is part of a general cerebellar disorder and may be correlatedanwith atrophy of the efferent dentate system of the cerebellum.In the other group the tremor disturbance is not purely Cerebellar, but is a mixed striocerebellar tremor associated with the central lesionsof pseudosclerosis (tremor typeof the hepatocerebral degeneration). It is probable that further pathologic investigations will show still more light on this interesting and comparatively rare groupof organic nervous disorders (57).
In between the two mentioned papers, Ramsay Hunt (58) reported an additional series of six cases combining DCP and myoclonus-epilepsy (according to his description this corresponds to spontaneous, action-induced and reflex myoclonus of focal, multifocal, or generalized distribution) (cf. Refs.59,60). Moreover, cases five and six, twin brothers, exhibited the characteristic clinical picture of FA. The onset of symptoms occurred in the first or second decadeof life. There was no evidence of hereditary factors, with the exception of the just mentioned FA cases, for whoman autosomal recessive inheritancemay be invoked. Autopsy 5 only and showed the spinal lesions typical of FA and severe was available in case atrophy of dentate nuclei, with the corresponding degeneration of superior cerebellar peduncles. Ramsay Hunt designated this type of dyssynergia with thetern dyssynergia cerebellais myoclonica (DCM), considering that it appears to be a well-defined type of nervous disease presenting the clinical picture of a progressive cerebellar disorder in association withmyoclonus-epilepsy. On the basis of his pathological study, he referred the progressive dyssynergia to a primary atrophy of the efferent dentate system of the Cerebellum, regarding this system as the essential neural mechanism underlying the production of the cerebellar or intention tremor.On thecontrary, Ramsay Hunt was very cautious in his pathophysiological interpretationof myoclonus, as demonstrated by the following comment: The relation of the cerebellar disorder to myoclonus-epilepsy in the group of cases whichI have described is quite obscure and in the present state of our knowledge but little lightcan be thrownon this question. Itis quite possible that the combination is only accidental and represents the association of two independent nervous disorders in a predisposed individual. Such combina-
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tions in the realm of the neuropathology are not by [any] means uncommon. Nevertheless, I think that one should not be tooinhasty concluding that here is a mere combination of separate clinical entities. We know so little of the underlying cause and pathologyof myoclonus and its relation to the various structures of the central nervous system that the possibility of a form related to the static or posture should be considered. Itis conceivable, for example, that sudden breaks in the continuity of postural control or synergy might express themselves in terms of compensatory movements ofa myoclonic type. InGreenfield’sclassification of thespinocerebellardegenerations (35), DCM was includedwithinpredominantlycerebellarformsundertherubric “dentato-rubral atrophy.” Henceforth, DCM was almost universally considered a type of spinocerebellar syndrome. However, not always was dentatorubral atrophy the pathological framework.To give an example, the patientof Bonduelle et because of the important myoclonic postural al. was diagnosed clinically DCM as syndrome, but postmortem examination revealed OPCA, with intact dentate nuclei (61,62). Starting from a studyon progressive myoclonic epilepsy, Andermann et al. (63,64) criticized Ramsay Hunt’s concept, indicating it “does not represent a specific disease, and its use should now be abandoned.” A long list of major (e.g., Unverricht-Lundborg disease,mitochondrialencephalomyopathy,sialidosis, Lafora’s disease, neuronal ceroid lipofuscinosis) or rare (e.g, Gaucher’s disease, GM, gangliosidosis, biotin-responsive encephalopathy, neuroaxonal dystrophy, dentatorubro-pallydoluysian atrophy, and others) causes of the Ramsay Hunt syndrome were mentioned. Furthermore they proposed that the syndrome is largely accounted for by the mitochondrial encephalomyopathies. From a different perspective and following Ramsay Hunt, Marsden and Obeso (59) defined the syndrome as the triad of (a) severe myoclonus, (b) progressive ataxia, and (c) mild epilepsy and cognitive change. Soon after they described a series of 30 patients fulfilling such a definition(65). A specific diagnosis was made in 17 (57%) of these patients (mitochondrial disease, UnverrichtLundborgdisease,orceliacdisease).Therefore,thereremainedasubstantial proportion of patients to whom several neurodegenerative diagnostic labels (e.g., multiple system atrophy or OPCA) could presumptively be applied. Perhaps it would be better to label these patients as cases of degenerative (or idiopathic) myoclonic-ataxic syndrome instead of Ramsay Hunt syndrome, but, as Anita Harding stated, it would not catch on (66).
G. Spinopontine Atrophy Boller and Segarra (67) reported a family with a clinical picture of autosomal dominant hereditary ataxia. Autopsy studyof two cases revealed lesions involving the spinal cord in its afferent pathways and, in addition, the pontine nuclei
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and the middle cerebellar peduncles. The cerebellum itself and the inferior olives were normal. The authors indicated that this family “differs from the classical forms into which the spinocerebellar degenerations are usually subdivided. its possible links with the families consideredby some as examplesof the so-called Marie ’S hereditary cerebellar ataxia have been discussed.” Several clinicopathological studies on spinopontine atrophy were reported afterward (68,69). Sequeiros and Suite (70) reviewed a large black family affected with Machado-Joseph disease (MJD). They demonstrated that this family, which was first studied by Boller and Segarra (67,69) and the one reported by Taniguchi and Konigsmark (68) were all related.It seems clear that spinopontine atrophy was the pathological framework of MJD, an emerging nosological entity in the 1970s. In their comprehensive literature review, Sequeiros and Coutinho (70,71) established the neuropathological criteria for the diagnosis of MJD (for further details, see Chapter 19, devoted to SCA-3). They defined MJD as multisystem degeneration involving: (a) cerebellar afferent (i.e., spinocerebellar, vestibulocerebellar, and pontocerebellar, but no olivocerebellar) and efferent cerebellar pathways (i.e., dentatorubral), sparing the cerebellar cortex; (b) extrapyramidal structures,suchasthesubstantianigra,locuscoeruleus,andthepallidoluysian complex; and (c) anterior horn cells and cranial motor nerve nuclei.
111.
CLASSIFICATIONOFTHEATAXIAS
Unravelling the classificationof the ataxias wasnot an easy task. Suffice it to say that none of the textbooks of neurology published up until a few years ago had ever coincided on this point.In this connection, it is timely to remember the reflexion madeby Refsum and Skre(72): “From the clinical viewpoint,it isnot an exaggeration to state that there are as many classifications as there are authors on the subject.’’
A.
Pathological Classification of theAtaxias
As outlined before, thefirst serious attempt at classificationwas made by Greenfield ( 3 3 , based on pathological criteria. He divided the underlying anatomical basis of heredoataxia into three groups: (a)predominant2y spinal forms (FA and hereditary espastic ataxia); (b)spinocerebellar forms (Menzel type of hereditary predominantly cerataxia and subacute spinocerebellar degeneration); and (c) ebellar forms (Holmes’ type of hereditary ataxia, diRuse atrophy of Purkinje cells, OPCA, and dentatorubral atrophy). in his Comprehensive literaturereview,Greenfieldseparatedautosomal dominant pedigrees into two main groups: type A (Menzel), which would enter into the general category of OPCA, and type B (Holmes). Concerning OPCA, thiswas,therefore,dividedintohereditarytype(Menzel)andsporadictype
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(Dejerine Thomas).The publication of cases with uncommon clinicopathological findings (e.g., dementia or blindness) led to the identification of a new type of OPCA called “special” (73), or “variant” (74). Using genetic, clinical, and pathological data Konigsrnark and Weiner (75) 11,recessive; type111, classified OPCA intofive categories (type I, dominant; type with retinal degeneration; type IV, Schut and Haymaker type; and type V, with dementia, ophthalmoplegia, and extrapyramidal signs). They added a further two categories for sporadic observations and for those do that not fit the previous five, although in their opinion such cases probably belong to type 11. Berciano (21,22) indicated that OPCA is a complex clinicopathological syndrome that made it difficult to sustain any classification based on clinical and pathological criteria. Thus, for example, the creationof “special types” or “variants’, ignores the fact that mental deterioration or atrophy of the anterior gray horn are seen inhalf the cases of familial OPCA. Furthermore, he indicated several omissions in the study by Konigsmark and Weiner (75) making the borderlines of their “types” somewhat hazy. Pathological classification of the ataxias has several drawbacks. It is not particularly helpful to clinicians who, not unnaturally, prefer to make some sort (2). Pathological of working diagnosis before the autopsy results are available classification ignores the fact that genetic heterogeneity affects not only the clinical picture, but also the pathological framework(2,32); that is, this classification is impossible within reported families in which autopsy findings were not consistent (cf. Ref. 32). Finally, it is hardly surprising that in a well-known symposium on spinocerebellar degenerations, when Oppenheimer was asked to say someam thing about the neuropathological contributions to this symposium, he “I said: painfully aware that histopathology seems to add very little to our understanding of the ataxic disorders” (76).
B. CiinicogeneticClassification We have seen that for almost a century clinicopathological studies in hereditary of these synataxias contributed to delineate a static, but also confused, nosology dromes. To find a new classification was a pressing need. This task was achieved by Harding, culminating in a series of exceptional contributions to the field of hereditary ataxias and related disorders (2,77). She proposed to start from genetic and clinical features, which are, certainly, the tools used by neurologists in clinical practice. In this way she proposed the clinicogenetic classification that apsoon universallyaccepted.Leavingasideataxic pearsinTable2,whichwas disorders with known metabolic or other causes, we will briefly update the remaining ataxic groups. With Harding’s classification we have established a prevalence ratio in Cantabria (Northern Spain)of 20.2 cases per 100,000 inhabitants (78).The most frequent phenotypes were “pure” HSP and FA.
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Table 2 Hading’s Clinicogenetic Classification of the Hereditary Ataxias and Paraplegia
1. Congenital disorders of unknown aetiology 1. Congenital ataxia with episodic hyperpnea, abnormal eye movements, and mental retardation (Joubert’s syndrome) 2. Congenital ataxia with mental retardation and spasticity (includes pontoneocerebellar hypoplasia) 3. Congenital ataxia rlr mental retardation (includes granule cell hypoplasia) 4. Congenital ataxia with mental retardation and partial aniridia (Gillespie syndrome) 5. Dysequilibrium syndrome 6. X-linked recessive ataxia with spasticity and mental retardation (Paine syndrome) 11. Ataxic disorders with known metabolic or other cause A.Metabolicdisorders l. Intermittent ataxic disorders (syndromes with hyperammonemia, aminoacidurias without hyperammonemias and disorders of piruvate and lactate metabolism) 2. Progressive uremitting ataxic syndromes (e.g., abetalipoproteinemia, hypobetalipoproteinemia, hexominidase deficiency, cholestenolosis, and others) 3. Metabolic disorders in which ataxia may occur as a minor feature (e.g., sphingomyelin storage disorders, metachromatic leukodystrophy, adrenoleukodystrophy, and such) B. Disorders characterised by defective DNA repair l. Ataxia telangiectasia 2. Xeroderma pigmentosum 3. Cockayne’S syndrome 111. Ataxic disorders of unknown aetiology A. Early onset cerebellar ataxia (usually before 20 years) l. Friedreich’S ataxia 2. Early onset cerebellar ataxia with retained tendon reflexes 3. With hypogonadism rlr deafness or dementia 4. With myoclonus (Ramsay Hunt syndrome, Baltic myoclonus) 5. With pigmentary retinal degeneration +- mental retardation or deafness ’ 6. With optic atrophy rlr mental retardation 7. With cataracts and mental retardation (Marinesco-Sjogren syndrome) 8. With childhood onset deafness and mental retardation 9. With congenital deafness 10. With extrapyramidal features 1l. X-linked recessive spinocerebellar ataxia B. Late-onset cerebellar ataxia (onset usually after 20 years) l. Autosomal dominant cerebellar ataxia with optic atrophy/ophthalmoplegi~ dementi~extrapyra~dal features/amyotrophy (probably includes Azorean ataxia) (ADCA type I)
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Table 2 Continued 2. Autosomal dominant cerebellar ataxia with pigmentary retinal degeneration
+- ophthalmoplegia or extrapyramidal features (ADCA type11) 3. “Pure” autosomal dominant cerebellar ataxia of later onset (older than 50 years) (ADCA type 111) 4. Autosomal dominant cerebellar with myoclonus and deafness (ADCA type
IV) 5. Periodic autosomal dominant ataxia 6. “Idiopathic” late-onset cerebellar ataxia TV. Hereditary spastic paraplegia A. “Pure” spastic paraplegia 1. Autosomal dominant: age of onset usually before 35 (type I) 2. Autosomal dominant: age of onset usually after 35 (type 11) 3. Autosomal recessive 4. ? X-linked recessive B. Complicated forms of spastic paraplegia l . With amyotrophy Of the small hand muscles Resembling peroneal muscular atrophy Troyer syndrome Charlevoix-Saguenay syndrome Resembling amyotrophic lateral sclerosis 2. Spastic quadriparesis with mental retardation 3. Sjogren-Larsson syndrome 4. With macular degeneration and mental retardation (Kjellin syndrome) 5. With optic atrophy 6. With extrapyramidal features 7. With ataxia and dysarthria 8. With sensory neuropathy 9. With disordered skin pigmentation
Congenitalataxiasarerare,andtheyareusuallyduetodevelopmental anomalies of the cerebellum or brain stern. The most common pattern of inheritance is autosomal recessive. Mental retardation, ataxia, motor delay, and nystagmus are theusualmanifestations. Theremay be specific clinical pictures, such as in Joubert’S and Gillepsie’S syndromes (see Table 2). Very recently, Barth et al. (’79,80) have distinguished two typesof pontocerebellar hypoplasia (PCH). In PCH-1thehallmarkisthepresence of spinalhorndegeneration,similar to Werdnig-Hoffmann disease. There is no linkage between spinal muscular atrophy locus (5q) and PCH-l. PCH-2 is characterized by gross chorea, which may change later in childhood to more dystonic patterns. Differential diagnosis of PCH should be carried out with carbohydrate-deficient glycoprotein syndrome
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(81,82). It is worth noting that ataxia of congenital onsetmay occur in autosomal a dominant pedigrees with marked anticipation; in fact, we have studied such case in a SCA7 family in which anticipation occurred throughout four generations, onset in one patient of the youngest generation being at age 2 years. FA is the most common formof autosomal recessive early-onset cerebellar ataxias (EOCA). Harding divided EOCA into two main groups (83,84): FA and other EOCA syndromes different from FA. This distinction is most appropriate because under the rubricof FA, a hodgepodge of syndromes has sometimes been included that we now know are genetically separate entities. As we have seen before, Nicolaus Friedreich outlined the main characteristics of “his” disease. Nowadays, the most usedFA diagnostic criteria are those proposed by Harding in 1981 (83) (for further details, see Chapter 6 devoted to FA). An important step in the disease was the location of the gene on chromosome 9p (85). Afterwards, families linked to chromosome 9 markers with onset later than 25 years or with retained tendon reflexes were recognized (78,86-90). We reported an FA pseudodominant pedigree (78), included in the genetic study by Chamberlain et al. (86), with four affected members whose clinical picture began in the fourth decade of life, one of them showing nomoreflexia in the lower limbs; intriguingly a comparable pseudodominant pedigree had already been reported by HardingandZilhka(91).Undoubtedly,theseobservations called for a modification of current diagnostic criteria of the disease. In 1993 Campuzano etal. reported that the molecular basisof FA is an intronic GAA triplet repeat expansion (92). Most patients are homozygous for this dynamic mutation, a few having an expansion in one allele and point mutation in the other. Screening of patients with progressive ataxia for GAA expansion in the frataxin gene has demonstrated that the clinical spectrum of FA is broader than previously recognized, to the extentof about one-quarter of patients, despite be6 for further deing homozygous, had atypical clinical picture (93) (see Chapter tails). It is worth noting that the FA phenotype has recently been identified in patients with selective vitamin E deficiency. ADCAs are clinically and genetically heterogeneous (see Table 2). Harding I-IV) studying periodic ataxias (PA) distinguished four main groups (ADCA separately (2,77,94). Afterward,it was established that ADCA IV is a type of mitochondrial cytopathy (95). The panorama of ADCA and PA has been drastically changed with the recent substantial discoveries that first located several responsible genes and, later on, with identificationof expanded triplet repeat sequencesas the most common molecular basisof gene mutation (see Refs.95-99 for review,and corresponding chapters in this book). Table 3 shows an updated clinicogenetic classificationof the dominant ataxias. Perhaps, in the future; thisclassification-necessarily provisional-will require some simplification because we are convinced that most of us, similar to Harding for hereditary motor and sensory neuropathies(loo), will
I
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havedifficultiesinrememberinganyclassification of diseasewithnumbers greater than 3. “Idiopathic” late-onset cerebellar ataxia (ILOCA) is characterizedby sporadic progressive pure cerebellar or cerebellar-plus ataxia, beginning after 20 years of age (101). Judging by computed tomography or magnetic resonance imaging, the usual presumptive pathological framework here is CCA for cases with pure cerebellar ataxia and OPCA for cases with cerebellar-plus syndrome (102). The most complex nosological problem of ILOCA is probably its relation to multiple system atrophy (MSA). Although there is some overlapping between both processes, we have proposed that a subset of ILOCA cases does not fit in well within MSA and, therefore, should be considered as a separate entity until any biological marker becomes available (cf. Ref. 32; see also Chapter 27). The last nosological entity in the clinicogenetic classification is HSP, divided by Hardingintotwo main categories(2,14,77):pureandcomplicated forms (see T&le 2). Transmission of pure forms may be autosomal dominant or recessive and rarely X-linked. On the basis of age of onset, two types of dominant pure HSP can be defined: typeI with onset before40 years, and typeI1 with lateronset (14,lS). However,thisageseparationhasnotalwaysbeenfound (103). Pure HSP is much more frequent than any complicated form. Linkage analysis studies have demonstrated three different loci for autosomal dominant pure HSP (14q, 2p, and lSq), one locus for autosomal recessive HSP (8q), and two differents mutations (Xq and Xq22) in X-linked pedigrees (cf. Ref. 104). Furthermore, a new locus on chromosome 16q has been described for both pure and complicated pedigrees with autosomal recessive inheritance.The product of this gene is called paraplegin, and its mutations impair the mitocondrial function, (10s). thus suggesting a mechanism for neurodegeneration is HSP-type disorders As in hereditary ataxias, molecular genetic studies corroborates that HSP isa genetically complex syndrome.
We thank John Hawkins for stylistic revisionof the manuscript and Marta dela Fuente for secretarial help. Supportedby grant 98/017-00 “FundacidnLa Caixa” (Barcelona, Spain).
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al. 98
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63. Andemann F, Berkovic S, Carpenter S, Andermann E. 2. The Ramsay Hunt syndrome is not longer a useful diagnostic category. Mov Disord 1989: 4:13-17. 64. Berkovic SF, Andermann F, CarpenterS, Wolfe LS. Progressive myoclonus epilepsies: specific causes and diagnosis. N Engl J Med 1986; 3 15:296-305. 65. Marsden CD, Harding AE, Obeso J. Progressive myoclonic ataxia (the Ramsay Hunt syndrome). Arch Neurol 1990; 47:1121-1125. 66. Harding AE. 3. Ramsay Hunt syndrome, Unvenicht-Lundborg disease, or what? Mov Disord 1989: 4:18-19. 67. Boller F, Segarra JM. Spino-pontine degeneration. Eur Neurol 1969;23356-363. 68. Taniguchi R, KonigsmarkBW. Dominant spinopontine atrophy: report of a family through three generations. Brain 1971;94:349-358. 69. Pogacar S, Ambler M, Conkin WJ, O'Neil WA, Lee HY. Dominant spinopontine atrophy. Report of two additional members of family F. Arch Neurol 1978; 35:156162. NDA. Spinopontine atrophy disputed as a separate entity the first 70. Sequeiros J, Suite description of Machado-Joseph disease. Neurology 1986; 36: 1408. 71. Sequeiros J, Coutinho P. Epidemiology and clinical aspects of Machado-Joseph disease. Adv Neurol 1993; 61:139-153. 72. Refsum S, S h e H. Nosology, genetics, and epidemiology of hereditary ataxias, with particular reference to the epidemiology of these disorders in western Norway. Adv Neurol 1978; 19:497-508. 73. Becker PE. Enfermedades de localizacitin preferente en el sistema espinocerebeloso. In: Genktica Humana. v01 V/l. Barcelona: Toray SA, 1969: 233-320. 74. Eadie MJ. Olivo-ponto-cerebellar atrophy (variants). In: Vi&en PJ, Bruyn GW, eds. Handbook of Clinical Neurology. v01 21, part 1. Amsterdam: Elsevier North Holland, 1975; 451-47. 75. Konigsmark SW, Weiner LP. The olivopontocerebellar atrophies: a review. Medicine (Baltimore) 1970; 49:227-241. 76. Sobue I ed. Spinocerebellar Degenerations. Tokyo: Tokyo University Press, 1978: 376. 77. Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet 1983; 1: 1151-1155. 78. Polo JM, CallejaJ, Combarros 0, Berciano J. Hereditary ataxias and paraplegias in Cantabria, Spain. Brain 1991; 114:855-866. 79. Barth PG, Vrensen GFJM, Uylings HBM, Oorthuys JWE, Stam FC. Inherited syndrome of microcephaly, dyskinesia and pontocerebellar hypoplasia: a systemic atrophy with early onset. J Neurol Sci 1990; 97:25"42. F, Pe80. Bath PG, Blennow G, Lennard HG, Begeer JH, van der Kley JM, Hanefeld ters ACB, Valk J. The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly, and extrapyramidal dyskinesia (pontocerebellar hypoplasia type 2): compiled data from 10 pedigrees. Neurology 1995; 45:311-317. 81. Harding BN, Dunger DB, Grant DB, Erdohazi M. Familial olivopontocerebellar atrophy with neonatal onset: a recessively inherited syndrome with systemic and biochemical abnormalities. J Neurol Neurosurg Psychiatry 1988; 5 1:385-390. 82. Horslen SP, Clayton PT, Harding BN, Hall NA, Keir G, Winchester B. Olivoponto-
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cerebellar atrophy of neonatal onset and disilalotransferrin developmental deficiency syndrome. Arch Dis Child 1991; 66: 1027-1032. Harding AE. Friedreich’s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain 1981;104:589-620. Harding AE. Early onset cerebellar ataxia with retained tendon reflexes: a clinical and genetic study of a disorder distinct from Friedreich’s ataxia. J Neurol Neurosurg Psychiatry 1981; 44:503-508. Chamberlain S, Shaw J, Rowland A, Wallis J, South S, Nakamura Y, Non Gabain A, Farral M, Williamson R. Mapping of mutation causing Friedreich’s ataxia to chromosome 9. Nature 1988; 334:248-250. Chamberlain S, Shaw J, Wallis J, Rowland A, Chow L, Farral M, Keats B, Richter A, Roy M, MelanconS, Deufel T, Berciano J, Williamson R. Genetic heterogeneity at the Freidreich ataxia locuson chromosome 9. Am J Hum Genet 1989: 44:518521. Keats BJB, Ward LJ, Shaw J, Wickremasinghe A, Chamberlain S. “Acadian” and “classical”foms of Friedreich ataxia are most probably caused by mutations at the same locus. Am J Med Genet 1989; 33:266-268. De Michele G, Filla A, Cavalcanti F, Di Maio L, Pianese L, Castaldo I, Calabrese 0, Monticelli A, VarioneS, Campanella G, Leone M, Pandolfo M, Cocozza S. Late onset Friedreich’s disease: clinical features and mapping of mutation to the FRDA locus. J Neurol Neurosurg Psychiatry 1994; 57:977-979. Klockgether T,Chamberlain S, Wullner U, Fetter M, Dittmann H, Petersen D, Dichgans J. Late onset Friedreich’s ataxia, molecular genetics, clinical neurophysiology, and magnetic resonance imaging. Arch Neurol 1993; 50:803-806. Palau F, De Michele G, Vilchez JJ, Pandolfo M, Monros E, Cocozza S, Smeyers P, Ldpez-Arlandis J, Campanella G, Di Donato S, Filla A. Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreich’s ataxia locus on chromosome 9q. Ann Neurol 1995; 37:359-362. Harding AE, Zilkha W. “Pseudo-dominant” inheritance in Friedreich’s ataxia. J Neurol Neurosurg Psychiatry 1981; 18:285-287. Campuzano V, Montemini L, Molt6 MD, Pianese L,CosseeM,Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Caiiizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michelle G, Filla A, De Fmtos R, Palau F, Pate1 PI, Di DonatoS, Mandel JL, CocozzaS, Koenig M, Pandolfo M. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996; 271: 1423-1427. DUrr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A,KoenigM.ClinicalandgeneticabnormalitiesinpatientsWithFriedreich’s ataxia. N Engl J Med 1996; 335:1169-1175, Harding AE. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias: a study of eleven families, including descendants of the “Drew family of Walworth.“ Brain 1982; 105:l-28. Hammans SR. The inherited ataxias and the new genetics. J Neurosurg PsyNeural chiatry 1996; 61:327-332.
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96. RosenbergRN.Autosomaldominantcerebellargenotypes.Thegenotypehas settled the issue. Neurology 1995; 45:1-45. 97. Nance MA. Clinical aspects of CAG repeat diseases. Brain Pathol 1997; 7:882900. 98. Robitaille Y, Lopes-Cendes I, Becher M, Rouleau G, ClarkAW. The neuropathology of CAG repeat diseases: review and update of genetic and molecular features. Brain Pathol 1997; 7:901-926. 99. Subramony H. The inherited ataxias. In: Jankovic J, Tolosa E, eds. Parkinson’s Disease and Movement Disorders. Baltimore: Williams & Wilkins, 1998: 887-907. 100. Harding AE. From the syndrome of Charcot, Marie and Tooth to disordersof peripheral myelin proteins. Brain 1995; 118:809-818. 101. Harding AE. “Idiopathic” late onset cerebellar ataxia. A clinical and genetic study of 36 cases. J Neurol Sci 1981; 51:259-271. 102. Ramos A, Quintana F, Diez C, LenoC, Berciano J. CT findings in spinocerebellar degeneration.Am J Neuroradiol 1987; 8:635-640. H, Dichgans J. Idiopathic cerebellar ataxia of late 103. Klockgether T, Schroth G, Diener onset: natural history and MRI morphology.J Neurol Neurosurg Psychiatry 1990; 50:297-305. 0, Agid U, 104. Dun S, Brice A, Sardaru M, Rancurel G, Derouesnk C, Lyon-Caen Fontaine B. The phenotypeof “pure” autosomal dominant spastic paraplegia. Neurology 1994; 44:1274-1277. 105. Casari G, de FuscoM, Garmatori S, Zeviani M, Mora M,Fernhdez P, De Michele G, Filla A, CocozzaS, Marconi R, Durr A, Fontine B, Ballabio A. Spastic paraplegiaandOXPHOSimpairmentcausedbymutationsinparaplegin, a nuclearencoded mitochondrial metalloprotease. Cell 1998; 93:973-983.
Clinical Approach to Ataxic Patients Thomas Klockgether University of Bonn, Bonn, Germany
I.DEFINITION
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OF ATAXIA
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111. FOCALCEREBELLARDISORDERS
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IV.ATAXIA DISORDERS WITH HIGHLY CHARACTERISTIC PHENOTYPES
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V.
DIAGNOSISINSPECIFICCLINICAL A.AutosomalDominantInheritance B.AutosomalRecessiveInheritance C.Early-OnsetSporadicDisease D.Late-OnsetSporadicDisease E.RapidDiseaseProgression F. Myoclonus G.RetinalDegeneration REFERENCES
SITUATIONS
105 105 106 107 107 108 109 l l0 111
I. DEFINITIONOF ATAXIA Ataxia literally means absence of order. In modern clinical neurology, the term ataxia is used to denote disturbances of coordinated muscle activity. Ataxia is caused by disorders of the cerebellum and its afferent or efferent connections. 101
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Diseases of the peripheral nervous system, such as chronic idiopathic demyelinating polyneuropathy,may also cause ataxia. However, ataxia is rarely the prominent symptom in these disorders. The afferent and efferent connections of the cerebellar cortex are topographically organized, resulting in functional specialization of different parts of the cerebellum. Dysfunction of the lower vermis (vestibulocerebellum) leads to truncal ataxia. Spinocerebellar lesions (upper vermis and anterior partsof hemispheres) are characterized by unsteadiness of gait and stance, which are more evident after eye closure (positive Rombergism). The most prominent symptom of neocerebellardamage(cerebellarhemispheres)isataxia of intendedlimb movements. Ataxic limb movements are irregular and jerky and tend to overshoot the target (past-pointing). They are often accompanied by rhythmic side-to-side movements as the target is approached (action or intention tremor). Dysarthria, characterized by slow and segmented speech with variable intonation and disturbances of ocular movements (broken-up smooth-pursuit, saccadic hypermetria, gaze-evoked nystagmus) almost invariably accompany ataxia of gait and limb movements (1,2). Knowledge of the topographical organization of the cerebellum is helpful for the localization of focal cerebellar disease. However, it is only of limited value in the differential diagnosis of nonfocal cerebellar disease, such as cerebellar degenerations or cerebellar encephalitis, because these disorders are usually associated with a pancerebellar syndrome involving all aspects of ataxia.
Table 1 ClassificationofAtaxia
Hereditary ataxias Autosomal recessive ataxias Recessive disorders with ataxia as a facultative symptom Mitochondrial disorders Autosomal dominant ataxias Spinocerebellar ataxias Episodic ataxias Spongiform encephalopathies Nonhereditary ataxias Multiple system atrophy, cerebellar type Symptomatic ataxias Alcoholic cerebellar degeneration Ataxias due to other toxic causes Paraneoplastic cerebellar degeneration Ataxia due to acquired vitamin deficiency or metabolic disorders Cerebellar encephalitis (including immune-mediated cerebellar degenerations other than paraneoplastic cerebellar degeneration) Ataxia due to physical causes
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The term ataxia is also used to denote nonfocal disorders affecting the cerebellum and its afferent and efferent connections that cause persistent or progressive ataxia as a prominent symptom (3). Classification of ataxias is a matter of long-standing dispute (see Chapter 3). However, recent progress in understanding the molecular basis of ataxia allows a rational classifaction (Table 1).
II.
DIAGNOSTICAPPROACHTOATAXICPATIENTS
Ataxic patients may cause considerable diagnostic problems because a variety of heterogeneous diseases are associated with a widely uniform clinical picture, The diversity of disorders associated with ataxia may lead clinicians to apply extensive laboratory screening programs to each individual ataxic patient. Although such an unspecific approach may be required in some patients, many ataxic patients have characteristic clinical features that allow one to select and apply appropriate diagnostic tests. A rational diagnostic approach implies a sequenceof three steps. The first step is to distinguish focal and nonfocal cerebellar disorders.The second step is to identify disorders with a highly characteristic clinical phenotype that can be diagnosed on purely clinical grounds and to confirm the suspected diagnosis by a specific laboratory test. After these initial two steps, there is still a considerable number of ataxic patients for whom the diagnosis remains unclear. The further diagnostic tests in these patients should be guided by considering the following aspects of the disease: modeof inheritance, age at disease onset, progression rate, and accompanying symptoms. Thus, the initial diagnostic program in a young ataxic patient will be different from that in a patient with disease onset in late adulthood. Similarly, patients with rapid disease progression require another approach than patients with stationary or slowly progressive ataxia. Finally, presence of a specific accompanying symptom, such as myoclonus, will guide the further procedures in a certain direction.
111.
FOCALCEREBELLARDISORDERS
The first step in the diagnosisof ataxia is to distinguish between focal cerebellar disease (tumor, abscess, ischemia, hemorrhage, focal demyelination) and nonfocal disorders. In many cases, this distinction is easily made by taking the history and examining the patient. Acute disease onset, headache, vomiting, and unilateral of a fosymptoms strongly argue in favor of a focal disease. A definite distinction cal and nonfocal cerebellar disorders is achieved by the use of imaging methods. Magnetic resonance imaging (NIRI) is preferable to computed tomography (CT) because MRI-in contrast toCT-is capable of imaging the cerebellum and brain stem at different planes, with high resolution and without major artefacts (4).
henotype
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Multiple sclerosis isan important differential diagnosis in the workup of an ataxic patient. Remitting-relapsing course and multifocal involvement will raise suspicion of multiple sclerosis (5). To definitely establish the diagnosis of multiple sclerosis, MRI studies and cerebrospinal fluid examinations are required. Demonstration of prolonged latencies of multimodal evoked potentials is also helpful in the diagnosisof multiple sclerosis. However, the specificity of delayed evoked potentialsis low because various degenerative ataxias are also associated with such potentials (6-9).
W.ATAXIA DISORDERSWITHHIGHLY CHARACTERISTIC PHENOTYPES A number of ataxias have a highly characteristic clinical phenotype that allows one to make a diagnosis on purely clinical grounds. In most instances, laboratory tests are available that serveto confirm the clinical diagnosis. Friedreich’s ataxia (FRDA) is an example for this type of diseases. The clinical diagnostic criteria for FRDA, as definedby Geoffrey et al. (10) and Harding (1l), include progressive ataxia with early disease onset, areflexia, dysarthria, and signs of posterior column dysfunction. These criteria have an almost 100% specificity. It is important to recall that the characteristic phenotypical features that establish a diagnosis of FRDA, although being specific, lack sensitivity. In other words, a considTable 2 Ataxia Disorders with a Highly Characteristic Clinical Phenotype
Disorder Friedreich’s ataxia
Ataxia telangiectasia
Cerebrotendinous xanthomatosis Spinocerebellar ataxia type 7 Multiple system atrophy
Clinical diagnostic criteria (early disease onset, areflexia, dysarthria, posterior column signs) Early disease onset, telangiectasias, immunodeficiency
Xanthomas Autosomal dominant inheritance, retinal degeneration Autonomic failure
Intronic GAA expansion of X2YFRDA gene
a-Fetoprotein Hypersensitivity of fibroblasts and lymphocytes to ionizing radiation Mutation of ATM gene Cholestanol CAG expansion of SCA7 gene Not available
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erable number of patients who do not have the typical FRDA phenotype may, nevertheless, suffer from FRDA. Demonstrationof an expanded GAA repeat of the X251E;RDA gene will confirm the clinically suspected diagnosis (12). Table 2 gives a list of disorders in which a diagnosis can be made on the basis of a characteristic clinical phenotype. Mostof these disorders are hereditary, with the notable exceptionof multiple system atrophy (MSA). MSA an is adult-onset sporadicdisorder(13).Ingeneral,differentialdiagnosis of adult-onsetsporadic ataxia disorders may be difficult and includes a wide variety of hereditary, degenerative, and acquired disorders (see Sec.V,D). Autonomic failure in association with ataxia, however, occurs almost exclusively in MSA (14,15). Demonstration of autonomic failure in a patient with sporadic adult-onset ataxia will thus establish the diagnosisof MSA without the necessity to perform a large battery of diagnostic tests.
V.
DIAGNOSIS IN SPECIFIC CLINICAL SITUATIONS
A.
AutosomalDominantInheritance
The presence of ataxia in subsequent generations is highly suggestive of autosomal dominant inheritance,in particular if the disease is transmitted by both sexes. In such families, diagnostic tests can be restricted to a small number of molecular genetic tests provided that all affected family members have the same disease. In cases, in which other affected family members are not available for personal examination, it may be difficult to decide whether they really suffer from the same disease or froman unrelated medical problem. In patients with proven autosomal dominant mode of inheritance, molecular genetic tests for SCA mutations should be performed (16-19). Although the various SCA mutations are associated with characteristic clinical phenotypes, there is large clinical overlap between the different mutations (20-23). Therefore, it is impossible to reliably predict the underlying mutation in an individual patient. For this reason, it is recommended to test for all known SCA mutations in patients with dominant ataxia. The only exception are patients from families with dominant ataxia and retinal degeneration. This clinical phenotype is always associated with the SCA7 mutation (see Chapter 23) (24). If tests for SCA mutations are negative in a patient with dominant ataxia, dentatorubral-pallidoluysian atrophy(DRPLA)(25)or Gerstmann-StrausslerScheinker disease (GSS), a dominantly inherited transmissible spongifom encephalopathy (26), should be considered as a differential diagnosis (see Chapter 26). Both disorders have a characteristic clinical presentation that usually allows one to distinguish them from SCA mutations. In up to 50% of all dominant ataxia families, all available molecular tests are negative. These families probably suffer from a yet unidentified SCA mutation (27,28).
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.
AutosomalRecessiveInheritance
Autosomal recessive inheritance is highly probableif there are several affecteds in one generation whereas the parents are healthy. In addition, consanguinity of parents is a strong argument for autosomal recessive inheritance. Nevertheless, as sporadicdiseases mostautosomalrecessivedisordersmanifestthemselves from nonconsanguinous marriages.Typically, autosomal recessive disorders start in childhood, adolescence, or early adulthood. Because acquired ataxia disorders are rare in young persons, sporadic ataxia disorders with early-onset disease are most often manifestations of an autosomal recessive disorder. Thus, all diagnostic considerations that refer to autosomal recessive disorders also apply for sporadic disorders with early-onset disease. Traditionally, early-onset disease is deof 25 years (3). Although 25 years may fined as onset of symptoms before the age serve as a general cutoff between early and late disease onset, autosomal recessive disordersmay occasionally start much later, in some instances even after the age of 50 years (29-31). Table 3 gives a list of autosomal recessive ataxias along with the laboratory tests that allow one to establish a definite diagnosis. According to general expe-
Table 3 AutosomalRecessiveAtaxias
Disorder Friedreich’s ataxia Ataxia telangiectasia
Abetalipoproteinemia Ataxia with isolated vitamin E deficiency Heredopathia atactica polyneuritifomis (Refsum’s disease) Cerebrotendinous xanthomathosis Metachromatic leukodystrophy Globoid cell leukodystrophy (=abbe’s disease) Neuronal ceroid lipofuscinoses
GM, gangliosidosis
Intronic GAA expansion of X25PRDA gene a-Fetoprotein Hypersensitivity of fibroblasts and lymphocytes to ionizing radiation Mutation of ATM gene Vitamin E Lipid electrophoresis Vitamin E Phytanic acid Cholestanol Arylsulfatase (3-Galactocerebrosidase Ultrastructural analysisof lymphocytes and skin (eccrine sweat gland epithelial cells) Gene mutations Hexosaminidase A and B
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rience, a definite diagnosis cannot be made in a considerable number of ataxic patients with disease onset before the ageof 25 years, whether or not they have affected siblings. These patients ususally receive the label of early-onset cerebellar ataxia (EOCA). EOCA comprises a group of heterogeneous ataxia disorders (see Chapter 8). Although many EOCA patients have several common clinical features, such as presence of muscle reflexes, absence of cardiac involvement, and relatively benign course, the diagnosis can be made only by exclusion. It is expected that at least some EOCA patients canbe assigned to novel gene mutations or biochemical defects in the future.
C. Early-OnsetSporadicDisease As discussed in the preceding section, most casesof early-onset sporadic ataxia are manifestations of an autosomal recessive disorder. Thus, the diagnostic tests recommended for autosomal recessive ataxias should be also applied to young patients with sporadic ataxia. In rare instances, sporadic ataxia starting at a young age may be due to maternal inheritance (mitochondrial disease; see Chapter 16), l( chromosomalinheritance(adrenoleukodystrophy) (32-34), orautosomal dominant inheritance (spinocerebellar; ataxias, SCA) (see Chapters 17-23, and 25). All these disorders may well start before the age of 25 years. Autosomal dominant ataxia may occur as a sporadic diseaseif it is due to a novel mutation. In addition, the family history may be uninformative,if parents died before manifestation of the disease, or if fatherhood is false. Furthermore, early-onset sporadic ataxiamay occur as an acquired disease (symptomatic ataxia), without any genetic background. The most frequent typeof Symptomatic ataxia in young persons is cerebellar encephalitis associated with viral infections (35). Although ataxia caused by paraneoplastic cerebellar degeneration typically starts in adulthood, paraneoplastic cerebellar degenerationmay affect children with neuroblastoma and young patients with malignant lymphoma (see Chapter 29). All other types of symptomatic ataxias are infrequent before the age of 25 years.
D.Late-OnsetSporadicDisease The late-onset sporadic ataxias can be divided into three major groups.The first group comprises the symptomatic ataxias that are due to identifiable exogenous causes. The second group includes hereditary ataxias that manifest themselves as sporadic late-onset disorders. The third group are nonhereditary degenerative ataxias, such as the cerebellar type of MSA. In 1981, Harding reported a series of 36 patients with sporadic late-onset ataxia of unknown etiology for which she coined the term idiopathic cerebellar ataxia (IDCA) (36). Since then, various genetic and nongenetic causes of late-
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onset sporadic ataxia have been identified, someof which may have been responsible for the disease in Harding’s patients (see Chapter 31). In addition, many IDCA patients suffered from MSA (see Chapter 27) (14,lS). Therefore, the further use of IDCA to denote sporadic ataxia patients is not advocated. Symptomatic ataxia denotes all typesof acquired disease in which a nongenetic cause can be identified. Usually, symptomatic ataxias start after the age in the foreof 25 years, although there are some exceptions that I have discussed going (see Sec. V.C). The most frequent causes of symptomatic ataxia are chronic alcoholism, other toxic causes (see Chapter28), malignant disease (paraneoplastic cerebellar degeneration; see Chapter 29), vitamin deficiency, other metabolic causes (see Chapter 30), inflammatory and immune-mediated cerebellar damage (see Chapter 31), and less frequently, heat stroke (see Chapter 32). Although autosomal recessive ataxias usually manifest themselves before with much later disease onset. For the age of 25 years, there are exceptional cases example, age of onset is beyond 25 years in about 15% FRDA patients (30,31). Because recessive ataxias occur sporadically in the majority of cases, a considerable portionof late-onset sporadic ataxia patients will suffer from an autosomal recessive ataxia with late disease onset. Similarly, negative family history does not exclude autosomal dominant ataxia. Family history may be uninformative because an affected parent died before onsetof symptoms. Not infrequently, this is true for spinocerebellar ataxia type6 (SCA6) because the age of onset is relatively late in SCA6so that affected parentsmay have died before ataxia became apparent (27,28). In addition, negative family historymay be due to false fatherhood or to novel mutations (37). After all known symptomaticand genetic causes havebeen ruled out, there remains agroup of sporadic late-onset ataxia patients in whom onehas to assume the presence of a sporadic neurodegenerative disease (comparablewith. sporadic amyotrophic lateral sclerosis or idiopathic Parkinson’s disease). Recent work has shown that a large proportion of these patients sufferfrom MSA, a disease entity that is neuropathologically characterized by the occurrence of oligodendroglial intracytoplasmatic inclusions (38). At present, it is not known whether there are sporadic cerebellar degenerations other than MSA.
E. RapidDiseaseProgression Most types of hereditary and nonhereditary ataxias are characterized by an insidious onset and continuous disease progression within years. Sudden disease onset and rapid progression are suggestiveof focal cerebellar disease. Nevertheless, several nonfocal cerebellar disorders may cause ataxia with subacute onset and rapid deterioration, These disorders include cerebellar encephalitis, associated with viral infection, Miller-Fisher syndrome (see Chapter 31), paraneoplas-
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tic cerebellar degeneration (see Chapter 29), transmissible spongiform encephalopathy (see Chapter 26), and Wernicke’s encephalopathy (see Chapter 30).
F. Myoclonus Myoclonus is associated with progressive ataxia in several disorders. Often, myoclonus and ataxia are part of a larger syndrome that is characterized by ataxia, myoclonus, epilepsy, and progressive dementia. This syndrome is known as progressive myoclonus epilepsy (PME) (39). In ataxic patients with accompanying myoclonus, all known causesof PME should be considered, evenif epilepsy and cognitive disturbances are not prominent. Table 4 gives a list of disorders that may cause PME along with the appropriate diagnostic tests. According to general experience, there are a substantial portion of patients in which careful diagnostic workup will not result in a definite diagnosis. In most of these patients, epilepsy and dementia are mild or absent. These patients should be diagnosed as earlyonsetcerebellarataxiawithmyoclonus(3).Thisdescriptivetermseemsto
Table 4 Disorders That May Cause Ataxia and Myoclonus
Disorder Lafora disease (41,42) Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPMl) (43) Myoclonus epilepsy with ragged red fibers (MERRF) (see Chapter 16) Sialidosis type 1 (44)
Neuronal ceroid lipofuscinosis (infantile, late infantile, juvenile, adult forms) (45) Dentato~bral-pallidoluysian atrophy
(DRPLA) (25) Early-onset cerebellar ataxia with myoclonus (see Chapter 8)
Diagnostic test Lafora bodies in skin, muscle, and liver biopsy Mutation of EPM2A gene Mutation of cystatin B gene Ragged red fibers in muscle biopsy 8344 point mutation of mitochondrial tRNALy” gene Retinal-macular cherry-red spot Sialooligosaccharides in urine Neuraminidase activity in white blood cells Mutation of neuraminidase gene Ultrastructural analysisof lymphocytes and skin (eccrine sweat gland epithelial cells) Different gene mutations (CLNl-3) CAG repeat expansion of DRPLA gene None
sorder
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be more appropriate than the traditional term Ramsay Hunt syndrome (40). A s discussed in detail in Chapter 3, Ramsay Hunt syndrome is a notoriously illdefined and controversial nosological category that should no longer be used.
G. RetinalDegeneration Symptoms of retinal degeneration include slowly progressive visual loss and poor night vision. Peripheral retinal degeneration causes constriction of visual fields to the extent of gun-barrel vision, whereas macular degeneration affects central vision and visual acuity. Progressive visual loss in ataxic patients requires an ophthalmological examination with detailed fundoscopy, followedby a number of ancillaryinvestigations(fluoresceinretinography,electroretiriogram). Table 5 gives a listof disorders thatmay cause retinal degeneration in association with progressive ataxia.
Table 5 Disorders That May Cause Ataxia and Retinal Degeneration
Ocular
Disorder Abetalipoproteinemia (see Chapter 9) Heredopathia atactica polyneuritiformis (Refsum’s disease) (see Chapter 11) Ataxia with isolated vitamin E deficiency Neuronal ceroid lipofuscinosis (infantile, late infantile, juvenile, adult forms) (45)
Retinitis pigmentosa (predominantly of posterior fundus) Retinitis pigmentosa Posterior subcapsular cataracts
Vitamin E Lipid electrophoresis
Retinitis pigmentosa
Vitamin E
Retinitis pigmentosa
Ultratructural analysis of lymphocytes and skin (eccrine sweat gland epithelial cells) Different gene mutations (CLN1-3) Sialooligosaccharides in urine Neuraminidase activity in white blood cells Mutation of neuraminidase gene CAG expansion of SCA7 gene
Sialidosis type 1
Retinal-macular cherry-red spot
Spinocerebellar ataxia type 7 (SCA7) (see Chapter 23) Cockayne’S syndrome (46)
Macular degeneration Retinal dystrophy
Phytanic acid
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to Approach Clinical
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28. Moseley ML, Benzow KA, Schut LJ, Bird TD, Gomez CM, Barkhaus PE, Blindauer
29. 30. 31. 32. 33. 34. 35. 36. 37.
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KA, Labuda M, Pandolfo M, Koob MD, Ranurn LP. Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology 1998; 51~1666-1671. KlockgetherT,Chamberlain S, Wullner U, Fetter M, DittmannH,PetersenD, Dichgans J. Late-onset Friedreich’s ataxia, Molecular genetics, clinical neurophysiology, and magnetic resonance imaging. Arch Neurol 1993; 50:803-806. Durr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, KoenigM. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med 1996; 335:1169-1175. Filla A, DeMicheleG,Cavalcanti F, Pianese L, Monticelli A, CampanellaG, Cocozza S. The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia.Am J Hum Genet 1996; 59:554-560. TakadaK,OnodaK,Takahashi K, NakamuraH,TalsetomiT.Anadultcaseof adrenoleukodystrophy with features of olivo-ponto-cerebellar atrophy: I. Clinical and pathological studies. Jpn J Exp Med 1987; 57:53-58. Kusalsa H, ImaiT. Ataxic variant of adrenoleukodystrophy: MRI and CT findings. J Neurol 1992; 239:307-310. KuriharaM,KumagaiK,Yagishita S, Imai M, Watanabe M, Suzuki Y, OriiT. Adrenoleukomyeloneuropathy presenting as cerebellar ataxia in a young child: a probable variant of adrenoleukodystrophy. Brain Dev 1993; 15:377-380. Klockgether T, Doller G, Wullner U, Petersen D, Dichgans J. Cerebellar encephalitis in adults. J Neurol 1993; 240:17-20. Harding AE. “Idiopathic” late onset cerebellar ataxia. A clinical and genetic study of 36 cases. J Neurol Sci 1981; 51:259-271. Schols L, Gispert S, Vorgerd M, Vieira-Saecker MM, Blanke P, Auburger G, AmoiridisG,Meves S, EpplenJT,Przuntek H, Pulst SM, Riess 0. Spinocerebellar ataxia type %”genotype and phenotype in German kindreds. Arch Neurol 1997; 54: 1073-1080. J Lantos PL, Papp MI. Cellular pathology of multiple system atrophy: a review. Neurol Neurosurg Psychiatry 1994; 57: 129-133. Berkovic SF, Cochius J, Andermann E, Andermann F. Progressive myoclonus epilepsies: clinical and genetic aspects. Epilepsia 1993; 34(suppl 3):S19-S30. Marseille Consensus Group. Classification of progressive myoclonus epilepsies and related disorders. Marseille Consensus Group. Ann Neurol 1990; 113-1 28: 16. Minassian BA, Lee JR,Herbrick JA, Huizenga J, SoderS, Mungall AJ, Dunham I, Chrdner R, Fang Cy, Carpenter S, Jardim L, SatishchandraP, Anderrnann E, Snead o c , Lopes CI, Tsui LC, Delgado EA, Rouleau GA, Scherer SW. Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet 1998; 20:171-174. Footitt DR, Quinn N, Kocen RS, Oz B, ScaravilliF. Familial Lafora body diseaseof late Onset: report of four cases in one family and a review of the literature. J Neural 1997; 244:40-44. MM, Lalioti MD, Mirotsou M, Buresi C, Peitsch MC, Rossier C, Ouazzani R, Baldy Bottani A, Malafosse A, Antonarakis SE. Identificationof mutations in cystatin B,
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the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPMl). Am J Hum Genet 1997; 60:342-351. 44.Pshezhetsky AV, Richard C, Michaud L, Igdoura S, Wang S, Elsliger MA, Qu J, Leclerc D, Gravel R, Dallaire L, Potier M. Cloning, expression and chromosomal mapping of human lysosomal sialidase and characterizationof mutations in sialidosis. Nat Genet 199’7; 15:316-320. 45. Goebel HH, Sharp JD.The neuronal ceroid-lipofuscinoses. Recent advances. Brain Pathol 1998; 8:151-162. 46. Traboulsi EI, De BI, Maumenee IH. Ocular findings in Cockayne syndrome.Am J Ophthalmol1992;114:579-583.
University Hospital Aachen, Aachen, Germany
INTRODUCTION I.
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11. UNILATERAL CEREBELLAR MALFORMATIONS
117
111. MIDLINEORVERMISMALFORMATIONS A. GeneralRemarks B. Dandy-Walker Malformation C. Dandy-Walker VBsiant andMegacisternaMagna D.ChiariMalformations E.Vernis Dysgenesis F. Vermis Agenesis G. RareSyndromeswith Vermis Agenesis
120 120 124 127 127 130 132 133
IV. PONTOCEREBELLARHYPOPLASIAS
136
V. NONPROGRESSIVECEREBELLARHYPOPLASIA REFERENCES
138 144
This chapter deals with cerebellar malformations that mostly have their origin in utero. Recognition of a cerebellar malformation immediately after or during the first months after birth often remains difficult because overt clinical signs of ataxia in the newborn and young infant will present only in a proportionof chil11
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dren after acquisition of developmental milestones, such as visual fixation, head control, grasping for objects, sitting, standing, and walking. Hypotonia in early infancy can sometimes be the first indication of a cerebellar malformation, followed by nystagmus, failure of head control with titubation, intention tremor on grasping for objects, and delayed motor development, with hypotonia and ataxia during postural control. However, early-onset hydrocephalus and spina bifida at birth in children with Chiari type I1 malformation will usually overshadow the presence of this cerebellar malformation. Likewise, in many other syndromes associated with a cerebellar malformation, signs caused by other affected parts within or outside the nervous system can initially mask the presence of a cerebellar malformation. On the other hand, clinical signs and symptoms of congenital ataxia might primarily suggest a cerebellar malformation, but the origin of ataxia can reside outside the cerebellum, for example, in a defect of visual, vestibular, or sensory inputs. Recent advances in the fieldof embryology, neuropathology, genetics, and the amelioration of brain imaging by the advent of magnetic resonance imaging (MRI),have given a new impetus to unravel the timing, cause, and pathogenesis of cerebellar malformations.A vast amount of literature on human cerebellar hypoplasia exists that has clearly established the causative role of fetal cytomegalovirus infection, ionizing radiation, certain toxins, and antimitotic drugs (1-5). Comparedwiththeseexogeneousnoxae,relativelittleprogresshasbeen achieved in the identificationof genetic and chromosomal factors and the pathogenesis underlying cerebellar malformations. Examples for which the genetic etiology has yet remained unidentified, represent, for example, familial DandyWalker malformation, autosomal recessive Joubert's syndrome, or the pontocerebellar hypoplasias type I and 11. First, a thorough history and clinical examination still remain the comerstones of the diagnostic approach. For the clinician, neuroimaging by MRI will be one of the first, and most important, tools to define the site, configuration, and extent of cerebellar structural abnormalities. This chapter will give an overview of the most important genetic and nongenetic nosological entities of cerebellar malformations. Based on the localization of the cerebellar structural abnormality, a useful (6). The anadiagnostic approach and differential diagnosis will be presented tomical classification by neuroimaging (Fig. l ) will delineate unilateral cerebellar hemisphere malformation or hypoplasia from bilateral or symmetrical cerebellar malformations. Depending on the site of involvement, the bilateral cerebellar malformations can be further classified into midline or vermis malformations, or malformations in which the vermis and both cerebellar hemispheres are The affected. latter group, with symmetrical midline and cerebellar hemisphere malformation, can be divided into either a group with static nonprogressive cerebellar hypoplasia, or a group with progressive atrophy of cerebellar white matter or cortical structures.
Cerebellar ~alformations Cerebellar
malformation
Unilateral
Bilateral
Pontocerebellar
Cerebellar
2
Vermis/Midline
I
Cerebellar hemispheres
Dandy-Walker Dysgenesis Agenesis Static Progressive Chiari malform
Figure 1 Anatomicalclassificationbased on neuroradiologicandneuropathological studies of cerebellar malformation syndromes.
For this purpose, follow-up neuroimaging studies with sufficiently long time intervals are mandatory to differentiate between static and progressive cerebellar diseases (in addition to documentationof the clinical evolution).The association of pontine hypoplasia with cerebellar malformation should be considered as a separate groupof disorders to be called pontocerebellar hypoplasias or malformations.
111.
UNILATERALCEREBELLARMALFORMATIONS
The finding of congenital structural lesions or hypoplasia in one cerebellar hemisphere on neuroimaging can virtually rule out a genetic cause or recognizable syndrome of human malformation. The most likely cause is not a malformation sequence, butis usually due to pre-, peri-, or postnatal insult, such as intracerebellar bleeding after mechanical birth trauma, or that associated with prematurity (7). Ischemic stroke confined to cerebellar arterial territories is probably an extremely rare condition in childhood. aInprevious study we identified unilateral cerebellar hypoplasia in two male patients from unrelated families accompaniedby microcephaly, severe psychomotor retardation with autistic features, and ipsilateral choroideoretinal coloboma. The cause of this disorder remains unknown(6). A possible genetic factor for unilateral cerebellar hypoplasia might be involved among first- or second-degree relatives of patients with the autosomal recessive acro-
11
callosal syndrome (8). For a unilateral cerebellar malformation the possibilityof c ~ o m o s o m a mosaicism l should be considered, but remains impossible to prove will in vivo.MRT images of infratentorial brain stem and cerebellar structures usually help differentiate between structural damage caused by ischemic, hemorrhagic, or infectious insults, on one hand, and unilateral developmental hypoplasia, on the other hand (as demonstrated by two examples in Fig. 2).
(a) An example of a prematurely born patient with unilateral cerebellar hypoplasia. The left cerebellar hemisphere remains grossly hypoplastic, but on coronal sections with Tl-weighted images the nascent formation of white matter and surrounding cerebellar cortex can be noted. Clinical features included severe psychomotor retardation and unilateral central visual disturbance, with decreased amplitude of cortical-evoked POtentials after monocular stimulation with Bash stimuli of the left eye.
11
(b) A remnant of the right cerebellar hemisphere with distorted structures after documented intracerebellar and supratentorial parenchymatous bleeding during the neonatal period of this prematurely born child. The resulting destruction by the bleeding affecting one cerebellar hemisphere and the midline vermis can be detected by early and follow-up MRI.
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111.
~
A.
GeneralRemarks
~
~ ORLVERMIS I ~ ~EA L F O R ~ A T I O ~ S
The vermis and midline structures are formed after fusion of the rhombencephalic lips at the midline. Development of the cerebellum starts during the fifth week of gestation when a bilateral thickening of the alar rhombencephalic plate occurs, 3). These rhombic lips develop into the cerwhich will form the rhombic lips (Fig. ebellar hemispheres and show medial outgrowth, which will beginto fuse superiorly in the midline during the 9th-gestational week. As the hemispheres grow, the midline fusion continues more inferiorly in a cephalocaudal direction, by and the endof the 15th week the entire vermis is formed. Thus, midline vermis defects will result from disruptionof medial outgrowth and fusionof the paired rhombic lips between the 9th and 15th week of pregnancy. The timing of complete midline vermis agenesis, such as present in Joubert’s syndrome, will have to arise very early in pregnancy (i.e., before the 9th week of gestation) (9). Another important aspect of cerebellar development is formation of the midline foramen of Magendie and bilateral foramina of Luschka, located most inferiorly behind the choroid ridge at the roof of the fourth ventricle.The timing of formation of these foraminal outletsof the fourth ventricle is completed by the end of the fourth gestational month. Delayed or disturbed opening of the foramina of Magendie will be associated with ballooning of the fourth ventricle
Figure 3 Stages of cerebellar development: (A) Dorsal view of the bottom of the fourth ventricle after removal of the covering plate in a 10-mm embryo (age5 weeks). At this stage the rhombic lips at the metencephalon appear, showing paired medial outgrowth toward the midline.On the right side the upper picturea is cross section at the metencephalon showing the originof the precursor cells at the germinal layer from which cerebellum and pontine nuclei will develop. The lower cross section through the myelencephalon shows the origin of the olivary nuclei from the alar plates. (B) In an 8-week-old embryo, the mesencephalon and rhombencephalon show formation of the vermis by midline fusion of the rhombic lips by medial outgrowth (arrows) occuring in a cephalocaudal direction (heavy broken arrow). On the right the migration of granular cells (dotted arrow) from the geminal zone in a lateral and tangential direction toward the cerebellar surface is shown where between 11 and 13 weeks the transitory external granular layer forms. (C) At 16 weeks, vermis and cerebellar hemispheres are formed with the fourth ventricle outlet foramina. On the right, the inward migration of cells from the transitory external granular layer to form the ultimate internal granular layer of cerebellar cortex can be seen (broken mow). From the germinal layerof the fourth ventricle, cells originate that will form the Purkinje cell layer of cerebellar cortex and the deep cerebellar nuclei. Purkinje cells provide the single output of the cerebellar cortex and exert their inhibitory action on deep cerebellar nuclei.
Cerebellar Malformations
A
B
C
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Main
Genetic and Nongenetic ~onditionsAssociated with Midline Cerebellar Malfo~ation,Vermis Dysgenesis, or Agenesis Syndrome Syndromes with midline malformation Enlarged cyst of posterior fossa, Dandy-Walker malformation complete or partial vermis agenesis, hydrocephalus Dandy-Walker variant Megacisterna magna
Mostly sporadic AD, AR, or X-linked forms Mostly Fourth ventricle dilation, sporadic hypogenetic vermis Mostly Posterior fossa enlargement, with sporadic normal vermis and fourth ventricle See text
Chiari malformation type I,II, and 111. Syndromes with vermis dysgenesis Cogan’s syndrome Oculomotor apraxia, motor retardation, and ataxia Ataxia telangiectasia Oculomotor apraxia, telangiectasias, cellular i m u n e deficit, raised a-fetoprotein Tectocerebellar dysraphia Vermian hypoplasia-aplasia with occipital encephalocele and hypoplastic cerebellar hemispheres, lying ventrolateral to the brain stem Rhombencephalosynapsis Vermian agenesis-hypogenesis with midline fusion of cerebellar hemispheres, peduncles, or fusion of dentate nuclei Lhermitte-Duclos Dysplastic gangliocytorna ofcerthe enlarged thickened with ebellum disease folia; sometimes associated with multiple hamartoma syndrome (Cowden’s disease) Syndromes with vermis agenesis Joubert’s syndrome Neonatal hyperpnea, abnormal ocular movements, mental retardation, ataxia. Dekaban’s syndrome Retinopathy, polycystic kidneys Cerebellar vermis agenesis, COACH syndrome oligophrenia, ataxia, coloboma, hepatic fibrosis
Sporadic AR
Sporadic or AD
AR AR
Table 1 Continued
Syndrome syndromes with vermis agenesis (continued) Walker-Warburg Cobblestone lissencephaly, AR eye syndrome abnormalities dysplasia), (retinal congenital muscular dystrophy +hydrocephalus, anterior chamber anomalies. Cerebrogyral Lissencephaly otheror oculomuscular abnormality, abnormalities eye (retina and anterior chamber), profound neurological dysfunction, congenital muscular dystrophy, hydrocephalus. Vermian hypoplasia Oligophrenia, cerebellar ataxia with coloboma (identical with COACH syndrome) hepatic and fibrosis Gillespie’s Oligophrenia, mental aniridia, ataxia retardation, syndrome X-linked dominant X-linked familial form with cerebellar vermis preponderance females in aplasia Vermis aplasia and X-linked familial syndrome with holoprosencephaly vermis aplasia and holoprosencephaly
?AR
AR
AR X-D
Genetic syndromes and nonmendelian genetic syndromes in which vermis agenesis isan occasional feature have been listed in the review by Bordarier and Aicardi (10).
intothecisternamagna. The resultingcysticspace,communicatingwiththe fourth ventricle, is the basis of the Dandy-Walker malformation complex. Majormalformations of thecerebellarmidlinestructuresincludethe Dandy-Walker malformation complex and the Chiari malformations type I, 11, and 111(Table 1). Less common syndromes featuring vermis and midline dysgenesis are Cogan’s syndrome (sporadic), ataxia telangiectatica (autosomal recessive), tectocerebellardysaphia, rhornbencephalosynapsis,and Lherrnitte-Duclos disease(autosomaldominant).Inheritedautosomalrecessivesyndromeswith vermis agenesis as a constant feature are Joubert’s syndrome, Dekaban’s syndrome, Walker-Warburg syndrome, cerebro-oculomuscular syndrome, vermian (COACH syndrome), and hypoplasiawithcolobornaandhepaticfibosis Gillespie’s syndrome. Rare syndromes of vermis aplasia constitute the X-linked dominant syndromeof cerebellar vermis aplasia and the X-linked syndrome with
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cerebellar vermis aplasia and holoprosencephaly. The most important syndromes will be described in the following.
The Dandy-Walker complex was proposed as a continuum of posterior fossa anomalies comprising the Dandy-Walker malformation, Dandy-Walker variant, ~ Z ~ ~e ~ ~ is defined o ~as ~ and megacisterna magna(10-12) The D a ~ ~ y - ~ a a large posterior fossa cystic dilation, with upward displacement of lateral venous sinuses and the tentorium, and having a wide midline communication with the fourth ventricle. As a consequence there is a complete or partial agenesis of the vermis. The posterior fossa cyst causes a significant obstructive hydrocephalus. Although the primary defect was formerly thought to be due to absent opening of the foramina of Magendie and Luschka, others did find patent foramina and considered a primary anomaly of cerebellar development as the cause (11,13). Another likely hypothesis mightbe delayed opening of the foramina after a cystic expansion of the fourth ventricle has been formed. The exact etiology of the Dandy-Walker ~alformationremains unknown. Familial occurrence has been described, particularly when the Dandy-Walker malformation is associated with other central nervous system (CNS) or extraneural malformations (autosomal dominant, recessive, X-linked forms; 14), but the majority of “pure” DandyWalker malformations are very rarely genetically determined, with a low recurrence risk in siblingsof between l and 5% (15). Clinical features of the DandyWalker malformation with hydrocephalus may be manifest soon after birth and usually become evident during thefirst year of life, with macrocephaly, a prominent occiput, and hydrocephalus caused by the posterior fossa cyst with blockage of cerebrospinal fluid (CSF), Other signs and symptoms may develop early, but usually develop later during the course and constitute cranial nerve palsies, nystagmus, and truncal ataxia. In a proportionof cases, other midline malformations can be present in the CNS,particularlycallosalagenesisandsupratentorialmidlinecysts,butalso malformations outside the CNS can sometimes be found, such as cleft palate or cardiac malformations (16). During clinical assessment, the presence of other intra- and extra-CNS malformations should be sought, because their presence negatively affects the prognosis. 50% of cases Mental handicap and seizures have been reported in up to with the Dandy-Walker malformation (17,18). For each child with this malformation neuroimaging by MRI and carefull clinical assessment are mandatory, and they should not be delayed for several reasons concerning the outcome, prognosis, and genetic advice.The early shunting of both the cyst and hydrocephalus is advocated because early management would ameliorate mental abilities and prognosis (Fig. 4; 10). Dandy-Walker malformation is inconstantly associated
Cerebellar Malformations
125
Figure 4 Prenatal ultrasound detected Dandy-Walker malformation in a girl who was treated with a ventriculoperitoneal shunt interconnected to a shunt placed within the posterior fossa cyst. (a) Before surgical intervention a CT scan within the axial plane shows the enlarged posterior fossa cyst with wide communication to the enlarged fourth ventricle.
Ramaekers
o n ~ i n(b)~Fifteen ~ ~ months after placement of a shunt draining the ventricles and posterior fossa cyst, the mechanically compressed cerebellar hemispheres can be noted to have ~ l ~ f o and ~ ~grown, ed
Cerebellar Maiformatio~s
with other recognizable patterns of human malformation, suchas the oral-facialdigital syndrome type I1 (Mohr syndrome), Meckel’s syndrome, or Aase-Smith syndrome. The etiologic heterogeneity of the Dandy-Walker malformation was illustrated by a long list of over 100 associated chromosomal disorders, sporadic and single-gene malformation syndromes, inborn errors of metabolism, and teratogenic agents (14).
y - ~ a l ~ eVariant r an The ~ U n ~ y - ~ a variant Z ~ e r is defined as a hypogenetic cerebellar vermis, which is typically less marked compared with the Dandy-Walker malformation, and a cystic dilation of the fourth ventricle without major posterior fossa enlargement. There is normal communication between the fourth ventricle and arachnoid spaces (1 1,16).Megacisterna magna is defined as posterior fossa enlargement without obvious anomalies at the fourth ventricle and vermis. However, for some cases the anatomical features are difficult to classify into either Dandy-Walker malformation, Dandy-Walker variant, or megacisterna magna (16). As with classic Dandy-Walker malformation, the clinical phenotype of the Dandy-Walker variant is extremely variable. In about one-third to one-half of prenatally diagnosed cases, accompanying non-CNS abnormalities were found to have a poor prognosis (with or without chromosomal abnormalities; 19). However, the importance of these subtle posterior fossa anomalies is that they might be indicators for other brain developmental disorders with neurological disability, although frequently, these CNS findings may exist without adverse clinical consequences (20). Although in a high proportion, up to 62% of their patients with megacisterna magna, some papers reported on neurological abnormalities (12), our own experience is that megacisterna is often found by chance in otherwise neurologically healthy children who have been referred for a brainCT scan because of trauma or headaches. Genetic advice for patients with Dandy-Walker variant and megacisterna magna should consider the rare inherited cases of familial Dandy-Walker variant with other neurological abnormalities (21), and one reportedofset identical twins with megacistema magna who also had ataxia and seizures (22).
D. ~ ~ i aMalformations r i Chiari malformations are developmental disturbances during early embryogenesis, resulting in an abnormal architectural relation between the rhornbencephalon (medulla oblongata, pons, and cerebellum) and the basicranium (bony floor of the posterior fossa) (16). Type I Chiari malformation is sometimes associated with basilar impression or occipital dysplasia in which there is upward displacement of the foramen magnum and occipital bony floor, giving rise to a small posterior fossa (23).
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Consequently, the undersized posterior fossa gives rise to downward herniation of inferior cerebellar tissues (i.e., posterior vermis and tonsils).The impediment to CSF flow dynamics causes intermittent raised intracranial pressure signs and cervical syringohydromyelia (Fig. 5). Most cases of Chiari type I malformation are sporadic, but dominant inheritance, with variable expression, has been reported (also under the heading inherited basilar impression and cervical syringomyelia; 24). For these families radiologic studies could be helpful in screening first-degree relatives. Type I Chiari malformation uncommonly presentsin early childhood, but symptoms can manifest during adolescence or late adulthood. Presenting complaints comprise occipital headaches and pain in the d i s ~ b u t i o nof the occipital nerves, sometimes exacerbatedby coughing, sneezing, or excercise, and relieved by lying down. Migraine-like vegetative symptoms, with pallor, nausea, and vomiting, may be associated. Some patients with cervical syringomyelia complain of weakness and sensory loss more in the arms than in the legs.
Figure 5 (a) Typical picture of Chiari type I malformation in a 15-year-old girl with a of history of weekly occipital headaches and vorniting relieved by lying down. Herniation inferior vermis and cerebellar tonsils through the foramen magnum are present.
ontinued (b) Combination of Chiari type I malformation with cervical syrinx in a 61-year-old man.
Funduscopy can reveal blurred margins of the optic discs with variable visual field defects on perimetry. A valuable oculomotor sign is downbeat nystagmus, characterized by primarypositionoscillatorymovementswiththefastphase beating downward. This sign is highly suggestive of an abnormality at the medulI malformation. Lower cranial nerve dislospinal junction, such as in Chiari type turbances with deglutitional failure, vertigo, and tinnitus can be noticed. Ataxia and weakness with sensory disturbances in the arm can point to a cervical syrinx. Careful MR studies can demonstrate the basilar impression with downward herniation of the cerebellar tonsils and inferior vermis through the foramen magnum and indicate the presenceof cervical syringomyelia. Sometimes, other associated anatomical anomaliesof the neck, such as theKlippel-Feil syndrome, can
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be present (25). Management of symptomatic type I Chiari malfor~ationincludes various operative procedures to decompress posterior fossa structures and arrest syringomyelia (26). Type II Chiari ma~ormationsare the most common among the Chiari malformations and consist of downward displacement of the medulla oblongata, together with the inferior cerebellar vermis and tonsils that impinge on theforamen magnum, thereby causing hydrocephalus. The majority of cases have an associated myelomeningocele (27). The features and complications of the associated neural tube defect are evident before or immediately after birth and overshadow the type I1 Chiari malformation. Neurological signs and symptoms of the ChiariI1malformation include hyas feeding and swaldrocephalus, and lower cranial nerve palsies can occur, such lowing difficulties, vocal cord palsies, and apneas. Immediate closureof myelomeningoceleandshuntimplantationtorelievehydrocephalusareperformed. Chiari typeI1 malformation shouldbe considered as partof the neural tube defect spectrum. Genetic counseling is based on the recent findings of periconceptional folic acid supplementationto prevent a recurrenceof the neural tube defect(28). Chiari type III ma~ormationis rare andis defined asa midline bony defect associated with a high neural tube defect and cerebellar encephalocele. Genetic counselingalsoincludespreventivemeasures of periconceptionalfolicacid supplements (16).
Cogan ’S congenital oculomotor apraxiais considered a sporadic and rare condition, which is more common in boys (29). The condition is found among those of rapid horizontal children classedas “clumsy.” Clinical features include defects eye movements, for instance, such as reading where the eyes scan from left to right. The patients instead tend to move and jerk their head from left to rightto bring their eyes into the desired positionhead-thrusting"). Oculomotor apraxia with compensating head-shaking movements can already be noted in children younger than the age of 1 year when they attempt to follow visual lures. Difficulty and unsteadiness in rapidly changing direction are noted on walking, runMRI of midline structures, ning, or riding, with a tendency to fall when turning. reported on in two patients, has revealed hypoplasia of upper vermian structures together with thin and elongated superior peduncles and sometimes fusion of the (30). Another study included congenital idiopathic colliculi at the mesencephalon oculomotor apraxia in16 children, andMR scans showednoma1 images in most children, except for 2 children with either enlarged ventricles or multiple, small, white matter lesions (31). Ataxia telangiectatica or Louis-Barr syndrome is a neurodegenerative au7. Neurotosomal recessively inherited condition that will be outlined in Chapter
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imaging reveals vermis dysgenesis at an early stage and later progressive cerebellar atrophy (32). Tectocerebellar dysraphia is a rare anomaly of vermian hypoplasia or aplasia with occipital encephalocele and dorsal traction of the brain stem.The hypoplastic cerebellar hemispheres are rotated lying in a ventrolateral position to the brain stem (33). ~hombencephalosynapsis hasbeenrecognizedsince1914asarare anomaly, characterized by complete or partial agenesis of the vermis associated with fusion in the midline of cerebellar hemispheres, dentate nuclei, and superior cerebellarpeduncles.Sometimesmesencephaliccolliculianddiencephalic thalami are also fused. Supratentorial midline structures can also show anomalies of the limbic system, and with septum pellucidum aplasia or dysplasia, anomalies hydrocephalus (34). Various nonneurological anomalies have been reported in associationwiththeclassiccerebellardeformity.Clinicalsymptomatologyis nonspecific and seldomly asymptomatic. Most patients have psychomotor retardation, with seizures, dysequilibrium, dysarthria, and apraxia (35). The embryological disturbance occurs between the 28th and 41 th postconceptional day, when the superior located anlageof the vermis is absent and alar rhombencephalic lips forming the cerebellar hemispheres will fuse at the midline. MRI can readily diagnosetheaforedescribedanomaliesandwilldemonstatetypicalpictures of fused structures in the midline. Lhermitte-Duclos disease wasreportedonin1920 (36,3’7). Itisalso known as diffuse hypertrophy of the cerebellar cortex and dysplastic cerebellar gangliocytoma. It is composed of focal enlarged cerebellar cortex, with sharply demarcated borders, originating from a portion of one cerebellar hemisphere and extending into the vermis or the contralateral hemisphere, with displacement of the fourth ventricle. Histopathologic examination demonstrates a thick layer of abnormal ganglion cells replacing the granular layer of the cerebellar cortex, a thick hypermyelinated layer replacing the molecular layer, and a thin Purkinje cell layer. Cerebellar folia appear as gross thickened, curvilinear structures, with or without mass effect (3’7). In some patients the abnormalities remain asymptomatic, but in others, the mass effect from the lesion can provoke intracranial hypertension and cerebellar signs and symptoms. Neuroimaging by CT shows a nonspecific hypo- or isodense cerebellar mass, mimicking a posterior fossa neoplasm, which does not enhance following contrast administration. Tl-weighted scans show a low-signal nonenhancing, laminated-appearing mass, whereas “2weighted scans show the thickened hyperintense enlarged folia, suggesting the diagnosis (3’7). Lhermitte-Duclos disease can exist as the single disorder, but may coexist with the neurocutaneousCowden’s syndrome, a multiple hamartoma syndrome of autosomal dominant inheritance (36). Recently, in some families with Lhemitte-Duclos and Cowden’s syndrome alterationsof a tumor suppressor gene (called PTEN) have been identified at chromosome 10-ql23.3 (38,39).
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In l969 Joubert reported onfive children with episodic hyperpnea and apnea, abnormal eye movements, with onset during the neonatal period, followed by mental retardation and ataxia (40). There is complete or nearly complete vermis agenesis with dysplasia and heterotopias of cerebellar nuclei, near total absence of pyramidal decussation, anomalies in the structureof the inferior olivary nuclei, descending trigeminal tract, solitary fascicle, and dorsal column nuclei (41). Lindbout reported on the association of Joubert’s syndrome with bilateral choroideoretinal coloboma and considered this as a separate entity (42). Saraiva and Baraitser classified patients with Joubert’s syndrome into two groups, depending on the presence or absenceof retinal dystrophy. Joubert patients with retinal dystrophy can also have abnormal kidney function owing to multiple small cortical cysts and chronic interstitial in~ammationand fibrosis, resembling renal nephronophthisis (43). Saraiva and Baraitser suggested that the combination of Joubert’s syndrome associated with renal cysts and retinal dystrophy should be better calledDekaban’s syndrome, who first reported on this autosomal recessive condition in 1969 (44). Other phenotypically multisystem disorders related to JouCOACH syndrome, combining cerebellar bert’ S syndrome are known, such as the vermis abnormality, oligophrenia, ataxia, coloboma and hepatic fibrosis (45). Computed tomography(CT)and MRI show the characteristic vermis agenesisandthinhorizontallyorientedsuperiorcerebellarpeduncles,givingthe middle of the fourth ventricle the shape of an inverted triangle on axial planes (37); near the pontornesencephalic junction the superior cerebellar peduncles are thin and give the pons and pontocerebellar connection a molar tooth appearance (the so-called tooth sign).At the latter level, the fourth ventricle has the appearThe genetic causeof the autosomal recessively transance of a bat wing (Fig. 6). mitted Joubert’s syndrome has not been identified. The hypothesis that the gene€or Joubert’s syndrome is partof a contiguous gene deletion syndrome in the region of the nephronophthisis-l gene could not s syndrome, be confirmed (46).The WNT-1 gene, as a candidate gene for Joubert’ was investigated, and no mutation has been found among 50 patients (47). An autosomal recessively inherited syndrome with congenital onset and poor prognosis is the Walker-Warburg syndrome, also designated HARD +- E syndrome, which stands for the important features hydrocephalus, agyria (lissencephaly), retinal dysplasia associated with or without the presenceof encephalocele (48). Based on 21 of our own patients and42 patients from the literature, lissencephaly, cerebelas reportedby Dobyns (49), all patients checked for I1 type lar malformation (~andy-Walker-li~e cyst, vermis agenesis, cerebellar agyriamicropolygyria), retinal dysplasia (microphthalmia, retinal and anterior chamber anomalies) and congenital muscular dystrophy. The two other abnormalities (i.e., dilation of the cerebral ventricles, with or without hydrocephalus, and the malformation at the anterior eye chamber) were not necessary diagnostic criteria (49).
Cerebellar
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The cerebral ocular dysplasia-muscular dystrophy (COD-MD) syndrome probably represents an identical, but milder expressed syndrome, as compared with the Walker-Warburg syndrome (SO).Fukuyama congenital muscular dystrophy (FCMD) differs from theWalker-Warburg syndrome by the less frequent and severe cerebellar and retinal abnormalities. Toda et al. presented evidence from haplotype analysis suggesting that Fukuyama and Walker-Warburg syndromes are identical disorders(51,52). In a consanguineous sibship in which one sib was thought to have Fukuyama muscular dystrophy and another sib was thought to have Walker-Warburg syndrome, analysis using polymorphic microsatellites flanking the FCMD-locus on 9q3 1-q33 showed that the two affected 9 haplotypes.Clinica1features ofWalkersibshadthesamechromosome Warburg syndrome include congenital blindness, severe psychomotor retardation, and sometimes, development of hydrocephalus with aquaductal stenosis as the most frequent cause. Prenatal diagnosisby ultrasound can demonstrate fetal hydrocephalus, occipital encephalocele, and sometimes the eye abnormalities (53). After birth MR studies can detect lissencephaly, with hydrocephalus, and vermis agenesis, with cerebellar hypoplasia or pontocerebellar hypoplasia, patchy disorganized regionsof heterotopia, microgyri, and clusters of downward-projecting leptomeningealandgliomesenchymalbundles,abnormalities Sometimes described as cobblestone lissencephaly(49,SO). Careful eye examination and demonstration of muscle disease should be performed by the appropriate investigations. The muscle biopsy inWalker-Warburg syndrome shows preserved merosin M-chain (or Iaminin-a,) expression, which can be used as a distinguishing feature from FCMD and merosin-deficient congenital muscular dystrophy (54). The prognosis remains poor, with high mortality in the first months and yearsof life.
G.
Rare Syndromes with Vermis Agenesis
Gillespie (55) described an autosomal recessive syndrome with oligophrenia, aniridia, and congenital ataxia. A similar case seen by us showed complete vermis agenesis on CT as the single finding. Verloes reported on the syndrome with the combination of cerebellar vermis hypoplasia, oligophrenia, ataxia, ocular coloboma, and hepatic fibrosis (45), which is the same constellation of findings as the COACH syndrome. Fenichel et al. reported on the autosomal dominant or X-linked dominant familial syndrome of vermis aplasia, with preponderance in females, for which there is genetic transmission of cerebellar vermis aplasia (56). Whiteford and Tolmie have reported on the syndrome of familial aplasia of the cerebellar vermis with holoprosencephaly caused by X-linkedinheritance (16). Bordarier and Aicardi have reported many on syndromes of human malformation where vermis agenesis or hypoplasia can be noticed, but does not represent a constant feature (10).
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Figure 6 (a) A 6-year-old girl with Joubert’s syndrome shows agenesis of the vermis with the inverted triangle at the level of the midst of the fourth ventricle.
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(b) At the pontomesencephalic junction the ventral indentation at the mesencephalon with the elongated thin superior cerebellar peduncles give the molar tooth sign appearanceof the brain stern. On the right side a small posterior retrocerebellar cyst is present.
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IV. PONTOCEREBELLARHYPOPLASIAS Severe hypoplasia of the cerebellum may be seen without any macroscopic affection of pons and brain stem volume, although at the microscopic'level one can note atrophy of tranverse pontine fiber bundles and large-fiber contingents derived from cerebellar-brain stem connections. However, in pontocerebellar hypoplasias not only is there atrophy of connecting fiber bundles, but the volume reduction is also due to depletion of neuronal populations within the pons and sometimes olivary nuclei. This distinctive fact has led Barth and others to delineate the pontocerebellar hypoplasias as a separate group of disorders (9). It can also be differentiated from the olivopontocerebellar atrophies (OPCAs), which imply a processof atrophy associated with degeneration and shrinkage as the inas volved mechanism. Another clinical argument for pontocerebellar hypoplasias separate disorders is that most pontocerebellar hypoplasias have major problems dominated by affection of other neuronal systems (e.g., the spinal anterior horn the various cells, extrapyramidal system, cerebral cortex). Table 2 lists syndromes with pontocerebellar hypoplasia with their main clinical and neuroradiologic features and their modeof inheritance. Most conditions have a prenatal onset of fetal maldevelopment, for which the insult affects the progenitor cells, giving rise to pontine nuclei and cerebellar structures. A correct diagnosis will rely on a careful family history and clinical assesment, neuroradiologic studies, electroneuromyography, EEG, eye exarnination, andisoelectricfocusing of serumtransferrintodiagnosethecarbohydratedeficient-glycoprotein (CDG) syndromes type I or 111. An autosomal recessive mode of inheritance is present in most of the pontocerebellar hypoplasias, for mostof which the responsible gene defect has not yet been identified. See Fig. 7 for an example of pontocerebellar hypoplasia type 2. Recently, the metabolic and genetic defect for CDG syndrome type I has been identified (65-71). The CDG syndrome type I is a multisystem disorder with major neurological involvement and sometimes phenotypic variability even within the same sibship. The most important features are dysmorphic features (internal strabism, large dysplastic ears, subcutaneous fat deposits at the lower back, orange peel skin), failure to thrive, skeletal abnormalities, with hypotonia and developmental delay during the first year of life; later tapetoretinal degeneration, hypogonadism, cognitive disability, and ataxia become manifest. Signs of additional polyneuropathy are present. In some instances complications can become manifest, such as stroke-like episodes, pericardial effusions, or cardiomyopathy. The serum glycoproteins can show either lowered or elevatedvalues,suchassimultaneouslyloweredlevelsforthyroxin-bindingglobulin, a,-antitrypsin, ceruloplasmin, haptoglobin, and apolipoproteinB, with elevations of a,-macroglobulin and arylsulfatase A. Isoelectric focusing of serum transferrin can identify the lack of sialic acid residues of the carbohydrate side
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Table 2 CausesofPontocerebellarHypoplasias
(Ref.)
Syndrome Chiari type IV (57)
Severe pons, brain stem, and cerebellar hypoplasia (without other CNS anomalies) Pontocerebellar hypoplasia, cobblestone Walker-Warburg lissencephaly, retinal dysplasia, syndrome (49) congenital muscular dystrophy Severe microcephaly at birth (c28 cm), Microlissencephaly agyria with lethal outcome (58759) Microcephaly, white matter gliosis, Fatal infantile neuronal loss in olivary and pontine olivopontocerebellar nuclei, with death in infancy hypoplasia (60) Microcephaly, severe pons, olivary, and Paine syndrome (61) cerebellar hypoplasia, mental handicap, epilepsy, and spasticity Respiratory insufficiency at birth, spinal PCH type I (9,62) anterior horn cell disease Microcephaly, extrapyramidal PCH type I1 (63) dyskinesias Progressive encephalopathy with PEHO syndrome (64) hypsarrhythmia and optic atrophy Dysmorphic features, failure to thrive, CDG syndrome type I mental retardation, retinopathy, ataxia, (65-70) hypogonadism. Variableclinicalphenotypedescribedin CDGsyndrometype I11 (71) patients. a few
Sporadic AR, gene
9q3 1-33 AR
AR
X-linked recessive AR
AR ?
AR (16P)
Abbrev: PCH,pontocerebellar hypoplasia; CDG, carbohydrate-deficient glycoprotein syndrome; AR, autosomal recessive inheritance.
chainswithsomeloss of the normally present tetrasialotransferrin band and typical appearance of asialo- and disialotransferrin moieties (Fig. S). The basic of mannose-6-phosphateinto biochemicaldefectisdeficienttransformation mannose- 1-phosphate owing to deficiencyof the enzyme phosphomannomutase necessary in the synthesis of mannose-rich oligosacharides within the endoplasmatic reticulum where synthesis of glycoproteins will take place. Consequently, a large number of glycoproteins become abnormal because of a deficiency of carbohydratesidechains,leadingtoaberrantconcentrationsandfunction. Twenty different missense mutations at the phosphornannomutase geneon chromosome 16p have been identified 50 in patients from different geographic origins (71). Patients with CDG syndrome type111have been described by Stibler et al.
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ure 7 Autosomalrecessivepontocerebellarhypoplasiatype 2 isaprenatal-onset condition with severe neurodeveloprnental delay, microcephaly, extrapyramidal features, and the absence of spinal muscular atrophy. (a) Pontine hypoplasia with a preserved vermis can be seenon sagittal T1-images, whereas (b) severe hypoplasia of cerebellar hemispheres can be noted on a parasagital section.
with less consistent clinical features, but MRI (72).
Dandy-Walker-like malformation on
Cerebellar hypoplasia can be caused by many well-recognized i n t r a u t ~ ~ nine sults (radiation, certain drugs, and viral agents) impinging on cerebellar progenitor cells or the developing cerebellar structures during embryological and fetal development (1-5,9). The most important known exogeneous factors have been listed in Table 3 as well as the many chromosomal and genetic disorders affecting cerebellar growth and development. The latter conditions constitute chomosoma1 trisomies 13, 18, and 21 (73,74) and genetically determined conditions that
are part of well-recognizable patterns of associated malformations of both the central nervous system and other organs (8,75102). Follow-up imaging studies and assessment of the clinical evolution can differentiate these static disorders of cerebellar hypoplasia from progressive disorders of cerebellar atrophy. The family history can often help in delineatinga genetic background for cerebellar hypoplasia among families with more than one affected member. However, a single index patient with cerebellar hypoplasia can often pose diagnostic problems, particularly for the groupof patients with autosomal recessive and X-linked (neo)cerebellar hypoplasia in whom other typical features in- or outside the GINS are not present (75-78). Only postmortem neuropathological studies can reveal the correct diagnosis. Two syndromes for which recent advances in the field of genetics have been made, will now be outlined. S ~ i t ~ - ~ e ~ Z i - O(SLO) ~ i t z syndrome types I and TI are autosomal recessively transmitted multimalformation syndromes featuring microcephaly, mental retardation, hypotonia, variable expression of incomplete development of male genitalia (hypospadia, cryptorchism, ambiguous genitalia); short nose, with anteverted nostrils; micrognathia, cleft palate; polydactylie, and syndactyly (between second and third toes) (96-98). The nervous system shows a variable association of multipleanomalieswithholoprosencephaly;cerebellarhypoplasia;and
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Figure 8 Serum transferrin isoelectric focusing for detectionof CDG syndrome type I: Transferrin is a glycoprotein onto which two antennae-like saccharide side chains are attached, each of which contains either two or three end-standing sialic acid residues; these negatively charged sialic acid residues can be used to differentiate between the different transferrin moieties; lanesA-D are healthy controls (C and D are the parents of the described patients), in which the normal transferrin molecule pattern with four to six sialic acidresiduescanbenoted;muchlessintensebandscansometimesbenotedforthe disialo- and trisialotransferrin moieties owing to normal transferrin heterogeneity; lanes E-I are the patterns typical for CDG syndrome type I (the described male and female siblings with CDG syndrome correspond to lane E and F). In patients there isa shift of the transferrin pattern with some loss of the tetrasialotransferrin band and typical appearance of asialotransferrin and disialotransferrin moieties.
reducedmyelination of cerebralhemispheres,cranialnerves,andperipheral nerves (96).The discovery of deficient 7-dehydrocholesterol reductase activity as a causative factorof SLO syndrome is reflectedby elevated 7-dehydrocholesterol levels and lowered plasma cholesterol levels (97). Porteretal.demonstratedthatcholesterolisthelipophilicmoiety covalently attached to theNH,-terminal signaling domain of hedgehog proteins, derived from one of the homeobox genes that function as transcriptional regulators and signaling systems of the body plan. The COOH-terminal domain of hedgehog proteins acts as an intramolecular cholesterol tranferase (99). They
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Cerebellar Malformations Table 3 Causes and Syndromes with Cerebellar Hypoplasia
Ionizing radiation Radiomimetic toxins Drugs Viral causes Chromosomal syndromes
Applied during maximum cerebellar growth in the second half of pregnancy (3,4) Phenytoin (S) Cytomegalovirus (1,2) Trisomie 13 (72) Trisomie l8 (73) Trisomie 21 (74) Chromosome 4 short arm deletion (72) Fragile X syndrome (72) Autosomal recessive with paucity of granule cells (7S,76) Autosomal recessive (77) X-linked (78) X-linked with hydrocephalus (79) Cerebral calcifications and cerebellar hypoplasia (80) With retinopathy (81) Cerebellar granule cell deficiency, microcephaly with progressive pancytopenia (82,83). ~
Familial (neo)cerebellar hypoplasia
Cerebellar hypoplasia with hematological disorders Cerebellar hypoplasia with hypogonadism
x
Cerebellar hypoplasia with hypogonadotropic hypogonadism (84) Cerebellar ataxia, hypogonadotropic hypogonadism, choroidal dystrophy (Boucher-Neuhauser syndrome) (85)
Cerebellar hypoplasia as part of complex malformation Phakomatoses Cerebellar hypoplasia with congenital bilateral cataract Bilateral porencephaly and internal malformations Smith-Lemli-Opitz syndrome BPNH/MR syndrome
Cerebellar hypoplasia with hypergonadotropic hypogonadism (infantile-onset spinocerebellar ataxia) (86-88) Marsden-Walker syndrome (89) Acrocallosal syndrome (8) Otopalatodigital syndromes (90) Oral-facial-digital syndromes (91) Ito's hypomelanosis (92) Marinesco-Sjogren syndrome (93,94) Bilateral porencephaly (distribution of the middle cerebral artery), cerebellar hypoplasia, and internal malformations (95) Microcephaly, mental retardation, ambiguous genitalia, poly- or syndactylie owing to '7-dehydrocholesterol reductase deficiency (chromosome 1lq12-ql3) (96-100) Bilateral periventricular nodular heterotopia, mental retardation, epilepsy, and cerebellar hypoplasia (mapped to Xq28) (101,102)
BPNHMR plus cerebellar hypoplasia in a 11-year old girl: (a>Coronal section demonstrates multiple pearl-like periventricular nodules, whereas on the sagittal image (bj, the cerebellar hypoplasia canbe seen.
postulatedthatsome of theeffects of perturbedcholesterolbiosynthesison animal development rnay be because cholesterol is used to modify embryonic signaling proteins. In SLO syndrome, in which cholesterol biosynthesis is defective, there may be defective modification of the hedgehog proteins and perhaps othersimilarlyprocessedproteins.Consequently,thespectrum of developmental brain malformationsseen in SLO syndrome rnay be due to lossof hedgehogproteinfunction. The experimentaldrug B M 15.766 was used to inhibit
7”dehydrocholesterol reductase in rats to study the teratogenic effects of low cholesterol and high ’7-dehydrocholesterol on rat brain development. Abnormalities resembling those reported in humans with SLO-syndrome have been observed, including abnormalities of the brain and face. Pathological examination on gestational day l1 revealed populations of abnormally rounded-up cells at the
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rim of the developing forebrain and in the alar plate of the lower midbrain and hindbrain (100). Another rare syndrome of bilateral periventricular nodular heterotopiamental retardation (BPNH/MS) with cerebellar hypoplasia has female preponderance in affected families and was considered to be inherited as an X-linked 9) (101). Most dominant trait with lethality or severe involvement in males (Fig. patients have epilepsy, cerebellar ataxia, and severe mental retardation. Linkage studies have mapped this syndrome to a region on chromosome Xq28, where the candidate genes LlCAM, a neural cell adhesion molecule, and the a,-subunitof the y-aminobutyric acid receptor reside (102).
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64. Haltia M, Somer M. Infantile cerebello-optic atrophy: neuropathology of the progressive encephalopathy syndrome with edema, hypsarrhythmia and optic atrophy (the PEHO syndrome). Acta Neuropathol 1993; 85241-247. 65. Stibler H, Jaeken J. Carbohydrate deficient serum transferrina new in systemic hereditary syndrome. Arch Dis Child 1990; 65: 107-111. 66. Horslen SP, Clayton PT, Harding BN, Hall NA, Keir G, Winchester B. Olivopontocerebellar atrophy of neonatal onset and disi~otransferrindevelopmental deficiency syndrome. Arch Dis Child 1991; 66:1027-1032. 67. Akaboshi S, Ohno K, Takeshita K. Neuroradiological findings in the carbohydratedeficient glycoprotein syndrome. Neuroradiology 1995; 37:491-495. 68. JensenPR,HansenOJ,SkovbyF.Cerebellarhypoplasiainchildrenwiththe carbohydrate-deficient glycoprotein syndrome. Neuroradiology 1995; 37:328-330. 69. Jaeken J, Casaer P. Carbohydrate-deficient glycoconjugate (CDG) syndromes: a new chapter of neuropaediatrics. Eur J Paediatr Neurol 1997; 1:61-66. 70. Matthijs G, Schollen E, Pardon E, Veiga-Da-Cunha M, Jaeken J, Cassiman JJ, Van SchaftingenE. Mutations in PMM2,a phosphomannomutase gene on chromosome 16~13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nat Genet 1997; 16:88-92. 71. Stibler H, Westerberg B, Hanefeld F, Hagberg B. Carbohydrate-deficient glycoprotein (CDG) syndrome-a new variant, type 111. Neuropediatrics 1993; 2451-52. 72. Kurnar AJ, Naidich TP, Stetter G. Chromosomal disorders: background and neuroradiology. AJNR Am J Neuroradiol 1992, 13:577-593. 73. Nakamura Y, Hashimoto T, Sasaguri Y. Brain anomalies found in 18 trisornie: CT scanning, morphologic and morphometric study. Clin Neuropathol 1986; 5:47-52. 74. Crome L, CowieV, Slater E. A statistical note on cerebellar and brainstem weight in mongolism. J Ment Defic Res 1966; 10:69-72. 75. Norman RM. Primary degeneration of the granular layer of the cerebellum: an unusualformoffamilialcerebellaratrophyoccurringinearlylife.Brain1940; 63l36.5-379. 19.50; Dis111:398-76. Jervis GA. Early familial cerebellar degeneration. J Nerv Ment 407. 77. Wichman L,Farnk LM, Kelly TE. Autosomal recessive congenital cerebellar hypoplasia. Clin Genet 1985; 27:373-382. 78. Young ID, Moore JR, Tripp JH. Sex-linked recessive congenital ataxia. J Neurol Neurosurg Psychiatry 1987; 50:1230-1232. 79. Riccardi VM, Marcus ES. Congenital hydrocephalus and cerebellar agenesis. Clin Genet 1978; 13:443-447. J, WillernseJ. Cerebral calcifications and cer80. Troost D, van Rossum A, Veiga Pires ebellarhypoplasiaintwochildren:clinical,radiologicandneuropathological studies-a separate neurodevelopmental entity. Neuropediatrics 1984; 15: 102-109. 81. Dooley JM, LaRoche GR, Tremblay F, Riding M. Autosomal recessive cerebellar hypoplasia and tapeto-retinal degeneration:a new syndrome. Pediatr Neurol 1992; 8:232-234. 82. Hoyeraal HM, Lamvik J, Moe PJ. Congenital hypoplastic thrombocytopenia and cerebral malfomations in two brothers. Acta Paediatr Scand 1970; 59:185-191.
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83. Hreidarsson S, Kristjansson K, Johannesson G, Johannsson JH. A syndrome of progressive pancytopenia with microcephaly, cerebellar hypoplasia and growth failure. Acta Paediatr Scand 1988; 77:773-775. 84. Abs R, Van VleymenE, Parizel PM,Van Acker K, Martin M, Martin JJ. Congenital cerebellar hypoplasia and hypogonadotropic hypogonadism. J Neurol Sci 1990; 98 1259-265. 85. Baroncini A, Franco N, Forabosco A. A new family with chorioretinal dystrophy, spinocerebellar ataxia and hypogonadotropic hypogonadism (Boucher-Neuhauser 1;39: 274-277. syndrome). Clin Genet 199 86. Koskinen T, Sainio K, RapolaJ, Pihko H, Paetau A. Sensory neuropathy in infantile onset spinocerebellar atraxia. Muscle Nerve 1994; 17:509-515. 87. Koskinen T, SantavuoriP, Sainio K, Lappi M, Kallio AK, Pihko H. Infantile onset spinocerebellar ataxia with sensory neuropathy-a new inherited disease. J Neurol Sci 1994; 12150-56. 88. Koskinen T, PihkoH, Voutilainen R. Primary hypogonadism in females with infantile onset spinocerebellar ataxia. Neuropediatrics 1995; 26:263-266. J. Early neu89. Garcia-Alix A, Blanco D, Cabanas F,Sanchez PG, Pellicer A, Quero rological manifestations and brain anomalies in Marsden-Walker syndrome. Am J Med Genet 1992; 44:41-45. I1 with X-linked cer90. Stratton RF, Bluestone DL. Oto-palato-digital syndrome type ebellar hypoplasi~hydrocephalus.Am J Med Genet 1991; 41:169-172. 91. Chitayat D, Stalker HJ, Azouz EM. Autosomal recessive oral-facial-digital syndrome with resemblance to OFD types II,III,IV and VI: a new OFD syndrome? Am J Med Genet 1992; 44:567-572. 92. Pini G, Faulkner LB. Cerebellar involvement in hypomelanosis of Ito. Neuropediatrics 1995; 26:208-210. 93. Marinesco G, DraganescoS, Vasiliu D. Nouvelle maladie familiale caracteriske par une cataracte congenitale et un arret du dkveloppement somata-neuro-psychique. Enckphale 1931; 26:97-109. 94. Torbergsen T, Aasly J, Borud 0, Linda1 S, Mellgren ST. Mitochondrial myopathy in Marinesco-Sjogren syndrome. J Ment Defic Res 1991; 35:154-159. 95. Bonnemann CC, Meinecke P. Bilateral porencephaly, cerebellar hypoplasia, and internal malformations: two siblings representing a probably new autosomal recessive entity. Am J Med Genet 1996; 63:428-433 96. Garcia CA, McGarry PA, Boirol M, Duncan C. Neurological involvement in the Smith-Lemli-Opitz syndrome. Dev Med Child Neurol 1973; 15:48. 97. Tint CS, Irons M, Elias ER, Batta AK, Frieden R, Chen TS, Salen G. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 1994; 330:107-113. 98. Opitz JM,Penchaszadeh VB, Holt MC, Spano LM, Smith VL. Smith-Lemli-Opitz (RSH) syndrome bibliography: 1964-1993. Am J Med Genet 1994; 50:339-343. 99. Porter JA,Young KE, Beachy PA. Cholesterol modification of hedgehog signaling proteins in animal development. Science 1996; 274:255-258. 100. Dehart DB, Lanoue L, Tint CS, SulikKK.Pathogenesis of malformations in a rodent model of Smith-Lemli-Opitz syndrome. Am J Med Genet 1997; 68:328-337.
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tricular heterotopia:an X-linked dominant epilepsy locus causing aberrant cerebral cortical development. Neuron 1996; 16:77-87.
Michel Koenig lnstitut de Genetique et de Biologie ~ o i ~ c u i a i et r e Celiulaire, university Louis Pasteur, Strasbourg, France
Alexandra Diirr Hopital de la Salp&triere, Paris, France
INTRODUCTION I.
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11. EPIDEMIOLOGY
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111. MOLECULAR PATHOGENESIS
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IV. NEUROPATHOLOGY
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V. CLINICAL FEATURES A.ClinicalPresentation B. Clinical-GeneticCorrelation C. NaturalCourseandPrognosis VI.ANCILLARYTESTS VII. MANAGEMENT REFERENCES
I.
155 155 155 157 157 158 158
INT~O~U~TION
Nicolaus Friedreich(1825-1 882) describeda familial form of cerebellar ataxia in 1863, clinically different from ataxias called “locornotrices” (motor) in 1858by 151
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Duchenne de Boulogne, for the tab&. The clinical entity emerged from the following observations: three sibships including nine patients, presented with balance difficulties in young adulthood, associated with muscular weakness and sensory loss. Scoliosis, foot deformation, and cardiac signs were frequent. At this time the loss of tendon reflexes was not mentioned because tendon reflexes were described by Erb only in 1875. Pathologically, the Friedreich cases showed spinocerebellar and posterior column degeneration. The clinical and pathological diagnostic criteria of Friedreich’s ataxia were founded ‘on this initial description, until the very recent discoveryof the responsible gene and mutation in 1996 (1). Since the discoveryof the unstable triplet repeat diseases, Friedreich’s ataxia was the first example of an autosomal recessive disorder causedby triplet repeat expansions. This was unexpected, because trinucleotide expansions had previously been found in autosomal dominant diseases such as Huntington’s disease, myotonic dystrophy, and several types of autosomal dominant cerebellar ataxias or X-linked disorders, such as fragile X or Kennedy syndromes.
II.
EPIDEMIOLOGY
Friedreich’s ataxia is the most common inherited degenerative ataxia and accounts for half of the inherited degenerative ataxias, and for three-quarters of thosewithonsetbeforeage25.Itsestimatedprevalenceisapproximately 1:50,000, but it is probably higher since GAA expansion carriers in French and German populations is of 1:85 (2,3). Given the high carrier frequency, the finding of a heterozygous expansion in a white patient should leadto the search for a point mutation in the other allele or to frataxin Western blot analysis, to confirm the involvement of the frataxin gene. Friedreich’s ataxia families revealing a pseudoautosomal inheritance, with incomplete penetrance, are not uncommon, again in relation to the high carrier frequency. Friedreich’s ataxia is rare in Finland and among black Africans, andis absent in Japan (S Tsuji, M Watanabe, N Tachi, personal communications).
111.
MOLECULARPATHOGENESIS
The frataxin genewas localized on the long arm of chromosome 9 in 1988(4). The identification of the responsible mutation was obtained 8 years after the chrornosoma1 mapping (1). The construction of a physical map and analysisof rare meiotic recombination events narrowed the disease locus to a final 150-kb interval, ex cluding several genes. Search for gross alterations in the noncoding partsof the frataxin gene revealed the presence of an enlarged fragment in the first intron in all patients. Sequencing showed that a short normal GAA trinucleotide isrepeat masThe gene encodes sively expanded into the100- to 1300-repeat range, in patients.
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a novel proteinof unknown function, that was named frataxin. The implication of frataxin has been proved by the identificationof point mutations in compound heterozygous patients (l), and by the fact that 94% of patients with Friedreich’s ataxia are homozygous carrier of the GAA expansion (1,5-8). The clinical equivalence between the GAA intronic expansion and the truncating mutations suggests that the expansion acts by loss of function of frataxin. Indeed, reverse transcriptase-polymerase chain reaction (RT-PCR) and RNAse protection experi(1,9). ments revealed that frataxin mRNA levels are markedly decreased The human frataxin gene encompasses 80 kb, and is composed of seven exons, two of which (5b and 6) are used only in a very minor alternative transcript. The major transcript is made from five exons (1-Sa) and encodes a protein of 210 amino acids, that has no resemblance to proteins of known function, although well-conserved homologues have been identified in the worm Caenorhabditis elegans and in the yeast (Saccharomyces cerevisiae). Expression of the frataxin gene correlates in part with the main sites of pathology of the disease (10,ll). In the mice, dorsal root ganglia are the major sites of expression in the nervous system, from embryonic day12 until adult life. Degenerationof the posterior columns, therefore, appears tobe a direct consequence of reduced frataxin level in these structures. Expression in the spinal cord is comparatively much lower, suggesting that degeneration of spinocerebellar tracts and Clarke columns, might be secondary to degenerationof the neurons in the dorsal root. Significant frataxin expression is also observed in the granular layerof the cerebellum. The as heart and panfrataxin gene is also expressed in nonneuronal tissues, such creas, which may account for hypertrophic cardiomyopathy and the increased incidence of diabetes observed in Friedreich’s ataxia patients. The same level of expression is found in tissues apparently not affected by the disease, suchas liver, muscle, thymus, and brown fat. All tissues highly expressing frataxin are rich in mitochondria, with brown fat, present in newborns, being particularly rich (10). The difference between nonaffected and affected tissues may lie in the nondividing nature of the latter (neurons, cardiocytes and beta cellsof the pancreas), implying that cells are not replaced when they die. Also, neurons and cardiocytes have an exclusive aerobic metabolism, making them more sensitive to a mitochondrial defect. A first suggestion that frataxin could abemitochondrial protein came from phylogenetic studies. Sequence comparisons showed the presence of more distant homologues in gram-negative bacteria, suggesting that the frataxin gene might be derived from the bacterial precursor of the mitochondrial genome, and that unit derwent transfer to the nuclear genome(12). Human and yeast frataxin were directly demonstrated to be mitochondrial proteins by epitope tagging experiments and colocalization with mitochondrial markers (10,13-15). ~itochondriallocalization of endogenous frataxin was demonstrated using specific monoclonal antibodies. Immunoelectron microscopy results indicate that frataxin is associated with mitochondrial membranes and crests (16).
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Yeast, as a model organism, provides a powerful system to study frataxin function. Three independent groups observed that deletion of the yeast frataxin gene results in impaired growth on glycerol, a nonfermentable source of carbon, accumulation of mitochondria-deficientrho-clones,andreducedrespiration markers (10,13-14). Moreover, the mutant yeast showed a higher sensitivity to hydrogenperoxide,iron,andcopper,thanthewild-typestrains. The yeast frataxin gene was independently isolated as a multicopy suppressor able to rescue a yeast mutant strain unableto grow on iron-limited medium.Yeasts deleted for the gene have a mitochondrial iron content tenfold higher than the wild-type, whereas total iron concentration is normal ( l 3). If the function of human frataxin is similar to that of the yeast protein, this of patients with Friedwould suggest that iron accumulates in mitochondria reich’s ataxia and could result in hypersensitivity to oxidative stress, as a consequence of the Fenton reaction (Fe2+-catalyzed production of hydroxyl radical). Indeed,irondepositshavebeenobservedinheartmyofibrils of Friedreich’s ataxia patients (1’7). Cardiomyopathy could thus be a result of iron overload or might reflect a selective sensitivity of heart mitochondria to frataxin deficiency. Selective deficienciesof the respiratory chain complexesI, 11, and 111and of both mitochondrial and cytosolic aconitase activities were found in heart biopsies of is that patients (18). The common link between all these enzymes and complexes they contain iron-sulfur (Fe-S) clusters in their active sites. Their inactivation is a direct proof of oxidative stress-affected tissues, because Fe-S proteins are remarkably sensitive to free radicals (19). As a consequence, Friedreich’s ataxia is part of nuclear-encoded mitochondropathies.
IV. ~ ~ ~ R O P ~ T H O L O G Y Degeneration of the posterior columns of the spinal cord is the hallmark of the disease. This is the consequence of the loss of large primary sensory neurons of the dorsal root ganglia, resulting in atrophy of axons, which causes thinning of the dorsal roots, particularly at the lurnbosacral level. The small unmyelinated fibers are well preserved, and interstitial connective tissue is increased. The motor component of peripheral nerves is well preserved. The spinocerebellar tracts are thinned, the dorsal being more affected than the ventral. Clarke columns, where the spinocerebellar tracts originate, show severe loss of neurons. Therefore, the sensory systems providing information to the brain and cerebellum about the position and speed of body segments, are severely compromised in Friedreich’s ataxia. Motor neurons in the ventral horns are well preserved, but the corticospinal tracts are atrophied. The pattern of atrophy of the corticospinal tracts suggests a “dying-back” process(20). In the brain stem, neuronal loss can be observedin the gracile and cuneate nuclei, where the dorsal column tracts terminate (21). Sen-
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sory cranial nerves also show myelin pallor and of loss fibers. The cerebellar cortex shows mild lossof Purkinje cells late in the disease course. Nevertheless, radiologic evidence of cerebellar atrophy in addition to cervical cord atrophy is observed in several patients. The deep cerebellar nuclei are severely affected with marked neuronal loss and gliosis in the dentate nucleus. As a consequence, the superior cerebellar pedunculi appear markedly atrophic. Other cerebral structures do not appear to be directly involved by the disease, with the exception of loss of pyramidal cells in the primary motor areas.
V.
CLINICAL FEATURES
A. ClinicalPresentation Friedreich’s ataxia is a progressive and unremitting cerebellar ataxia with onset usuallyclosetopuberty.Sincethediscovery of theresponsiblemutations, the range of age at onset is larger than previously thought: mean age at onset is 15.5 rt 8 years, ranging from 2 to 51 years (5-8,22-24). The presenting symptom is usually gait ataxia, except for scoliosis and cardiomyopathy, whichbecan present before the gait ataxia. Speech and coordination of the upper limbs may be normal in the first 5 years of the disease. Decreased reflexes in the lower limbs, extensor plantar response, decreased vibration sense at the ankles, axonal of Friedneuropathy, andCardiomyopathy constitute the complete clinical picture of the Friedreich’s ataxia pareich’s ataxia and are present in more than 70% tients. In the majority of the patients the reflexes are decreased in the upper limbs, and there is proximal weakness in the lower limbs. Scoliosis and pes cavus are present in 60% of the patients. Nystagmus is present in less thanhalf of the patients, decreased visual acuity and hypoacousia may be present late in the course of the disease. In contrast, fixation instability, expressed as square waves when registered on ocular movement recording, are a typical finding when cerebellar ataxia is evident. Optic atrophy is a rare finding. Atypical presentation in patients homozygous for the GAA expansion are observed, such as ophthalmoplegia, dystonia, myoclonus (5,22); ptosis (22); chorea (25); seizures, dysmorphia, menand tal retardation (5). The diagnostic criteria proposed by several studies before the discovery of the gene were revisedby Harding to include patients with onset up to 25 years and to take into account incomplete clinical presentations in patients in whom the disease duration was less than 5 years (26). The major diagnostic criteria and the typical phenotypes are shown in Tables 1 and 2.
B. Clinical-GeneticCorrelation There is no clinical difference between patients homozygous for the GAA expansion and the compound heterozygotes. A studyof 25 patients with a point mutation on one allele and a GAA expansion on the other showed that most of the
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Table 1 Major Clinical Diagnostic and Exclusion Criteria for Friedreich’s Ataxia
criteria exclusion Usual criteria diagnostic Positive
oplegia ranuclear limbs
Autosomal recessive transmission Autosomal dominant transmission, but pseudodominant inheritance is observed Cerebellar gait ataxia Decreased or loss of reflexes in the in inbred populations lower Extrapyramidal features Extensor plantar response Decreased vibration sense at ankles Mental retardation Decreased or abolished sensitive nerve Normal sensory nerve conduction conduction potentials motor with potentials conduction velocity >40 d s Cardiomyopathy on echocardiography Impaired glucose tolerance
compound-heterozygotes present as typical Friedreich’s ataxia (27). Moreover, there is no clinical correlation between the consequence of the mutation (missense or truncating) and the clinical presentation. Nevertheless, the clinical presentation associated with theC130V missense mutation was remarkable because of the absence of cerebellar ataxia in one out of five patients, and mild cerebellar ataxia in the others, the presenceof brisk reflexes in four outof five and spastic S and 15 years, gait as a presenting and lasting sign. Despite early onset, between Table 2 Phenotype of 140 Patients with Friedreich’s Ataxia
Frequent features Cerebellar gait ataxia Axonal neuropathy Cerebellar dysarthria Decreased or absent reflexes in the lower limbs Decreased vibration sense at ankles Cardiomyopathy on echocardiography Extensor plantar response Scoliosis Pes cavus Diabetes mellitus or impaired glucose tolerance Rare features Horizontal nystagmus Swallowing difficulties Visual loss Hearing loss Present or increased reflexes in the lower limb Optic atrophy
%
100 97 91 87 87 84 79 60 55 32 40 27 13 13 12 3
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disease progression remains mild in G130V mutation carriers. No patient who was compound-heterozygote or homozygote for two point mutations has been reported to date. This might be explained bothby the very low likelihood of its ocof consanguincurrence (< 4: 10,000Friedreich’s ataxia patients, in the absence ity)and by possiblelethalityassociatedwith two mutationsinactivatingthe frataxin gene, without residual expression of frataxin. Therefore, the absence of the expansion almost excludes the Friedreich’s ataxia diagnosis. Rare nonallelic heterogeneity may be present (28’29). Friedreich’s ataxia was distinguished from late-onset Friedreich’ S ataxia (LOFA) (30’31) and Friedreich’s ataxia with retained reflexes in the lower limbs (FARR) (32). By genetic linkage studies someof these families were recognized to be partof Friedreich’s ataxia, and after the discovery GAA expansions in these patients, the clinical spectrum of Friedreich’s ataxia has been recognized to be broader than previously thought. The direct involvement of the GAA expansion as the cause of Friedreich’s ataxia is demonstratedby the very significant inverse correlation between the size of the smaller of the two expansions and the ageof onset (r = -0.69 to -0.75). The same is true for the correlation with disease severity and frequency of signs, such as cardiomyopathy, scoliosis, and diabetes. The smallest pathological expansions are in the range of 90-110 repeats, usually found in patients with lateonset and atypical presentationof the disease, although exceptions exist (3). Carriers of small expansions(< 400 repeats) often show onsetof the symptoms after age 25 or have retained tendon reflexes, features previously considered as exclusion criteria for Friedreich’s ataxia diagnosis.
C. NaturalCourseandPrognosis Friedreich’s ataxia is a disabling condition and leads to physical dependence. The mean age at wheelchair use is 25 years. Childhood onset appears to be a predictor of a faster rate of disease progression (7’33). Cardiomyopathy and the complications of insulin-dependent diabetes shorten life expectancy. Wheelchair use and severity of cardiomyopathy are correlated with the sizeof the smallest GAA expansion, indicating that the best prognosis and the slowest courseof the disease is expected in patients with repeats smaller than 400 units. Nevertheless, individual predictionof life expectancy isnot possible. The occurrence of diabetes or optic atrophy is possible, but seemsbeto independent of the GAA expansion size.
VI. ANCILLARY TESTS Detection of the expansion mutation provides a useful diagnostic test. The test should be done in patients with progressive cerebellar ataxia with sensory axonal neuropathy, compatible with autosomal recessive inheritance. The length of ex-
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pansion has little value for individual prognosis, given the large scattering of points along the correlation curve and should not be used for individual prognosis. Given the high frequency of carriers, the finding of a heterozygous GAA expansion should lead to look for a point mutation.The important test is a conduction nerve study to assess the nearly constant finding of decreased amplitudes of sensory nerve action potentials with normal motor conduction velocities. Cerebral MRI can show cerebellar atrophy, but is usually nomal. Cervical MRI shows the thinning of the cervical spinal cord. Regular echocardiographic examinations are vital and Holter recording should be performed to detect arrhythmias. Blood glucose and oral tests for glucose tolerance are part of the follow-up.
Vll.
~ANAGEMENT
The early assessment and regular follow-up of cardiomyopathy and arrhythmia allows one to prevent complications.No cure is available today to avoid the progression of cerebellar symptoms and sensory neuropathy. Physical therapy, especially combined with swimming, is necessary to work againstloss theof strength and muscles. Since the discovery of mitochondrial consequences of the loss of frataxin, treatment trials using derivates of coenzyme Q10 look promising but no conclusive result has yet been reported (34).
We wish to thank our colleagues and collaboratorsV. Campuzano, M. Coss6, H. Koutnikova, H. Sadoulet-Puccio, M. Schmitt, J.-L. Mandel, A. Brice, A. Rotig, P. Rustin, E Foury, M. Pandolfo, L. Monterrnini, S. Jiralerspong, K. Ohshima, and L. Cova. Research in our laboratories is supported by the Centre National de la Recherche Scientifique, the Hijpitaux Universitaires de Strasbourg, and the AD), and the Institut Human Frontier Science (toMK), the Hijpitaux de Paris (to National de la Santk et de la Recherche Mkdicale and the AssociationFranGaise contre les Myopathies (to ME;and AD).
REFERENCES l. Campuzano V,Monterrnini L, Molt6 MD, PianeseL, Cossee M, CavalcantiF, Mon-
ros E, Rodius F, Duclos F, Monticelli A, Zara F, Cafiizares J, Koutnikova H, Bidichandani S, Gellera C, BriceA, Trouillas P, De Michele G, Filla A, de Frutos R, Palau F,Pate1 PI, Di Donato S, Mandel J-L, Cocozza S, Koenig M, Pandolfo M.
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Friedreich ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996; 271:1423-1427. Coss6e M, SchmittM, Campuzano V, Reutenauer L, Moutou C, Mandel J-L, Koenig M. Evolution of the Friedreich’s ataxia trinucleotide repeat expansion: founder effect and premutations. Proc Natl Acad Sci USA 1997; 94:7452-7457. Epplen C, Epplen JT, Frank G, Miterski B, Santos EJM, SchZils L. Differential stability of the (GAAjn tract in the Friedreich ataxia gene. Hum Genet 1997; 99:834836. Chamberlain S, Shaw J, Rowland A, WallisJ, SouthS, Nakamura U, von Gabain A, Farrall M, Williamson R. Mapping of mutation causing Friedreich’ ataxia to human chromosome 9. Nature 1988; 334:248-250. Dun A, Coss6e M, AgidY, Campuzano V, Mignard C, Penet C, Mandel J-L, Brice A, Koenig M. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med 1996; 335: 1169-1 175. Filla A, De Michele G, Cavalcanti F, Pianese L, Monticelli A,Campanella G, Cocozza S. The relationship between trinucleotide (GAAj repeat length and clinical features in Friedreich ataxia.Am J Hum Genet 1996; 59:554-560. Montermini L, Richter A, Morgan K, Justice CM, Julien D, Castelloti B, Mercier J, Poirier J, CapazzoliF, Bouchard JP, Lemieux B, Mathieu J, Vanasse M, Seni MH, Graham G, Andermann F, Andermann E, Melanqon S, Keats BJB, Di Donato S, Pandolfo M. Phenotypic variability in Friedreich ataxia: role of the associated GAA triplet repeat expansion. Ann Neurol 1997; 41:675-682. Geschwind DH, Perlman S, Grody W, Telatar M, Montemini L, Pandolfo M, Gatti RA. Friedreich’s ataxia GAA repeat expansion in patients with recessive or sporadic ataxia. Neurology 1997; 49: 1004-1009. Bidichandani S, Ashizawa T, Patel PI. The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. Am J Hum Genet 1998; 62:lll-121. Koutnikova H, Campuzano V, Foury F, Doll6 P, Cazzalini 0, Koenig M. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat Genet 1997; 16:345-351. Jiralerspong S, Liu Y, Montermini L, StifaniS, Pandolfo M. Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 1997; 4~103-113. Gibson TJ, Koonin EV, Musco G, Pastore A, Bork P. Friedreich’s ataxia protein: bacterialhomologspointtomitochondrialdysfunction.TrendsNeuroscie1996; 19:465-468. Babcock M, de Silva D, Oaks R, Davis-Kaplan S, Jiralerspong S, Monterrnini L, Pandolfo M, Kaplan J. Regulation of mitochondrial iron accumulation by Yfhl, a putative homolog of frataxin. Science 1997; 276: 1709-1712. Wilson RB, Roof DM. Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Nat Genet 1997; 16:352-357. Priller J, Scherzer CR, Faber PW, MacDonald ME, Young AB. Frataxin gene of Friedreich’s ataxia is targeted to mitochondria. Ann Neurol 1997; 42:265-269. Campuzano V, Montemini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, Trottier
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Y, Kish SJ, Faucheux B, TrouillasP, Authier FJ, Durr A, Mandel J-L, Vescovi AL, Pandolfo M, Koenig M. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet 1997; 6:1771-1780. Lamarche JB, Shapcott D, C M M, Lemieux B. Cardiac iron deposits in Friedreich’s ataxia. In: Lechtenberg R, ed. Handbook of Cerebellar Diseases. New York: Marcel Dekker.1993:453-458. Rotig A, deLonlayP,Chretien D, Foury F, Koenig M, Sidi D, Munnich A, Rustin P. Frataxin gene expansion causes aconitase and mitochondrial iron-sulfur protein deficiency in Friedreich ataxia. Nat Genet 1997; 17:215-217. FridovitchI.Superoxideradicalandsuperoxidedismutases.AnnuRevBiochem 1995; 64:97-112. Said G, Marion MH, Selva J, Jamet C. Hypotrophic and dying-back nerve fibers in Friedreich’s ataxia. Neurology 1986; 36: 1292-1299. Oppenheimer DR,Esiri MM. Disease of the basal ganglia, cerebellum and motor neurons. In: Adams JH, Corsellis JAN, Duchen LW, eds. Greenfield’s Neuropathology. 5th ed. London: Arnold, l992:1015-1018. Schols L, Amoiridis G, Przuntek H, Frank G, Epplen JT, Epplen C. Friedreich’s ataxia.Revisionofthephenotypeaccordingtomoleculargenetics.Brain1997; 120~2131-2140. Gellera C, Pareyson D, Castellotti B, Mazzucchelli F, Zappacosta B, Pandolfo M, Di Donato S. Very late onset Friedreich’s ataxia without cardiomyopathy is associated with limited GAA expansion in the X25 gene. Neurology 1997; 49:1153-1155. Ragno M, De Michele G, Cavalcanti F, Pianese L, Monticelli A, Curatola L, Bollettini F, CocozzaS, Caruso G, Santoro L, FillaA. Broadened Friedreich’s ataxia phenotype after gene cloning. Minimal GAA expansion causes late-onset spastic ataxia. Neurology 1997; 49:1617-1620. Hanna MC, Davis MI3, Sweeney MC, Noursadeghi M, Ellis CJ, Elliot P,Wood NW, Marsden CD. Generalized chorea in two patients harboring the Friedreich’s ataxia gene trinucleotide repeat expansion.Mov Disord 1998; 13:339-340. Harding AE. Friedreich’s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnosis criteria and intrafamilial clustering of clinical features. Brain1981;104:589-620. CosskeM,DurrA,SchmittM,Dah1N,Trouillas P, Allinson P, KostrzewaM, Nivelon-Chevallier A, Gustavson KH, Kohlschutter A, Muller U, Mandel J-L, Brice S, Labuda A, Koenig M, Cavalcanti F, Tammaro A, DeMichele G, Filla A, Cocozza M, Montennini L, Poirier J, Pandolfo M. Friedreich ataxia: point mutations and clinical presentationof compound heterozygotes. Ann Neurol 1999; 45:200-206. KostrzewaM,KlockgetherT,DamianMS,Muller U. Locusheterogeneityin Friedreich ataxia. Neurogenetics 1997; 1 :43-47. Cbristodoulou K, Deymeer F, SerdarogluP,Ozdernir C, Georgiou DM, Papadopoulou E, Zamba E, Middleton LT. Genetic heterogeneity in Friedreich’s ataxia: indication for a second locus on chromosome 9. Am J Hum Genet 1997;63:A27l. Klockgether T, Chamberlain S, Wullner U, Fetter M, Dittmann H, Petersen D, Dichgans J. Late-onset Friedreich’s ataxia. Molecular genetics, clinical neurophysiology, and magnetic resonance imagine. Arch Neurol 1993: 50:803--806.
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0, 31. De Michele G, Filla A, CavalcantiF, Di MaioL, Pianese L, Castaldo I, Calabrese
Monticelli A, VarroneS, CampanellaG, Cocozza S. Late onset Friedreich’s disease: clinical features and mapping of mutation to the FRDA locus.J Neurol Neurosurg Psychiatry 1994; 57:977-979. 32. Palau F, De Michele G, Vilchez JJ, Pandolfo M, Monros E, Cocozza S, Smeyers P, Lopez-Arlandis J,Campanella G,Di Donato S, Filla A. Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to Friedreich’s ataxia locus on chromosome 9q. Ann Neurol 1995; 37:359-362. 33. De Michele G, Perrone F, Filla A, Mirante E, Giordano M, De Placid0 S, Campanella G. Age of onset, sex, and cardiomyopathy as predictors of disability and survival in Friedreich’s disease: a retrospective study119 onpatients. Neurology 1996; 47:1260-1264. 34. Rustin P, Munnich A, Rotig A. Control of iron-induced damage to iron-sulphur proteins in Friedreich ataxia: the effect of quinones, antioxidants, and iron-chelators (abstr). 1st Conf Int CoQlO Assoc 1998:SO-51.
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Ataxia-Telangiectasia NadaJabado McGill University, Montr~al, Canada
Patrick Concannon Virginia Mason Research Center, Seattle, Washington
Richard A. Gatti
UCLA School of Medicine, Los Angeles, California
INTRODUCTION I.
164
1 1 . EPIDEMIOLOGY
164
111. MOLECULAR PATHOGENESIS
164
IV. NEUROPATHOLOGY
171
V.
CLINICAL FEATURES A.DiagnosticCriteria €3. NeurologicalFeatures C.CutaneousManifestations D.ImmuneDeficiency Malignancies E. F. OtherManifestations
VI.ANCILLARYTESTS
171 171 172 173 173 175 176 177
VD. MANAGEMENT A.GeneralMeasures €3. Vaccinations C.GeneticCounseling D. PsychologicalSupport of Families
179 179 180 181 181
VIII. CONCLUSION
181
REFERENCES
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I.
INTRODUCTIO~
Ataxia-telangiectasia (A-T) is a progressive cerebellar ataxia with onset in early childhood and an autosomal recessive patternof inheritance. It was first referred to as “the maladyof Madame CecileVogt” by two Czech physicians, Syllaba and Henner (1) who were impressedby the bilateral athetosis. Judging from their accompanying drawings of striking ocular telangiectasia, there can be little doubt that the diagnoses were correct in the four patients they described, although they did not call them telangeictasia.in 1941, another patient (“with telangiectasies”) was reported by Madame Louis-Bar (2) and the disorder bore this name for many years thereafter. In the late1950s, eight cases were carefully described and compared by Boder and Sedgwick (3,4)--with no knowledge of the two earlier reports. By 1963, these physicians had identified an additional 101 probable cases in the literature (S) and the modern era of A-T research was launched. in 1995, after a 14-year effort, the gene was isolated by positional cloning (6-8).
II. EPIDEMIOLOGY The incidence of A-T in the population has been variously estimated at between 1:40,000 and 1:400,000 live births, and the disease is found in all races(9). A-T displays autosomal recessive inheritance. Complementation studies, in which cell lines derived from different A-T patients were fused and assayed for radiationresistant DNA synthesis, suggested the existence of multiple complementation (IO), implyingalsothatmultiplegeneswouldbe groupsforthedisorder involved;however, when thegenewas finally isolated,allcomplementation groups were accounted for by mutations in the single ATM (A-TT mutated) gene (8). The carrier frequency is estimated at 0.5-l% in the general population.
111.
MOLECULARPATHOGENESIS
The ATM protein is what might be called “a hierarchical kinase,” phosphorylating more than eight different substrates; thereby, setting in motion several different signal transduction pathways that result in at least three distinct cell cycle checkpoints ( l 1-13). The ATM protein also forms partof the synaptonemal complex and plays a role in both meiotic and mitotic recombination, probably by sensing the presence of double-strand breaks (DSB) in DNA (14). DBSs occur not only during meiotic synapsis, but during V(D)J recombination of maturing lymphocytes and as a natural productof oxidative stress and free radical formation from metabolism of food. Thus, DSB are an ever-present substrate for the ATM protein. This may account for why genetic abnormalities in a single gene
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165
can lead to such a pleiotropic syndrome, and with such uniformity from patient to patient. In the absenceof ATM protein, chromosomal aberrations accumulate. To compound this problem, theATM protein also influences whether a damaged cell will undergo apoptosis (15,16,114); in its absence, some damaged cells may not apoptose and may accumulate chromosomal aberrations. These factors may also explain the increased cancer risk since damaged cells have increased malignant potential. In 1988, evidenceof genetic linkage (cosegregation) was reported between markers on the longarm of chromosome 11, and the inheritanceof A-T in a large multigeneration A-T pedigree of Amish origin (6). Subsequent pooling of linkage data from a variety of unrelated A-T families of diverse ethnic and geographic that these famiorigins increased the evidence for linkage, despite possibility the lies potentially represented a variety of different complementation groups (1719). An international consortiumof A-T researchers pursued further linkage studies, ultimately localizing a gene (or genes) to a region of 500 kb at 11q23 (7,19). All but two A-T families studied were consistent with linkage to this region (20,21). Thus, the linkage studies, involving more than 300 families, provided no evidence for genetic heterogeneity in A-T, unless there existed multiple closely spaced genes responsible for the disorder (see later discussion). Two additionaldisorders,Nijmegenbreakagesyndrome(NBS)and A-TFRESNO had been described as potential clinical variants of A-T (22,23).NBS patients lack the characteristic ataxia and telangiectasia of A-T and are microcephalic and growth retarded. However, they share many other clinical and cellular phenotypes (e.g., being radiation sensitive, immunodeficient, and prone to development of lymphoid cancers). NBS families did not show evidenceof linkage to markers in the1lq23 region, suggesting that mutations in the A-T gene were not likely to be the cause of NBS (24). Recent positional cloning studies in NBS families have resulted in the identification of a gene,NBSI, that is mutated in the majority of NBS families (25-27). A-TFRES,, patients combine allof the phenotypes of both NBS and A-T. These patients are exceptionally rare, numbering perhaps five worldwide. A-TFmsNo families display linkage to markers in the 1lq23 region (20) and, basedon mutational analyses described later, appear be to bonafide A-T patients. ,'TA thegenemutatedinallA-Tpatients,wasisolatedin1995 by a positional-cloning approach.The gene is exceptionally large, spanning more than 150 kb with 66exons (28). A transcript of 12 kb in length encodes a protein of 3056 amino acids andan observed molecular weight of approximately 370 kDa. The protein is a member of the phosphoinositol-3 kinase (Pl-3K) family of related proteins. This family includes a numberof mammalian members involved in cell cycle checkpoint control and DNA repair such as the catalytic subunitof the DNA-dependent protein kinase (DNA-PK) and the ATR kinase, as well asorthologous proteins from lower eukaryotes such as the Mei-41 protein of Dro-
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Jabado et al.
sophila and the Rad3 proteinof Schizosaccharomyces pombe (11-13,29,30). All of the proteins share the common featuresof significant size (> 2500 amino acids) anda highly conserved COOH-terminal kinase domain. Although this kinase domain shares substantial homology with that from PZ-31(, there is no evidence that any of these molecules, includingATM, can act as kinases for phosphoinositols, and all appear to act as serine-threonine protein kinases (31-33). More than 200 distinct mutations and more than 300 total mutations in the ATM gene have been described in A-T patients (8,34-41,42). For a current tally, thereader is directedtothe ATM MutationDatabase (http:Nwww. vmresearch.org/atm.htm). The reported A-T mutationsareevenlydistributed throughout the gene, affecting every coding exon. Mutations inATM the gene are found in A-T cell lines of all complementation groups and, occasionally; the same mutation has been detected in complementing cell lines (8). Thus, neither the linkage data, nor direct examination of mutations supports the existence of the previously described complementation groups A-T for (6,7,10). Itis presently unclear whether they represent a technical artifact or have biological validity. The large number of ATM mutations that have been catalogued to date reflectsthefactthatthemajority of A-Tpatientscarryuniquemutations.On screening, most patients prove to be compound heterozygotes with two distinct mutations, particularly in outbred populations, such as thatof the United States. Therefore, mutation screening, whichis arduous in a gene as large and complex as ATM,is not a viable diagnostic tool in most populations. Prenatal diagnosis is still performed primarily by haplotype segregation, except in cases for whom mutations have already been identified ina family (43). Some ethnic groups display founder effects for ATM,segregating only a limited number of ATM mutations, One well-characterized example is the Costa Rican population, in whom 98% of A-T patients (36,40,44). Other six haplotypes account for more than populations with significant founder effect mutations include Norwegians, Poles, Italians, North African Jews, Sardinians, and the British Isles (Table 1). Within these populations, it may be more practical to use mutation screening as a diagnostic tool in A-T (36). Furthermore, given concerns about possible health risks in A-T heterozygotes, the populations that allow for mutation-specific population screening may be ideal for assessing such risks (44). Initial reports suggested that the majority (90%) of A-T mutations were predicted to result in truncationof the ATM protein (34). More recent populationbased studies have suggested that the percentage of truncating mutations is probably closer to 70% (40,49). The remaining 10-30% of mutations appear to be made upof missense mutations and short deletions or insertions that maintain the readirig frame. Whereas truncating mutations are readily identifiable, mutations that potentially leave the coding region intact have proved difficult to distinguish from rare polymorphic variants (42). Therefore, this population of mutations (i.e., missense and short in-frame insertions or deletions)may be underrepresented in 70% of the mutations mutation databases; the failure to identify much more than
Ataxia-Telangiectasia
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Table 1 ATM MutationsinEthnicPopulations (%)
Frequency Mutation Ethnicity Costa Rican EA1 [B1
K1 [D1 [El [F3 Polish EA1 [B1 ECl CD1 EE1 Italian [AI [B1
[S11
[S21 United Kingdom (49) [FM1-111 [FM71 [FMIO] N Afr Jews (121) Amish Utah Mormon
E11
P1
~31 African American
D1
E21 ~31 E41 Japanese [AI
W1
5908C>T IVS63del37kb 7449G>A(de170) 4507C>T 8264de15 1120C>T IVS53-2A>C(de1159) 6095G>A(de189) 70 1OdelGT 5932G>T(de188) 5546gelT 7517de14 3576G>A 3 894insT
56 7 12 12 4 2 9 7 4.5 4.5" 4.5 20 7 Sardinia (> 95%) Sardinia (< 5%) 73
5762ins 137 7636de19 103C>T 1563delAG IVS32-12A>G 8494C>T IVS62+ 1G>A
IVS16- 1OT>G 28 10insCTAG 7327C>T 7926A>C
18b
15"
>99 >99 -
Rapid assay Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
-
Yes Yes Yes Yes __.
__
-
-
-
-
7883de15 IVS33 +2T>C
25 25
Yes -
3245ATC>TGAT 5 mutations 4 mutations
55 31
Yes -
___
Norwegian
EA1
Turkish Iranian "Also found in Mennonites. bMilder phenotype? "Widely disseminated.
55
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Jabado et al.
on A-T allelesby protein truncation testing (PTT) indicates thatthey must exist. by polyAlternatively, larger deletionsmay exist, but would be not be detectable merase chain reaction (PCR)-based assays if found in a heterozygous form. Western blotting and immunoprecipitation studies indicate that ATM exists as a 370-ma phosphoprotein in human cells (45). It is ubiquitously expressed and its levels do not appear to vary with cell cycle progression. Although most studies find that ATM is confined largely to the nucleus, some investigators report association of ATM with vesicular structures in the cytoplasm (33,46). These differences in reports of subcellular localization may reflect differences in specific cell types, states of differentiation, or the specificity of ATM antibodies used in each study. Western blotting of B-lymphoblastoid cell lines (B-LCL) and fibroblasts from A-T patients indicates that most patients (e.g.,106 out of 126 in one study) do not accumulate detectable levels (i.e., >lo% of nomal) of ATM protein (47). There areno reports of detection of truncated ATM protein in patients or no with mutations predicted to have this effect, and patients with only one truncating mutation often make no detectable ATM protein. Thus, in a situation where a diagnosis of A-T is suspected, a Western blot for ATM protein may be a helpful diagnostic tool. The capability of producing even modest amountsof ATM protein and the difference between missense and overtly truncating mutations in A-Tmay have additional prognostic implications (48). In a studyof A-T patients in the British Isles, Stankovic et al. (49) noted an association between the incidence of leukemia and lymphoma in A-T patients and the ability of their cells to produce detectable amounts of ATM. Given the increased incidence of leukemias and lymphomas in A-T patients, several studies have examined sporadic cases of such cancers, in particularT-cell prolymphocytic leukemia(T-PLL) and B-cell chronic lymphocytic leukemia (B-CLL), for mutations in the ATM gene (50-54). Exarnination of tumor tissue from sporadic T-PLL cases reveals that approximately 46% have mutations in the ATM gene. Becauseof the unavailabilityof gemline tissue samples from mostT-PLL patients and frequent lossof heterozygosity in the tumor tissue, it has been difficult to conclusively demonstrate constitutional A-T heterozygosity in these patients. However, the current data support a model in which T-PLL arises in A-T heterozygotes through loss of heterozygosity for a normal ATM allele in a clone of T-cells. Thus, in this context, ATM would appear to act as a classic tumor suppressor gene. Whereas it has been difficult to demonstrate A-T heterozygosity in T-PLL patients, two studies of B-CLL have suggested that up to 20% of these cases may be in A-T heterozygotes (5233). Of particular interest in bothT-PLL and B-CLL is the natureof the ATM mutations detected; unlike the spectrum of mutations seen in A-T patients, the mutations seen in sporadic T-PLL and B-CLL are largely (68%) missense mutations. Functional studies of the ATM protein have been hamperedby several aspects of the gene that encodes it. First, intact cDNA copies of the gene are dif-
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ficult to assemble invectors-host systems that allow long-term expression (115). Second, forced high-level expression of ATM, as would be accomplished with the types of viral promoters frequently used in eukaryotic expression vectors, appears to be toxic for many cells. These two problems have severely limited the ability of investigators to exploreATM function through in vitro mutagenesis approaches or structural studies. Nevertheless, two groups have reported complementation of the cellular phenotypes of A-T by transfection with episomal expression constructs, one of which allowed for inducible expression (55,56,116). Subfragments of the ATM gene can be more readily transfected and expressed. Morgan et al. (55) reported complementationof the A-T phenotype usinga construct that contained only the kinase domain portion of ATM. They also found that an NH,-terminal fragment of ATM, containing a putative leucine zippermoan tif, hada “dominant-negative,’ effect when expressed in normal cells, inducing A-T-like phenotype. Significant progress that provides insight into the function of ATM has protein-protein come in two areas:(a)identifying other molecules that engage in interactions withATM, and (b) defining targetsof the ATM kinase activity. Yeast two-hybrid-screening techniquesorcoimmunoprecipitationapproacheshave beenusedtodemonstrateinteractionsbetween ATM andc-Abl,p53,and P-adaptin (31-33,57). The interaction with c-Ab1 appears to be constitutive, and is mediated by an SH, domain in ATM. This interaction facilitates radiationinduced phosphorylation of c-Ab1 by ATM, but is not required for this phosphorylation step, because introduction into A-T cells of ATM expression constructscontainingthekinasedomain,butlackingthec-Abl-bindingsite,are reported to restore this phosphorylation step. Interactions with p53 have been detected at both the NH,-terminal and COOH-terminal endsof ATMby using GSTfusions with subfragmentsof ATM to “pull down” p53. As with c-Abl, p53 both interacts with ATM and is a substrate for ATM kinase activity. P-Adaptin is a component of the AP-2 adaptor complex and is involved in clathrin-mediated endocytosis (33,117).The potential for interaction between ATM and P-adaptin was by in vitro first revealed ina yeast two-hybrid screen and subsequently confirmed coimmunoprecipitation experiments and in vivo by colocalization. This finding is a functional role forATM in the cytoplasm, intriguing for two reasons: it suggests and it implicates ATM in vesicular or protein transport. Such a role might help to clarify some as yet unexplained aspects of the cellular phenotype, such as reduced responsiveness to growth factors, and impaired secretion of IgA and IgE. In addition to the interactions with specific proteins described in the foregoing, additional physical interactions with other proteins and possibly DNA are implied by studies in which meiotic chromosomes in mouse are stained with antibodies directed against Atm protein (14,58,59). Foci containing bound Atm protein are observed during zygonema and early pachynema specifically on synapsed axes. The sites of these foci seem to correspond to those observed by
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staining for Rad51 (14). However, the timingof their appearance is different. In contrast, immunochemical staining for Atm and for the related Atr protein displays mutually exclusive patterns (14). Atr foci are observed only on unpaired axes. As they begin to synapse, Atr foci are lost along the paired axes, and Atm foci appear. These results indicate a coordinated role for the function of Atm and Atr in meiosis. Atm colocalizes on the paired axes with the protein Chkl, and the binding of Chkl is dependent on the presence of Atm (59). Replication protein A (RPA) also localized spatially and temporally with Atm during meiosis (58). Direct protein-to-protein interactions between Atm and Chkl or Atm andRPA in this process have not, as yet, been demonstrated. Insightsinto ATM functionhavealsocomethroughtheidentification of proteins that serve as substrates for the ATM kinase activity in vivo and in vitro. ATM appears to autophosphorylate. In addition, there are reports indicating that it can phosphorylate c-Ab1 (5’7), p53 (31,32), Chk1(59), IKBCX (60), and RPA (58), all proteins that have been observed to either directly interact with ATM oratleastcolocalizewith ATM incells. The phosphorylation of p53 occurs at serine-l5 and can be directly assayed with an antibody specific for p53peptidecontainingphosphoserineatthisposition (3 1,32).Phosphorylation can be induced in vitro by ionizing radiation to LCLs and is apparently responsible for the stabilization and accumulation of p53 observed postirradiation. When cell lines from suspected A-T patients are available and irradiated, assaying for the phosphorylation of serine-l5 on p53 provides a useful assay of ATM function that may have diagnostic implications. What remains unclear is whether other factors can also influence postirradiation p53 serine-l5 phosphorylation. Several different mouse models have been constructed in which the Atm gene has been inactivated by the insertion of transgenes (i.e., Atm-knockout mice) (16,61-63). In all cases, the resulting nxice have undetectable levelsof Atrn protein. The mice recapitulate many of the features of A-T in humans, including radiationsensitivity,immunodeficiency,poorcellularproliferativeresponses, features of premature aging, and a strong predisposition to develop lymphoid malignancies. The mice do not develop overt ataxia, although rotarod tests and open field tests suggest modest defects in balance and gait, respectively (61,63). However, loss of cerebellar Purkinje cells-a hallmark of A-T-is not generally observed in Atm-knockout mice. Electron microscopy of Purkinje cells in one knockout mouse strain did reveal some evidence of subcellular defects in these cells, but this did not correlate with any cell loss (64). Several of the phenotypesof Atm-knockout mice are consistently enhanced over what is observed in A-T patients. For example, almost all mice develop fatal thymomas in thefirst 8-12 weeks of life, whereas only about3 0 4 0 % of A-T patients develop some kind of lymphoid malignancy (65). Atm-knockout mice are
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uniformly sterile owing to defects in meiosis. Although no patients with classical A-T have been reported to have offspring, production of sperm or eggs is not impaired in all patients and secondary sexual characteristics develop in most male and female A-T patients.
IV. NEUROPATHOLOGY The cerebellum is grossly atrophic, predominantly throughout the vermis and less in the lobules (5,64,66-68). The atrophy of the cerebellar cortex reflects marked thinning of the molecular layer, diminution in the number of Purkinje cells, and thinning of the underlying internal granule layer. Silver staining of Purkinje cells shows abnormal arborization, with torpedo formations and swelling or unusual stellate structures within the cells (69,70). Ectopic Pukinje cells are also found in the molecular layer of the Cerebellum, a lesion that would have to occur in midpregnancy (69). In older patients, “empty” basket cells in the cortexprovide proof of in situ degeneration of Purkinjecells,theirnumber diminishingwithage.Despitethesefindings,itremainsunclearwhetherthe loss of Purkinje cells represents the central neuropathology of A-T or occurs by either anteriograde or retrograde deterioration. This becomes a crucial issue when attempting to design new therapeutic approaches, such as neural stem cell engraftment.
V.
CLINICAL FEATURES
A.
DignosticCriteria
Ataxia-telangiectasia is a multisystem disease characterized by cerebellar ataxia, ,oculocutaneous telangiectasia, a high incidence of neoplasia, radiosensitivity, recurrent sinopulmonary infections, and a variable immunodeficiency state involving the humoral and cellular immune systems (5,71-73,76). The minimal diagnostic criteria fora definitive diagnosisof A-Tare progressive cerebellar ataxia, with disabling mutationsin both allelesof the ATM gene, or a prior affected sib. A probable diagnosis can be based on progressive cerebellar ataxia, ocular apraxia, elevated alpha-fetoprotein (AFP), 7; l 4 translocations, radiosensitivity, and immunodeficiency. A possible diagnosis might include mild cerebellar ataxia, no ocular apraxia, normalAFP, normal immunoglobulins, no telangiectasia, normal speech, no ’7;14 translocations, and in vitro radiosensitivity. Criteria for exlusion include microcephaly, severe mental retardation, and nonprogressive ataxia. Very infrequently, a patient with microcephaly and mental retardation may have A-TFresno, a syndrome that encompasses symptoms of both A-T and NBS (22,23).
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NeurologicalFeatures
Neurological symptoms are usually the presenting problem of patients with A-T. Cerebellar ataxia is the clinical hallmark of the disease and usually the first sympat years tom to appear. It is presentall incases and usually becomes apparent 2-4 A staggering gait causedby a predominantly of age, after the child learns to walk. truncal ataxia is first noted and insidiously becomes associated with other manifestations of cerebellar dysfunction, suchas dysarthria, muscular hypotonia, slow voluntary movements, hypotonic facies and posture, and drooling. Other cerebellar signs, including dysmetria or intention tremormay appear later in the course of the disease. Cerebellar degeneration progresses steadily with age until adulthood. Typically, patients need a wheelchair by the age of 10 years. They have speech and writing problems that impair their social life and school work (71). Extrapyramidal features are also frequently observed in patients with A-T. Choreoathetosis occurs in about 90% of patients and, when severe, can initially mask the presence of ataxia (5). This feature, noted in the first report of Syllaba and Henner (l),provides a disturbing reminder thatnot all neurological symptoms in as the central lesion. Dystonia also is found, mostly A-T implicate the cerebellum in adolescents and adults. all patientswithA-Tand Oculomotorsignsarepresentinvirtually precedetheappearance of telangiectasia.Thus,theyprovide an important diagnostic criterion (74). The apraxia steadily progresses and may eventually simulate ophthalmoplegia. When the head is fixed, voluntary eye movements are initiated slowly and are frequently interrupted but, in contrast to ophthalmoplegia,canbecompletedsuccessfully if givensufficienttime.Whenthe head is suddenly turned toward a target, the eyes first deviate tonically in the oppositedirectionandthenslowlyfollowthedirection of thehead. Eye as when movements are smooth and full in range on involuntary movement, the head is moved passively from side to side. Abnormalities of conjugate gaze areseenonlyonvoluntarymovement.Optokineticnystagmus is absent. OculomotorsignsinA-Tareunusualinthattheycombinefeatures of cerebellarandextrapyramidaldisorders. The progression of thesesigns also makesitmoreandmoredifficultforthepatienttoread small print.When preparing study cards for school, it is best to place only a few words in the center of each card in large print, thereby minimizing the need to initially scan the card for content. Most younger patients with A-T have normal muscle strength and deep of the disease retendon reflexes. Beyond adolescence, the neurological features as semble those of a spinocerebellar degeneration with peripheral neuropathy well as variable loss of vibratory and position sense. A significant portion of older patients develop progressive spinal muscular atrophy affecting mostly hands and feet. Because flexor muscles are normally stronger than extensor muscles, con-
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tracturesformasallmusclesatrophy.Thesecanbeprevented by aggressive physical exercise (i.e., they do not appear in physically active patients.) MostpatientswithA-Thavenormalcognitivedevelopment.Their IQ scores are within normal.Some patients in their20s or 30s have an unexpectedly severe loss of short-term memory, which is suggestive of premature aging (73). The presence of mental retardation should challenge a diagnosis of A-T.
C. CutaneousManifestations Telangiectasias are the second hallmark of the disease and are eventually noted in almost all patients. They consist of dilated venules, which appear between ages 2 and 8. The most commonly affected area is the conjunctiva, where they first appear in the angleof the eye and then spread toward the border of the cornea (Fig. 1).With time, they cover the entire conjunctiva bilaterally. They can also be found on the external earlobe, the eyelid, the flexure folds of the neck, the anticubital and popliteal spaces, and, less frequently, on the extremities and palate-or on the even over the entire body. Telangiectasias may reflect progeric changes. Other cutaneous abnormalities, whichmay also reflect progeric changes, include gray hair, vitiligo, cafk-au-lait spots, and sclerodermoid changes of the skin, especially obvious on the face. Seborrheic dermatitis of the scalp, hirsutismof the r n s and legs in both sexes, and senile keratosis or basal cell carcinomas have also been reported. All those manifestations are progressive with age (75).
D. ImmuneDeficiency Immunodeficiency is present in approximately 60% of the children with A-T and involves both humoral and cellular responses. The severity is variable and, inter-
Figure 1 Telangiectasia on the conjuntiva of an 8-year-old patient with A-T.
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estingly, even affected siblings bearing the same mutation may vary in the severity of the immunodeficiency (71,113). Conversely,30% of A-T patients have no discernible immunodeficiency (76). Thus, the absence of immunological abnormalities does not preclude a diagnosis of A-T. Clinical manifestations are characterized by recurrent sinopulmonary infections, a feature of A-T that was noted even in the early reports (4). These infections are mostly reminiscent of humoral immune deficiencies. They begin as multiple discrete episodes and become chronic and persistent in one-third of the patients, leading to pulmonary fibrosis and insufficiency.The unremitting course is similar to what is observed in patients with cystic fibrosis. Infections remain the first causeof death in patients with A-T, despite early treatments and the wide use of antibiotics and polyvalent standard immunoglobulin (Ig) preparations. The bacteria associated with infections are frequently extracellular high-grade pathogens, such as Staphylococcus, Streptococcus, and Haemophilus species. Opportunistic infections arenot characteristic of A-T, unlike with other primary immunodeficiencies. The severity of the neurological manifestations is not directly associated with the severity of the infections. Despite this, children with A-T have major coordination problems and this may affect their ability to cough effectively. Swallowing problems with saliva stagnation and chronic aspiration often lead to pneumonia, and this situation is cumulative and progressive.No specific treatmentisavailable to improvetheseaggravatingfactors,although steroids often minimize the pulmonary fibrosis that ensues. Sinopulmonary infections, therefore, should be treated early and aggressively in order to avoid or delay irreversible pulmonary damage. Clubbing of the fingers, similar to that which is associated with cardiopulmonary insufficiency, has been observed in Costa Rican and Italian patients (75,77). Autoimmune manifestations are also reported in patients with A-T. They mainly concern the hematopoietic lineages, with peripheral thrombopenia and hemolytic anemia.The role of autoimmunity in the pathogenesis of A-T has been considered periodically (78,79); however, it seems unlikely that autoimmunity to plays a significant role in the central neurological pathology, which begins manifest itself well before the immune system matures. However, it is possible that autoimmunity may play a role in the degenerative phaseof A-T. Hemolytic autoimmune manifestations can be severe. They are responsive to high-dose corticosteroids and sometimes also require immunosuppressive agents; however, the latter are difficult to manage in the presence of immunodeficiency and chronic lung disease. One of the most striking and consistent pathological features of A-T is that the thymus is small or absent, and lacks corticomedullary architecture and Hassall’s corpuscles; it is embryonic in appearance (79). A progressive T-cell lymphopenia is commonly noted by immunophenotyping, with an occasionally observed increase in the proportionof yS T-cell receptor-expressing cells. Striking
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increases in the NK cell proportions have been reported in some studies; however, confusingly, not in others (75,80). Patients with A-T respond appropriately to challenge witha variety of antigens, although IgG responses to polysaccharide antigens are impaired in almost all patients (81,82). Cellular responses to viral antigen immunization and the antibody responses following infections with viruses are generally poor. Patients show impaired T-cell responsiveness to a battery of “skin test” antigens in 85% of cases. Disorders of antibody responses are associated with low B-lymphocyte counts and abnormalitiesof immunoglobulin levels. Eighty percent have low molecular weight monomeric(8s)IgM in their serum. Most patientsalso have a reduced serum concentrationof the IgG2 and IgG4 subclasses, whichmay partially account for the encapsulated bacteria encountered in sinopulmonary infections. Seventy percentof patients havean extreme deficiency or absence of IgE, as well as of serum and secretory IgA. These abnormalities are thoughtto result from a defect in immunoglobulin synthesis becauseof defective terminal maturation of B cells into IgA- or IgE-producing plasma cells. This may be due to either inefficient V(D)J gene rearrangements to or T-cell control of immunoglobulin class switching, or a combination of both. Antibodies produced against IgA havealso been observed in some patients; this rnay further account for the low or absent serum IgA levels (71,78,79) and should serve to caution against the administration of immunoglobulin preprations containing IgA (more information later).
E. Malignancies Malignancy isa frequent occurrence in patients with A-T (5,65,11 8). One in three A-T patients will develop a malignancy at some time during their lives. Before the age of 20 years, 85% of cancers are lymphoid, either leukemia or lymphoma. After the age of 20 years, solid tumors are more frequent, consisting mainly of epithelial carcinomas. Cancer is the second most common causeof death in patients with A-T (66,83,84). An occasional A-T patientrnay present first with cancer, beforea diagnosis of A-T is suspected.If such a child were treated with conventional doses of radiation, the outcome would most probably prove fatal. For a diagnosis of A-T inaZE cancer this reason, pediatric oncologists should consider patients younger than 5 years of age-before radiotherapy is administered. In A-T patients, there isa 70-fold and 250-fold increased incidenceof leukemia and lymphoma, respectively (65). T-cell malignancies predominate over B-cell malignancies (49,83,84). Acute T-cell leukemias andT-cell lymphomas are frequently observed. In older A-T patients, chronic T-cell prolymphocytic leukemia (T-PLL) accounts for 10% of the T-cell malignancies-even though it is extremely rare in the general population. Recent studies have demonstrated that two-thirds of patients withT-PLL who do not have A-T have at least one inactive
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ATM gene (50-52). Similar results have been reported for patients with B-cell chronic lymphoblastic leukemia (B-CLL); however, in this case there is more convincing evidence that as many as 20% of B-CLL patients may be ATM heterozygotes (5334). Loss of heterozygosity in the region of the ATM gene has also been associated with ovarian cancer. These findings suggest a tumor suppressor role in leukemogenesis for theATM gene product (as discussed earlier). TCL-1 also plays a role in the development of T-PLL, in A-T patients and in non-A-T patients with clonal proliferations or leukemia (85,86), apparently involving chromosomal inversions at 14q12 and 14q32. B-cell malignancies are mostly seen in older children and consistof acute B-cell leukemia and lymphoma. They do not demonstrate any cytogenetic or clinical specificity as compared with B-cell malignancies in the general population. Hodgkin’s disease is responsible for5% of lymphoid malignancies in A-T. Interestingly, there are no published reportsof myeloid malignancies in patients with A-T. This is compatible with the cytogenetic observation that chromosomal aberrations in A-T lymphocytes are nonrandom, whereas in fibroblasts they appear tobe random (87). Translocations involving chromosomes7 and 14 are seen in about 5-l0% of peripheral blood lymphocytes of A-T patients after stimulation with phytohemagglutinin(88,89). Most epithelial neoplasms in A-T patients involve stomach, brain, parotid gland, ovaries, skin, liver, or breast. Their frequencies are only slightly different from those of the general population. Are A-T carriers predisposed to cancer? This highly debated question has been the subject of multiple investigations. Swift and associates reported a increased risk of breast cancer in A-T heterozygotes (90-92). Results from other groups do not generally confirm this increased risk (93-98). As discussed earlier, when ATM mutations are found in cancer patients, they tendbetoprimarily nontruncating mutations, in contrast with thoseof A-T patients who show primarily truncatingmutations (99-101). Alternatively,certain ATM mutations may be more likely to confer cancer risk than others, based not only on the type of mutation, but also on the position and the effect of the mutation on the protein. For example, when the Norwegian “Rendal ‘Valley”ATM mutation was sought in about 800 Scandinavian breast cancer patients [because it accounts for 55% of theNorwegianA-Tmutations(102)],itsfrequency was notincreasedover normal-despite that two of the Norwegian A-T families with this mutation included women with breast cancer (A-L Borresen-Dale, personal communication). On the other hand, a recent analysis of loss of heterogeneity patterns in 918 breast cancer patients suggests that one or more genes in thellq23.1 region are associated with breast cancer survival (103).
F. OtherManifestations More than 50% of French patients with A-T manifest glucose intolerance associated with insulin resistance and hyperglycemia (N Jabado, unpublished obser-
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vations). Growth retardation is present in many of these children. By adolescence, their weight and height have dropped below the third percentile, especially in patients with chronic sinopulmonary manifestations. Patients who attain puberty are likely to achieve growth within noma1 range ('71). Female patients with A-T often have delayed menstruation, with equally delayed development of secondary sexual characteristics. The ovaries are sometimes absent or hypoplastic and females with A-T may be sterile. In male patients, hypogonadismis frequent and these patientsmay also be sterile. However, many male patients ejaculate and at least those few who have been studied produced sperm. Atm-knockout mice are anovulatory and aspermic, respectively. Despite this, many American and British patients have normal growth and fully developed secondary sex characteristics. One patient who was homozygous for an ATM missense mutation had a very mild phenotype, walking unassisted at50 years of age; she also conceived a child (49). The increased incidence of breast cancer in this family also supports the hypothesis that the phenotypes of missense and nonsense mutations may be quite distinct. as alkalinephosMildliver-associatedlaboratoryabnormalities,such phatase and serum transaminase levels, are elevated in about half of children with A-T. Fatty infiltration and portal round cell infiltration have been observed in some liver biopsies ('71). However, these manifestations are not diagnostic, or life-threatening, and they do not require any specific treatment. Thus, a liver biopsy is seldom justifiable for diagnosis or follow-up care of patients with A-T. Neither do these changes explain the elevated AFP.
VI. ANCILLARY TESTS The clinical diagnosis of A-T is unequivocal if a child presents with an earlyonset cerebellar ataxia and oculocutaneous telangiectasia, but this is seldom the case because the telangiectasia usually does not appear for 1-3 years after the onset of the ataxia. Elevated levels of AFP are present in 90% of patients with A-T (71,104). Other diagnostic findings include cerebellar atrophy on magnetic resonance imaging (MRI), chromosomal instability specifically involving chromosomes 7 and 14, radiosensitivity testing, and lastly, characterization of mutations in theATM gene. Some patients have dysgammaglobulinernia or even gammopathies with lymphopenia (21). More recently, it has become clear that the level of ATM protein is either absent or markedly reduced in A-T cells. However, because the resting level of ATM protein is low, even in normal peripheral blood lymphocytes, it is not yet possible to use protein expression as a diagnostic tool. When cell lines were established on 126 A-T patients, 85% had no detectable ATM protein by Western blotting, and all but four(3%) of the remaining patients had clearly reduced levATM protein levels, els of the protein(4'7). Nonetheless, four patients had normal
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N 1231 Range 28-83% SD 13%
Figure 2 CSA (colony survival assay) for radiosensitivity. See Ref. details.
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despite having a classic A-T phenotype; these were not clinical variants. These patients probably make a protein that is stable but nonfunctional and this is under study. Radiosensitivity (RS) testing is available in a few A-T research laboratories. Most of these laboratories test fibroblasts. This requires a skin biopsy, and A-T fibroblasts grow very slowly. One laboratory (RA Gatti, unpublished data) uses 10 rnL of heparinized blood to establish anLCL and performs a clonogenic colony survival assay on these cells (Fig. 2) (105). The assay has a turnaround
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time of several months. On the other hand, in difficult diagnostic situations, the presence of RS confirms a diagnosis of A-T; normal levels of RS argue strongly against the diagnosis. Approximately 4% of patients have intermediateRS levels. These have been mostly very young patients who may not have developed a full A-Tsyndrome.Alternatively,they may be A-Tvariants,ornotA-Tatall (48,119,120).
VII.
MANAGEMENT
A.
GeneralMeasures
There is no curative or preventive treatment for the neurological degeneration of A-T. There is also no specific treatment to halt or slow its progression. However, supportive care is very effective and is mandatory to improve the qualityof life of patients. Physical therapy is an essential aspect of the treatment of patients with AT. It shouldbe initiated early in the course of the diseaseto prolong the autonomy and physical activities of the child. It should be highly individualized, adapted to the needsof each child, and customized in accordance with the degree of handicap for that child at that time in the course of the disease.The goal should be to maintain the highest level of autonomy at each stage of the neurological disease. This can be achieved through active postural physical therapy, prevention of contractures, and maintenance of muscular tone. Also, the patient needs to receive advice about which physical activities are easiest for them (such as swimming and horseback riding) to avoid the frustration of repeated failures to achieve a given task, Appropriate decisions must be made to introduce orthesis or a wheelchair when needed. Physical therapy can be provided on an outpatient basis. Drugsshouldbeprescribedon an individualbasis(106).Theyconsist mainly of muscle relaxants for the treatment of contractures and specific drugs forextrapyramidalmanifestations,whichdiminishinefficiencywithtime. Drooling can be diminished by certain medications or by ligating the salivary ducts. Some medications may even relieve the ataxia slightly; however, the effects are always short-lived. Treatment of infections should be administered early in the course of an infection and maintained on a long-term basis to prevent chronic irreversible lung damage. Wide-spectrum antibiotics can be administered orally or intravenously. On the other hand, most well-nourished A-T patients do not require or benefit from prophylactic antibiotics or immunotherapy. In patients with recurring infections, treatment with standard IgG preparations, given either intravenously or subcutaneously, should be started at the onset of sinopulmonary manifestations and administered regularly to achieve and maintain IgG levels above 8 g L . In about 30% of patients, standard immunoglobulin preparations are poorly toler-
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ated owing to the presence of anti-IgA antibodies. A switch to IgG preparations with low or absent levels of IgA is then necessary. Additionally, a longer infusion time and the use of antihistaminic drugs or small doses of corticosteroids at every infusion may improve clinical tolerance. Physical therapy is essential in the treatment of bronchopulmonary infections in A-T patients. It should be realized that the neurological degeneration in these patients may include dysregulation of cough, swallowing problems, and poorcoordination of evenreflexmovements.Furthermore,physicaltherapy should not beconfused by healthcareadministratorswith“rehabilitation therapy.” Although the two terms are sometimes used interchangeably and the care is often provided by the same personnel, physical therapy attempts to improve health status and outcome, whereas rehabilitation therapy aims at returning a patient to a functional life. The latter is usually not relevant to the care of an A-T patient. Because of the few patients and the variety of cancers observed, no one center sees enough patientsto formulate a consensus experience on the treatment of malignancies in A-T. Radiation therapy withconventional doses results in destruction of normal tissue and unacceptable toxicity levels. Conventional chemotherapy includes agents that interfere with DNA repair and may also result in increased toxicity in A-T patients if given at full dose. Topoisomerase inhibitors should probably be avoided. Two different lines of treatment are presently considered as reasonable compromises: (a)The administration of a highly individualized chemotherapy, with systematic reductionof doses and exclusion of radiotherapy, have achieved favorable results and even cures in some patients (10’7). (b) Alternatively, the administration of standard dose chemotherapy has also been proposed. A recent report on the treatmentof lymphoid malignancies with standard chemotherapy described 16 complete remissions in 21 A-T patients (108). However, only2 patients remain alive and disease free, the rest died from pulmonary infections, recurrence of cancer, or other causes, A high incidenceof hemorrhagic cystitis was also reported in7 of 14 A-T patients treated with full-dose cyclophosphamide. To aid in the accrual of further experience with treating malignancies in A-T patients, anew center is being established at St. Jude’s Hospital in Memphis, Tennessee. Consultations should be sought before initiating chemotherapy.
B. Vaccinations A long-standing recommendation for patients with immunodeficiency diseases has been to avoid live vaccines. However, these have inadvertently been administered to many A-T patients, usually before a diagnosis was established. There have been no serious sequelae observed. A particularly important situation involves varicella, which can cause severe illness in A-T patients. Data from sev-
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era1 large A-T centers argue strongly in favorof giving varicella vaccinations to A-T children who do not have severe immunodeficiency. Thus, a thorough immunological evaluation should first be completed before this decision is undertaken.
C.GeneticCounseling With recent molecular advances, genetic counseling has become an important feature in the careof patients and families withA-T. The localization of the gene made prenatal diagnosis possible for young families(43). Determination of carrier status of parents and siblings can be achieved by genetic haplotyping. Despite this, there is still no reliable test for identifying heterozygotes in the general population (109-112). Furthermore, from the foregoing discussion it is clear that the extent of cancer risk or clinical radiation sensitivity for A-T carriers remains a research question, and it is probably bestnot to burden members of A-T families prematurely until ongoing studies have been conclusively completed, especially for breast cancer and possible adverse reactions to radiation or radiotherapy. Mammography is presently recommended in accordance with routine schedules, even for A-T carriers. c).
PsychologicalSupport of Families
Psychological support is essential for any chronic disease.It should be offeredby all health care centers, beginning with the physician primarily in charge of the patient. A psychotherapist can counsel the family and unaffected siblings on their relationships toward the affected child and to one another. Family Internet “chat groups” also offer great comfort and insights about caring forA-T patients. Unfortunately, if such interactions are not monitored by a professional, inaccurate information is frequently passed between families. An annual check-up is essential. Admission to a chronic care facility should be avoided unless it becomes unavoidable. It is always best to maintain the patient in a home environment with the aid of home care. On the other hand,many U. S. children have moved outof their childhood home to become more autonomous. With a government stipend for the handicapped, independent living becomes possible.
Vlll.
CONCLUSION
Where is A-T therapy going? It is hoped that recent advances in neural stem cell engraftment will allow the replacement of degenerated cell lineages within the cerebellum and basal ganglia. However, before this can become a reality, we need
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to better understand the site of the underlying neurological lesion(s). We also need to better understand whether the type(s) of cells that need replenishment are available in the laboratory and whether their implantation can be achieved with safety and with longlasting effects. One hopes that during this same period of investigation, functional and structural analyses of the ATM protein will identify new pharmacological agents.
REFERENCES 1. Syllaba L, Heiiner K. Contribution a l’independance de l’athetose double idiopathique et congenitale. Rev Neurol 1926; 1541-562. 2. Louis-Bar D. Sur un syndrome progressif comprenant des tt5langiectasies capillaires cutanees et conjonctivales symetriques, a disposition naevoide et de troubles cerebelleux. Confin Neurol (Basel) 1941; 4:32-42. 3. Boder E. Sedgwick RP. Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculcutaneous telangiectasia and frequent pulmonary infection. A preliminary report on seven children. an autopsy and a case history. Univ South California Med Bull 1957: 9:15. 4. Boder E, Sedgwick RP. Ataxia-telangiectasia: a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics 1958: 21:536-554. 5. Boder E, Sedgwick RP. Ataxia-telangiectasia: a review of 101 cases. In Walsh G, ed: Little Club Clinics in Developmental Medicine, No. 8. Lotidon. Heinetnann Medical Books. 1963, pp 110-1 18. 6. Gatti RA, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, Ersoy E Foroud T. Jaspers NGJ, Lange K. Lathrop GM. Leppert M, Nakamura Y, O’Connell P, Paterson M. Salser W, Sanal 0. Silver J, Sparkes RS, Susi E. Weeks DE, Wei S. White R. Yoder F. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature 1988; 336:577-580. 7. Lange E. Borresen A-L, Chen X, Chessa L, Chiplunkar S, Concannon, Dandekar S, Gerken S, Lange K, Liang T, McConville C. Polakow J. Porras 0. Rotnian G. Sanal 0, Sheikhavandi S, Shiloh Y, Sobel E, Taylor M, Telatar M, Teraoka S, Tolun A, Udar N, Uhrhammer N. Vanagaite L, Wang Z, Wapelhorst B, Yang H-M, Yang L, Ziv Y. Gatti RA. Localization of an ataxia-telangiectasia gene to a -500 kb interval on chromosome 1 lq23.1: linkage analysis of 176 families in an international consortium. Ainer J Hum Genet 57: 1 12-1 19, 1995. 8. Savitsky K. Bar-Shira A, Gilad S . Rotman G, Ziv Y, Vanagaite L. Tagle DA, Sniith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA. Sartiel A, Gatti RA, Chessa L, Sanal 0, Lavin MF, Jaspers NGJ, Taylor MR, Arlett CF, Miki T, Weissmati SM, Lovett M. Collins FS, Shiloh Y. A single ataxia-telangiectasia gene with a product similar to PI-3 kinase. Science 1995; 26811749-1753. 9. Swift M, Morrell D, Croniartie E. Chamberlin. AR, Skolnick MH, Bishop DT. The
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Early-Onset Cerebellar Ataxia with Retained Tendon Reflexes Alessandro Filla and Giuseppe De Michele Federico II Universit~Naples, Italy
I, INTRODUCTION
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11. EPIDEMIOLOGY
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111. MOLECULAR PATHOGENESIS
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IV. NEUROPATHOLOGY
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V. VI.
CLINICAL FEATURES
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ANCILLARY TESTS
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VI1. DIFFERENTIAL DIAGNOSIS VIII. MANAGEMENT REFERENCES
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INTRODUCTION
Friedreich was the first to recognize a hereditary formof ataxia. He gave an accurate clinical and pathological description of nine patients in three papers between 1863 and 1877. After Erb's paper on tendon reflexes in 1875 (l), he reported absence of lower limb tendon reflexes in his last paper (2). In 1893, Marie collected from the literature four heterogeneous families affected by a form of 191
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hereditary ataxia clinically distinct from that described by Friedreich (3). Onset age was variable, tendon reflexes increased, and eye movements frequently abnormal. In two families, those reported by Fraser (4) and Nonne (5),onset occurred by the age of 20 years and heredity was recessive, whereas in the other two, reported by Brown (6), and Klippel and Durante(7),onset was after age 20 years and heredity was dominant. Since then, the eponym “Marie’s hereditary ataxia” was used widely to indicate hereditary formsof ataxia, either recessiveor dominant, with variable-onset age, retained or exaggerated tendon reflexes, and usually some degree of spasticity. However, because the families reported by Marie were clinically, genetically, and pathologically heterogeneous, this term was criticized by Holmes (8) and Greenfield (9) and its use is no longer recom( 3 , cases of mended (10). Besides the families reported by Fraser (4) and Nonne early-onset autosomal recessive ataxias with retained knee jerks have also been described by Hodge (1l), Sinkler (12), Harris (13), Soderbergh (14), Fickler (15), and Hogan and Bauman (16). Additional features were present in some patients, such as mental deficiency (5, 15), optic atrophy (4, 5), and wasting of the small hand muscles (11). In 198 1, Warding described a personal series of 20 patients with progressive cerebellar ataxia, developing in thefirst two decades, associated with dysarthria, pyramidal weakness, and retainedor increased knee jerks(17). Inheritance was consistent with an autosomal recessive transmission of the disease. Other important differences with Friedreich’s ataxia were absenceof cardiomyopathy, better prognosis. optic atrophy, diabetes mellitus, severe skeletal deformity, aand She proposed the name of early-onset cerebellar ataxia with retained tendon reflexes (EOCA) for this entity. EOCA patients are clinically and genetically heterogeneous (18,19). The molecular genetic advances led to a definite classification for onlya small percentageof these patients. Therefore, this clinical category remains still useful. We hope that molecular genetics will provide a better classification, as it has already happened for other forms of hereditary ataxias.
111.
EPIDEMIOLOGY
Early-onsetcerebellarataxiarepresents 9% of allhereditaryataxiapatients in a personal series and runs the second position after Friedreich’s ataxia among the early-onset forms, accounting for 18% of them. The ratio of EOCA families to those with Friedreich’s ataxia is 1:4. This ratio is probably underestimated,because of a referralbiasthatfavorsFriedreich’sataxia.Indeed,the few epidemiological studies available in Europe give prevalence ratios ranging to 1.5 X (20-22), whichisabout half that of Friedreich’s from0.8 X ataxia.
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Ill. ~ O L E C ~ L APATHOGENESIS R Fourout of the five studiesavailableinliteratureonEOCAreportedhigh consanguinityrate(15-40%),suggesting an autosomalrecessiveinheritance (17-19,23,24). Three of them reported the segregation ratio (0.1 1-0.16), which was below that expected in an autosomal recessive disorder(17-19). This finding together with the predominance of males in four studies (17-19,23) suggested that some forms may be X-linked, new dominant mutations, or nongenetic phenocopies. We reviewed a personal series of 43 EOCA patients from 38 families, and we found consanguinity in24% of marriages and a segregation ratioof 0.25, which are clearly consistentwith an autosomal recessive disorder (unpublished). The distribution of onset ages was different from the normal one and onset (18). These findings favored the hypothages significantly varied among families esis of genetic heterogeneity within EOCA. The molecular advancestheinrecent years achieved a better classification of hereditary ataxias, but yielded limited success on solving the EOCA heterogeneity. An infantile-onset spinocerebellar ataxia (IOSCA), which comprises besides ataxia, epilepsy, athetosis, optic atrophy, ophthalmoplegia, hearing loss, sensory neuropathy, and hypogonadism in females, has been mapped to 10q23.3-24.1 in few Finnish families (26). Autosomal recessive spastic ataxiaof Charlevoix-Saguenay (ARSACS) is characterized by onset in childhood, ataxia, marked spasticity, distal amyotrophy, and prominent nerve fiber layer in the optic fundi. More than 300 patients have been described in Northeastern Quebec.The ARSACS locus has been localized in chroa mosome region 13q11, close to the y-sarcoglican gene (27). Unfortunately, molecular classification is not possible for the remaining EOCA patients.
IV. ~E~ROPATHOLOGY Three postmortem examinations are available.Two were performed more thana century ago and one at the beginning of this century. The autopsy of one of the two patients reported by Fraser (4) showed a small cerebellum. The cerebellar cortex was half the normal thickness with fewer Purkinje cells. The spinal cord was normal. The autopsyof one among the three patients reportedby Nonne (5) showed small brain with cerebellum and brain stem disproportionately small. The cerebellum did not show any microscopical abnormality, and it was describedas a “cerebellum in miniature.” The spinal cord was also small, but appeared otherwise normal. The autopsy of one of the two patients reported by Fickler (15) showed atrophy of the cerebellum, affecting mainly the hemispheres, and more upper than lower surface. Microscopy showed lossof Purkinje cells, thinning of granular layer, atrophyof the dentate nucleus, thinned nuclei of the pons, and loss
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of transverse fibers. In the medulla olives were small. No tract degeneration was observed in the spinal cord.
V.
CLINICALFEATURES
Besides early-onset (within 25 years) progressive ataxia, the diagnostic criteria for EOCA are retained knee jerksand exclusion of a known etiology (metabolic or defective DNA repair), or associated features suchas hypogonadism and myoclonus. In our personal series, half of the patients present as sporadic cases and half have an affected sib. Mean onset age2r: SD is 10.4 +- 8.1 years (range 2-25). The frequency distribution of onset age is not normal (Fig. 1). Gait ataxia is usually the first symptom, but rarely, the disease might manifest with dysarthria, intention tremor, lowerlimb weakness, or clumsiness. The overall clinical
45 40 35 30
rje c
25
Q)
g E LA
20 15
10 5 0
1-4
5-8
9-12
7 3-16
17-20
21-24
Onset age (years) Figure 1 Frequency distribution of onset age in 43 EOCA patients.
>24
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picture is that of a cerebellar syndrome, associated with signs of corticospinal impairment (extensor plantar response or brisk tendon jerks associated with increased tone) in two-thirds of the patients. Both cerebellar and corticospinal signs more severely affect lower than upper limbs. Clinical signs of peripheral neuropathy (decreased vibration sense and decreased or absent ankle jerks) are present in one-third of the patients. The clinical features are summarized in theTable 1.Gait and stance ataxia is constant. Dysarthria isvery frequent. It is usuallymild to moderate and exceptionally leads to explosive voice. Nystagmus affects three-fourths of the patients. Jerky smooth pursuit is present in almost all. Saccades are usually dysmetric, with normal velocity. Gaze paralysis is absent. Dysphagia, usually for liquids, affects one-third of the patients. Knee jerks and tone are increased in about half of the patients. Ankle jerks are brisk in one-third, and weak or absent in another third, Thus, the association Table 1 PercentageOccurrence of Clinical Findings in 43 EOCA Patients
Mean age at onset tr: SD (yr) Mean disease duration tr: SD (yr)
10.4 Ict 8.1 17.4 +- 9.8 %
Dysarthria Nystagmus Jerky smooth-pursuit Knee jerks Brisk Normal Weak Ankle jerks Clonus Brisk Normal Weak Absent Tonus Increased Normal Decreased Lower limb weakness Extensor plantar response Lower limb decreased vibration sense Scoliosis Pes cavus
90 72 94 62 20 18 8 28 31 8 25 53 14 33 51 36 68 67 61
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of brisk knee jerks and absent ankle jerksmay occur. About half of the patients show proximal weakness at the lower limbs and one-third have extensor plantar response. Two-thirds of the patients have decreased vibration sense at external malleolus, slight scoliosis, and pes cavus. Urinary symptoms, the most common being urgency, nonprogressive mentaldeficiency, and slight distal amyotrophymay occur. Very few patients might present head titubation, epilepsy, psychosis, hypoacusia, dystonia, and perioral fasciculations. No patient has diabetes or echocardiographic findings of hypertrophic cardiomyopathy. Progression is usuallyslow. Klockgether et al. calculated a median time to wheelchair of 22 years from disease onset(28). Chib et al. reported death rate four times higher inEOCA than in the general population and77% survival rate after 20 years from onset (29).
VI. ANCILLARY TESTS Neurophysiological investigations show peripheral neuropathy in 50% of the patients. The abnormalities consist of a severe amplitude reduction of the sensory potentials, with a slight slowing of sensory and motor conduction. These findings are consistent with a mainly sensory axonal neuropathy. The presence of periph(30). The pathologieral neuropathy is not related to disease duration and severity cal findingsof the sural nerve biopsy are consistent with neurophysiology and vary from normality to a marked loss of large myelinated fibers, with unimodal dis-
Figure 2 Semithin transverse section of the sural nerve showing marked loss of large myelinated fibers in a 19-year-old EOCA patient (left), compared with a control (right). Bar = 30 pm. Toluidine blue stainX 360. (Courtesy of F Barbieri and the Department of Neurological Sciences, Federico I1 University, Naples, Italy)
Early-Onset Cerebellar Ataxia
Figure 3 T1-weighted axial (left) and sagittal (right) magnetic resonance images of a 30-year-old EOCA patient showing atrophy of the vermis and enlargement of the fourth ventricle.
tribution of the axon diameters (Fig. 2). Short-latency, central somatosensoryevoked potentials are abnormal after stimulation of the tibial nerve in three-fourths of the patients. They are more frequently abnormal than after stimulationof the median nerve, indicating a more severe impairment of the longest pathways (19). Brain stem auditory-evoked potentials are abnormal in about two-thirdsof the patients. Central motor- and visual-evoked potentials are abnormal in half of the patients, (31-33). Magnetic resonance imaging (MRI) findings are heterogeneous Most, butnot all, patients have cerebellar atrophy, the cerebellar vermis being the structure most frequently and severely affected. Cerebellar atrophy, which is usually slight, may be severe in some instances. Among patients showing cerebellar 50% have an associated atrophy atrophy, 50% have a pure cerebellar atrophy and of brain stem or cervical spinal cord (Fig.3). Cortical atrophy may be rarely observed. Extensive white matter abnormalities would exclude EOCA and suggest an alternative diagnosis. Technetium 99m-HMPAO single-photon emission tomography shows cerebellar hypoperfusion in most patients and cerebral cortical hypoperfusion halfin of them (34).
VII.
~IFFERENTIAL~ ~ A ~ N O S I S
Preservation of knee jerks is the clinical hallmark that separates EOCA from typical Friedreich’ S ataxia. Fixation instability, finger-to-nose dysmetria, lower
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limb weakness and wasting, extensor plantar response, and skeletal deformities are more frequent in Friedreich’ ataxia than in EOCA (17-19). More useful in differentiating these two entities, are the abnormalities of peripheral nerve conduction studies and somatosensory-evoked potentials, which are always present in Friedreich’s ataxia, in which the pathological involvement of the spinal ganglia is constant. Echocardiographic signs of hypertrophic cardiomyopathy are absent in EOCA. Cervical cord atrophy at MRI, which is very frequent in Friedreich’s ataxia, may also occur in EOCA. Severe cerebellar atrophy may be found only in EOCA. The differential diagnosis is more difficult with the Friedreich’s ataxia variants. About 10% of the Friedreich’s ataxia patients have retained tendon reflexes (FARR; 35’36).The molecular test can easily differentiate EOCA from Friedreich’s ataxia, showing in the latter the GAA expansion in homozygous or heterozygous state. Fourteen percentof our patients with EOCA phenotype received a molecular diagnosis of Friedreich’s ataxia. Progressive metabolic ataxias should be considered in differential diagnosis. Table 2 summarizes the diagnostic tests. Patients with ataxia and isolated vitamin E deficiency (AVED) may retain lower limb reflexes. Head titubation and
Table 2 Differential Diagnosis in EOCA: Laboratory Tests in Metabolic Ataxias
Disease Ataxia with isolated vitamin E deficiency GM,-gangliosidosis Niemann-Pick type C Late-onset globoid cell leukodystrophy (&abbe’s disease) Adult neuronal ceroid lipofuscinosis (Kufs’ disease) Adrenomyeloneuropathy Kearns-Sayre syndrome MERRF NARP Cerebrotendinous xanthomatosis Wilson disease
Serum vitamin E level Serum, leukocyte, and fibroblast hexosaminidase A Fibroblast exogenous cholesterol esterification Leukocyte and fibroblast galactosylcerarnidase Eccrine sweat gland biopsy Plasma and fibroblast very long-chain fatty acid (C26 :0) Mitochondrial DNA deletions in muscle Point mutations in the tRNALys gene of mitochondrial DNA in leukocytes and muscle Point mutation in ATPase 6 gene of mitochondrial DNA in leukocytes and muscle Serum cholestanol level Serum ceruloplasmin level
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fasciculations of the tongue point to the diagnosisof AVED, which is confirmed by low levels of serum vitamin E (37). Ataxia may be present in lysosomal, peroxisomal, and mitochondrial dis(GM,orders. Among the storage diseases there are hexosaminidase A deficiency gangliosidosis), Niemann-Pick type C disease, late-onset globoid cell leukodystrophy (Krabbe’s disease), and adult variety of neuronal ceroid lipofuscinosis (Kufs’ disease). A few patients, mainly of Jewish descent, have been described by with hexosaminidaseA deficiency and early-onset cerebellar ataxia, followed development of upper and lower motor neuron signs. Dementia, psychosis, and ophthalmoplegia are also present. Lamellar cytoplasmic inclusions are found in rectal biopsy specimens. Loss of serum and leukocyte enzyme activities varies from partial to complete. Elevated levels of serum lactate dehydrogenase are present in several patients andmay point to the diagnosis(38). In Niemann-Pick type C, onset age varies from6 months to 18 years, and the clinical picture comprises ataxia, mental impairment, supranuclear vertical gaze paralysis, dystonia, seizures,pyramidalsigns,organomegaly,andpulmonaryinvolvement.Lipidladen macrophages (foam cells) are present in the bone marrow aspiration and liver biopsy specimen. Impaired esterification of exogenous cholesterol is present in cultured fibroblasts(39). Onset occurs by the age of 10 years in most patients with &abbe’ S disease, rarely later. Mental retardation, psychomotor deterioration, impaired vision, progressive spasticity, ataxia, and a demyelinating peripheral neuropathy may be present. Most patients show rapid deterioration initially, followed by a more gradual progression lasting for years. Assays for galactosylceramidase (galactocerebroside P-galactosidase) in peripheral leukocytes or cultured fibroblasts offer the most reliable means for the diagnosis (40). Onset age ranges from adolescence to the fifth decade, with clusters around the age of 30 in the adult variety of neuronal ceroid lipofuscinosis (Kufs’ disease). It is clinically heterogeneous. Psychiatric, cognitive, extrapyramidal and cerebellar features, myoclonus, and seizures may be prominent. Visual problems are usually absent. Diagnosis requires the demonstration of the characteristic inclusions by electron microscopy. Fingerprint profiles or granular osmiophilic deposits are found in eccrine secretory cell, rectal biopsy, and usually in skeletal muscle (41). Adrenomyeloneuropathy is a peroxisomal disorder that presents with spastic paraplegia and distal sensoryloss in affected males, but cerebellar signsmay be prominent. Hypoadrenalism and MRI findings of diffuse demyelination may lead to the diagnosis, which is confirmed by measurement of very long-chain fatty acids showing elevated C 26: 0 levels in plasma and fibroblasts (42). Ataxia is a common feature in mitochondrial disorders, such as KeasSayre syndrome (KSS), myoclonic epilepsy with ragged red fibers (MERRF), and neuropathy, ataxia, and retinitis pigmentosa (NARP).KSS is a form of sparadic chronic progressive ophthalmoplegia, that begins before theofage 20 years and it is characterized by pigmentary retinopathy, elevated levels of cerebrospi-
Filla and De Michele
nal fluid protein, ataxia, and heart block. Almost all patients have large, single deletions in mitochondrial DNA. MERRFis characterized by action myoclonus, myoclonic epilepsy, cerebellar ataxia, weakness, and short stature. Dementia and hearing loss may be present. Onset varies from the first to the fifth decade. Maternal inheritance rnay be evident. Plasma pyruvate, lactate, alanine, and creatine phosphokinase are increased, and muscle biopsy shows accumulation of abnormalsubsarcolemmaland inte~yofibrillarmitochondria(ragged red fibers). of the miPathogenic point mutations have been shown in the lysine tRNA gene tochondrial DNA, resulting in defective translation of all mtDNA-encoded genes. NARP is a maternally inherited multisystem disorder characterized by developmental delay, retinitis pigmentosa, dementia, seizures, ataxia, and sensory neuropathy. It is associated with a point mutation in ATPase the 6 gene of mitochondrial DNA (43). Onset is in childhood in cerebrotendinous xanthomatosis (cholestanolosis). Xanthomata, especially of the Achilles tendon, and cataracts appear early, and neurological impairment develop later. The most prominent clinical feature is spastic ataxia, associated with pseudobulbarpalsy, dementia, palatal myoclonus, and peripheral neuropathy, Serum cholestanol (a metabolite of cholesterol) is increased. The lack of the sterol 27”hydroxylase can be shown in fibroblast cultures (44). “Pseudosclerotic” form of Wilson’s disease presents with ataxia, dysarthria, and intention tremor. Onset usually occurs in the second decade. Signs of hepatic dysfunction, greatly reduced serum ceruloplasmin, and increased urinary copper excretion point to the diagnosis. Liver copper is greatly increased, and its (45). measurement represents the most sensitive and accurate test for the disease Table 3 shows other autosomal recessive disorders, characterized by cerebellar ataxia and associated features, which might be considered in differential diagnosis with EOCA, Details may be found in Harding (10). Diseases other than hereditary ataxias can mimic EOCA phenotype. MRI is useful in demonstrating platybasia and basilar impression, conditions in which spastic quadriparesis and cerebellar signs may occur, and in diagnosing ataxic paraparesis causedby progressive multiple sclerosis. Detection of antigliadin and antiendomysial antibodies points to a diagnosis of celiac disease, which rnay cause a progressive and treatable cerebellar syndrome (46).
Lecithin, 5-hydroxytryptophan, thyrotropin-releasing hormone, and amantadine have been tried with conflicting results in different types of hereditary ataxias, including EOCA patients. Physiotherapy is helpful in enhancing independence and improving the quality of life.
Early-Onset Cerebellar Ataxia
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ACKNO~LED~~ENT This work was supported by a grant from the Italian Ministry of Education (Genetic Encephaloneuromyopathies to A.F.)
REFERENCES 1. Erb WH. Uber Sehnenreflexe bei Gesunden und bei Ruckenmarkskranken. Archiv Psychiatr Nervenkr 1875; 5:792-802. 2. Friedreich N. Uber Ataxie mit besonderer Beriicksichtigung der heredit2iren Formen. Virchows Archiv Pathol Anat Physiol 1877; 70: 140-152. 3. Marie P. Sur I’hCrCdoataxie cCrCbellouse. Sem MCd (Paris) 1893; 13:444-447. 4. FraserD.Defectofthecerebellumoccurringinabrotherandsister.Glasgow Med J 1880; 13:199-210. 5. Nonne M. Uber eine eigenthumliche familiae Erkrankungskfrom des Centralnervensystem. Archiv Psychiatr Nervenkr 1891; 22:283-3 16. 6. Brown S. On hereditaryataxy,withaseriesoftwenty-onecases.Brain1892; 151250-282. 7. Klippel M, Durante G. Contribution a1‘Ctudedes affections nerveuses familialeset hCrCditaires.RevMCd 1892; 12:745-785. 8. Holmes G.A n attempt to classify cerebellar disease, with a note on Marie’s hereditary cerebellar ataxia. Brain 1907; 30555-567. 9. Greenfield JG. The Spino-cerebellar Degenerations. Oxford: Blackwell, 1954. 10. Harding AE. The Hereditary Ataxias and Related Disorders. Edinburgh: Churchill Livingstone,1984. 11. Hodge G. Three cases of Friedreich’s disease all presenting marked increase of knee jerks. Br Med J 1897; 1:1405-1406. 12. Sinkler W. Friedreich’s ataxia, with a report of thirteen cases. N Y J Med 1906; 83:65-72. 13. Har~.-isW. Two cases of cerebellar ataxy. Proc R SOC Med 1908; 152-54. 14. Soderbergh G. Un cas de maladie familiale. Rev Neurol 1910; 20:7-12. 15. Fickler A. Klinische und pathologisch-anatomische Beitrege zu den erkrankungen des Kleinhirns. Dtsch 2 Nervenheilkd 1911; 41:306-375. 16. Hogan GR, Bauman ML. Familial spastic ataxia: occurrence in childhood. Neurology 1977; 27:520-526. 17. Harding AE. Early onset cerebellar ataxia with retained tendon reflexes: clinical and genetic study of a disorder distinct from Friedreich’s ataxia. J Neurol Neurosurg Psychiatry 1981; 44:503-508. F, Perretti A, SantoroL, Barbieri F, D’ ArienzoG, 18. Filla A, De Michele G, Cavalcanti Campanella G. Clinical and genetic heterogeneity in early onset cerebellar ataxia with retained tendon reflexes. J Neurol Neurosurg Psychiatry 1990; 53:667-670. 19. Klockgether T, Petersen D, GroddW, Dichgans J. Early onset cerebellar ataxia with retainedtendonreflexes.Clinical,electrophysiologicalandMRIobservationsin comparison with Friedreich’s ataxia. Brain 1991; 114:1559-1573.
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20. Polo GM, CalleiaJ, Combarros 0, Berciano J. Hereditary ataxias and paraplegias in Cantabria, Spain.An epidemiological and clinical study. Brain 1991; 114:855-866. 21. Filla A, De Michele G, Marconi L, Bucci L, Carillo C, Castellano AE, Iorio L, KniahynickiC,Rossi F,Campanella G. Prevalence ofhereditaryataxiasandspastic paraplegias in Molise, a region of Italy. J Neurol 1992; 239:351-353. 22. Chib A, Orsi L, Mortara P, Schiffer D. Early onset cerebellar ataxia with retained tendon reflexes: prevalence and gene frequency in an Italian population. Clin Genet 1993; 43~207-211. 23. Ozeren A, Arac; N, olku A. Early-onset cerebellar ataxia with retained tendon reflexes. Acta Neurol Scand 1989; 80:593-597. 24. Serlenga L, TrizioM, Pozio G, OteriG, CaldarazzoM. Le eredoatassie recessive ad esordio precoce. Studio clinic0 di 27 casi. Riv Neurol 1987; 57:285-289. 25. Campuzano V, Montemini L, Molt6MD, Pianese L,CossBe M, CavalcantiF, Monros E, Rodius F, Duklos F, Monticelli A, Zara F, Canizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F,Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996; 271:1423-1427. 26. Nikali K, Suomalainen A, Terwilliger J, Koskinen T, Weissenbach J, Peltonen L. Random search for shared chromosomal regions in four affected individuals: the assignmentof a new hereditary ataxia locus. Am J Hum Genet 1995; 56:10881095. 27. Richter A, Rioux JD, Bouchard JP, MercierJ, Mathieu J, Ge B, PoirierJ, Julien D, Gyapay G, WeissenbachJ, Hudson TJ, Me1anc;on SB, Morgan K. Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of CharlevoixSaguenay, in chromosome region 13qll. Am J Hum Genet 1999; 64:768-775. 28. Klockgether T, Ludtke R, Kramer B, AbeleM, Burk K, Schols L, Riess0, Laccone F, Boesch S, Lopes-Cendes I, Brice A, Inzelberg R, Zilber N, Dichgans J. The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain 1998; 121~589-600. 29. Chib A, Orsi L, MortaraP, Schiffer D, Reduced life expectancy in 40 cases of early onset cerebellar ataxia with retained tendon reflexes: a population-based study. Acta Neurol Scand 1993; 88:358--362. A, De Michele G, LanzilloB, Barbieri F, Crisci C, Gasp30. Santoro L, Perretti A, Filla aro Rippa P, Caruso G. Is early onset cerebellar ataxia with retained tendon reflexes identifiable by electrophysiologic and histologic profile? A comparison with Friedreich’s ataxia. J Neurol Sci 1992; 113:43-49. 31. Wullner U,Klockgether T, Petersen D, Naegele T, DichgansJ. Magnetic resonance imaging in hereditary and idiopathic ataxia. Neurology 1993; 43:318-325. 32. Omerod IEC, Harding AE, Miller DH, Johnson G, MacManus D, du Boulay EPGH, Kendall BE, Moseley IF, McDonald “I. Magnetic resonance imaging in degenerative ataxic disorders. J Neurol Neurosurg Psychiatry 1994; 57:51-57. 33. De MicheleG, Di Salle F, Filla A, D’Alessio A, Ambrosio G, Viscardi L, Scala R, Campanella G. Magnetic resonance imaging in “typical” and “late onset” Fried-
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reich’s disease and early onset cerebellar ataxia with retained tendon reflexes. Ita1 J Neurol Sci 1995; 16:303-308. De Michele G, Mainenti PP, Soricelli A, Di Salle F, Salvatore E, Longobardi R, Postiglione A, Salvatore M, Filla A. Single photon emission tomography in spinocerebellar degeneration.J Neurol 1998; 245:603-608. Palau F, De Michele G, VilchezJJ, Pandolfo M, MonrosE, Cocozza S, Smeyers P, Lopez-Arlandis J, Campanella G, Di DonatoS, Filla A. Early onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreich’s ataxia locus on chromosome 9q. Ann Neurol 1995; 37:359-362. Coppola G, De Michele G, Cavalcanti F, Pianese L, Perretti A, Santoro L, Vita G, Toscano A, Amboni M, Grimaldi G, Salvatore E, Caruso G, Filla A. Why some Friedreich’s ataxia patients do retain tendon reflexes? A clinical, neurophysiological and molecular study. J Neurol 1999; 246:353-357. Ben Hamida M, BelalS , Sirugo G, Ben Hamida C, Panayides K, Ionannou P, Beckmann J, Mandel JL, HentatiF,Koenig M, Middleton L. Friedreich’s ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families. Neurology 1993; 43:21792183. Willner JP, Grabowski GA, Gordon RE, Bender AN, Desnick RJ. Chronic GM, gangliosidosis masquerading as atypical Friedreich ataxia: clinical, morphologic, and biochemical studies of nine cases. Neurology 1981; 31:787-798. FinkJK,Filling-KatzMR,Sokol J,CoganDG,PikusA,Sonies B, SoongB, Pentchev PG, Comly ME, Brady RO, Barton NW. Clinical spectrum of NiernannPick disease type C. Neurology 1989; 39:1040-1049. Suzuki K, SuzukiY, Suzuki K. Galactosylceramide lipidosis: globoid-cell leukodystrophy (Krabbe disease). In: Scriver CR, Beaudet AL, Sly WS, Vale D, eds. The MetabolicandMolecularBases of InheritedDisease. NewYork:McGraw-Will, 1995:2671-2692. Berkovic SF, Carpenter S, Andermann F, Anderrnann E, Wolfe LS. Kufs’ disease: a critical reappraisal. Brain 1988; 111:27-62. Moser HW. The peroxisome: nervous system role of a previously underrated organelle. Neurology 1988; 38: 1617-1627. DiMauro S, Moraes CT. Mitochondrial encephalornyopathies. Arch Neurol 1993; 50:1197-1208. Bjorkhem I, Boberg KM. Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. In: Scriver CR, Beaudet AL, Sly WS, Vale D, eds. The MetabolicandMolecularBases of InheritedDisease.NewYork:McGraw-Hill, 1995:2073-2099. of delayed diagnosis. J NeuWalshe JM, Yealland M. Wilson’s disease. The problem rol Neurosurg Psychiatry 1992; 55:692-696. Pellecchia MT, Scala R, Filla A, De Michele G, Ciacci C, Barone P. Idiopathic cerebellar ataxia associated with celiac disease: lack of distinctive neurological features. J Neurol Neurosurg Psychiatry 1999; 66:32-35.
Alfried Kohlschutter University of Hamburg, Warnburg, Germany
I. INTRODUCTION
206
11. EPIDEMIOLOGY
206
111, MOLECULAR PATHOGENESIS A.BiochemicalDefect B, The Role of Vitamin E Deficiency in Neurological ~ysfunction
206 206
IV. PATHOLOGY A.
ExtraneuralPathology Neuropathology B.
208 208 208
CLINICAL FEATURES A.MalabsorptionSyndrome B. NeurologicalandMentalDisturbances C.PeripheralNerves Myopathy D. E.OcularProblems F. Prognosis
210 210 21 1 21 1 211 212 213
V.
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VI.ANCILLARYTESTS Imaging A. B. Electrophysiology C.LaboratoryTests
213 213 213 214
VII.MANAGEMENT Diet A. B. Vitamin E Supplements C.OtherTreatments
215 215 216 217
REFERENCES
217 205
206
1.
Kohlschutter
~NT~OD~CTION
Abetalipoproteinemia is an autosomal recessively inherited inborn error of lipoprotein metabolism, associated with clinical manifestations of malabsorption and a variety of progressive neurological symptoms, including ataxia and retinitis pigmentosa. Biochemical abnormalities in the patients’ plasma lead to a peculiar “thorny” deformationof erythrocytes called acanthocytosis, a term that has been used as a synonym for the disease some time after its first description by Bassen and Kornzweig in 1950 (1). The neurological symptoms are directly related to a deficiency of vitamin E, an etiological factor to be considered in the workup of all patients with ataxia (2).
!I.
EPIDEMIOLOGY
The disorder seems to be very rare. Most earlier reported patients were Jewish, (3) and from but the disease was also reported in patients from African origin Japan(4).Consanguineousparentageandoccurrence of thesamediseasein siblings,asistypical of autosomalrecessiveconditions,werefrequently observed.
111.
~ O L E C ~ LPATHOGENESIS A~ Biochemical Defect
~betalipoproteine~ia is caused by mutations (most of them private family mutations; Table 1) in a gene on chromosome 4q22-24 coding for a subunit of the microsomal triglyceride transfer protein (MTP) (5-9). This proteinis physiologically expressed in intestinal and liver cells and is needed for the transfer of lipids to lipoproteins that contain apoprotein B. The protein is absent in abetalipoproteinemicpatients,whoareunabletosecretestableapoproteinB-containing lipoproteins in their liver (10). Their blood is, therefore, virtually freeof chylomicrons, very low-densitylipoproteins,lowdensitylipoproteins(alsocalled beta-lipoproteins), and lipoprotein (a). Becauseof these deficiencies, patients are unable to absorb fat from their intestine and to transport fat-soluble vitamins in their circulation, thus resulting in the clinical syndrome of fat malabsorption and in neurological sequelae, which are related to the degeneration of structures depending on an adequate supply of vitamin E (see following section). The retinopathy may also be partially related to vitamin A deficiency, because a certain functional improvement was noted in some patients receiving vitamin A supplements (11,12), but vitamin A deficiency is not thought tobe a key factor in the retinal degeneration.
207
Table 1 MutationsoftheMicrosomalTriglyceride-TransferProtein (MTP) Gene on Chromosome 4q22-24 in 11 Patients with Abetalipoproteinemia
Mutation Allele 1
2 Allele
Homozygous 1147de11 1344+5-+11, de17 2212, dell 1867+5, G+A 215 dell 1783, C-+T 2593, G+T 419 insl
1147de11 1344+5-+11, de17 2212, dell 1867t-5, G-+A 215 dell 1783, C+T 2593, G-+T 419 ins 1
419 ins1 1867+ 1, G+A 419 insl
1401 ins1 1989, G-+A 1867+5, G+A
Compound heterozygous
Source: Ref. 8.
B. The Role of Vitamin E Deficiency in Neurological Dysfunction Since vitamin E is mainly transported in plasma lipoproteins that are virtually absent in abetalipoproteinemia, patients are at risk for vitamin E deficiency in their tissues (13). It is now clear that vitamin E is essential for normal neurological structure and function in both humans and experimental animals, with severe deficiency resulting in a characteristic neurological syndrome. The compelling evidence for this comes from clinical, histological, and therapeutic response observations. The functionalandpathologicallesionswithintheneuromuscular systems of patients with abetalipoproteinemia are very similar (albeit not completely identical) to those found in other conditions with vitamin E deficiency, such as chronic childhood cholestasis, cystic fibrosis, familial isolated vitamin E deficiency (tocopherol transport protein deficiency), veterinary diseases, and in experimentally vitamin E-deficient animals(14-16). The primary manifestations of a prolonged vitamin E deficiency include spinocerebellar ataxia, skeletal myopathy, and retinopathy. Other common symptoms are diminished proprioception, vibratory sensation, and ophthalmoplegia.The overall pattern of neurologicalsymptoms may vary accordingtothedifferentunderlyingcauses of the vitamin E-deficient state. Patients with tocopherol transport protein deficiency,
Kohlschutter
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for example, do not suffer from retinopathy, as do patients with abetalipoproteinemia. Why specific componentsof the neurological system should be particularly susceptible to a deficiency of this fat-soluble vitamin, and the mechanisms involved, are unknown,Vitamin E deficiency results in a “distal or dying-back” axonal neuropathy, which involves predominantly the centrally directed fibers of sensory neurons, with the large-caliber myelinated fibers being particularly affected. Both pathological and electrophysiological studies indicate that the primary abnormality is a degeneration of the axons, which then results ina secondary demyelination. It is assumed that lipid peroxidationof neuronal membranes, as a consequence of a deficiency of the major lipid-soluble antioxidant in vivo, is part of the mechanisms involved (15).
IV. PATHOLOGY A.
ExtraneuralPathology
Pathological changes in the small intestine are characterized by fat-engorged enterocytes (Fig. l), resulting in a so-called “snow-white duodenum’’ seen on endoscopy. The liver is enlarged and contains numerous fat-filled hepatic parenchymal cells. The fat-loaded enterocytes and hepatocytes develop secondary to the inability of these cells to assemble triglycerides into lipoprotein particles and to secrete them (10). Micronodularciahosis may develop (17), eventually requiring liver transplantation (l@,but the fine architecture of the liver may also remain intact for many years (19). A cardiomyopathy may develop, probably also as a consequence of vitamin E deficiency (20).
B. Neuropathology The characteristic sites of the degenerative process are the large sensory neurons of the spinal ganglia and their myelinated axons that enter the cord lateral to the posterior funiculus.The axons degenerate and lead to a secondary demyelination of the fasciculus cuneatus and fasciculus gracilis (20-22).
1. Peripheral Nerves Investigation of sural nerve biopsies showed a decreased numberof large fibers (greater than7 pm)that appear tobe selectively affected(23,24) (Fig. 2). In a patient with a neuropathy of short duration, small fibers and clusters of regenerating fibers indicated regeneration, whereas in two patients with advanced neuropathy half of the segments of teased fibers showed paranodal demyelination. Some un-
Abetalipoproteinemia
209
Figure 1 Duodenalmucosaofan8-month-oldboywithchronicdiarrheacausedby abetalipoproteinernia. Note vacuolization of the cytoplasma of absorptive cells. (From Ref. 53. Copyright 0 1992 Massachusetts Medical Society. All rights reserved.)
myelinated fibers also showed evidence of regeneration (24). Such signs of regeneration may hint at the potential curability or preventability of the process.
2. Skeletal Muscle A muscle biopsy in a 26-year-old patient revealed accumulation of ceroid pigment. A few fibers showed severe degeneration of the myofibrils. Fibroblasts and macrophages in the interstitial tissue contained abundant ceroid (25). In the biopsy of the quadriceps femoris muscleof a 29-year-old patient, the abnormalities consisted in fibers containing dense lipid inclusions (ceroid and lipofuscin), an increase in central nuclei, and a predominance of type I fibers. After1 year of vitamin E therapy, a shift to a predominance of type I1 fibers was demonstrated. of fibers containing lipid and ceroid Despite an apparent reduction in the number granules in the second biopsy, neuromyopathic changes worsened (26).
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Kohlschutter
Figure 2 Suralnerveofa14-year-oldpatientwithabetalipoproteinemia,showinga marked decrease in the numbers of large-caliber axons. (From Ref. 14.)
3. Eyes In autopsy cases, the eyes showed the changes seen in advanced retinitis pigmentosa. There was predominant involvementof the posterior fundus, characterized by a loss of photoreceptors, loss or attenuation of the pigment epithelium, preservation of the subrnacular pigment epithelium, withan excessive accumulation of lipofuscin (including bizarre laminar profiles by electron microscopy), and invasion of the retina by macrophage-like pigmented cells.The retina and pigment (27). In frozen sections epithelium in the periphery were morphologically normal of the optic nerve and tract, a large number of rounded bodies were seen that did not stain with Oil Red 0, or Sudan black, but were periodic acid-Schiff (PAS)and Alcian blue-positive. Many of these bodies showed birefringence (28).
V.
CLINICALFEATURES
A.
MalabsorptionSyndrome
The initial symptoms of the disease are nonneurological and consist in failure to thrive in early childhood owing to malabsorption of fat. As early as in the neonatal period, chronic diarrhea and inadequate gain of weight are noted. Endos-
Abetalipoproteinemia
211
copy shows pale discolorationof the duodenal mucosa (29) owing to lipid accumulation in enterocytes (see Fig. 1). The inability of intestinal cells to secrete lipids in chylomicrons results in insufficient absorption of fat calories, essential fatty acids, and the fat-soluble vitamins A, E, and K. Vitamin A is normally esterified in enterocytes, Although the transport of its esters into blood depends on chylomicrons and plasma levels of vitamin A are low in abetalipoproteinemia, normal plasma levels can easily be achieved by vitamin A supplements(22). Viis unimpaired by the tamin L)has its own transport protein; hence, its absorption lack of chylomicron formation (30). Absorption of vitamin K is poor and may cause intestinal bleeding owing to prothrombindeficiency, which is the presenting problem of the disorder in children (31).
B. NeurologicalandMentalDisturbances Neurological and visual symptoms are late complications of the specific malabsorption syndrome. The first neurological sign is the diminution of deep tendon reflexes, whichmay appear in the first weeks of life. Vibratory sense and proprioception tend to be lost progressively, and an ataxic gait appears. The Romberg sign may be present. Before the adventof effective vitamin E treatment, patients were often unable to stand by the third decade, and dysmetric movements and dysarthria had become severe. Muscle contractions were common, leading to pes cavus, pes equinovarus, and kyphoskoliosis. Babinski responses were reported in some patients, but spastic paralysis does not develop (22). Mental retardation occurs in some cases, but cannot be directly attributed to the basic metabolic defect. There is no evidence of cerebral cortical disease. Multiple nutritional deficiencies may be related to the general failure to thrive and to a slow psychomotor development noted in some infants with abetalipoproteinemia. In some cases coexisting other rare autosomal recessive disorders, possibly affecting the brain, could not be excluded.
C.
PeripheralNerves
Although neurophysiological studies prove a frequent involvement of peripheral nerves, clinical peripheral neuropathy is infrequently present. Characteristically, this is a progressive sensory neuropathy(24). Hypesthesia in the stocking-glove distribution was described, as was the diminished response to local anesthetics. Cranial nerves are generally spared (22).
Myopathy D. Skeletal myopathy may be present (25), but the muscular weakness, which is a common feature of abetalipoproteinemia, may also be secondary to a relatively
212
Kohlschutter
mild degenerative neuropathy that escapes detection by motor nerve conduction velocity studies, but is suggested by subtle electromyogaphic (EMG) changes compatible with partial chronic denervation (24).
E. Ocular Problems Loss of night vision is frequently the earliest symptom
of the pigmentary retinopathy. The severity of the retinopathy parallels that of the other neurological symptoms, suggesting a common mechanism. A decrease of visual acuity occurs in the first decade, but many patients maintain normal vision until adulthood. Ultimately, blindness can occur. Reported ophthalmoscopic findings (Fig. 3) included the predorninant involvement of the posterior fundus and loss or attenuation of thepigmentepithelium,producingsharply a demarcatedwhite appearance (27). Some patients may have fundoscopic changes very similar to retinitis pigmentosa. A pattern of acquired exotropia and nystagmus on lateral gaze was found in three patients (32). Angioid streaksof uncertain pathogenetic relation to the metabolic defect were observed in at least two patients with abetalipoproteinemia (33). For a more detailed discussionof ocular aspects of abetalipoproteinemia, please see C m (34).
Figure 3 Fundoscopy in a patient with abetalipoproteinemia, demonstrating pigmented retinal atrophy. (From Ref. 47.)
Abetalipoproteinemia
213
F. Prognosis Literature data on survival are scarce, differ widely, and are irrelevant becauseof the advent of effective nutritional intervention with adequate supplements of lipid-soluble vitamins. If such therapy is instituted, thereis reasonable hope that the neurological disorder will at least not progress and that the life-span is not significantly shortened (for details see later discussion).
VI. ANCILLARY TESTS A.
Imaging
1. CT and MR Standard cranial imaging is not contributory to the establishment of the diagnosis. With improving technology, spinal tomography may reveal changes in severe cases.
2.
PET
With "F-dopa positron emission tomography, (PET), twovery disabled patients, who had severe and prolonged vitamin E deficiency caused by abetalipoproteinemia, showed reduced uptake of dopa in both putamen and caudate, similar to patients with Parkinson's disease (35).
B. Electrophysiology 1. Peripheral NerveStudies Nerveconductionstudiesshowednormalsensorynerveconductionvelocity, However,theamplitude of theresponsewasoftenreducedorabsent. The changes were initially most marked in distal portions of the nerves. Motor conduction was normal.The studies support a modelof axonal loss of large myelinated fibers with secondary demyelination (24,36,37).
2. Electromyography In spite of normal motor conduction results, the EMG may indicate subclinical signs of partial chronic denervation (24).
3.
EvokedPotentials
~s~aZ-evokedpotentiaZs are of normal amplitude, butmay have increased latencies (36,37).Somatosensory-evoked potentials are frequently delayed, suggesting
Kohlschutter
214
dorsal column dysfunction (36,37). noma1 (36,37).
4.
Brain stern auditory-evoked potentials are
Electroretinography
Electroretinograms were frequently reported as abnormal (12,37). Ina 13-monthold boy, the electroretinogram was unrecordable (3).
C. Laboratory Tests 1. Hematology On blood smears, acanthocytes (Fig. 4) account for 50 to nearly 100% of erythrocytes, but these are not seen in bone marrow. The abnormalities of the red cell membrane reflect the abnormal lipid composition of plasma lipoproteins (38). The abnormal erythrocytes cannot form rouleaux, which is the cause for the unusually low sedimentation rates sometimes found in patients with abetalipoproteinemia (39). Acanthocytosis, apart from abetalipoproteinemia, occurs in association with at least two further neurological syndromes, neuroacanthocytosis(a
Figure 4 Electron micrograph o f an acanthocyte, adjacent to a discoid erythrocyte, from a patient with abetalipoproteinemia. (From Ref. 40. Courtesy o f Oxford University Press.)
Abetalipoproteinemia
215
familial condition with chorea) and the McLeod syndrome, which is characterized by an abnormal expression of Kell blood group antigens (40,41). In abetalipoproteinemia, red cell survival maybe shortened, hyperbilirubinemia, reticulocytosis, and erythroid hyperplasia may be present, suggesting that erythropoiesis perse isnot notably impairedby the basic defect (42). Severe anemia, sometimes described in infants, reflects deficienciesof iron, folate, or other nutrients that occur in such a malabsorption syndrome.
2.
Serum Lipids
Total cholesterol is low( c 7 0 mg/dL); triglycerides are almost undetectable. A lipoprotein profile showsvirtuallyabsentlow-densityandverylow-density lipoprotein cholesterol.
3.
UrinaryOrganicAcidAnalysis
These analyses are frequently performed in suspected metabolic disorders and may show an elevated excretion of mevalonic acid, indicating an imbalance of cholesterol metabolism (43) or vitamin B,, deficiency.
The severe neurodegenerative complications of abetalipoproteinemia belong to the potentially treatable or preventable conditions associated with vitaminE deficiency (44,45), provided the disorder is recognized early and that great care is used with the theoretically simple treatment. Therapy consists in a dietary regimen and vitamin supplements, but requires sophisticated studies and long-term attention by a specialized metabolic team.
A.
Diet
Because of the difficulty of absorbing fats that contain long-chain fatty acids, the intake of fat has to be reduced. A proportion of the ingested fat can be replaced by medium-chain triglycerides, which can be absorbed without the formation of chylomicrons (46,47), but their prolonged use was associated with hepatic fibrosis (48). It should be kept in mind that medium-chain triglycerides serve only as energy carriers and do not contain essential fatty acids. The diet should supply adequate amountsof fatty acids of the n-6 andof the n-3 type, and regular fatty acid analysis of plasma and erythrocytes must ensure that there is no essential fatty aciddeficiency. The n-3-type fatty acids are particularly important for retinal function (49), and most published treatment attempts do not adequately address this aspect.It is possible that some of the reported hepatic com-
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Kohlschutter
Table 2 DietaryTreatmentofPatientswith Abetalipoproteinemia" (for Indispensable Vitamin supplements Please Refer to Text)
Calculate total daily energy requirement (kcal/day) according to age, sex, body weight, and physical activity. Composition of diet (percent of total daily energy requirement): Proteinb 15% (or more) SO% (or more) Carbohydrates Fat" 25% (maximum) 1/3 as fat from food sources, 2/3 as MCTd oils or fat. If necessary, use essential fatty acid-rich oils." "These recommendations are meant to serve the dietary long-term needs is modifiedwhen of patientswithabeta~ipoproteinemia.Treatment started in a severely undernourished patient and part of the intake of natural food is replaced by artificial mixtures. bProtein intake is not restricted, as long as fat contentof protein-rich food is not too high. Lean meat and fish are recommended. 'Basic principle: reduce total dietary fat, use MCT fats to supply energy, avoid essential fatty acid deficiency. obdMCT (medium-chain triglyceride) fat and oil preparations can be tained from Mead Johnson Nutritionals, Evansville, Indiana; Nutricid Royal Numico, Zoetermeer, the Netherlands. "Depending on the choice of MCT preparations, which contain variable so that proportions of essential fatty acids, use safflower oil or walnut oil essential fatty acids make up 3.5% of total daily caloric intake.
plications of dietary treatment are the consequence of a deficiency of essential fatty acids (or other nutrients), a condition already described in an early report on abetalipoproteinemia (50). For a practical scheme of dietary management see Table 2.
B. Vitamin E Supplements
Overcoming the consequences of a tissue deficiency of vitamin E is the major therapeutic goal. Although the patients lack the major lipoproteins needed for vitamin E transport, they are apparently able to secrete very small numbers of apolipoproteinB-containinglipoproteinswhich may allowsometransport of (51).Apart from a parenteral application during a-tocopherol to peripheral tissues an initial phase of treatment, vitamin E can be given as an oral a-tocopherol acetate preparation. The dosages used were massive compared with normal requirements and were in the range of 1,000 mg/day for infants to over 10,000 mg/ (22,47,52). It seems reasonable to start treatment day for older children and adults of with a dose of 50 mgkg per day given in three divided doses. Administration a water-miscible vitamin E preparation was also advocated (53).
Abetalipoproteine~ja
21 7
Repeated evaluationof the vitaminE status (16) is necessary to monitor the effectiveness of treatment. This can be done by measuring the concentration of compounds with vitaminE activity [a-and y-tocopherol in plasma and in erythrocyte membranes (54)] and by detecting the functional effect of vitamin E deficiency in membranes [measuring free radical resistance of erythrocytes (55)]. Concomitant supplements of vitamin A are recommended (15,000-20,000 IWday), monitoredby serum levelsof vitamin A to avoid toxicity(46). In a pregnant patient who was treated with vitaminA, a benign intracranial hypertension with bilateral papilledema was reported (56). The authors advised caution when treating abetalipoproteinemia patients with high doses of vitamin A,because hypervitaminosis A is a typical causeof elevated intracranial pressure (57). Supplements of vitamin K have to be given if hypoprothrombinemia is present. It is now apparent that such a supplementation inhibits the progression of the neurological disease and probably leads to some regression of symptoms, even when it is started in adulthood (37,46,47,52,58-60). Indirect impressive evidence for the effectivenessof large doses of vitamin E in preventing neurodegeneration comes also from the long-term observation of patients with tocopherol transport protein deficiency (isolated familial vitamin E deficiency) (61,62). The retinopathy can also be prevented or substantially modified by early A alone did not prevent treatment with vitaminE, whereas treatment with vitamin or arrest the progressionof the retinal lesion (63). In a 13-month-old patient with unrecordableelectroretinogram,thescotopicelectroretinogramimprovedto about 30% of normal following dietary modification and vitamin supplementation (3). However, once irreversible neurological or retinal damage has occurred, vitamin treatment seems to have only limited effects (64).
C. OtherTreatments Liver transplantation because of development of cirrhosis was reported ( l 8,65). The serum lipoprotein profileof a 16-year-old girl was corrected after such a procedure. However, fat malabsorption and steatorrhea persisted because the primary defect remained expressed in the intestine (18).
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4. Naganawa S, Kodama T, Aburatani H, et al. Genetic analysisof a Japanese family with normotriglyceridemic abetalipoproteinemia indicates a lack of linkage to the apolipoprotein B gene. Biochem Biophys Res Common, 1992; 182:99-104. 5. Wetterau JR, Aggerbeck LP, Bouma ME, et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science 1992; 258:9991001. 6. Shoulders CC, Brett DJ, Bayliss JD, et al. Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein. Hum Mol Genet 1993; 2:2109-2116. 7. Sharp D, Blindeman L, Combs KA, et al. Cloning and gene defects in microsomal triglyceridetransferproteinassociatedwithabetalipoproteinaemia.Nature1993; 365~65-69. 8. NarcisiTM,ShouldersCC,Chester SA, etal.Mutationsofthemicrosomal triglyceride-tra~sfer-proteingene in abetalipoproteinemia.Am J Hum Genet 1995; 57:1298-1310. 9. Raabe M, Flynn LM, Zlot CH, Wong JS, Veniant MM, Hamilton RL, Young SG. Knockout of the abetalipoproteinemia gene in mice: reduced lipoprotein secretion in heterozygotes and embryonic lethality in homozygotes. Proc Natl Acad Sci USA 1998; 95~8686-8691. 10. Gregg RE, Wetterau JR. The molecular basis of abetalipoproteinemia. Curr Opin Lipidol 1994; 5:81-86. 11. Gouras P, C m RE, Gunkel RD. Retinitis pigmentosa in abetalipoproteinemia: effects of vitamin A. Invest Ophthalmol 1971; 10:784-793. 12. Sperling MA, Hiles DA, Kennerdell JS. Electroretinographic responses following vitamin A therapy in A-beta-lipoproteinemia. Am J Ophthalmol 1972; 73:342-351. RV, Brewer HV, Jr, Kayden HJ. Discrimination between 13. Traber MG, Rader D, Acuff RRR- and all-racemic-alpha-tocopherols labeled with deuterium by patients with abetalipoproteinemia. Atherosclerosis 1994; 108:27-37. 14. Sokol RJ. Vitamin E and neurologic function in man. Free Radical Biol Med 1989; 6 189-207. 15. Muller DP,Goss-SampsonMA.Neurochemical,neurophysiological,andneuropathological studies in vitamin E deficiency. Crit Rev Neurobiol 1990; 5:239-263. 16. Sokol RJ. Vitamin E and neurologic deficits. Adv Pediatr 1990; 48:119-148. 17. Partin JS, Partin JC, Schubert WK, McAdams AJ. Liver ultrastructure in abetalipoproteinemia:evolution of micronodular cirrhosis. Gastroenterology 1974; 67:107-118. 18. Braegger CP, Belli DC, Mentha G, Steinmann G. Persistence of the intestinal defect in abetalipoproteinaemia after liver transplantation. Eur J Pediatr 1998; 157576-578. 19. Avigan MI, Ishak KG, Gregg RE, Hoofnagle JH. Morphologic features of the liver in abetalipoproteinemia. Wepatology 1984;4: 1223-1226. 20. Dische MR, PorroRS. The cardiac lesions in Bassen-Kornzweig syndrome. Report of a case, with autopsy findings. Am J Med 1970; 49:568-571. 21. Sobrevilla LA, Goodman ML, Kane CA. Demyelinating central nervous system disease,macularatrophyandacanthocytosis(Bassen-Kornzweigsyndrome).AmJ Med1964:37:821-828.
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22. MalloyJM,KaneJP,Disordersoflipoproteins.InRosenbergRN,etal.eds. The Molecular and Genetic Basis of Neurological Disease, Boston: ButterworthHeinemann,1997:1003-1018. 23. Miller RG, Davis CJ, Illingworth DR, BradleyW. The neuropathy of abetalipoproteinemia. Neurology 1980; 30: 1286-1291. 24. Wichman A, Buchthal F, Pezeshkpour GH, Gregg RE. Peripheral neuropathy in abetalipoproteinemia[publishederratumappearsinNeurology1986Ju1;36(7): 10091. Neurology 1985; 35:1279-89. 25. Kott E, Delpre G, Kadish U, Dziatelovsky M, Sandbank U. Abetalipoproteinemia (Bassen-Kornzweigsyndrome).Muscleinvolvement.ActaNeuropath011977; 37:255-258. 26. Lazaro RP, Dentinger MP, Rodichok LD, Barron KD, Satya-Murti S. Muscle pathology in Bassen-Kornzweig syndrome and vitamin E deficiency. Am J Clin Pathol 1986; 86~378-387. 27. CoganDC,RodriguesM,ChuFC,SchaeferEJ.Ocularabnormalitiesinabetalipoproteinemia. A clinicopathologic correlation. Ophthalmology 1984; 91:991-998. 28. KornzweigAL.BassenKornzweigsyndromepresentstatus.MetabOphthalmol 1976;1:51-54. 29. Delpre G, KadishU, Glantz I, Avidor I. Endoscopic assessment in abetalipoproteinemia (Bassen-Kornzweig-syndrome). Endoscopy 1978; 1059-62. 30. Avioli LV. Absorption and metabolism of vitamin D,in man. Am J Clin Nutr 1969; 22:437-446. 31. Caballero FM, Buchanan GR. Abetalipoproteinemia presenting as severe vitamin K deficiency. Pediatrics 1980; 65:161-163. 32. YeeRD,Cogan DC, ZeeDS.Ophthalmoplegiaanddissociatednystagmusin abetalipoproteinemia. Arch Ophthalmol 1976;9457 1-575. 33. Gorin MB, Paul TO, Rader DJ. Angioid streaks associated with abetalipoproteinemia. Ophthal Genet, 1994; 15:151-159. 34. CarrRE.Abetalipoproteinemiaandtheeye.BirthDefectsOrigArtSer,1976; 12:385-408. 35. Dexter DT, Brooks DJ, Harding AE, et al. Nigrostriatal function in vitamin E deficiency: clinical, experimental, and positron emission tomographic studies. Ann Neurol 1994; 35:298-303. 36. Lowry NJ, Taylor MJ, Belknapp W, Logan WJ. Electrophysiological studies in five cases of abetalipoproteinemia. Can J Neurol Sci 1984; ll:60-63. 37 BrinMF,PedleyTA,LovelaceRE,et al.Electrophysiologicfeatures of abetalipoproteinemia: functional consequences of vitamin E deficiency. Neurology 1986; 36:669-673. 38. Lange Y, Steck TL. Mechanismof red blood cell acanthocytosis and echinocytosis in vivo. J Membr Biol 1984; 77:153-159. 39. Khachadurian AK, Sha‘afi RT, Murad S. Studies on the sedimentation rate and membrane permeability of acanthocytes in abetalipoproteinemia. Lebanese Med J 1973; 26:425-434. 40. Hardie RJ. Acanthocytosis and neurological impairment-a review, Q J Med 1989; 71:291-306. 1
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41. Hardie RJ, Pullon HW, Harding AE, et al. Neuroacanthocytosis. A clinical, haematological and pathological study of 19 cases. Brain 1991 ;114: 13-49. 42. Rane JP, Have1 RJ, Disorders of the biogenesis and secretion of lipoproteins containing the B apolipoproteins. In: Scriver CR, et al., eds. The Metabolic and Molecular Bases of Inherited Disease, New York: McGraw-Hill, 1995:1853-1885. 43. Illingworth DR, Pappu AS, Gregg RE. Increased urinary mevalonic acid excretion in patients with abetalipoproteinemia and homozygous hypobetalipoproteinemia. Atherosclerosis 1989; 76:21-27. role in neurological function. Postgrad Med J 1986; 44. Muller DP.VitaminE-its 62:107-1 12. 45 Kohlschiitter A. Vitamin E and neurological problems in childhood: recognition of a curable neurodegenerative process. DevMed Child Neurol 1993; 35:664-668. 46. Azizi E, Zaidman JL, Eshchar J, Szeinberg A. Abetalipoproteinemia treated with parenteral and oral vitamins A and E, and with medium chain triglycerides. Acta Paediatr Scand 1978; 67:796-801. 47. Triantafillidis JK, Kottaras G, Sgourous S, et al. A-beta-lipoproteinemia: clinical and laboratory features, therapeutic manipulations, and follow-up studyof three members of a Greek family. J Clin Gastroenterol 1998; 26:207-211. of two cases 48. Illingworth DR, Connor WE, Miller RC. Abetalipoproteinemia. Report and review of therapy. Arch Neurol 1980; 37559-62. 49. Birch EE, Birch DG, Hoffman DR, Uauy R. Dietary essential fatty acid supply and visual acuity development. Invest Ophthalmol Vis Sci 1992; 33:3242-3253. 50. Phillips GB, Dodge JT. Phospholipid and phospholipid fatty acid and aldehyde compositionofredcellsofpatientswithabetalipoproteinemia(acanthocytosis). Evidence for essential fatty acid deficiency in man. J Lab Clin Med 1968; 7 l:629637. 51. Aguie GA, Rader DJ, ClaveyV, et al. Lipoproteins containing apolipoprotein B isolated from patients with abetalipoproteinemia and homozygous hypobetalipoproteinemia: identification and characterization. Atherosclerosis, 1995 118: 183-191. 52. Muller DP, Lloyd JK. Effect of large oral doses of vitamin E on the neurological sequelae of patients with abetalipoproteinemia. AnnEr Acad N Sci 1982; 393: 133-144. 53. Anonymous. Case records of the Massachusetts General Hospital. Case 35-1992. An eight-month-oldboywithdiarrheaandfailuretothrive. N Engl J Med 1992; 3271628-635. 54. Finckh B, Kontush A, Comrnentz J, Hiibner C, Burdelski M, Kohlschiitter A. Highperformance liquid chromatography-coulometric electrochemical detection of ubiquinol-10, ubiquinone- 10, carotenoids, and tocopherols in neonatal plasma. In: Packer L. ed. Oxidants and Antioxidants. New York: Academic Press, 1998:341348. 55. Boda V, Finckh B, Durken M, Commentz J, Wellwege HH, Kohlschutter A. Monitoring erythrocyte free radical resistance in neonatal blood rnicrosamples using a peroxyl radical-mediated haemolysis test. Scand J Clin Lab Invest 1998; 58:317322. 56. Manor RS, Berrebi A. Papilledema in Bassen-Rornzweig syndrome. Metab Ophthalmol 1978; 2:45-52. *
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10 Ataxia with Isolated Vitamin E Deficiency Michel Koenig lnstitut de Genetique et de Siologie Moleculaire et Cellulaire, University Louis Pasteur, Strasbourg, France
I. INTRODUCTION
223
11. EPIDEMIOLOGY
224
111. MOLECULAR PATHOGENESIS
224
IV. NEUROPATHOLOGY
226
V.
CLINICAL FEATURES
227
VI.
ANCILLARY TESTS A. Laboratory Tests B. Electrophysiology C. Imaging
229 229 229 230
VII. MANAGEMENT REFERENCES
230 23 1
I. INTRODUCTION Chronic vitamin E deficiency has been suspected for 30 years to cause a progressive neurodegenerative disease, based on studies of rats fed on low vitamin E diet and from the observation of patients with primary vitamin E deficiency (1,2) or 223
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224
secondary to fat malabsorption, chronic cholestasis, pancreatic insufficiency, or cysticfibrosis (3-6) (seeChapter30). Vitamin E,oritsmajoractiveform a-tocopherol, is a major liposoluble antioxidant molecule, protecting biological membranes against lipid peroxidation ('7). Ataxia and neuropathy secondary to vitamin E deficiency are thought to result from reduced protection against oxidativestresscaused by freeradicaltoxicity. The neuronalspecificity,affecting mostly large sensory neurons, such as in Friedreichs's ataxia (FRDA), is not explained by the ubiquitous localizationof vitamin E in human tissues. Some forms of severe vitamin E deficiency are autosomally inherited diseases. One of them is abetalipoproteinemia, in which vitamin E deficiency is secondary to fat malabsorption caused by mutations in the gene encoding the microsomal triglyceride E deficiency transfer protein (see Chapter 9). In ataxia with isolated vitamin (AVED), the sole and primary biochemical abnormality is very low vitamin E levels. The first case of AVED was described in 1981 by Burck and colleagues (1). For 10 years, AVED was considered to be an extremely rare entity, until the discovery of an important founding group in North Africa (8,9).
II. EPIDEMIOLOGY From the first case described in 1981 to 1991, only 11 cases were reported, from Europe (1,10,1l), North America (2,12-14) and in Japan(15). In these countries, the prevalence seems to be well below 1:1 million. Since 1993, many families have been reported in North Africa(8,9). The prevalence of AVED is as high as 1:100,000 in Tunisia, where it is as frequent as FRDA. With one exception, all North AfricanAVED patients share the same mutation, inherited from a common ancestor (see later discussion). This mutationis also the most frequent mutation in Italy and France, owing to past and recent emigration from North Africa. Three other mutations are more commonly seen in Europe and in North America.The most frequent mutation in Japan has been traced back to a small island 290 lsrn south of mainland Japan and was not reported outside Japan. Because of the rarity of the mutations, the majority of patients are born from consanguinous parents, even in developed countries (16).
111.
MOLECULARPATHOGENESIS
Vitamin E ispresentinnatureineightdifferent forms: a-, p-, y-, and S-tocopherols and a-, p-,y-, and S-tocotrienols. In turn, a-tocopherol exists in eight different stereoisomers,only one of which, RRR-a-tocopherol,is present in the serum of mammals. Vitamin E is considered the most potent biological anti-
Vitamin Isolated withAtaxia
E Deficiency
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oxidant and protects membranes against lipid peroxidation. In accordance, erythrocytes from AVED patients revealed increased peroxidation sensitivity on hemolysis by acidifiedglycerol(17)or H202 or NaN, (14,18-20) andshowed evidence of lipid peroxidationby the thiobarbituric acid method(17-20). Hemolysis was totally (l4,18-20) or partially (17) corrected by vitamin E administration to the AVED patients. Oxidative damage presumably also explains the slow neurodegenerative process of the disease. In normal subjects, vitamin E is absorbed and secreted from the intestine into plasma in chylomicrons. During chylomicron catabolism in the plasma, vitamin E is transferredtocirculatinglipoproteinparticles(IDL,LDL,HDL), which can deliver vitamin E to tissues. The chylomicron remnants are taken up by the liver, which then selects only RRR-a-tocopherol from all the forms of vitamin E for secretion in nascent very low-density lipoproteins (VLDL) (21). Other isomers and stereoisomers are eliminated, presumably through the bile. The specific transferof vitamin E to nascent VLDL is the work of a liver-specific protein, the a-tocopherol transfer protein (a-TTP), purified and microsequenced by the group of Arai and colleagues from rat liver (22,23). Unlike abetalipoproteinemic patients, AVED patients absorb vitaminE normally, but their conservation of plasma RRR-a-tocopherol is poor owing to impaired secretion of RRR-atocopherol in VLDL (24,25), suggesting that a-TTP is the primary defective protein. In the absence of recycling, the entire plasma pool of vitamin E is rapidly eliminated in a little more than a day (26). The defective gene was localized by homozygosity mapping with the Tunisian AVED families on chromosome 8q13 (27),a region that was subsequently shown to contain the humana-TTP gene (28). This gene is composed of 5 exons and encodes a 278-amino-acid protein that exhibits structural homologies with protein (CRALBP; present only in the retina) and the c~~-retinalde~yde-binding the yeast Sec14 protein, involved in phosphatidylinositol and phosphatidylcholinetransferintomembranes(23,28). Thea-TTP gene is predominantly expressed in the liver, but also at very low levels in the retina, cerebellum, and fibroblasts (29-32). Mutations are scattered throughout all five exons in AVED patients (16,33-35). Up to now, 15 mutations have been described (16,20,31,36) (Table 1). The North African mutation, 744delA, results in truncationof the last 30 amino acids. Haplotype analysis has demonstrated the founder origin of the 744delA mutation (33). Mutations 513insTT, 486delT, and R134X have been found in several unrelated European and North American. families (16). The R134X mutations might represent several recurrent changesa CpG on mutational hot spot, whereas the 513insTT mutations might spread from a common ancestor, as suggested by haplotype analyses (16). The most frequent mutation in Japan is a missense change,HlOlQ (29,34), associated witha very mild phenotype (discussed later).
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226 Table 1 Mutations in the a-TTP GeneofAVED Patients
(Corresponding amino-acid in rat
TTP,
Nucleotide 14p”) on sequence SEC coding
Effect change Exon 1 2
175C+T 205- 1G+C
2
306A”+G 303T+G 358G”+A 400C-+T 42 G-+A 1 486delT 5 13insTT 530AG-6 5481°C 552G+A
4 4 5
575G+A 661C+T 744delA
R59W Exon 2 skipping and frameshift after R68 No change on G102 (possible splice site activation) HlOlQ A 1201: R134X (protein truncation) E141K Frameshift after G1 62 Frameshift afterI 171 Frameshift after A176 L1 83P Exon 3 skipping and frameshift after T184 R192H R221W Frameshift after E248
16
“For missense mutations only (h-CRALBP, human cis-retinaldehyde-binding protein; SEC14p, yeast SEC14 protein)
IV. NEUROPATHOLOGY A single neuropathological study of an AVED patient has been reported (37). The patient, homozygous for the 744delA mutation, died at age 29 from heart failure after 23 years of disease duration. The cerebral hemispheres and the cerebellum were moderately atrophic, and the brain stem and the spinal cord were markedly atrophic. The main histological features was demyelinationof the spinal sensory system (gracile and cuneate nuclei of the medulla and posterior columns), with marked neuronal atrophy, spheroids (swollen and dystrophic axons), and corpora amylacea. The moderate involvment of the spinal ganglion cells and the dorsal roots suggests that demyelination is secondary to axonal degeneration caused by a dying-back axonopathic mechanism. Moderate myelin pallor was seen in the lateral corticospinal tracts, more obvious at the lumbar than cervical level, again suggesting dying-back axonopathy. The cerebellum showed important Purkinje
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cell loss, but moderate cell lossof the dentate nucleus, in contrast with the situation in Friedreich ataxia. Anotherimportanthistologicalfeaturewaswideneuronallipofuscin accumulation-namely, in the third cortical layer of the cerebral cortex, thalamus, lateral geniculate body, striatum, hypoglossal and ambiguus nuclei, spinal horns, and posterior root ganglia (37). Ultrastructurally, the lipopigments were of uniform granularity without lipid droplets.Vacuolar lipofuscin pigment deposits were also found in muscle biopsies, arranged between myofibrils. The deposits were autofluorescent, electron-dense, membrane-bound, and phosphatase acidpositive, suggesting a lysozomal origin(1,2,11-13,15). Fiber type grouping was also observed in muscle biopsies. In a study of superficial peroneal nerve biopsy in 15 AVED patients homozygous for the 744delA mutation, Zouari and colleagues found normal to moderate reductionof large myelinated fibers and normal small myelinated fibers (38). Regeneration was frequently noted, contrary to Friedreich ataxia nerve biopsies. Onion bulbs were not observed, and dense bodies were noted in the cytoplasm of Schwann cells (38). Similar findings were reported from the sural nerve biopsy of patients with the HlOlQ (15,29) mutation and 552G+A splice mutation (31). In contrast, the sural nerve biopsyof the patient homozygous for the 530AG+GTAAGT mutation showed considerable loss of myelinated axons, particularlythose of largecaliber,andnosigns of axonaldegenerationand regeneration (1).
V.
CLINICAL FEATURES
The main clinical feature of AVED is progressive sensory and cerebellar ataxia (1,2,10,12,15). In several instances,AVED appeared strikingly similar to FRDA (8,11,12,17,27),withonsetbefore20years,gaitandlimbataxia,dysarthria, areflexia of the lower limbs, loss of vibration and position sense in the lower limbs, and bilateral extensor plantar response (Table 2, 16). Scoliosis and pes cavus are often present. Despite much clinical overlap between AVED and FRDA, significant differences can be found between the two groups of patients. In a study of 42 AVED patients, cardiomyopathy was present in only 19% of cases. Head titubation, which is not a feature of FRDA, was found in 28% of cases. OtherAVED patients with head titubation, not compiled in the Cavalier et al. study (16), have been reported (10,17,3 1,39). Some cases present with prominent dystonic posturing, 10 years of disease duration without treatusually following early onset and over ment (13,16,19,39). Dystonia has been found in 13% ofAVED patients (16). Retinal deposits, which are never found in FRDA, have been found in 12% of
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Table 2 Compared Frequency of Clinical Signs Between Friedreich's Ataxia and AVED Patients
Friedreich's ataxia Clinical sign
Harding DUE al. et 1996 (45) %
Gait and limb ataxia Dysarthria Lower limb areflexia Loss of vibratory sense Extensor plantar reflexes Muscle weakness in lower limb Head titubation Cardiomyopathy Diabetes or impaired glucose tolerance
99 98 91 87 78 86 79 58 67
na
140
0
63 (75) 32 (61) 10
1981 (46) % 77 85 35
AVED Cavalier et al. 1998 %
99 97 99 73 89 88 - (39) -
(31) 37 19 (42) 0 (16)
115
43
(39) (40)
"Number of patients, unless otherwise noted (in parentheses after the corresponding frequency)
AVED patients(16).Retinitispigmentosa,whichis a diagnosticcriteria of abetalipoproteinemia and Refsum's disease, was found in N E D patients having the late-onset form associated with the HlOlQ mutation in Japan (29,4O), but 57also in some patients with the North African 744delA mutation (19) andain year-old patient with an homozygous L183P mutation (36). White-yellowish white spots in the peripheral retina were seen in other patients (17,41). Age of onset, ranging from 2 to52 years, and severity appeared extremely of mutation (16). All truncating muvariable and correlated in part with the type tations (frame-shift, nonsense, splice sites) and three homozygous nonconservative missense mutations(R59W, E141K, R221W) were associated with early onset (mean age at onset 9 Ifr: 5, range 2-19 years). Homozygous HlOlQ mutation was associated with the mildest phenotype, with onset at 38,52, 30, and 52 years in the four reported cases (15,29). The R192I-I mutation, present in compound heterozygote sibs (16,35), also appeared associated with milder presentation, for two sibs were asymptomatic at age 21 and 27, when vitamin E supplementation 6 years (12). An homozygous was initiated, whereas their sister had onset at age A120T patient had onset at 21 yearsof age (1 6).The milder phenotype of these patients is presumably accounted forby partial lossof function of a-TTPas a reQ, A1 20T, and R192H missense mutations. Support for this hysult of the H 101 pothesis is providedby studies using deuterated formsof a-tocopherol stereoisomers (RRR and SRR) (25) in patients with the HlOlQ and R192H mutations. These patients were still able, to a lesser extent than normal subjects, to prefer-
Ataxia with Isolated Vitamin E Deficiency
entially incorporate the natural RRR stereoisomer into VLDL, in contrast with patientshomozygousforseveretruncatingmutations (530AG-+GTAAGT, loss of the capacity to pref744delA, 486delT, and R134X) who had a complete erentially select for the natural a-tocopherol stereoisomer. In the absence of treatment, ataxia progressively worsens and the patients become wheelchair-bound after 6-22 years of disease duration (mean 13 years) (16). However, two patients homozygous for the 744delA mutation were still 30 years of disease duration in the absence of ambulant with a walker after treatment.
VI. A ~ ~ I L L A R TESTS Y
A.
LaboratoryTests
Diagnosis of AVED is made by low serum vitamin E dosage in absence of fat (< 2.5 mgL, ofmalabsorption. Serum vitamin E is well below the normal range ten < 1 mgL, with 6