Handbook of Ataxia Disorders (Neurological Disease and Therapy)

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

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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

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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

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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

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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%

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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-

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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

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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

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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;

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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,

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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).

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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

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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

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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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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

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&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-

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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-

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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

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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.

REFERENCES Aas JE, Brodal P (1988). Demonstration of topographically organized projections from the hypothalamus to the pontine nuclei: an experimental anatomical study in the cat. J Comp Neurol 268:313-328. Aas JE, Brodal P (1989). Demonstration mamillo-ponto-cerebellar of a pathway-a multitracer study in the cat. Eur J Neurosci 1:61-74. Abeles M, BergmanH, Margalit E, Vaadia E (1993). Spatiotemporal firing patterns in the frontal cortex of behaving monkeys. J Neurophysiol 70:1629-1638. Aiba A, Kano M, Chen C, Stanton ME, Fox GD, Herrup K, Zwingman TA, Tonegawa S (1994). Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice. Cell 79:377-388. Airaksinen MS, Eilers J, Garaschuk 0, Thoenen H, Konnerth A, Meyer M (1997). Ataxia and altered dendritic calcium signaling in mice carrying a targeted null mutation of the calbindin d28k gene. Proc Natl Acad Sci USA 94:1488-1493. Albus JS (1971). A theory of cerebellar function. Math Biosci 10:25--61. Allen GI, KornH, Oshima T (1969). Monosynaptic pyramidal activation of pontine nuclei cells projecting to the cerebellum. Brain Res 15:272-275. Allen GI, Korn H, Oshima T, Toyama K (1970). Time course of pyramidal activation of pontine nuclei cells in the cat. Brain Res 19:291-294. Allen GI, Oshima T, ToyamaK (1971). Unitary components in corticopontine activation of the cat. Brain Res 35:245-249. Allen GI, Korn H, Oshima T (1975a). The mode of synaptic linkage in the cerebro-pontocerebellar pathway of the cat. I. Responses in the brachium pontis. Exp Brain Res 24: 1-14. Allen GI, KornH, Oshima T (1975b). The mode of synaptic linkage in the cerebro-pontocerebellar pathway of the cat. 11. Responses of single cells in the pontine nuclei. Exp Brain Res 24:15-36. Alley K, Baker R, Simpson JI (1975). Afferents to the vestibulo-cerebellum and the origin of the visual climbing fibers in the rabbit. Brain Res 98:582-589. Altman J (1972). Postnatal development of the cerebellar corte in the11.rat. Phases in the maturation of Purkinje cells andof the molecular layer. J Comp Neurol 145:399464. Altman J (1976). Experimental reorganization of the cerebellar cortex. VII. Effects of late

34

Sultan et al.

x-irradiation schedules that interfere with cell acquisition after stellate cells are formed. J Comp Neurol 165:65-75. Altman J, Bayer SA (1978). Development of the diencephalon in the rat. I. Autoradiographic study of the time of origin and settling patterns of neurons of the hypothalamus. J Comp Neurol 182:945-971. Altman J, Bayer SA (1985a). Embryonic development of the rat cerebellum. 111. Regional differences in the timeof origin, migration, and settlingof Purkinje cells.J Comp Neurol 23 1 :42-65. Altman J, Bayer SA (1985b). Embryonic development of the rat cerebellum. 11. Translocation and regional distribution of the deep neurons. J Comp Neurol 231:27"41. Andersen BB, KorboL, Pakkenberg B (1992). A quantitative study of the human cerebellum with unbiased stereological techniques. J Comp Neurol 326:549-560. Andersson G, Armstrong DM (1987). Complex spikes in Purkinje cells in the lateral vermis (b zone) of the cat cerebellum during locomotion. J Physiol 385:307-134. Angaut P (1970). The ascending projections of the nucleus interpositus posterior of the cat cerebellum: an experimental anatomical study using silver impregnation methods. Brain Res 24:377-394. AngautP, Sotelo C (1987). The dentato-olivary projection in the rat as a presumptive GABAergic link in the olivo-cerebello-olivary loop-an ultrastructural study. Neurosci Lett 83:227-23 1. Ariens Kappers CU, Huber C, Crosby EC (1960). The Comparative Anatomy of the Nervous System of Vertebrates, Including Man. New York: Hafner Publishing. Armstrong DM, Eccles JC, Harvey RJ, Matthews PBC (1968). Responses in the dorsal accessory olive of the cat to stimulation of hindlimb afferents. J Physiol 194:125145. Armstrong DM, Schild RF (1970). A quantitative study of the Purkinje cells in the cerebellum of the albino rat. J Comp Neurol 139:449"456. Asanuma C, Thach WT, Jones EG (1983). Brainstem and spinal projections of the deep cerebellar nuclei in the monkey, with observations on the brainstem projections of the dorsal column nuclei. Brain Res Rev 5:299-322. Bal T, McCormick DA (1997). Synchronized oscillations in the inferior olive are controlledbythehyperpolarization-activatedcationcurrent I,. Neurophysiol J 77~3145-3156. Baldissera F, Roberts WJ (1975). Effects on the ventral spinocerebellar tract neurones from Deiter' nucleus and the medial longitudinal fascicle in the cat. Acta Physiol Scand 93:228-249. Baldissera F, Ten Bruggencate G (1976). Rubrospinal effects on ventral spinocerebellar tract neurones. Acta Physiol Scand 96:233-249. Barmack NH, Baughman RW, Eckenstein FP, Shojaku H (1992a). Secondary vestibular cholinergic projection to the cerebellum of rabbit and rat as revealed by choline acetyltransferase immunohistochemistry, retrograde and orthograde tracers. J Comp Neurol 3173250-270. Barmack NH, Baughman RW, EckensteinFP (1992b). Cholinergic innervation of the cerebellum of rat, rabbit, cat, monkey as revealed by choline acetyltransferase activity and immunohistochemistry. J Comp Neurol 317:233-249.

Architecture System Cerebellar of the

35

Batini C, Compoint C, Buisseretdelmas C, Daniel H, Guegan M (1992). Cerebellar nuclei and the nucleocortical projections in the rat-retrograde tracing coupled to GABA and glutamate immunohistochemistry. J Comp Neurol 315:74-84. Batton RR 111, Jayaraman A, Ruggiero D, Carpenter MB (1977). Fastigial efferent projections in the monkey: an autoradiographic study. J Comp Neurol 174:281-306. Baude A, Molnar E, LatawiecD, McIlhinney RA, Somogyi P (1994). Synaptic and nonsynaptic localizationof the GluR1 subunitof the AMPA-type excitatory amino acid receptor in the rat cerebellum. J Neurosci 14:2830-2843. Bayer SA, Altman J (1987). Directions in neurogenetic gradients and patterns of anatomical connections in the telencephalon. Prog Neurobiol 29:57-106. Benardo LS, ForsterRE (1986). Oscillatory behaviour in inferior olive neurons: mechanism, modulation, cell aggregates. Brain Res Bull 17:773-784. Benevento LA, Fallon JH (1975). The ascending projections of the superior colliculus in the rhesus monkey (Macaca mulatta). J Comp Neurol 160:339-362. Blackstone CD, SupattaponeS, Snyder SH (1989).Inositolphospholipid-linkedglutamate receptorsmediatecerebellarparallel-fiber-Purkinje-cellsynaptictransmission. Proc Natl Acad Sci USA 86:4316-4320. Bloedel JR, Courville J (1981). Cerebellar afferent systems. In: JM Brookhart, VB Mountcastle, eds. The Nervous System. Sect.1 Handbook of Physiology. Bethesda, MD: American Physiology Society, pp 357-416. Bloedel JR, Bracha V, Kelly, TM, Wu, J-Z (1991). Substrates for motor learning. Does the cerebellum do it all? Ann NY Acad Sci 627:305-318. Boehme CC (1968). The neural structure of Clarke’s nucleus of the spinal cord. J Comp Neurol 132:445-462. Bolk L (1906). Das Cerebellum der Suugetiere. Jena: G Fischer. Border BG, Mihailoff GA (1985). GAD-immunoreactive neural elements in the basilar pontine nuclei and nucleus reticularis tegmenti pontis of the rat. I. Light microscopic studies. Exp Brain Res 59:600-614. Bosco G, Rankin A, Poppele R (1996). Representation of passive hindlimb postures in cat spinocerebellar activity. J Neurophysiol 76:7 15-726. Bourinet E, Soong TW, Sutton K, Slaymaker S, Mathews E, Monteil A, Zamponi GW, Nargeot J, Snutch TP (1999). Splicing of alpha 1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. Nat Neursci 2:407-415. Bower JM, Woolston DC (1983). Congruence of spatial organization of tactile projections to granule cell and Purkinje cell layers of cerebellar hemispheres of the albino rat: vertical organization of cerebellar cortex. J Neurophysiol 49:745-766. Bower J, Llinhs R (1982). Simultaneous sampling analysis of the activity of multiple, closely adjacent, cerebellar Purkinje cells. SOC Neurosci Abst 8:830. Braitenberg, V (1967). Is the cerebellar cortex a biological clock in the millisecond range? In: CA Fox, RS Snider, eds: Progress in Brain Research: The Cerebellum. v01 25. Amsterdam: Elsevier, pp 334-346. Braitenberg V, Atwood RP (1958). Morphological observations on the cerebellar cortex. J Cornp Neurol 109:l-34. Braitenberg V, Heck D, Sultan F (1997). The detection and generation of sequences as a key to cerebellar function: experiments and theory. Behav Brain Sci 20:229-277.

36

al.

Sultan et

Brodal A (1940). Experimentelle Untersuchungen iiber die olivo-cerebellar Lokalisation. Z Ges Neurol Psychatr 169:l-153. Brodal A, Brodal P (1971). The organization of the nucleus reticularis tegmenti pontis in the cat in the light of experimental anatomical studies of its cerebral cortical afferents. Exp Brain Res 13:90-110. Brodal P (1978). The corticopontine projection in the rhesus monkey. Origin and principles of organization. Brain 101:251--283. Brodal P (1979). The pontocerebellar projection in the rhesus monkey: an experimental studywith retrograde axonal transport of horseradishperoxidase.Neuroscience 4~193-208. Brodal P (1980a). The cortical projection to the nucleus reticularis tegmenti ponits in the rhesus monkey. Exp Brain Res 38:19-27. Brodal P (1980b). The projection from the nucleus reticularis tegmenti pontis to the cerebellum of the rhesus monkey. Exp Brain Res 38:29-36. Brodal, A (1981). Neurological Anatomy in Relation to Clinical Medicine. New York: Oxford University Press. Brodal P (1982). Further observationson the cerebellar projections from the pontine nuclei and the nucleus reticularis tegmenti pontis in the rhesus monkey. J Gomp Neurol 204:44-55. Brodal P, Bjaalie, JG (1997). Salient anatomic features ofthe cortico-ponto-cerebellar pathway. Prog. Brain Res 114:227-249. Brodal P, Walberg F (1977). The pontine projection to the cerebellar anterior lobe. An experimental study in the cat with retrograde transport of horseradish peroxidase. Exp Brain Res 29:233-248. Brodal A, Destombes J, Lacerda AM, Angaut P (1972). A cerebellar projection onto the pontine nuclei: an experimental anatomical study in the cat. Exp Brain 16:Res 115139. BrodalP,MihailoffGA,BorderB,OttersenOP,Storm-MathisenJ(1988).GABAcontaining neurons in the pontine nuclei of the rat, cat and monkey. An immunocytochemical study. Neuroscience 25 :27-45. Burke R, Lundberg A, Weight(1 F971). Spinal border cell origin of the ventral spinocerebellar tract. Exp Brain Res 12:283-294. Caddy KW, Biscoe TJ (19’79). Structural and quantitative studies on the normal C3H and Lurcher mutant mouse. Philos Trans R Soc Lond B Biol Sci 287: 167-201. CasagrandeVA, Hating JK,Hall WC, Diamond ET (1972). Superior colliculus of the tree shrew: a structural and functional subdivision into superficial and deep layers. Science 177:444-447. Chan-Palay V (1977). Cerebellar Dentate Nucleus: Organization, Cytology and Transmitters. New York: Springer-Verlag. Chen S, Hillman DE (1993). Colocalization of neurotrans~ttersin the deep cerebellar nuclei. J Neurocytol 22:8 1-91. Clendenin M, Ekerot CF, Oscarsson0, Ros6n I (1974). The lateral reticular nucleus in the cat. 11. Organization of component activated from bilateral ventral flexor reflex tract (bVFRT). Exp Brain Res 21:487-500. Colbert CM, Johnston D (1998). Protein kinase C activation decreases activity-dependent

Architecture of the System Cerebellar

37

attenuation of dendriticNafcurrentinhippocampalCA1pyramidalneurons. J Neurophysiol 79:491-495. Cooke JD, Larson B, Oscarsson0, Sjolund B (1971a). Origin and termination of cuenocerebellar tract. Exp Brain Res 13:339-358. Cooke JD, Larson B, Oscarsson0, Sjolund B (1971b). Organizationof afferent connections to cuenocerebellar tract. Exp Brain Res 13:359-377. Cooper MH, Fox CA (1 976). The basilar pontine gray in the adult monkey (Macaca muZatta): a Golgi study. J Comp Neurol 168:145-174. 0,Walberg F (1977). The lateral reticular nucleus in the Corvaja N, Grofovii I, Pompeiano cat. I.An experimental anatomical study of its spinal and supraspinal afferent connections. Neurosci 2537-553. Courville J, Augustine JR, Martel P (1977). Projections from the inferior olive to the cerebellar nuclei in the cat demonstrated by retrograde transport of horseradish peroxidase. Brain Res 130:405-419. Crandall WF, Keller EL (1985). Visual and oculomotor signals in nucleus reticularis tegrnenti pontis in alert monkey. J Neurophysiol 54:1326-1345. Cr6pel F, Audinat E (1991). Excitatory amino acid receptors of cerebellar Purkinje cells: development and plasticity. Prog Biophys Mol Biol 55:31-46. Crill WE (1970). Unitary multiple-spiked responses in cat inferior olive nucleus. J Neurophysiol 33: 199-209. Czubayko U, Schwarz C, Sultan F, Thier P (2000). Two types of neurons in the rat deep cerebellar nuclei as determined by intrinsic electrophysiological properties. J Neurophysiol (in press). Daniel H, Levenes C, Crepe1 F (1998). Cellular mechanisms of cerebellar LTD. Trends Neurosci 21:401-407. Demo16 V (1927). Structure et connexion des noyeaux dentel6es du cervelet. I. Schweiz Arch Neurol Psychiatr 20:27 1-294. De Montigny C, LamarreY (1973). Rhythmic activity induced by harmaline in the olivocerebello-bulbar systemof the cat. Brain Res 53:81-95. Desclin JC (1974). Histological evidence supporting the inferior olive as the major source of cerebellar climbing fibers in the rat. Brain Res 77:365-384. De Schutter E (1995). Cerebellar long-term depression might normalize excitation of Purkinje cells: a hypothesis. Trends Neurosci 18:291-295. De Schutter E, Bower JM (1994a). An active membrane model of the cerebellar Purkinje cell. I. Simulation of current clamps in slice. J Neurophysiol 71:375-400. De Schutter E, Bower JM (1994b). An active membrane model of the cerebellar Purkmje cell. 11. Simulation of synaptic responses. J Neurophysiol 71:401-419. De Zeeuw CI, Holstege JC, CalkoenF, Ruigrok TJ, Voogd J (1988). A new combination ofWGA-HRP anterograde tracing and GABA immunocytochemistry applied to afferents of the cat inferior olive at the ultrastructural level. Brain Res 447:369-375. De Zeeuw CI, Holstege JC, Ruigrok TJ, Voogd J (1989). Ultrastructural study of the GABAergic, cerebellar, mesodiencephalic innervation of the cat medial accessory olive: anterograde tracing combined with immunocytochemistry. J Comp Neurol 284:12-35.

al.

38

et

Sultan

De Zeeuw CI, Holstege JC, Ruigrok TJ, Voogd J (1990a). Mesodiencephalic and cerebellar terminals terminate upon the same dendritic spines in the glomeruliof the cat and rat inferior olive: an ultrastructural study using a combination of [3H]leucine andwheatgermagglutinincoupledhorseradishperoxidaseanterogradetracing. Neuroscience 341645-655. De Zeeuw CI, Ruigrok TJH, Holstege JC, Jansen HG, Voogd J (1990b). Intracellular labeling ofneuronsinthemedialaccessoryolive of thecat. 11. Ultrastructure of dendritic spines and their GABAergic innervation. J Comp Neurol 300:478494. De Zeeuw CI, Ruigrok TJH, Holstege JC, Schalekamp MP, Voogd (1990~). J Intracellular labeling of neurons in the medial accessory olive of the cat: 111. Ultrastructure of axon hillock and initial segment and their GABAergic innervation. J Comp Neurol 3001495-510. De Zeeuw CI, Hertzberg EL, Mugnaini E (1995). The dendritic lamellar body: a new neuronal organelle putatively associated with dendrodendritic gap junctions. J Neurosci 15:1587-1604. De Zeeuw CI, Lang EJ, Sugihara I, Ruigrok TJ, Eisenman LM, Mugnaini E, Llinris R (1996). Morphological correlatesof bilateral synchrony in the rat cerebellar cortex. J Neurosci 16:3412-3426. De Zeeuw CI, Koekkoek SK, Wylie DR, Simpson JI (1997). Association between dendritic lamellar bodies and complex spike synchrony in the olivocerebellar system. J Neurophysiol 77: 1747-1758. De Zeeuw CI, Simpson JI, Hoogenraad CC, Galjart N, Koekkoek S E , Ruigrok TJH (1998). Microcircuitry and functionof the inferior olive. Trends Neurosci 21 :391400. Dicke PW, Thier P (1999). Saccade-related neurons in the monkey dorsal pontine nuclei do not respond to “catch-up” saccades during smooth-pursuit eye movements. SOC Neurosci Abstr 25: 1397. Dicke PW, Thier P, Barash S, Ilg U (2000). Single-unit evidence fora contribution of the dorsal pontine nucleus to goal-directed saccades. (submitted). Dietrichs E (1988). Cerebellar cortical and nuclear afferents from the feline locus coeruleus complex. Neuroscience 27:77-9 1. DumesnilbousezN,SoteloC(1992).EarlydevelopmentofthelurchercerebellumPurkinje cell alterations and impairment of synaptogenesis. J Neurocytol 21506529. Dupont JL, CrCpel F (1979). Correlations among climbing fiber responses of nearby cerebellar Purkinje cells in the immature rat. Exp Brain Res 37525-535. Dupont JL, Fournier E, Gardette R, CrCpelF (1984). Effectof excitatory amino acidson Purkinje cell dendrites in cerebellar slices from normal and staggerer mice. Neuroscience 12:613-619. Eccles JC, Oscarsson0, Willis WM (1961). Synaptic actionof group I and I1 afferent fibers of muscle on the cells of the dorsal spino-cerebellar tract. J Physiol 158517543. Eccles JC, Llinds R, Sasaki K (1966a). Parallel fibre stimulation and the responses induced thereby in the Purkinje cells of the cerebellum. Exp Brain Res 1:17-39.

Architecture of the System Cerebellar

39

Eccles JC, Llinhs R, Sasaki K (1966b). The excitatory synaptic action of climbing fibers on the Purkinje cells of the cerebellum. J Physiol 182:268-296. Eccles JC, Ito M, Szentagothai J (1967). The Cerebellum as a Neuronal Machine. Berlin: Springer-Verlag. Edwards SB (1972). The ascending and descending projections of the red nucleus in the cat: anexperimentalstudyusinganautoradiographictracermethod.BrainRes 48:4-63. Eide E, Fedina L, Jansen J, Lundberg A, Vicklicky L (1969a). Properties of Clarke’s column neurones. Acta Physiol Scand 77:125-144. Eide E, Fedina L, Jansen J, Lundberg A, Vicklicky L (1969b). Unitary components in the activation of Clarke’s column neurones. Acta Physiol Scand 77: 145-158. Ekerot C-F, Larson B (1972). Differential termination of the exteroceptive and proprioceptive components of the cuenocerebellar tract. Brain Res 36:420-424. Eller T, Chan-Palay V (1976). Afferents to the cerebellar lateral nucleus. Evidence from retrograde transportof horseradish peroxidase after pressure injections through micropipettes. J Comp Neurol 166:285-302. EscobarA,SampedroED,DowRS(1968).Quantitativedata on theinferiorolivary nucleus in man, cat and vampire bat. J Comp Neurol 132:397-404. Exton JH (1996). Regulation of phosphoinositide phospholipases by hormones, neurotransmitters and other agonists linked to G-proteins. Annu Rev Pharmacol Toxicol 36:481-509. Fierro L, Llano I (1996). High endogenous calcium buffering in Purkinje cells from rat cerebellar slices. J Physiol 496:617-625. Fortier PA, Kalaska JF, Smith AM (1989). Cerebellar neuronal activity related to wholearm reaching movements in the monkey. J Neurophysiol 62: 198-21 1. Frankfurter A, Weber JT, Harting JK (1977). Brainstem projections to lobule VI1 of the posterior vermis in the squirrel monkey: as demonstrated by the retrograde axonal transport of tritiated horseradish peroxidase. Brain Res 124: 135-139. Fries W (1990). Pontine projection from striate and prestriate visual cortex in the macaque ‘ monkey: an anterograde study. Vis Neurosci 4:205-216. GSihwiler BH, Llano I (1989). Sodium and potassium conductances in somatic membranes of rat Purkinje cells from organotypic cerebellar cultures. J Physiol 417:105-122. Gamlin PD, Clarke RJ (1995). Single-unit activity in the primate nucleus reticularis tegmentipontisrelatedtovergenceandocularaccommodation.JNeurophysiol 73~2115-2119. Gerrits NM, VoogdJ (1987). The projection of the nucleus reticularis tegmenti pontis and adjacent regions of the pontine nuclei to the central cerebellar nuclei in the cat. J Comp Neurol 25852-69. Gerrits NM, Willemse-vd Geest L, Kornet M (1984). Some observations of the cerebellopontine projections in the cat-with a hypothesis to explain species differences. Neurosci Lett 44:65-70. Glickstein M, Cohen JL, Dixon B, Gibson A, Hollins M, Labossiere E, Robinson F (1980). Corticopontine visual projections in macaque monkeys. J Comp Neurol 190:209229. Glickstein M, May JG 111, Mercier BE (1985). Corticopontine projection in the macaque:

40

Sultan et al.

the distributionof labelled cortical cells after large injections of horseradish peroxidase in the pontine nuclei. J Comp Neurol 235:343-359. Gould BB, Rakic P (1981). The total number, time or origin and kinetics of proliferation of neurons comprising the deep cerebellar nuclei in the rhesus monkey. Exp Brain Res 44: 195-206. Grant G (1962). Projection of the external cuneate nucleus onto the cerebellum in the cat. An experimental study using silver methods. Exp Neurol 5:179-195, Gray EG (1961). The granule cells, mossy synapses and Purkinje spine synapses of the cerebellum: light and electron microscope observations. J Anat 95:345-356. GraybielAM (19’74). Visuo-cerebellar and cerebello-visual connections involving the ventral lateral geniculate nucleus. Exp Brain Res 20:303-306. Graybiel AM, Hartwieg EA (1974). Some afferent connections of the oculomotor complex in the cat. Brain Res 81543-551. Groenewegen HJ, Voogd J, Freedman SL (1979). The parasagittal zonation within the olivocerebellar projection. IT. Climbing fiber distribution in the intermediate and hemispheric parts of cat cerebellum. J Comp Neurol 183:551--602. Gwyn DG, Nicholson GP, Flumerfelt BA (1977). The inferior olivary nucleus of the rat: a light and electron microscopic study. J Comp Neurol 174:489-520. Hager G, Dodt HU, ZieglgansbergerW, Liesi P (1995). Novel forms of neuronal migration in the rat cerebellum. J Neurosci Res 40:207-219. Hartmann-von-Mon~owK, Akert K, Kiinzle H (1981). Projections of precentral, premotor, prefrontal cortex to the basilar pontine gray and the nucleus reticularis tegmenti pontis in the monkey (Macaca fascicularis). Arch Suisse Neurol Neurochirg Psychol 129:189-208. on the mammalian cerebellum. Prog Harvey RJ, Napper RMA (1991). Quantitative studies Neurobiol 36~437463. Harvey RJ, Porter R, Rawson JA (1977). The natural discharge of Purkinje cells in paravermal regions of lobules V and VI of the monkey’s cerebellum. J 1Physiol27 :515536. Harvey RJ, Porter R, Rawson JA (1979). Discharge of intracerebellar nuclear cells in monkeys. J Physiol 297559-580. Hausser M, Roth A (1997). Dendritic and somatic glutamate-receptor channels in rat cerebellar Purkinje-cells. J Physiol 501:77-95. Hawkes R, HerrupK (1995). Aldolase ClzebrinI1 and the regionalizationof the cerebellum. J Mol Neurosci 6:147-158. Hawkes R, LeclercN (1987). Antigenic map of the rat cerebellar cortex: the distribution of parasagittalbandsasrevealedbymonoclonalanti-Purkinjecellantibody mabQ113. J Comp Neurol 256:29-41. Hrimori J, Somogyi J (1983). Differentiation of cerebellar mossy fiber synapses in the rat: a quantitative electron microscope study. J Comp Neurol 220:365--377. Hrimori J, Szentagothai J (1966). Identification under the electron microscope of climbing fibers and their synaptic contacts. Exp Brain Res 1:65-81. Heinemann U, Hamon B, Konnerth A (1984). GABA and baclofen reduce changes in extracellularfreecalciuminareaCAI ofrathippocampalslices.NeurosciLett 47~295-300.

Architecture of the System Cerebellar

41

Herrup K, Kuemerle B (1997). The compartmentalization of the cerebellum. Annu Rev Neurosci 20:61-90. HerrupK,WilczynskiSL(1982).CerebellarcelldegenerationintheLeanermutant mouse. Neuroscience 7:2185-2196. Hillman DE (1969). Morphological organization of frog cerebellar cortex: a light and electron microscopic study. J Neurophysiol 32:8 18-846. HillmanDE,Chen S, AckmanJ(1988).Perinatalmethylazoxymethanolacetateuncouplescoincidence of cerebellarfoliaandparallelfibers.Neuroscience24: 99-110. Hirai N, Hongo T,Sasaki S (1978). Cerebellar projection and input organizationsof the spinocerebellar tract arising from the centarl cervical nucleus in the cat. Brain Res 1571341-345. Hockberger PE, Tseng HY, Connor A (1987). Immunocytochemical and electrophysiological differentiation of rat cerebellar granule cells in explant cultures. J Neurosci 7~1370-1383. Hoddevik GH (1975). The pontocerebellar projection onto the paramedian lobe and the paraflocculus studied by means of retrograde axonal transport of horseradish peroxidase as a tracer. Brain Res 95:291-307. Hoddevik GH (1978). The projection from nucleus reticularis tegmenti pontis onto the cerebellum in the cat. Anat Embryol 153:227-242. Hoddevik GH, Brodal A, Kawamura K,Hashikawa T (1977). The pontine projection to the cerebellar vermal visual area studied by meansof the retrograde axonal transport of horseradish peroxidase. Brain Res 123:209-227. Holmqvist B, LundbergA,Oscarsson 0 (1956). Functional organization of the dorsal spinocerebellar tract in the cat. V Further experiments on convergence of excitatory and inhibitory actions. Acta Physiol Scand 38:76-90. Holmqvist B, Oscarsson 0, Uddenberg N (1963). Organization of ascending spinal tracts activated from forelimb afferents in the cat. Acta Physiol Scand 58:68-76. Hounsgaard J, Midtgaard J (1988). Intrinsic determinats of firing pattern in Purkinje cells of the turtle cerebellum in vitro. J Physiol 402:731-749. Huerta MF, Harting JK (1984). The mammalian superior colliculus: studies of its morphology and connections. In: H Vanegas, ed. Comparative Neurology of the Optic Tectum. New York: Plenum, pp 687-773. Ito M,Kano M (1982). Long-lasting depression of parallel fiber Purkinje-cell transmission induced by conjunctive stimulationof parallel fibers and climbing fibers in the cerebellar cortex. Neurosci Lett 33:253-258. Ito M, Yoshida M, Obata K (1964). Monosynaptic inhibition of the intracerebellar nuclei induced from the cerebellar cortex. Experientia 20:575-576. Jahnsen H (1986). Extracellular activation and membrane conductances of neurons in the guinea-pig deep cerebellar nuclei in vitro. J Physiol 372:149-168. Jakab K, Hiimori J (1988). Quantitative morphology and synaptology of cerebellar glomeruli in the rat. Anat Embryol 179:81-88. Jansen J, Brodal A (1940). Experimental studieson the intrinsic fibersof the Cerebellum. 11. The corticonuclear projection in the rabbit and the monkey. J Comp Neurol 73:267-321.

al.

42

et

Sultan

Jansen J, Brodal A (1954). Aspects of Cerebellar Anatomy. Oslo: Forlagt Johan Grundt Tanum. Jansen J, Brodal A (1958). Das Kleinhirn. In: Mollendorff's Handbuch der mikroskopischen Anatomie des Menschen, IV/8. Berlin: Springer-Verlag, Jansen JKS, Nicolaysen K, Rudjord T (1966). Discharge pattern of neurons of the dorsal spinocerebellar tract activated by static extension of primary endings of muscle spindles. J Neurophysiol 29:1061-1086. Jansen JKS, Nicolaysen K, Walloe T (1969). The firing pattern of dorsal spinocerebellar tract neurones during inhibition. Acta Physiol Scand 77:68-84. Kana M, Kato M (1987). Quisqualate receptors are specifically involved in cerebellar synaptic plasticity. Nature 325:276-279. Kano M, Hashimoto K, Chen C, Abeliovich A, Aiba A, Kurihara H, Watanabe M, Inoue U,Tonegawa S (1995). Impaired synapse elimination during cerebellar development in PKC-gamma mutant mice. Cell 83:1223-1231. Kano M, Hashimoto K, Kurihara H, Watanabe M, Inoue Y, Aiba A, Tonegawa S (1997). Persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking mGluR1. Neuron 18:71-79. Karachot L, Kado RT, Ito M (1994). Stimulus parameters for induction of long-term depression in in-vitro rat Purkinje-cells. Neurosci Res 21:161-168. Kashiwabuchi N, Ikeda K, Araki K, Hirano T, Shibuki K, Takayama C, Inoue Y, Kutsuwada T, Yagi T, Kang Y, Aizawa S, Mishina M (1995). Impairmentof motor coordination, Purkinje cell synapse formation, cerebellar long-term depression in GluR2 mutant mice. Cell 81:245-252. Kawamura K (1975). The pontine projection from the inferior colliculus in the cat. An experimental anatomical study. Brain Res 95:309-322. Kawamura K, Brodal A, Hoddevik G (1974). The projection of the superior colliculus onto the reticular formation of the brainstem. An experimental anatomical study in the cat. Exp Brain Res 19:l-19. Kennedy PR, Gibson AR, Houk JC (1986). Functional and anatomic differentiation between parvicellular and magnocellular regions of red nucleus in the monkey. Brain Res 364: 124-136. Kerr CW, Bishop GA (199 1). Topographical organization in the origin of serotoninergic projections to different regions of the cat cerebellar cortex. J Comp Neurol 15:502-515. Knopfel T, Vranesic I, Staub C, Giihwiler BH (1991). Climbing fibre responses in olivocerebellar slice cultures. 11. Dynamics of cytosolic calcium in Purkinje cells. Eur J Neurosci 3:343-348. Konnerth A, Llano I, Armstrong CM (1990). Synaptic currents in cerebellar Purkinje cells. Proc Natl Acad Sci USA 87:2662-2665. Konnerth A, Dreessen J, Augustine GJ (1992). Brief dendritic calcium signals initiate long-lasting synaptic depression in cerebellar Purkinje cells. Proc Natl Acad Sci USA 89:7051-7055. Kooy FH (19 17). The inferior olive in the vertebrates. Folia Neurobiol 10:205-369. Korbo L, Andersen BB, Ladefoged 0, Moller A (1993). Total numbers of various cell types in rat cerebellar cortex estimated using an unbiased stereological method. Brain Res 609:262-268.

rchitecture of the

43

Korlin D, Larson B (1970). Differences in cerebellar potentials evoked by the group I and cuteaneous components of the cuenocerebellar tract. In: P Andersen, JKS Jansen, eds. Excitatory Synaptic Mechanisms. Oslo: University Press, pp 237-241. Kotchabhakdi N, Hoddevik CH, Walberg F (1978) Cerebellar afferent projections from the perihypoglossal nuclei: an experimental study with the method of retrograde axonal transport of horseradish peroxidase. Exp Brain Res13:13-29. Korneliussen HK (1968). Comments on the cerebellum and its division. Brain Res 8:229236. Kuno M, Miyahard JT (1968). Factors responsible for multiple discharge of neurons in Clarke’s column. J Neurophysiol 31:624-638. Kiinzle H (1975). Autoradiographic tracing of the cerebellar projections from the lateral reticular nucleus in the cat. Exp Brain Res 22:255-266. Y, WaKurihara H, Hashimoto K, Kano M, Takayama C, Sakimura K, Mishina M, Inoue tanabe M (1997). Impaired parallel fiber-Purkinje cell synapse stabilization during cerebellar development of mutant mice lacking the glutamate receptor delta 2 subunit. J Neurosci 17:9613-9623. Kuypers HGJM (195th). Some projections from the peri-central cortex to the pons and lower brainstem in monkey and chimpanzee. J Comp Neurol 110:221-255. Kuypers HGJM (1958b). Cortico-bulbar connections to the pons and lower brain stem in man. An anatomical study. Brain 81:364-388. Ladpli R, Brodal A (1968). Experimental studiesof the commisuarl and reticular formation projections from the vestibular nuclei in the cat. Brain Res 8:65-96. Landsend AS, Arniry MM, Matsubam A, Bergersen L, Usami S, Wenthold RJ, Ottersen OP (1997). Differential localization of delta glutamate receptors in the rat cerebellum: coexpression with AMPA receptors in parallel fiber-spine synapses and absence from climbing fiber-spine synapses. J Neurosci 17:834-842. Lang E, Chou M, SugiharaI, Llinsis R (1989). Intraolivary injection of picrotoxin reorganization of complex spike activity. SOCNeurosci Abst 15:179. Lang EJ, Sugihara I, Llinsis R (1996). GABAergic modulation of complex spike activity by the cerebellar nucleoolivary pathway in rat. J Neurophysiol 76:255-275. Lange W (1975). Cell number and cell density in the cerebellar cortexof man and some other mammals. Cell Tissue Res 157:125”-40. Lannoo MJ, Hawkes R (1997). A search for primitive Purkinje cells: zebrin I1 expression in sea lampreys (Petromyzon marinus). Neurosci Lett 23753-55. Lannoo MJ, Ross L, Maler L, Hawkes R (1991). Development of the cerebellum and its extracerebellar Purkinje cell projection in teleost fishes as determined by zebrin I1 immunocytochemistry. Prog Neurobiol 37:329-363. Leclerc N, Schwarting GA, Herrup K, Hawkes R, Yamamoto M (1992). Compartmentation in mammalian cerebellum: zebrin I1 and P-path antibodies define three classes of sagittally organized bandsof Purkinje cells. Proc Natl Acad Sci USA 89:50065010. Leichnetz GR, Smith DJ, Spencer RF (1984). Cortical projections to the paramedian tegmental and basilar pons in the monkey. J Comp Neurol 228:388“408. Lemkey-Johnston N,Larramendi LMH (1968). Morphological characteristics of mouse stellateandbasketcellsandtheirneuroglialenvelope:anelectronmicroscopic study. J Comp Neurol 134:39-72.

44

Sultan et al.

Llano I, Marty A, Armstrong CM, Konnerth(lA 99 a). 1 Synaptic- and agonist-induced excitatory currents of Purkinje cells in rat cerebellar slices. J Physiol 434: 183-213. Llano I, Dreessen J, Kano M, Konnerth A (1991b). Intradendritic releaseof calcium induced by glutamate in cerebellar Purkinje cells. Neuron 7:577-583. Llin6sR(1974).Bodwitchlecture:motoraspectsofcerebellarcontrol.Physiologist 17:19-46. Llinlis R (1982). Radial connectivity in the cerebellar cortex:a novel view regarding the functional organization of the molecular layer. In: SL Palay, V Chan-Palay, eds. The Cerebellum, New Vistas. New York: Springer, pp 189-192. Llinlis R (1991). The noncontinuous nature of movement execution. In: DR Humphrey, H-J Freund, eds. Motor Control: Concepts and Issues. New York: John Wiley & Sons, pp 223-242. Llinlis R, Muhlethaler M (1988). Electrophysiology of guinea-pig cerebellar nuclear cells in the in vitro brain stem-cerebellar preparation. J Physiol 404:241-258. Llinlis R, Sasaki K (1989). The functional organization of the olivo-cerebellar systemas examined by multiple Purkinje cell recordings. Eur J Neurosci 1:587-602. Llinlis R, Sugimori M (1980a). Electrophysiological properties of in vitro Purkinje cell somata in mammalian cerebellar slices. J Physiol 305:171-195. Llinlis R, Sugimori M (1980b). Electrophysiological properties of in vitro Purkinje cell dendrites in mammalian cerebellar slices.J Physiol 305: 197-213. Llinlis R, Volkind RA (1973). The olivocerebellar system: functional properties as revealed by h~aline-inducedtremor. Exp Brain Res 18:69-87. Llinlis R, YaromY (19814. Electrophysiology of mammalian inferior olivary neurones in vitro. Different types of voltage-dependent ionic conductances.J Physiol 3 15549567. Llinlis R, Yarom Y (198lb). Properties and distribution of ionic conductances generating electroresponsivenessof mammalian inferior olivary neurones in vitro. J Physiol 315:569--584. Llinlis R, Yarom Y (1986). Oscillatory propertiesof guinea-pig inferior olivary neurones and their pharmacological modulation: an in vitro study.J Physiol 376:163-1 82. Llinlis R, Baker B, Sotelo C (1974). Electrotonic coupling between neurones in cat inferior olive. J Neurophysiol 37:560-571. Llinlis R, Yarom Y, Sugimori M (1981). The isolated mammalian brain in vitro: a new technique for the analysis of the electrical activity of neuronal circuit function. Fed Proc 40:2240-2245. Llinas R, Sugimori M, Lin JW, Cherksey B (1989). Blocking and isolation of a calcium channel from neurons in mammals and cephalopods utilizing a toxin fraction (FTX) from funnel-web spider poison. Proc Natl Acad Sci USA 86:1689-1693. Loewy AD (1970). A study of neuronal types in Clarke's column in the adult cat. J Comp Neurol139:53-80. Lundberg A (1964). Ascending spinal hindlimb pathways in the cat. In: JC Eccles, JP Schadk, eds. Progress in Brain Research. v01 12: Physiology of Spinal Neurons. Amsterdam, Elsevier, pp 135-163. Lundberg A (1971). Function of the ventral spinocerebellar tract-a new hypothesis. Exp Brain Res 12:317-330.

Architecture of the System Cerebellar

45

Lundberg A, Oscarsson 0 (1960). Functional organizationof the dorsal spinocerebellar tract in the cat. VII. Identification of unitsby antidromic activation from the cerebellar cortex with recognition of fine functional subdivisions. Acta Physiol Scand 50:356-374. Lundberg A, Weight F (1971). Functional organization of connections to the ventral spinocerebellar tract. Exp Brain Res 12:295-316. Maat GJR (1981). Histogenetic aspects of the cerebellar cortex in man. Acta Morpho1 Neerl-Scand 17:33-52. Marr D (1969). A theory of cerebellar cortex.J Physiol 202:437-470. Mason CA, Gregory E (1984). Postnatal maturation of cerebellar mossy and climbing fibers: transient expression of dual features on single axons. J Neurosci 4:1715-1735. MasonCA,Christakos S, Catalan0 SM (1990).Earlyclimbingfiberinteractionswith Purkinje cells in the postnatal mouse cerebellum. J Comp Neurol 297:77-90. Masu M, Nakajima Y, Moriyoshi K, Ishii T, Akazawa C, NakanashiS (1993). Molecular characterization of NMDA and metabotropic glutamate receptors. Ann NY Acad Sci 707:153-164. Matsushita M,Ikeda M (1976). Projections from the lateral reticular nucleus to the cerebellar cortex and nuclei in the cat. Exp Brain Res 24:403-421. Matsushita M, Hosoya Y (1979). Cells of origin of the spinocerebellar tract in the rat, studied with the method of retrograde transport of horseradish peroxidase. Brain Res 173: 185-200. Matsushita M, Okado N(1981). Spinocerebellar projections to lobulus I and I1 of the anterior lobe in the cat, as studied by retrograde transportof horseradish peroxidase. J Comp Neurol 197:411-424. May JG, Andersen RA (1986). Different patterns of corticopontine projections from separate cortical fields within the inferior parietal lobule and dorsal prelunate gyrus of the macaque. Exp Brain Res 63:265-278. May JG,KellerEK,SuzukiDA(1988).Smoothpursuiteyemovementdeficitswith chemical lesions in the dorsolateral pontine nucleus of the monkey. J Neurophysiol 59:952-977. Mayhew T M (1991). Accurate prediction of Purkinje cell number from cerebellar weight can be achieved with the fractionator. J Cotnp Neurol 308:162-168. McCleskey EW (1994). Calcium channels: cellular roles and molecular mechanisms. Curr Opin Neurobiol 4:304-312. McCormick DA, Pape H-C (1994). Properties of a hyperpolarization-activated cation currentanditsroleinrhythmicoscillationsinthalamicrelayneurones.JPhysiol 431~291-318. McCrea RA, Bishop GA, Kitai ST (1977). Electrophysiological and horseradish peroxidase studies of precerebellar afferents to the nucleus interpositius.11. Mossy fiber system. Brain Res 122215-228. Mehler WR, Feferman ME, Nauta WJH (1960). Ascending axon degeneration following anterolateral cordotomy. An experimental study in the monkey. Brain 83318-750. Midtgaard J, Lasser-Ross N, Ross WN (1993). Spatial distribution of Ca2' influx in turtle Purkinje cell dendrites in vitro: role of a transient outward current. J Neurophysiol 70:2455-2469.

46

Sultan et al.

Mihailoff GA (1993). Cerebellar nuclear projections from the basilar pontine nuclei and nucleus reticularis tegmenti pontis as demonstrated with PHA-L tracing in the rat. J Comp Neurol 330:130-146. Mihailoff GA (1995). Orthograde axonal transport studies of projections from the zona incerta and pretectum to the basilar pontine nuclei in the rat. J Comp Neurol360:301318. Mihailoff GA, Kosinski RJ, Azizi SA, Border BG (1989). Survey of noncortical afferent projectionstothebasilarpontinenuclei:aretrogradetracingstudyintherat. J Comp Neurol 282:617-643. Mishina M, Mori H, Araki K, Kushiya E, Meguro H, Kutsuwada T, Kashiwabuchi N, Ikeda K, Nagasawa M, Yamazakj M, Masaki H, Yamalsura T, Morita T, Sakimura K (1993). Molecular and functional diversity of the NMDA receptor channel. Ann N Y Acad Sci 707:136-152. Mlonyeni M (1973). The number of Purkinje cells and inferior olivary neurons in the cat. J Comp Neurol 147:l-10. Moatamed F (1966). Cell frequencies in the human inferior olivary nuclear complex. J Comp Neurol 128: 109-1 16. Mock M,Schwarz C, Thier P (1997). Electrophysiological properties of neurons in the rat. IT. Postsynaptic potentials. J Neurophysiol 78:3338-3350. Mock M, SchwarzC , Thier P (1998). Serotonin decreases excitatory postsynaptic potentials but increases the membrane excitability of rat pontine nuclei neurons in vitro. SOC Neurosci Abstr 24:666. Mock M, Schwarz C, Wahle P, Thier P (1999). GABAergic inhibition in the rat pontine nuclei is exclusively extrinsic: evidence from an in situ hybridization study for GAD,, mRNA Exp Brain Res 124529-532. Mouginot D, Gahwiler BH (1995). Characterization of synaptic connections between cortex and deep nuclei of the rat cerebellum in vitro. Neuroscience 64:699-712. Mustari MJ, Fuchs AF, Wallman J (1988). Response properties of dorsolateral pontine units during smooth pursuit in the rhesus macaque. J Neurophysiol 60:664-686. Napieralski JA, Eisenman LM (1993). Developmental analysis of the external granular layer in the meander tail mutant mouse-do cerebellar microneurons have independent progenitors? Dev Dynam 197:244-254. Napper W, HarveyRJ(1988).Numberofparallelfibersynapsesonanindividual Purkinje cell in the cerebellum of the rat. J Comp Neurol 274: 168-177. Nelson BJ, Mugnaini E (1988). The rat inferior olive as seen with imunostaining for glutamate decarboxylase. Anat Embryo1 179: 109-127. Noda H, Sugita S , Ikeda Y (1990). Afferent and efferent connections of the oculomotor region of the fastigial nucleus in the macaque monkey.J Comp Neurol 302:330348. Nyby 0, Jansen J (1951). An experimental investigation of the cortico-pontine projection in Macaca mulatta. Nors Vidensk Akad Avh I Math Naturv K1 3:1-47. Oberdick J, Smeyne RJ, Mann JR, Zackson S , Morgan JI (1990). A promoter that drives transgene expression in cerebellar Purkinje and retinal bipolar neurons. Science 248:223-226. Onodera S (1984). Olivary projections from the mesodiencephalic structures in the cat

rchitect~reof the Cere

studied by means of axonal transport of horseradish peroxidase and tritiated amono acids. J Comp Neurol 227:37-49. Ophoff RA, Terwindt GM, FrantsRR, Ferrari MD (1998). P/Q-type Ca2+ channel defects in migraine, ataxia and epilepsy. Trends Pharmacol Sci 19:121-127. Ophoff RA, Tenvindt GM, Frants RR,Fenari MD (1999). P/Q-type Ca2+ channel defects in migraine, ataxia and epilepsy. Trends Pharmacol Sci 19:121-127. Oscarsson 0 (1965). Functional organization of the spino- and cueno-cerebellar tract. Physiol Rev 45:495-522. Oscarsson 0 (1969). The sagittal organizationof the cerebellar anterior lobe as revealed by the projection patterns of the climbing fiber system. In: R LlinBs, ed. Neurobiology of Cerebellar Evolution and Development. Chicago: American Medical Association, pp 525-537. Oscarsson 0 (1973). Functional organization of spinocerebellar paths. In: A Iggo, ed. Handbook of Sensory Physiology. vol. 12: Somatosensory System. Berlin: Springer, pp 339-380. Oscarsson 0 (1980). Functional organizationof olivary projections to the cereballar anterior lobe. In: J Courville, C de Montigny, Y Lamarre, eds. The Inferior Olivary Nucleus: Anatomy and Physiology. New York: Raven Press, pp 279-289. Oscarsson 0, Uddenberg N (1964). Identificationof a spinocerebellar tract activated from forelimb afferents in the cat. Acta Physiol Scand 62:125-136. Oscarsson 0, Uddenberg N (1965). Properties of afferent tract to the rostral spinocerebellar tract in the cat. Acta Physiol Scand 64:143-153. Pakkenberg B, Gundersen HJ (1997). Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 384:312-320. Palkovits M, Magyar P, Szentagothai J (1971). Quantitative histological analysis of the cerebellar cortexin the cat. I. Number and arrangement in space of Purkinje cells. Brain Res 32:1-1 3. Palkovits NI, Mezey E, HBmoriJ, SzentagothaiJ (1977). Quantitative histological analysis of the cerebellar nuclei in the cat. I. Numerical data on cells and on synapses. Exp Brain Res 28: 189-209. Plioplys AV,Thibault J, HawkesR (1985). Selective stainingof a subsetof Purkinje-cells inthehumancerebellumwithmonoclonal-antibodymabq113.JNeurolSci. 70:245-256. Pouzat C, Kondo S (1996). An analysis of neurobiotin-filled stellate cell axons in the rat cerebellum. Soc Neurosci Abstr 22: 1632. Ralcic P(1972). Extrinsic cytological determinants of basket and stellate cell dentritic pattern in the cerebellar molecular layer. J Comp Neurol 146:335-354. Rakic P, Sidman RL (1973). Sequenceof developmental abnormalities leading to granule cell deficit in cerebellar cortex of weaver mutant mice. J Comp Neurol 152:103132. Ram6n y Cajal S (1909). Histologie du Systkme Nerveux de l’Homme etdes Vertdbrds. Paris: Maloine. Rapp M, Segev I,Yarorn Y (1994). Physiology, morphology and detailed passive models of guinea-pig cerebellar Purkinje cells. J Physiol 474:101-118. Renno WM, Lee JH, Beitz AJ (1997). Light and electron-microscopic immunohistochemi-

48

Sultan et al.

cal localizationof N-acetylaspartylglutamate (NMG). in the olivocerebellar pathway of the rat. Synapse 26:140-154. RCthelyiM(1970).UltrastructuralsynaptologyofClarke'scolumn.ExpBrain Res 11:159-174. Riley HA (1928). A comparative study of the arbor vitae and the folia1 pattern of the mam malian cerebellum. Arch Neurol Psychatr 20:895. Rosina A, Provini L, Bentivoglio M, Kuypers HGJM (1980). Pontoneocerebellar axonal branching as revealed by double flourescent retrograde labeling technique. Brain Res 195:461-466. Ross ME, Fletcher C, Mason CA, Hatten ME, Heintz N (1990). Meander tail reveals a discrete developmental unit in the mouse cerebellum. Proc Natl Acad Sci USA 87:4189-4192. Ruggiero D, BattonRR 111, Jayaraman A, Carpenter MB (1977). Brain stem afferents to the fastigial nucleus in the cat demonstrated by transport of horseradish peroxidase. J Comp Neurol 172189-210. Ruigrok TJ (1997). Cerebellar nuclei: the olivary connection. Prog Brain Res 114:167192. Ruigrok TJ, Voogd J (1990). Cerebellar nucleo-olivary projections in rat. An anterograde tracing study with Phaseolus vulgaris leucoagglutinin (PHA-L). J Comp Neurol 298~315-333. Ruigrok TJ, De Zeeuw CI, Van Der Burg J, Voogd J (1990). Intracellular labelingof neurons in the medial accessory olive of the cat. I. Physiology and light microscopy. J Comp Neurol 300:462-477. Sasah K, Kawagutchi S, Shimono T, Prelevic S (1970). Electrophysiological studiesof the pontine nuclei. Brain Res 20:425-438. Sasaki K, LlinhsR (1985). Dynamic electrotonic coupling in mammalian inferior olive as determined by simultaneous multiple Purkinje cell recordings. Biophys J 47:53a. Sasaki K, Bower JM, LlinhsR (1989). Multiple Purkinje cell recordings in rodent cerebellar cortex. Eur J Neurosci 1:572-586. Sakai ST, Inase M, Tanji J (1996). Comparison of cerebellothalamic and pallidothalamic projections in the monkey (Macaca-fuscata)-a double anterograde labeling study. J Comp Neurol 368:215-228. ScheibelME,ScheibelAB(1955).Theinferiorolive.AGolgistudy.JCompNeurol 102:77-132. Schmahmann JD, Pandya DN (1991). Projections to the basis pontis from the superior temporal sulcus and superior temporal region in the rhesus monkey. J Comp Neurol 3081224-248. Schmahmann JD, Pandya DN (1993). Prelunate, occipitotemporal, parahippocampal projections to the basis pontis in rhesus monkey. J Comp Neurol337:94-112. Schmahmann JD, Pandya DN (1997). Anatomic organizationof the basilar pontine projections from prefrontal cortices in rhesus monkey. J Neurosci 1:17:438"458. Schwarz C, Schmitz Y (1997). Projection from the cerebellar lateral nucleus to precerebellar nuclei in the mossy fiber pathway is glutamatergic: a study combining anterograde tracing with immunogold labeling in the rat. J Comp Neurol 381:320334.

Architecture of the System Cerebellar

49

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-

ultan et al.

lar cortex-simple constraints may underlie a remarkably regular design.NIn: Elsner, H Breer, eds. Sensory Transduction. Stuttgart: Thieme. Sultan F, Dortenmann M, Braitenberg V (1992). The synapse distribution on the cerebellar mossy fibers. Eur J Neurosci 15:215. Sunderland S (1940). The projectionof the cerebral cortex on the pons and cerebellum in the monkey. J Anat (Lond) 74: 201-226. Suzuki DA, Keller EL (1984). Visual signals in the dorsolateral pontine nucleus of the alert monkey: their relationship to smooth-pursuit eye movements. Exp BrainRes 53:473-478. SzentiigothaiJ, Rajkovits K (1959). Ueber den Ursprung der Kletterfasern des Kleinhirns. Z Anat Entwickl Gesch 121: 130-141. Takacs J, Hdmori J (1994). Developmental dynamics of Purkinje-cells and dendritic spines in rat cerebellar cortex. J Neurosci Res 38:515-530. P, De-Camilli P Takei K, Stukenbrok H, Metcalf A, MigneryGA,SudhofTC,Volpe (1992). Ca2+ stores in Purkinje neurons: endoplasmic reticulum subcompartments demonstratedbytheheterogeneousdistribution of theInsP3receptor, Ca(2')ATPase, calsequestrin. J Neurosci 12:489-505. Tank DW, Sugimori M, Connor JA,Llinhs R (1988). Spatially resolved calcium dynamics of mammalian Purkinje cells in cerebellar slice. Science 242:773-777. Thach WT (1970). Discharge of cerebellar neurons related to two maintained postures and two prompt movements. I. Nuclear cell output. J Neurophysiol 33:527-536. Thach WT (1972). Cerebellar output: properties, synthesis and uses. Brain Res 40:89-97. Thier P,Erickson RG (1992a). Responses of visual-tracking neurons from cortical area MSTI to visual, eye and head motion. Eur J Neurosci 4:539-553. Thier P,Erickson RG (1992b). Vestibular input to visual-tracking neurons in area MST of awake rhesus monkeys. AnnN Y Acad Sci 656:960-963. Thier P, Koehler W (1987). Morphology, number and distribution of putative GABAergic neurons in the basilar pontine grey of the monkey. J Comp Neurol265:311-322. Thier P,Koehler W, Buettner UW (1988). Neuronal activity in the dorsolateral pontine nucleus of the alert monkey modulated by visual stimuli and eye movements. Exp Brain Res 70:496--5 12. Thier P, Koehler W, Buettner UW (1989). Investigationof the dorsolateral basilar pontine grey of the alert monkey. Brain Behav Evol 33:75-79. Thier P,Bachor A, Faiss W, Dichgans J, KoenigE(1991).Imperfectvisualtracking eye movements due to an ischemic lesion of the basilar pons. Ann Neurol29:443448. Thier P,Herbst H, Thielert C-D, Erickson RG (1994). A cortico-ponto-cerebellarpathway for smooth-pursuit eye movements. In:J M Delgado-Garcia, E Godaux, P-PVidal, eds. Information Processing Underlying Gaze Control. Oxford: Pergamon Press, pp 237-249. Thielert C-D, Thier P (1993). Patterns of projections from the pontine nuclei and the nucleus reticularis tegmenti pontis to the posterior vermis in the rhesus monkey: a study using retrograde tracers. J Comp Neurol 337:113-126. cortico-ponto-cerebellarsystem. Tomasch J (1969). The numerical capacity of the human Brain Res 13:476-484.

Architecture of the System Cerebellar

51

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

52

Sultan et al.

corticopontineprojectionintheprimate (Macaca fascicularis and Saimiri sciureus). 11. The projection from frontal and parietal association areas. Neuroscience 4:747-765. Wiksten B (1979). The central cervical nucleus in the Icat. .A Golgi study. Exp Brain Res 36: 143-154. Yamada J, Noda H (1987). Afferent and efferent connections of the oculomotor cerebellar vermis in the macaque monkey. J Comp Neurol265:224-241. Yamada T,Suzuki DA, Yee RD (1996). Smooth pursuit-like eye movements evoked by ~crostimulationin macaque nucleus reticularis tegmenti pontis. J Neurophysiol 76~3313-3324. Yamamoto T,Fukuda M, LlinAs R (1986). Bilateral synchronizationof climbing fiber activity. SOC Neurosci Abst12577. Yoss RE (1952a). Studies of the spinal cord. Part I. Topographic localization within the dorsal spino-cerebellar tract inMacaca mulatta. J Comp Neurol 975-20. Yoss RE (1952b). Studiesof the spinal cord. Part11. Topographic localization within the ventral spino-cerebellar tract inMacaca mulatta. J Comp Neurol 97:613-638. YuzakiM,ForrestD,VerselisLM, Sun SC,CurranT,ConnorJA(1996).Functional NMDA receptors are transiently active and support the survival of Purkinje-cells in culture. J Neurosci 164651-4661.

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

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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

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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-

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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-

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63

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

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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

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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).

REFERENCES 1. Dow RS, Moruzzi G. The Physiology and Pathology of the Cerebellum. Minneapolis: University of Minnesota Press, 1958. 2. Brodal A. Neurological Anatomy. New York: Oxford University Press, 1981. 3. Gilman S, Bloedel JR, Lechtenberg R. Disorders of the Cerebellum. Philadelphia: FA Davis, 1981. 4. Dichgans J. Clinical symptomsof cerebellar dysfunction and their topodiagnostical significance. Hum Neurobiol 1984; 2:269-279. 5. Zee DS, Yee RD, Cogan DG, Robinson DA, Engel WK. Ocular motor abnormalities in hereditary cerebellar ataxia. Brain 1976; 99:207-234.

68

Top ka

6. Fetter M, Klockgether T, Schulz JB, Faiss J, Koenig E, Dichgans J. Oculomotor abnormalitiesand MRIfindingsinidiopathiccerebellarataxia.JNeurol1994; 241 :234-241. 7. Arpa J, Sarria J, Cruz MA, Lopez PR, Ferrer T, Palomo F, Alonso M, Vivancos F, Nos J, Ivanez V. Electro-oculogram in multiple system and late onset cerebellar atrophies. Rev Neurol 1995; 23:969-974. 8. Robinson DA. Adaptive gain control of vestibuloocular reflex by the Cerebellum. J Neurophysiol 1976; 39:954-969. 9. Babinski J. De l’asynergie ckrkbelleuse. Rev Neurol 1899; 753064316. 10. Jackson JH. A study of convulsions. In: Taylor L, ed. Selected Writings of John Hughlings Jackson (1932). New York: Basic Books, 1870:8-36. 11. Luciani L. Das Kleinhirn. Neue Studien zurNomalen und Pat~ologischenPhysiologie. Leipzig: Besold, 1893. 12. Flourens P.RecherchesExpkrimentalessurlesPropritesetlesFonctionsdu SystBme Newaux, dans les Animaux VertBbres. Paris: Crevot, 1824. 13. Babinski J. Asynergie et inertie ckrkbelleuse. Rev Neurol 1906; 14:685-686. 14. Thach WT,Goodhn HP, Keating JG. The cerebellum and the adaptive coordination of movement. Annu Rev Neurosci 1992; 15:403-442. 15. Holmes G. The symptoms of acute cerebellar injuries due to gunshot injuries. Brain 1917; 40~461-535. 16. Holmes G. TheCerebellumofman.(TheHughlingJacksonmemoriallecture). Brain 1939; 62: 1-30. 17 Wacholder K. Untersuchungen uber die Innervation und Koordination der Bewegungen mit Hilfe der Aktionsstrome. Pfliigers Arch Ges Physiol 1923; 199:625650. 18. Flament D,Hore J. Movement and electromyographic disorders associated with cerebellar dysmetria. J Neurophysiol 1986; 55:1221-1233. 19. Hore J, Wild B, Diener HC. Cerebellar dysmetria at the elbow, wrist, and fingers. J Neurophysiol 1991; 65563-571. 20. Hallett M, Massaquoi SG. Physiologic studies of dysmetria in patients with cerebellar deficits. Can J Neurol Sci 1993; Suppl. 3:S83-92. 21. Hallett M,Shahani B, Young RR. EMG analysis in patients with cerebellar deficits. J Neurol Neurosurg Psychiatry 1975; 38: 1163-1169. 22. Wild B, Klockgether T, DichgansJ. Acceleration deficit in patients with cerebellar lesions. A study of kinematic and EMG parameters in fast wrist movements. Brain Res 1996; 713:186-191 23. Spidalieri G, Busby L, Lamarre Y. Fast ballistic arm movements triggered by visual, auditory, and somesthetic stimuli in the monkey. 11. Effects of unilateral dentate lesion on discharge of precentral cortical neurons and reaction time. J Neurophysiol 1983; 50:1359-1379. 24. Butler EG, Home MK, Hawkins NJ. The activity of monkey thalamic and motor cortical neurones in a skilled, ballistic movement. J Physiol Lond 1992; 445:25-48. 25. Topka H, Wild B, DichgansJ. Motor cortex excitability during motor prepartion in patients with cerebellar degeneration. Mov Disord 1994; 9: 125. V, Nitschke MF, Malin JP. Enhancement 26. Wessel K, Tegenthoff M, Vorgerd M, Otto

Normal Functions of the Cerebellum

27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43

*

44.

69

of inhibitory mechanisms in the motor cortex of patients with cerebellar degeneration: a study with transcranial magnetic brain stimulation. Electroencephalogr Clin Neurophysiol1996;101:273-280. Becker WJ, Kunesch E, Freund HJ. Coordination of a multi-joint movement in normal humans and in patients with cerebellar dysfunction. Can J Neurol Sci 1990; 17:264-274. Bastian AJ, Martin TA, Keating JG, Thach WT. Cerebellar ataxia: abnormal control of interaction torques across multiple joints.J Neurophysiol 1996; 76:492-509. Topka H, Dichgans J. The cerebellum and the physics of movement. Behav Brain Sci 1997; 20:266. Topka H, Konczak J, Schneider K, Boose A, Dichgans J. Multijoint arm movements in Cerebellar ataxia: abnormal control of movement dynamics. Exp Brain Res1998;119:493-503. Bernstein N. The Co-ordination and Regulation of Movement. Oxford: Pergamon Press, 1967. Massaquoi SG, Hallett M. Kinematics of initiating a two-joint arm movement in patients with cerebellar ataxia. Can J Neurol Sci 1996; 23:3-14. Topka H, Konczak J, Dichgans J. Coordination of multi-joint arm movements in cerebellar ataxia: analysis of hand and angular kinematics. Exp Brain Res 1998; 119:483-492. Boose A, DichgansJ, Topka H. Deficits in phasic muscle force generation explain insufficient compensation for interaction torque in cerebellar patients. Neurosci Lett 1999; 261:53-56. Gottlieb GL, SongQ, Hong DA, Almeida GL, Corcos D. Coordinating movement at two joints: a principle of linear covariance. J Neurophysiol 1996; 75: 1760-1764. Keating JG, Thach WT. No clock signal in the discharge of neurons in the deep cerebellar nuclei. J Neurophysiol 1997; 77:2232-2234. Braitenberg V. Is the cerebellar cortex a biological clock in the millisecond range? Prog Brain Res 1967; 25:334-346. Ivry RB, Keele SW, Diener HC. Dissociation of the lateral and medial cerebellum in movement timing and movement execution. Exp Brain Res 1988; 73:167-180. Keele SW, Ivry R. Does the cerebellum provide a common computation for diverse tasks? A timing hypothesis. Ann NY Acad Sci 1990; 608:179-207. Ivry R. Cerebellar timing systems. Int Rev Neurobiol 1997; 41:555-573. Agid Y. Fromposturetoinitiationofmovement.RevNeurol(Paris)1990; 146:536-542. Traub MM, Rothwell JC, Marsden CD. Anticipatory postural reflexes in Parkinson’s disease and other akinetic-rigid syndromes and in cerebellar ataxia. Brain 1980; 103:393-412. Diener HC, Dichgans J, Guschlbauer B, Bacher M, Langenbach P. Disturbances of motor preparation in basal ganglia and cerebellar disorders. Prog Brain Ees 1989; 80:481-488. Diener HC, Dichgans J, Guschlbauer B, Bacher M, Rapp H, Klockgether T. The coordination of posture and voluntary movement in patients with cerebellar dysfunction. Mov Disord 1992; 7:14”22.

170

Top ka

45. Horak FB, Diener HC. Cerebellar control of postural scaling and central set in stance. J Neurophysiol 1994; 72:479-93. 46. Deuschl G, BainP, Brin M. Consensus statement of the Movement Disorder Society on Tremor.AdHocScientificCommittee.MovDisord1998;13(Suppl3): 2-23. 47. Flment D, Vilis T, HoreJ. Dependence of cerebellar tremoron proprioceptive but not visual feedback. Exp Neurol 1984; 84:314-25. 48. Carrea RME,Mettler FA. Function of the brachium conjunctivum and related structures. J Comp Neurol 1955; 102:151-322. 49. Carrea RME, Mettler FA. Physiologic consequences following extensive removal of cerebellar cortex and deep cerebellar nuclei and effect of secondary cerebral ablation in the primate. J Comp Neurol 1947; 87:169-288. 50. Flament D, Hore J. Comparison of cerebellar intention tremor under isotonic and isometric conditions. Brain Res 1988; 439:179-186. 51. Nakamura R, KamakuraK, Tadano Y, Hosoda Y, Nagata N, TsuchiyaK, Iwata M, Shibasaki H. MR imaging findings of tremors associated with lesions in cerebellar outflow tracts: report of two cases. Mov Disord 1993; 8:209-212. 52. Bastian AJ, Thach WT. Cerebellar outflow lesions: a comparison ofmovement deficits resulting from lesions at the levels of the cerebellum and thalamus. Ann Neurol 1995; 38:881-892. 53. Hore J, Flament D. Evidence that a disordered servo-like mechanism contributes to tremor in movements during cerebellar dysfunction. J Neurophysiol 1986; 56: 123136. 54. Mauritz m,Schmitt C, Dichgans J. Delayed and enhanced long latency reflexes as the possible cause of postural tremor in late cerebellar atrophy. Brain 1981 ; 104:97-116. 55. Friedemann HH, Noth J, Diener HC, Bacher M. Long latency EMG responses in hand and leg muscles: cerebellar disorders. J Neurol Neurosurg Psychiatry 1987; 50171-77. 56. Topka H, Mescheriakov S, Boose A, Kuntz R, Hertrich I, Seydel L, Dichgans J, Rothwell J. A cerebellar-like terminal and postural tremor induced noma1 in man by transcranial magnetic stimulation. Brain 1999;122: 1551-1562. 57. Marr D. A theory of cerebellar cortex. J Physiol (Lond) 1969; 202:437-470. 58. Albus JSA. A theory of cerebellar function. Math Biosci 1971; 10:25-66. 59. Ito M, Kano M. Long-lasting depression of parallel-fiber-Pur~nje cell transmission induced by conjunctive stimulation of parallel fibers and climbing fibers in the cerebellar cortex. Neurosci Lett 1982; 33:253-258. 60. Watanabe E. Role of the primate flocculus in adaptation of the vestibulo-ocular reflex. Neurosci Res 1985; 3:20-38. 61. GlicksteinM.Thecerebellumandmotorlearning.CurrOpinNeurobiol1992; 21802-806. 62. Thompson RF, Bao S, Chen L, Cipriano BD, Grethe JS, Kim JJ, Thompson JK, Tracy JA, Weninger MS, Kjrupa DJ. Associative learning. Int Rev Neurobiol 1997; 41~151-189. 63. Woodruff-Pak DS.Classical conditioning. Int Rev Neurobiol 1997; 41:341-366.

Functions Normal

of the Cerebellum

71

64. Ye0CH,HardimanMJ,GlicksteinM.Classicalconditioningofthenictitating membrane response of the rabbit: 11. Lesions of the cerebellar cortex. Exp Brain Res 1985; 60:99-113. 65. Ye0 CH, Hardiman MJ. Cerebellar cortex and eyeblink conditioning: a reexamination. Exp Brain Res 1992; 88:623-638. 66. Lavond DG, Steinmetz JE. Acquisitionof classical conditioning without cerebellar cortex. Behav Brain Res 1989; 33:113-164. Glickstein M. Classical conditioning of thenictitating 67. Ye0CH,HardimanMJ, I. Lesions of the cerebellar nuclei. Exp Brain Res membrane response of the rabbit: 1985; 60:87-98. 68. Welsh JP, Harvey JA. Cerebellar lesions and the nictitating membrane reflex: performance deficits of the conditioned and unconditioned response. J Neurosci 1989; 91299-311. 69. Lavond DG, Logan CG, Sohn JH, Garner WD, Kanzawa SA. Lesions of the cerebellar interpositus nucleus abolish both nictitating membrane and eyelid EMG conditioned responses. Brain Res 1990; 514:238-248. 70. Berthier NE, Moore JW. Activity of deep cerebellar nuclear cells during classical conditioning of nictitating membrane extension in rabbits. Exp Brain Res 1990; 83:44-54. 71. Topka H, Valls-Sole J, Massaquoi SG, Hallett M. Deficit in classical conditioning in patients with cerebellar degeneration. Brain 1993; 116:961-969. J, Birbaumer N. 72. Daurn I, Schugens MM, Ackermann H, Lutzenberger W, Dichgans Classical conditioning after cerebellar lesions in humans. Behav Neurosci 1993; 107:748--756. 73. Bracha V, Zhao L, Wunderlich DA, Morrissy SJ, Bloedel JR. Patients with cerebellar lesions cannot acquire but are able to retain conditioned eyeblink reflexes. Brain 1997;120:1401-1413. 74. Kelly TM, Zuo CC, Bloedel JR. Classical conditioning of the eyeblink reflex in the decerebrate-decerebellate rabbit. Behav Brain Res 1990;38:7-18. 75. Welsh JP, Harvey JA. Pavlovian conditioning in the rabbit during inactivation of the interpositus nucleus. J Physiol 1991; 444:459-480. 76. Lisberger SG. The neural basis for learning of simple motor skills. Science1988; 242:728-735. 77. Lisberger SG. Physiologic basis for motor learning in the vestibulo-ocular reflex. Otolaryngol Head Neck Surg 1998; 119:43-48. 78. Weiner MJ, Hallett M, Funkenstein HH. Adaptation to lateral displacement of visioninpatientswithlesionsofthecentralnervoussystem.Neurology1983; 33:766-772. 79. Martin TA, Keating JG, Goodkin HP, Bastian AJ, Thach WT. Throwing while looking through prisms.I. Focal olivocerebellar lesions impair adaptation. Brain 1996; 119~1183-1198. C. Cer80. Timmann D, Kolb FP, Baier C, Rijntjes M, Muller SP, Diener HC, Weiller ebellar activation during classical conditioning of the human flexion reflex: a PET study. Neuroreport 1996; 7:2056-2060. 81. Timmann D, Musso C, Kolb FP, Rijntjes M, Juptner M, Muller SP, Diener HC,

72

Topka

Weiller C. Involvement of the human cerebellum during habituation of the acoustic startle response: a PET study. J Neurol Neurosurg Psychiatry 1998; 65771-773. 82. Mumme1 P, Timmann D, Krause W,Boering D, Thilmann AF, DienerWC, Horak FB. Postural responses to changing task conditions in patients with cerebellar lesions. J Neurol Neurosurg Psychiatry 1998; 65:734-742. 83.GilbertPF,ThachWT.Purkinjecellactivityduringmotorlearning,BrainRes 1977;128:309-328. 84. Ojakangas CL, Ebner TJ. Purkinje cell complex and simple spike changes during a voluntary arm movement learning task in the monkey. J Neurophysiol 1992; 68:2222-2236. 85. Deuschl G, Toro C, Zeffiro T, Massaquoi S, Hallett M. Adaptation motor learning of arm movements in patients with cerebellar disease. J Neurol Neurosurg Psychiatry 1996; 60:515-519. 86. Friston KJ,Frith CD, Passingham RE, Liddle PF, Frackowiak RS. Motor practice and neurophysiological adaptation in the cerebellum: a positron tomography study. Proc R SOC Lond Biol 1992; 248:223-228. Roland E, Bohm C, Greitz T, Stone ES. Motor learning in man: a positron 87. Seitz RJ, emission tomographic study. Neuroreport 1990; 157-60. 88. SeitzRJ,CanavanAG,YaguezL,HerzogH,TellmannL,Knorr U, Huang Y, Homberg V. Successive rolesof the cerebellum and premotor cortices in trajectorial learning. Neuroreport 1994; 5:2541-2544. 89. Sanes JN, Dimitrov B, Hallett M. Motor learning in patients with cerebellar dysfunction. Brain 1990; 113:103-120 90. Topka H, Massaquoi SG, Benda N, Hallett M. Motor skill learning in patients with cerebellar degeneration. J Neurol Sci 1998; 158: 164-172. 91. Timmann D, Shimansky Y,Larson PS, Wunderlich DA, StelmachGE, Bloedel JR. Visuomotor learning in cerebellar patients. Behav Brain Res 1996; 81:99-113. 92. Hallett M, Pascual-Leone A, Topka H. Adaptation and skill learning. evidence for different neural substrates. In: BloedelJR, Wise S, eds. Acquisition of Motor Behavior in Vertebrates. Cambridge, MA: MIT Press, 1996. 93. Braitenberg V. The cerebellum and the physics of movement: some speculations. In: Clickstein M, Ye0 C, Stein J, eds. Cerebellum and Neuronal Plasticity. New York: Plenum Press, 1987: 193-207. 94. Sainburg RL, Poizner H, Ghez C. Lossof proprioception produces deficits in interjoint coordination. J Neurophysiol 1993; 70:2136-2147. 95, Sainburg RL,Ghi1ar-i MF, Poizner H, Ghez C. Control of limb dynamics in normal subjects and patients without proprioception. J Neurophysiol 1995; 73:820835. 96. Sainburg RL, Ghez C, Kalakanis D. Intersegmental dynamics arecontrokd by sequential anticipatory, error correction, and postural mechanisms. J Neurophysiol 1999; 81:1045-1056. 97.Ghez C , Sainburg R. Proprioceptivecontrol of interjointcoordination.CanJ Physiol Pharmacol 1995; 73:273-284. 98. AllenGI,Tsukahara N. CerebrocerebellarcommunicationSystems.PhysiolRev 1974; 54:957-1006.

Functions Normal

of the Cerebellum

73

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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138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156.

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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

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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

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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

I un

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U

U

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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).

REFERENCES 1. Bell J, CarmichaelEA. On hereditary ataxia and spastic paraplegia. In: FisherRA, ed. Treasury in Human Inheritance. v01 IV, part 111. Cambridge: Cambridge at University Press, 1939:248-566.

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2. Harding AE. The Hereditary Ataxias and Related Disorders. Edinburgh: Churchill Livingstone,1984. 3. Friedreich N. Uber degenerative Atrophie der spinalen Hinterstrange. Virchows Arch Pathol Anat Physiol 1863; 22:1-26. 4. Friedreich N. Uber degenerative Atrophie der spinalen Hinterstrange. Virchows Arch Pathol Anat Physiol 1863; 26:391-419. S. Friedreich N. Uber degenerative Atrophie der spinalen Hinterstrange. Virchows Arch Pathol Anat Physiol 1863; 26:433-459. 6. Friedreich N. h e r Ataxie mit besonderer Beriicksichtigung der hereditaren Formen. Virchows Arch Pathol Anat Physiol 1876; 68:145-245. 7. Friedreich N. Uber Ataxie mit besonderer Berucksichtigung der hereditaren Formen. Virchows Arch Pathol Anat Physiol 1877; 70:140-152. 8. Ladame P. Friedreich’s disease. Brain 1890; 13:467-537. 9. Strumpell A. Beitrage zur Pathologie des Ruckenmarks. Arch Psychiatr Nervenkr 1880;10:676-717. primben combiniertenSyste10. StriimpellA.UebereinebestimrnteFormder merkrankung des Ruckenmarks. Arch Psychiatr Nervenkr 1886; 17:217-238. 2Nervenheilk 11. Strumpell A. Ueber die hereditbe spastische Spinalparalyse. Dtsch 1893; 4~173-188. 2 primbe Seitenstrangsklerose (spastische Spinalparalyse). Dtsch 12. Striimpell A. Die Nervenheilk 1904; 27:291-339. 13. Striimpell A. Degeneracidn primitiva delas vias piramidales. In: Tratado de Patologia y Terapkutica Especiales de las Enfermedades Internas.v01 11, 3rd ed. Barcelona: Francisco Seix, 1924: 601-609. 14. Harding AE. Hereditary “pure” spastic paraplegia: a clinical and genetic study of 22 families. J Neurol Neurosurg Psychiatry 198 1; 44:87 1-883. 15. Polo JM,Calleja J, Combarros 0,Berciano J. Hereditary “pure” spastic paraplegia: a study of nine families. J Neurol Neurosurg Psychiatry 1993; 56:175-181. 16. BugeA,EscourolleR,RancurelG,GrayF,PertuisetBF.Laparaplkgie spasmodique familiale de Strumpell-Lorrain: une nouvelle observation anatomoclinique. Rev Neurol (Paris) 1979; 13S:329-337. 17. Grassin D-Y. Laparaplkgiespasmodiquefamiliale(maladiedeStriimpellLorrain). Apropos del1 gknealogies. Doctoral dissertation, University Claude Bernard, Lyon, France, 1975. 18. Lorrain M. Contribution ii l’dtude de la paraplkgie spasmodique familial. Doctoral dissertation, Universityof Paris, Stenheil G, ed., 1898. 19. Dejerine-ThomasA.L’atrophie olivo-ponto-ckrkbelleuse. NouvIconogrSalpet 1900; 131330-370. 20. MenzelP. Beitrage zur Kenntniss der hereditben Ataxie und Kleinhirnatrophie. Arch Psychiatr Nervenkr 1891;22: 160-190. 21. Berciano J. Nuevascontribuciones a1 conocirnientoclinic0ypatoldgicodela atrofia olivopontocerebelosa. Doctoral dissertation, University of Bilbao, Spain, 1978. 22. Berciano J. Olivopontocerebellar atrophy. A reviewof117cases. J Neurol Sci 1982; 53~253-272.

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23. LoewP. L’atrophie olivo-ponto-cdrdbelleuse. Doctoral dissertation, Universityof Paris, France, 1903-1904. of heredity 24. Keiller N. Four casesof olivo-ponto-cerebellar atrophy giving a history with three autopsies. South Med J 1926; 19:518-522. 25. HassinGB,HarrisTH.Olivopontocerebellaratrophy.ArchNeurolPsychiat (Chicago) 1936; 35:43-63. 26. Welte E. Die Atrophie des Systems der Brackenfusses und der unteren Oliven. Arch Psychiatr Nervenkr 1939; 109:649-698. 27. Scherer HJ. Beitrage zur pathologischen Anatomie des Kleinhirns: 3. Mitteilung (genuine ~leinhi~atrophien). 2; Ges Neurol Psychiatr 1933; 145:335-405. 28. Scherer HJ. Extrapyramidale Storungen bei der olivopontocerebelliiren Atrophie: ein Beitrag zum Problem des lokalen vorzeitigen Alterns.Z Ges Neurol Psychiatr 1933; 145:406-419. 29. Critchley M, Greenfield JC. Olivo-ponto-cerebellar atrophy. Brain 1948; 7 1:343364. 30. GuillainG,MathieuP,Bertrand 1. Etudeanatorno-cliniquesurdeuxcases d’atrophie olivo-ponto-c&dbelleuse avec rigiditd. Ann Mdd 1926; 20:417-459. 31. Guillain G, Thdvenard A, Jonesco. Un cas de syndrome cdrdbelleux du type de I’atrophie olivo-ponto-cdrdbelleuseavec developprnent progressif d’un etat hypertonique. Rev Neurol (Paris) 1928; 50:890-895. 32. Berciano J. Olivopontocerebellar atrophy. In: Jankovic J, Tolosa E, eds. Parkinson’s Disease and Movement Disorders. Baltimore: Williams & Wilkins, 1998: 263-295. 33. Berciano J,Combarros 0, Polo JM, PascualJ, Oterino A. An early description of striatonigral degeneration. J Neurol 1999; 24k462-466. 34. Holmes G. Aform of familial degeneration of the cerebellum. Brain 1907; 30:466489. 35. Greenfield JG. The Spino-Cerebellar Degenerations. Oxford: Blackwell, 1954. 36. Marie P, Foix C, Alajouanine T. De l’atrophie cdrdbelleuse tardive B prddominance corticale. Rev Neurol (Paris) 1922; 2:849-885, 1082-1111. 37. Marie P. Sur I’hdrddoataxie cdr6belleuse. Sem in M&d (Paris) 1893; 13:444-447. 38. Nonne N. Ueber eine eigenthumliche familiare Erkrankungsform des Centralnervensystern. Arch Psychiat Nervenkr 1891; 22:283-3 16. 39. Fraser D. Defect of the cerebellum occurring in 2, a brother and sister. Glasgow Med J 1880; 13:199-210. 40. Klippel M, Durante G. Contribution a l’dtude des affections nerveuses familiales et hdrdditaires. Rev Med (Paris) 1892; 12:745-785. 41. Brown S. On hereditaryataxiawithaseries of twenty-onecases.Brain1892; 15:250-260. 42. Nonne M. Ein weiterer anatomischer Befund bei einem Fall von familiiirer Kleinhirnataxie. Arch Psychiat Nervenkr 1905; 39: 1221 -1 251. 43. Meyer A. The morbid anatomyof a caseof hereditary ataxia. Brain 1897; 20:276289. 44. Barker LF. A description of the brains and spinal cords of two brothers dead of hereditary ataxia cases XVIII and XX of the series in the family described by Dr Sanger Brown. Trans Assoc Am Physicians 1903; 18:637-709.

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*

46. 47. 48. 49. 50. 51. 52.

53. 54. 55. 56. 57. 58. 59. 60. 61. 62.

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Switalsky.Surl’anatomiepathologiquedel’hkrkdoataxieckrkbelleuse.Nouv Iconogr Salpet 1901; 14:373-387. Thomas A, Roux JC. Sur une forme d’hkrkdoataxie ckrkbelleuse. A propos d’une observation suivie d’autopsie. Rev Mkd (Paris) 1901; 21:762-792. Rydel A. Sur l’anatomie pathologique d’une forme d’hkrkdo-ataxie ckrkbelleuse. Nouv Iconogr Salpet 1904; 17:289-303. Guillain G, Bertrand I, Godet-Guillain J. Etude anatomique d’un cas d’hkrkdoataxie c6rkbelleuse. Rev Neurol (Paris) 1941;73:609-611. Berciano J, Rebollo M, CoriaF, Perez JL, Leno C. Heredotaxia de Marie. Nuevas consideraciones sobre su us0 e independencia nosolbgica. Med Clin (Barc) 1983; 80:506-508. Hassin GB. Marie’S ataxia (olivopontocerebellar atrophy): clinical and pathological considerations. Arch Neurol Psychiatry (Chicago) 1937; 37: 1371-1 382. Ben Amor M, North P,Collard M, Wackneim A, Rohmer F. Hkrkdo-ataxie ckrkbelleuse de Pierre Marie. Nouv PressMkd 1972; 1:177-1 81. Ben Harnida M, MadaniS , Zmerli S , Chami I. Les hkrkdo-dkgknkrescences spinockrkbelleuses en Tunisie, avec ktude cystornanomktrique des troubles sphinctkriens. 204 cas de maladies de Friedreich, de Pierre-Marie et de Strumpell-Lorrain. Rev Neurol (Paris) 1980; 136:495-501. Ben Hamida M, Attia-Romdhane N, Triki C, Oueslati S , Hentati F. Analyse clinique et gknktique de188 familles d’hkrkdo-dkgknkrescence spino-ckrkbelleuse: maladies de Friedreich et hkrkdo-ataxiesP.de Marie. Rev Neurol (Paris) 1991; 147:798-805. Holmes G. An attempt to classify cerebellar disease, with a note on Marie’s hereditary cerebellar ataxia. Brain 1907; 30:545-567. Radermecker J. Epilepsy in the degenerative diseases. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. v01 15. Amsterdam: North Holland, 1974: 325-372. A chronic progressiveof cerRamsay Hunt J. Dissinergia cerebellaris progressiva. ebellar tremor. Brain 19 14; 37: 247-268. Ramsay Hunt J. The striocerebellar tremor. A study of the nature and localization of the combined form of organic tremor. Arch Neurol Psychiatry (Chicago) 1922; 8:664-67 8. Ramsay Hunt J. Dissinergia cerebellaris myoclonica. Primary atrophy of the dentate system:a contribution to the pathology and symptomatology of the cerebellum. Brain 1921; 443490-538. Marsden CD, Obeso JA. 1. The Ramsay Hunt isa useful clinical entity,Mov Disord 1989; 4:6-12. Berciano J, Combarros0. Disinergia cerebelosa mioclbnica (sindrome de Ramsay Hunt). Med Clin (Barc) 1986; 86:78-82. BonduelleM,EscourolleR,Bouygues P, Lormeau G, Gray F. Atrophie olivo-ponto-c&kbelleuse myoclonique (syndrome de Ramsay-Hunt). Rev Neurol (Paris)1976;132:113-124. Rondot P, de Recondo J, Davous P, Vedrenne C. Menzel’s hereditary ataxia with slow eye movements and myoclonus. A clinico-pathological study. J Neurol Sci 1983; 61:65-80.

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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-

Research History of Ataxia

83. 84. 85.

86.

87. 88.

89. 90.

91.

92.

93. 94. 95.

99

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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Berciano et al.

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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REFERENCES

1. Diener HC, Dichgans J. Pathophysiology of cerebellar ataxia. Mov Disord 1992; 7:95-109. 2. Thach WT, Goodkin HP, Keating JG. The cerebellum and the adaptive coordination of movement. Annu Rev Neurosci 1992; 15:403-442. 3. Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet 1983; 1:1151-1155. 4. Wllner U, Klockgether T, Petersen D, Naegele T,Dichgans J. Magnetic resonance imaging in hereditary and idiopathic ataxia. Neurology 1993; 43:318-325. S. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13:227-231. 6. Vanasse M, Garcia-Larrea L, Neuschwander P, Trouillas P, Mauguiere F. Evoked potential studies in Friedreich’s ataxia and progressive early onset cerebellar ataxia. Can J Neurol Sci 1988; 15:292-298. 7. Arpa J, Lopez-Pajares R, Cruz-MartinezA, et al. Multimodal evoked potentials in multiple system and late onset cerebellar atrophies. Neurologia 1995; 10:288296. 8. 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. S, Brice A, Cancel G, 9. Abele M, Burk K, Andres F, Topka H, Laccone F, Bosch Dichgans J, KlockgetherT.Autosomaldominantcerebellarataxiatype I. Nerve conduction and evoked potential studies in families with SCA1, SCA2 and SCA3. Brain1997;120:2141-2148. 10. Geoffroy G, Barbeau A, Breton G, Lernieux B, Aube M, Leger C, Bouchard JP. Clinicaldescriptionandroentgenologicevaluation of patientswithFriedreich’s ataxia. Can J Neurol Sci 1976; 3:279-286. 11. 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. Brain1981;104589-620. 12. Cmpuzano V, Montermini L, Molt6MD, Pianese L, Coss6e M, 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 Michele G, Filla A, De Frutos R, Palau F, Pate1 PI, Di DonatoS, Mandel JL. Friedreich’s ataxia: autosomal recessive diseasecausedbyanintronicGAAtripletrepeatexpansion.Science1996; 271:1423-1427. 13. Quinn N. Multiple system atrophy-the nature of the beast. J Neurol Neurosurg Psychiatry 1989; Suppl:78-89. 14. Wenning GK, Ben ShlomoY, Magalhaes M, Daniel SE, Quinn NP. Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain 1994; 117:835-845. 15. Schulz JB, Klockgether T, Petersen D, Jauch M, Muller-SchauenburgW, Spieker S, Voigt K, DichgansJ. Multiple system atrophy: natural history, MRI morphology, and

112

16. 17.

18.

19.

20.

21

I)

22. 23.

24.

25. 26. 27

Klockgether

dopamine receptor imaging with 123IBZM-SPECT. J Neurol Neurosurg Psychiatry 1994; 5711047-1056. Orr HT, Chung MY, Banfi S, Kwiatkowski TJJ, Servadio A, Beaudet AL, McCall AE, Duvick LA, Ranum LP, Zoghbi HY. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 1993; 4:221-226. PulstSM,NechiporukA,NechiporukT,Gispert S, ChenXN,Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, DeJong P, Rouleau GA, Auburger G, Korenberg JR, Figueroa C, Sahba S. Moderate expansion of a normally biallelictrinucleotiderepeatinspinocerebellarataxiatype2.NatGenet1996; 14:269-276. Kawaguchi Y, OkamotoT,TaniwakiM,AizawaM,lnoue M, Katayama S, Kawakami H, NakamuraS, Nishimura M, AkiguchiI, Kimura J, Narumiya S, Kakizuka A. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 1994; 8:221-228. Zhuchenko 0,Bailey J, BonnenP, Ashizawa T,StocktonDW, AmosC, Dobyns WB, Subramony SH, ZoghbiHY, Lee CC. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the a,,-voltage-dependent calcium channel. Nat Genet 1997; 15~62-69. Durr A, Stevanin G, Cancel G, Duyckaerts C, Abbas N, Didierjean 0, Chneiweiss H, Benomar A, Lyon-Caen 0, Julien J, Serdaru M, Penet C, Agid Y, Brice A. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol 1996; 39:490-499. Schols L, Amoiridis G, Buttner T, Przuntek H, Epplen JT, Riess 0.Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol 1997; 42~924-932. Burk K, Abele M, Fetter M, Dichgans J, Skalej M, LacconeF, Didierjean 0, Brice A, Klockgether T. Autosomal dominant cerebellar ataxia type I-clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain 1996; 119:1497-1505. Filla A, De Michele G, Campanella G, Perretti A, Santoro L, Serlenga L, Ragno M, Calabrese 0, Castaldo I, De Joanna G, Cocozza S. Autosomal dominant cerebellar ataxia type I. Clinical and molecular study in 36 Italian families including a comparison between SCAl and SCA2 phenotypes. J Neurol Sci 1996; 142:140-147. David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, Weber C, Imbert G, Sa dou F, Antoniou E, Drabkin H, Gemmill R, Giunti P, Benomar A, Wood N, Ruberg M, AgidY, Mandel JL, Brice A. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 1997; 17:65-70. Koide R, Ikeuchi T, Onodera0, et al.Unstable expansion of CAG repeat in hereditary dentato~bral-pallidoluysianatrophy (DRPLA). Nat Genet 1994; 6:9-13. Hsiao K, Baker HF, Crow TJ, Poulter M, Owen F, Terwilliger JD, WestawayD, Ott J, Prusiner SB. Linkage of a prion protein missense variant to Gerstmann-Straussler syndrome. Nature 1989; 338:342-345. Riess 0, Schauols L, Bottger H, Nolte D, Vieira Saecker AM, Schimming C, Kreuz F, Macek M Jr, Krebsova A, Macek M-S, Klockgether T, Zuhlke C, Laccone FA. SCA6 is caused by moderate CAG expansion in the alpha,,-voltage-dependent calcium channel gene. Hum Mol Genet 1997; 6:1289-1293.

to Approach Clinical

113

28. Moseley ML, Benzow KA, Schut LJ, Bird TD, Gomez CM, Barkhaus PE, Blindauer

29. 30. 31. 32. 33. 34. 35. 36. 37.

38. 39. 40. 41

42. 43.

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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Klockgether

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.

115

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

121

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).

1. Sugita K, Ando M, Makino M, TakanashiJ, FujimotoN, Niimi H. Magnetic resonance imaging of the brain in congenital rubella virus and cytomegalovirus infections. Neuroradiology 1991; 33:239-242. 2. Perlman JM, Argyle C. Lethal cytomegalovirus infection in preterm infants: clinical, radiological, and neuropathological findings. Ann Neurol 1992; 3154-68. 3. Van Bogaert L, Radermecker MA. Une dysgenesie cerebelleuse chez un enfant du radium. Rev Neurol 1955; 93:65-82. 4. Johnston MV, Barks J, Greenamyre T, Silverstein F. Use of toxins to disrupt neurotransmitter circuitry in the developing brain. In: Boer GJ, Feenstra MGP, Mirmiran M, Swaab DF, van Haaren F, eds. Biochemical Basisof Functional Neuroteratology. Amsterdam: Elsevier, 1988:425-446. 5. Lindvall 0, Nilsson B. Cerebellar atrophy following phenytoin intoxication. Ann Neurol1984;16258-260. 6. Ramaekers V T, Heimann G, ReulJ, Thron A, JaekenJ. Genetic disorders and cerebellar structural abnormalitiesin childhood. Brain 1997; 120: 1739-175 1. Pediatr 7. Grunnet ML, Shields WD. Cerebellar hemorfhage in the premature Jinfant. 1976; 88:605-608. 8. Hendriks HJ, Brunner HG, Haagen TA, Hamel BC. Acrocallosal syndrome. Am J Med Genet 1990; 35:443-446. 9. Barth PG. Pontocerebellar hypoplasias.An overview of a group of inherited neurogenerative disorders with fetal onset. Brain Dev 1993; 15:411-422. 10. Bordarier C, Aicardi J. Dandy-Walker syndrome and agenesis of the cerebellar vermis: diagnostic probems and genetic counselling. Dev Med Child Neurol 1990; 32~285-294. 11. Barkovich AJ, Kjos BO, Norman D, Edwards MS. Revised classificationof posteon the results of multiplanar MR rior fossa cysts and cyst-like malformations based imaging. AJNR Am J Neuroradiol 1989; 10:977-988. 12. Bodensteiner JB, Gay CT, Marks WA, et al. Macro cisterna magna: a marker for maldevelopment of the brain. Pediatr Neurol 1988; 4:284-286.

13. Benda CE. The Dandy-Walker syndrome or the so-called atresia of the foramen of

Magendie. J Neuropath01 Exp Neurol 1954; 13:14-29. K, 14. Chitayat D, Moore L, Del Bigio MR, MacGregor D, Ben-Zeev B, Hodgkinson Deck J, StothersT, Ritchie S, Toi A. Familial Dandy-Walker malformation associatedwithmacrocephaly,facialanomalies,developmentaldelay,andbrainstem dysgenesis:prenataldiagnosisandpostnataloutcome in brothers. A new syndrome? Am J Med Genet 1994; 52:406-415. 15. Murray JC, Johnson JA, Bird TD. Dandy-Walker malformation: etiologic heterogeneity and empiric recurrence risks. Clin Genet 1985; 28:272-283. 16. Tolmie J. Neural tube defects and other congenital malformations of the central nervous system. In: Rimoin DL, Connor JM, Pyeritz RE, eds. Emery and Rimoin’s Principles and Practice of Medical Genetics. New York: Churchill Livingstone. 199612145-2176. 17. Hirsch JF,Pierre-Kahn A, Renier D. The Dandy-Walker malformation. J Neurosurg 1984; 61:515-522. F. 18. Pascual-Castroviejo I, VelezA,Pascual-PascualSI,RocheMC,Villarejo Dandy-Walker malformation: an analysis of38 cases. Child Nerv Syst 1991 ;7:88-97. 19. Estroff JA, Scott MR, Benacerraf BR. Dandy-Walker variant: prenatal sonographic features and clinical outcome. Radiology 1992; 185:755-758. 20. Toi A, Chitayat D, Blazer S. Prenatal diagnosis of the Dandy-Walker variant. An abnormality or a transient finding?Am J Hum Genet 1993; 53:1465A Y, Terrade E, Maitrot D. Dandy-Walker variant malfor21. Stoll C, Huber C, Alembik mation, spastic paraplegia, and mental retardation in two sibs. Am J Med Genet 1990; 37:124-127. 22. Schaefer GB, Bodensteiner JB, Thompson JB. Subtle anomalies of the septum pellucidurn and neurodevelopmental deficits. Dev Med Child Neurol 1994; 36554559. 23. Coria F, Quintana F, Rebollo M, Combarros 0, Berciano J. Occipital dysplasia and Chiari type I deformity in a family. J Neurol Sci 1983; 62:147-158. 24. Stovner LJ, Cappelen J, Nilsen G, Sjaastad 0. The Chiari type I malformation in two monozygotic twins and first-degree relatives. Ann Neurol 1992; 31:220-222. 25. ElsterAD,Chen MYM. Chiari 1 malformations: clinical and radiological reappraisal. Radiology 1992; 183:347-353. 26. Dyste GN, Menezes AH, VanGilder JC. Symptomatic Chiari malformations. An analysis of presentation, management and long term outcome. J Neurosurg 1989; 71~159-168. 27. Dah1 M, Ahlsten G, Carlson H. Neurological dysfunction above the cele level in children with spina bifida cystica: a prospective study to three years. Dev Med Child Neurol 1995; 37:30-40. 28. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the MRC vitamin study. Lancet 1991; 338:132-137. 29. Cogan DG. A type of ocular motor apraxia presenting jerky head movements. Trans Am Acad Ophthalmol Otolaryngol 1952; 56:853-862.

30. Whitsel EA, Castillo M, D’Cruz 0. Cerebellar vermis and midbrain dysgenesis in

oculomotor apraxia: MR findings. AJNR Am J Neuroradiol 1995; 16:83 1-834. B, Russell-Eggitt l, Taylor DSI, Harris C M. Neuroradiological and eye movement correlates in children with intermittent saccade failure: “ocular motor apraxia.” Neuropediatrics 1995; 26:298-305. Savitsky K, Bar-Shira A, Gilad S, et al.A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995; 268:1749-1753. Friede RL. Uncommon syndromes of cerebellar vermis aplasia,11: tectocerebellar dysraphia with occipital encephalocele. Dev Med Child Neurol 1978; 20:758-763. Truwit CL, Barkovich AJ, Shanahan R, Maroldo TV, MR imaging of rhombencephalosynapsis.AJNR Am J Neuroradiol 1991; 12:957-965. Simmons G, Damiano TR, Truwit CL. MRI and clinical findings in rhombencephalosynapsis. J Comput Asst Tomogr 1993; 17:211-214. Williams DW, Elster AD, Ginsberg LE, Stanton C. Recurrent Lhermitte-Duclos disease: report of two cases and association with Cowden’s disease.AJNR Am J Neuroradiol1992;13:287-290. Barkovitch AJ. Congenital malformations of the brain and skull. In: Barkovitch AJ, ed. Pediatric Neuroimaging. New York: Raven Press, 1995: 177-276. Liaw D, Marsh DJ, Li J,Dahia PLM, Wang SI, Zheng Z, Bose S, Call K M , Tsou HC, Peacocke M, Eng C, Parsons R. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet 1997;16: 64-67. Nelen MR, van Staveren WCG, Peeters EAJ, Ben HasselM, Gorlin RJ, Hamm H, Lindboe CF, Fryns JP, Sujmons RH, Woods DG, Mariman ECM, Padberg GW, Kremer H. Germline mutations in the PTENIl\IlMACl gene in patients with Cowden disease. Hum Mol Genet 1997; 6:1383-1387. Joubert M, Eisenring JJ, Robb JP,Andeman F. Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia and retardation. Neurology l 969; l 9:813-825. Friede RL, Boltshauser E. Uncommon syndromes of cerebellar vermis aplasia. I: Joubert syndrome. Dev Med Child Neurol 1978; 20:758-763. Lindhout D, Barth PG, Valk J, Boen-Tan TN. The Joubert syndrome associated with bilateral chorioretinal coloboma. Eur J Pediatr 1980; 134:173-176. Saraiva JM, Baraitser M. Joubert syndrome: a review. Am J Genet 1992; 43:726731. Dekaban AS. Hereditary syndrome of congenital retinal blindness (Leber), polycystic kidneys and maldevelopment of the brain. Am J Ophthalmol 1969; 68: 10291037. Verloes WO, Lambotte C. Further delineation of a syndrome of cerebellar vermis hypo/alloplasia, oligophrenia, congenital ataxia, coloboma and hepatic fibrosis. Am J Med Genet 1989; 32:227-232. Hildebrandt F, Nothwang HG, Vossmerbaumer U, Springer C, Strahm B, Hoppe B, Keuth B, Fuchshuber A, Querfeld U, Neuhaus TJ, Brandis M. Lack of large, homozygous deletions of the nephronophthisis 1 region in Joubert syndrome typeB. APN Study group. Arbeitsgemein Padiatr Nephrol. Pediatr Nephroll998; 12:16-19.

31. Shawkat FS, Kingsley D, Kendall

32. 33.

34. 35. 36. 37. 38.

39.

40. 41. 42. 43. 44. 45. 46.

Cerebellar

147

47. Pellegrino JE, LenschMW, Muenke M, Chance PF. Clinical and molecular analysis in Joubert syndrome. Am J Med Genet 1997; 72:59-62. 48. Pagon RA, Chandler JW, Collie WR, Clarren SK, Moon J, Minkin SA, Hall JG. Hydrocephalus, agyria, retinal dysplasia, encephalocele (HARD E) syndrome: an autosomal recessive condition. Birth Defects Orig Art Ser 1987; 14(6B):233-241. 49. Dobyns WB, Pagon RA, Armstrong D, Curry CJR, Greenberg F, Grix A, Holmes LB, Laxova R, MichelsVV, Robinow M, Zimmerrnan RL. Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet 1989; 32:195-210. 50. Heggie P, Grossniklaus HE, Roessmann U, Chou SM, Cruse RP. Cerebro-ocular dysplasia-muscular dystrophy syndrome: report of two cases. Arch Ophthalmol 1987;105:520-524. 51. Dambska M, WisniewskiK, Sher JH, Solish G. Cerebro-oculo-muscular syndrome: a variant of Fukuyama congenital cerebromuscular dystrophy. Clin Neuropath01 1982;1:93-98. 52. Toda T, Yoshioka M, NakahoriY, Kanazawa I, Ndkamura U, Nakagome Y. Genetic identity of Fukuyama-type congenital muscular dystrophy and Walker-Warburg syndrome. Ann Neurol 1995; 37:99-101. 53. Rodgers BL, Vanner LV, Pai CS, Sens MA. Walker-Warburg syndrome: report of three affected sibs. Am J Med Genet 1994; 49:198-201. 54. Voit T, Sewry CA, MeyerK, Hermann R, StraubV, Muntoni F, Kahn T, Unsold R, Helliwell TR, Appleton R, Lenard HG. Preserved merosin "chain [or lamininalpha (2)] expression in skeletal muscle distinguishes Walker-Warburg syndrome fromFukuyamamusculardystrophyandmerosin-deficientcongenitalmuscular dystrophy. Neuropediatrics 1995; 26: 148-155. 55. Gillespie FD. Aniridia, cerebellar ataxia, and oligophrenia in siblings. Arch Ophthalmol 1964; 73:338-341. 56. FenichelGM,PhillipsJA.Familialaplasia of thecerebellarvermis:possible X-linked dominant inheritance. Arch Neurol 1989; 46:582-583. 57. Boyer RS. Posterior fossa malformations and cysts. In: Osborn AG, ed. Diagnostic Neuroradialogy. St Louis: Mosby, 1994:59-71. 58. Kroon AA, Smit BJ, Barth PG, Hennekam RCM. Lissencephaly with extreme cerebral and cerebellar hypoplasia. A magnetic resonance imaging study. Neuropediatrics 1996; 27:273-276. s9. Barth PG, Mullaart R, Starn FC, Slooff JL. Familial lissencephaly with extreme neopallia1 hypoplasia. BrainDev 1982; 4:145-15 1. 60. Young ID, McKeever PA, Squier MV, GrantJ. Lethal olivopontoneocerebellar hypoplasia with dysmorphic features in sibs. J Med Genet 1992; 29:733-735. 61. Paine RS. Evaluation of familial biochemically determined mental retardation in children, with special reference to aminoaciduria. N Engl J Med 1960; 262658665. 62. Weinberg AG, Kirkpatrick JB. Cerebellar hypoplasia in Werdnig-Hoffmann disease. Dev Nled Child Neurol 1975; 17:511-516. 63. Bath 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.

I 48

Ramaekers

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.

Cerebellar Malformations

149

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.

150

Ramaekers

101. Fink JM, Dobyns WB, Guerrini R, Hirsch BA. Identification of a duplication of Xq28 associatedwithbilateralperiventricularnodularheterotopia.AmJHum

Genet 1997; 61:379-387. 102. Eksioglu YZ, Scheffer IE, CardenasP, Knoll J, DiMario F, Ramsby G, Berg M, Kamuro K, Berkovic SF, Duyk GM, Parisi J, Huttenlocher PR, Walsh CA. Periven-

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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2. 3. 4. 5. 6.

7.

8.

9. 10. 11. 12. 13. 14. 15. 16.

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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

160

17. 18.

19. 20. 21. 22. 23. 24.

25. 26. 27.

28, 29, 30.

Koenig and Durr

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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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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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

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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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21. 22.

183

incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 1986; 39:573-583. Jaspers NGJ, Gatti RA, Baan C, Linssen PCML, Bootsma D. Genetic complementation analysisof ataxia-telangiectasia and Nijmegen breakage syndrome: a survey of 50 patients. Cytogenet Cell Genet 1988; 49:259-263. Lavin MF, Khanna KK, Beamish H, Spring K, Watters D, Shiloh Y. Relationship of the ataxia-telangiectasia proteinATM to phosphoinositide 3-kinase. Trends Biol Sci 1995; 20:382-383. Zakian VA. ATM-related genes: what do they tell us about functions of the human gene? Cell 1995; 82:685-687. Shiloh Y. Ataxia-telangiectasia: closer to unraveling the mystery. Eur HumJ Genet 1995; 3:116-138. Keegan KS, Holtzman DA, Plug AW, Christenson ER, Brainerd EE, Flaggs G, Bentley NJ, Taylor EM, Meyn MS, Moss SB, Cam AM, Ashley T, Hoekstra MF. The Atr and Atrn protein kinases associate with different sites along meiotically pairing chromosomes. Genes Dev 1996; 10:2423-2437. Meyn MS, Strasfeld L, Allen C. Testing the role of p53 in the expression of genetic instability and apoptosis in ataxia-telangiectasia. Int J Radiat Biol 1994; 66:S141149. Herzog K-H, Chong MJ, Kapsetaki M, Morgan JI, McKinnon PJ. Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system. Science 1998; 280:1089-1091. Sanal 0,Wei S, Foroud T, Malhotra U, Concannon P, Charmley P,Saker W, Lange K, Gatti RA. Further mapping of an ataxia-telangiectasia locus to the chromosome 11q23 region. Am J Hum Genet 1990; 47;860--866. Foroud T, Wei S, Ziv Y, Sobel E, Lange E, Chao A, GoradiaT, Huo Y, Tolun A, Chessa L, Charmley P, Sanal 0, Salman N, Julier C, Lathrop GM, Concannon P, McConville C, Taylor M, ShilohY, Lange K, Gatti R.A. Localization of an ataxiatelangiectasia locus to a 3-CM interval on chromosome 11q23: linkage analyses of 111 families by an international consortium. Am J Hum Genet. 1991; 49: 1263-1279, Uhrhammer N, LangeE, Porras 0,Naeim A, ChenX, SheikhavandiS, Chiplunkar S, Yang L, Dandekar S, Liang T, Patel N, Udar N, Concannon P, Gerken S, Shiloh Y, Lange K, Gatti RA. Sublocalization ofan ataxia-telangiectasia gene distal to DllS384 by ancestral haplotyping in Costa Rican families. Am J Hum Genet, 1995; 57~103-111. Gatti RA, Lange E, Rotman G, Chen S, Uhrhammer N, Liang T, Chiplunkar S, Yang L, Udar N, Dandekar S, Sheikhavandi S, WangZ,YangU-M,Polakow J, Elashoff M, Telatar M, Sanal 0, Chessa L, McConville C, Taylor M, Shiloh Y, Porras 0, Borresen A-L, Wegner R-D, Curry C, Gerken S, Lange K, Concannon P. Genetic haplotyping of ataxia-telangiectasia families localizes the major gene to an -850 kb region on chromosome 11q23.1. Int J Radiat Biol 1994; 66:S57-S62. Gatti RA. Ataxia-telangiectasia. In: Vogelstein B, Kinzler KW, eds. The Genetic Basis of Human Cancer. New York: McGraw-Hill, 1998:275-300. Weemaes CMR, Hustinx TWJ, Scheres JMJC, Van Munster PJJ, Bakkeren JAJM, Taalman RDFM. A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatr Scand 1981; 70:557-662.

184

Jabado et al.

23. Curry CJR, O’Lague P,Tsai J, Hutchinson HT, Jaspers NGJ, Wara D, Gatti RA. ATF,,,: a phenotype linking ataxia-telangiectasia with the Nijmegen breakage syndrome. Am J Hum Genet 1989; 45:270-275. 24. Sturnm M, Seemanova E, Gatti RA, Sperling K, Reis A, Wegner R-D. The ataxiatelangiectasia variant genes1 and 2 show no linkage to the AT candidate regionon chromosome 11q22-23. Am J Hum Genet 1995; 57:960-962. 25. Saar K, Chrzanowska €CH,Stumm M, Jung M, Nurnberg G, Wienker W, Seemanova E, Wegner R-D, Reis A, Sperling K. The gene for the ataxia-telangiectasia variant, Nijmegen breakage syndrome, maps to a l-cM interval on chromosome 8q21. Am J Hum Genet 1997; 60:605-610. 26. Cerosaletti KM, Lange E, Stringham HM, Weemaes CMR, Smeets D, Solder B, Belohradsky BH, Taylor AMR, Marnes P, Elliott A, Komatsu K, Gatti RA, Boehnke M, ConcannonP. Fine localizationof the Nijmegen breakage syndrome gene to8q21:evidencefor a commonfounderhaplotype.AmJHumGenet1998; 63:125-134. 27 Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanova E, Cooper PR, Now& NJ, Stumm M, Weemaes CMR, Gatti RA, Wilson RK, Digweed M, Rosenthal A, Sperling K, Concannon P, ReisA. Nibrin, a novelDNAdouble-strandbreakrepairprotein,ismutatedinNijmegen breakage syndrome. Cell 1998; 93:467-476. 28. PlatzerM,RotmanG,BauerD,SavitskyK,Shiloh Y, RosenthalA.Ataxiatelangiectasialocus:analysis of 184kbDNAprovidesevidenceformosaic genomicstructureandcomplextranscriptionalregulationofthe ATM gene. Genome Res 1997; 7592-605. N, Lees-Miller SP, Anderson 29. Hartley KO, Gel1D, Smith GCM, Zhang H, Divecha CW,JacksonSP.DNA-dependentproteinkinasecatalyticsubunit: a relative of phosphatidylinositol 3-kinase and the ataxia-telangiectasia gene product. Cell 1995; 82~849-856. 30. Keith CT, Schreiber SL. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science 1995; 27050-51. 31. Banin S, Moyal L, Shieh S-Y, Taya Y,Anderson CW, ChessaL, Smorodinsky NI, Prives C, Reiss Y, Shiloh U,Ziv Y. Enhanced phosphorylation of p53 byATM in response to DNA damage. Science 1998; 281:1674-1677. 32. Canman CE, Lim D-S, Cimprich KA, Taya Y,Tamai K, Sakaguchi K, Appella E, Kastan MB, Silician JD. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 1998; 281:1677-1679. 33. Lim D-S, Kirsch DC, Canman CE, Ahn J-H, ZivY,Newman LS, Darnell RB, Shiloh Y,Kastan MB, ATMbinds to p-adaptin in cytoplasmic vesicles. Proc Natl Acad Sci USA 1998; 95:101146-10151. P, Parkhill J, StankovicT, McGuire GM, Thick 34. Byrd PJ, McConville CM, Cooper JA, Taylor AMR. Mutations revealed by sequencing the 5’ half of the gene for ataxia-telangiectasia. Hum Mol Genet 1996;5:145-149. 35. Gilad S, Khosravi R, Shkedy D, Uziel T, Ziv Y, Savitsky K, Rotman G, Smith S, Chessa L, Jorgensen TJ, Harnik R, Frydman M, Sanal 0, Portnoi S, Goldwicz Z, Jaspers MGJ, Gatti RA, Lenoir G, Lavin M, Tatsumi K, Wegner RD, Shiloh Y,

Ataxia-Telangiectasia

36.

37. 38. 39.

40.

41.

42. 43. 44.

45. 46.

47. 48.

185

Bar-Shira A. Predominance of null mutation in ataxia-telangiectasia. Hum Mol Genet 1996; 5:433-439. Telatar M, Wang Z, Udar N, Liang T, Bernatowska-Matuszkiewicz E, Lavin M, Shiloh U,Concannon P, Good, RA, Gatti RA. Ataxia-telangiectasia: mutations in ATMcDNAdetectedbyprotein-truncationscreening.AmJHumGenet1996; 59:40-44. Wright J, Teraoka S, Onengut S, Tolun A, Gatti RA, Ochs HD, Concannon P. A high frequency of distinct ATM mutations in ataxia-telangiectasia. Am J Hum Genet 1996; 59:839-846. Broeks A, de Klein A,Floore AN, Muijtjens M, Kleijer WJ, Jaspers NG, van? Veer LJ. ATM germline mutations in classical ataxia-telangiectasia patients in the Dutch population. Hum Mutat 1998; 12:330-337. SandovalN,Platzer M, Rosenthal A, Dork T, Bendix R, Skawran B, Stuhrmann M, Wegner R-D, SperlingK, Banin S, Shiloh Y, Baumer A, Mernthaler U, Sennefelder H, Brohm M, Weber BHF, Schindler D. Characterizationof ATM gene mutations in 66 ataxia-telangiectasia families. Hum Mol Genet 1999; 859-79. TelatarM,Teraoka S, Wang Z, ChunHH,LiangT,Castellvi-Bel S, UdarN, Borresen-Dale A-T, Chessa L, Bernatowska-Matuszkiewicz E, Porras 0, Watanabe M, Junker A, Concannon P, Gatti RA. Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet 1998; 6286-97. Teraoka S, Telatar M, Becker-Catania S, Liang T, Onegut S, Tolun A, Chessa L, Sanal 0, Bernatowska E, Gatti RA, Concannon P. Splicing defects in the ataxiatelangiectasia gene,ATM: underlying mutations and phenotypic consequences. Am J Hum Genet 1999; 64:1617-1631. Castellvi-Bel S, SheikhavandiS, Telatar M, Tai L-Q, Hwang M, WangZ, Yang Z, Cheng R, Gatti RA. New mutations, polymorphisms, and rare variants inATM the gene detected by modified SSCP. Hum Mutat 1999; 14:156-162. Gatti RA, PetersonKL, Novak J, Chen X,Yang-Chen L, Liang T, LangeE, Lange K. Prenatal genotyping of ataxia-telangiectasia. Lancet 1993; 342:376. TelatarM,Wang Z, Castellvi-Bel S, TaiL-Q,Sheikhavandi S, RegueiroJG, Porras 0, Gatti RA. A model forATM heterozygote identification ina large population: four founder-effect ATM mutations identify most of Costa Rican patients with ataxia-telangiectasia. Mol Genet Metab 1998; 64:36-43. Chen G, Lee EY-HP. The product of the ATMgene isa 370-lsDa nuclear phosphoprotein. J Biol Chem 1996; 271:33693-33697. Watters D, Khanna KK, Beamish H, Birrell G, Spring K, Kedar P, Gatei M, Stenzel D, Hobson K, KozlovS, Zhang N, Farrell A, Ramsay J, Gatti R, Lavin M. Cellular localisation of the ataxia-telangiectasia(ATM) gene product and discrimination between mutated and normal forms. Oncogene 1997; 14:1911-1921. Becker-Catania S, Hwang MJ, Chen G, Wang Z,H0 MK, Sanal 0, Bernatowska E, Chessa L, Lee EY-HP, Gatti RA. Variability of ATM expression and function in ataxia-telangiectasia. (submitted). Gilad S, Chessa L, Khosravi R, Russel P, Galanty Y, Piane M, Gatti RA, Jorgensen TJ, Shiloh Y, Bar-Shira A. Genotype-phenotype relationships in ataxiatelangiectasia and variants. Am J Hum Genet 1998; 62:551-561.

186

Jabado et al.

49. Stankovic T, Kidd AMJ, Sutcliffe A, McGuire GM, Robinson P, WeberP, Bedenham T, Bradwell AR, Easton DF, Lennox GG, Haites N, Byrd PJ, Talyor AMR. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and therisk of leukemia, lymphoma, and breast cancer. Am J Hum Genet 1998; 62:334-345. 50. Vorechovsky I, Luo L, Dyer MJS, Catovsky D, Amlot PL, Yaxley JC, Foroni L, Hammarstrom L, Webster ADB, Yuille MAR. Clustering of missense mutations in theataxia-telangiectasiagenein a sporadicT-cellleukaemia.NatGenet1997; 17:96-100. 51. Stilgenbauer S, Schaffner C, Litterst A, Liebisch P, Gilad S, Bar-Shira A, James MR,Lichter P, DohnerH.EvidenceforATM as a tumorsuppressorgenein T-prolymphocytic leukemia. Nat Med 1997; 3: 1155-1161. 52. Yuille MR, Colgnet LJ, Abraham SM, Yaqub F, Luo L, Matutes E, Brito-Babapulle V, VerechovskyI,DyerMJ,CatovskyD.ATMisusually rearranged in T-cell prolymphocytic leukemia. Oncogene 1998; 16:789-796. 53. StankovicT, Weber P, Stewart G, Bedenham T, Byrd PJ, Moss PA, Taylor AM. Inactivation of ataxia-telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet 1999; 353:26-29. 54. Bullrich F, TasioD, Kitada S, Starostik P, Kipps T, Keating M, Albitar M, Reed JC, Croce CM. ATM mutations in B-cell chronic lymphocytic leukemia. Cancer Res 1999; 59:24-27. Y, Kastan MB. Fragments of ATM which 55. Morgan SE, Lovly C, Pandita TK, Shiloh have dominant-negative or complementing activity. Mol Cell Biol 1997; 17:20202029. 56. Zhang N, Chen P, Khanna KK, Scott S, Gatei M, Kozlov S, Watters D, Spring K, Yen T, Lavin MF.Isolation of full-lengthATM cDNA and correction of the ataxiatelangiectasiacellularphenotype.ProcNatlAcadSciUSA1997;94:80218026. 57. Shafman T, KhannaKK, Kedar P, Spring K, Kozlov S, Yen T, HobsonK, Gatei M, Zhang N, Watters D, EgertonM, Shiloh Y, Kharbanda S, Kufe D, Lavin MF. Interaction betweenATM protein and c-ab1 in response to DNA damage. Nature 1997; 387:520--523. 58. Plug AW, Peters AHFM, XuY, Keegan KS, Hoekstra MF, Baltimore D, de Boer P, Ashley T. ATM and RPA in meiotic chromosome synapsis and recombination. Nat Genet 1997; 17:457-461. 59. Flaggs G, Plug AW, Dunks KM, Mundt KE, Ford JC, Quiggle MRE, Taylor EM, Westphal CH, Ashley T, Hoekstra MF, Carr AM. Atm-dependent interactions of a mammalian Chkl homolog with meiotic chromosomes. Curr Biol 1997; 7:977-986. 60. Jung M, Kondratyev A, Lee SA, Dimtchev A, Dritschilo A. ATM gene product phosphorylates I kappa B-alpha. Cancer Res 1997; 57:24-27. 61. Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A. Atm-deficient mice: a paradigm of ataxia-telangiectasia. Cell 1996; 86: 159-17 1. 62. XuY, Ashley T, Brainerd EE, Bronson RT, Meyn MS, Baltimore D. Targeted dis-

Ataxia-Telangiectasia

63. 64. 65. 66. 67. 68. 69.

70. 71. 72. 73. 74. 75. 76. 77.

187

ruption of ATM leads to growth retardation, chromosomal fradmentation during meiosis,immunedefects,andthymiclymphoma.GenesDev1996;10:24112422. Gu Y, Borghesani PR, Bottaro A, Aksoy S, Davidson L, Rathbun GA, Roberts TM, Segal RA, Alt W. Abnormal development of Purkinje cells and lymphocytes in Atm-deficient mice. Proc Natl Acad Sci USA (in press). Kuljis RO, Xu Y, Aguila MC, Baltimore D. Degenerataion of neurons, synapses, andneuropilandglialactivationinamurineAtmknockoutmodel of ataxiatelangiectasia. Proc Natl Acad SciUSA 1997; 94: 12688-12693. Morrell D, Cromartie E, Swift M. Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J Natl Cancer Inst 1986; 77:89-92. Boder E. Ataxia-telangiectasia: an overview. In: RA Gatti, M Swift, eds. AtaxiaTelangiectasia: Genetics, Neuropathology, and Immunology of a Degenerative Disease of Childhood. New York: Alan R Liss, Publ., 1985:l-63. Sedgwick RP, Boder E. Ataxia-telangiectasia. In: JMBV de Jong, ed. Handbook of ClinicalNeurology. Vol 16.HereditaryNeuropathiesandSpinocerebellarAtrophies. Amsterdam: Elsevier Science 1991 :347-423. DeLeonGA,GroverMD,HuffDS.Neuropathologicchangesinataxiatelangiectasia. Neurology 1976; 26:347-35 1. Vinters HV, Gatti RA, RakicP. Sequence of cellular events in cerebellar ontogeny relevant to expression of neuronal abnormalities in ataxia-telangiectasia. In: RA Gatti, M Swift, eds. Ataxia-Telangiectasia: Genetics, Neuropathology, andI m u nologyofaDegenerativeDisease of Childhood. NewYork:AlanRLiss, 1985:233-255. Gatti RA, Vinters HV. Cerebellar pathology in ataxia-telangiectasia. In: RA Gatti, M Swift, eds. Ataxia-telangiectasia: Genetics, Neuropathology, and Immunology of a Degenerative Diseaseof Childhood. New York: Alan R Liss, 1985:225-232. GattiRA,Boder E., Vinters, HV,SparkesRS,NormanA,LangeK.Ataxiatelangiectasia:aninterdisciplinaryapproachtopathogenesis.Medicine199 1; 70:99-117. Gatti RA. Ataxia-telangiectasia. In: CR Scriver, AL Beaudet,WS Sly, D Valle, eds. Metabolic and Molecular Basisof Inherited Disease. 8th ed. New York: McGrawHill,1999. Crawford TO. Ataxia-telangiectasia. Semin Pediatr Neurol 1998; 5:287-294. Baloh R, Yee RD, Boder E. Eye-movements in ataxia-telangiectasia. Neurology 1978; 28:1099-1104. Porras 0, Arguendas 0, Arata M, Barrantes M, Gonzalez L, Saenz E. Epidemiology of ataxia-telangiectasia in Costa Rica. In:RA Gatti, RB Painter, eds. AtaxiaTelangiectasia. Heidelberg: Springer-Verlag, 1993: 199-208. Woods CG, Taylor AMR. Ataxia-telangiectasia in the British Isles: the clinical and laboratory features of 70 affected individuals.Q J Med NewSeries 1992;298:169179. Chessa L, Fiorilli M. Epidemiology of ataxia-telangiectasia in Italy. In: RA Gatti, RB Painter, eds. Ataxia-Telangiectasia. Heidelberg: Springer-Verlag. 1993: 191198.

188

Jabado et al.

78. McFarlinDE,Strober W,WaldmannTA. Ataxia-telangiectasia. Medicine 1972; 51:281-314. 79. Peterson RDA, Kelly WD, Good RA. Ataxia-telangiectasia: its association with a defectivethymus,immunological-deficiencydisease,andmalignancy.Lancet 1964;1:1189. 80. Peter HH. The origin of human NK cells. An ontogenic model derived from studies in patients with immunodeficiencies. Blut 1983; 46:239-248. 81. Sanal 0, Smeets D, Aksoy Y, Berkel AI, Ersoy F, Gariboglu S, Metin A, Ogus H, Weemaes C, Ye1 L. Heterogenicity in ataxia-telangiectasia: various laboratory features of 47 patients. Seventh International Workshop on Ataxia-Telangiectasia. Nov 22-24, 1997. Clermont-Ferrand, France. Abst 65. 82. Zielen S, Schubert R, Schindler D, Buhring I. Patients with A-T are unable to produceIgGantibodiestopneumococcalpolysaccharides.InternationalWorkshoponAtaxia-Telangiectasia.Nov22-24,1997.Clermont-Ferrand,France. Abst 53. 83. Taylor AMR. Ataxia-telangiectasia genes and predisposition ot leukaemia, lymphoma and breast cancer. Br J Cancer 1992; 665-9. ET-F. Leukemia and lymphoma in ataxia84. Taylor AMR, Metcalfe JA, Thick J, Mak telangiectasia. Blood 1996; 87:423-438. 85. Castellvi-Bel S, Wang Z, Plaeger S, Nagourney RA, Naeim F, Rao N, Sparkes RS, Gatti RA. TCL-1 and MTCP-1 gene expression in ataxia-telangiectasia patients with clonal proliferations or lymphoid malignancy. (submitted). 86. Croce CM. Role of TCL1 and ALL1 in human leukemias and development. Cancer Res 1998; 59:177S-178S. 87. Kojis TL, Schreck RR, Gatti RA, Sparkes RS. Tissue specificity of chromosomal rearrangements in ataxia-telangiectasia. Hum Genet 1989; 83:337-353. 88. Hecht F, Koler RD, Rigas DA, Dahnke G, Case M, TisdaleV, Miller RW. Leukaemia and lymphocytes in ataxia-telangiectasia. Lancet 1966; 2: 1193. 89. Gatti RA, Aurias A, Griscelli C, Sparkes RS. Translocations involving chromosomes 2p and 22q in ataxia-telangiectasia. Dis Markers 1985; 3:169-175. of cancer in 161 families af90. Swift A, Morrell D, Massey RB, Chase CL. Incidence fected by ataxia-telangiectasia. N Engl JMed 1991; 325: 1831-1836. 91. Swift M, Reitnauer PJ, Morrell D, Chase CL. Breast and other cancers in families with ataxia-telangiectasia. N Engl JMed 1987; 316: 1289-1294. SwiftM.Moleculargenotypingshowsthatataxia92. AthrnaP,RappaportR, telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet 1996; 92: 130-1 34, 93. FitzGerald MG, Bean JM, Hegde SR, Unsal H, MacDonald DJ, Harkin DP, Finkelstein DM, Isselbacher KJ, Haber DA. HeterozygousATM mutations do not contribute to early onset of breast cancer. Nat Genet 1997; 15:307-310. 94. Vorechovsky I, Luo L, Lindblom A, Negrini M, Webster DB, Croce CM, HammarstromL.ATMmutationsincancerfamilies.CancerRes1996;56:41304133. 95. Vorechovsky I, RasioD,LuoL,MonacoC,HammarstromL,WebsterDB, Zaloudik J, Barbanti-Brodano G, James M, Russo G, Croce CM, Negrini M. The

Ataxia-Telangiectasia

96. 97. 98. 99. 100. 101. 102. 103.

104. 105. 106. 107. 108.

109.

189

ATM gene and susecptibility to breast cancer: analysis of 38 breast tumors reveals no evidence for mutation. Cancer Res 1996; 56:2726-2732. Chen J, Birksholtz GC, Lindblom P, Rubio C, Lindblom A. The role of ataxiatelangiectasia heterozygotes in familial breast cancer. Cancer Res 1998; 58: 13761379. Appleby JM, Barber JB, Levine E, et al. Absence of mutations in ATM thegene in breast cancer patients with severe responses to radiotherapy. Br J Cancer 1997; 76: 1546-1549. Bay J-0, Grancho M, Pernin D, Presneau N, Rio P, Tchirkov A, Uhrhammer N, Verrelle P, Gatti RA, Bignon Y-J. No evidence for constitutional ATM mutation in breasugastric cancer families. Int J Oncol 1998; 12:1385-1390. Bishop DT, Hopper J. AT-tributable risks? Nat Genet 1997; 15:226. LavinMF,Concannon P, GattiRA.EighthInternationWorkshoponAtaxiaTelangiectasia (ATW8). Cancer Res 1999; 59:3845-3849. Gatti RA, Tward A, ConcannonP. Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Genet and Metab 1999; 68:419-423. Laake K, Telatar M, Geitvik CA, Hansen RO, Heiberg A, Andresen AM, Gatti RA, Borresen-Dale A-L. Identical mutation in the ATM gene in55% of Norwegian A-T families; evidence for a founder effect. Eur J Hum Genet 1998; 6:235-244. Laake K, Launonen V, Niederacher D, GudlaugsdottirS, Seitz S, Rio P, Champeme M-H, Biech I, Birnbaum D, Wtite G, Sztan M, Sever N, Plumrner S, Osorio A, Broeks A, HuuskoP, Spun N, Borg A, Cleton-Jansen A-M, Van’t Veer L, Benitez J, Casey G, Peterlin B, OlahE, Varley J, Bignon Y-J, Scherneck S , Sigurdardottir V, Lidereau R, Eyfjord J, Beckmann W, Winqvist R, Skovlund E, Borresen-Dale A-L,BreastCancerSomaticGenetics consortium.Loss ofheterozygosityat llq23.1 andsurvivalinbreastcancer:resultsof a largeEuropeanstudy.Gene Chromosom Cancer 1999; 25:2 12-221. WaldmannTA,McIntire K R . Serumalpha-fetoproteinlevelsinpatientswith ataxia-telangiectasia. Lancet 1972; 2: 112-1 15. Huo YK, WangZ,Hong 5-H, Chessa L, McBride WH, Perlrnan SL, Gatti RA. Radiosensitivity of ataxia-telangiectasia, X-linked agammaglobulinemia and related syndromes. Cancer Res 1994; 54:2544-2547. PerlrnanSL.Treatmentofataxia-telangiectasia.In:RAGatti,RBPainter,eds. Ataxia-Telangiectasia. Heidelberg: Springer-Verlag, 1993:269-278. Arush WB, RosenthalJ, DaleJ. Ataxia-telangiectasia and lymphoma:an indication for highly individualized chemotherapy dosing. Report of treatmenta highly in inbred Arab family. Pediatr Hematol Oncol 1995; 12:163-169. Sandoval C, Swift M. Treatment of lymphoid malignancies in patients with ataxiatelangiectasia. Med Pedtiatr Oncol 1998; 31:491-497. Paterson MC, Mac Farlane SJ, Gentner NE, Smith BP. Cellular hypersensitivity to chronic gama-radiation inculturedfibroblastsfromataxia-telangiectasiaheterozygotes. In:RA Gatti, M Swift, eds. Ataxia-Telangiectasia: Genetics, Neuropathology, and Immunology of a Degenerative Disease of Childhood. NewYork: Alan R Liss, 1985:73-87.

190

Jabado et al.

110. Weeks DE, Paterson MC, Lange K, Andrais B, Davis RC, Yoder F, Gatti RA. Assessment of chronic gamma radiosensitivity as an in vitro assay for heterozygote identification of ataxia-telangiectasia. Radiat Res 1991;128:90-99. 111. Parshad R, Sanford KK, Jones GM, Tarone RE. G2 chromosomal radiosensitivity of ataxia-telangiectasia heterozygotes. Cancer Genet Cytogenet 1985; 14: 163-168. 112. Djozenova CS, Schindler D, Stopper H, Hoehn H, Flentje M, Oppitz IT. Identification of ataxia telangiectasia heterozygotes, a cancer-prone population, using the single-cell gel electrophoresis (Comet) assay. Lab Invest 1999; 79:699-705. 113. Gatti RA, Bick MB, Tam CF, Medici MA, Oxelius V-A, Holland M, Goldstein AL, Boder E. Ataxia-telangiectasia: a multiparameter analysis of eight families. Clin I m u n o l Immunopathol 1982; 23501-516. l 14. Westphal CH, Rowan S, Schmaltz C, Elson A, Fisher DE, LederP. Atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nat Genet 1997; 16:397-401. 115. ZivShiloh Y, Bir-Shira A, Galanty Y, Ziv Y. Cloning and expression of large mammalian cDNAs: lessons from ATM. Genet Eng 1998; 20:239-248. 116. Ziv Y, Bar-Shira A, Pecker I, RussellP, Jorgensen TJ, Tsarfati I, Shiloh Y. Recombinant ATM protein complements the cellular A-T phenotype. Oncogene 1997; 15:159-167. 117. March M, McMahonHT,Thestructuralera of endocytosis.Science1999; 285:215-220. 118. Gatti RA, GoodRA.Occurrenceofmalignancyinimmunodeficiencydiseases. Cancer 1971; 28:89-98. 119. Taylor AMR, McConville CM, Woods GW, Byrd PJ, Hernandez D. Clinical and cellularheterogeneityinataxia-telangiectasia.In:RAGatti,RBPainter,eds. Ataxia-Telangiectasia. Heidelberg: Springer-Verlag, 1993:209-233. 120. Gatti RA. Ataxia-telangiectasia: genetic studies. SIn:Gupta, C Griscelli, eds. New & Sons, ConceptsinImmunodeficiencyDiseases.NewYork:JohnWiley 1993:203-229. 121. Gilad S, Bar-Shira A, Harnik R, Shkedy D, Ziv Y,Shosravi R, BrownIC,Vanagaite L, Xu G, FrydmanM, Lavin MF, HillD, Tagle DA, Shiloh Y. Ataxia-telangiectasia: founder effect among North African Jews. Hum Mol Genet 1996; 5:2033-2037.

Early-Onset Cerebellar Ataxia with Retained Tendon Reflexes Alessandro Filla and Giuseppe De Michele Federico II Universit~Naples, Italy

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IV. NEUROPATHOLOGY

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V. VI.

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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

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25

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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.

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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.

ebellar

Early-Onset

203

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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34. 35.

36.

37

*

38. 39. 40.

41. 42. 43

I)

44.

45

*

46.

Filla and De Michele

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

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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,

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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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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-

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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

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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.)

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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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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).

REFERENCES 1. Bassen FA, Kornzweig AL. Malformation of the erythrocytes in a case of atypical retinitis pigmentosa. Blood 1950; 5:381-387. 2. Kayden HJ. The neurologic syndrome of vitaminE deficiency: a significant cause of ataxia [editorial; comment]. Neurology 1993; 43:2167-2169. 3. Judisch GF, Rhead WJ,Miller DK. Abetalipoproteinernia. Report of an unusual patient. Ophthalmologica 1984; 189:73-79.

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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. *

Abetalipoproteinemia

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A, Valance J. Benign intracranial hypertension due chronic to 57. Drouet A-hypervitaminosis. Rev Neurol 1998; 154:253-256. 58. Muller DP, Lloyd JK, Wolff OH. Vitamin E and neurological function. Lancet 1983; 1:225-228. 59. Hegele RA, Angel A. Arrest of neuropathy and myopathy in abetalipoproteinemia with high-dose vitamin E therapy. Can Med Assoc J 1985; 132:41-44. 60. Fagan ER, Taylor MJ. Longitudinal multimodal evoked potential studies in abetalipoproteinaemia. Can J Neurol Sci 1987; 14517-621. 61. Kohlschutter A, Huebner C, Jansen W, Lindner SG. A treatable familial neuromyopathy with vitaminE deficiency, normal absorption, and evidence of increased consumption of vitamin E. J Inher Metab Dis 1988; ll(supp1 2):149-152. 62. Cavalier L, OuahchiK,Kayden HJ, Di Donato S, ReutenauerL,Mandel JL, Koenig M. Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet 1998; 62:301310. 63. Runge P, Muller DP, McAllister J, Calver D, Lloyd JK, Taylor D. Oral vitamin E supplements can prevent the retinopathy of abetalipoproteinemia. Br J Ophthalmol 1986; 70:166-173. 64. MacGilchrist AJ, Mills PR, Noble M, Foulds WS, Simpson JS, Watkinson G. Abetalipoproteinaemia in adults: role of vitamin therapy. J Inher Metab Dis 1988; 1l :184190. 65. Black DD, Hay RV, Rohwer-Nutter PL, et al. Intestinal and hepatic apolipoprotein B gene expressionin abetalipoproteinemia. Gastroenterology 199 1;101:520-528.

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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

Koenig

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

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225

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).

Koenig

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
B.

Electrophysiology

Motor nerve amplitudes and conduction velocities are usually normal.The electromyogram (EMG) is either normal or neurogenic, with polyphasic recordings. Sensory nerve action potentials (SNAP) and conduction velocities (SNCV) are (11-14,17,20,29,38,39,42). In normal (1,2,10,15,19,41) or moderately reduced the absence of treatment, SNAP and SNCV deteriorate with time (12,412). In general, peripheral neuropathy is less pronounced than in FRDA, in which markedly decreased or absent SNAP may be observed even early in the disease (38).

230

Koenig

Somatosensory-evoked responses obtainedby stimulation at the wrist (median nerve) and medial malleolus (tibial nerve) revealed normal or subnormal conduction velocitiesof the peripheral sensory axons, but significant delays at the cervical and cortical levels(10,13-15,20,29,38,42), with one exception in whom the opposite was observed (12). The data were interpreted as evidence of minimal involvement of the peripheral branchof the sensory neurons compared with significantinvolvement of theposterior c o l u m s of thespinalcord(central branch). The results are in agreement with the observations of the single neuropathological examination (37) and the nerve biopsy studies (see foregoing).

C. Imaging Braincomputedtomographicscanning(CT)ormagneticresonanceimaging (MRI) are usually normal. On three occasions, anomalies were seen in patients after a long disease duration without treatment. Hypersignals of the periventricular white matter on T2-weighed sequences was seen on MRI in the most affected of the of a sibshipof four, after11 years of disease duration (19). Marked dilation cisterna magna was seen on MRI in a 57-year-old patient (36). Generalized atrophy of the brain, with enlargment of lateral ventricules, was seen onCT scan in two patients with 30 yearsof disease duration (27).The cosegregation of AVED and adenomaof the hypophysis in one family is likely to be due to the coincidental segregation of two distinct loci (43).

VII. M A N A ~ E M E ~ T There is no limitation or difficulty with the absorption of vitamin E by the intestinal tract in AVED patients (44). The administration of vitamin E supplements in divided doses daily has resulted in cessation of progression of the neurological symptoms and signs, and some amelioration of established neurological abnormalities in a number of patients (17,18,20,29,42). Administrationto adults of 800 mg of RRR-a-tocopherol given twice daily with meals that contain fat, results in plasma a-tocopherol levels that are at or above the normal range (16). This dose is far below the recommended dose for patients with abetalipoproteinemia, which is 150 mg RRR-a-tocopherol per kilogram body weight daily, but here the malabsorption and lipoprotein abnormalities make transfer into the central nervous system extremely difficult. Despite the difference between the clinical presentationof AVED patients and FRDA patients, 19 N E D patients (out of 38) were initially diagnosed as having FRDA several years before serum vitamin E measurement was undertaken, resulting in late initiation of vitamin E supplementation. The important number of new cases recently reported (16,20,3 1,36) indicates that AVED, origi-

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nally thought to represent only a very small proportion of all recessive ataxias, is not so rare, stressing again the importance not to miss the diagnosis in this treatable condition and to institute therapy promptly.

I wish to thankmy colleagues and collaboratorsL. Cavalier, J.-L. Mandel, C. Ben Hamida, F. Hentati, and H. J.Kayden for invaluable discussions and comments.

1. Burck U, Goebel HH, Kuhlendahl HD, Meier C, Goebel K M . Neuromyopathy and vitamin E deficiency in man. Neuropediatrics 1981; 12:267-278.

2. Laplante P, Vanasse M, MichaudJ, Geoffroy G, Brochu P. A progressive neurological syndrome associated with an isolated vitamin E deficiency. Can J Neurol Sci 1984; 11:561-564. 3. Kayden HJ, Silber R, Kossmann CE. The role of vitamin E deficiency in the abnormal autohemolysis of acanthocytosis. Trans Assoc Am Physicians 1999; 78:334342. 4. Landrieu P, Said G. Peripheral neuropathy and chronic cholestasis due to paucity of interlobular bile ducts. Arch Fr Pediatr 1980; 37:445-449. 5. Elias E, Muller DP, Scott J. Association of spinocerebellar disorders with cysticfibrosis or chronic childhood cholestasis and very low serum vitaminE. Lancet 1981; 2~1319-1321. 6. Muller DP, Lloyd JK, Wolff OH. VitaminE and neurological function. Lancet 1983; 1:225-228. 7. Di Mascio P, Murphy ME, Sies H. Antioxidant defense systems: the role of carotenoids, tocopherols, and thiols. Am J Clin Nutr 1991; 53: 194s-200s. 8. Ben Hamida M, BelalS, Sirugo G, Ben Hamida C, Panayides K, Ioannou P, Beckmann J, Mandel J-L, Hentati F, 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. 9. Derflinger N, Linder C, Ouahchi K, Gyapay G, WeissenbachJ, Le Paslier D, Rigault P, Belal S, Ben Hamida C, Hentati F,Ben Hamida M, Pandolfo M, diDonato S, Sokol R, Kayden HJ, Landrieu P, Durr A, Brice A, Goutihres F, Kohlschiitter A, Sabouraud P, Benomar A, Yahyaoui M, Mandel J-L, Koenig M. Ataxia with vitamin E deficiency: refinement of genetic localisation and analysis of linkage disequilibrium using new markers in 14 families. Am J Hum Genet 1995; 56:1116-1 124. 10. Harding AE, Matthews S, Jones S, Ellis CJ, Booth IW, Muller DP. Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. N Engl J Med 1985; 313:32-35.

Koenig

232 11. Trabert W, Stober T, Mielke V, SiuHeckF,

12. 13. 14.

15. 16.

Schimigk K. Isolierter Vitamin-EMangel. Fortschr Neurol Psychiat 1989; 57:495-501. Stumpf DA, Sokol R, Bettis D, Neville H, Ringel S, Angelini C, Bell R. Friedreich’s disease: V. Variant form with vitamin E deficiency and normal fat absorption. Neurology 1987; 37:68-74. Krendel DA, Gilchrist JM, JohnsonAO, Bossen EH. Isolated deficiencyof vitamin E with progressive neurologic deterioration. Neurology 1987; 37:538-540. Sokol RJ, Kayden HJ, Bettis DB, Traber MG, Neville H, Ringel S, Wilson WB, Stumpf DA. Isolated vitamin E deficiency in the absence of fat malabsorptionfamilial and sporadic cases: characterization and investigation of causes. J Lab Clin Med 1988; 111548-559. Yokota T, Wada Y, Furukawa T, TsukagoshiH, Uchihara T, WatabikiS. Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency. Ann Neurol 1987; 22184-87. Cavalier L, OuahchiK, Kayden HJ, Di Donato S, Reutenauer L, Mandel J-L, Koenig M. Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet 1998; 62:301310.

17. Shorer Z,Parvari R, Bril G, Sela B-A, Moses S. Ataxia with isolated vitaminE deficiency in four siblings. Pediatr Neurol 1996; 15:340-343. W, Lindner SG. A treatable familial neurornyopa18. Kohlschutter A, Hubner C, Jansen thy with vitamin E deficiency, normal absorption, and evidence of increased consumption of vitamin E. J Inherited Metab Dis 1988; 11:149-152. 19. Arniel J, Maziere JC, Beucler I, Koenig M, Reutenauer L, Loux N, Bonnefont D, F60 C, Landrieu P. Familial isolated vitaminE deficiency. Studyof a multiplex family with a 5 years therapeutic followup. J Inherited Metab Dis 1995; 18:333-340. 20. Schuelke M, Mayatepek E, Inter M, Becker M, Pfeiffer E, Speer A, Hubner C, Finckh B. Treatment of ataxia in isolated vitamin E deficiency caused by alphatocopherol transfer protein deficiency. J Pediatr 1999; 134:240-244. E deficiency: a significant cause of 21. Kayden HJ. The neurologic syndrome of vitamin ataxia. Neurology 1993; 43:2 167-2 169. 22. Sat0 Y, Hagiwara K, Arai W,Inoue K. Purification and characterization of the alphatocopherol transfer protein from rat liver. FEBS Lett 1991;288:41-45. 23. Sat0 Y, Arai H, Miyata A, TokitaS, Yamamoto K, Tanabe T, Inoue K. Primarystructure ofalpha-tocopheroltransferproteinfromratliver.JBiolChem1993; 268:17705”-7710. HJ. 24. Traber MC, Sokol RJ, Burton GW, Ingold KU, Papas AM, Huffaker JE, Kayden Impaired ability of patients with familial isolated vitamin E deficiency to incorporate alpha-tocopherol into lipoproteins secreted by the liver. J Clin Invest 1990; 85:397407. 25. Traber MC, Sokol RJ, Kohlschiitter A, Yokota T, Muller DPR, Dufour R, Kayden HJ. Impaired discrimination between stereoisomersof alpha-tocopherol in patients with familial isolated vitamin E deficiency. J Lipid Res 1993; 34:201-210. 26. Traber MG, Ramakrishnan R, Kayden HJ. Human plasma vitamin E kinetics demonstrate rapid recycling ofplasmaRRR-a-tocopherol.ProcNatlAcadSciUSA 1994; 91:10005-10008.

Vitamin Isolated with Ataxia

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27. Ben Hamida C, Dcerflinger N, Belal S, Linder C, Reutenauer L, Dib C, Gyapay G, Vignal A, Le Paslier D, Cohen D, Pandolfo M, Mokini V, Novelli G, Hentati F, Ben Harnida M, Mandel J-L, Koenig M. Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nat Genet 1993; 5:195-200. 28. Arita M, SatoU, Miyata A, Tanabe T, Takahashi E, Kayden HJ, Arai H, Inoue K. Human a-tocopherol transfer protein: cDNA cloning, expression and chromosomal localisation. Biochem J 1995; 306:43’7-443. 29. Yokota T,Shiojiri T, Gotoda T, Arita M, Arai H, Ohga T, Kanda T, Suzuki J, Imai T,MatsumotoH,Harino S, Kiyosawa M, Mizusawa H, Inoue K. Friedreich-like ataxiawithretinitispigmentosacausedbytheHislOlGlnmutationofthe a-tocopherol transfer protein gene. Ann Neurol1997; 41 :826-832. Arita M, Aoki J, Arai 30. Hosomi A, Goto K, Kondo H, Iwatsubo T, Yokota T,M,Ogawa H, Inoue K. Localization of alpha-tocopherol transfer protein in rat brain. Neurosci Lett 1998; 256: 159-162. 31. Tamaru U, Hirano M, Kusaka H, Ito H, Imai T, Ueno S. alpha-Tocopherol transfer proteingene:exonskippingof all transcriptscausesataxia.Neurology1997; 49:584-588. 32. Copp RP, WisniewskiT, Hentati F, Larnaout A, Ben Hamida M, Kayden HJ. Localization of alpha-tocopherol transfer protein in the brains of patients with ataxia with vitamin E deficiency and other oxidative stress related neurodegenerative disorders. Brain Res 1999; 822:80-87. 33. Ouahchi K, AritaM, Kayden HJ, HentatiF, Ben Hamida M, Sokol R, Arai H, Inoue K, Mandel J-L, Koenig M. Ataxia with isolated vitamin E deficiency is caused by mutations in the a-tocopherol transfer protein. Nat Genet 1995; 9:141-145. 34. Gotoda T, AritaM, Arai H, Inoue K, Yokota T, Fukuo U, Yazaki Y, Yamada N. Adultonset spinocerebellar dysfunction caused by a mutation in the gene for a-tocopherol transfer protein. N Engl J Med 1995; 333:1313-1318. 35. Hentati A, Deng HX, Hung WY, Nayer M, AhmedMS, He X, Tim R, Stumpf DA, Siddique T. Human a-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. Neurology 1996; 39:295-300. 36. ShimohataT, Date H, Ishiguro H, Suzuki T, Takano H, Tanaka H, Tsuji S, Hirota K. AtaxiawithisolatedvitaminEdeficiencyandretinitispigmentosa.AnnNeurol 1998; 43:273. 37. Larnaout A, Belal S, Zouari M, Feki M, Ben Hamida C, Goebel HH, Ben Hamida M, Hentati F. Friedreich’s ataxia with isolated vitamin E deficiency:a neuropathological study of a Tunisian patient. Acta Neuropath01 1997; 93:633-637. 38. Zouari M, Feki M, Ben Hamida C, Larnaout A, Turki I, Belal S, Mebazaa A, Ben Hamida M, Hentati F. Electrophysiology and nerve biopsy: comparative study in Friedreich’s ataxia and Friedreich’s ataxia phenotype with vitamin E deficiency. Neuromusc Disord 1999; 8:4 16-425. 39. Jackson CE, Arnato AA, Barohn RJ. Isolated vitamin E deficiency. Muscle Nerve 1996; 19:1161-1165. 40. Yokota T, Shiojiri T, Gotoda T, Arai H. Retinitis pigrnentosa and ataxia caused aby mutation in the gene for the a-tocopherol transfer protein. N Engl J Med 1996; 335:1770-1771.

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41. Rayner RJ, Doran R, Roussounis SH. Isolated vitamin E deficiency and progressive ataxia. Arch Dis Child 1993; 69:602-603. 42. Martinello F, Fardin P, Ottina M, Ricchieri CL, Koenig M, Cavalier L, Trevisan CP. Supplemental therapy in isolated vitaminE deficiency improves the peripheral neuropathy and prevents the progression of ataxia. J Neurol Sci 1998; 156:177-179. 43. Benomar A, Uahyaoui M, Marzouki N, Birouk N, Bouslam N, Belaidi H, Amarti A, Ouazzani R, Chkili T. Vitamin E deficiency ataxia associated with adenoma. J Neurol Sci 1999; 162:97-101. 44. Kayden HJ, Traber MC. Absorption, lipoprotein transport, and regulation of plasma concentrations of vitamin E in humans. J Lipid Res 1993; 34:343-358. 45. Durr A, CossCe M, Agid U, 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: 1169-1175. 46. Harding AE.Friedreich’s ataxia:a clinical and genetic study of 90 families with an analysis of early diagnosis criteria and intrafamilia1 clusteringof clinical features. Brain1981;104:589-620.

Heredopathia Atactica Polyneuritiformis Refsum’s Disease Frederick B. Gibberd Chelsea and Westminster Hospital, London, England

Anthony S. Wierzbicki St. Thomas’s Hospital, London, England

INTRODUCTION I.

236

11. EPIDEMIOLOGY

237

111. MOLECULAR PATHOGENESIS A. ClinicalBiochemistry B.Origin of PhytanicAcid C.Transport of PhytanicAcid D. Biochemistry of Phytanic Acid Metabolism E. Genetics of Heredopathia Atactica Polyneuritiformis F. PhenotypicandGenotypicHeterogeneity

238 23 8 238 240 240 242 243

IV. PATHOLOGY Neuropathology A. B.ExtraneuralPathology

243 243 244

V.

CLINICAL FEATURES A.BonyAbnormalities B. Symptoms and Signs that Come on Gradually C. Symptoms and Signs that Can Change Rapidly D. Prognosis

244 245 245 246 248 235

236

VI.

Gibberd and Wierzbicki

ANCILLARYTESTS

VII. MANAGEMENT A. SymptomaticManagement B. PhytanicAcid-LoweringMeasures Diet C. D.PlasmaExchange REFERENCES

i.

248 249 249

250 25 1 252 252

INTRODUCTION

Heredopathia atactica polyneuritiformis (HAP) (McKusick Classification number 266500) or Refsum’s disease is a clinical entity. It is also known as phytanic acid oxidase deficiency disease, and it is a hereditary motor and sensory neuropathy of group 4 (HSMNIV). It has a characteristicofset physical signs and symptoms, with a raised serum phytanic acid level that can become very high without any other gross biochemical abnormality. Clinically, it behaves as an autosomal recessive disease. It usually presents between the ages of 10 and 20 years with retinitis pigmentosa, causing night blindness and restricted peripheral vision that can progress to complete blindness. Anosmia is common. In the early stages there may be no other symptoms and signs. Ataxia develops later, associated with a neuropathy. Deafness, myopathy, and ichthyosis occur in more severe cases.The untreated condition is characterized by acute exacerbations brought on by intercurrent illness or weight loss. During these episodes, weakness of the limbs, ichthyosis, and fatal cardiac arrhythmia may occur. The first patient with probable heredopathia atactica polyneuritiformis was described in 1939 in the French literature (1) and was later recognized as being similar to the cases described by Refsum (2). In 1945 Refsum suggested the illness was a novel disease (3), and in 1946, he published the first full description of HAP occurring in several members of two families (4). In 1963 Mlenk and Mahlke (S) reported the association of heredopathia atactica polyneuritiforrnis with a raised level of phytanic acid in the plasma. Phytanic acid is a fatty acid with methyl side chains that prevent its metabolismby the normal processof beta-oxidation. Patients with HAP are unable to clear phytanic acid (6); therefore, it accumulates in the body tissues that contain fat or phospholipids. The plasma phytanic acid in normal persons is0-33 pmolL (7). In the past, different units were used; 1 pmolL is equivalent to 0.0312 mg/100 ml. In our series of patients with HAP the plasma level before treatment ranged between 992 and 6400 pmol/L. After several years treatment it may fall to nor-

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mal. Some patients with peroxisomal diseases and relatives of patients with HAP may have a slightly raised level of phytanic acid in the plasma. Phytanic acid originates from plant chlorophyll. Bacteria in the digestive systems of herbivores andfish can metabolize the chlorophyll to liberate the phytol side chain that is later oxidized to phytanic acid (see subsequent text). Humans are unable to breakdown chlorophyll or synthesize phytanic acid. Heredopathiaatacticapolyneuritiformis(Refsum’sdisease)needstobe distinguished from infantile Refsum’s disease(8) (McKusick 266510). This syndrome describes an illness in neonates with very different clinical features in (9), and menwhich ataxia is not a prominent feature, a neuropathy is inconstant tal retardation frequent. Infantile Refsum’s disease is a peroxisomal assembly disorder causing a raised plasma phytanic acid, among other biochemical abnormalities. Infantile Refsum’s disease is a clinical syndrome caused by mutations of peroxisomal transport proteins, peroxines, rather thanof enzymes involved in lipid metabolism. Infantile Refsum’s disease is the mildest form of a clinical spectrum of diseasesencompassingneonataladrenoleukodystrophyandZellweger’s syndrome. It is fortuitous that the early literature focused on the phytanic acid abnormality.

II. EPIDEMIOLOGY Patients with HAP have been reported from Northern Europe, especially Scandinavia, and Western Europe. Elsewhere in the world the patients reported were postulated to be descendants from immigrants from Scandinavia and Western Europe, but systematic surveys have not been performed to define the prevalence of the disease. It had been suggested that the original mutation arose in Scandinavia, but the fact that more than one chromosome (Table 1) has been implicated in the etiologyof HAP makes thisunlikely. Cases may be difficult to diagnose in the absence of physiological stress on the metabolic pathways caused by intercurrent illness or diets rich in phytanic acid. Heredopathia atactica polyneuritiformis is a rare disease, and there are no accurate estimates of its prevalence. The authors have seen or knowof about 50 cases in the United Kingdom so the incidence is likely to be about 1 :1 million in the United Kingdom. Consanguinity is known within the authors’ cases, and this makes an estimation of the gene’s frequency difficult.The disease is rare in Africa and Asia. Many cases have remained undiagnosed for many years and some may have been missed completely.If in a family with retinitis pigmentosa only males are affected, the diagnosis of X-linked retinitis pigmentosa may be made erroneously; the possibility of HAP being ignored(10). The presentation of neurological signs may be delayed, adding to the difficulty of making the diagnosis. In one seriesof 23 patients with HAP(1 1)there was an averageof 11 years

238 Wierzbicki

and

Gibberd

Table 1 MutationsinPhytanoyl-CoAHydroxylaseGenes

Mutation

Number 1.

2. 3. 4. 5. 6. 7. 8. 9.

10.

Effect del T164 del Tl64 del 111 bp (135-246) del 111 bp (135-246) del 111 bp (135-246) A8O5C C823T C823T G6l OA C8237 Exon skip

1

Homozygote Homozygote Homozygote Homozygote Heterozygote Heterozygote Homozygote Homozygote Homozygote Homozygote Heterozygote

Frameshift-stop AA-66 Frameshift-stop AA-66 del AAs 46-82 del AAs 46-82 d,.s~~-~~s82}

Arg-275-Trp Arg-275-Trp Gly-204-Ser Arg-275-Trp del 88 AAs 138-225

between the recognitionof retinitis pigmentosa and the diagnosisof HAP. However if one assesses selected patients,HAP may be discovered. In a group of 52 patients with retinitis pigmentosa, not diagnosed as having HAP (12), 14 had additional neurological signs or symptoms, One of these, who was deaf and had anosmia, was discovered to have previously undiagnosed HAP. Most of the authors’ cases have been referred from ophthalmologists, and only a few have been diagnosed following neurological problems. As anosmia is not common in the general population, patients with retinitis pigmentosa and anosmia should be particularly suspected of having HAP. If they have any short digits in the hands or feet, the chancesof HAP being the diagnosis is increased. In general, all patients with retinitis pigmentosa and neurological signs or symptoms or with recessive inheritance of the retinitis pigmentosa should have the plasma phytanic acid measured.

111.

MOLECULARPATHOGENESIS

A.

ClinicalBiochemistry

The clinical biochemical feature of HAP is a raised, more than three times the upper limit of normal (ULN)(i.e., more than100 pmolL), plasma phytanic acid, which is an isoprenoid fatty acid-l ,5,9,13-tetramethylhexadecanoicacid.

B. Origin of PhytanicAcid Phytanic acid is formed from the metabolism of phytol, which is the alcohol anchor moiety of a molecule of chlorophyll. Chlorophyll cannot be metabolized by

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mammals, but is broken down by bacteria that occur in the digestive tracts of herbivores. Phytol, when it is no longer bound to chlorophyll, is rapidly converted to phytanic acid by hydrogenation and oxidation in all animals. When bound to chlorophyll phytol remains inert. Hence, if humans and other nonherbivores eat chlorophyll, phytanic acidis not formed and none is available for absorption from the intestines. However,if a herbivore eats chlorophyll, the bacteria in the gut digest the chlorophyll and release phytol, which is absorbed and rapidly converted to phytanic acid, Hence, the lipids of herbivores and their dairy products contain large amountsof phytanic acid. If a human eats thesefd$Q,the phytanic acid is absorbed and if the person cannot metabolize the phytanic acid it accumulates in the body. The typical intake onan average Western diet is about 50 mg daily, of which only 50% may be absorbed. The clinical biochemistry of phytanic acid has been little studied. Alhough the fatty acid was initially isolated from sheep’s milk in 1947 in New Zealand, its role in HAP wasnot noticed until 1963by Klenk and Kahlke(5), and later investigated by Steinberg and his colleagues (13). Some patients with early HAP, or those receiving special diets, may have levels between normal and twice ULN which is within the range associated with deficiencies of phytanic acid metaboas Zellweger’s lism secondary to primary peroxisomal biogenesis disorders, such syndrome, neonatal adrenoleukodystrophy and infantile Refsum’s disease (14). Generally, in adult patients with HAP, plasma levels are ten times the ULN and overall the investigation has a diagnostic specificity of 100% and sensitivity of 85%. The use of phytanic acid/pristanic acid ratios may be more accurate in the diagnosis of HAP, but require the availabilityof gas chromatography-mass spectrometry (GC-MS). Phytanic acid alone can be measured by conventional GC with flame ionization detection. The previous lack of suitable standards, which have only recently been provided through the European Quality Control Scheme (ERNDIM), has led to great variability in interlaboratory results by a factor of up to 600%. As a result many cases of HAP may have been left undiagnosed owing to the insensitivity and lack of standardization of local assays. Generally, the rest of the biochemical profile is normal in HAP, although there is an elevated cerebrospinal fluid (CSF) protein. The creatine kinase (CIS) may be raised in these patients. It’s level correlates well with the neurological status. For patients with only minimal neurological disease, the CK will be normal, but with ataxia, especially if muscle weakness occurs, theCIS rises. Its level Weakis, therefore, a good guide to changes in the patient’s metabolic condition. ness without a rise in the CK is likely to be due to chronic muscle wasting and nerve damage, rather than to an exacerbation of the HAP. Many patients evenbefore dietary therapy havea low plasma cholesterol and triglyceride concentration that falls further once they are placed on a low phytanic acid diet. Atypical features include hypokalemia caused by renal potassium loss (15). There is one family with HAP associated with clinical leukodystrophy, psychomotor retarda-

240

Gibberd and Wierzbicki

tion, dysmorphic features, and pipecolic acidemia, which was initially thought to be caused by another disease not classic HAP (16). This has subsequently been disproved, as the abnormal gene in this patient was mapped to the HAP of biochemical abnorlocus 1 (17) at 10s191. It is likely that the spectrum malities associated with mutations in the HAP gene will increase as the full substrate specificity profileof the responsible enzyme is defined both clinically and in vitro.

C. Transport of PhytanicAcid Phytanic acid is absorbed from the diet and alimentary tract, although until recently its transport has been obscure. Early work determined that some phytanic acid comigrated with low-density lipoproteins (LDL) on electrophoresis, but successful treatment by plasmapheresis removed any urgency to clarify its exact mechanism of transport to liver and adipose tissue. One study identified that50% of the liver fatty acid pool was phytanic acid in patients with HAP, and significant levelsof phytanic acid accumulate in adipose tissue, with final concentration per gram of fat being about 5% of average plasma levels (1 8,19). Newer techniques, including lipid apheresis, have shown some benefit HAP, in implying that at least some phytanic acid was transferred by LDL, although there is no direct evidence to support this. Recently, it has been clarified that phytanic acid is transported initially on chylomicrons and later resecreted by the liver invery low densitylipoproteins(VLDL).Significantcross-paxticleexchangeoccurringin plasma leads to equilibrium of phytanic acid between LDL and high-density lipoprotein (HDL) in plasma (20). The lipoprotein particle subfraction distribution of phytanic acid more closely followed thatof cholesterol than other fatty acids, and this could be accounted forby the lipophilicity of phytanic acid and the resistance of phytanoyl-glycerides to lipase degradation.

I). Biochemistry of PhytanicAcidMetabolism The metabolism of phytanic acid (1,5,9,13-tetramethylhexadecanoic)acid has beenclarified. The studies by Steinberg(13)andhiscolleagues defined that alpha-oxidation was responsible for 90% of the initial metabolism of phytanic acid (Fig. 1) and that 10% was degraded by omega-oxidation (Fig. 2). Both processes utilize beta-oxidation of the fatty acid for mostof its further metabolism, with the difference that alpha-oxidation is complete yielding carbon dioxide, whereas omega-oxidation is incomplete yielding 3-methyl-adipic acid, which is excreted in the urine (21). The exact site of phytanic acid metabolism was disputed for many years, with mitochondria and peroxisome being candidates as the responsible organelle. Work in Amsterdam by Verhoeven and his colleagues (22-25) and North Carolinaby Singh and colleagues(26,127) has clarified the po-

241

Refsum's Disease

Phytanic acid COOH

~

Long chain acyl-CoA synthase Phytanoyl-CoA

Phytanoyl-CoA hydroxylase(PAHX) CoA

ci

OH

CO2 .IIFormyl-CoA

CH0

~

2-hydroxy-phytanoyl-CoA

Phytanoyl-CoA dehydratase(?) Pristanal (oxidised to pristanic acid)

Figure 1 Metabolic pathway for metabolism of phytanic acid

by alpha-oxidation.

sition by identification of the differences between rat and human metabolismof phytanic acid andproof that the relevant enzymeis located in the peroxisome in humans. The metabolic pathway involves a typical activation for a fatty acid to a phytanoyl-CoA derivative, transport into the peroxisome, and then an alphaoxidation step catalyzed by a specific hydroxylase as part of a putative fourenzyme complex (Fig. 3). The phytanoyl-CoA hydroxylase (PAHX) is a hemecontaininga-ketoglutarate-andpossiblycitrate-dependentdioxygenasethat yields pristanic acid as a product through an aldehyde, rather than a ketone, in-

? COOHKoA Phytanic acidPhytanoy1-CoA

I

'f

Q-Oxidation step(s)

? COOWCoA

HOOC

f f f

P-Oxidations

HOOC

COOH

acid Methyl-adipic

Figure 2 Metabolic pathway for omega-Oxidation of phytanic acid.

242 PA-COA

-

Gibberd and Wierzbicki

1-

~-

l PEROXISOME

MITOCHONDRION

Figure 3. Subcellular localization ofphytanicacidmetabolism:Thepathwayof accepted phytanic metabolism is shown showing import of phytanic acid into the peroxisome after activation by phytanoyl-CoA ligase followed by alpha- and beta-oxidation and export of the 11-carbon metaboliteas a carnitine derivative to the mitochondrion for further beta-oxidation. CNT, carnitine; CNTOT, carnitine octanoyl transferase; CPT, carnitine phosphoryl transferase; LCCoAS, long-chain acyl-CoA synthase; PA, phytanic acid.

termediate, and the production of formyl-CoA, which is degraded to carbon dioxide. Later (12-2)derivatives of pristanic acid are exported from the peroxisome to the mitochondria via carnitine octanoyl transferase and carnitine derivatives forfurtherbeta-oxidationespeciallyfor n 10derivatives(seeFig. 3) (24).

E. Genetics of HeredopathiaAtacticaPo~yneuritiformis The genetics of HAP remained obscure after the initial identificationof the disease as an autosomal recessive condition. Screening for association with retinitis pigrnentosa (RP) loci has shown that HAP is genetically distinct from candidate genes, including rhodopsin (chromosomes 3q), RP7 and RP8, and Usher’s syndrome type l b on chromosome 6q,7p and l p (28). The isolation of PAHX by protein sequencing (29) and screening for cDNAs related to thiolasePST-2 peroxisomal transport signal domain(30) enabled the enzyme to be located on chromosome lop13 in the region, between markers D10S249 and D10S547, very close to the markerD 10s191. A number of mutations have been identified in pa-

tients with HAP (see Table l ) (31,32). Most patients are homozygous for the same mutation, possibly indicating strong founder effects for local populations in whom HAP is known. The most common mutation aisdeletion of l llbp in the midregion of the gene (20%), and most other identified mutations are frameof gene translation. The shifts, leading to premature or abnormal termination comparative rarityof point mutation inPAHX, to date, implies that cases of HAP may be more common than originally thought (1 :l million) and possibly may have a different and milder phenotype than the classic syndrome.

There is evidence for phenotypic heterogeneity in HAP. There is one unusual case report of perinatal presentation progressing to the full syndrome by the age of 4 years (33). In another instance, the disease in a consanguineous family with“Refsumsyndrome”withearly-onsetleukodystrophyandphytanicand pipecolic acidemia has been linked to D 10s1091 (17). This indicates that there may be major clinical heterogeneity in the disease and that some cases of HAP may occur in the clinical spectrumof mild adrenoleukodystrophy. The disease is also genetically heterogeneous, as genetic mapping studies indicate that 50% of U.K.cases, as defined by strict clinical and biochemical criteria, are not caused by mutation in PAHX, because genetic linkage to chromosome lop has been conclusivelyexcluded(34). The identification of theotherlociforHAPis awaited.

Phytanic acid is deposited in the brain, spinal cord, and peripheral nerves (35). Accumulation of phytanic acid as seen in biopsies of peripheral nerves leads to demyelination in the early stages, but in severe cases, axonal degeneration can a pathognomonic feaoccur. Peripheral nerve hypertrophy used to be considered ture of HAP. Autopsy studies, performed before therapy was available, showed proximal nerve hypertrophy (36), reduction in the numberof myelinated nerves (37), and crystalline inclusion bodies in the Schwann cells. Abnormal lipid depositioncanoccurwidelyinthenervoussystem,includingthemeninges, ependyma,choroidplexus,and gray matter. Morerecentstudies(9) of sural nerve biopsies, performed on patients with less-advanced disease or receiving therapy, failed to show such marked changes.The peripheral nerve hypertrophy is not a universal feature, although Schwann cell proliferation and lipid deposition are seen (38).

~ i b b e and r ~ ~ierzbjckj

244

xtraneural Pathology Deposits of phytanic acid have been described in the kidney and liver (37), although no recent large formal histological studies have been performed.

1. Skin If ichthyosis is present, there are histological changes in the skin, with epidermal hyperkeratosis and fat globules within the vacuolated basal cells. Electron microscopy of the epidermal basal cells confirmed the presence of lipid-laden droplets (39). In these cases, thereis a high levelof phytanic acid in the skin (1 8,40); therefore, the enhanced skin turnover could result in a significant of phytanic loss acid by this route. However, as the patient improves, the ichthyosis clears, and, hence, the amount of phytanic acid that can thenbe lost by this route returns to insignificance.

2. AdiposeTissue Fat biopsies show a raised phytanic acid level that varies depending on the patient’s condition and the length of time the patient has been on a low phytanic acid diet. The level of the phytanic acid in the fat changes slowly compared with the level in the blood (18). Phytanic acid is poorly cleared and is slowly added to adipose tissue, for phytanoyl glycerides are resistant to hormone-sensitive lipase, and transport into the tissues is poor. Levels in the adipose tissue average about 5% of those in the plasma. The rate of phytanic turnover in adipose tissue is unclear, although a half-life of months seems likely.

3. Myocardium Cardiac pathology has been described (41), but isnow rarely seen since therapy has become available and patients need not die suddenly,

4.

Kidneys and Liver

The kidneys may show sclerosed glomeruli and inclusion bodies within the tubularepithelium,withlipidvacuoles.Deposits of phytanicacidhavebeen described in the kidney and liver(3’7),although no recent large formal histological studies have been performed.

V.

CLINICAL FEATURES

The clinical features of HAP can be divided into three groups (18). First, bony abnormalities that seem immutable. Second, symptoms and signs that come on

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245

gradually, involve the special sense organs and are usually associated with irreversible changes such that they do not alter much with transient fluctuations in the plasma phytanic acid level. Third, there are symptoms and signs that respond quickly if their severityis related to the phytanic acid plasma level. These manifestations are reversible, at least partially. The most prominent of these symptoms is ataxia.

A.

BonyAbnormalities

If present, these are found at the onsetof the illness and predate any symptoms. They could be congenital, but there is insufficient knowledge of the premorbid status of patients to know whether skeletal changes are present at birth.The abnormalities do not progress with age, apart from what might be expected from the ageing process. In a full radiological study of 17 patients from 13 families with HAP, six patients from different families had bone changes(42). The most common finding was shortening of the terminal phalanges of the thumb in all of the six affected patients. Shortening of individual metacarpals or metatarsals occurred in four patients; the changes were asymmetrical and usually only one or two bones were affected; most commonly the fourth metatarsal. Radiological changes in the intercondylar notch of the knees and irregularities in the distal humerus were noted in several patients, but were not associated with obvious clinical signs. The mechanism for these bony changes is unknown. They are very helpful in the clinical screening of patients with retinitis pigmentosa for HAP, as the presenceof a short terminal phalanx of the thumb markedly increases the possibility of HAP, although the absence of this sign does not exclude the diagnosis.

B. Symptoms and Signs that Come on Gradually

1. The Eye (11) The most common and the earliest of the eye signs is retinitis pigmentosa, which is always present. The presenting symptom is night blindness thatmay come on The retinitis is initially patchy and graduinsidiously so that it is initially missed. ally becomes more extensive.By the time HAP is diagnosed the visual fields are usually severely restricted.The visual acuity is grossly affected, but its measurement does not correlate with the plasma levelof phytanic acid at the timeof diagnosis. Posterior subcapsular cataracts are common, and the vision in selected cases can be improved by cataract extraction. Most patients have small pupils, with sluggish responses to light and poor iatrogenic mydriasis. The vision of some patients may benefit from therapeutic mydriatics or a broad iridectomy. Acute angle closure glaucoma is common even when the patient is not receiving

mydriatics. Occasionally, narrow drainage angles can be noted on gonioscopy. Corneal involvement has been reported (43). From the pointof view of the ataxia itis interesting that some patients with HAP may have nystagmus at presentation(1 1)when they are acutely ill, but with as the ataxia treatment of the acute condition, the nystagmus resolves, recovering improves.

2. Smell All patients have anosmia on presentation(18). This bad occurred before the vision was severely affected and therefore, is very helpful in screening patients with retinitis pigmentosa for HAP. In a few patients there has been a slight improvement in the sense of smell after years of treatment.

3.

Hearing

Hearing loss iscommon (44) andisusuallysensorineural (45). Whentested nearly all patients have hearing loss, but its extent and later progression vary considerably. In 18 of our patients assessed, 10 had bearing loss that caused a significant hearing impairment.The severity of hearing loss does not correlate directly with the visual loss or the plasma phytanic acid level.

These manifestations correlate directly with the level of the plasma phytanic acid. In contrast to the plasma level of phytanic acid, the level in the adipose tissue turns over too slowly to have significant clinical effects. If a patient mobilizes a lipolytic stimulus, all the fatty acids exfatty acids from the fat stores following cept phytanic acid will be metabolized and, hence, the level of phytanic acid in the blood will rise very rapidly. When a patient is fasted the plasma phytanic acid level can double within24 h (18) and within a few days a patient can deteriorate from walking adequately to not walking at all. The major manifestations in this category are the following:

1. Neurological Ataxia is seen to some degree in most patients with HAP who have more just than retinitis pigmentosa. Initially, the ataxia has often not been considered abnormal and the patient frequently gives a history of clumsiness at school before it was realized to bea significant symptom. In childhood these patients were never good at ball games, and this was not just because of poor sight. Occasionally, truncal ataxia can be associated with vertigo. If this was associated with night blindness, then falling at night or hitting objects in the dark was often a symptom understood only later when the diagnosis was made.

47 Clinically recognized ataxia can develop quickly and involve particularly the legs, although in severe cases the arms can be involved. The ataxia can be of a mixed type, involving cerebellar, sensory, and motor components. In the mildest cases, there may be truncal ataxia with no peripheral sensory changes. In the slightly more severe cases, there may still be no weakness, but sensory changes develop, that are due to peripheral neuropathy, but the ataxia is usually moremarkedthancanbeexpectedfromthesensorychangesalone.Thisis especially so when the symptoms are associated with an acute exacerbation of the disease. As the patient improves, the ataxia and the sensory signs diminish. In a mild situation there is a diminution of vibration sensation at the ankle and the ankle tendon reflexes are lost, As the situation deteriorates, ataxia worsens and then position sense becomes affected and the tendon reflexes at the knees are lost. Later light touch, pain, and temperature sensation in the leg worsens. Inseverecasesmuscleweakness,usuallyfirstinfootdorsiflexion,develops and the symptoms and signs spread to involve the upper leg and the arms. If the arms are involved one of the first signs is ataxia in the fingers. With the muscularweaknessmuscleatrophyoccurs,butwithoutfasciculation.On recoverymusclepowerimproves,butitisrareformusclebulktobefully restored. These neurological signs are very responsive to treatment, unlike many other formsof ataxia and metabolic neurological disease. This is an added reason to diagnose HAPearly. With early treatment it is possible to prevent the onset of neurological symptoms and signs. The longer neurological signs persist without treatment, the slower and less complete will be the recovery after therapy is instituted. The initial neuropathy, both peripheral and central, is reversible, but if it is prolonged permanent changes occur. The recovery pattern is characteristic of a demyelinating neuropathy with initial preservation of the axon. The peripheral nerves may be enlarged in severe cases, but most patients who have received appropriate management for several years do not have palpable nerves.

2.

CardiacDisease

Sudden death occurred during acute exacerbations before therapy was available (46) and was probably due to cardiac arrhythmia( l 8). In severe cases, a dilated of or hypertrophic cardiomyopathy(47) associated with a rhabdomyoletic picture cardiac enzyme release develops. However for patients who are treated, the cardiomyopathy recovers and there are no cardiac symptoms.

3.

ichthyosis

Ichthyosis occurs only in ill patients with very high levels of phytanic acid in the blood. When the patient is treated and the phytanic acid level decreases the ichthyosis clears (39). The accumulation of phytanic acid in the epidermis leads to

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248

an imbalance in the fatty acids and the adhesiveness of the epidermal cells. When xanthomata are present they contain large amounts of phytanic acid (48).

4.

Kidney

Occasionally, a nephropathy occurs during an acute exacerbation of the illness. (15) that, although it imThis can be manifest as a potassium-losing nephropathy proves with treatmentof the NAP never completely recovers. Aminoaciduria has been noted (49), indicating that the causeis probably proximal tubule pathology, analogous to a “Fanconi-like” syndrome.

D. Prognosis

The prognosis depends on the patient’s age, the severity at presentation, the patient’s diet, and management. Vegetarians who have never eaten fat from herbivores orfish are unlikely to develop neurological or other systemic disease. However, most patients develop retinitis pigmentosa and anosmia as children and if HAP is not diagnosed and treated with a suitable diet, they proceed to develop t other manifestations of the disease. Progressive blindness and deafness can occur. The onset of neurological manifestations is very variable, but nearly always begins at the time of an acute intercurrent illness or weight loss.If the patient’s health improves and their weight recovers, the acute neurological manifestations improve, although the patient may remain moderately ataxic. If their health does not improve as the neurological condition deteriorates, other organs, such as the skin, heart, and kidneys, become involved. Patients if therapy is instituted may die laterof a cardiomyopathy or arrhythmia. However and the plasma phytanic acid level is reduced, the neurological and other acute manifestation improve, and the patient will recover almost completely. After many years, progressive blindness and deafness can occur, although there is evidence that, with appropriate dietary management, hearing loss does not deterio(50) and the rate of deterioration of visual acuity rate over a decade or more decreases (5 1). There is evidence that persistent treatment preserves sensory nerve action potentials and motor function (52). In contrast with the early literature on HAP that chiefly reported patients who have died, with adequate therapy, life expectancy is now normal.

VI. ANCILLARY TESTS Neurophysiological testsof the eye (11) in those without gross disturbance of visual acuity showan increased latencyof the visual-evoked potentials, but normal

249

amplitudes. This would suggest that in addition any to pathology in the eye itself there is an abnormality of conduction in the central nervous system. Electrooculograms areflat as are electroretinograms, but this not is surprising in patients with retinitis pigmentosa and confirms the conclusion that these patients have pigment epithelial and retinal dysfunction. Nerve conduction studies show a demyelinating form of neuropathy with slowing of conduction. This canbe particularly severe duringan acute exacerbation when nerve conduction can be lost. With clinical recovery there is an improvement in nerve conduction. The cerebrospinal fluid protein level is markedly raised when the patient is ill, but decreases when the clinical situation improves (53). The creatine kinase(CK) may be raised in these patients. Its level correlates well with neurological status. For patients with only minimal neurological disease if muscle weakness occurs, the the CK will be normal, but with ataxia, especially CK rises. Its level, therefore, is a good guide to changes in the patient’s metabolic condition. Weakness without a rise in CK theis likely tobe dueto chronic muscle wasting and nerve damage, rather than to an exacerbation of the HAP. Hypokalaemia, causedby a potassium-losing nephropathymay occur in the acute illness but, fortunately, improves with treatment, although the recovery may never be complete.

NT The management of HAP consists of general measures to deal with the patient’s symptoms and signs and specific measures to lower the plasma and body stores of phytanic acid (18). The body may contain up to 400 g of phytanic acid (54).

A. ~ y m ~ t o ~ a t i c The general health of the patient is very important because anything that causes weight loss will lead to mobilizationof phytanic acid from the fat stores into the blood where the rising plasma level is associated an with increase in the signs and symptoms discussed in the foregoing. Patients have poor vision owing to the retinitis pigmentosa, but unfortunately, there is little that can be done to improve this, although there is evidence that minimizing the plasma phytanic acid level decreases the rate of progression of the retinitis pigmentosa (51).The patients frequently have cataracts and occasionally glaucoma, and these conditions are treatable. Unfortunately, there is no therapy for the anosmia, but a slight return of smell may occur after prolonged dietary treatment. The effects of hearing loss can be improved by suitable hearing aids.

In most Western countries, the diet contains about 50-100 mg of phytanic acid a day (55), but there is considerable variation. Most phytanic acid comes to humans by eating fish, meat, dairy, and other products of herbivores that have fed on chlorophyll-containing vegetation. Bacteria in the digestive systems of herbivores digest the chlorophyll and release the phytol thatis converted to phytanic acid that is, therefore, present in the animal’s fat, together with the other fatty acids. If one wishes to know precisely the intake for an individual patient, the phytanic content of the food the patient is eating mustbe known. Unfortunately, the phytanic acid content of foods are not given on the labels, consequently, the individual foods need to be measured (56,57). Phytol, the precursor of phytanic acid, is contained in chlorophyll, but cannotbe released insigni~cantamounts by human digestion (58); therefore, patients with HAP can safely eat green vegof the body, but the etables (59). Phytanic acid is held in most compartments clinical effect of the phytanic acid in the adipose tissue is insignificant. It is the blood level of phytanic acid that correlates with clinical condition. The turnover of fatty acids, including phytanic acid, between the adipose tissue and the blood is slow. Transferring phytanic acid from the blood to the adipose tissue improves the patient’s condition and vice versa. Hence, when a patient is ill, it is important to maintain the patient’s nutritional state so that lipolysis is minimal. Increasing the calorie intake above the metabolic requirement will cause phytanic acid,together with other fatty acids, to leave the blood and enter the adipose tissue where it will be clinically inactive. This general principle is important in devising a policy for patient management. When the blood level of phytanic acid has fallen, then it is possible to allow the patient to lose weight slowly if this is indicated for other reasons. However,an overweight patient with a high plasma phytanic acid level should notbe encouraged to lose weight until the plasma phytanic acid level has improved. Althoughpatientswith HAP areunable to carryouttheinitialalphaoxidation and, hence, metabolize phytanic acid in the usual way, there is an alternative pathway, through omega-oxidation, for metabolizing phytanic acid that is not affected in HAP. The amount of phytanic acid that can be metabolizedby 10 mg/day. It is possible for a patient to reduce the daily this method is only about intake of phytanic acid to below 10 mglday so that the amount in the body will decrease gradually and can fall to the normal level in the plasma of 0-33 kmolni after several years, Therefore, low a phytanic acid diet will achieve control of the phytanic acid level in the body.The routine method of management is to devise a diet to achieve this. However, if the patient is very ill or for some reason the diet is not successful in lowering the plasma phytanic acid level, plasmapharesis (60) or lipapheresis can beused to rapidly reduce the plasma level (61). This will often bring quick relief in life-threatening situations, such as a cardiomyopathy

efsu

1

or when cachexia is so severe that an appropriate diet cannot be taken. However, it is not useful in long-term therapy for two main reasons. ifFirst, the patient returns to a “normal” diet containing more than 10 mg of phytanic acid a day, the phytanic acid will accumulate again, and the plasma exchange will need to be repeated forever. Second, the plasma exchange reduces the plasma level only transiently (18) because phytanic acid is released from adipose tissues and liver.As the pbytanic acid is present inmany tissues, reducing the plasma level suddenly leads to only a short-term benefit. A low phytanic acid diet is needed to significantly reduce total body phytanic acid in the long-term.

a diet Food analysis for phytanic acid content gives the information on which can be based (5’7). Foods of vegetable origin alone contain no phytanic acid. There are significant amounts of phytanic acid in foods derived from ruminant animalsand fish. Thus,beef,lamb,andmilkproductsfromcowsandsheep contained large amounts of phytanic acid, up to 175 mg/100 g of the food. The amount of phytanic acid in fish is approximately proportional to their amount of fat, with fish oils containing up to ’753 mg/l00 g. Blended commercial fats, such as some margarine, and products such as biscuits and cakes, made from them contain variable amounts of phytanic acid, sometimes at high levels, but in some phytanic acid is absent. Cream contains about 44 mg of phytanic acid per 100 g, but liquid or powdered skimmed milk none. Many foods, such as ceA dietitian with reals, egg yolk, pork, and poultry, contain no phytanic acid. knowledge of the phytanic content of the foods that the patient may eat can devise a palatable diet with as lowa phytanic acid content as possible. Palatability is important because the patient will need to stay on a low-phytanic acid diet permanently. If the total average daily intake can be kept below10 mg/day, then because of the omega-oxidation that can remove this amount, the total body in falling plasma phyphytanic acid will gradually fall, and this will be reflected tanic acid levels and subsequently lower,levels of phytanic acid in the adipose tissue. As explained earlier, in the initial stages, the diet must supply sufficient calories to prevent mobilizationof phytanic acid from the adipose tissue. Phytol within the chlorophyll molecule is not released during human digestion; therefore, no restriction on green vegetables is necessary. Free phytol is present in some foods ( 5 7 , but the amounts are small and are not a significant source of phytanic acid. Patients who are very ill and cachexic have a very poor appetite and may find it difficult to eat sufficiently to increase theirbody weight. In these circumstances an enteral liquid diet, high in calories and with no phytanic acid, is required (56,62). ‘Very ill patients may be unable to swallow easilyso a liquid diet, such as Fresubin (63) may need to be given through a nasogastric tube. Fresubin

252 Wierzbicki

and

Gibberd

has a high nutritional status and contains no phytanic acid.As these patients recover, a solid diet canbe introduced slowly whilethey continue on the liquid diet. For patients who are well, but are not taking sufficient calories,a liquid supplement, such as Fresubin, can be added. In the United Kingdom, Fresubin, which contains no phytanic acid, is accepted as a food, either as the sole source of nutrition or as a supplement, which may be prescribed under the National Health Service for patients with HAP (63).

l a m a Exchange When patients are acutely ill, relatively large amounts of phytanic acid canbe removed from the blood by plasma exchange (60) or lipapheresis (61). These are associated with rapid clinical improvement. Depending on the plasma phytanic 4000 pm01 can be removed ata single exchange.The acid level, up to more than main indication for plasma exchange i s a severe or rapidly worsening clinical situation. It is particularly helpful when a patient has developed a cardiomyopathy and an arrhythmia because these can be fatal and are rapidly relieved by plasma exchange. A lesser indication is failure of dietary management to reduce a high plasma phytanic acid level. It should be used in conjunction with an appropriate diet and not as a substitute. The ataxia of HAP can be considerably improved, in many patients removed, or prevented by appropriate management.

We should like to thank Dr. Margaret Sidey for help in writing this chapter.

EFERENCES 1. ThiebautM,Lemoyne J, GuillaumatL.Deuxsyndromesotoneuro-oculistiques d’origine congenitale Leurs rapports avec les phacomatoses de van der Hoeve et autres dysphasies neuro-ecodermiques. Rev Neurol 1939; 72:71-75. ; 2. Thiebaut M, Lemoyne J, GuillaumatL.MaladiedeRefsumRevNeurol1961 104:152--154. 3. Refsum S. Heredotaxia hemeralopica polyneuritiformis et tidligere i&e beskrevet syndrom Nord Med 1945; 28:2682-2685. A familial syndrome not hitherto 4. Refsum S. Heredopathia atactica polyneuritiformis. described. A contribution to the clinical study of the hereditary disorders of the nervous system. Acta Psychiatr Scand. 1946; Suppl 38. 5. Klenk E, KahlkeW.UberdasVorkommender3.7.11.15-Tetramethylhexadecansaure (Phytansaure) in den Cholesterinestern und anderen Lipoidfraktionen der Or-

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6. 7. 8.

9. 10. 11. 12. 13. 14. 15. 16. 17.

18. 19. 20.

253

gane bei einem Krankheitsfall unbekannter Genese (Verdact auf Heredopathia AtacticaPolyneuritiformisRefsumsyndrome).Hoppe-SeylerZPhysiolChem1963; 333~133-139. Stokke 0, Try K, Eldjarn L. alpha-Oxidation as an alternative pathway for the degradation of branched-chained fatty acids in man, and its failure in patients with Refsum’s disease. Biochim. Biophys Acta 1967; 144:271-284. Britton TC, Gibberd FB, Clemens ME, Billimoria JD, Sidey MC. The significance ofplasmaphytanicacidlevelsinadults.JNeurolNeurosurgPsychiatry1989; 52:891-894. Lazarow PB, MoserW .Disorders of peroxisome biogenesis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed., v01 2. New York: McGraw-Hill, 1995:2287-2314. Thomas PK, Landon DN, King RHM, Diseases of the peripheral nerves. In: Adams JH, DuchenLW, eds. Greenfield’s Neuropathology, 5& ed. Edward Arnold: London, 1992:1185-1187. Britton TC, Gibberd FB, A family with heredopathia atactica polyneuritiformis (Refsum’s disease). J R SOCof Med 1988; 81:602-603. Claridge KG, Gibberd FB, Sidey MC Refsum’s disease: the Presentation and ophthalmic aspects of Refsum’s disease in a series of 23 patients. Eye 1992; 6:371-375. Goldman JM, Clemens ME, Gibberd FB, Billimoria JD. Screeningof patients with retinitis pigmentosa for heredopathia atactica polyneuritiformis (Refsum’s disease). Br Med J 1985; 85:1109-1110. Steinberg D. Refsum’s disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Stanbury JB, Wyngaarden JB, Fredrickson DS, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed, v01 2. New York: McGraw-Hill, 1995:2351-2370. Wanders RJA, Barth PG, Schutgens RBH, Heymans HAS. Peroxisomal disorders: post and pre-natal diagnosis basedon a new classification with flowcharts. Int Paediatr 1996; 11:203-214. Dick JPR, Meeran, Gibberd FB, Clifford Rose F. Hypokalaemia in acute Refsum’s disease. J R SOC Med 1993; 86:171-172. Tranchant C, Auborg P, Mohor M, Rocchiccioli F, Zaenker C, Warter JM. A new peroxisomal disease with impaired phytanic and pipecolic acid oxidation. Neurology 1993; 43:2044-2048. Nadal N, Rolland M-0, Tranchant C, Roetenauer L, Gyapay G, Warterj M, Mandel J-L, Koenig M. Localisation of Refsum’s disease with increased pipecolic acidaemia to chromosome lop by homozygosity mapping and carrier testing in a single nuclear family. Hum Mol Genet 1995; 4:1963-1966. Gibberd FB, Billimoria JD, Goldman JM, Clemens E, Evans R, Whitelaw MN, Retsas S, Sherratt W. Heredopathia atactica polyneuritiformis: Refsum’s disease. Acta Neurol Scand 1985; 72:l-37. Yao JK, Dyck PJ. Tissue distribution of phytanic acid and its analogues in a kinship with Refsum’s disease. Lipids 1987; 22:69-75. Wierzbicki AS, Sankaranlingam A, Lumb PJ, Hardman TC, Sidey M, Gibberd FB. Transport of phytanic acidon lipoprotein in Refsum’s disease. J Inherited Metab Dis 1999; 22~29-36.

254

erd and ~ i e r ~ ~ i c k i

21. Brenton DP, Krywawych S. 3-Methyl-adipic excretion in Refsum’s disease. Lancet 1982; 1:624 22. Verhoeven NM, Schor DSM, Roe CR, Wanders RJA, Jakobs C. Phytanic acid alphaoxidation in peroxisomal disorders: studies in cultured human fibroblasts. Biochim Biophys Acta 1997; 1361:281-286. 23. Verhoeven NM, Wanders RJA,Schor DSM, Jamsen GA, Jakobs C. Phytanic acid alpha-oxidation: decarboxylationof 2-hydroxy-phytanoyl-CoA to pristanic acid in human liver. J Lipid Res 1997; 38:2062. 24. Verhoeven NM, Roe DS, Kok RM, Wanders RJA, Jakobs C, Roe CR. Phytanic acid and pristanic acid are oxidised by sequential peroxisomal~tochondrial and reaction in cultured fibroblasts. J Lipid Res 1998; 39:66-74. 2s. Verhoeven NM, Jakobs C, Carney G, Sorners MP, Wanders RJA,Rizzo WB. Phytanic acid alpha-oxidation in man. Resolution of the complete pathway and involvement of microsomal fatty aldehyde dehydrogenase. Society for the Study of Inborn Errors Conference,York 1998 .J Inherited Metab Dis 1998; 21(suppl 2):212. 26. Singh I, Pahan K, Singh AK, Barbosa E. Refsum’s disease: a defect in the alphaoxidation of phytanic acid in peroxisomes. J Lipid Res 1993; 34:1755-1764. 27. Pahan K, Khan M, SinghI. Phytanic acid oxidation;noma1 activation and transport yet defective alpha-oxidationof phytanic acid in peroxisome from Refsum’s disease and rhizornelic chondrodysplasia punctata. J Lipid Res 1996; 37:1137-1143. 28. Wierzbicki AS, SankaralingamA, Lumb PJ,Hardman TC, Sidey MC, Gibberd FB. Exclusion of linkage of Refsum’s disease to major loci associated with retinitis pigmentosa. J Cell Biol 1994; 18A521. 29. Jansen GA, OfrnanR, Ferdinandusse S, Ijlst L, MuisersAO, Skjeldal OH, Stokke0, Jakobs C, Besley GTN, Wraith JE, Wanders JE. Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene. Nat Genet 1997; 17: 190-1 94. 30. Mihalik SJ, Morrell JC,Kim D, Sackstder KA,WatkinsPA, Gould SJ. Identification of PAHX. A Refsum disease gene. Nat Genet 1997; 17:185-189. 31. Jansen GA, FerdinandusseS, Skjeldal OH, Stokke0, de Groot CJ, Jakobs C, Wanders RJA. Molecular basis of Refsum’s disease: identification of new mutations in the phytanoyl-CoA hydroxylase cDNA. J Inherited Metab Dis 1998; 21:288--291. 32. Chalal A, Khan M, Pai SG, Barbosa E, Singh I. Restoration of phytanic acid oxidation in Refsum disease fibroblasts from patients with mutations in the phytanoylGOA hydroxylase gene. Fed Eur Biochem Soc Lett 1998; 429:119-122. 33. Herbert MA, Clayton PT. Phytanic acid alpha-oxidase deficiency (Refsum disease) presenting in infancy. J Inherited Met Dis 1994; 17:2 11-214. 34. Wierzbicki AS, Lambert-Hammill M, Mitchell J, Bmston D, Greenwood J, Sidey MC, de Belleroche J, Gibberd FB. Genetic heterogeneity in Refsum’s disease. 48th Annual Meeting of the American Society of Human Genetics. Am J Hum Genet 1998; 63(suppl):A277 (1598). 3s. MacBrinn MC, O’Brien JS. Lipid composition of the nervous system in Refsum’s disease. J Lipid Res 1968; 9:552-561. 36. Lapresle J, Man HX, Metreau R. Documents anatomiques concernant un cas de maladie de Refsum. Rev Neurol 1974; 130:103-110. 37. Cammermeyer J. Refsum’sDisease.Neurophathologicalaspects.In:VinkenPJ,

255

38. 39. 40. 41. 42. 43. 44.

45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55.

Bruyn GW, eds. Handbookof Clinical Neurology. v01 21, part1. Amsterdam; North Holland,1975:231-261. Fardeau M, Abelanet R, Laudat P, Bonduelle M. Maladie de Refsum; etude histologique, ultrastructurale et biochimique d’une biopsie denerf peripherique. Rev Neurol1970;122:185-196. Ramsay BC, MeeranR, Woodrow D, Judge M, Cream JJ, Clifford Rose F, Gibberd FB. Cutaneous aspects of Refsum’s disease. J R Soc Med. 1991; 84:559-560. Dykes PJ, Marks EA, Davies MG, Reynolds DJ. Epidermal metabolism in heredopathiaatacticapolyneuritiformis(Refsum’sdisease) J InvestDermatol1978; 70326-129. Gordon N, Hudson REB. Refsum’s syndrome (heredopathia atactica polyneuritiformis): a report of thee cases, includinga study of the cardiac pathology. Brain 1959; 82:41-55. Plant GR, Hansel1 DM, Gibberd FB, Sidey MC. Skeletal abnormalities in Refsum’s disease (heredopathia atactica polylleuritifo~mis). Br Radio1 J 1990; 63:537-541. Baum JL, Tannenbaum M, Kolodny EH. Refsum’s syndrome with corneal involvement. Am J Ophthalmol 1965; 60599-708. Richterich R, Moser H, Rossi E. Refsum’s disease (heredopathia atactica polyneuritiformis). An inborn error of lipid metabolism with storage of 3,7,11,15, tetramethyl hexadecanoic acid. A review of the clinical findings. Humanagenetik 1965; 1~322-332. Bergsmark J, Djupesland G. Heredopathia atactica polyneuritiformis (Refsum’s disease). An audiological examination of two patients. Euro Neurol 1968; 1:122-130. Ashenhurst EM, Millar ER, Milliken TG. Refsum’s syndrome affecting a brother and two sisters. Br Med J 1958; 2:415-417. Millaire A, Warembourg A, Leys D, Tison E, Tondeux S, De GrooteP, Ketelers JY, Fourrier F, Petei H, Ducloux G. La maladie de Refsum. Ann Cardiol Angelol 1990; 39: 173-178. Kark RAP, Blass JP, Baker L. Accumulation of phytanic acid in Refsum’s disease. Lancet 1969; 2: 1140. Pabico RC, Gruebel BJ, McKenna RA, Griggs RC, Hollander J, Nusbacher J, Panner BJ. Renal involvement in Refsum’s disease. Am J Med 1981; 70:1136-1143. Djupesland G, Flottorp G, RefsumS. Phytanic acid storage disease. Hearing maintained after 1s years dietary management. Neurology 1983; 33:237-239. Hansen E, Bachen NI, Flage T. Refsum’s disease. Eye manifestations in a patient treated with low phytol low phytanic acid diet. Acta Ophthalmol 1979; 57:899-913. LouJS,SnyderR,GriggsRC.Refsum’sdisease:longtermtreatmentpreserves nerve action potentials and motor function. J Neurol, Neurosurg Psychiatry 1997; 62:671-672. Campbell AMG, Williams ER. Natural historyof Refsum’s syndrome ina Gloucestershire family. Br Med J 1967; 3:777-779. Malmendier CL, Jonniaux G,Voet W, Van Den Bergen CJ. Fatty acid composition of tissues in Refsum’s disease. Biomedicine 1974; 20:398-407. Eldjarn L, Stokke 0, Try K. Biochemical aspectsof Refsum’s disease and principles for the dietary treatment. Vinken PJ, Bruyn GW, Klawans ML, eds. Handbook of

256 Wierzbicki

56.

57

58.

59. 60.

61. 62. 63.

and

Gibberd

v01 Clinical Neurology: Metabolic and Deficiency Diseases of the Nervous System. 27. Amsterdam: North Holland. 1976575-578. Masters-Thomas A, Bailes J, Billimoria JD, Clemens ME, Gibberd FB, Page NGR. Heredopathiaatacticapolyneuritiformis2.Estimation ofphytanicacidinfood. J Hum Nutr 1980; 34:251-254. Brown PJ, Mei G, Gibberd FB, Burston D, Mayne PD, McClinchy JE,M. Sidey Diet and Refsum’s disease. The determination of phytanic acid and phytol in certain foods and the application of this knowledge to the choice of suitable convenience foods for patients with Refsum’s disease. J Hum Nutr Diet 1993; 6:295-305. Baxter JH. Absorption of chlorophyll and phytol in normal man and in patients with Refsum’s disease. J. Lipid Res 1968; 9:636-641. Coppack SW, Evans R, Gibberd FB, Clemens ME, Billimoria JD. Can patients with Refsum’s disease safely eat green vegetables? Br Med J 1988; 88:296-828 Harari D, Gibberd FB, Dick JPR, Sidey MC. Plasma exchange in the treatment of Refsum’s disease (heredopathia atactica polyneuritifomis). J Neurol Neurosurg Psychiatry 1991; 54:614-617. Gutsche HU, Siegmund JB, Hoppmann1. Lipapheresis: an immunoglobulin-sparing treatment for Refsurn’s disease. Acta Neurol Scand 1996; 94:190-193. Masters-Thomas A, Bailes J, Billimoria JD, Clemens ME, Gibberd FB, Page NGR. Heredopathia atactica polyneuritiformis 1. Clinicalfeaturesanddietarymanagement. J Hum Nutr 1980; 34:245-250. Fresubin. Br Nat Form 1993; 36:638.

inous Xanthomatosis Vardiella Nleiner and Eran Leitersdorf Hadassah University Hospital, Jerusalem, Israel

INTRODUCTION I.

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11. EPIDEMIOLOGY

25 8

111. MOLECULAR PATHOGENESIS

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CLINICAL FEATURES

VI.ANCILLARYTESTS VII. MANAGEMENT REFERENCES

26 1 262 263 263

Cerebrotendinous xanthomatosis (CTX), a rare progressive sterol storage disorder, is characterized by the accumulation of cholestanol and cholesterol in tendons, in central nervous system, and in the bile. It was first described by van Bogaert, Scherer, and Epstein in 1937 (l), who reported a patient and a related family member with dementia, ataxia, cataract, and xanthomas (1-3). Additional patients with similar symptoms were subsequently diagnosed with “van Bogaert” disease, and were shown to have increased levels of cholestanol in the central nervous system (4-6). Cholestanol accumulation in these patients was indeed ap257

parent in various other locations:namely, blood, xanthomas, and bile(7-16). Interestingly, cholesterol accumulated in various peripheral tissues, although its plasma levels in affected patients were not increased. In 1971, Salen demonstrated that these patients have an abnormal compositionof bile, with diminished levels of chenodeoxycholic acid (9). A key observation was made in 1974 when CTX patients were shown to havedefectivebileacidbiosynthesis,withincompleteoxidation of the C,,-steroid side chain of cholesterol. As a result, these patients excreted large j. In liver biopsies from amounts of (?,,,-bile alcohols in bile, feces, and urine (17 CTX patients, no 27-hydroxylated bile acids were found, with increased concentrations of various substrates for the 27-hydroxylase (18,19j. Thus, the results of various in vivo studies with labeled intermediate metabolites of bile synthesis supported the claim that deficiency of mitochondrial27-hydroxylaseis the metabolic defect behind CTX. In 1991, Cali and Russell cloned the human sterol 27-hydroxylase cDNA and described the first two mutations in this gene known to cause CTX(20,21). We have characterized the human gene structure and mapped the exon intron boundaries (22). Ever since numerous mutations have been identified in different populations, as will be further outlined below. SalenandcollaboratorsshowedthebeneficialeEect of replacement therapy with chenodeoxycholic acid on both cholestanol synthesis and the clinical manifestations of the disease (23,24j.

Although the disease has a panethnic distribution, with few hundred reported cases around the world, there are some distinctive clusters in Japan (25-30), in the Netherlands (3 1,32j, and in Israel (22,33j. CTX is an autosomal recessive disease. Many reported cases resulted from consanguineous marriages. It is possible that the disease is underdiagnosed owing to its multiple clinical findings that may be ascribed to other causes rather than CTX. Interestingly, within various populations bearing a relatively increased frequency of the disease (e.g., Japan, and North African Jews) there are multiple disease-causing mutations. This phenomenon is not fully understood and may possibly reflect a beneficial effect for a founder effectmay have a role in the muthe carriers.Yet, it is conceivable that tations, as shown in the North African Jews (33).

Cerebrotendinous xanthomatosis isa lipid storage disorder with predominantaccumulation of cholestanol and cholesterol in almost every tissue, including the

central nervous system. This accumulationrnay be due to increased synthesis or to increased influx of the two sterols from the circulation. A possible alternative mechanism is a reduced rate of efflux from the tissues ora reduced degradation. Salen and collaborators have shown that both cholesterol and cholestanol synthesis are increased in the livers of CTX patients (34). Moreover, the primary defect in patients with CTX is localized to bile acid biosynthesis (17) and the increased biosynthesis and accumulation of neutral sterols are secondary. Specifically, a defect in the side chain degradationof cholesterol leads toan abnormal bile acid synthesis and is responsible for the CTX phenotype. In the past, there has been a controversy over the location of the defectin the side chain degradationof cholesterol. However, it isnow well established that the basic metabolic defect is in the mitochondrial 27-hydroxylase (35). Cultured skin fibroblasts from CTX patientslack27-hydroxylaseactivity,whereasfibroblastsfromobligatecarriers (e.g., parents of affected patients) have about50% reduction in enzyme activity. The human 27-hydroxylase cDNA was cloned and the gene mapped to chromosome 2 (20,21).Subsequently,thegenestructurewascharacterized (22),andvarioushumanmutationswereidentifiedindiversepopulations (22,25-30,33,36-47). Different forms of genetic changes were reported, including nucleotide substitutions leading to either missense, nonsense, or splice junction mutations, as well as nucleotide deletions and insertions. In fact, distinctive mutations in an African American, in a Japanese, and in a Dutch patient are localized to the same codon mapping to the adrenodoxin-binding region (20,29,41). Similarly, various mutations in Canadian and Japanese patients map to the heme ligand-binding site (20,26). Both the adrenodoxin-binding region and the heme ligand-binding domain are essential for the proper function of this enzyme, as known for other members of the P450 family (20). The lack of the mitochondrial 27-hydroxylase activity leads to extensive accumulation of several substrates for the enzyme and to activation of various metabolic pathways. These metabolic pathways cause the formationof different a thorough discussion bile alcohols that are excreted daily in urine and feces (for of these pathways see Ref.49). Cholestanol is an important bile alcohol that accumulates in various tissues in CTX patients. At least three different mechanisms for the accumulation of cholestanol have been proposed: increased production owing to an up-regulated normal pathway(49); increased biosynthesisof cholestanol secondary to increased productionof cholesterol; and increased production owing to an abnormally high levels of bile acid intermediates that serve as substrates for cholestanol production. According to the third hypothesis, the bile acid intermediates accumulating in patients with CTX becauseof the lack of the 27hydroxylase rnay be shunted into the cholestanol pathway. The third hypothesis has the best experimental support and evidently at least part of the cholestanol is synthesized by this pathway in patients with CTX. In addition, the rationale for various proposed treatments sterns from this hypothesis, as will be discussed later.

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Accumulation of cholesterol in diverse tissues is an additional feature observedinCTXpatients.Thisphenomenon may besecondarytoeither up-regulated 7a-hydroxylase or to the lack of 27-hydroxycholesterol that is considered to be a potent suppressorof cholesterol synthesis in various cell systems (50). In addition, it was recently suggested that sterol 27-hydroxylaseahas transport function leading to cholesterol efflux from peripheral tissues (51). Hence, it rnay beconceivablethatinpatientswithCTX,thesterol27-hydroxylasemediated transport function is abolished, leading to decreased efflux of cholesterol from cells and to its net accumulation. In summary, the relative importance of each of these mechanisms leading to cholesterol accumulation remainsto be examined, and it now seems that the developmentof xanthomas in patients with CTX rnay be due to a combinationof factors, resulting inan imbalance between cholesterol uptake, synthesis, and efflux from cells. The understanding of the pathway leading to the accumulation of cholestanol and cholesterol in the central nervous system is not completely clear. Bile acid metabolism is not carried out in the brain; hence, it could be postulated that cholestanol and cholesterol shouldbe transported to the brain. However, because of the existence of the blood-brain barrier, it is not evident that increased levels of cholesterol and cholestanol in the circulation would lead to their accumulation in the brain. Itwas previously shown that in CTX patients the cerebrospinal fluid contained increased levels of apolipoprotein B and other lipoproteins (52). Increased levelsof cholestanol was demonstrated in the cerebrospinal fluid of these patients, and it was thus claimed that the permeability of the blood-brain barrier is increased in CTX by unknown mechanisms.

V.

LOGY

A detailed descriptionof the central nervous system in CTXwas obtained in the early reports of the disease by van Bogaert in 1937(1-3, 7). The most prominent changes occur in the cerebellum where yellow xanthomas seem to replace most of the white matter, with atrophy and demyelination of specific partsof the white matter (53). In the areasof demyelination, cystic spaces and needle-shaped clefts that contain large mononuclear cells with foamy, vacuolated cytoplasm are apparent (54) in addition to multinucleated giant cells. There is a loss of Purkinje cells, with degeneration of olivocerebellar fibers in the demyelinated zones. As compared with the remarkable findings in the cerebellum, only slight changes are detected in the cerebral cortex. The forebrain may contain xanthomas, specifically in the cerebral peduncles and the globus pallidus. Mononuclear cells with foamy cytoplasm are also found in the caudate nucleus, basal ganglia, thalamus, and in the periventricular areas (1,2). Cerebral demyelination has been documented in the peduncles, in the fibers of ansa lenticularis (1,7,54), and in parts of the globus pal-

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lidus and corona radiata(7). Lesions have also been reported in the midbrain and (l,2,53). the brain stem as well as in the spinal cord Sterol analysisof various parts of the nervous system was obtained and reported by Menkes (6). Up to 25% of the total free sterol fraction from affected parts of the cerebellum was composed of cholestanol. The total esterified sterol fraction from affected partsof the cerebellum contained 49% cholestanol ester.Yet, in apparently normal components 20% of the total free sterol fraction. of the cerebrum cholestanol content reached In addition, increased content of cholesteryl esters have been found in both normal and in abnormal brain tissue from patients with CTX (9,54). It was recently proposed that increased levels of cholestanol may induce apoptosis in cultured cerebellar neuronal cells (55). Yet, it remains to be shown whether apoptosis is indeed a mechanism leading to the neurological manifestations of the disease.

V.

CLINICALFEATURES

CTX is characterized by the progressive accumulation of different clinical signs during life. These include both neurological and extraneurological manifestations. Among the extraneurological manifestations, one of the first to be recognized is juvenile cataracts. It was previously proposed that the finding of bilateral cataractsassociatedwithchronicdiarrhea, may representtheearliestclinical manifestation of CTX (8). Additional extraneurological signs include tendon xanthomas, whichmay affect the Achilles tendon may or be found over extensor tendons of the fingers and toes, on the tibial tuberosities, and in the triceps. The histological findings in the xanthomas are similar to those developed in familial hypercholesterolemia; however, once analyzed for sterol derivatives, the increased fractionof cholestanol reveals the diagnosis. Some of the CTX patients develop respiratory insufficiency and cardiovascular disease. Osteoporosis was shown to be a common manifestation in CTX, predisposing the patients to early bone fractures (56). Various neurological symptomes and signs have been described in CTX (57). Initially, the clinician may observe borderline intelligence, with mild or moderate mental retardation, especially evident when compared with normal development of nonaffected siblings.The mental retardation progresses slowly and often ends in severe presenile dementia. In addition, behavioral changes are observed and are expressed as irritability, agitation, and aggressiveness. In fact, psychiatric disorders may precede the onset of neurological manifestations (58). Convulsions were frequently demonstrated as part of the neurological clinical spectrum (59) CTX patients and may include, during Pyramidal signs are present in most childhood, increased deep tendon reflexes, in addition to pathological reflexes.

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Later on, in the second and third decade, spastic paraparesis progressing to tetraparesis and tetraplegia. Bulbar palsy with dysphagia may also become prominent. Cerebellar signs, specifically ataxia and dysarthria, are found in most patients affected with CTX and may it be oneof the first presenting symptoms.The peculiar association of brisk tendon reflexes representing pyramidal signs, accompanied by muscular hypotonia owing to cerebellar insufficiency is well documented in CTX patients. In addition, peripheral neuropathy is a predominant finding in CTX patients (60-62). During the fourth or fifth decades, spasticity, tremor, and ataxia increase leading to complete incapacitation of these patients. Death usually occurs between the fourth and the sixth decades.

VI.

A~C~LLA TESTS ~Y

Neuroimaging studies, including computed tomography (CT) and magnetic resonance imaging (MRI) may show various changes in CTX patients (63-68). Diffuse cerebral atrophy was often observed, especially in patients who are affected with dementia. Furthermore, cerebral white matter hypodensity reflecting demyelination and diffuse leukodystrophy have been shown in several cases. In addition, cerebellar white matter hypodensity, correlating with the clinical symptoms of ataxia and dysarthria, is prevalent in affected patients. In CTX, in addition to central nervous system involvement, one may also detect cervical cord atrophy. Interestingly, the neuroimaging findings are often less severe than the clinical manifestations. A recent study used positron emission tomography (PET) for the analysis of CTX-affected patients (69). Pathological electroencephalography (EEC) has been described in CTX (59,70). Background activity is abnormal, and is characterized by diffuse irregular slow theta and delta activity, with frequent sharp wave discharges. Although this EEC pathology is not specific and cannot be regarded as pathognomonic, it is definitely characteristic and consistently found. Electrophysiological studies represent a useful, sensitive tool for the assessment of the long-pathway function for supporting the diagnosis and for monitoring the treatment. Somatosensory-evoked potentials and motor-evoked potentialswerestudiedinvariousCTXpatientsandshoweddecreasedvelocities, improving on specific treatment (71-73).We have previously shown that the electrophysiological studiesmay be abnormal long beforeany clinical symptoms occur (81). The specific diagnosisof CTX may be madeby quantitation of cholestanol in suspected individuals using gas chromatography (14). High-performance liquid chromatography (HPLC) of the benzoyl derivative of cholestanol (74) and and reversed-phase thin-layer chromatography (75) are also suitable methods for quantitation. Additional various methods have been introduced for the measure-

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ment of cholestanol in suspected individuals (75-78). However, these tests call for advanced biochemical laboratory setup. An alternative molecular diagnostic test is the identification of specific gene mutations in the 27-hydroxylase gene. Commongenemutationshavebeenidentifiedinseveralworldpopulations (22,25-30,33,36"47). Increased prevalence in these populations may justify the utilization of DNA diagnosis as a rapid and inexpensive tool for clinical diagnosis (79). The importance of early diagnosis of CTX cannot be overemphasized. It is clear that detection of the disease in the early childhood and providing specific treatment may preventtheoccurrence of irreversibleneurologicaldamage (80,81).

Vll.

M~NA~EME~T

Salen (23) showed that by treatment with chenodeoxycholic acid (CDCA), expansion of the deficient bile acid pool resulted in a marked drop in plasma cholestanol. Later on it was shown that treatment withHMG CoA reductase inhibitors could further decrease plasma cholestanol levels in CTX patients (87-92). Treatment with CDCA reduces plasma levelsof cholestanol dramatically in patients with CTX. Becauseof feed-back inhibition, treatment with CDCA inhibits the cholesterol 7a-hydroxylase7 which leads to reduction in the amounts of 7ahydroxylated precursors to cholestanol. Yet, treatment with other kinds of bile salts, such as ursodeoxycholic acid, does not change the clinical course of the disease (93). It is now well documented that in some CTX patients, treatment of the neurological symptoms, with with CDCA results in at least partial reversal clearing of the dementia, a rise in IQ, and improved strength and orientation (24,82-92). Recent prospective studies showed the improvement in various neuEEG studrological parameters, including sensory and motor conduction studies, ies, and cognitive function (80). Certainly, early initiation of treatment is important. Treatment does not seem to improve nonneurological manifestations such as osteoporosis (94). Chenodeoxycholic acid should be administered at a dosage of 750 mg/day (15 mg/kg/day), given orally in three divided doses (24).

REFERENCES 1. van Bogaert L, Scherer HJ, Epstein E. Une Forme C6r6brale de la Cholestkrinose G6nkralis6e. Paris: Masson et Cie, 1937. 2. vanBogaert L, Scherer HJ, Froelich A, Epstein E. Une deuxikme observation de

cholest6rinosetendineusesymktriqueavecsymptomsc6r6braux.AnnMed1937; 42:69-101.

Leitersdorf 264

and

Meiner

3. vanBogaertL.Lesaspectsneuroiogiquesdescholestkrinosesgknkraliskes.Prog Med (Paris) 1938; 22:785. 4. Epstein E, Lorenz K. Beitrag zur Pathologie und Pathochemie der cholesterinigen Lipidose vom Typus van Bogaert-Scherer. Klin Wochenschr 1937; 16: 1320-1323. 5. Epstein E, Kreitner H. Beitrag zu einer vergleichenden Pathologie und Pathochemie der allgemeinen Cholesterinlipidosen. Virchows Arch Path01 Anat 1940; 30653-69. 6. Menkes JH, Schimschock JR, Swanson PD. Cerebrotendinous Xanthomatosis. The storage of cholestanol within the nervous system. Arch Neurol 1968; 19:47-53. 7. Philippart M, van Bogaert L. Cholestanolosis (cerebrotendinous xanthomatosis). A follow-up study on the original family. Arch Neurol 1969; 21:603-610. 8. Cruysberg JR, Wevers RA, van Engelen BC, Pinckers A, van Spreeken A, Tolboom JJ. Ocular and systemic manifestations of cerebrotendinous xanthomatosis. Am J Ophthalmol1995;120597-604. 9. SalenG.Cholestanoldepositionincerebrotendinousxanthomatosis. A possible mechanism. Ann Intern Med 1971; 75:843-851. 10. Bhattacharyya AK, Connor WE. Familial diseases with storage of sterols other than cholesterol. Cerebrotendinous xanthomatosis, and p-sitosterolemia and xanthomatosis. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, eds. The Metabolic Basis of Inherited Diseases. New York: McGraw-Hill, 19783656-669. 11. Farpour H, Mahloudji M. Familial cerebrotendinous xanthomatosis. Report of a new family and review of literature. Arch Neurol 1975; 32:223-225. 12. De Jong JG, van Gent CM, Delleman JW. Cerebrotendinous cholestanolosis in relation to other cerebral xanthomatoses. Clin Neurol Neurosurg 1977; 79:253-272. 13. Brasseur G, Marx P, Langlois J, Houdent G. One case of cerebrotendinous xanthomatosis. Bull SOC Ophtalmol Fr 1978; 78:913-916. 14. Seyama Y, Ichikawa K, Yamakawa T. Quantitative determinationof cholestanol in plasmawithmassfragmentography.Biochemicaldiagnosisofcerebrotendinous xanthomatosis. J Biochem (Tokyo) 1976; 80:223-228. 15. Ohnishi A, YamashitaY, Goto I, KuroiwaY, Murakami S, Ilseda M. De- and remyelinationandonionbulbincerebrotendinousxanthomatosis.ActaNeuropath01 (Berl) 1979; 45:43-45. 16. Kuritzky A, Berginer VM, Korczyn AD. Peripheral neuropathy in cerebrotendinous xanthomatosis. Neurology 1979; 29:880-881. 17. Setoguchi T, Salen G, Tint GS, Mosbach EH. A biochemical abnormality in cerebrotendinous xanthomatosis. Impairment of bile acid biosynthesis associated with incomplete degradation of the cholesterol side chain. J Clin Invest 1974; 53: 1393-1401 18. Oftebro H, Bjorkhem I, Skrede S, Schreiner A, Pederson JI. Cerebrotendinous xanthomatosis: a defect in mitochondrial 26-hydroxylation required for normal biosynthesis of cholic acid. J Clin Invest 1980; 65:1418-1430. 19. Bjorkhem I, Oftebro H, Skrede S, Pedersen JI. Assay of intermediates in bile acid biosynthesis using isotope dilution-mass spectrometry: hepatic levels in the normal state and in cerebrotendinous xanthomatosis. 5 Lipid Res 1981; 22:191-200. 20. Cali JJ, Hsieh CL, Francke U, Russel DW. Mutations in the bile acid biosynthetic enzymesterol27-hydroxylaseunderliecerebrotendinousxanthomatosis.JBiol Chem 1991; 266:7779-7783.

Cerebrotendinous Xant~omatosis

265

21. Cali JJ, Russel DW. Characterization of human sterol 27-hydroxylase. A mitochondrial cytochrome P-450 that catalyzes multiple oxidation reactions in bile acid biosynthesis. J Biol Chem 1991; 266:7774-7778. 22. Leitersdorf E, Reshef A, MeinerV, Levitzki R, Schwartz SP, Dann EJ, Berkman N, Cali JJ, Klapholz L Berginer VM. Frameshift and splice-junction mutations in sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis in Jews of Moroccan origin. J Clin Invest 1993; 91:2488--2496. TW, Nicolau G. Chenodeoxycholic acid inhibits increased cho23. Salen G, Meriwether lesterol and cholestanol synthesis in patients with cerebrotendinous xanthomatosis. Biochem Med 1975; 14:57-74. 24. Berginer VM, Salen G, SheferS. Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med 1984; 26:1649-1652. 25. Nakashima N, Sakai Y, Sakai H, Yanase T, Haji M, Umeda F, Koga S, Hoshita T, Nawata H. A point mutation in the bile acid biosynthetic enzyme sterol 27-hydroxylase in a family with cerebrotendinous xanthomatosis. J Lipid Res 1994; 35:663-668. 26. Kim KS, Kubota S, Kuriyarna M, Fujiyama J, Bjorkhem I, Eggersten G, SeyamaY. Identification of new mutations in sterol 27-hydroxylase gene in Japanese patients with cerebrotendinous xanthomatosis (CTX). J Lipid Res 1994; 35:1031-1039. 27. Nagai Y, Hirano M, Mori T, T&akura Y,Tarnai S, Ueno S. Japanese triplets with cerebrotendinous xanthomatosis are homozygous for a mutant gene coding for the sterol 27-hydroxylase (Arg441Trp). Neurology 1996; 46571-574. 28. Okuyama E, Tomita S, Takeuchi H, IchikawaY. A novel mutation in the cytochrome P450(27) (CYP27) gene caused cerebrotendinous xanthomatosis ina Japanese family. J Lipid Res 1996; 37:631-639. 29. Chen W, Kubota S, Nishimura Y, Nozaki S, Yamashita S, Nakagawa T, KamedaTakekura K, Menju M, Matsuzawa Y, Bjorkhern I, Eggertsen G, SeyamaY. Genetic analysis of a Japanese cerebrotendinous xanthomatosis family: identification of a novel mutation in the adrenodoxin binding region of the CYP 27 gene. Biochim Biophys Acta 1996; 1317:119-126. 30. Chen W, Kubota S, Kim KS, Cheng J, Kuriyama M, EggertsenG,BjorkhemI, Seyama Y. Novel homozygous and compound heterozygous mutations of sterol 27hydroxylase gene (CYP27) cause cerebrotendinous xanthomatosis in three Japanese patients from two unrelated families. J Lipid Res 1997; 38:870--879. 31. Waterreus RJ, Koopman BJ, Wolthers BG, Oosterhuis HJ. Cerebrotendinous xanthomatosis (CTX): a clinical survey of the patient population in The Netherlands. Clin Neurol Neurosurg 1987; 89:169-175. 32. Koopman BJ, Wolthers BC, van der Molen JC, van der Slik W, Waterreus RJ, van Spreeken A. Cerebrotendinous xanthomatosis: a review of biochemical findings of the patient population in The Netherlands. J Inherited Metab Dis 1988; 11:56-75. 33. Reshef A, MeinerV, Berginer VM, Leitersdorf E. Molecular genetics of cerebrotendinous xanthomatosis in Jews of north African origin. J Lipid Res 1994; 35:478-483. 34. Salen G, GrundySM. The metabolism of cholestanol, cholesterol, and bile acids in cerebrotendinous xanthomatosis. J Clin Invest 1973; 52:2822-2835. 35. Skrede S, Bjorkhem I, Kvittingen EA, Buchmann MS, Lie SO, East C, Grundy S.

36. 37. 38. 39. 40.

41. 42.

43

I

44. 45.

46.

47. 48.

Demonstrationof 26-hydroxylation of C27-steroids in human skin fibroblasts, and a deficiency of this activity in cerebrotendinous xanthomatosis. J Clin Invest 1986; 78~729-735. Meiner V, Marais DA, Reshef A, Bjorkhem 1, Leitersdorf E. Premature termination codon at the sterol 27-hydroxylase gene causes cerebrotendinous xanthomatosis in an Afrikaner family. Hurn Mol Genet 1994; 3:193-194. Leitersdorf E, Safadi R, MeinerV, Reshef A, BjorkhemI, Friedlander Y, Morkos S, Berginer VIM. Cerebrotendinous xanthomatosis in the Israeli Dnnze: molecular genetics and phenotypic characteristics. Am J Hum Genet 1994; 55:907-915. Segev H, Reshef A, Clavey V, Delbart C, Routier G, Leitersdorf E. Premature termination codon at the sterol 27-hydroxylase gene causes cerebrotendinous xanthomatosis in a French farnily. Hurn Genet 1995; 95:238-240. Garuti R, Lelli N, Barozzini M, DottiMT, Federico A, Bertolini S, Calandra S. Partial deletionof the gene encoding sterol 27-hydroxylase in a subject with cerebrotendinous xanthomatosis,J Lipid Res 1996; 37:662-672. Garuti R, Lelli N, Barozzini M, Tiozzo R, Dotti MT, Federico A, Ottoman0 AM, Croce A, Bertolini S, Calandra S. Cerebrotendinous xanthomatosis caused by two new mutations of the sterol-27-hydroxylase gene that disrupt rnRNA splicing. Lipid Res 1996; 37:1459-1467. Verrips A, Steenbergen-Spanjers GC, Luyten JA, van den Heuvel LP, Keyser A, Gabreels FJ,Wevers RA. Two new mutations in the sterol 27-hydroxylase gene in two families lead to cerebrotendinous xanthomatosis. Hum Genet 1996; 98:735-737. Ahmed MS, Afsar S, Hentati A, Ahmad A, PashaJ, Juneja T, Hung WY, Ahmad A, Choudhri A, Saya S, SiddiqueT. A novel mutation in the sterol 27-hydroxylase gene of aPakistanifamilywithautosomalrecessivecerebrotendinousXanthomatosis. Neurology 1997; 48:258-260. Verrips A, Steenbergen-Spanjers GC, Luyten JA, Wevers RA, WokkeJ.H, Gabreels FJ, Wolthers BG, van den Heuvel LP. Exon skipping in the sterol 27-hydroxylase gene leads to cerebrotendinous Xanthomatosis. H u Genet ~ 1997; 100:284-286. Garuti R, CroceMA, Tiozzo R, Dotti MT, Federico A, Bertolini S, Calandra S. Four novel mutations of sterol 27-hydroxylase gene in Italian patients with cerebrotendinous xanthomatosis. J Lipid Res 1997; 38:2322-2334. Chen W, Kubota S, Seyama Y. Alternative pre-mRNA splicing of the sterol 27hydroxylase gene (CUP 27) causedby a G to A mutation at the last nucleotide of exon 6 in a patient with cerebrotendinous xanthomatosis(CTX).J Lipid Res 1998; 39:509-517. Chen W, Kubota S, Teramoto T, Nishimura Y, Yonemoto K, Seyama Y. Silent nucleotide substitution in the sterol 27-hydroxylase gene (CYP 27) leads to alternative pre-mRNAsplicingbyactivatingacryptic5’splicesiteatthemutantcodonin cerebrotendinous xanthomatosis patients. Biochemistry 1998; 37:4420-4428. Chen W, Kubota S, Ujike H, Ishihara T, SeyamaY. A novel Arg362Ser mutationin the sterol 27-hydroxylase gene (CYP27): its effects on pre-mRNA splicing and enzyme activity. Biochemistry 1998; 37: 15050-15056. Bjorkhem I, Skrede S. Familialdiseaseswithstorage of sterolsotherthancholesterol.Cerebrotendinousxanthomatosis,andphytosterolemia.In:ScriverCR,

49. 50. 51.

52. 53. 54. 55. 56.

57. 58.

59. 60. 61.

62. 63.

64. 65. 66,

Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Diseases. New York: McGraw-Hill, 1989: 1283-1302. SalenG,Shefer S, TintGS.Transformationof4-cholesten-3-oneand7alphahydroxy-4-cholesten-3-oneinto cholestanol and bile acids in cerebrotendinous xanthomatosis. Gastroenterology 1984; 87:276-283. Javitt NB. 26-Hydroxycholesterol: synthesis, metabolism, and biologic activities. J Lipid Res 1990; 31:1527-1533. Ejorkhern I, Andersson 0, Diczfalusy U, Sevastik B, Xiu RJ, Duan C, Lund E. Atherosclerosis and sterol 27-hydroxylase: evidence for a role ofthis enzyme in elirnination of cholesterol from human macrophages. Proc Natl Acad Sci USA 1994; 91:8592-8596. Salen G, Tint S, Shefer S. Increased cerebrospinal fluid cholestanol and apolipoprotein B concentrations in CTX: effect of chenodeoxycholic acid [abstr]. IX Int Bile Acid Meeting, Basel, 198659. SchimschockJR,AlvordECJr,SwansonPD.Cerebrotendinousxanthomatosis. Clinical and pathological studies. Arch Neurol 1968; 18588-698. Giampalmo A. Les lipidoses cholesteriniques due systkme nerveaux. Acta Neurol Belg 1954; 54:786. Inoue K, Kubota S, Seyama Y. Cholestanol induces apoptosis of cerebellar neuronal cells. Biochem Biophys Res C o m u n 1999; 256:198-203. Berginer VM, Shany S, Alkalay D, Berginer J, Dekel S, Salen G, Tint GS, Gazit D. Osteoporosis and increased bone fractures in cerebrotendinous xanthomatosis. Metabolism 1993; 42359-74. BerginerVM,SalenG,Shefer S. Cerebrotendinousxanthomatosis.NeurolClin 1989; 7155-74. Berginer VM, Foster NL, Sadowsky M, Townsend JA 3d, Siege1 GJ, SalenG. Psychiatric disorders in patients with cerebrotendinous xanthomatosis Am J Psychiatry 1988;145:354-357. Arlazoroff A, Roitberg B, Werber E, Shidlo R, Berginer VM. Epileptic seizure as a presenting symptom of cerebrotendinous xanthomatosis. Epilepsia 199 1;32557661. Argov Z, Soffer D, Eisenberg S, Zimmerman Y. Chronic demyelinating peripheral neuropathy in cerebrotendinous xanthomatosis. Ann Neurol 1986; 20:89-91. Katz DA, Scheinberg L, Horoupian DS, Salen G. Peripheral neuropathy in cerebrotendinous xanthomatosis. Arch Neurol 198.5; 42: 1008-1010. Kuritzky A, Berginer VM, Korczyn AD. Peripheral neuropathy in cerebrotendinous xanthomatosis. Neurology 1979; 29:880-88 1. Berginer VM, Berginer J, Salen G, SheferS, Zimmerman RD. Computed tomography in cerebrotendinous xanthomatosis. Neurology 198 l ;3 l :1463-1465. Swanson PD, Cromwell LD. Magnetic resonance imaging in cerebrotendinous xanthomatosis. Neurology 1986; 36: 124-126. Fiorelli M, Di PieroV,Bastianello S, Bozzao L, Federico A. Cerebrotendinous xanthomatosis: clinical and MRI study (a case report). J Neurol Neurosurg Psychiatry 1990; 53~76-78. Hokezu U, Kuriyama M, Kubota R, Nakagawa M, FujiyamaJ, Osame M. Cerebro-

268

Meiner and Leitersdorf

tendinous xanthomatosis: cranial CT and MRI studies in eight patients. NeuroradiOlOgy 1992; 34:308-3 12. 67. Berginer VM, Berginer J, Korczyn AD, Tadmor R. Magnetic resonance imaging in cerebrotendinous xanthomatosis:a prospective clinical and neuroradiological study. J Neurol Sci 1994; 122:102-108. 68. Dotti MT, Federico A, Signorini E, Caputo N, Venturi C, Filosomi G, Guazzi GC. Cerebrotendinousxanthomatosis(vanBogaert-Scherer-Epsteindisease):CTand MRI findings. AJNR Am J Neuroradiol 1994; 15:1721-1726. 69. KuwabaraK,Hitoshi S, NukinaN,IshiiK,Momose T, Kubota S, Seyama Y, Kanazawa I. PET analysis of a case of cerebrotendinous Xanthomatosis presenting hemiparkinsonism. J Neurol Sci 1996; 138:145-149. 70. Berginer VM, RadwanH, Korczyn AD, Kott E, Salen G, SheferS. EEG in cerebrotendinous xanthomatosis (CTX). Clin Electroencephalogr 1982; 13:89-96. 71. Tokimura Y, Kuriyama M, Arimura K, FujiyamaJ, Osame M. Electrophysiological studiesincerebrotendinousxanthomatosis.NeurolNeurosurgPsychiatry1992; 55~52-55. 72. Mondelli M, Rossi A, ScarpiniC, Dotti MT, Federico A. Evoked potentials in cerebrotendinousxanthomatosisandeffectinducedbychenodeoxycholicacid.Arch Neurol 1992; 49:469-475. 73. Restuccia D, Di Lazzaro V, Servidei S, Colosimo C, Tonali P. Somatosensory and motor evoked potentials in the assessment of cerebrotendinous xanthomatosis before and after treatment with chenodeoxycholic acid: a preliminary study. J Neurol Sci 1992; 112: 139-146. 74. Kasama T, Byun DS, Seyama Y. Quantitative analysisof sterols in serum by highperformance liquid chromatography. Application to the biochemical diagnosis of cerebrotendinous xanthomatosis. J Chromatogr 1987; 400:241-246. 75. Kasama T, SeyamaY. Biochemical diagnosisof cerebrotendinous xanthomatosis using reversed phase thin layer chromatography. J Biochem (Tokyo) 1986; 99:771775. 76. Koopman BJ, Van der Molen JC, Wolthers BG, Waterreus RJ. Screening for cerebrotendinous xanthomatosis by using an enzymatic assay for 7 alpha-hydroxylated steroids in urine. Clin Chem 1987; 33:142-143. HW, Wolthers BG. Detection of carriers 77. Koopman BJ, Waterreus RJ, Van den Brekel of cerebrotendinous xanthomatosis. Clin Chim Acta 1986; 158: 179-185. 78. Egestad B, Pettersson P, Skrede S, Sjovall J. Fast atom bombardment mass spectrometry in the diagnosis of cerebrotendinous xanthomatosis. Scand J Clin Lab Invest 1985; 45:443"446. 79. Chen W, Kubota S, Teramoto T, IshidaS, Ohsawa N, Katayama T, Takeda T, Kuroda K, Yahara 0, Kusuhara T, Neshige R, Seyama Y. Genetic analysis enables definite and rapid diagnosis of cerebrotendinous xanthomatosis. Neurology 1998; 5 1:865867. WO, Tolboom JJ. Treat80. van Heijst AF, Verrips A, Wevers RA, Cruysberg JR, Renier ment and follow-up of children with cerebrotendinous xanthomatosis. Eur J Pediatr 1998;1571313-316. 81. Meiner V, Meiner Z, Reshef A, Bjorkhem I, Leitersdorf E. Cerebrotendinous xan-

matosis

Cerebrotendinous

82.

83. 84. 85. 86. 87.

88.

89.

90. 91. 92. 93. 94.

269

thomatosis: molecular diagnosis enables presymptomatic detection of a treatable disease. Neurology 1994; 44:288-290. Wolthers BG, Volmer M, van der Molen J, Koopman BJ, de Jager AE, Waterreus RJ. Diagnosis of cerebrotendinous xanthomatosis (CTX) and effect of chenodeoxycholic acid therapy by analysis of urine using capillary gas chromatography. Clin Chim Acta1983;131:53-65. Pedley TA, Emerson RG, Warner CL, Rowland LP, Salen G. Treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. Ann Neurol 1985; 18:5 17518. White SW. Cerebrotendinousxanthomatosisistreatable.PediatrDermatol1985; 2:294-296. Koopman BJ, Wolthers BG, van der Molen JC, Waterreus RJ. Bile acid therapies applied to patients suffering from cerebrotendinous Xanthomatosis. Clin Chim Acta 1985;152:115-122. Waterreus RJ, Koopman BJ. Cerebrotendinous xanthomatosis: more on diagnosis and treatment. Neurology 1987; 37:1091-1092. Nakamura T, MatsuzawaY, Takemura K, Kubo M, Miki H, Tarui S. Combined treatment with chenodeoxycholic acid and pravastatin improves plasma cholestanol levels associated with marked regression of tendon xanthomas in cerebrotendinous xanthomatosis. Metabolism 199 ;140:741-746. Peynet J, Laurent A, De LiegeP, Lecoz P, Gambert P, Legrand A, Mikol J, Warnet A.Cerebrotendinousxanthomatosis:treatmentswithsimvastatin,lovastatin,and chenodeoxycholic acid in 3 siblings. Neurology 1991; 41:434-436. Verrips A, WeversRA,VanEngelenBG,KeyserA,Wolthers BC, BarkhofF, Stalenhoef A, De Graaf R, Janssen-ZijlstraF, Van Spreeken A, Gabreels FJ. Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis. Metabolism 1999; 48:233-238. WattsGF, Mitchell WD, Bending JJ, Reshef A, Leitersdorf E. Cerebrotendinous xanthomatosis: a family study of sterol 27-hydroxylase mutations and pharmacotherapy. Q J Med 1996; 89:55-63. Salen G, Batta AK, Tint GS, Shefer S. Comparative effectsof lovastatin and chenodeoxycholic acid on plasma cholestanol levels and abnormal bile acid metabolism in cerebrotendinous xanthomatosis. Metabolism 1994; 43: 1018-1022. Kuriyama M, Tokimura Y, Fujiyama J, Utatsu Y, Osame M. Treatment of cerebrotendinous xanthomatosis: effects of chenodeoxycholic acid, pravastatin, and cornbined use. J Neurol Sci 1994; 125:22-28. Chang m, Lui CC. Failure in the treatment of long-standing osteoporosis in cerebrotendinous Xanthomatosis. J Formosa Med Assoc 1997; 96:225-227. Kirnura S, Beppu T, KugaiN, Koide Y, Fujita T, Iida K, Yamashita N, Yamashita K, Seyama Y. A case of cerebrotendinous xanthomatosis: effects of administration on serum bile acids and cholestanol. Jpn J Med 1982; 21:210-215.

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Children’s University Hospital, Zurich, Switzerland I.

INTRODUCTION

11. ADRENOLEUKODYSTROPHY 111. METACHROMATIC LEUKODYSTROPHY IV. V.

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GLOBOID CELL LEUKODYSTROPHY (KRABBE’S DISEASE)

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VANISHING WHITE MATTER DISEASE

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VI. VAN DER KNAPP LEUKOENCEPHALOPATHY VII.

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UNKNOWN LEUKODYSTROPHIES

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VIII. NEURONAL CEROID LIPOFUSCINOSES

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IX. X. XI.

NIEMANN-PICK DISEASE TYPE C

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LATE-ONSET GM,-GANGLIOSIDOSIS

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GLUTARIC ACIDURIA TYPE 1

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XI1. L-~-HYDROXIGLUTARIC ACIDURIA

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XIII. CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME TYPE IA

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SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY (4-HYDROXYBUTYRIC ACIDURIA)

285

METABOLIC DISORDERS WITH INTERMITTENT ATAXIA

285

REFERENCES

289 2-71

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1.

Boltshauser

INTRODUC~~ON

This section points to some rare metabolic disorders of autosomal recessive inheritance not covered in other book chapters. The emphasis is on conditions that may-usually or occasionally-present with ataxia as relevant clinical symptom, while diseases with ataxia as symptom in an advanced stage will be notcovered. Many metabolic disorders result in abnormal cerebellar imaging (1,2). A pattern recognition approach will assist in further diagnostic workup. In some diseases with abnormal cerebellar imaging (i.e., nonketotic hyperglycinemia, Menkes disease) patients are too severely affected to present with ataxia; these conditions will not be reviewed. For further reading may I refer to the following relevant textbooks: Metabolic disorders (3-5) Neuroimaging (6,7) Genetics (8)

II. A~RENOLEUKODYSTROP~Y The name adre~oZeukodystro~hy (ALD) was coinedby Blaw in l970 (9). Important historical discoveries related to ALD have been summarized (10). The estimated minimum incidence is 1.6 :100,000 (3 1). X-linked recessive inheritanceof ALD was already recognized in the early in 1993 the gene was iso1960s. The X-ALD gene was mapped to xq28 in 1; 198 lated by positionalcloning(10).Itcontainstenexonsandspans20-kb of genomic DNA. The protein product ALDP contains 745 amino acids. It is a peroxisomal membrane protein that belongs to the ATP-binding cassette (ABC) protein family. Alterations in the ALD gene are considered as the primary defect, affecting peroxisomal input functions. Numerous missense, frame-shift, nonsense, deletions, and insertions mutations have been identified. Most affected families have their private mutation (12). Clinical features are variable, even within a given family. Six clinical phenotypes have been defined (10,12): childhood cerebral ALD, adolescent cerebral ALD, adult cerebral ALD, adrenomyeloneuropathy, Addison only, and asymptomatic. Ataxia is not a relevant feature in these forms; however, rare instances presentingascerebellarataxiahavebeenreported. The patientreported by Kurihara et al. had ataxia as the first sign at 5.5 years (12). Magnetic resonance imaging (MRI) revealed high-intensity areas in the cerebellar hemispheres and subsequent cerebellar atrophy. by neuroimaging and The suspecteddiagnosis of ALDissupported biochemical analysis: characteristic MRI findings are T2-weighted demyelinat-

273

inglesionsintheparieto-occipitalareasinvolvingthesplenium(6,7). The borders enhance with (gadolinium) contrast. In the course of the disease the lesion spreads to the frontal lobes. In a few patients, the process has its onset in the frontal white matter. Involvement of the pontomedullary cortical spinal (14). Laboratoryconfirmationisbasedon tractsisacharacteristicfinding demonstration of abnormally high levelsof saturated very long-chain fatty acids in plasma. The effect of a dietary therapy with “Lorenzo’s Oil” in clinically affected patients is still unproved, but it appears that dietary measures in asymptomatic individuals may postpone clinical presentations. Bone marrow transplantation is the most promising in selected patients (10).

Hagberg has estimated the frequencyof infantile metachromatic leukodystrophy (MLD) to be 1:40,000 in Sweden. The frequency is likely to be lower in other countries. MLD characteristically presents in infancy, leading to developmental arrest and lossof acquired milestones, resulting in spasticity, optic atrophy, and feeding difficulties. The infantile form goes along with neurophysiological evidence of a peripheral demyelinating polyneuropathy. Forms with later onset and protracted course may occur at any age. However, in late presentions behavioral and cognitive, occasionally psychiatric, problems, predominate whereas, evidence of peripheral neuropathy may be absent (15). In late-onset forms, dysfunctionof motor coordination and upper neuron involvementmay be present, but ataxia isnot a presenting sign. This disorderis caused by a low activityof the enzyme arylsulfataseA. The biochemical diagnosis of MLD may present great challenges: gene polymorphism may lead to lowered enzymatic activity without clinical disease (pseudodeficiency alleles). Very rare cases of MLD are caused by an activator protein (called saposin B) deficiency with apparently normal levels of arylsulfatase A in leukocytes or fibroblasts (3,5,16). Enzymatic analysis must be supplemented by investigations revealing storage material and may require mutational analysis in selected instances (17,18). Neuroirnagingsupportsthediagnosis.Ittypicallyshowssymmetrical periventricular white matter involvement, consistently affecting the corpus callosum (6,7). Initially subcortical U-fibers are spared. Proton magnetic resonance spectroscopy (PMRS) reveals increased peaks for choline and myoinositol. We have recently seen a juvenile MLD patient at the age of l 0 years because of failure in school achievements. Although MRI at this stage very was impressive, there was only minimal motor discoordinationon clinical examination.

Globoidcellleukodystrophy(GLD)isanautosomalrecessive,inheriteddisordercaused by deficiency of galactocerebrosidase, a lysosomalenzymeresponsible for the degradation of the myelin glycolipid galactocerebroside. The human gene is located on chromosome 14q31 and consists of 17 exons. A variety of mutations (missense, nonsense, deletions, abberrant splicing) have been identified (19,20). General prevalence figures for GLD are not available, but the classic infantile form is assumed to be most prevalent in Sweden. By far the most common formof this rare condition is the classic infantile form presenting in thefirst year of life. Later presentations (infantile, juvenile, or adult) have been reported. Various presenting features have been described: visualfailure,ataxia,“gaitabnormalities,”spasticparaparesis,ortetraparesis (19,21,22). Many patients have neurophysiological evidence of large fiber sensorimotor polyneuropathy. The diagnosis is based on low to absent functional activity of the enzyme P-galactocerebrosidase in leukocytes or fibroblasts. In selected situations verification of the diagnosis at the molecular level may be attempted. Neuroimaging may be helpful in guiding additonal investiations. Although the classic infantile form usually goes along with thalamic signal alterations and hypodensities of cerbellar white matter (6,7), patients with late-onset forms have MRI hypodensities of the central (predominantly parietal) white matter and pyramidal tracts (20,22). The possible benefit of bone marrow transplantation has still to be determined.

The designation “vanishing white matter disease” or “CACH” (childhood ataxia with central hypomyelination) is emerging as a new type of leukoencephalopathy, initially described by Hanefeld et al. in 1993 (23) and Schiffmann et al. in 1994 (24). Inview of affected siblings, the disorder isof autosomal recessive inheritance. The underlaying metabolic basis and gene location are still unknown. Following early normal development, patients present with rather rapidly progressivemotorsymptoms(ataxia,spasticity),leadingtoseverehandicap within a few years. Characteristically episodesof deterioriation following infections and minor head traumas, have been repeatedly observed (25,26). This white matter diseaseis characterized by a typical pattern of MRI and MR spectroscopy (MRS)findings: T2-weighted MRI reveals diffuse hypodensity of white matter

almost identical with the signalof the ventricles. However, on FLAIR or proton density images periventricular white matter initially has low signal, whereas subcortical white matter has high signal. Proton MRS from cortex gives increased lactate and glucose resonances, MRS of affected white matter shows almost complete disappearanceof all normal signals and the presenceof glucose and lactate. On MRI the pontine segmental white matter is involved as well.

(27) reported on eight children withan identical patIn 1995 van der Knaap et al. tern of neurological and neuroimaging findings. They used the descriptive title “leukoencephalopathy with swelling anda discrepantly mild clinical course.” Patients presented with megalencephaly and very slowly progressive ataxia and spasticity,withintellectualfunctionspreservedforyears. MRI abnormalities were diffuse signal alterations and swelling of the cerebral hemispheric white matter, with the appearance of cyst-like spaces in the frontoparietal and anterotemporal subcortical areas. MRS studies were relatively mildly abnormal. Subsequently similar patients from various ethnic groups have been reported by different authors (28,29). The designation “van der Knaap leukoencephalopathy” has emerged. The condition is recessively inherited. At present (January 1999) the gene is not yet mapped. Despite extensive investigations the metabolic origin is unknown.

1. About 30% of white matter disorders presentingin childhood, as evident by impressive neuroimaging findings, are still of unknown etiology (J Vilk, personal communication). Among these are children presenting with ataxia or gait abnormality as initial findings. Imaging may particularly involve the cerebellar peduncles (30).

The neuronal ceroid lipofuscinoses (NCL) represent another groupof disorders. On the basis of age of onset, clinical course, ultrastructural morphology, and recently, genetic analysis, several forms have emerged (31-33); they are summarized in Table l. “Target organs” are brain and retina, clinical features are thus dominated by progressive cognitive impairment, increasing motor signs, epilepsy, and progressive visual failure.

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Table 1 NeuronalCeroidLipofuscinoses(NCL) ~

Gene Subtype locationproduct Gene symbol Childhood Infantile

CLNI

Late infantile

CLN2

Variant late infantile Finnish variant late infantile Juvenile

CM6

Juvenile with granular osmiophilic deposits Adult Kuf‘s disease

Palmitoyl protein thioesterase, PPT Pepstatin-insensitive lysosomal peptidase

CLNl

CLN4

llp15 15q21-q23 13q22

CM5

CLN3

lp32

438-amino membrane acid16p12 protein, function unknown Palmitoyl protein thioesterase. PPT

l lp32

Unassigned

There are ethnic and regional variations of the frequency and type distribu(7.7 :100,000and 4.8 :100,000 tions of NCL. The incidence is highest in Finland live births for the infantile and juvenile types, respectively). In Western Europe the total incidence for all NCL forms (consisting largely of late infantile andjuvenile forms) was calculated at 1.2: 100,000-1.6: 100,000 live births. In a discussion about ataxia the late-infantile and juvenile form are mainly of relevance. The late-infantile form presents with slowing of cognitive and of head circumference, and speech development, vague visual problems, slowing T2 epilepsy. Neuroimaging(34) shows consistently early cerebellar atrophy, high signal of periventricular white matter and later cerebral atrophy (Fig. 1). If mutation analysis is unavailable, the diagnosis is confirmed by ultrastructural examination of lymphocytes or skin biopsy demonstrating “curvilinear bodies.’’ Juvenile NCL typicallypresentswithprogressivevisualfailure;occasional convulsions may occur early in the condition. Motor impairment is a subsequent finding. In this type vacuolated peripheral lymphocytes are present.The diagno(35), which are essentially comparable sis is supported by neuroimaging findings with the late-infantile form andby demonstration of “fingerprint bodies’’ in skin biopsy. Adult NCL (Kufs’ disease) is a clinically and genetically heterogeneous disorder. Typical clinical symptoms are progressive myoclonus epilepsy accompanied by ataxia and dementia. The in vivo diagnosis of Kuf‘s disease is a challenge because mutation analysis is not available, and no consistent neuroimaging

Disorders Ataxia Metabolic in Rare

27777

pattern has emerged. Brain biopsy is often required to demonstrate fingerprint profiles or granular osmophilic deposits; occasionally, rectal and skin biopsy has been diagnostic. M.

NIENIANN-PICKDISEASETYPEC

The incidence of Niemann-Pick disease is not documented. Niemann-Pick disease types A and B are due to deficiency of the lysosomal enzymesphingomyelinase,whereas Niemann-Pick diseasetypeC(NPC)is caused by a problem of “intracellular cholesterol handling” (36,37). NiemannPick disease typeD, particularly common in Nova Scotia, isan allelic variant of NPCl (38). NPC is an autosomal recessive, neurovisceral storage disease. There is genetic heterogeneity. The NPCl gene was mapped to 18ql1,but the NPC2 gene is not yet known. NPCl and NPC2 are no different clinically (36). Cultured NPC fibroblasts were deficient in their ability to esterify exogeneously derived cholesterol and stored abnormal amounts of unesterified cholesterol in an intravesicular compartment. The primary lesion appears to block intracellular relocation and utilization of lysosomal cholesterol, but the primary site of disruption is still speculative. There is a wide spectrum of clinical presentation of NPC, ranging from the perinatal period into adulthood (39,40). The most common presentation (approx. 70-80%) are the late-infantile and juvenile forms. Children are reported to slow down in their motor and cognitive development. Ataxia is an early sign. Impaired vertical down gaze is almost constantly present, as is splenomegaly in childhood presentation. Subsequently, the typical course is a progressive loss of function, with evolving spasticity, dystonia, lossof speech, swallowing difficulty, often accompanied by seizures. Neuroimaging typically reveals early cerebellar atrophy, followed by cerebral atrophy (Fig. 2). Characteristically, a high T2 signal is present in periventricular white matter. This constellation is also typical for the late-infantile neuronalceroidlipofuscinosis(1).Abnormalbonemarrowstoragecellsarea constant finding and a first and easy step if the diagnosis is considered(40). Currently, cellular biology tests of cultured fibroblasts are required for diagnostic confirmation.

X.

LATE-ONSETGM,-GANGLIOSIDOSIS

GM, gangliosidosis is caused by a deficiencyof isoenzymes of two proteins that, together, confer p-1,4 N-acetyl galactosaminidase (hexaminidase) activity. The two isoenzymes are called hexosaminidase A (or Hex A) and B (Hex B). InTaySachs disease (also called variant B) only Hex A activity is missing; in Sandhoff

278

Figure 1 MRI of3-year-oldboywithlate-infantileneuronalceroidlipofuscinosis: (a) Cut through posterior fossa revealing cerebellar atrophy with enlarged fourth ventricle and dilated interfoliar sulci.

disease (also called variant 0), Hex A and B are deficient. These variants are clinically indistinguishable. For the classic infantile Tay-Sachs disease, the carrier frequency in the Ashkenazi Jewish population is approximately 1 :30; in the non-Jewish population it is estimated at l :300. In addition to the classic infantile formof GM, gangliosidosis (Tay-Sachs disease and Sandhoff disease), late-onset presentations (with both enzyme variant constellations) have been reported. There is considerable clinical variation

279

Figure 1 ~ o ~ t i ~(b) uT2w e ~MRI at level of lateral ventricles: There is increasedsignal of periventricular white matter.

among these chronic forms, including progressive dystonia, motor neuron disease, psychosis, and spinocerebellar symptoms (5,41). In the latter, cerebellar signs dominate the clinical phenotype(42). A patient seen by the author is illustrated in Fig. 3. This boy had a slowly progressive ataxia, with onset at about 3 years, he was still ambulant at 10 years. Additional findings were slowly developing spasticity and dementia. Fundoscopy was normal. Neuroimaging showed cerebellar atrophy, but no involvement of basal ganglia, thalamus, or cerebral white matter. onf firm at ion of the diagnosis requires appropriate enzyme analy-

280

Boltshauser

Figure 2 MRI of 12-year-old girl with juvenile-onset Niemann-Pick disease type presenting with mild ataxia and vertical downgaze impairment: (a)axial.

C,

sis, preferably in cultured fibroblasts. Mutation analysis is available in specialof ized laboratories. GM,-gangliosidosis has to be included in the “checklists” slowly progressive cerebellar ataxia of childhood and adolescence.

XI. GLUTARIC ACIDURIA TYPE 1 Glutaric aciduria (CA-l) was described in 1975 by Goodman et al. It is an autosomal recessive condition, with an estimated minimum incidence of l :40000.

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Figure 2 Continued (b) sagittal MRI revealing moderate cerebellar atrophy.

The mutated gene maps to chromosome 19~11.2.In recent years a number of (43). Deficiency of glutaryl-CoAvariousmutationshavebeenreported dehydrogenase (GDH) results in accumulation of glutaric acid, glutaryl carnitines, and of secondary metabolites in body fluids. GDA activity can be measured in leukocytes or fibroblasts. The pathogenesis of GA-1 is still poorly understood, both of the frontotemporal hypoplasia (see following) andof “brain toxicity” in metabolic crises. Clinical presentation is variable (44,45). Most patients are macrocephalic. Early development in the first few months is usually normal or may be slightly delayed. Between the first weeks and thefifth year of life acute encephalopathy,

MRI of 13-year-old boy withchronicGM,-gangliosidosis,withonset ataxia in preschool age: (a) coronal.

of

often suggesting encephalitis, can occur, probably triggered by intercurrent illnesses. Most patients are left with marked residual findings, in particular dystoA smaller proportionof patients presents with nia, inability to sit, walk, or speak. delayed gross motor development: hypotonia and ataxia may be presenting signs. Rare presentations are subdural effusions. Some individuals remained asymptomatic. A spectrum of neuroradiologic features is known in CA-l even before the onsetof brain injury. Hypoplasiaof frontal and temporal lobes, and arachnoid In symptomatic patients high T2 cysts in the temporal pole, are characteristic, signals in basal ganglia, and loss of volume of putamen and caudate nuclei is characteristic (6,45,46).

(b) sagittal MRI demonstrating enlarged fourth ventricle, markedly dilated cerebellar sulci. There is a megacisterna magna. The finding of increased glutaric acid in urine and plasma in the absence of other pathological productsof disturbed fatty acid oxidation is diagnostic. However, occasional patients may excrete only little glutaric acid, requiring repeated analysis or straightforward measurement of enzyme activity. Oral carnitine supplementation is the cornerstone of treatment. There is strong evidence that this supplementation prevents further neurological progression and new onset of metabolic crises. The role of dietary treatment (reducing intake of lysine and tryptophan) is controversial.

L-2-Hydroxiglutaric aciduria (LHGA) was first reported in 1980 (47). About 50 patients were identified before 1997 (48). Autosomal recessive inheritance can be

284

6oltshauser

assumed in view of affected siblings. The majority of patients are of Mediteranean origin (49,50). The metabolic basis of LHGA is still unknown, Enzyme activity of L-2(48). hydroxiglutarate dehydrogenase in liver of two affected patients was normal Histology (postmortem, brain biopsy) confirmed loss of myelin, sponginess of white matter, and reactive gliosis (49). Although there is some clinical heterogeneity even in sibs (SO), a comparable clinical pattern has emerged (49-51): Almost all patients present in infancy or early childhood with cognitive and speech delay, as well as motor retardation, often with gait ataxia. Abouthalf of the patients are described as macrocephalic. Seizures developed in many. The longtern prognosis is not yet fully documented. Many patients are saidbetoin stable condition over years, whereas others have slow progression. The diagnosis is based on biochemical analysis: There is consistent increased L-2-hydroxyglutaric acid in urine and plasma, but not in cerebrospinal fluid (CSF), whereas lysine is elevated in plasma andCSF. A charasteristic neuroimaging pattern on MRI has emerged (49-52). The subcortical cerebral white matter is involved, revealingT2 hyperintensity. Globus pallidus and putamen are mostly involved, also displaying increased signal intensity. The dentate nuclei are typically of high intensity. Cerebellar atrophy may evolve. This combination of neuroimaging features is characteristic and may allow the diagosis. A typical case is illustrated in Fig. 4. D-2-Hiydroxyglutaricaciduria is a different condition. The clinical phenotype is more variable, most patients have hypertonia, mental retardation, and seizures.

Xlll. CARBO~YDRATE-DE~I~IENT GLYCOPROTEIN SYNDROME TYPE IA Carbohydrate-deficient glycoprotein (CDG) syndromes are a family of biochemically and clinically different disorders (5354). They have in common a partial deficiency of the carbohydrate moiety of secretory and membranous glycoproteins. Thus, it is understandable that these are complex multisystem diseases with broad biochemical and clinical spectrum(55). The first patients were reported in 1980 (56). At present, this familyof disorders is classified into several types according to transferrin isoelectric focusing (53). At present five types have been recognized, by far the most common is type IA-the only type relevant to discussion in relation to ataxia. The estimated prevalence for CDG-IA is in the order of 1:50,000. CDG-IAismostlyduetodeficiency of phosphomannomutase. However, additonal defects are discussed because this enzyme activity has been , found normal in some patients with CDG-IA (5’7,58). The gene is on 1 6 ~ 1 3the enzyme can be measured in leukocytes, fibroblasts, or liver.

Disorders Ataxia Metabolic in Rare

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Most patients with CDG-IA present in early infancy with psychomotor retardation,usuallycombinedwithslightfacialdismorphicfeatures,some degree of hepaticdysfunction,andoftensubcutaneouslipodystrophy. The neurological picture comprises hypotonia, ataxia, and often hyporeflexia (55). After infancy, common findings are retinitis pigmentosa, stroke-like episodes, and occasional seizures. The majority of patients do not achieve independent walking. Fig. 5 illustrates typical MRI findings. Neuroimaging reveals constantly reduced cerebellar volume. Although some patients clearly have cerebellar hypoplasia, others have evidenceof still on-going cerebellar atrophy, probably superimposed on hypoplasia (1).The diagnosis is confirmed by transferrin isoelectric focusing and further enzymatic analysis. Treatment of CDG-IA is not possible.

XIV. SUCCINICSEMIALDEHYDEDEHYDROGENASE DEFICIENCY (4-HYDROXYBUTYRIC ACIDURIA) Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal, recessively inherited defect in y-aminobutyric acid (GABA) degradation. The enzyme activity can be measured in cultured cells or isolated peripheral lymphocytes. The biochemical hallmark is accumulation of 4-hydroxybutyric acid (GHB), which accumulates in physiological fluids (59,60). The clinical phenotype of SSADHD is highly heterogeneous, even within sibships. It seems difficult to define a common phenotype for the disorder. Common manifestations are delayed motor and mental development, hypotonia, and delayed expressive speech development. Ataxia is apparently a frequent manifestation (61,62).The manifestations are nonspecific and not unique to SSADHD. If suspected the diagnosis needs careful biochemical verification, optimally by determination of urine and CFS metabolites by proton MRS. Neuroimaging is not contributory (61). Treatment for SSADHD was attempted with the antiepileptic drug vigabatrin (61). This therapy has been encouraging in some, but was of little value in other patients.

XV.

METABOLICDISORDERSWITH INTERMITTENT ATAXIA

A number of rare metabolic disordersmay present with intermittent or recurrent ataxia (4,5). This includes amino acid disorders (in particular maple syrup urine disease), organic acidurias (methylmalonic acidemia, propionic acidemia, isova-

286

oltshauser

Figure 4 T2-weighted MRI of 6-year-old boy presenting with delayed motor development, moderate truncal ataxia, and expressive speech delay: (a) hyperintensity of dentate nuclei.

leric acidemia), urea cycle defects (ornithine transcarbamylase deficiency, argininosuccinatesynthetasedeficiency),aswellaspyruvatedehydrogenasedeficiency. These attacks of ataxia may be triggered by minor viral infection, fever, or catabolic states in general; however, sometimes no overt cause is found. For further workup, analysisof body fluids during such an attack is crucial.The presence or absence o f hyperglycemia, ketoacidosis, hypera~mon~mia, and hyper-

287

Figure 4 Continued (b) section through centrum semiovale revealing hyperintensity of subcortical white matter involving U-fibers; this results in an appearance of “empty gyri.” Diagnosis: L-Zbydroxiglutaric aciduria.

lactacidemia will help distinguish the aforementioned metabolic conditions. The analysis of body fluids should include Plasma: glucose, lactate, ammonia, blood gases, ketone bodies Urine: amino acids, organic acids, ketone bodies Cerebral spinal fluid: glucose, lactate

288

Boltshauser

Figure 5 Axial T2-weighted MRI through posterior fossa in 9-year-old boy withCDG syndrome type IA:There is marked (isolated) cerebellar atrophy.

Hartnup disorder, named after the family nameof the index case, isan autosomal recessive impairmentof neutral amino acid transport, limited to the kidneys and small intestine (5). In the past, a few individuals with Wartnup disorder had intermittent ataxia, other symptoms included photosensitive skin rash, psychotic behavior, and mental retardation. Because the great majority of identified subjects are clinically normal, Wartnup disorder is now considered a benign transport defect, andnot a “disease.” Additional factors are considered responsible for the occasional manifestation of symptoms.

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*

ACKNO~LE~G~ENT

Many thanks to colleagues who have contributed to diagnosing patients with ataxia, particularly to Drs.E Martin, MA Spycher, I3 Steinrnann, and A SupertiFurga.

REFERENCES 1. Steinlin M, BlaserS, Boltshauser E. Cerebellar involvement in metabolic disorders: a pattern recognition approach. Neuroradiology 1998; 40:347-354. 2. Ramaekers VT, Heimann G, Reul J, Thron A, Jaeken J. Genetic disorders and cerebellar structural abnormalities in childhood. Brain 1997;120:1739-1751. & 3. Applegarth DA, Dimmick JE, Hall JG. Organelle Diseases. New York: Chapman Hall, 1997. of 4. Blau N, Duran M, Blaskovics. Physician’s Guide to the Laboratory Diagnosis Metabolic Diseases. New York: Chapman & Hall, 1996. In5. Scriver C, Beaudet AL, Sly WS, Valle D. The Metabolic and MolecularofBases herited Disease. 7th ed. New York: McGraw-Hill, 1995. 6. Barkovich AJ. Pediatric Neuroimaging. 2nd ed. New York: Raven Press, 1995. J. MagneticResonanceofMyelin,Myelination,and 7. Van derKnaapMS,Valk Myelin Disorders. 2nd ed. Berlin: Springer, 1995. 8. MC Kusick VA. Mendelian Inheritance in Man. 12th ed. Baltimore: Johns Hopkins University Press, 1998. Online access: http://www.ncbi.nlm.gov/ornim. 9. Blaw ME. Melanodermic type leucodystrophy (adrenoleukodystrophy). In: Vinken PJ,BruynGW, eds. Handbook of Clinical Neurology. v01 10. Amsterdam: North Holland,1970:128-133. 10. Moser HW. Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain 1997; 120:1485-1508. 11. Bezman L, MoserH W , Incidence of X-linked adrenoleukodystrophy and the relative frequency of its phenotypes. Am J Med Genet 1998; 76:415-419. 12. Gaertner J, Braun A, Holzinger A, Roerig P, Lenard HG, Roscher AA. Clinical and genetic aspects of X-linked adrenoleukodystrophy. Neuropediatrics 1998; 29:3-13. 13. KuriharaM,KumagaiK,Yagishita S, ImaiM,WatanabeM,Suzuki U, Orii T. Adrenoleukomyeloneuropathy presenting as cerebellar ataxia in a young child: a probable variant of adrenoleukodystrophy. Brain Dev 1993; 15:377-380. 14. Barkovich AJ, Ferriero DM, Bass N, Boyer R. Involvementof the pontornedullary corticospinal tracts: a useful finding in the diagnosis of X-linked adrenoleukodystrophy. AJNR Am J Neuroradiol 1997; 18:95-100. 15. Vella G, Loriedo C, Raccah R, Baldassarre P, Paolillo A. Successful paroxetine treatment of major depression in an adult form of metachromatic leukodystrophy with cognitive disturbances. Can J Psychiatry 1998; 43:748-749. 16. Landrieu P, BlancheS, Vanier MT, Metra1S, Husson B, Sandhoff K, Fischer A. Bone marrow transplantation in metachromatic leukodystrophy caused by saposin-B deficiencv: a case reuort with a 3-vear follow-uu period. J Pediatr 1998: 133:129-132.

17. Kurosawa K, Ida H, EtoY.Prevalence of arylsulphatase A mutations in1l Japanese patients with metachromatic leukodystrophy: identification of two novel mutations. J Inherited Metab Dis 1998; 21 :781-782. 18. Gieselmann V, Matzner U, Hess B, Luellmann-Rauch R, Coenen R, Hartmann D, D'Hooge R, DeDeynP, Nagels G. Metachromatic leukodystrophy: molecular geneticsandananimalmodel.JInheritedMetabDis1998; 21 :564--574. : 19. De Gasperi R, Gama Sosa MA, Sartorato EL, Battistini S, MacFarlane H, Gusella JF, Krivit W, Kolodny EH. Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy. Am J Hum Genet 1996; 59:1233-1242. 20. Be~ardiniGL, Herrera DG, Carson D, DeGasperi R, Gama Sosa MA, Kolodny EH, Trifiletti R. Adult-onset &abbe's disease in siblings with novel mutations in galactocerebrosidase gene. Ann Neurol 1997; 41: 111-1 14. 21. Barone R, Bruehl K, Stoeter P, Fiumara A, Pavone L, Beck M. Clinical and neuroradiological findings in classic infantile and late-onset globoid-cell leukodystrophy (&abbe disease). Am J Med Genet 1996; 63:209-217. 22. Arvidsson J, Hagberg B, Mansson JE, Svennerholm L. Late onset globoid cell leukodystrophy (Gabbe' disease)-Swedishcasewith 15 years of follow-up.Acta Paediatr 1995; 84:218-221. 23. Hanefeld F, Holzbach U, Kruse B, Wilichowski E, Christen HJ, Frahm"J. Diffuse white matter disease in three children: an encephalopathy with unique features on magnetic resonance imaging and proton magnetic resonance spectroscopy. Neuropediatrics 1993; 24:244-248. 24. Schiffmann R, Moller JF, Trapp BD, Shih HH-L, Farrer RG, Katz DA, Alger JR, Parker CC, Hauer PE, Kaneski CR, Heiss JD, Kaye EM, Quarks RH, Brady RO, Barton W.Childhood ataxia with diffuse central nervous system hypomyelination. Ann Neurol 1994; 35:331-340. E, BegeerJH,StroinkH, 25, Van derKnaap,BarthPG,GabreelsFJM,Franzoni Rotteveel JJ,Valk J. A new ~eukoencephalopathy with vanishing white matter. Neurology 1997; 48:845--855. 26. Van der Knaap MS, KamphorstW, Barth PG, Gaaijeveld CL, Gut E, Valk J. Phenotypic variation in leukoencephalopathy with vanishing white matter. Neurology 1998; 51 1540-547. 0, ArtsWFM, 27. Van der h a a p MS,BarthPG,StroinkH,vanNieuwenhuizen Hoogenraad F, Valk J. Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 1995; 37:324-334. 28. Singhal BS, Gursahani RD, UdaniVP, Biniwale AA. Megalencephalic leukodystrophy in an Asian lndian ethnic group. Pediatr Neurol 1996; 14:291-296. 29. Goutikres F, Boulloche J, Bourgeois M, Aicardi J. Leukoencephalopathy, megalencephaly, and mild clinical course. A recently individualized familial leukodystrophy. Report on five new cases. J Child Neurol 1996; 11:439"444. 30. Sugama S, Kusano K. A sporadic caseof very slow progressive leukodystrophy involving the cerebellar peduncles. Brain Dev 1995; 17:280-282. 31. Goebel HH, Sharp J. The neuronal ceroid-lipofuscinoses. Recent advances. Brain Pathol 1998; 8:151-162. P. Clinical and 32. Jaervelae I, Autti T, Lamminranta S, Aberg L, Raininko R, Santavuori '

l

33. 34.

35. 36. 37. 38. 39.

40. 41. 42. 43. 44. 45. 46. 47. 48.

magnetic resonance imaging findings in Batten disease: analysis of the major mutation (1.02-kb deletion). Ann Neurol 1997; 42:799-802. Munroe PB, Mitchison HM, O'Rawe AM, Anderson JW, Boustany EM, Lerner TJ, Taschner PEM, De Vos N, Breuning MH, Gardiner RM, Mole SE. Spectrum of mutations in the Batten disease gene, CLN3. Am J Hum Genet 1997; 61:310-3 16. Seitz D, Grodd W, Schwab A, SeegerU, Klose U, Naegele T. MR imaging and localized proton MR spectroscopy in late infantile neuronal ceroid lipofuscinosis. Am J Neuroradiol 1998; 19:1373-1377. Autti T, Raininko R, Vmhane SL, Santavuori P. MRI evaluation of neuronal ceroid lipofuscinosis, partI. Cranial MRI of 30 patients with juvenile neuronal ceroid lipofuscinosis. Neuroradiology 1996; 38:476-482. VanierMT,Suzuki K. RecentadvancesinelucidatingNiemann-PickCdisease. Brain Pathol 1998; 8:163-174. Morris JA, Carstea ED. Niemann-Pick C disease: cholesterol handling gone awry. Mol Med Today 1998; 525-53 1. Greer WL, Riddell DC, Gillan TL, Girouard GS, SparrowSM, Byers DM, Dobson MJ,NeumannPE.TheNovaScotia(typeD)form ofNiemann-Pick disease is caused by a G,,,,-+T transversion in NPC1. Am J Hum Genet 1998; 63:52-54. Tedeschi G, BonavitaS, Barton NW, Bertolino A, Frank JA, Patronas NJ, Alger JR, Schiffmann R. Protonmagneticresonancespectroscopicimagingintheclinical evaluation of patients with Niemann-Pick type C disease. J Neurol Neurosurg Psychiatry 1998; 65:72-79. Lossos A, Schlesinger I, Okon E, Abramsky 0, Bargal R, Vanier MT, Zeigler M. Adult-onset Niemann-Pick type C disease. Clinical, biochemical and genetic study. Arch Neurol 1997; 54:1536-1541. Specola N, Vanier MT, Goutikres F, Mikol J, Aicardi J. The juvenile and chronic formsofGM, gangliosidosis:clinicalandenzymaticheterogeneity.Neurology 1990; 40: 145-150. Beck M, Sieber N, Goebel HH. Progressive cerebellar ataxia in juvenile GM,-gangliosidosis type Sandhoff. Eur J Pediatr 1998; 157:866-867. Goodman SI, Stein DE, SchlesingerS, Christensen E, Schwartz M, Greenberg CR, Elpeleg ON. Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): revieiv and report of thirty novel mutations. Hum Mutat 1998; 12:141-144. Superti-Furga A, Hoffrnann GF. Glutaric aciduria type l (glutaryl-CoAdehydrogenase deficiency): advances and unanswered questions. Eur J Pediatr 1997; 156:1821-828. Baric I, Zschocke J, Christensen E, Duran M, Goodman SI, Leonard JV, Mueller E, Morton DH, Superti-Furga A, Hoffmann GF. Diagnosis and management of glutaric aciduria type 1. J Inherited Metab Dis 1998; 21 :326-340. Brismar J, Ozand PT. CT and MR of the brain in glutaric acidemia type1: a review of 59 published cases and a report of 5 new patients. AJNR Am J Neuroradiol 1995; 16:675-683. Duran M, Karnerling JP, B&er HD, et al. L-2-Hydroxyglutaric aciduria: an inborn error of metabolism? J Inherited Metab Dis 1980; 3:109-112. WandersRJA,Vilarinho L, HartungHP,HoffmannGF,MooijerW, Jansen GA,

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49. 50.

51. 52. 53. 54.

55.

56.

57. 58.

59. 60.

61. 62.

oltshauser

HuijmansJGM,deKlerkJBC,tenBrinkHF,Jakobs C, DuranM.L-2Hydroxyglutaricaciduria:normalL-2-hydroxyglutaratedehydrogenaseactivityin liver from two new patients. J Inherited Metab Dis 1997; 20:725-726. Barbet C, Fineza I, Diogo L, Maia M, Melo J, Guimaraes A, Melo Pires M, Cardoso ML, Vilarinho L. L-2-Hydroxyglutaric aciduria: clinical, biochemical and magnetic resonance imaging in six Portuguese pediatric patients. Brain Dev 1997; 19268-273. De Klerk JBC, Huijmans JGM. Stroink H, Robben SGF, Jakobs C, Duran M. L-2Hydroxyglutaric aciduria: clinical heterogeneity versus biochemical homogeneity in a sibship. Neuropediatrics 1997; 28:314-317. Bath PG, Hoffmann GF, Jaeken J, Lehnert W, Hanefeld F, Van Gennip AH, Duran M, Valk J, Schutgens RBH, TrefzFE;,Reimann G, Hartung HP. L-2-Hydroxyglutaic acidemia: a novel inherited neurometabolic disease. Ann Neurol 1992; 32:66-71. D’Incerti L, Farina L, Moroni I, Uziel G, Savoiardo M. L-2-Hydroxyglutaric aciduria: MRI in seven cases. Neuroradiology 1980; 40:727-733. Freeze HH. Disorders in protein glycosylation and potential therapy: tip of an iceberg? J Pediatr 1998; 133593-600. Niehues R, Hasilik M, Alton G, Koerner C, Schiebe-Sukumar M, Koch HG, Zimmer K-P, Wu R, Harms E, Reiter K, von Figura K, Freeze HH, Harms HK, Marquardt T. Carbohydrate-deficient glycoprotein syndrome type lb. Phosphomannose isomerase deficiency and mannose therapy. J Clin Invest 1998; 101:1414-1420. Jaeken J, Matthijs G, Barone R, Carchon H. Carbohydrate deficient glycoprotein (CDG) syndrome type I. J Med Genet 1997; 34:73-76. Jaeken J, Vanderschueren-Lodeweyckx M, Caesar P, Snoeck L, Corbeel L, Eggermont E, Eeckels R. Familial psychomotor retardation with markedly fluctuating serum proteins, FSH and GH levels, partial TBG deficieny, increased serum arylsulphatase A and increased CSF protein:a new syndrome? Pediatr Res 1980; 14: 179. AcarreguiMJ,GeorgeTN,RheadWJ.Carbohydrate-deficientglycoproteinsyndrome type l with profound thrombocytopenia and normal phosphomannomutase and phosphomannose isomerase activities. J Pediatr 1998; 133:697-700. Burda P, Borsig L, Rijk-van Andel J, Wevers R, Jaeken J, Carchon H, Berger EG, Aebi M. A novel carbohydrate-deficient glycoprotein syndrome characterized bya deficiencyinglucosylation ofthedolichol-linkedoligosaccharide.JClinInvest 1998;102:647-652. Gibson KM, Hoffmann GF, Hodson AK, Bottiglieri T, Jakobs C. 4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism. Neuropediatrics 1998; 29: 14-22. Gibson KM, Sweetman L, KozichV, Pijackova A, Tscharre A, Cortez A, Eyskens F, Jakobs C, Duran M, Poll-The BT. Unusual enzyme findings in five patients with metabolicprofilessuggestiveofsuccinicsemidehydedehydrogenasedeficiency (4-hydroxybutyric aciduria). J Inherited Metab Dis 1998; 2 1:255-261. DietzB,AksuF,Aguigah G,Witting W,Aygen S, Lehnert W, Jakobs C. Vigabatrintherapiebeieinem7jaehrigenJungenmitSuccinat-SemialdehydDehydrogenase-Mangel. Monatsschr Kinderheilkd 1996; 1443797-802. Opp J, Raab K,Jakobs C, LehnertW, Gibson KM. Sukzinatsemialdehyddehydrogenase (SSADH)-Mangel bei Geschwistern. 2 Monatsschr Kinderheilkd 1996; 144~695-698.

Infantile-Onset Spinocerebellar Ataxia Tuuia Lonnqvist, Anders Paetau, and Helena Pihko University of Helsinki, Helsinki, Finland

Kaisu Nikali National Public Health Institute, Helsinki, Finland

INTRODUCTION I.

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NEUROPATHOLOGY A.PeripheralNerve B. CentralNervousSystem C.Discussion of Etiopathogenesis

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CLINICAL FEATURES A. Clinical Presentation of the Disease B. Peripheral Neuropathy C. Ataxia, Pyramidal Signs, Athetosis, and Muscle Hypotonia D. Speech and Hearing Deficit E. Ophthalmoplegia and Optic Atrophy F. Epilepsy G. Puberty and Growth H. Communication and Mental Capacity I. Life Span

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ANCILLARY A. Neuroimaging Studies B. Neurophysiological C. Tests D.DifferentialDiagnosis:MitochondrialStudies Laboratory Tests

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VII. REFERENCES

Infantile-onset spinocerebellar ataxia (IOSCA) is an early-onset hereditary ataxia of unknown etiology.The disease manifests close to the age of 1 year as acute or subacute clumsiness, athetoid movements in hands and face, hypotonia, and loss of deep tendon reflexes in the legs. Ophthalmoplegia and a sensorineural hearing deficit are found by school age, sensory neuropathy (decreased sensory nerve conduction velocities) and optic atrophy by the age of 10-15 years, and female hypogonadism and epilepsyby the age of 15-20 years. Most patients are nonambulatory by the age of 20. The gene defect of IOSCA has been localized to chromosome 1Oq24 (1 ,2). The first patients, two pairs of siblings with infantile onset ataxia, hypotonia, athetosis, and loss of deep tendon reflexes, were found at the Children's Hospital, University of Helsinki, Finland, in the early 1970s.The patients developed ophthalmoplegia and becamedeaf by the age of 5. In 1985, hearing deficit in 11 patients was reported (3), and the disease was named OHAHA according to the first clinical symptoms: ~phthalmoplegia-~ypoacusis-ata~ia-~ypotoniaathetosis. As we investigated these patients in more detail, it became evident that the typical features of the disease were sensory axonal neuropathy and progressive atrophy of the cerebellum, brain stem, and spinal cord. The disease could, therefore, be classified as an infantile-onset spinocerebellar ataxia (4).

Today, 21FinnishIOSCApatients(10females, 11 males)belongingto l5 nuclear families have been identified.The gene frequency of the disease among to 1.0"~.The the 5 millionFinnishpopulationcanbeestimatedtolieclose IOSCA families include six pairsof affected siblings, and there is consanguinity in two families. So far no patients have been found outside Finland. IOSCA is a

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part of the Finnish disease heritage, which comprises more than 30, mostly autosomal recessive inherited, diseases overrepresented in the Finnish population. Moreover,someinheriteddisorderscommonelsewherearenotencountered among the Finns at all. The clustering of uncommon hereditary diseases in Finland can be explained by the founder effect, resulting from a small number of original settlers, genetic drift, and long-term regional isolation (5,6). AsexpectedtheIOSCApatientsseemtoshareonefoundermutation. Traces of the ancient IOSCA founder haplotype around the disease gene locus on chromosome 10q24 can be observed inall current IOSCA chromosomes justifying this assumptionof a single IOSCA founder mutation. The conservation of the ancient founder haplotype of 4 CM in genetic length in mostof the present-day disease chromosomes implies that the IOSCA mutation was introduced into the Finnish population some30-40 generations, or 750-1000 years, ago. Genealogical data on IOSCA with patients’ ancestors originating from a relatively kide geographic area and their distribution bearing close resemblance to a settlement movement from eastern Finland in the 16th century support this hypothesis and suggest that the 30 to 40-generation-old IOSCA mutation spread within Finland during the migration wave northwest (2,7).

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The absence of biochemical markers or chromosomal rearrangements in IOSCA patients left us with positional cloning as the suitable method to isolate the defective gene. The IOSCA gene locus maps to chromosome 10q24, with no other ataxia (1). loci assignednearby, providing evidenceof IOSCA as a distinct disease entity Extendeddiseasehaplotypesaroundthelocusrevealoldrecombinations by means of which the IOSCA region can be restricted to between two close-by markers, IllOS1265 and 74f6ac2 (2,8). The physical map (Fig.1) constructed with several overlapping PI-derived artificial chromosome (PAC) and bacterial artificial chromosome (BAC) clones of the region yields a length estimation of (8). Analyses of trinucleotide repeat tracts 150 kb for the critical IOSCA interval within this region was not suggestive of a dynamic mutation underlying IOSCA. Of positional IOSCA candidate genes, the gene encoding neurofilament-66 (NF-66/cx-internexin),putatively involvedin early axonal formation proved to lie somewhat outside the IOSCA region (2), and immunohistoche~calanalyses re(9). No mutations could be obvealed no defects in this protein in IOSCA tissues served in the coding sequence of CYP17, a cytochrome P450 gene with major role in steroid biosynthesis (10) in IOSCA patients (2). The single gene known within the IOSCA interval to date encodes pairedbox protein 2, PAX2. PAX2 plays a fundamental role in the regulatory cascade necessary for the development of the neural structures most severely affected in

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Figure 1 Physical and transcript map around the IOSCA locus on lOq24:The squares represent theST% used in the map construction, the spheres known genes (shadowed) and novel EST'S in the region. The transcripts with no predicted function are indicated with their EST codes. The YAC, BAC, and PAC clones below the horizontal axis are not to scale. (ST& sequence-taggedsite; EST, expressedsequencetag;YAC,yeastartificial chromosome; BAC, bacterial artificial chromosome; PAC, PI-derived artificial chromosome; CMOAT, canalicular multispecific organic anion transporter; COX15, cytochrome C oxidaseassemblyprotein;Cytob561,cytochrome b 561; MRS4, mitochondrial mA.. splicing protein).

IOSCA. However, the coding sequence of PAX2 seems to be normal in IOSCA patients (2).The IOSCA gene thus remains to be identified from the region containing some five genes on average.

IV. NEUROPATHOLOGY IOscA is a progressive neurological disease, which severely affects the sensory system. The only nonneurological finding is female hypogonadism. The discusis based on sural nerve biopsies sion of the neuropathological findings in IOSCA of 13 patients (2.2-28.8 years of age) and three autopsy cases (21, 24, and 26 years of age).

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A severe loss of especially large myelinated fibers was the main microscopic 2). The transverse sectionsof myelinated fibers were finding in sural nerves (Fig. microscopically normal only in the two youngest patients (ages 2 and 3); fiber loss was seen in all older patients. Although the biopsies in the two youngest as a reduction of large myelinated patients appeared normal, axonal loss seen fibers was noticed in the morphometric measurements (11). The early morphometric changes may indicate not only a loss, but also a poor maturation of large myelinated fibers. The sensory axonal neuropathy of IOSCA with a severe loss of large myelinated axons isvery similar to the neuropathy in Friedreich’s ataxia (FRDA) (11-14). The pathological mechanism behind this axonal neuropathy is unknown. The first and most widely accepted theory is that of a dyingback as neuropathy (15,16), or central peripheral distal axonopathy (17). In FRDA well as in IOSCA this hypothesis is supportedby the decreased density of large of degenerating fibers, myelinated fibers in young children, the low incidence and that the myelin sheath of some surviving fibers was too thin for the axon size (11,18).

F120 Figure 2 Lightmicroscopyofdistalsuralnerveininfantileonsetspinocerebellar ataxia: Note the progressive loss of especially large myelinated fibers. Their density appears almost normal in (M/3, male, 3 years of age), partly preserved in (M/l5, male, 15 years of age), and only scattered small fibers (arrows) remain in (F/20, female, 20 years of age). l-pm Epon section; toluidine blue; original magnifications X425 (M/3, MM), and x950 (F/20).

igure 3 (A) Dorsal root ganglion Th 8; SMI-32 neurofilament imrnunostaining. Note the degenerating ganglion cells with capsule cell proliferation (arrows). (B) Posterior rootlets C-5, plastic section. Note the dramatically reduced axonal density compared with (C): Anterior rootlets, C-5, plastic section. (D) Cervical cord C-7, SMI-3I l neurofilament immunostaining. Note the severely degenerated gracile (g) and cuneate (c) posterior columns, posterior and anterior spinocerebellar tracts (asterisks) and, less severely, the lateral

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ra The pathological findings of the central nervous system were almost uniform in all IOSCA cases (9). The weight of the infratentorial parts represent only about 60% of what normally could be expected. Accordingly, the macroscopic appearance of the cerebrum was within normal range, but the brain stem was atrophic, with flattened pons, atrophic medulla oblongata, and moderate atrophy of the cerebellum. The optic nerves and chiasm were slightly atrophic, and the cranial nerves, especially the eighth, seemed thin. Coronal sections of the cerebrum revealed no clearcut focal pathology of the cortex, white matter structures, deep gray matter or ventricular system. The dorsal roots of the spinal cord were severely atrophic, thinned, and brownish. In the following section we present and discuss the main findings at different levels by combined macroscopic and microscopic observations.

1. Spinal Cord InIOSCAthedorsalrootgangliaexhibitedslighttomoderatedegenerative changes in the form of neuronal loss and Nageotte nodules (Fig. 3A). There was a moderate to severe loss of myelinated fibers in semithin sectionsof the dorsal The posterior columns roots as compared with the anterior roots (see Fig. 3B,C). were severely shrunken, with myelin loss and gliosis more marked in the gracile than on the cuneate (see Fig.3D). The spinocerebellar tracts, especially the posterior, were severely affected. Pyramidal tracts were only mildly affected. There was a severe neuron loss in the dorsal nucleus (Clarke’s column). The intermediolateral column was slightly atrophic in one of the cases. Spinal pathology with degeneration of the dorsal root ganglia and severe atrophy of the dorsal roots and columns are very similar in IOSCA and FRDA (9,19,20).

2. Brain Stern At the level of medulla oblongata, the dorsolateral portionsof the inferior olives were atrophic and gliotic, as were the inferior cerebellar peduncles and medial lemniscus (Fig. 4A,B). The accessory cuneate nucleus was also affected. The pyramids were somewhat reduced. The eighth cranial nerve and nuclei were atrophic (see Fig. 4C,D). At the levelof pons, the middle and, especially, the superior cerebellar peduncles were atrophic. Also, in the ventral pons, there was slightly to moderately reduced neurons in pontine nuclei. The sensory tegmental nuclei and tracts were more affected than the motor ones. At the levelof mesencephalon

and anterior pyramidal tracts (p). Quite well-preserved anterior horn cells can be seen (arrow). Original magnifications: X 160 (A-C) and X25 (D). A-C: a 26-year-old female patient, D: a 24-year-old male patient.

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Figure 4 Brain stem structures of a 24-year-old male patient: (A) Rostral medulla, dorsolateral corner, MAP-2 neuronal immunostai~i~g. Note the practically complete depletion of neurons in the dorsal and ventral cochlear nuclei (asterisks); two neurons are seen to be shrunken (arrows), and the restiform body (rb)appears to be fiber-depleted. (B) Yen tral part of medulla. The dorsal leaf(arrows) of the inferior olive (io), above the pyramid (p), is depleted of neurons. (C) Cochlear part and(D) vestibular part of the eighth cranial

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the substantia nigra seemed preserved in one case, but was moderately atrophic in two others. All three cases showed atrophy of the oculomotor nuclear complex, fourth cranial nerve nuclei, and periaqueductal gray matter. The atrophic changes at the levelof brain stem are more severe in IOSCA than in FRDA (9,21,22). Atrophy of the inferior olives, cerebellar peduncles, and posterior spinocerebellar tracts and pontine nuclei cause pontocerebellar dysfunction. These changesmay explain the difficulties experienced in the coordination of skilled movements, the jerky arm movements and the early loss of speech in IOSCA patients. Ophthalmoplegia in IOSCA is most likely a consequence of degeneration of the oculomotor complex and periaqueductal gray matter. Furthermore, the fourth and sixth cranial nerve nuclei were moderately atrophic. All IOSCA patients are deaf by school-age, but in FRDA, the hearing deficit is less severe, leading to deafness in only some cases(23). In our patients, there was a bilateral, complete loss of the ganglion cells in the modiolus of the organ of Corti, and the intraganglionic spiral bundle was absent. The degeneration of the vestibular nerve was not equally severe (24). A severe loss of ganglion cells in the organ of Corti has also been found in FRDA (25). The question of why all IOSCA patients, but only a few FRDA patients are deaf, remains unanswered.

3. Cerebellum and Cerebellar Connections The cerebellar cortex showed quite mild and patchy atrophy histologically, with a thinned molecular layer and lossof Purkinje cells. In two cases the cortical atrophy was severe at superior and posterolateral aspects of the cerebellar hemispheres. The dentate nuclei were severely affected, with a subtotal neuronal loss and prominent gliosis.The patchy atrophy of the cerebellar cortex and the severe atrophy of the dentate nucleus found in IOSCA are possibly not caused by a primary cerebellar defect, but partlyby a loss of afferent input. This includes the lesions in the somatosensory pathways, as in FRDA (21,26). In IOSCA, other important losses of input evidently derive from pontine and olivary atrophy. In IOSCA, the atrophy at the dorsal aspect of the inferior olive was most severe. This is of interest, relative to the known topographic organization of the olivocerebellar connections and the patchy cerebellar cortical atrophy in IOSCA. The medial part of the olivary complex projects to the vermis, whereas the major lateral part of the inferior olive sends fibers preferentially to the lateral neocerebellum. Fibers from the dorsal tier of the inferior olive project to the superior sur-

nerve, and (E) facial (seventh cranial) nerve, plastic sections. Observe the almost total depletion of myelinated axons in the cochlear nerve (C); two remaining fibers can be seen (arrows). Compare with the moderate density of fibers in the vestibular(D) nerve and with the preserved density in the facial nerve (E). Original magnifications: X25 (A and B), X 400 (C-E) .

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face of the cerebellum, whereas those of the ventral part project to the inferior surface (27). The focally severe cortical cerebellar atrophy in two of our cases could also, at least partly,be due to anoxia-ischemia related to the prolonged epileptic statuses. Ischemic etiology for the focal dropofout Purkinje cells in FRDA has also been suggested (21).

4. Cerebrum In one of our patients, there were no clearcut atrophic changes above or at the level of the mesencephalon, except for neuronal loss in the optic pathways and mild atrophy in the medial thalami. In FRDA, however, quite prominentloss cell and gliosis have been found in the red nucleus, subthalamic nuclei, and thalamus (20,21). This was also true in two of our patients, but the changes were accompanied by patchy cortical laminar necrosesof varying degree. One possible etiological factor behind these cortical changes could be ischemia caused by status epilepticus.

iscussion of Etio~atho~enesis Both FRDA and IOSCA are childhood ataxias that sharemany clinical and neuropathological features. FRDA is associated with an intronic guanine-adenineadenine (GAA) repeat expansion (28) and lack of frataxin (the protein product of FRDAgene).Frataxinismostlikelyanuclear-encodedproteindownregulating mitochondrial iron uptake. Loss of frataxin results in mitochondrial iron accumulation, oxidative stress, and impaired mitochondrial function through iron-catalyzed toxic oxygen free radical formation (29,30). IOSCA patients have acute crises with vomiting and prolonged epileptic seizures, which resemble the acute crises of porphyria (22,31). Because of these crises we investigated heme metabolism in IOSCA patients and found subnormal levels of fenochelatase (see the last paragraph on p. 307) suggestive of a defect in heme metabolism, which might lead to, or be caused by, disturbances in iron homeostasis. However, we have not observed iron accumulation in IOSCA tissues with routine iron stainings.

V.

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CLI~ICAL~ E A T ~ ~ E S

Clinica~Presentation of theDisease

Patients with IOSCA develop normally until the end of the first year (4). The first a ~anifestationof the disease-clumsiness-appears eithersuddenlyduring common infection or develops gradually within some weeksor months between 10 and 18 monthsof age. As a rule the patients are able to stand or walk unsupported before the symptoms begin.

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The deep tendon reflexes are lost in the lower extremities at the time the motor symptoms, ataxia, hypotonia, and athetosis, are manifested. Pain and temperature sensation remain normal, but tactile, and especially proprioception and kinesthetic, sensation is impaired.The patients with.severe hypotonia have pes planus; others have pes cavus. In advanced cases there is atrophy of thigh, leg, and distal hand muscles. Most adolescent patients have scoliosis. Several young patients as increased and all adults have autonomic nervous system dysfunction, such perspiration and laborious micturion,as well as daytime incontinence of the urinary bladder from time to time.

yramidal Signs, Athetosis, and Muscle Hypotonia All patients have moderate to severe progressive cerebellar ataxia and need either a rollator or a wheelchair by adolescence. Writing and other precise hand movements become more laborious with age. The Babinski sign becomes positive with disease progression. The severity of athetosis varies between kindreds and also within sibships. Patients with severe hypotonia and athetosis never regain their ability to walk. Athetoid movements are prominent in hands and face. The patients with severe hypotonia may have hypomimia and ptosis.

D.SpeechandHearingDeficit The development of speech slows down in all children after the onset of clumsiness. A mild to moderate sensorineural hearing deficit, progressing to deafness, is noticed between ages 2 and 5.

phthalmoplegia and Optic Atrophy Loss of vertical eye movements precedes the lossof horizontal eye movements, and restricted eye movements are found inall patients by the age of 5. Optic atrophy develops in all patients by adolescence, otherwise optic fundi are normal.

F" Epilepsy Ten out of 21 Finnish IOSCA patients have had seizures. Two patients had a few generalized and complex partial seizures at teenage, and 8 patients had one or a more acute crisis preceded by abdominal pain and emesis or dizziness for couple of days. The crisis always started with abdominal pain or vomiting and

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seizures, and progressed to a therapy-resistant status epilepticus.The acute phase, when the patients were tetra or paraparetic and had frequent seizures, lasted for 2-4 weeks. Three patients never regained consciousness and diedof pneumonia within 2 months after the onsetof the acute crisis with seizures. The others have, so far, recovered over several weeks or months, but never regained their previous condition.

G. PubertyandGrowth The female patients have amenorrhea and their secondary sex characteristics are poorly developed. The male patients’ secondary sex characteristics develop normally, and they are much more interested in the opposite sex than the females. The males masturbate and have ejaculations, whereas the females have no sexual interest. The males’testicularvolumewasnormal(32). The malepatients’ growth is normal.The female patients’ growth is steady without pubertal growth fiacceleration. The growth of the females continues beyond their 20s, and their nal height is within the expected limits (32). At autopsy the uterus and ovari<es of two IOSCA females were hypoplastic, with no sign of hormonal effect.

H. CommunicationandMentalCapacity

All IOSCA patients communicate with sign language. Some patients may use speech in their daily communication, too, but their vocabulary is limited, and the phrases are short and dysarthric. Although the patients’ primary capacity isnormal, all have had learning difficulties: only two-thirds of those school-aged or older can read and write. All IOSCA patients need a special education for deaf children. According to the Finnish follow-up study, the patients with an unsucce ful early rehabilitation are moderately mentally retarded in adolescence, whereas (4). the patients with a proper rehabilitation and education are mildly retarded

1.

LIFESPAN

The oldest Finnish IOSCA patients are now in their30s. The occurrence of a lifethreatening crisis in eight patients between years20 and 30 suggests that the life span of these patients may not be normal.

VI. ANCILLARYTESTS

A.

Neuroimaging

Neuroimaging studies ( CT or MR) of IOSCA show progressive cerebellar cortical and brain stem atrophy (22). The first signs of the progressive cerebellar

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atrophy were seen 4.5 years after the onset of symptoms, but a more severe cerebellar atrophy was seen at the endof the second decade (Fig.5). The cerebellar white matter showed patchy hyperintensity in T2-weighted images in some older patients, and in one patient the involvementof the dentate nuclei could be visualized. The cerebral hemispheres and basal ganglia were initially normal in all patients, with no evidenceof atrophy or parenchymal changes, but mild cerebral atrophy was seen in patients with prolonged epileptic seizures.

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~ e u r o ~ ~ y s i o l o g i Studies cal

The characteristic sensory axonal neuropathyof IOSCA can be demonstratedby electrophysiological studies. In our studies the sensory action potentialsnorhad a mal amplitude before the ageof 2, after which they started to decrease and often

Figure 5 T1-weightedsagittal MR.image of a19-year-oldmalepatient.Thereisa marked atrophyof the cerebellum.No flattening of the basis pontisis noted. The prepontine cistern and the fourth ventricle are slightly widened, indicating a mild brain stem atrophy. Atrophy of the upper cervical spinal cord can also be seen.

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become unrecordable at the ageof S-15 years (1l ).There was variability in the sensory conduction velocities. In some patients wasitalready slow at the age of 5 , whereas in other patients it stayed normal until it became unrecordable. Motor nerve conduction velocities were normal at the beginning, but there was a gradual decrease, especially in the nerves of lower limbs after the age of 10-15 years. The somatosensory-evoked potentials were normal until the ageof 3. The peripheral by the ageof 15. responses disappeared after the age of 3, and the cortical ones The marked finding in repeated electroencephalographs was the progression of background abnormality with advancing age. Electroretinographs were normal. The latencies of visual-evoked potentials were delayed, and the shape of the wave was either flat or abnormal in some IOSCA patients (4).

The follicle-stimulating hormone (FSH) and luteinizing hormone (LH) responses are normal in males and prepubertal girls in the gonadotropin-releasing hormone (GnRH) test. In postpubertal girls the high basal FSH and LH values increases after GnRH stimulation.The female hypogonadism isof hypergonadotropic type: the estradiol values are low and FHS and LW values are high (32).

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differentia^ Diagnosis: and Other Laboratory Tests

The clinical symptoms of IOSCA patients are very similar to those found in mitochondrial diseases (33,34.), but no ragged red fibers or abnormal mitochondria were seen in muscle biopsy. The patients had no lactic acidosis, and the examination of the respiratory chain enzymes revealed no clearcut enzyme deficiencies in IOSCA patients. No mitochondrial DNA deletions were found on Southern blot analysis (4.). In differential diagnosis of IOSCA, the other well-known metabolic dis(3S,36) must be excluded eases with early-onset ataxia and peripheral neuropathy by proper laboratory tests (i.e.,by measuring the serum concentrationsof alphafetoprotein,immunoglobulins,carnitine,copper,ceruloplasmin,disialotransferrin, vitamin E, transaminases, free fatty acids, cholesterol, phytanic acid, very long-chain fatty acids, and serum lipoprotein electrophoresis),as well as plasma concentrations of ammonia and amino acids, urine metabolic screening, and organic acid analysis, chest X-ray films, and electrocardiogram.

The treatment of IOSCA is symptomatic: rehabilitation and treatment of epilepsy. IOSCA patients are deaf and severely handicapped, all of them are in a wheel-

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chair by adolescence. Because of deafness IOSCA patients need special education and communication therapy. They need physiotherapy all through life because of theprogressivesensoryaxonalneuropathyandataxia.Preventive medication for the urinary tract infections is needed in those patients, who have incontinence and laborious micturition as a sign of autonomic nervous system dysfunction. Because the acute crisis in IOSCA resembles the neurological crisis in seen porphyria and tyrosinemia (3 1,37,38), we measured the blood levelsof heme enzymes in IOSCA patients, and found subnormal levels of ferrochelatase (heme synthase). Ferrochelatase is the last enzyme in the biosynthesis of heme (Feprotoporphyrin IX) responsible for the incorporationof iron into protoporphyrin IX (39). The conventional antiepileptic drugs (barbiturates, phenytoin, valproic acid, and carbamazepine) metabolizedby cytochrome P450 complex, consisting of enzymes containing heme prosthetic groups, have been ineffective in IOSCA. Today we use oxcarbazepine (40), which is not metabolized by the cytochrome P450 pathway, as the primary anticonvulsant. Benzodiazepines (midazolame or diazepam) are used to treat status epilepticus.

REFERENCES J, Koskinen T, Weissenbach J, Peltonen L,. Random search for shared chromosomal regions in four affected individuals: the assignment of a new ataxia locus. Am J Hum Genet 1995; 56:1088-1095. Nikali K, Isosomppi J, Lonnqvist T, Mao JI, Suomalainen A, Peltonen L. Toward cloning of a novel ataxia gene: refined assignment and physical map of the IOSCA locus (SCA8) on 10q24. Genomics 1997; 39:185-91. Kallio AK, Jauhiainen T. A new syndromeof ophthalmoplegia, hypoacusis, ataxia, hypotonia and athetosis (OHAHA). Adv Audio1 1985; 3234-90. Koskinen T, Santavuori P, Sainio K, Lappi M, Kallio AK, Pihko H. Infantile onset spinocerebellar ataxia with sensory neuropathy-a new inherited disease. J Neurol Sci1994;121:50--56. Norio R, Nevanlinna H, PerheentupaJ. Hereditary diseases in Finland; rare flora in rare soil. Ann Clin Res 1973; 5:109-141. Norio R. Diseases of Finland and Scandinavia. In: Rothschild H, ed. Biocultural Aspects of Diseases. New York: Academic Press, 1981:359-415. Varilo T, Nikali K, Suomalainen A, Lonnqvist T, Peltonen L. Tracing an ancestral mutation: genealogical and haplotype analysisof the infantile onset spinocerebellar ataxia locus. Genome Res 1996; 6:870--875. Nikali K. Molecular Genetics of Infantile Onset Spinocerebellar Ataxia. Helsinki, Finland: National Public Health Institute, 1998. Lonnqvist T, Paetau A, von Boguslawski K, Nikali K, Pihko H. Infantile onset spinocerebellar ataxia with sensory neuropathy (IOSCA): neuropathological features. J Neurol Sci 1998; 161:57-65.

1. Nikali K, Suomalainen A, Terwilliger

2. 3.

4. 5. 6. 7. 8.

9.

308

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10. Picado-Leonard J,MillerWL.Cloningandsequenceofthehumangenefor P450C17(steroid 17alfa-hydroxylase/17,20-lyase):similaritywiththegenefor P450C21. DNA 1987; 6:439-448. 11. Koskinen T, Sainio K, RapolaJ, Pihko H, Paetau A. Sensory neuropathy in infantile onset spinocerebellar ataxia. Muscle Nerve 1994; 17:509-5 15. 12. McLeod JG. An electrophysiological and pathological study of peripheral nerves in Friedreich’s ataxia. J Neurol Sci 1971; 12:333-349. 13. Ouvrier RA, McLeod JG, Conchin TE. Friedreich’s ataxia. Early detection and progression of peripheral nerve abnormalities. J Neurol Sci 1982; 55:137-145. 14. Santoro L, Perretti A, Crisci C, et al. Electrophysiological and histological follow-up study in 15 Friedreich’s ataxia patients. Muscle Nerve 1990; 13:536-540. 15. Hughes T, Brownell B, Hewer LH. The peripheral sensory pathway in Friedreich’s ataxia. Brain 1968; 91:803-820. 16. Cavanagh JB. The ‘dying back’ process. A common.denominator in many naturally occurring and toxic neuropathies. Arch Path01 Lab Med 1979; 103559464. 17. Spencer PS, Sabri MI, Schaumburg HH, Moore CL. Does a defect of energy metabolism in the nerve fiber underlie axonal degeneration in polyneuropathies? Ann Neurol 1979; 5:501-507. 18. Said G, Marion M-H, Selva J, Jamet C. Hypotrophic and dyingback nerve fibers in Friedreich’a ataxia. Neurology 1986; 36: 1292-1299. 19. Lamarche J,Luneau C, Lemieux B. Ultrastructural observationson spinal ganglion biopsy in Friedreich’S ataxia: a preliminary report. Can J Neurol Sci 1982; 9: 137-139. 20. Lamarche JB, Lemieux B, Lieu HB. The neuropathology of “typical” Friedreich’s ataxia in Quebec. Can J Neurol Sci 1984; 11:592-600. 21. OppenheimerDR.BrainlesionsinFriedreich’sataxia.CanJNeurolSci1979; 61173-176. 22. Koskinen T, Valanne L, Ketonen L, Pihko H. Infantile onset spinocerebellar ataxia: MR and CT findings. AJNR Am J Neuroradiol 1995; 16:1427-1433. of 90 families with an 23. Harding AE. Friedreich’s ataxia. A clinical and genetic study analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain1981;104:589-620. A,Lonnqvist T. Labyrinthine pathology in a deaf patient 24. Johnsson L, Felix H, Paetau with infantile onset of spinocerebellar ataxia (IOSCA). In: Iurato S, Veldman J, eds. Progress in Human Auditory and Vestibular Histopathology. New York Kugler Publications,1997:103-108. 25. Spoendlin H. Optic and cochleovestibular degenerations in hereditary ataxias. IT. Temporal bone pathology in 2 cases of Friedreich’s ataxia with vestibulo-cochlear disorders. Brain 1974; 97:41“48. 26. Greenfield JG. The Spino-cerebellar Degenerations. Oxford: Blackwell Scientific, 1954. & Wilkins, 27. CarpenterM,Sutin J. HumanNeuroanatomy.Baltimore:Williams 1983:477. 28. Campuzano V, Montemini L, Molto MD, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996; 271~1423-1427.

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29. Rotig A, de Lonlay P, Chretien D, et al. Aconitase and mitochondrial iron sulphur protein deficiency in Friedreich ataxia. Nat Genet 1997:21S-217. 30. Babcock M, de SilvaD, Oaks R, et al. Regulationof mitochondrial iron accumulation by Yfhlp, a putative homolog of frataxin. Science 1997; 276:1709-1712. 31. King pH, Bragdon AC. MRI reveals multiple reversible cerebral lesions in an attack of acute intermittent porphyria. Neurology 199 1;41: 1300-1302. 32. Koskinen T, Pihko H, Voutilainen R. Primary hypogonadism in females with infantile onset spinocerebellar ataxia. Neuropaediatrics 1995; 26:263-266. 33. Yiannikas C, McLeod JG, Pollard JD, Baverstock S. Peripheral neuropathy associated with mitochondria1 myopathy. Ann Neurol 1986; 20:249-257. 34. DiMauro S, Bonilla E, LombesA, Shanske S, Minetti C, Moraes CT. Mitochondrial encephalomyopathies.In:BodensteinerJB,ed.NeurologicClinics.Philadelphia: WB Saunders,1990:483-506. S, DiMauro S, Mamoli A, Rowland 3s. Harding AE. The inherited ataxias. In: DiDonato LP, eds. Molecular Geneticsof Neuromuscular Diseases. Vol.48. New York: Raven Press, 198R37-46. 36. Hagberg B, Blennow G, Kristiansson B, Stibler H. Carbohydrate-deficient glycoprotein syndromes: peculiar group of new disorders. Pediatr Neurol 1993; 9:255--262. 37. Bonkowsky HL, Schady W. Neurologic manifestations of acute porphyria. Semin Liver Dis 1982; 2:108-124. 38. Mitchell G, LarochelleJ, Lambert M, et al.Neurologic crisisin hereditary tyrosinemia. N Engl J Med 1990; 322:432-437. 39. Bottomley SS, Muller-Eberhard U.Pathophysiology of heme synthesis. Semin Hematol 1988; 25:282-302. 40. FaigleJW,MengeGP. Metabolic characteristics of oxcarbazepine (Trileptal) and their beneficial implications for enzyme induction and drug interactions. Behav Neurol 1990; 3(supp1):21-30.

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15 Autosomal Recessive Spastic Ataxia (Charlevoix-Saguenay) Jean-Pierre Bouchard Centre Hospitalier Affilie Universitaire de Quebec, Pavillon Enfant-Jesus, Quebec Citx Quebec, Canada

Andrea Richter and Serge B. Melanqon Hdpital Sainte-Justine, Universite de Montreal, Montreal, Quebec, Canada

Jean Mathieu Complexe Hospitalier de la Sagamie, Chicoutimi, Quebec, Canada

Jean Michaud University of Ottawa, Ottawa, Ontario, Canada 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

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VI.ANCILLARYTESTS

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VII. MANAGEMENT A. Spasticity B. Pain C.AxonalNeuropathy D. Incontinence E. Seizures F. Counseling

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VIII.ADDENDUM

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REFERENCES

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I~TRO~UCTIO~

Hereditary spastic ataxia is a familial neurological disorder showing both pyramidal tract and cerebellar progressive involvement (1). Because the association of lower limb spasticity and cerebellar features is frequent in most spinocerebellar disorders (SCD), spastic ataxia was formerly referred to as a “forme de passage” between the classic form of Friedreich’s ataxia (FA), the spinocerebellar ataxias (SCA), and the familial spastic paraplegia (FSP). In 1939, Bell and Carmichael (2) summarized the published cases of the already frequent syndromes of spastic ataxia and provided evidence for two major forms:an early-onset autosomal recessive one, and a second, with late-onset and dominant inheritance. Because the spasticity is the first and most disabling symptom in the spastic ataxia syndromes, the latter have often been included under the “complicated forms of spastic paraplegia” in the classification of the hereditary ataxias and paraplegias, such as the one published by Harding in 1984 (3). Dominant spastic ataxia was reviewed by Eadie ( l ) in 1991. He emphasized that different pathological entities appear to have fallen within the clinical syndrome of hereditary spastic ataxia. He also indicated the associationof spastic ataxia with optic atrophy or other eye involvement. Finally, he concluded that it might be more realistic to use the term “hereditary spastic ataxia” for what is openly acknowledged as a clinical syndrome with more than one pattern of inheritance as well as more than one pathological basis. Reports of recessive spastic ataxia with various accompanying neurological and ocular signs have been only sporadic(4-6). The reports described a limited number of patients from communities considered as genetic isolates. Autosomalrecessivespasticataxia of Charlevoix-Saguenay(ARSACS) was first described, in 1978 (7), in patients originating from such an isolate in the Charlevoix and the Saguenay regions of Quebec, Canada. The main clinical features of ARSACS are compared(Table 1) with thoseof Troyer Syndrome (4), which is quite similar to ARSACSin evolution and shows mostof the same clinical signs, except for ocular features. of The ARSACS syndrome, identified 20 years ago as a recessive form spastic ataxia, has shown consistency and homogeneity on clinical, electrophysiological, and morphological grounds. These characteristics have led to the localization of the ARSACS gene (8) on chromosome13q. On a practical aspect, the imaging features, the early findings in nerve conduction studies (NCS), and the ocular signs are diagnostic evidence of ARSACS and help distinguish it, not only from other forms of hereditary ataxias, but also from cerebralpalsy, with which it is most often mistaken in youngsters. Although molecular genetics has shed light on some of the more classic forms (9), the classification of the SCDs remains a challenge. Neither the morphological nor the imaging or the electrodiagnostic studies could do more than

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Table 1 Clinical Features of Two Spastic Ataxia Syndromes

ARSACS (7)

syndrome

Onset Unsteadiness at gait initiation at 1-2 yr Progressive signs Pyramidal Increasing spasticity mostly to the lower limbs Increased deep tendon reflexes Abnormal plantar response Pes cavus Urgency and incontinence Cerebellar Slurred, later dysrythmic speech Dysdiadokinesia Polyneuropathy (in 3rd decade) Discrete to severe distal amyotrophy Absent ankle jerks Absent vibrations to toes Nonprogressive signs Ocular Prominent myelinated fibers embedding retinal blood vessels Marked saccadic alteration of ocular pursuit Other Normal intelligence Generalized seizures (7%)

Troyer

(4)

Difficulty learning to walk at 1-2 yr Yes Yes Yes Yes No Yes Yes Yes No No Not reported Not reported Yes Not reported

provide help in ascertaining a few of the many rare clinical SCD syndromes. Nonetheless, on clinical grounds, we now believe that spastic ataxia should be of the excluded from the “complicated forms of FSP’ in the general classification SCDs. Contrary to FSP, cerebellar involvement is overt in spastic ataxia. Peripheral nervous system involvement also seems more frequent and severe in spastic ataxia than in FSP, where it is rare (10).

11.

EPIDEMIOLOGY

Withmorethan 300 affectedindividualsknowntoliveintheProvince of of all inherited spastic ataxias. In Quebec, Canada,ARSACS is the most common northeastern Qukbec, mostof the patients’ families originate from a region where

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the 300,000-plus inhabitants share a limited numberof common French ancestors who settled in the Charlevoix region back in the 17th and early 18th centuries. Thirteen founders common to 264 of 265 obligate carriers were found through computed genealogical reconstruction (11). Because all the common ancestors originated from France, it is probable than the ARSACS gene was present in France in the 17th century. The estimated carrier frequencyof ARSACS gene is1:22 in the SaguenayLac-Saint-Jean population for the 1941-1985 period (1 1).All ascertained cases show an autosomal recessive transmission pattern. There has been no report of vertical transmission as none of the patients had an affected parent or offspring in the last four generations. The male/female patient ratio is even (12). Because the patients present an obvious motor disorder early in life, nuptiality islow, especially in males. Among the 215 ARSACS patients living in the same area, only 3 affected males have children. However, conception, pregnancy, and delivery seem normal in affected females. Nineteen women have had39 pregnancies; 31 normal children were born, 3 by cesarean section. There were four spontaneous abortions and four voluntary pregnancy termination. Description of clinical entities similar to ARSACS elsewhere in the world are very rare in the literature. The apparent linkage with the ARSACS locus on chromosome 13qS1 of a limited number of cases outside Quebec (8,13) suggests that other progressive combined pyramidal tract and cerebellar deficiencies could be part of a rare, yet universal, autosomal recessive spastic ataxia syndrome.

111.

MOLECULARPATHOGENESIS

Recently, we reported that the ARSACS locus mapped to DS3S787 in chromosome region 13qSl and that the candidate region appeared to be 5.5 CM by inspection of haplotypes in recombinant individuals (8). Subsequently, we constructed a genetic map of the region based on combined linkage and physical 175, D13S 1236, mapping data from our study and public databases for loci D13S D13S1275, D13S232, D13S292, D13S787, D13S1243, D13S283, and D13S 1285. The ARSACS locus was mapped more precisely by location score analysis. We constructed haplotypes to significantly narrow the candidate gene region, Given the result of the location score analysis, the most likely position of the ARSACS locus would be 0.49-CM distal to D13S232.2-lod-unit The support intervalforthemapposition of theARSACSlocusextendsdistalfrom D13S 1275 and proximal to D13S292. Thus, the likely candidate region for the ARSACS gene has been narrowed 1.58 CM (14). We are currently creating a sequence-tagged site (STS)-based physical and transcript map using CEPH mega YAC and bacterial artificial chromosome (BAC) clones of the candidate region to facilitate the identification of the ARSACS gene.

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NEUROPATHOLOGY

The pathological findings in a postmortem examination of a 21-year-old man were described previously (12).The superior cerebellar vermis was grossly atrophic, especially the anterior structures (central lobule and culmen). In this area Purkinje cells were practically absent, without significant Bergman's glia prolifloss of myelin eration. In the spinal cord there was a severe bilateral symmetrical staining centered on the lateral corticospinal tracts, extending into the adjacent dorsal cerebellar tracts. There was no significant alteration of the posterior columns. It must be emphasized that the patient was young. A second autopsy on a 59-year-oldman revealed the presence of the same anomalies, but more pronounced with mild to moderate involvement of the gracilis and cuneiform fasciculi. Neuronalloss and gliosis were found in the anterior horn, thoracic nuclei, and globus pallidus. Swollen perikarya were found in several of their neurons as well as in the thalamus, dentate nuclei, Purkinje cell layer, and, to a minor degree, in several other structures. In the thalamus, this swelling was occasionally associated with an increased amount of abnormal lipofuscinlike coarse granules. Tau-positive neurofibrillar degeneration was found in the hippocampus, the neocortex, the basal nucleus of Meynert, and rarely in other deep gray or brain stem structures. The activity of 18 lysosomal enzymes was studied and found to be within normal limits (15). Sural nerve biopsies were performed in two of Peyronnard' S cases (16) and in fourof ours (12).An important loss of large myelinated fibers was seen at both the calf and ankle levels, and implied fibersof smaller sizes as well. On teasing, there was an increased variability of the internodal length along the same fiber, but this was quite variable. There was no sign of active myelin breakdown and changessuggestingactiveaxonalbreakdownwereonlyoccasional.Proximal muscle biopsies were obtained in eight patients (12). There was moderate to marked grouping of fiber types in five cases. Type I fiber hypotrophy was seen in five patients, and typeI1 fiber hypotrophy in one.No sign of chronic or active denervation and reinnervation was observed. On the whole, the changes noted in the peripheral nervous system would suggest an early involvement and a possible developmental defect in this disease, as underlined by early abnormalities inmotor and sensitive nerve conduction studies.

V.

CLINICALFEATURES

All ARSACS patients exhibit early-onset signsof spasticity in the lower limbs, usually observed at gait initiation (12-18 months). There is no foot deformation at birth. Pes cavus, equinus, and clawing of the toes progressively develop in the first two decades in most, but not all, patients. The clinical picture from early childhood is always that of gait ataxia, with a tendency to fall (",K?). Passive

316

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movements of the lower limbs reveal increased tonus. Plantar response is always a b n o r ~ a leither , equivocal or indifferent in youngsters, and extensor thereafter. The deep tendon reflexes are usually increased, often with clonus at the ankles and patellae in the early adulthood.Walking is essentially stiff at the beginning, with little movementof the knees that are often partially flexed. Dynamic muscle function studies have shown disabling cocontractionof agonistic and antagonistic muscles during movementof the lower limbs(1’7).Urgency and incontinence of urine and sometimes feces are seen in50% of the cases in the fourth decade. Spasticity is present early when there is little signof cerebellar dysfunction. Speech canbe slightly slurred in childhood and becomes explosive in adulthood. Hand and tongue dysdiadochokinesis are detected early. At the tongue level, this could be exaggerated by spasticity, for the tongue often shows normal alternating lateral movements in other cerebellar syndromes. Overt dysmetria in upper limbs occurs later in the course of the disease, usually after the loss of ambulation. The eye signs are most typicalof the disease. These early nonprogressive signs include saccadic alterationof smooth ocular pursuit and prominent myelinated fibers radiating from the optic disc and embedding the retinal blood vessels at fundoscopy (Fig. 1). This highly unusual feature is indicative of an early ab-

Figure 1 Increased visibility of myelinated retinal nerve fibers, embedding parts of the blood vessels. This is a hallmark of ARSACS, which as been observed in all ascertained cases of the disease.

317

normal myelination process. To our knowledge, there is no clinical deficit in counterpart for the early defect in myelination in retinal and peripheral nerve fibers. Ophthalmological examinations, including electroretinography, visual acuity and fields, color vision, slit lamp, and tonometry didnot disclose any further abnormalities. In peripheral nerves, although there is a moderate to severe slowing of motor conduction velocities in children (1 8,19), there is no further progressive deterioration. Although there is a slower motor development in ARSACS preschoolers, no intellectual deficiency is observed. However, during elementary schooling, so to write; abouthalf of them have enough they are slow to learn and even more instrumental problems to drop outof school before orby the end of high school. Despite their motor handicap, several of our patients have completed college and university degrees. Repeated neurospychological testing in adult ARSACS patients have shown that the verbal IQ is usually within normal limits (7), but the handling of visuospatial material is poor and deteriorates with time (20). The disease shows a more obvious progression in teenagers and young adults. There is a progressive increase in muscle tone and in deep tendon reflexes. The gait is often jerky, sometimes accompanied by scissoring. Discrete to marked distal amyotrophy is usually seen later, but it can be an early feature in some families. Ankle jerks disappear around the age of 25, having been brisk and polyclonic in most patients. At this time, electromyography shows signsof denervation in the distal muscles, especiallyin the feet (18). These progressive signs are mobelieved to be the result of axonal degeneration in both the upper and lower tor neurons. To summarize the clinical findings (Fig. 2), there is first a diffuse spastic syndrome that progresses throughout life, Cerebellar signs are sparse at the be2 .Cerebellarfeatures Spasticity p r e d o ~ n a n ~iny lower limbs Paraparesis after30-40 years of age Increased deep tendon reflexes Bilateral abnormal plantar response Contractures and tendon retractions Pes c a w s and sometimes club feet Incontinence

Decreased proprioception in lower limbs Absent anklejerk ailer25 years of age Discrete to severe distal amyotrophy Clawing of the toes and sometimes hands

The spectrum of clinical features in ARSACS.

Nystagmus with saccadicp m u i t Progressive ataxiaof the 4 limbs Dysarthria

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ginning, but increase slowly from adolescence on.In the mid-20s, motor axonal polyneuropathy appears and aggravates the deficits. Over a 20-year period, 320 ARSACS patients were identified and followed in the local neuromuscular clinics. ARSACS patients become wheelchair-bound at a mean age of 41, with a 34 patients is5 1 (12); some wide rangeof 17-57 years. The mean age at death for survive into their 70s, but become bedriddenby that time, and mostof them die of recurrent infections. There is no cardiac involvement in ARSACS and no other associated disease.

VI.

ANCILLARY TESTS

Besides the clinical assessment, the basic investigation of new ARSACS patients includes ophthalmoscopic evaluation, electrophysiological studies, and head imaging. Initially, there were no abnormalities seen in endocrine functions, blood chemistry, and cerebrospinal fluid (7). In most patients, electromyography shows signs of severe denervation in distal muscles by the end of the 20s (18). Nerve conduction studies (NCS) demonstrate signs of both early dysmyelination and progressive axonal neuropathy (12,19), the latter confirmed by nerve biopsy (16). Motor nerve conduction velocitiesaremoderatelyreduced(mediannerve: 29-44 nds; peronealnerve: 17-35 m/s), but do not worsen with time on subsequent examinations. Usually, by the end of the third decade, the distal motor latencies can no longer be recorded in the feet. Sensory action potentials are absent in the four limbs. brain stem auditory (BAEP)-, and pattern-reversal Somatosensory (SEP)-, visual(VEP)-evokedpotentialswererecordedin67ARSACSpatients(age: 5-56; mean 25). The results (21) showed a widespread axonal degeneration process in the primary sensory neurons as well as in the central nervous system. Electroencephalographic (EEG) abnormalities occur in more than 60% of the cases (20). Burstsof generalized slow wavesof subcortical origin are seen in most patients. Epileptic activity is rarely seen on the tracings, but7% of the patients have generalized epilepsy, which starts in the late teens. In ARSACS, epilepsy is easily controlled with an antiepileptic drugin monotherapy. No correlation could be drawn between the degree of EEG abnormalities and age, sex, or severity of the disease. Electronystagmographic recordings of oculomotor and vestibular function were carried out in 11 patients (22). Horizontal gaze nystagmus, marked impairment of smooth ocular pursuit, and optokinetic nystagmus, as well as defective fixation suppression of caloric nystagmus were found in all ARSACS patients. These findings suggest a diffuse cerebellar disease with particular involvement of the vermis and vestibulocerebellum. Atrophy of the superior cerebellar vermis (Fig. 3) is always present on computedtomography(CT)scanormagneticresonanceimaging(MRI)

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(12,23), even in younger patients, and progressesslowly. The inferior vermis remains thicker throughout the disease, but there is a progressive cerebellar cortical atrophy. Furthermore, there is a conspicuous cerebral atrophy in late life. Nevertheless, the cerebral white matter never shows abnormal signals, even late in the disease. The cervical spinal cord is flattened and markedly reduced. There is no scoliosis.

VII. MANAGEMENT A. Spasticity Although spasticity is the main feature of ARSACS during childhood, patients and their families cope with it and rarely seek medical advice. In teens, spasticity becomes more obvious in the lower limbs, and the gait becomes more spastic and or without varus, jerky, sometimes with scissoring. Increasing pes cavus, with may add to gait instability. Foot surgery may be required. Stretching exercises and other rehabilitative approaches have some beneficial effects if they are applied early. Benzodiazepines or baclofen may help reduce spastic gait, but they often cause somnolence and increased imbalance. Intrathecal delivery system is being tested in some younger cases to investigate the advantagesof early optimal spasticity treatment on the developmentof retraction and abnormal gait pattern. As opposed to other SCDs, no improvement in speech, upper limb clumsiness, or spastic gait has been observed using amantadine. Furthermore, many ARSACS patients have experienced light-headedness, dizziness, or urinary retention when taking amantadine. As the disease progresses, walking aids are often required either through the use of a cane, Canadian crutches, or a walker. Most patients walk unassisted until they fall frequently and sustain injuries. Thereafter, they become wheelchair-bound, but remain autonomous for many years.

B. Pain In some ARSACS patients, muscle cramps are experienced in variousofareas the body and different states (rest, sleep, and exertion). They are usually short in duration and infrequent, so treatment is not required. More troublesome is, in rare instances, central “neuropathic” pain in the pelvis or the lower limbs. This symptom does not always improve significantly with classic pain therapy, which combines tricyclic antidepressive drug (e.g., amytriptyline) and Na channel blockers (phenyntoin, carbamazepine, gabapentin). A combination of these drugs, however,isworthtrying. ~ n t i - i n ~ a m m a tdrugs o ~ may helpinsomeinstances. Stretchingexercisesandotherrehabilitativeapproaches,suchasintermittent electrical stimulation with TENS, are sometimes the only beneficial treatments. Spinal cord stimulation has not been tried. Opioids should be avoided.

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C. AxonalNeuropathy Distal amyotrophy in hands and feet, either discrete or severe, is usually seen in the third or fourth decade, but it can be an earlier feature, especially in some families. Although it may cause difficulties in handling small objects or writing, it mainly contributes to foot deformation. Because of residual spasticity and equinovarus deformation, tibial ortheses are rarely helpful. Foot surgery is not warranted in older cases because it may increase pain in otherwise deafferentated feet, without gait improvement. In fact, late in the disease, the feet turn cold and cyanotic, but skin ulcers have not been observed. Patients often complain of cold feet. Calcium channel blockers, such as nifedipine or amlodipine, may provide symptom relief.

D. Incontinence Incontinence of urine and feces, to a lesser degree, is found with increasing frequency as the disease progresses. Urinary urgency is common, but retention and urinary infections are seldom seen. Nycturia affects one-fourth of the patients. Symptomatic patientsmay present normal cystometric studies and normal bladder capacity. External sphincter electromyography reveals increased activity in only a whole, urodynamic evaluation favors a mixed cerebelone-third of the cases. As lar and pyramidal effect on voluntary inhibition of the detrusor and abnormal external sphincter behavior (24). There is no proprioceptive deficit. Anticholinergic a day, help control drugs, especially oxybutynin, taken orally, three or four times urgency, incontinence, and nycturia. Imipramine or amitriptyline at bedtime may prevent nycturia. Intermittent or indwelling catheterization is rarely required. Severe constipation is seldom noted, but may require symptomatic treatment.

.E. Seizures Electroencephalographic findings are nonspecific, with various abnormalities occurring in more than 60% of the cases (12,20). There are bursts of slow waves of subcortical origin, often lateralized, in most patients, but epileptic activity is seldom observed on the tracings. Nonetheless, generalized epilepsy is present in more than 7% of the cases. It is easily controlled with either phenytoin, carbamazepine, or valproic acid. There is no increase in epileptic manifestations with age and no patients have ever experienced a status epilepticus.

Figure 3 Midsagittal (a) and axial (b) MRI views of the brain in a 45-year-old female ARSACS patient. Thereis severe atrophyof the superior cerebellar vermis, as well as enlarged dorsal cisterns. The size of the fourth ventricle is slightly increased. Ponsis normal.

Bouchard et al.

F. Counseling For the past 10 years, an information program on hereditary diseaseswas put together in the Saguenay area, Conferences are given by well-trained nurses to explain the mechanisms of human heredity and to describe the more prevalent geneticdisordersfound in theSaguenayandCharlevoixregions.Information pamphlets are available. This program is intended for the general population, but is more frequently given to high-school and college students. This program has reached over 20,000 people, for whom sound advice is provided to prevent the recurrence of genetic disorders. Four other recessive diseases have a high prevalence in this population, with respective carrier frequencyof 4-6%. Besides ARSACS and cystic fibrosis, there are (a) a severe sensorimotor polyneuropathy with agenesis of the corpus callosum (gene locus 15q13-ql5) (25); (b) tyrosinemia, an inborn error of metabolism, related to a splice mutationof intron 12 in the fumarylacetoacetate hydrolase gene on chromosome 15q (26); and (c) congenital lactic acidosis associated with a cytochrome oxydase deficiency (gene locus on chromosome 2p) (27). Because no cure is yet available for any of these diseases, the identification of gene carriers and genetic counseling of at-risk individuals and couples are consequently the only preventive measures at hand. Different carrier-detection strategies for these populations have yet to be developed.

VIII. ADDENDUM Since the completion of this chapter, mutations were identified in ARSACS patients in a novel gene called Sacs, encoded by a single 11.5 kb open reading frame (28). As predicted from haplotype studies (14), two mutations were identified. Both are believed to cause premature truncationof the sacsin protein. Although the function of sacsin is still unknown, the presence of heat-shock domains suggests that it may play a role in chaperone-mediated protein folding.

ACKNOWLEDGMENTS We would like to thank MS C Prevost,F. Gosselin, and J. Mercier for their sustained contribution to this work. Drs. J Rioux, K. Morgan, and TJ Hudson were instrumental in locating the gene. Over the years, this research was supported by grants from the Association Canadienne de1’Ataxie de Friedreich, the Muscular Dystrophy Association of Canada, the Reseau de Genetique medicale appliquee (RMGA) ot the Fonds de Recherche en Sant6 du Quebec (FRSQ), and the Medical Research Council (MRC) of Canada.

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REFERENCES

1. EadieJM.Hereditaryspasticataxia.In:JMBVdeJong,ed.HereditaryNeuropathies and Spinocerebellar Atrophies, Handbook of Clinical Neurologyv01 16 (60). Amsterdam: Elsevier Science, 1991:461-466. 2. Bell J, Carmichael EA. On hereditary ataxia and spastic paraplegia. In: Treasuryof Human Inheritance. v01 4. London: Cambridge Press, 1939:141-281. 3. Harding AE. Complicated forms of hereditary spastic paraplegia. In: The Hereditary Ataxias and Related Disorders. New York: Churchill Livingstone, 1984: 191-204. 4. Cross HE, McKusick VA. The Troyer syndrome. A recessive form of spastic paraplegia with distal muscle wasting. Arch Neurol 1967; 16:473-485. 5. Mousa AM, Al-Din ASN, Al-Nassar KE, Al-Rifai KMJ, Rudwan M, Sunba MSN, Behbehani K. Autosomallyinheritedrecessivespasticataxia,macularcorneal dystrophy,congenitalcataracts,myopiaandverticallyovaltemporallytilted discs. Report of a Bedouin family-a new syndrome. J Neurol Sci 1986; 76:105121. 6. Gustavson K-H, Modrzewsza K, Erickson A, Anderson U. New type of spinocerebellar degeneration syndrome in a northern Swedish population. Clin Genet 1987; 32:306-312. 7. Bouchard J-P, Barbeau A, Bouchard R, Bouchard RW. Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Can J Neurol Sci 1978; 5:61-69. 8. Bouchard J-P, Richter A, Mathieu J, Brunet D, Hudson TJ, Morgan K, MelanGon SB. Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Neuromusc Disord 1998; 8:474-479. 9. Dun: A, Brice A, Agid Y. Un nouveau regard sur les hkrkdodkgknkrescences spinoc6rkbelleuses. Rev Prat (Paris) 1995; 45:536-540. 10. McLeod JG, Morgan JA, Reye C. Electrophysiological studies in familial spastic paraplegia. J Neurol Neurosurg Psychiatry 1977; 40:611-615. 11. De Braekeleer M, Giasson F, Mathieu J, Roy M, Bouchard J-P, Morgan K. Genetic epidemiology of autosomalrecessivespasticataxiaofCharlevoix-Saguenayin northeastern Quebec. Genet Epidemiol 1993; 10: 17-25. 12. Bouchard J-P. Recessive spastic ataxia of Charlevoix-Saguenay. In: JMBV de Jong, ed. Hereditary Neuropathies and Spinocerebellar Atrophies, Handbook of Clinical Neurology. v01 16 (60). Amsterdam: Elsevier Science, 1991:451-459. 13. Chaigne D, Brauer E, Rub D, Jouart D, Juif JG. L’ataxie spastique autosornique rkcessive: 6tude clinique, neurophysiologique, ophtalmologique et IRM de deux cas familiaux [abstr]. Rev Neurol (Paris) 1993; 149:585. 14. Richter A, Rioux J, Bouchard J-P, Mercier J, Mathieu J, Ge B, Poirier J, Julien D, Gyapay G, WeissenbachJ, Hudson TJ, MelanGon SB, Morgan K. Location score and haplotype analysisof the locus for autosomal recessive spastic ataxia of CharlevoixSaguenay in chromosome region 13qll. Am J Hum Genet 1999; 64:’768-7’75. J, Lamarche J, Rioux J, Hudson T, 15. Richter A, Morgan K, Bouchard J-P, Mathieu MelanGon SB. ARSACS: possibly a lysosomal storage disease? [abstr]. Am J Hum Genet 1996; 59:A379. 16. Peyronnard JM, Charron L, Barbeau A. The neuropathy of Charlevoix-Saguenay

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17. 18. 19.

20. 21. 22. 23. 24. 25.

26.

27

B

28.

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ataxia:anelectrophysiologicalandpathologicalstudy.CanJNeurolSci1979; 6: 199-203. Richards C, BouchardJ-P, Bouchard R, Barbeau H. A preliminary study of dynamic muscle function in hereditary ataxia. Can J Neurol Sci 1980; 7:367-377. Bouchard J-P, BarbeauA, Bouchard R, Bouchard RW. Electromyography and nerve conduction studies in Friedreich's ataxia and autosomal recessive spastic ataxia of Charlevoix-Saguenay. Can J Neurol Sci 1979; 6:185-189. BouchardJ-P,BouchardRW,GagnitF, Rithter A, Melanqon S. Recessive spastic ataxia of Charlevoix-Saguenay (RSACS): clinical, morphological and genetic studies. In: R. Lechtenberg, ed. Handbook of Cerebellar Disease. New York: Marcel DeMter, 1993:491494. Bouchard RW, Barbeau A, Bouchard R, Bouchard J-P. Electro-encephalographic findings in Friedreich's ataxia and autosomal recessive spastic ataxia of CharlevoixSaguenay. Can J Neurol Sci 1979; 6:191-194. DeL6an J, MathieuJ, Bouchard J-P. Central pathway conduction in recessive spastic ataxia of Charlevoix-Saguenay [abstract]. Can J Neurol Sci 1989; 16:272. Dionne J, Wright G, Barber H, Bouchard R, Bouchard J-P. Oculomotor and vestibular findings in autosomal recessive spastic ataxia of Charlevoix-Saguenay. Can J Neurol Sci 1979; 6:177-184. Langelier R, Bouchard J-P, Bouchard R. Computed tomography of posterior fossa in hereditary ataxias. Can J Neurol Sci 1979; 6:195-198. Vezina J-G, Bouchard J-P, Bouchard R. Urodynamic evaluation of patients with hereditary ataxias. Can J Neurol Sci 1982; 9:127-129. Casaubon LK, Melanson M, Lopes-Cendes I, Marineau C, Andermann E, Andermann F, WeissenbachJ, Pritvost C, Bouchard J-P, MathieuJ, Rouleau GA. The gene responsible for a severe formof peripheral neuropathy associated with agenesis of the corpus callosum is localized to chromosomeAm 1Sq. J HumGenet 1996; 58:2834. Poudrier J, St-LouisM, Lettre F, Gibson K, Pr6vost C, Larochelle J, Tanguay R M . Frequency of the IVS12+5g"+a splice mutation of the fumarylacetoacetate hydrolase genein carriers of hereditary tyrosinemia in the French-Canadian population of Saguenay-Lac-St-Jean. Prenat Diagn 1966; 1659-64. Lee HRN, Rioux JD, Daly MJ, Lander ES, Hudson TJ, Morin CC, Robinson BH. Genetic mapping of the Saguenay-Lac-St-Jean cytochrome oxidase deficiency [abstr]. Am J Hum Genet 1998; 63(suppl):A296. Engert JC, B6rubit P, Mercier J, Dor6 C, LepageP, Ge B, Bouchard J-P, MathieuJ, Melaqon SB, SchallingM, Lander ES, Morgan K, Hudson TJ, Richter A. ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5 kb ORE Nat Genet 2000; 24: 120-1 25.

Universi~yof Dresden, Dresden, Germany

INTRODUCTIQN 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.

VI.

CLINICAL FEATURES A. ChronicProgressiveExternalOphthalmoplegia(CPEO), Ophthalmoplegia Plus, and the Kearns-Sayre Syndrome (KSS) B. Myoclonus Epilepsy with Ragged Red Fibers C.MitochondrialEncephalomyopathy,LacticAcidosis, with Stroke-Like Episodes D. Leber’sHereditaryOpticNeuropathy E. Leigh’sDisease(MaternallyInheritedForm),NARP Syndrome F. MultipleSymmetricLipomatosis(MorbusMadelung)

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VII. MANAGEMENT REFERENCES

33 1 332 333 334 334 334

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I. I ~ T ~ O ~ U C T I O N Mitochondrial disorders include a broad varietyof diseases such as chronic progressiveexternalophthalmoplegia(CPEO), Kearns-Sayre syndrome (KSS), Pearson syndrome, maternally inherited Leigh’s disease, MERRF, MELAS and NAIW syndromes, Leber’s hereditary optic neuropathy, and others. In the early 1960s Luft and co-workers(1) described a defect of the respiratory chain for the first time, Since that time diagnosis of a mitochondrial myopathy had to include morphological abnormalities of mitochondria and a characteristic biochemical defect with a clinical picture as the consequence. Soon it became obvious that not only muscle was afflicted by crisis of mitochondrial energy metabolism but also other energy-dependent organs such as brain, liver, kidney, retina, ear, heart, and others. For that reason Egger et(2)al.created the term “mitochondrialcytopathy”whichunderlinesthefactthat many organscan is molecupresent with energy abnormalities. A fourth prerequisite for diagnosis lar analysisof the mitochondrial and nuclear genome. The seminal articleby Holt and colleagues (3) in 1988 described, for the first time, abnormalitiesof the mitochondrial genome in patients with CPEO orKSS. Since then, many mitochondrial disorders have been associated with deletions, duplications, depletion or point mutations of the mitochondrial genome, Lately, new insights in the crosstalk between nuclear and mitochondrial genome indicate that diseases such as Friedreich’s ataxia, Wilson’s disease, and familial spastic paraplegia may be due to such problems of cross-talk. The broad variety of symptoms in patients with mitochondrial disorders lead to the questionof whether to split or to lump. Before molecular analysis was is a continuum between CPEO, ophthalmopleavailable, it was shown that there gia plus, and KSS. After the introduction of molecular biology and the description of “typical” deletions and point mutations for certain diseases, such CPEO as (common deletion), MELAS (point mutation at position 3243 of the mitochondrial [mt] genome), or MERRF (point mutation at position 8344 of the mt genome), it was hoped that molecular biology would allow us to split and to describe pathognomonic features for mitochondrial disorders.Today we know that the MELAS point mutation may cause CPEO, or that persons, harboring the MERRF point mutation may never develop myoclonus epilepsy. Although it is thus arbitrary to subdivide the mitochondrial disorders,I shall do so anyway for practical reasons. Although the classic mitochondrial disorders are rather rare, there is increasing evidence that neurodegenerative disorders, such as Parkins o d s and Alzheimer’s diseases, Huntington’s disease, and even amyotrophic lateral sclerosis are partly due to mitochondrial abnormalities. Thus, abnormalities in mitochondrial energyproduction. cause or influence frequent neurological disorders. In light of the cerebellar focus of this book I will concentrate on abnor-

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malities of the respiratory chain (which cause phenotypes with ataxia) and will not discuss P-oxidation or pyruvate metabolism. The respiratory chain consists of five complexes, each composed of various subunits. The mt genome codes for seven subunitsof complex I, one subunit of complex 111, three subunits of complex IV, and two subunits of complex V, whereas the other subunits are encoded by the nuclear genome. The respiratory chain converts reduction products such as NADHH,O to by transporting protons and electrons, building up a gradient that allows transformationof ADP to ATP at complex V (ATP synthase); therefore, the respiratory chain is central for energy (ATP) production. It reasons thatabnor~alitiesof aerobic energy production caused by malfunctioning of the respiratory chain cause abnormalities in organs that are highly dependent on this energy pathway. The brain has no energy storage and almost no lipid metabolism, but instead, depends almost totally onglucose metabolism.The cerebellum is a highly energy-consuming part of the brain. Therefore, many patients with mitochondrial disorders present with cerebellar ataxia.

II.

EPI~EMIOLOGY

There are no data available on the epidemiology of mitochondrial cytopathies. They are found worldwide. Apparently, there is no gender or ethnic propensity.

111.

MOLECULAR PATHOGENESIS

Classic mitochondrial disorders are associated with or are due to abnormalities of the mt genome. Mostly, patients show either deletionsor point mutations of the of mtgenome. The mitochondrialgenome is acircularmoleculeconsisting 16,569 base pairs (Fig. 1). As mentioned earlier, mt thegenome codes for13 proteins, all of which are subunits of four different complexes of the respiratory 2 rRNAs and 22 tRNAs that allow synthesisof the chain. In addition, it codes for 13 proteins within the mitochondria. There are various special features of the mt genome:

1. Maternalinheritance:becausealmostnopaternalmitochondrion of theovum,themtDNA is exclusively passesthecellmembrane transmitted from the mother to the offsprings. 2. It does not follow the universal genetic code: Although the nuclear DNA uses 3’2 tRNAs for encoding 20 amino acids the mtDNA has only 22 tRNAs and uses STOP-codons other than those of the nuclear genome.

3

n

\

L

7.4 kb

ure 1 DiagramofthemitochondrialDNA.Regionsencodingfortherespiratory 22 tRNAs are marked aswell as two regions that encode for the chain subunits and for the rRNAs,

3. 4. 5. 6.

DNAreplication is donebidirectionally. mtDNA has no introns and only three noncoding regions. It has no histones and a rather insuf~cientrepair mechanism. Replicativesegregation is thereasonforvariablephenotypes.Itis a comspeculated that already in the oocyte or at least in the blastocyte bination of normal and mutated mtDNA molecules are located in cells (i.e., heteroplasmy). The percentage of mutated mitochondrial DNA molecules seemsto be the crucial factor for each cell (threshol~effect). The If a certain threshold is passed the cell or the organ malfunctions. threshold level may vary from organ to organ.

Ataxia in ~ i t o c ~ o n d r iDisorders ai

Single deletions are found mostly in patients with the

329 KSS and in about

50% of patients with CPEO. There are very rarely familial cases, with both diseases normally occurring sporadically whereby the deletion has to arise in the ovum or early in embryogenesis. Interestingly, although patients are normal at birth, they develop their symptoms later on in life (in KSS before age 20). This is thought to be due to an increase of mtDNA deletions during life because deleted DNA molecules may replicate more rapidly than normal DNA molecules. We and others have shown that the amount of deleted mitochondria increas,es during life ( 4 3 . Patients with KSS normally have a mitochondrial DNA deletion, in the absence of which, the MELAS point mutation should be checked. Only 50% of patients with CPEO harbor deletions, whereas the others have point mutations. Interestingly, there are CPEO patients with the MELAS point mutation who never have a stroke-like episode. The clinical variability in this group of patients certainly stems from the fact that owing to the heteroplasmic segregation each patient is different, and the threshold effect is different in each individual. Of the patients with a deletion of the mtDNA, 3 0 4 0 % present with the so-called common deletion that spans over 4977 bp isand flanked by an identical 13-bp direct repeat (6). The mtDNA deletions range from 2 to 10.4 kb. Mita et al. (7) subdivide deletions into two categories: (a) those with direct repeats, and (b) those without. Because most of the patients present with class I (direct repeats) deletions they speculate that deletions are caused by homologous recombination events. Multiple deletions are commonly found in patients with autosomal dominant CPEO (8,9).We have described a patient with multiple symmetrical lipomatosis (lo), and there are patients with the MNGIE (mitochondrial neuropathy, gastrointestinal encephalomyopathy) syndrome who show multiple DNA deletions. Point mutations are typically associated with the MERRF (myoclonus epilepsy and ragged red fibers) syndrome which was first described clinically by Fukuhara et al. in 1980 (1 1).The typical point mutation is localized at position 8344 of the mt genome and afflicts the tRNALys (12). Meanwhile, a second tRNA Lys point mutation at position 8356 has been found in a family with typical MERRF features (1 3). The point mutation causes a significant decrease in protein synthesis (14) so that not enough ATP can be produced. Masucci et al. (15) showed in rho-0 cells that both mutations lead to a decrease in protein synthesis and oxygen consumption. mo-0 cell lines are cells without their own mtDNA which are transfected with mtDNA from patients with a mitochondrial cytopathy such as MERRF. A second mitochondrial disorder that is commonly associated with a point mutation is the MELAS syndrome (16). Up to 90% of the MELAS patients have a tRNALeu point mutation at 3243 bp (17). A second point mutation at 3271 (tRNALeu), and a third one in a region that encodes for the subunit of complex 4

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I have been described. Altogether there are now eight point mutations associated with MELAS. Our own results in cell cultures withup to 80% mutated mtDNA showed a qualitative protein synthesis abnormality, with proteins lacking leucine (18). Thus, the clinical phenotype is dependent on the percentage of mutated mtDNA, the mtDNA tissue distribution, and the specific tissue threshold. Neuropathy, ataxia, and retinitis pigmentosa (NARP) is associated with a point mutation at position 8993 (ATPase 6 gene) of mtDNA (19). This is an especially interesting point mutation, which supports the threshold concept. Patients with more than 90% mutated mtDNA present with a maternally inherited Leigh’s disease, patients with 70-90% of mutated DNA show the NARP syndrome, and those with less than 70% appear clinically normal. Although many mitochondrial disorders can be associated with mtDNA abnormalities, and pathophysiologyconsistsinabnormalproteinsynthesisforrespiratorychaincomplexes, it is not fully understood how and why these relatively distinct diseases result from the mtDNA abnormalities,

IV. NEUROPATHOLOGY Traditionally, mitochondrial disorders are diagnosed in muscle, mostly resulting in so-called ragged red fibers in the modified Gomori trichrome stain (20). In adc oxidase (COX) defidition, many patients present with a partial cytochrome ciency in which some fibers lack COX staining. Such fibers demonstrate a very high content of deleted or point-mutated mtDNA.With succinate dehydrogenase staining, subsarcolemmal increases in staining have been shown, which we called ragged blue fibers (21). Since the mt genome does not encode for complex I1 (succinate dehydrogenase) of the respiratory chain, this staining reflects the mitochondrial volume. In lightof the fact that mtDNA analyses in platelets may be normal, whereas in muscle a deletion can be demonstrated, a muscle biopsy should be performed in patients with mitochondrial cytopathy. Point mutations are commonly found in platelets; hence, muscle biopsy not is mandatory. In general mitochondria are numerous, abnormal in shape (megaconial, pleoconial), with abnormal cristae that can be demonstrated by use of electron microscopy. In addition, an increase in lipids is found in muscle fibers, and there are more type I than type I1 muscle fibers. In the brain MELAS presents with focal cortical lesions, capillary proliferation, loss of neurons, gliosis, and microcyst formation (22). Various authors have shown abnormal and numerous mitochondria in endothelial and smooth muscle cells in arterioles and capillaries (23,24). MERRF loss in patientsshowsignificantcerebellarabnormalities,suchasneuronal of the cerethe nucleus dentatus, or inferior olivary nucleus. There is gliosis bellar white matter and of the brain stem as well as in the posterior column of the spinal cord.

Ataxia in Mitochondrial Disorders

V.

CLINICAL FEATURES

A.

ChronicProgressiveExternalOphthalmoplegia(CPEO), Ophthalmoplegia Plus, and the Kearns-Sayre Syndrome (KSS)

331

These are sporadic diseases, and there are only a few families reported with maternal inheritance, Although CPEO patients are characterized by ophthalmoparesis or ophthalmoplegia, with mostly bilateral ptosis and horizontal and vertical ophthalmoparesis and with proximal myopathy, the term ophthalmoplegia plus is used when further organs are involved in the disease (heart, kidney, liver, brain, . . .).The criteria for diagnosing a KSS are onset before age 20 (some 13), ophthalmoplegiaandpigmentary authorsevenrequireonsetbeforeage retinopathy.Atleastone of thefollowingsymptomsshouldalsobefound: cerebrospinal fluid (CSF) protein levels higher than l00 mg/dL, cerebellar syndrome,orcardiacconductionblock.Thus,thepredominantclinicalfeatures are found in the central nervous system, skeletal muscle, and heart. Many patients with the KSS additionally show short stature; hypoacusis; mental retardation;dementia;endocrineabnormalities,suchasdiabetesmellitus,hypoparathyroidism, or lack of growth hormone; and delayed puberty. In contrast to the MERRF and MELAS patients, seizures and strokes are uncommon in patients with KSS or CPEO. It is not the size of deletion, but rather, the percentage of deleted mtDNA molecules that causes the specific phenotype. Naturally, organs with a high-energy demand, such as brain, retina, muscle, heart, liver, and kidney, are functionally most impaired. Patients with nephropathy present with DeToni-Fanconi-Debre syndrome. In KSS the first symptoms are ptosis and ophthalmoparesis, onset of the disease is in childhood. Insteadof ophthalmoparesis patients rarely complain of blurred or double vision. It is most important to perform heart control on a regular basis.If a heart block is present, a pacemaker should be inserted in time. Prognosis is rather varied owing to the individual percentage of deleted mtDNA in each organ. A complete heart block is life-threatening, major CNS involvement results in debilitating ataxia, spasticity, and dementia. There are patients who presented with Pearson syndrome (siderblastic aneKSS. We and mia and exocrine pancreatic dysfunction), but who later on develop others have found deletions not only in blood cells, but also in muscle and bone marrow in thesepatients.Interestingly,some of thepatientssurviveanemia, which means that the percentage of deleted DNA molecules decreases in the bone marrow. If this mechanism were understood it could be a most important model for therapy. In this context, it is important to stress that a patientwith K S S may well be perfectly normal on Southern blot analysisof blood cells, whereas a deletion is found in his or her muscle. Therefore, we recommend muscle biopsyif blood analyses results are normal. The morphological typical feature are ragged

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Figure 2 Typical ragged red fibers, the morphological hallmark for all major mitochondrial cytopathies, which are due to biochemical dysfunction of the respiratory chain.

red fibers (Fig. 2). CK analyses, electromyography, and magnetic resonance imaging (MRI) (25) are often normal. Patientswithmultipledeletionsnormallyshowanautosomaldominant trait. Zeviani(8) was the firstto report on an Italian familiy with ptosis, facial and limb weakness, exercise intolerance, dysphonia, dysphagia, cataracts, ageof onset 24-30 years, and death between age 43 and 59. All patients showed ragged red fibers and cytochrome c oxidase-negative fibers, thought to be due to a mitochondrial cytopathy causedby a trans-acting nuclear-encoded factor. The point mutation of the tRNALys gene leads to a decrease in protein synthesis, predominantly affecting complex IV (COX) and variable other decreases in respiratory chain complex activities. Molecular analyses can be performed both in muscle and in blood cells because both tissues normally express the defect. About 90% of all patients have RRF, and there is a close correlation between percentage of point mutation and clinical phenotype.

B. Myoclonus Epilepsy with RaggedRed Fibers Typicalfindingsinpatientswithmyoclonusepilepsyandraggedredfibers (MERRF) are myoclonus or myoclonic epilepsy, generalized or focal epilepsy,

Ataxia

333

ataxia, and proximal myopathy with ragged red fibers (11). Some patients also show dementia, pyramidal tract signs, peripheral neuropathy, optic atrophy, short stature,exerciseintolerance,lacticacidosis,andimpairedhearing.Cerebellar loss in the dentate signs are prominent because there is considerable neuronal nucleus and inferior olivary nucleus. Onset of the disease is normally in childhood, but adult onset is also possible. Up to80% of patients with MERRF have a positive familyhistory. Members of these familiesmay be asymptomatic or oligosymptornatic. Rarely, patients with MERRF develop stroke. Interestingly, patients with MERRF often present with neck lipomas resembling those found in multiple symmetrical lipomatosis (10). We have described a patient with multiple symmetrical lipomatosis who presented with the typical MERRF point mutation at position 8344 of the mtDNA (26). This patient had considerable cerebellar ataxia when standing or walking, with intention tremor. Another example for patients with the MERRF syndrome’s point mutation who do not present with the classic clinical picture are those who have stroke at a young age and, therefore, are considered as MERRFIMELAS overlap syndrome with the MERRF point mutation at position 8356of the tRNALys gene (27). For analysis of the 8344-nt-point mutation we normallyusethemethod of mispairingpolymerasechainreaction (PCR) according to Seibel and colleagues (28). Prognosis is rather variant, with patients who died at the ofage 7 and of 79 years (29).We lost one patient owing to liver failure after valproic acid treatment, initially the onlyway to stop her seizures. Other complications may be blindness and cardiac failure.

C. Mitochon~rialEncephalomyopathy,LacticAcidosis, with Stroke-Like Episodes Typical clinical features are proximal myopathy, with intolerance to endurance exercise, ophthalmoparesis, cardiomyopathy, endocrine abnormalities, cerebellar ataxia in 26%, hearing loss, and dementia. Some patients also present with short stature, limb weakness, and elevated CSF protein. The most prominent signs are, (loo%), onset before age 40 according to Hirano et al. (22), exercise intolerance (loo%), stroke (98%), ragged red fibers (97%), seizures (94%), lactic acidosis (91%), and normal early development (91%). Because many patients report recurrent headaches before stroke development we were interested in testing patients with migraine or cluster headache for mtDNA abnormalities. Our results showed no significant abnormalities (30,3l). During stroke-like episodes, many patients have severe headache. As reported for KSS, some patients also present with short stature, exercise intolerance, and elevated CSF protein. In agreement with other mitochondrial disorders, patients with MELASmay also present with ataxia, optic nerve atrophy, cardiomyopathy, cardiac conduction block, diabetes

334

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mellitus, hirsutism, and nephropathy, although these symptoms occur in only a minority of patients. In contrast toKISS, there are large families with the MELAS syndrome ( 3 3 , showing maternal inheritance. Our family spins over four generations, with rather heterogeneous clinical phenotypes, Lactic acid is elevated in both serum and CSF, which is a helpful clinical diagnostic criterion, Molecular analyses can be performed in muscle and blood cells (32). Autopsy was performed in several patients with MELAS, and cerebellar affection couldbe demonstrated in seven of nine cases (23). Prognosis is rather variable. There is a tendency that the younger the patient is at onset and the more stroke-like episodes occur, the earlier the patient will die from MELAS syndrome.

D. Leber’sHereditaryOpticNeuropathy In the white population the most frequent mt abnormality is found at position mutation. In contrast with MERRF or MELAS, 11778, which results in an ACto this nt region does not code for a tRNA, but for a protein (subunitof4 complex I of the respiratory chain). That why is biochemical measurements most often reveal a decrease in complex I activity. Clinically, LHON is most often found in young male adults, who acutely or subacutely develop a partial or total visual loss. Beside the classic mutation, there are more than ten other point mutations associated with LHON. Interestingly, there is a point mutation in the ND6 gene (subunit 6 of complex I) at nt 14459 that resultsin a maternally inherited dystonia (33). Ataxia is not a leading feature in LHON.

E. Leigh’sDisease(MaternallyInheritedForm), NARP Syndrome Leigh’ S disease can be inherited followingan autosomal recessive or a maternal trait. Children present clinically with ataxia, dystonia, cranial nerve abnormalities, respiratory dysfunction, and failure to thrive. Neuroradiology an important is diagnostic tool because it reveals characteristic bilateral symmetrical hyperintense signals in T2-weighted MRIs in the brain stem, cerebellum, basal ganglia, and periaqueductal regions. Maternal inheritanceis due to a point mutation at nt 8993, and Leigh’s syndrome occurs only if more than 90%of mtDNA molecules show the point mutation. Patients with more than’70% and less than 90% of the point mutation often present with the NARP syndrome. This acronym stands for neuropathic myopathy, ataxia, and retinitis pigmentosa (1 9).

F. MultipleSymmetricLipomatosis(MorbusMadelung) Berkovic and co-workers (34) andwe were able to analyze a large cohortof patients with MSL.The 14patients investigatedby us most often showedRRF and, as a group, revealed a significant decrease in biochemically assessed cytochrome

AtaxiaDisorders in Mitochondrial

335

c oxidase (10). One of our patients presented with multiple deletions of the mtDNA. Clinically, these patients showed both impairment of the CNS with cerebellar ataxia (3 out of 17), and 12 out of 14 patients presented with predominantly axonal polyneuropathy (35,36). In one patient, just described, we found the typical MERRF-associated point mutation in muscle, sural nerve, and fat tissue at position 8344 of the mt genome associated with typical lipomatosis and without any seizures at the age of 70. The point mutation was not only present in muscle, but also in sural nerve and in adipose tissue (26).

VI.

ANCILLARY TESTS

Luft etal. (1) established three criteria for the diagnosis of a mitochondrial cytopathy: (a> morphological abnormalities in muscle, (b) a clinical picture compatible with a mitochondrial dysfunction, and (c) a biochemical defect. Nowdays, a genetic defectmay also be included. Characteristic morphological abnormalities are ragged red fibers, COX-negative fibers, and an increase in type I fibers. On the electron microscopic level, abnormal mitochondria and, especially, subsarcolemmally located mitochondria, are increased in number, which is also seen in interfibrillarly regions to a lesser extent. There are mitochondria with abnormal cristae. Although morphological analyses do not allow the diagnosis of a specific mitochondrial cytopathy, they are, inmy view, the most reliable diagnostic tool. Biochemical analyses arepedomed in muscle or fibroblasts and, to various degrees, show decreases in activity of respiratory chain complexes. Again, these studies do not allow the diagnosis of a specific disease. Even molecular analyses do not allow KSS present withan MELAS point mua specific diagnosis because patients with tation, patients with MSL present with an MERRF point mutation, and so on. Thus, the clinical picture with consideration of specific clinical definitions of mitochondrial encephalomyopathy syndromes allows the diagnosis (Table 1). Inheritance should be looked for, and a maternal inheritance should suggest to mitochondrial cytopathy. In light of the biochemical defect in the respiratory chain, lactate should be analyzed in the serum and in the CSF. An increase in lactate in CSF is a rather specific finding. Bicycle ergometrymay be useful because it detects an unusual increase in lactate under exercise conditions and, most importantly, a delayed decrease in serum lactate after the exercise (37,38). Measurement of creatine kinase activity in the serum is quite often normal and electromyographic analyses are also very often totally normal and show no myopathic pattern. Neuroradiology is mandatory for Leigh’s disease and MELAS, as discussed earlier. An MRI from patients withKSS may reveal basal ganglia calcification, cerebral or cerebellar atrophy, and leukoencephalopathy. Basal ganglia calcification and brain atrophy is also often found in advanced stages of MERRF. In most MELAS patients, angiography and transcranial sonography have excludedocclusion of largevessels.MRIorcranial CT scansshowtypical

Reichmann

336

Table 1 Important Clinical Features in Patients with or MELASMERRF

feature Clinical Impairment of cranial nerves Visual impairment Ophthalmoplegia Pigmentary retinopathy Ptosis Hearing loss Cerebellar syndrome Ataxia Dysmetria Tremor Muscle weakness Seizures Myoclonus Stroke-like episodes Dementia Short stature Episodic vomiting Headache Cardiac conduction block Pathologic EEG Pathologic EMG Pathologic cranial CT Increased CSF protein Increased creatine hnase Increased serum lactate Ragged red fibers

KSSMERRFMELAS MELAS MERRF

+++ ++ +++ +++ +++ ++ ++ ++ + +

++ +

-

(+>

++ ++

(+>

(+l

++ ++ ++ ++ ++ + ++ ++

++ + (+> (+> (+> ++ +++ +++ + + ++ ++ +++ ++ + (+>

(+l

-

+++ ++ + + + ++ +++

KSS, MERRF,MELAS,

++ (+> (+> (+> (+>

+ ++ +

(+> (+>

++ ++ +++ ++ ++ ++ ++ + ++ + +++ + + +++ ++ __

+++ + -

+

++ ++

+ + ++ ++

(+>

+++ +++ ++ ++ ++ ++

+ + ++ + + ++

++c

++c

++,frequently present; +,often present; (+),occasionaHy

++ +,always or almost always present; present; -not present.

strokes, especially in the occipital lobe, with hemianopia or patterns of hypodensities that are not typical for the distributio~of large intracranial vessels(39). An MRI helps make the correct diagnosis while the patient is still alive. There is T1 and T2 prolongation and symmetrical involvementof basal ganglia, thalami, inferior olivary nuclei, periaqueductal gray matter, superior cerebellar peduncules, and the tegmentum. Spectroscopy reveals increased lactate levels and decreased N-acetylaspartate which is an estimate for neuronal loss. Similar findings were reported for MELAS.

Ataxia in ~ i t o c ~ o n d rDisorders ia~

VII.

33’7

MANAGEMENT

Because gene therapy is not yet available, we have to concentrate on symptomatic treatment. Most physicians use coenzymeQ, for this is an important part of the respiratory chain and transports electrons from complexes II1and to complex 111. It is also possible that coenzyme Q stabilizes the mitochondrial respiratory chain complexes and acts as a radical scavanger. Although patients with a mitoQ deficiency, in our experience, about chondrial cytopathy rarely have coenzyme 40-60% of the patients improve relative to endurance using a bicycle exertion test (38,40). Normally, we prescribe 150-300 mg coenzyme Q per day. Side effects have never occurred. Coenzyme Q treatment is possible in patients with KSS, CPEO, MELAS, andMERRF. Whether itis helpful for other mitochondrial cytopathies is still unclear. Because we believe that patients with mitochondrial cytopathies have an increase in free radical formation in the respiratory chain, we searched for an appropriate radical scavanger. Lipoic (thioctacid) acid is able to lower the lactate concentration (41) in the brain and most probable to scavange radicals, as was 600 mg thiocshown in diabetes mellitus; accordingly, we treat our patients with tic acid perday. An interesting report demonstrated a good response to 10 mg viI11 tamin K and 1g of vitamin C given every6 h (42) in a patient with a complex defect. Some reportsindicatethat,especiallypatientswiththeMELAS syndrome, may profit from treatment with dichloroacetate, which inhibits pyruvatedehydrogenasekinase,thusactivatingpyruvatedehydrogenase(43,44). Otherauthors,however,claimedthatdichloroacetate may not penetratethe blood-brain barrier and may even present with toxic effects (45). In other patients we are studying the application of creatine, which is not only a natural constituent of muscle, but also seems to scavange radicals. Conclusive results are not yet available. Idebenone is another interesting and promising drug because it passes the blood-brain barrier and is a potent radical scavanger. There are reports that idebenone may be especially suitable in patients with MELAS syndrome (46), in a dosage between 90 and 180 mg/day. One further paper indicates improvementof both stroke-like episodes and headache in patients with MELAS with steroid therapy (47). Becauseof anecdotal reports on serious side effects, we try to avoid steroids in patients with KSS. Beside metabolic treatment, specific treatment is KSS, endocrine disorders, and seinecessary for cardiac conduction block in zures, for which anticonvulsants are used. We avoid vaiproic acid for these patients because it may result in a decrease in carnitine, andwe have seen hepatic coma in a patient with MERRF (48). Blood transfusions often allow young patients to survive severe anemia in Pearson’s syndrome. In summary, our basic treatment of patients with a mitochondrial cytopathy consists of 300 mg coenzyme Q and 600 mg thioctic acid per day.

338

Reichmann

We and others striveto establish gene therapy (49,50). The two most promising concepts are either to stop replication of deleted or mutated mtDNA molecules (50) or to transport normal mtDNA into mitochondria (49). For this purDNA pose, a leader protein from the urea cycle was connected with an arbitrary molecule that included sequences for replication and the sequence that was missing in MELAS.At present, we are investigating whether this construct replicates and how we could transport the chimera through the cell membrane because successful passage through the mitochondrial membrane was already shown in our first paper (49). Even though this work is exciting, it will be years from now before gene therapy will be available for these patients.

REFERENCES 1. Luft R, Ikkos D, Palmieri G, Ernster L, Afzelius B. A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical and morphological study. J Clin Invest 1962; 41:1776-1804. 2. Egger J, Lake BD, WilsonJ. Mitochondrial cytopathy. A multisystem disorder with ragged-red-fibers on muscle biopsy. Arch Dis Child 1981; 56:741-752. 3. Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988; 331:717-719. 4. Reichmann H, Gold R, Meurers B, Naumann M, Seibel P,Walter U, Klopstock T. Progression of myopathology in Kearns-Sayre syndrome: morphological a follow-up study. Acta Neuropath01 1993; 85579-681. 5. Larsson NG, HolmeE, Kristiansson B, Oldfors A, Tulinius M. Progressive increase of the mutated mitochondrial DNA fractions in Kearns-Sayre syndrome. Pediatr Res 1990; 28:131-136. 6. Schon EA, Rizzuto R, Moraes CT, Nakase H, Zeviani M, DiMauro S. A direct repeat is a hotspot for large-scale deletions of human mitochondrial DNA. Science 1989; 244:346-349. 7. Mita S, Rizzuto R, Moraes CT, Shanske S, Arnaudo E, Fabrizi GM, Koga ,'l DiMauro S, Schon EA. Recombination via flanking direct repeats is a major cause of large-scaledeletions ofhuman mitochondrialDNA.NucleicAcidsRes1990; 18:561-567. 8. Zeviani M, ServideiS, Gellera C, BertiniF, DiMauro S, DiDonato D. An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature 1989: 339:309-3 11. 9. SuomalainenA,MajanderA,HaltiaM,SomerH,LonnqvistJ,SavontausML, Peltonen L, Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia. J Clin Invest 1992; 9051-66. 10. Klopstock T, Naumann M, Schalke B, Bischoff U, Seibel P,Kottlors M, Eckert P, Reiners K, ToykaKV,Reichmann H. Multiple symmetric lipomatosis: abnormalities

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11.

12.

13. 14.

15.

16.

17.

18.

19. 20. 21. 22. 23, 24.

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incomplexIVandmultipledeletionsinmitochondrialDNA.Neurology1994; 441862466. Fukuhara N, Tokigushi S, Shirakawa K, Tsubaki T. Myoclonus epilepsy associated with ragged-red fibers (mitochondrial abnormalities): disease entity or syndrome? Light and electron microscopic studies of two cases and review of the literature. J Neurol Sci 1980; 47:117-133. Shoffner J, Lott M, Lezza AMs, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA Lys mutation. Cell 1990; 61:931-937. Silvestri G, Moraes C, Shanske S, Oh SJ, Di Mauro S. A new mtDNA mutation in thetRNALy"geneassociatedwithmyoclonicepilepsyandragged-redfibers (MERRF). Am J Human Genet 1992; 5l: 1213-1217. Seibel P, Degoul F, Bonne G, Romero N, Francois D, Paturneau Jouas M, Ziegler F, Eymard B, Fardeau M, Marsac C, Kadenbach B. Genetic, biochemical and pathophysiological characterization of familial mitochondrial encephalomyopathy (MERRF). J Neurol Sci 1991; 105:217-224. Masucci JP, Davidson M, Koga Y, Schon EA, King MP. In vitro analysis of mutationscausingmyoclonusepilepsywithragged-redfibersinthemitochondrial tRNALy"gene:twogenotypesproducesimilarphenotypes.MolCellBiol1995; 15:2872-2881. Pavlakis SD, Phillips PS, DiMauroS, DeVivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a distinctive clinical syndrome.Ann Neurol 1984; 16:481-488. Goto Y-I, Nonaka I, HoraiS. A mutation in the tRNALL""(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.Nature1990; 348:651-653. Flier1 A, Reichmann H, Seibel P. Pathophysiology of the MELAS 3243 transition mutation. J Rio1 Chem 1997; 272:27189-27196. Holt IJ, Harding AE, Petty RKH, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondial DNA heteroplasmy. Am J Hum Genet 1990; 46:428-433. EngelWK,CunninghamGG.Rapidexaminationofmuscletissue:animproved trichrome stain method for fresh-frozen biopsy sections. Neurology 1963; 13:919923. Reichmann H, Vogler L, Seibel P. Ragged red or ragged blue fibers. Eur Neurol 1996; 36~98-102. Hirano M, Ricci E, Koenigsberger R. MELAS: an original case and clinical criteria for diagnosis. Neuromusc Disord 1992; 2: 125-135. Ohama E, Ohara S, Ikuta F, Tanaka K, Nishizawa M, Miyatake T. Mitochondrial angiopathyincerebralbloodvesselsofmitochondrialencephalomyopathy.Acta Neuropath01 (Berl) 1987; 74:226-233. Kishi M, Yamamura Y, Kurihara T, Fukuhara N, Tsuruta K, Matsukura S, Hayashi T, Kakagawa M, Kuriyama M. An autopsy case of mitochondrial encephalomyopathy: biochemical and electron microscopic studies of the brain. J Neurol Sci 1988; 86:31-40.

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25. Lindner A, Georgiadis D, Hofmann E, Becker G, Reiners K, Reichmann H. Ophthalmoplegia plus: clinical relevance of magnetic resonance tomography findings, Eur J Med Res 1997; 2:311-314. 26. Naumann M, Kiefer R, Toyka KV, S o m e r C, Seibel P, Reichmann H. Mitochondrial dysfunction with myoclonus epilepsy and ragged-red fibers point mutation in nerve, muscle, and adipose tissue of a patient with multiple symmetric lipomatosis. Muscle Nerve 1997; 20:833-839. 27. Zeviani M, MuntoniF, Savarese N, et al. A MERRFMELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNALy" gene. Eur J Hum Genet 1992; 1530-87. 28. Seibel P, Degoul F,Romero N, Marsac C, Kadenbach B. Identification of point mutations by mispairing PCR as exemplified in MERRF disease. Biochem Biophys Res Commun1990;173:561-565. S. Clinical featuresof mitochondrial myopathies and encepha29. Hirano M, Di Mauro lomyopathies. In: Lane RJM, ed. Handbook of Muscle Disease. New York: Marcel Dekker,1996:479-504. 30. Seibel P, Griinewald T, Gundolla A, Diener HC, Reichmann H. Investigation on the mitochondrial transfer RNALeU(UuR) in blood cells from patients with cluster headache. J Neurol 1996; 243:305-307. 31. Klopstock T, May A, Seibel P, Papagianulli E, Diener HC, Reichmann H. Mitochondrial DNA in migraine with aura. Neurology 1996; 46:1735-1738. 32. Darnian MS, Seibel P, Reichmann H, Schachenmayr W, Laube H, Bachmann G, Wassill KH, DorndorfW. Clinical spectrumof the MELAS point mutation in a large pedigree. Acta Neurol Scand 199.5; 92:409-415. 33. Novotny Ej, Singh G, Wallace DC, Dorfman LJ, Louis A, Sogg RL, Steinman L. Leber's disease and dystonia: a mitochondrial disease. Neurology 1986; 36:10.531060. 34. Berkovic SF, Andermann, Shoubridge EA. Mitochondrial dysfunction in multiple symmetric lipomatosis. Ann Neurol 1991; 29:566-569. 35. NaumannM,Schalke B, KlopstockT,ReichmannH,LangeKW,WiesbeckG, Toyka KV, Reiners KH. Neurological multisystem manifestation in multiple symmetric lipomatosis: a clinical and electrophysiological study. Muscle Nerve 1995; 181693-698. 36. Klopstock T, Naumann M, Seibel P, Schalke B, Reiners W, Reichmann H. Mitochondrial DNA mutations in multiple symmetric lipomatosis. Mol Cell Biochem 199'7;174:271-275. 37. Reichmann H, Rohkamfn R, Zeviani M, Servidei S, Ricker K, DiMauro S. Mitochondrialmyopathydue to complex I11 deficiencywithnormalreduciblecytochrome b concentration. Arch Neurol 1986; 43:957-961. 38. Chan A, Reichmann H, Kogel A, Beck A, Gold R. Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J Neurol 1998; 245:681-685. 39. Lindner A, Hofmann E, Naumann M, Becker G, Reichmann H. Clinical, morphological, biochemical, and neuroradiological features of mitochondrial encephalomyopathies. Presentationof 19 patients. Mol Cell Biochem 1997; 174297-303.

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40. Gold R, SeibelP, Reinelt G, Schindler R, LandwehrP, Beck A, Reichmann H. Phosphorus magnetic resonance spectroscopy in the evaluation of mitochondrial myopathies:results ofa6-monththerapystudywithcoenzyme Q. EurNeurol1996; 36:191-196. S, 41. Barbiroli B, Medori R, Tritschler H-J, Klopstock T, Seibel P, Reichmann H, Iotti Lodi R, Zaniol P. Lipoic (thioctacid) acid increases brain energy availability and skeletal muscle performance as shown by in vivo 3'P-MRS in a patient with mitochondrial cytopathy. J Neurol 1995; 242:472--477. 42. Eleff S, Kennaway NG, Buist NRM, Darley-Usmar VM, Capaldi RA, Bank WJ, Chance B.31PNMR study of improvement in oxidative phosphorylation by vitamins K3 and C in a patient with a defect in electron transport at complex 111 in skeletal muscle. Proc Natl Acad Sci USA 1984; 81:3529-3533. al. Dichloroacetate treatment of MELAS43 DeVivoDC,JacksonA,WadeC,et associated lactic acidosis. Ann Neurol 1990; 28:437. 44. Saijo T, Naito E, Ito M, Takeda E, Hashimoto T, Kuroda Y.Therapeutic effectsof sodiumdichloroacetateonvisualandauditoryhallucinationsinapatientwith MELAS. Neuropediatrics 1991; 22:166-167. 45. Stacpoole PW. The pharmacology of dichloroacetate. Metabolism 1989; 38: 11241144. 46. Ihara Y, Namba R, KurodaS, Sat0 S, Shirabe T. Mitochondrial encephalomyopathy (MELAS):pathologicalstudyandsuccessfultherapywithcoenzyme Q10 and idebenone. J Neurol Sci 1989; 90:263-271. 47 ShapiraY, Cederbaum SD, Cancilla PA, Nielsen D, Lippe BM. Familial poliodystrophy, mitochondrial myopathy, and lactic acidemia. Neurology 1975; 25:614-621. 48. MiillgesW, Dorn T,Paulus W, Seibel P, Reichmann H. Acase of myoclonus epilepsy and lactic acidosis: difficulties in diagnosis and treatment of terminal mitochondrial cytopathy. Intensive Care Med 1994; 20: 613-614. 49. Seibel P, Trappe J, Villani G, Klopstock T, Papa S, Reichmann H. Transfection of mitochondria:strategytowardsagenetherapyofmitochondrialDNAdiseases. Nucleic Acids Res 1995; 23:lO-17. 50. Taylor RW, Chinnery PF,Turnbull DM, LightowlersRN. Selective inhibitionof mutant human mitochondrial DNA replication in vitro by peptide nucleic acids. Nat Genet1997;15:212-215. *

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17 Spinocerebellar Ataxia 1 Harry T. Orr University of Minnesota, ~inneapolis,Minnesota

Thomas Klockgether University of Bonn, Bonn, Germany

I.

11. EPIDEMIOLOGY

111. MOLECULAR PATHOGENESIS A. 345 B. Gene Product Mice Transgenic in C. Studies tranuclear ions Neuronal D. E. Hypothetical Model of the Molecular Pathogenesis of SCAl IV, NEUROPATHOLOGY V. Presentation

peat

CLINICAL FEATURES A. Progression, Survival Disease Onset, 353and B. Clinical C. Correlation of Clinical Presentation with Disease Duration and

VI.ANCILLARYTESTS A.NerveConduction B. EvokedPotentials C.MagneticResonanceImaging D, PositronEmission Tomography

345

35 1 352 353

354 354 355 355 355

VII. REiFERENCES

357 343

Orr and Klockgether

344

1.

I~T~ODUCTIO~

Spinocerebellar ataxia 1 (SCAl) is an autosomal dominant disorder that is clinically characterized by progressive limb and gait ataxia, dysarthria, and variable degrees of pyramidal tracts signs, brain stem symptoms, and peripheral neuropathy. The neuropathological findings in SCAl include neuronal loss in the cerebellar cortex and brain stem, as well as degeneration of the spinocerebellar tracts. The SCAl locus was the first ataxia disease locus that has been defined. Based on linkage to HLA loci, the SCAl gene was mapped to chromosome 6p (1). In 1993, Orr et al. (2) isolated the SCAl gene and showed that the mutation is an unstable CAG trinucleotide repeat expansion within a translated region of the gene. As in other CAG repeat disorders, the pathogenetic mechanism is not the loss of physiological function of ataxin-1, but rather the gain of a new deleterious function.

II. EPIDEMIOLOGY Recentepidemiologicalstudiesyieldedprevalencerates of dominantataxias ranging from 0.9 :100,000 to 1.3:100,000 (3-5). The proportion of SCAl among all mutations causing dominant ataxia varies considerably among different populations. In Germany, 27% o f all families with dominant ataxia harbor the SCAl mutation (6). In contrast, no singleSCAl family was identified among100 Japanese ataxic families (7). Three recent studies of American families of different ethnic origin reported a frequency of SCAl ranging from 3 to 6% among dominant ataxias (8-10). A large SCAl kindred with more than 1200 affecteds members has been identified among the Iakut population in eastern Siberia (11-13). Table 1 gives an overview of several recent large series reporting the frequency of SCAl. Table 1 Frequency of SCAl Among Families with Dominant Ataxia in Different Populations SCA1 (%)

families Frequency Country Number of Gemany Japan United States France United States Japan United States

184 100 149 91 47 64 178

27

0 3 15

6 3 6

Ref. 6 7 8 61 9 62 10

Spinocerebellar Ataxia 1

111.

MOLECULARPATHOGENESIS

A.

Mutation

345

The SCAl mutation is an unstable CAG trinucleotide repeat expansion within a translated region of the gene. Although the normal repeat length varies between 6 and 39 trinucleotides, SCAl patients have one allele within a range of 40-81 repeat units (2). The mutated SCAl genes contain uninterrupted CAG stretches. In contrast, normal alleles have a midstream CAT interruption (14). Repeatlengthandthepresence or absence of theinterruptionappearto be critical for the stability of trinucleotide repeats. Repeats in the normal-sized range containing a CAT interruption are stable in parent-to-offspring transmission. Expanded uninterrupted repeats occurring in SCAl patients are unstable, with a tendency to further expansion during meiosis, in particular during spermatogenesis. This mechanism leads to larger expansion in offspring of affected men. of theexpandedrepeats,leadingtovaryThereisalsomitoticinstability ing repeat lengths in different body tissues. Surprizingly, the smallest expansions are found in the Cerebellum, whereas larger expansions are seen in other brain regions. A possible explanation for these findings is the assumption that frequent cell divisions lead to greater heterogeneity and larger expansions. This applies for spermatozoa that undergo a greater number of cell divisions than oogonia.Similarly,mostbrainregionscontainmoredividingnonneuronal cells than the cerebellum, leading to greater instability in noncerebellar brain regions (15). In SCA1, there is an inverse correlation between the length of the CAG repeat and the age of onset, with the largest alleles occurring in patients with juvenile-disease onset. As a consequence of the instability of expanded repeats during gametogenesis, age of onset is variable with featuresof anticipation. Anticipation is most pronounced in offspring of affected men (2,16).

B. GeneProduct The wild-type SCAl gene encodes ataxin- 1 ,a 87-Wa protein that contains a polyglutamine stretch of variable length. Ataxin-1 is a novel protein without homology with previously described proteins. Itis expressed in a varietyof neuronal and nonneuronal tissues. The mutated ataxin-l, which contains an expanded uninterrupted polyglutamine stretch, is expressed ubiquitously within the body at levels comparable with thoseof normal ataxin-l. It has a predominantly nuclear localization in most brain regions.The Purkinje cells are a notable exception, in j. The physithat ataxin-l has both a nuclear and cytoplasmatic localization (17 ological function of ataxin-l is only poorly understood. During cerebellar development, there is a transient burst of SCAl expression at postnatal day 14 when the. murine cerebellar cortex becomes physiologically functional, suggesting that

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the normal SCAl gene has a role at specific stages of cerebellar development (18). Mice lacking ataxin-l are viable, fertile, and do not show any evidence of ataxia or neurodegeneration. However, SCAl -null mice demonstrate decreased exploratory behavior, pronounced deficits in the spatial version of the Morris water maze test, and impaired performance on the rotating rod apparatus. Furthermore, neurophysiological studies performed in area CA1 of the hippocampus revealed decreased paired-pulse facilitation in SCAl-null mice, whereas long-term and posttetanic potentiations were normal. These findings point to the possible role of ataxin- 1 in learning andmemory (19).

C. Studies in TransgenicMice The molecular basis of SCAl pathogenesis has been pursued using both patient material and experimental models. In SCAl, mice carrying an allele of ataxin-l with 82 glutamines, the expressionof which was directed specifically to Purkinje cells, were developed shortly after the cloning of the SCAl gene (20). Transgenic mice expressing high levels of a wild-type allele of SCAl with 30 CAG repeats failed to develop any signs of Purkinje cell pathology or ataxia. Only those animals expressing the expanded alleleof SCAl developed Purkinje cell pathology and an associated ataxia. Disease progression in the transgenic mice expressing a mutant allele of SCAl has been examined in considerable detail. Similar to the human disease, the SCAl transgenic mice presented with a progressive neurological disorder (20,21). Results of behavioral tests demonstrated that at 5 weeks of age cerebellar impairment appeared to be limited to a decreased ability to improve motor performance, as assessedby the accelerating rotating rod apparatus. At this age, the SCAl mutant animals perform as well as the wild-type littermate controls on the first dayof trials, impairment was noted in the mutant miceonly on successive days of trials. The latter observation indicates that a training or learning phase is required for the deficiency in the SCAl mutant mice to manifest itself on the rotating The rod. absence of gait abnormalities, and normal motor activity, balance, and coordination supported the conclusion that the impairment on the rotating rod was due to a decreased ability of the mutant mice to learn the task, as opposed to impairment in motor activity, fine motor control, or coordination. With increasing age, as the cerebellar impairments of SCAl mutant mice worsened to reach a stageof severe ataxia, deficiencies in motor activity and gait became apparent (Fig. 1). By l year of age, when there was substantial loss of cerebellar function, the mutant mice were never able to match the performance of wild-type animals on the rotating rod, even on the first day of trials, and did not demonstrate any abilityto improve their performance with training. These results suggested that, in theSCAl mutant mice, cerebellar dysfunction canbe divided into two phases. In thefirst phase, dysfunction is limited toan impairment

347

Spinocerebellar Ataxia 1

A

B

" -

5 weeks

$+so0

l - "

y400

5400

-

300

If 300

g 200 -

F200

6oo

v500

Ift

6oo

_.

- dB -

Q,

S

-

3 100d

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22 100 -

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D

19 Weeks

600

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3500

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-I

300

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. :

Figure 1 Development of neurological alterations in SCAl transgenic mice:(A-D) progressive loss of performance on the accelerating rotating rod with advancing age; (E) the footprint patternof a l-year-old nontransgenic wild-type mouse; and (F)the footprint pattern of a l-year oldSCAl transgenic mouse revealinga clearly ataxic gait. (From Ref. 21.)

348

Orr and Klockgether

of motor learning. At a later stage, impairment advances to a point at which motor activity and coordination become abnormal and severe ataxia ensues. The morphological alterations that were noted in the SCAl mice (Fig. 2), after they became ataxic, as judged by home cage behavior at 12 weeks, developed after the cerebellar cortex has matured; therefore, they were not a result of maldevelopment induced by expression of the mutant transgene. There were no histological alterations during the first 3 weeks of postnatal life, At the time of decreased motor learning on the rotating rod apparatus, a loss of proximal dendritic branches and a decrease in the number of dendritic spines was observed in Purkinje cellsof SCAl mice. At the time that ataxia was established inSCAl the mice (12-15 weeks), as assessed by home cage behavior, there was little evidence of loss of Purkinje cells, but there were significant alterations in dendritic and perikaryal morphology as well as evidence of perikaryal heterotopia thatwas not seen in younger animals. These changes then became more widespread and severe as the animals aged. Another striking feature of SCAl transgenic mice that followed the onset of ataxia was the presence of numerous Purkinje cells, with their perikarya heterotopically located in the intermediate levels of the molecular layer. Histological examination of young animals revealed no heterotopia during development, nor in the early stages of the disease; however, heterotopic cells were frequent by the time of overt ataxia. Therefore, the heterotopia is not due to an abnormal migration of Purkinje cells during development. Several postmortem studies of the cerebellum in patients with SCAl have shown structural abnormalitiesof Purkinje cells, as well as cell loss. Using Golgi techniques and immunohistochemical methods, dendritic simplification with loss of spines, similar to that detected in the SCAl transgenic mice have been described (22,23).A pathological hallmarkof SCAl inhumans is the occurrenceof frequent proximal axonal dilations (torpedoes), a featurenot found in the SCAl mice. It is clear from autopsy studies of SCAl patients that morphological alterations antedate cell death in at least someof the Purkinje cells of these patients. The results of these investigations have been difficult to interpret for several reasons. Because of the complexity of the disease process and the involvement of multiple neuronal populations, it is difficult to distinguish between transynaptic effects and events in the cell that are the direct consequence of expression of a mutant SCAl gene. In addition, autopsy studies are typically performed late in the course of the disease, when cell degeneration is more extensive. Targeting of the SCAl mutation to a single cell type known to be involved in the native disease, the Purkinje cell, has allowedan evaluation of the relative effects of structural alterations and cellular loss on the development of ataxia in theSCAl transgenic mice. In the SCAl mutant mice, onset of ataxia occurred at a time when loss of Purkinjecells was barelydetectable.Thisobservation,coupledwiththe

349

Figure 2 Progression of Purkinje cell pathology in SCAl mice: Calbindin immunohistochemistry of cerebellar sections (A) from a 16-day-old SCAl transgenic mouse; (B) a 24-week-old SCAl transgenic mouse. The section from the 16-day-old mouse demonstrates the normal organization of the cerebellar cortex at this time. In contrast, the section from the 24-week-old SCAl mouse reveals substantial Purkinje dendritic atrophy within the molecular layer and the presenceof heterotopic Purkinje cell bodies in the molecular layer. (From Ref. 63.)

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numerousmorphologicalabnormalitiesfoundinPurkinjecellsfrom SCAl transgenicanimals,indicatesthatexpression of themutantform of ataxin-l is vulnerableinthehumandisease,canleadtocellular in a cellthat dysfunction sufficient to induce ataxia, without causing death of the affected neuronal population. Therefore, it is likely that in the SCAl transgenic mice, the disease is not caused by cell loss. Rather, loss of Purkinje cells seen at later stages of diseaseismostlikelytheresult of thedysfunctioninducedat an earlier stage.

D. NeuronalIntranuclearInclusions An interesting feature of expanded polyglutamine proteins, observed in both transgenic mice and patient material, is the presence of neuronal intranuclear inclusions or aggregates that contain the polyglutamine protein. These aggregates, or inclusions, have been detected inSCAl and HD transgenic mice (24,25), and in human postmortem HD (26,27), SCAl (24), SCA3 (28), DRPLA (29), SCA7 (30), and SBMA brains (31). The two most striking characteristics of these inclusions are their specific occurrence in cells affectedby the disease, despite widespread expressionof the expanded proteins, and their generally consistent nuclear location, despite widely varying subcellular localizations of the nonaggregating forms of the protein. Besides containing the polyglutamine protein, these intranuclear aggregates are also ubiquinated and contain elements of the proteasome apparatus (32). Thus, it has been proposed that the formationof the aggregates reflects an impaiment of cellular proteolytic degradation by the polyglutamine disease protein. To directlyexaminetherole of nuclearataxin-laggregatesin SCAl pathogenesis,twoadditionalseries of transgenicmicewereestablished. The development of these SCAl mice was based on work performed using trans,a deletion fected COS cells in tissue culture. In contrast with intact ataxin-l (33) was transfected mutant of ataxin-l that lacks the self-association region into COS cells and did not form nulcear aggregates (34). The same result was a diffuse observed in transgenic Purkinje cells, in which the nuclei stained in pattern, without evidence of inclusions (34). Interestingly, mice expressing the ataxin-l deletion mutant with an expanded number of glutamines developed an ataxicphenotypedespitetheabsence of microscopicaggregates.Thesemice developed both the histopathological changes and the associated motor disabilitycharacteristics of theoriginal SCAl mouselines(20,21).Theseresults demonstrate that aggregation of mutant ataxin-l is not a primary component of pathogenesis (i.e., the aggregates do not cause the disease). Because the mice have not yet been followed to advanced age, it remains quite possible that the aggregates do have a secondary effect that augments the primary pathogenesis of the disease.

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Another fundamental point relative to the molecular basis of SCAl pathogenesis, which stemmed from work with transfected COS cells, was the importance of the subcellular localization of ataxin-l in pathogenesis. As in Purkinje cells, ataxin-l localizes to the nucleusof COS cells. A series of COS cell transfections demonstrated that ataxin-1 contains a functionalarginine-lysine nuclear localizationsequence(NLS)centeredatlysine-772neartheCOOH-terminus (34). The mutation K772T completely eliminated the activity of this NLS in COS cells. Transgenic mice expressing ataxin-l [82Q]K772T also accumulated the protein primarily in the cytoplasm. In contrast with the previous SCAl transgenic mice that expressed nuclear ataxin-l ,the ataxin-l [82Q]K772T mice did not develop the characteristic histopathological changes and associated phenotype of the disease, even at advanced ages. Thus, nuclear localization of intact ataxin1[82Q]protein is essentialfor SCAl pathogenesis, at leastinthetransgenic mouse model.

E. HypotheticalModel of theMolecular Pathogenesis of SCAl The fundamental molecular processes governing the initiation and progression of polyglutamine diseases, in general, and SCA1, in particular, remain uncertain. Yet it is possible, taking into consideration the datanow available, to generate a hypothetical model. In a vulnerable neuron after translation, a substantial portion of ataxin-l is transported into the nucleus. While in the cytoplasm, it exerts no pathogenic effects and forms no aggregates, even when present in the cytoplasm at elevated concentrations for extended periods, as in the ata~in-l[82Q]~~~~~ mice. After recognition of the intact NLS by the transport system and docking with the nuclear membrane pore complex, cytoplasmic ataxin-l is translocated into the nucleus. The process of recognition and translocation is regulated by cell-specific mechanisms, as ataxin- 1 has been observed to distribute quite differently in various cell types (17). Once mutant ataxin-l is in the nucleus, there is a change associated with the gain-in-function that initiates SCAl pathogenesis; perhaps, on the basis the interaction of ataxin-l with other nuclear proteins such as leucine-rich acidic nuclear protein (LANP)(35). This gain in functionmay affect any one of various nuclear processes, such as transcription or RNA processing, ormay, it more generally, affect nuclear architecture. In the self-association region deletion mice, the nuclear population of ataxin-l molecules appears to consist entirely of this species. It is soluble, diffusely distributed, and pathogenic. If the expanded ataxin-l in the pathogenic configuration hasan intact selfassociation region, it does not remain indefinitely in the soluble, diffuse state, but goes on to form insoluble aggregates. Ataxin-l within the aggregates may have a conformation or binding configuration different from either the cytoplasmic

352

state or the soluble nuclear state.The presence of ubiquitin, proteosome components, and the chaperone protein HDJ-2/HSDJ within the aggregates suggests that they may arise from ataxin-l misfolding and subsequent ineffectual turnover by the proteosome system (32).It ispDssible that the aggregates mediatea pathogenic effect that is distinct from thatof the soluble pathogenic form of ataxin-l. of pathogenesis, but itmay If so, then this effect is not necessary for the initiation have a role in disease progression. There is still much that is uncertain. It is not understood why ataxin-l is nuclear in some cells, nuclear plus cytoplasmic in others, and exclusively cytoplasmic in still others. Also, it isnot clear which nuclear factors are responsible for the cell- and compartment-specific transformation of ataxin-l to a pathogenic form and, then, to an aggregated form. The aggregates themselves are stillof unknown significance in disease progression. One hopes that the answers to these and other aspects of SCAl pathogenesis and pathology will become known and lead to therapeutic opportunities for this disease,

a limited numberof necropsy studies in SCAl .The findings typically There is only involve degenerative changes, with neuonal cell loss and gliosis in the cerebellar cortex, pontine nuclei, and inferior olives, compatible with a neuropathological diagnosis of olivopontocerebellar atrophy. Often, there is additional cell loss in the caudal cranial nerve nuclei, Degeneration within the basal ganglia, thalamus, and cerebral cortex are less frequent. In the spinal cord, axonal loss and pallor of myelin is observed in the dorsal column pathways, spinocerebellar tracts, and less frequently, in the pyramidal tracts(11,3641). Cerebellar Purkinje cells are usually most severely affected. By using Golgi techniques and immunohistochemical methods, dendritic simplification with lossof spines has been described(22,123). In general, the distribution and severity of neuropathological changes inSCAl is quite variable, even within one family. Thus, two patients (IV.26, IV.27) of the Schut-Haymaker family had no definite changes in the pons, whereas most other family members had typical olivopontocerebellar atrophy (38,412). Recently, the presence of ubiquitin-positive nuclear inclusions, containing ataxin-l, has been demonstrated in surviving neurons of the nucleus centralis pontis (24). Nuclear inclusions are ultratructural hallmarks of most CAG-repeat disorders. Their significance for the pathogenesis of SCAl is discussed in the foregoing (see Sec. 11I.D). Autopsy examination of one SCAl patient revealed additional neuropathological alterations, reminiscentof multiple system atrophy with demonstration of oligodendroglial cytoplasmatic inclusions (41). However, the density of these inclusions in the SCAl brain was much lower than in multiple system atrophy.

Spinocerebellar Ataxia 1

V.

CLINICALFEATURES

A.

DiseaseOnset,Progression,andSurvival

353

Disease onset in SCAl varies between adolescence and late adulthood. On average, the disease starts at about the age of 35 years (36,39,43-48).The earliest reported disease onset occurred in a patient from a Iakut kindred in eastern Siberia SCAl patients who noticed onsetof ataxia at the ageof 15 years (13). Almost all develop first symptoms before the age of 55 years. As in other CAG repeat disorders, there is an inverse correlation between CAG repeat length and of age onset. Anticipation has been observed in many SCAl families. SCAl always takes a progressive course, and may it lead to severe disability and premature death. A recent epidemiological study reported a median latency to become wheelchair-bound after disease onset of 14 years. Median survival after onset of symptoms was 21 years, and median age at death 56 years (43). This result corresponds well with data from a seriesof 14 autopsied SCAl cases in which mean age at death was 54 years (36).

B. ClinicalPresentation All SCAl patients suffer from a progressive cerebellar syndrome, with ataxia of gait and stance, ataxiaof limb movements, dysarthria, and cerebellar oculomotor abnormalities (36,39,44-48). The oculomotor abnormalities include gaze-evoked nystagmus, saccade hypermetria, broken-up smooth pursuit, reduced optokinetic nystagmus,andimpairedsuppression of vestibulo-ocularreflex by fixation (48,49). In most patients, there are additional noncerebellar symptoms. About half of the patients have supranuclear gaze palsy or saccade slowing; or both. Pyramidal tract signs with spasticity, extensor plantar responses, and hyperreflexia are found in more than 50%of patients with SCAl. In contrast, depressed or absent tendon reflexes and amyotrophy are only rarely encountered. Usually, there are no severe sensory disturbances. However, decreased vibration sense is found in up to 80% of the SCAl patients. Dysphagia is a frequent complaintof SCAl patients, and it is a particular clinical problem in late disease stages. Disturbances of sphincter control, mainly bladder dysfunction, occur less frequently, and are encountered in about 20% of the patients. Basal ganglia symptoms, with parkinsonism or dystonia have been observed only in single patients. Clinical data of several large series of SCAl patients are summarized in Table 2 (36,39,44-48). Mental disturbances are encountered in fewer than10% of SCAl patients. In advanced disease stages, mnestic and cognitive deficits may occur. Some patients develop clinically manifest dementia (39,45,50). In addition, affective disturbances, personality changes, and behavioural disorders have been observed. These disturbances include irritability, inadaequate euphoria, aggressiveness, and

Orr and Klockgether

354

Table 2 Frequency of Extracerebellar Symptoms in Clinical Series of SCAl Patients

Ref.

39 26

n

Pale discs Supranuclear gaze palsy Slow saccades Dysphagia Amyotrophy Depressed or absent reflexes Increased reflexes Extensor plantar responses Spasticity Basal ganglia symptoms Sensory symptoms Dementia Sphincter disturbances

44 103

15

?

77

65

?

54 54 23 93 62 19 15 31 8 ?

?

42 ?

15 69 ? ?

14 38 8 ?

45 42

36 22

?

? ? ?

22 ?

51 5 5 31 40 ?

20 51 5 18

100 41

46 20

47 16

60 40 55 45

38 44 SO 6

?

?

?

45 45 45

75 45

? ?

36 ?

? ? ? ?

15

?

0

13 38 75

48 9 56 33 56 89 l1 11 89 33 78

?

0

44 38 38

78 ?

44

nocturnal crying (36,50). These clinical observations are in good accord with the results of a study in 11 SCAl patients that used standardized neuropsychological tests. This study reported deficits of verbal and nonverbal intelligence, memory dysfunction, and disturbancesof executive functions.The degree of these deficits was correlated with the severity of ataxia (51).

C.Correlation of ClinicalPresentationwithDisease Duration and Repeat Length Clinical presentation of SCAl patients and severity of symptoms partly depends on disease duration and on the length of the CAC repeat. Although ataxia and pyramidal tract signs are usually present in early stages of the disease, the frequency of dysphagia, amyotrophy, hyporeflexia, sensory signs, and supranuclear gaze palsy increases with progressionof the disease (39). A recent study from a large Siberian SCAl kindred suggested that the severityof associated symptoms, such as dysphagia, skeletal muscle atrophy, and tongue atrophy, increases with CAGrepeat length (13).

VI.ANCILLARYTESTS A.

NerveConduction

Nerve conduction studies in SCAl patients suggest presence of mild, predorninantly sensory neuropathy with features of both axonal loss and demyelination

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(52-54). Motor and sensory nerve conduction velocities are in the lower-normal range. However, conduction velocities tend to be lower than in other SCA mutations, and distal latencies may be mildly prolonged (52). In a study of nine patients with SCAl, amplitudes of compound muscle action potentials were reduced in only one. In contrast, more than half of the patients had low antidromic sensory nerve action potentialsof the sural nerve(53). Needle electromyography discloses chronic neurogenic changes, but usually no pathological spontaneous activity (52).

B. EvokedPotentials Motor-evoked potentials by transcranial magnetic stimulation, are almost always abnormal in SCAl. The abnormalities include prolonged central motor conduction time, reduced amplitudes, and raised thresholds(53-56). Visual-evoked potentials have been studied by two groups, yielding conflicting results. Schols et al. (52) found delyed P100 responses in only one of ten SCAl patients (52), whereas Abele et al.(53) reported a frequencyof abnormal visual-evoked potentials of almost 80%. Somatosensory-evoked potentials and brain stem auditoryevoked potentials are abnormal in more than half of SCAl patients (53).

C. MagneticResonanceImaging Tl-weighted magnetic resonance images (MRI) reveal global atrophy of brain structuresintheposteriorfossa,suggestive of olivopontocerebellaratrophy (52,57). A typical MR imageis depicted in Fig. 3. In addition, there is often visible atrophyof the cervical spinal cord (48). Quantitative studies, using planimetric and volumetric evaluation of MRI scans show that cerebellum, brain stem, and cervical spinal cord are, on average, shrunken to 70-80% of their normal size. These studies didnot provide evidence for additional atrophyof basal ganglia nuclei (57).The question of whether there is also atrophy of the cerebral cortex has not yet been addressed. There are no obvious signal abnormalitiesT2on weighted images; however, this question has not been studied systematically.

D. PositronEmissionTomography A positron emission tomography (PET) study in three SCAl patients, using fluorodeoxyglucose, revealed hypometabolism not only in the cerebellum and brain stem, but also in the cerebral cortex, basal ganglia, and thalamus (41). Because neuropathological and MRI studies do not indicate severe degeneration in these latter brain structures, hypometabolism in the cerebral cortex, basal ganglia, and thalamus is most probably due to remote effects of cerebellar and brain stem degeneration.

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Figure 3 T1-weighted MRI of infratentorialbrainstructuresshowingtheposterior fossa: (upper left) the midsagittal plane; (upper right) axial images at the level of the middle cerebellar peduncles; (lower left) inferior olive complex; (lower right) dens of axis a 44-year-old male SCAl patient.

Vil.

MANAGEMENT

There is still no specific treatment for SCA1. Several studies suggest moderate symptomaticbenefit of 5-hydroxytryptophan,amantadine,andbuspironein (58ataxic patients, whereas other studies were unable to confirm these findings 60). All studies have been performed in heterogeneous groups of ataxic patients. In addition, most of the studies were only poorly controlled. There is no study that specifically addresses the question of whether or not one of these compounds is particularly beneficial for SCAl patients. Spasticity in SCAl usually does not require medical treatment. Physical and speech therapyis recommended, although there are no studies providing convincing evidence that these therapies are effective in patients with progressive ataxia. Many SCAl patients are dependent on canes or wheelchairs

357

within years after disease onset. Patients with severe dysphagia should be by fed gastric tubing to avoid undernourishment and aspiration.

CE 1. Yakura H, Wakisaka A, Fujimoto S,-Itakura K,#.Vereditary ataxia and HLA [letter]. N Engl J Med 1974; 293:154-155. 2. Orr HT, Chung MY, Banfi S, Kwiatkowski TJJ, Servadio A, Beaudet AL, McCall AE,DuvickLA,RanumLP,ZoghbiHY.Expansionofanunstabletrinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 1993; 4:221-226. in 3. Polo JM, Calleja J, Combarros0, Berciano J. Hereditary ataxias and paraplegias Cantabria, Spain. An epidemiological and clinical study. Brain 1991; 114:855-866. S. Hereditaryataxiasand 4. LeoneM,BottacchiE,D’AlessandroG,Kusterrnann paraplegias in Valle d’ Aosta, Italy: a study of prevalence and disability. Acta Neurol Scand 1995; 91:183-187. 5. Sridharan R, Radhakrishnan K, Ashok PP, Mousa ME. Prevalence and pattern of spinocerebellar degenerations in northeastern Libya. Brain 1985; 108:831-843. F, 6. Riess 0, Schols L, Bottger H, Nolte D, Vieira Saecker AM, Schimming C, Kreuz Macek M Jr, Krebsova A, Macek M, Klockgether T, Ziihlke C, Laccone FA. SCA6 is caused by moderate CAG expansion in the alpha,,-voltage-dependent calcium channel gene. Hum Mol Genet 1997; 6:1289-1293. Sobue G. Fre7. Watanabe H, Tanaka F, Matsumoto M, Doyu M, Ando T, Mitsuma T, quency analysis of autosomal dominant cerebellar ataxias in Japanese patients and clinical characterizationof spinocerebellar ataxia type 6. Clin Genet 1998; 53: 13-19. 8. Ranum LPW, Lundgren JK, Schut LJ, Ahrens MJ, PerlmanS, Aita J, Bird TD, Gomez C, Orr HT. Spinocerebellar ataxia type I and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia. Am J Hum Genet 1995; 57:603-608. 9. Geschwind DH, PerlrnanS, Figueroa CP, Treiman LJ, Pulst SM. The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia. Am J Hum Genet 1997; 60:842850. 10. Moseley NIL, BenzowKA, Schut LJ, Bird TD, Gornez CM, Barkhaus PE, Blindauer 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. 11. Goldfarb LG, Chumakov MP, Petrov PA, Fedorova NI, Gajdusek DC. Olivopontocerebellaratrophyin a largeIakutkinshipineasternSiberia.Neurology1989; 39: 1527-1530. 12. Lunkes A, Goldfarb LG, Platonov FA, Alexeev VP, Duenas-Barajas E, Gajdusek DC, Auburger G. Autosomal dominant spinocerebellar ataxia (SCA) in a Siberian founder population: assignment to theSCAl locus. Exp Neurol 1994; 126:310-312. V, Kononova S, 13, GoldfarbLG,Vasconcelos 0, PlatonovFA,LunkesA,Kipnis Chabrashvili T, Vladimirtsev VA, Alexeev VP, Gajdusek DC. Unstable triplet repeat ~

358

14. 15. 16. 17. 18. 19.

20. 21.

22. 23. 24. 25.

26. 27.

Orr and Klockgether

andphenotypicvariabilityofspinocerebellarataxiatype1.AnnNeurol1996; 39:500--506. Chung MY, Ranum LP, Duvick LA, Servadio A, ZoghbiHY, Orr HT. Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I. Nat Genet 1993; 5:254-258. Chong SS, McCall AE, Cota J, Subramony SH, O n HT, Hughes MR, Zoghbi HY. Gametic and somatic tissue-specific heterogeneity of the expanded SCAl CAG repeat in spinocerebellar ataxia type 1. Nat Genet 1995; 10:344-350. Banfi S, Servadio A, ChungMY, Kwiatkowski TJ Jr, McCall AE, Duvick LA, Shen Y, Roth EJ, Orr HT, Zoghbi HY. Identification and characterization of the gene causing type l spinocerebellar ataxia. Nat Genet 1994; 7:513-520. Servadio A, Koshy B, Armstrong D, Antalffy B, Orr HT, Zoghbi HY. Expression analysis of the ataxin-l protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nat Genet 1995; 10:94-98. Banfi S, Servadio A, Chung M, Capozzoli F, Duvick LA, Elde R, Zoghbi HY, Orr HT. Cloning and developmental expression analysis of the murine homolog of the spinocerebellar ataxia type 1 gene (SCAl). Hum Mol Genet 1996; 5:33-40. Matilla A, Roberson ED, BanfiS , Morales J, Amstrong DL, Burright EN, Orr HT, Sweatt JD, ZoghbiHY, Matzuk MM. Mice lacking ataxin-l display learning deficits anddecreasedhippocampalpaired-pulsefacilitation.JNeurosci1998;18:5508-55 16. Burright EN, Clark HB, Servadio A, Matilla T, Feddersen RM, Yunis WS, Duvick LA,ZoghbiHY, Orr HT. SCAl transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 1995; 82:937-948. Clark HB, Burright EN, Yunis WS, Larson S, Wilcox C, Hartman B, Matilla A, ZoghbiHY, Orr HT. Purkinjecellexpression of amutantalleleof SCAl in transgenic mice leads to disparate effects on motor behaviors, followed by a progressivecerebellardysfunctionandhistologicalalterations.JNeurosci1997; 17:7385-7395. Koeppen AH. The Purkinje cell and its afferents in human hereditary ataxia. J Neuropathol Exp Neurol 199l ;50505-5 14. Ferrer I, Genis D, Davalos A, Bernado L, Sant F, Serrano T. The Purkinje cell in olivopontocerebellar atrophy. A Golgi and immunocytochemical study. Neuropath01 Appl Neurobiol 1994; 20:38-46. Skinner PJ, Koshy BT, Cummings CJ, Klement IA, Helin K, Servadio A, Zoghbi HY, Orr HT. Ataxin-lwithanexpandedglutaminetractaltersnuclearmatrixassociated structures. Nature 1997; 389:971-974. Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997; 90:537-548. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997; 277: 1990-1993. Scherzinger E, Lurz R, Turmaine M, Mangiarini L, Hollenbach B, Hasenbank R,

axia

Spinocerebellar

28. 29.

30.

31. 32. 33. 34. 35. 36.

37. 38. 39. 40.

41.

1

359

Bates GP, Davies SW, Lehrach H, Wanker EE. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 1997; 90:549-558. Paulson HL, Perez MK, TrottierY, Trojanowski JQ, Subramony SH, DasSS, Vig P, Mandel JL, Fischbeck KH, Pittman RN. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 1997; 19:333-344. Becher MW, Rubinsztein DC, Leggo J, Wagster MV, Stine OC, Ranen NG, Franz ML, Abbott MH, Sherr M, MacMillan JC, Barron L, Porteous M, Harper PS, Ross CA. Dentatorubral and pallidoluysian atrophy (DRPLA). Clinical and neuropathological findings in genetically confirmed North American and European pedigrees. Mov Disord 1997; 12:519-530. Holmberg M, Duyckaerts C, Durr A, Cancel G, Gourfinkel AI, Damier P, Faucheux B, Trottier Y, Hirsch EC, Agid Y, Brice A. Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet 1998; 71913-918. Li M, Miwa S, Kobayashi Y, Merry DE, Yamamoto M, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol 1998; 44:249-254. Cumings CJ, Mancini MA, Antalffy B, DeFranco DB, On HT, Zoghbi HY Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCAl. Nat Genet 1998; 19:148--154. Burright EN, Davidson JD, Duvick LA, Koshy B, Zoghbi HY, Orr HT. Identification of a self-association region within the SCAl gene product, ataxin-1. Hum Mol Genet 1997; 6:513-518. Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, Zoghbi HY, On HT. Ataxin- 1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCAl transgenic mice. Cell 1998; 95:41-53. Matilla A, Koshy BT, Cummings C, Isobe T, Orr HT, Zoghbi HY. The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-l. Nature 1997; 389:974978. Genis D, Matilla T, Volpini V,Rose11 J, Dgvalos A, Ferrer I, Molins A, Estivill X. Clinical, neuropathologic, and genetic studies of a large spinocerebellar ataxia type 1 (SCAl) kindred: (CAG), expansion and early premonitory signs and symptoms. Neurology 1995; 45:24-30. Schut JW. Hereditary ataxia. Clinical study through six generations. Arch Neurol Psychiatry 1950; 63:535-568. Greenfield JG. The Spino-Cerebellar Degenerations. Springfield: Charles C Thomas, 1954. Spadaro M, GiuntiP, Lulli P, et al. HLA-linked spinocerebellar ataxia: a clinical and genetic study of large Italian kindreds. Acta Neurol Scand 1992; 85:257-265. Durr A, Stevanin G, Cancel G, Duyckaerts C, Abbas N, Didierjean 0, Chneiweiss H, Benomar A, Lyon-Caen 0, Julien J, Serdaru M, Penet C, Agid Y, Brice A. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features.Ann Neurol 1996; 39:490-499. Gilman S. Sima AA. Junck L. Kluin KJ. Koeme RA. Lohman ME. Little R. SDino.

cerebellar ataxia typel with multiple system degeneration and glial cytoplasmic inclusions. Ann Neurol 1996; 39:241-255. 42. Schut JW, Haymaker W. Hereditary ataxia: a pathological study offive cases of common ancestry. J Neuropath01 Clin Neurol195l ;1:183-2 13. 43. Klockgether T, LiidtkeR, Krarner B, Abele M, Biirk K, Schols L, Riess0, Laccone F, Bosch S, Lopes CendesI, Brice A, Inzelberg R, Zilber N, DichgansJ. The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain 1998; 121:589-600. 44. Giunti P, Sweeney MG, Spadaro M, Jodice C, Novelletto A, Malaspina P, Frontali M, Harding AE. The trinucleotide repeat expansion on chromosome 6p (SCAI) in autosomal dominant cerebellar ataxias. Brain 1994; 117:645-649. 45. Dubourg 0, Diirr A, Cancel G, Stevanin G, Chneiweiss H, Penet C, Agid Y, Brice A. Analysis of the SCAl CAG repeat in a large number of families with dominant ataxia: clinical and molecular correlations. Ann Neurol 1995; 37:176-180. 46. Karneya T, Abe K, Aoki M, Sahara M, Tobita M, Konno H, Itoyarna Y. Analysis of spinocerebellar ataxia typel (SCA1)-related CAG trinucleotide expansion in Japan. Neurology 199.5;45:1587-1594. 47. Filla A, De Michele G, Campanella G, Perretti A, Santoro L, Serlenga L, Ragno M, Calabrese 0, Castaldo I, De Joanna G, Cocozza S. Autosomal dominant cerebellar ataxia type I. Clinical and molecular study in 36 Italian families including a comparison between SCAl and SCA2 phenotypes. J Neurol Sci 1996; 142:140-147. 48. Burk K, Abele M, FetterM, Dichgans .l,Skalej M, LacconeF, Didierjean 0, Brice A, Klockgether T. Autosomal dominant cerebellar ataxia type I-clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain 1996; 119:1497-1505. S, Pulst SM, BalohRW. Oculomotor phe49. Buttner N, Geschwind D, Jen JC, Perlrnan notypes in autosomal dominant ataxias. Arch Neurol 1998; 55:1353-1357. SO. Nino HE, Noreen HJ, Dubey DP, Resch JA, Namboodiri K, Elston RC, Yunis EJ. A family with hereditary ataxia: HLA typing. Neurology 1980; 30: 12-20. 51. Kish SJ, el Awar M, Schut L, Leach L, Oscar Berman M, Freedman M. Cognitive deficits in olivopontocerebellar atrophy: implications for the cholinergic hypothesis of Alzheimer’s dementia. Ann Neurol 1988; 24:200-206. 52. Schols L, Amoiridis G, Biittner T, Przuntek H, Epplen JT, Riess0.Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol 1997; 42:924-932. 53. Abele M, Biirk K, Andres F, Topka H, Laccone F, Bosch S, Brice A, Cancel G, Dichgans J, Klockgether T. Autosomal dominant cerebellar ataxia type I. Nerve conduction and evoked potential studies in families with SCA1, SCA2 and SCA3. Brain 1997;120:2141-2148. 54. Perretti A, Santoro L, Lanzillo B, Filla A, De Michele G, Barbieri F, Martino G, Ragno ‘M, Cocozza S, Caruso G. Autosomal dominant cerebellar ataxia type I: rnultimodal electrophysiological study and comparison between SCAl and SCA2 pa$ients. J Neurol Sci 1996; 142:45-53. S, Przuntek H. Motor evoked potentials 55. Schols L, Amoiridis G, Langkafel M, Schols in the spinocerebellar ataxias type 1 and type 3. Muscle Nerve 1997; 20:226-228. 56. Yokota T, Sasaki H, Iwabuchi K, Shiojiri T, Yoshino A, Otagiri A, Inaba A, Yuasa T.

xia

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57.

58. 59.

60. 61. 62.

63.

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Electrophysiological featuresof central motor conduction in spinocerebellar atrophy type 1, type 2, and Machado-Joseph disease. J Neurol Neurosurg Psychiatry 1998; 65~530-534. Klockgether T, Skalej M, Wedekind D, Luft AR, Welte D, Schulz JB, Abele M, Burk K, Laccone F, Brice A, Dichgans J. Autosomal dominant cerebellar ataxia type I. MRI-based volumetry of posterior fossa structures and basal ganglia in spinocerebellar ataxia types 1, 2 and 3. Brain 1998; 121:1687-1693. Lou JS, Goldfarb L, McShane L, Gatev P, Hallett M. Use of buspirone for treatment of cerebellar ataxia-an open-label study. Arch Neurol 1995; 52:982-988. Trouillas P, Xie J, Adeleine P, Michel D, %ghetto A, HonnoratJ, Dumas R, Nighoghossian N, Laurent B. Buspirone, a 5-hydroxytryptamineIA agonist, is active in cerebellar ataxia-results of a double-blind drug placebo study in patients with cerebellar cortical atrophy. Arch Neurol 1997; 54:749-752. Botez MI, Botez-Marquard T, Elie R, Pedraza OL, Goyette K, Lalonde R. Amantadine hydrochloride treatment in heredodegenerative ataxias: a double blind study. J Neurol Neurosurg Psychiatry 1996; 61 :259-264. Stevanin G, Durr A, David G, Didierjean 0, Cancel G, RivaudS, Tourbah A, Warter JM, Agid Y, Brice A. Clinical and molecular features of spinocerebellar ataxia type 6. Neurology 1997; 49: 1243-1246. Matsurnura R, Futarnura N, Fujimoto Y, Yanagirnoto S, Horikawa H, SuzumuraA, Takayanagi T. Spinocerebellar ataxia type6-molecular and clinical featuresof 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology 1997; 49~1238-1243. Burright EN, Orr HT, Clark HR. Mouse models of human CAG repeat disorders. Brain Pathol 1997; 7:965-977.

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18 Spinocerebellar Ataxia Type2 Katrin Burk and Johannes Dichgans

University of Tibingen, Tibingen, Germany

INTRODUCTION I.

364

11. EPIDEMIOLOGY

364

111. MOLECULAR PATHOGENESIS A. TheSCA2Mutation B. The GeneProduct:Ataxin-2 C.DiagnosisandGeneticCounseling

365 365 367 368

IV. NEUROPATHOLOGY A.MacroscopicFindings B. MicroscopicFindings

369 369 369

V.

VI.

CLINICAL FEATURES A. Age of Onset and Disease Progression B. ClinicalFindings C.DifferentialDiagnosis

373 373 373 376

ANCILLARY TESTS A. Imaging Studies B. ElectrophysiologicalFindings

376 376 377

VII. MANAGEMENT REFERENCES

377 380

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Burk and Dichgans

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1.

I~T~ODU~TION

The autosomal dominant cerebellar ataxias (ADCAs) area heterogeneous group of dominantlyinheritedneurologicaldisorders,characterized by progressive ataxia that results from degenerationof the cerebellum and its afferent and efferent connections. In most families, there is clinical and neuropathological evidence for additional involvement of brain stem, basal ganglia, spinal cord, and peripheral nervous system (1 ,2). Hading clinically distinguished several typesof ADCA, with typeI being characterized by vwious combinations of ataxia with cognitive impairment, optic atrophy, ophthalmoplegia, pyramidal tract signs, basal ganglia symptoms, sensory loss, and amyotrophy(2). Genetic heterogeneity of ADCA I has been estabas spinocerebellar ataxia (SCA) 1-6 lished with six different gene loci known (3-8). SCA2 was first described by Orozco in a large Cuban founder population from the Cuban province of Holguin (9). Genetic analysis yielded linkage to chromosome 12q (4). In 1996, three independent groups cloned the SCA2 gene. The mutation is another unstable CAG trinucleotide repeat expansion present within the coding region of the causative gene (10-12).

II. EPIDEMIOLOGY The prevalence of all dominantly inherited ataxias is estimated as 1 :100,000 to 10:100,000 (13-17). In founder populations, such as that from the Holguin province of Cuba or from the Lake of Neusiedel in Austria, the prevalence is much higher. In Holguin, it has been calculated to be 133 :100,000 (4). Among populations of different geographic and ethnic origin, the regional frequency of the Table 1 The Frequency of the SCA2 Mutation in Different Ethnic Populations

Frequency (%)

Population

4 6-12 9 10 13 13 15 18 40

Portugal China Brazil Germany Various (USA) Germany Europe Various (USA) Various (UK)

Ref.

39 28, 29 27 32 34

(Ataxia Base Tubingen) 33 31 37

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SCA2 mutation varies between 4 and 40% of dominantly inherited cerebellar ataxias (Table 1). In Europe, SCA2 corresponds to 15%of all dominantly inherited ataxias (1 8).The SCA2 mutation has been reported in families of German, Austrian, French, Italian, Serbian, Portuguese, North African, Ethiopian, North American,Canadian, West Indian,Cuban,Brazilian,Argentinean,Jordanian, Saudi Arabian, Indian, Chinese, Singaporean, and Japanese descent(19-39). Interestingly, theSCA2 mutation has also been detected in patients with apparently “sporadic” ataxia (16,18).

111.

MOLECULARPATHOGENESIS

A. The SCA2 Mutation In 1993, linkage to the long arm of chromosome 12 was established in ADCA I kindreds of Cuban descent (4). Further studies mapped the SCA2 locus to a 32-CM region between markers D12S58 and phospholipase-A2 (PLA2) (40) and, Dl2S 1333or subsequently, to a l-cM intervalbetweenD12S1328and D12S 1329 in the same pedigrees (40). Linkage to this locus was confirmed in several kindreds of distinct ethnic origin (19,20,41). In 1996, three independent groups identified the causative mutationof SCA2 as an expanded CAG repeat in the translated sequence of a gene encoding a protein of 13 12amino acids, with a molecular weight of 140 m a , called ataxin-2 (10-12). The base triplet CAG a polyglutamine encodesglutamine,andthe (CAG), blockistranslatedinto stretch located at theNH,-terminus of the ataxin-2 molecule. The SCA2 gene is locatedin a gene-richregion of thegenome:thegenesforthecalciumtransporting ATPase (ATP2A2), they-subunit of proteinphosphatase-y (PPPlCC), the human adrenoleukodystrophy-relatedprotein (hALDR), the human low molecular weight 2’-5’ oligo(A) synthetase-E (IFI-4), and Darier disease are located in the vicinity of the SCA2 gene on chromosome 12q (42). There is little variation of the size of normal SCA2 alleles, the 22-CAGrepeat allele accounting for about 90% of all alleles (1 0,18). Except for very short CAG numbers, normal alleles are usually interrupted by one to three CAA repeats, which also encode glutamine (10,18). In SCA2, alleles with 32-77 CAG are associated with the disease, the most frequent allele carrying 37 CAG repeats (10,43). Normal chromosomes contain 13-33 CAG repeats (43). Because there may be an overlapof normal and expanded alleles in the intermediate range from 32 to 33GAG repeats, predictive genetic testing should be handled with particular caution in these cases. Another difficulty may arise because even short alleles may be unstable and undergo expansion in the following generation: Riess and co-workers reporteda 50-year-old asymptomatic carrierof 34 CAG repeats trans(16). There is indirect evidence from previous mitting the disease to her children studies that longer repeat expansions (more than ten repeat units) depend on the

,

Dichgans

366

Burk and

length and the sequenceof the repeat, with repeat numbers higher than a critical threshold forming stable hairpin structures predisposed to further expansion (44). In SCA2, the loss of interruptions is predicted to cause formation of a perfect hairpin, whereas an energetically less-stable, branched hairpin is contingent on the presence of two CAA interruptions (10). Expansions and contractions of fewer than four repeat units may result in polymerase slippage. In SCA2, the latter mechanism may account for the variability of normal alleles with 22 or 23 CAG repeat units (44). Although haplotype analysis failed to identify a single haplotype predisposed to expansion (lo), its results are suggestive of multiple ancestral mutations or recurrent mutations on an at-risk haplotype (37,43). onThere is an inverse correlation between the repeat length and theof age set, the size of the expanded allele accounting for at least 66%of the variability in the ageof onset (18) (Fig. 1). Juvenile cases are characterizedby larger expan50 years tend to have alleles sions, whereas patients with an onset after the of age shorter than 40 CAG repeats (1 1). Small differences in the CAG repeat have a major effect on the age of onset (-3.24 years per CAG repeat) (18). Expanded alleles are unstable during most transmissions, with a mean increase of 2.2 CAG repeats (10,33). The marked variation of the allele size in sperm (gonadal mosaicism), reflecting both expansions and contractions, is consistent with the higher instability of repeat length on paternal transmission (18,19,36,37).

65

55 45

35 25 I5

5

35

37

39

41

43

45

Repeat length Figure 1 Correlationof repeat length and age of onset in52 SCA2 patients (seen at the Neurology Department Tubingen). Pearson’s correlation coefficient r = 0.8; p <0.0001.

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As in other trinucleotide repeat disorders, this intergenerational instability, at least partly, accounts for the phenomenonof anticipation with decreasing ages of onset in successive generations (25,30,45). In SCA2, anticipationof up to 31 years has been observed (25). As reported, because the reported anticipation differs considerably from expected anticipation-as derived from the correlation between the ageof onset and the CAG repeat number-one has to assumean observation bias in the assessment of the age of onset in parent-offspring pairs.

6. The GeneProduct:Ataxin-2 The coding region of the SCA2 gene consists of a 4.5-kb transcript, including 25 exons spanning 130 kb of genomic DNA (10,46). The exon sizes vary from 37 The CAG repeat is to over 800 bp, exon 1 being the largest with 890 bp (46). contained in the 5”coding region in exon1. Therefore, the polyglutamine stretch is located at theNH,-terminus of the ataxin-2 molecule (46). Mostof the 4.5-kb transcript (3936 bp) is translated (46). The function of the novel protein ataxin-2is not yet understood; the amino acid sequence yielding no significant homologies to proteinsof known function or the gene productsof HD, SCA1, SCA3, SCA7, or DRPLA (10,47). Sequence comparisons revealed significant homologies only with a protein of unknown function named ataxin-2-related protein (A2RP). Interestingly, the polyglutamine tract is not conserved in A2RP (10). Ataxin-2 is a highly basic protein, owing to the high numberof glutamine residues (48). It contains Sml and Sm2 motifs and a high number of proline (14%), serine (13.4%), and glutamine(7.7.%) residues (48). The presence of Sml or Sm2 motifs in proteins involved in RNA splicing suggest a possible role for ataxin-2 in RNA splicing (48). Ataxin-2 is a cytoplasmatic protein expressed at varying levels in a variety of neuronal and nonneuronal tissues, except the lung and kidneys (10,4’7,48). The presence of ataxin-2 in medulla, cerebral cortex, and cerebellum has been shown by RNA expression and immunohistochemical studies, with the highest levelof wild-type ataxin-2 in Purkinje cells (48). Huynh and colleagues could demonstrate expression of both the wild-type and the mutated ataxin-2 inSCA2 brains, with a higher level of immunoreactive ataxin-2 in SCA2 brain tissue than in controls (48). Interestingly, the expanded ataxin-2 was not detected in SCA2 cerebellum, a phenomenon possibly related to the severe loss of Purkinje cells (48). Alternative splicing of exons 10 and 11 does not affect the reading frame contains the full and gives rise to at least three isoforms in the mouse (46): Itype cDNA sequence, whereas type11lacks exon 10, and typeI11 lacks both exons 10 and 11, Interestingly, the latter isoform has not been found in human tissue, whereas type I1 is predominantly found in human cerebellum, and the full transcript is more abundant in human brain and spinal cord (46).The mouse homologue of the SCA2 gene shows 89% identity at the nucleotide and 91% at the amino acid level (47). Interestingly, the murine SCA2 cDNA has no extended

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Burk and

polyglutamine tract, suggesting that the physiological function of SCA2 probably is not dependent on this domain, but on the regions flanking the CAG repeat (47). It has been postulated that unstable CAG expansions within coding regions of the respective genes lead to a deleterious gain of function, causing specific cell death. In other polyglutamine expansion disorders, such as Huntington's disease (HI)), SCA1, and SCA3, the formation of insoluble intranuclear inclusion bodies has been demonstrated exclusively in affected neurons (49-51). In SCA2, the presence of similar inclusion bodies has not yet been established (48). A possible explanation is the small polyglutamine elongation compared with other trinucleotide disorders, the smallest expanded alleles in SCA2 being within the range of normal SCA3 alleles (43,52). That mutated alleles could be transcribed gives support to the hypothesis of a new, pathogenic gainof function. The steep inverse correlation between the age of onset and the CAG number is suggestive of a higher sensitivity to the polyglutamine length in SCA2 compared with other polyglutamine disorders (1 1). The lack of homologies of the different gene products in polyglutamine disorders, and the relation between the repeat length and the age of onset, suggest an important pathogenic role for the polyglutamine expansion per se. On the other hand, the high selectivity of the neurodegenerative process that is in contrast to the widespread expression of the respective genes, the phenotypical differences, and the specificity of critical repeat length of the polyglutamine disorders, point to interacting target proteins as being essential for neurodegeneration and argue against toxicity based on simply the polyglutamine stretch (53). Given this hypothesis, the high clinical inter- and intrafamilial variby polymorphism of the ability inSCA2 (see Sec.V)could possibly be explained interacting proteins, or by differential expression regulation.

C.DiagnosisandGeneticCounseling The expanded CAG repeat can be detected with the polymerase chain reaction (PCR)(10-12). Alleles of more than the thresholdof 33 repeats are clearly in the pathological range. As normal and pathological repeat numbers show an overlap, the gene carrier status and its pathological implications appear difficult to predict in asymptomatic individuals carrying 32-33 repeats. Therefore, predictive testing may be delicate or even impossible in these cases. Genetic counseling should also take into account that transmission bears a high risk for anticipation and juvenile onsetintheoffspring(16,25,32).Additidgal'sequencing may behelpfulin asymptomatic gene carriers, because the absence of CAA codon interspersion points to repeat instability, with possible expansion during gametogenesis and transmission to successive generations (10,ll ,16). Another problem of genetic counseling is the marked variability in the age of onset for a given number of repeats: the ageof onset may differ up to27 years in individuals carrying identical expansions (unpublished observations; 10'25).

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369

W. NEUROPATHOLOGY A.

MacroscopicFindings

Total brainweightisusuallyconsiderablyreduced(9,20,54).Macroscopic changes comprise atrophy of cerebellum, brain stem, spinal cord, and cerebral hemispheres, prominent in the frontal lobes (9,20,30,54) (Table 2).

B. MicroscopicFindings Microscopic examination (seeTable 2) reveals severeloss of Purkinje and granular cells as well as considerable degeneration of the inferior olives, pontine nuclei,andpontocerebellarfibers.Changes of thedentatenucleiaremoderate (9,20,30,54). Flocculus and nodulus seem relatively spared compared with other parts of the cerebellum (20,54). Buettner and colleagues demonstrated marked loss of large and medium-sized neurons in a restricted area of the parapontine reticular formation (PPRF) of SCA2 brains, corresponding to the premotor saccadic burst and omnipause neurons in the PPRF of cat and monkey (55). Burst neurons of the parapontine reticular formation of the brain stem are of critical importance for the generationof saccades (56,57): lossof these neurons or a failure to recruit an appropriate number of them leads to saccade slowing (55). AlthoughDurrandcolleaguesfoundneuronalloss,demyelination,and gliosis in the nuclei of the oculomotor nerve (20), Orozco and Sasaki emphasized preservation of these structures (9,35). Degenerative changes of the sixth nerve have not yet been reported, although data are limited in this field (20,25). Interestingly, there is considerable loss of neurons in the substantia nigra. Parkinsonism is extremely rare among SCA2 individuals of different ethnic origin(9,20,25,29).Degenerativechanges of pallidum,thalamus(dorsomedial nucleus), red nuclei and subthalamic nuclei are limited. The striatum does not undergo major neurodegeneration (9,20,30,54). In most patients, there is degenerationof the dorsal columns and posterior roots (9).The corticospinal tracts are spared, whereas the number of anterior horn cells may be reduced (9,20,30,54). Both, clinical and electrophysiological data, with loss of proprioception, absence of pyramidal tract signs, abnormal sensoryevoked potentials, and normal motor-evoked potentials reflect the pattern of spinal degeneration present in SCA2 (25,4 l,%). Sural nerve biopsies demonstrate loss of myelinated fibers, even in patients asymptomatic for peripheral neuropathy (22,54,59,60). Although several investigators reported gyral atrophy, mainly in the frontotemporal lobes of SCA2 brains (9,20,54), microscopic studies failed to demonstrate loss of neuronal cell somata in the cortex (9,20). A possible explanation is the difficulty of quantitative assessment of neurons in atrophic brain tissue because shrinkagemay pretend an apparently normal densityof neurons. Oligoden-

370 Burk and Dichgans

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droglial cytoplasmatic inclusions that area characteristic feature of multiple sysSCAl brains(62);their tematrophy (MSA) (61)havebeendocumentedin presence has not yet been established in SCA2 (20,30).

Some individuals first comAtaxia of gait is the initial symptom in most patients. plain of other symptoms alone or in combination with cerebellar ataxia, such as dysarthria, dysphagia, intention tremor, muscle cramps, or chorea (20,23-25). a range from 6 months to 78 years The mean age of onset is about 30 years, with (25,37). Juvenile cases have been reportedin several kindreds (19-25). The median latency before becoming wheelchair-bound after disease onset is 14 years. Median survival has been calculated to be 17 years (63). Pisease progression is influenced not only by the underlying mutation, with increasing CAG repeat length resulting ina faster progression, butalso by gender: female SCA2 patients have an increased riskof reaching advanced disease stages and death, suggesting the presence of as yet unidentified biological factors accelerating progression in women (63).

in 1

m

CerebellarSymptoms

Progressiveataxiaanddysarthriarepresenttheuniversalclinicalfeaturesin SCA2: 100% of the patients present with ataxiaof stance, gait, limbs (dysmetria (9,18--20,23,24,29,30,32,35-37,41,45, and dysdiadochokinesis), and dysarthria 5439). Tremor is found to a variable extent in different families and represents a predominant symptom in Cuban and Indian SCA2 kindreds (9,18-20,23,24, 29,30,32,35,36,41,54) (Table 3).

2.

Oculomotor Function

Severesaccadeslowing is a highlycharacteristicfeature of SCA2:several authors have emphasized the prevalence of slow saccades in the majority of SCA2patients (9,18,23,24,29,30,32,35-37,41,54,59): mean velocityfor 20" horizontal saccades is considerably reduced compared with age-matched controls (25) (see Table 3). The presence of severe saccadic slowing correlates well with the degree of pontine involvement in the SCA2 mutation because saccade velocity is closely correlated with pontine size on MRI of ADCA patients (64). Another frequent finding is gaze palsy, usually affecting upward gaze first (see Table 3). Later, combined limitationof lateral and vertical gaze become obvious

Frequency

urk and Dichgans

374 Table 3 Frequency of Clinical Features of 80 SCA2 Patientsa from Nine Kindreds Seen at the Neurology Department of Tubingen from 1992 to 1998

Feature Ataxia of stance, gait, limbs Dysarthria Impaired smooth pursuit Hyporeflexia Impaired proprioception Saccade slowing Facial fasciculations Cramps Urinary incontinence Amyotrophy Gaze palsy Dysphagia Intention tremor Pyramidal signs Dementia Gaze-evoked nystagmus Diplopia Pale discs Myoclonus Dystonia

(%)

100.0 100.0 96.6 86.0 81.2 77.6 73.2 72.2 60.3 57. 1 52.6 52.6 35.l 28.1 25.O 19.3 15.8 7.0 1.7 1.7

“Thepatientsare of German,Austrian,andJordanian tz 15.6 yr descent. The mean age at examination was 46.7 (range 21-80 yr), disease duration of 11.6 tz 10.4 yr and the mean age of onset 34.7 rt: 12.7 yr (range: 10-65 yr).

(9,18,19,24,25), Complaintsof diplopia on lateral gaze are rare (25) Table (see 3). Impairedoptokineticreflexandbroken-upsmoothpursuitarealsocommon findings in SCA:! individuals (25). Gaze-evoked nystagmus, however, is not a typical finding in clinical and electro-oculographic studiesof SCA2 (25,65) (see Table 3).

3.

Cognitive Function

The reported prevalence of dementia in unselected clinical series of SCA2 pa5 to 29% (18,20,25,54). Howtients with different ethnic background ranges from ever, there are also exceptions: Pulst and co-workers reported a SCA2 kindred characterized by predominant dementia anda mild cerebellar syndrome(18). On

Spi~ocerebe~lar Ataxia Type 2

375

the other hand, dementia was reported in only one individual out of 263 Cuban SCA2 subjects (24). In German patients with SCA2, neuropsychological testing revealed dementia in almost25% of cases. In nondemented SCA2 subjects, there was evidence of verbal memory and executive dysfunction. Tests of visuospatial memory and attention werenot significantly impaired in the nondemented SCA2 group compared with controls (66).

4.

PyramidalSigns

Pyramidal tract signs with extensor plantar responses or spasticity are found in fewer than one-third of the patients (9,18-20,23,24,29,30,32,35-37,41,54,59).

5.

PeripheralNerveSigns

Deep tendon reflexes are often diminished or absent in SCA2 individuals (9,1820,23,24,29,30,32,35-37,41,54,59). Hyporeflexia is likely to be contingent on prominent degeneration of sensory axons and posterior roots (see Table 2). Amyotrophy becomes prominent in late stages of the disease (25). Fasciculations of face, tongue, and limb muscles have been described by many investigators in SCA2 individuals (18,20,23,29,32,35,37,41)(see Table 3).

6.

Basal Ganglia Signs

Dystonicandchoreaticmovements may beseeninsomeSCA2kindreds (9,18,20,29,35,41,54). This is rather surprising because striatal structures have been reported to be unaffected in this disorder (20,54). On the other hand, significant lossof neurons of the substantia nigra not is associated with parkinsonian signs in most patients (9,20,24,25,29). The high interfamilial variability points to unknownfactorsinfluencingtheincidence of basalgangliainvolvementin SCA2. In some families, there is additional myoclonus (20,24,32).

7. Other Clinical Features Painful muscle cramps have been reported in SCA2 kindreds of German, Austrian, and Cuban descent (9,23-25,32) (see Table 3). Impaired proprioception is present in most patients (18,23,25,32). Many SCA2 patients complainof dysphagiaandurinaryincontinence(18,20,23,25,32,35,59).“Palediscs”arerarely foundin SCA2 individuals(18,20,24,29,37,41,54);degeneration of theoptic nerve in SCA2 does not result in impaired visual acuity, as it does in Friedreich’s ataxia. The comparative analysis of clinical reports in the field of SCA2 yields a considerable phenotypical variability. Nevertheless, the typical case of SCA2 is characterized by cerebellar ataxia associated with severe saccade slowing, hyporeflexia, and absence of pyramidal tract signs.

37

. omi in ant Ataxias

1.

Patients carrying the SCAl mutation are characterized by a higher incidence of pyramidal tract signs, dysphagia, and pale discs, whereas patients with SCA2 have reduced or absent ankle jerks (37,41,59).MEP abnormalities are more frequent in SCAl than in SCA2 (58,60). SCA3 individuals frequently complainof diplopia and a higher incidence of basal ganglia symptoms (41,67). SCA4 is characterized by peripheral neuropathy. In contrast SCA2, to patients do not have oculomotor abnormalities (68). Persons withSCA5 present with symptoms confined mostlytothecerebellum (7). InSCA6,extracerebellarsymptornsare mostly restricted to mild loss of deep sensation (69-75). SCA7 corresponds to of visual acuity, a ADCAII associated with retinal degeneration, causing loss finding that has not been reported in SCA2 (24,25,76).

2.

Recessive Ataxias with Slow Saccades

There have been several reports on cerebellar ataxia with slow eye movements of autosomal recessive inheritance (77,78).The onset is usually during the first decade. Cerebellar symptoms are associated with dementia and mixed sensory neuropathy. Imaging studies show atrophy of cerebellar and brain stem structures (78). Recessive ataxia with slow saccades cannot be solely distinguished on its different mode of inheritance, but is characterized by an earlier onset and a more benign course, with less disability and longer survival.

Sporadic Ataxia

3.

There have been several reports SCA2 on inpatients with negative family history (16,33). Clinical features, such as the presenceof saccade slowing, or dementia, are suggestive of SCA2, even in the absence of a positive family history (64). Molecular genetic testing is, therefore, recommended in all spoardic cerebellar patients who do not have clinical features of multiple system atrophy and in whom a symptomatic case of ataxia is not evident.

. ies Imaging studies show atrophy of cerebellar structures (22,30,41). In most patients, there is additional shrinkage of brain stem, middle cerebellar peduncles, andmedulla (19,20,22,30,31,35,36,41760)(Fig. 2). Thus,MRIfindingsare l), Quantitative imcompatible with olivopontocerebellar atrophy (OPCA) (25,4

377

aging studies show that volume reduction is more pronounced in the cerebellar hemipheres than in the vermis (41,79). In correspondence with neuropathological findings, volumetric studies of caudate and putamina1 structures failed to establish any significant changes in SCA2 subjects compared with controls (79). Atrophyof the cervical spinal cord is a common feature in SCA2 (22,41). Volumetric investigations of corticalstructureshavenotyetbeenperformed, but semiquantitative assessment of the frontal lobe frequently demonstrates atrophic changes (35; and unpublished observations).

1. Nerve Conduction Studies Nerve conduction studies showa sensory neuropathyof the axonal type, with reduced nerve action potentials and normal or slightly reduced nerve conduction loss of sensoryaxonsinmostpatients velocitiespointingtoprogressive (22,25,37,58,60). Motor compound muscle action potentials of the tibial nerve are usually noma1 in SCA2 (22,58). In some patients, motor nerve conduction velocity may be delayed (25).

2.

Evoked Potentials

Cortical-evoked potentials after stimulation of the tibial nerve (SEP) are pathological in 70-100% of SCA2 individuals, with delayed or absent P40 responses (25,58,60), thus reflecting degeneration of the dorsal columns associated with the SCA2 mutation (9,20). Visual-evoked potentials (VEP) are preserved in the majority of patients (25,58) whereasbrain. stem auditory evoked-potentials (BAEPs) show abnormalities, with loss of waves or increased interpeak latencies in 5080% of the patients (22,58,60). Because detailed neuropathological studies of the cochlear nerveand auditory pathways have not been performed in SCA2, is not it possible to precisely define the morphological substrate abnormality. In accordance with neuropathological studies demonstrating preservationof the pyramidal tract (9), motor-evoked potentials (MEPs) after transcranial magnetic stimulation are normal in '75-90% of SCA2 patients (22,25,58,60). In the remaining individuals, responses may be delayed or absent (25,58).

VII.

T

Because the metabolic defects of SCA2 are unknown,a rational therapy is not yet a available. All patients should receive physiotherapy and speech therapy on

T1-weighted MRI of infratentorialbrainstructuresshowingtheposterior fossa in (a) the midsagittal plane, (b) parasagittal plane.

(c) axial images at the level of the middle cerebellar peduncles, and (d) inferior olivesof a 32-year-old femaleSCA2 patient. Note (a) marked shrinkage of cerebellar vermis and pons, (b) hemispheres, (c) rniddle cerebellar peduncles, and (d) medulla.

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regular basis. In our experience, symptomatic treatment of cerebellar ataxia with SCA2 mutation. In “antiataxic” drugs is not effective in patients carrying the some patients, episodesof sustained depression require antidepressant treatment. It is unclear to what extent depression is a symptomof an underlying degenerative disease or a reaction to the disease.

REFERENCES 1. Greenfield J. TheSpino-cerebellarDegenerations.Springfield,IL:CharlesC

Thomas,1954. 2. HardingAE.Theclinicalfeaturesandclassificationofthelateonsetautosomal dominant cerebellar ataxias.A study of 11 families, including descendants of “the Drew family of Walworth.” Brain 1982; 105:l-28. 3. Zoghbi HY, Jodice C, Sandkuijl LA, etal. The gene for autosomal dominant spinocerebellar ataxia(SCAl) maps telomeric to the HLA complex and is closely linked to the D6S89 locus in three large kindreds. Am J Hum Genet 1991; 49:23-30. 4. Gispert S, Twells R, Orozco G, et al. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23-24.1. Nat Genet 1993; 4:295-299. 5. Stevanin G, Le Guern E, Ravise N, et al.A third locus for autosomal dominant cerebellar ataxia type I maps to chromosome 14q24.3-qter: evidence for the existence of a fourth locus. Am J Hum Genet 1994; 54: 11-20. 6. Flanigan K, GardnerK,Alderson K, et al. Autosomaldominantspinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 1996; 59:392-399. 7. Ranum LP, Schut LJ, Lundgren JK,On HT, Livingston DM. Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet 1994; 8:280-284. 8. Zhuchenko 0, BaileyJ,Bonnen P, et al. Autosomaldominantcerebellarataxia (SCA6)associatedwithsmallpolyglutamineexpansionsinthealpha,,-voltagedependent calcium channel. Nat Genet 1997; 15:62-69. 9. Orozco G, Estrada R, Perry TL, et al. Dominantly inherited olivopontocerebellar atrophyfromeasternCuba.Clinical,neuropathological,andbiochemicalfindings. J Neurol Sci 1989; 93:37-50. 10. Pulst SN, Nechiporuk A, Nechiporuk T, etal. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 1996; 14:269276. 11. Imbert G, SaudouF, Yvert G, et al. Cloningof the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet 1996; 14:285-29 1. S, et al. Identification of the spinocerebellar ataxia type 12. Sanpei K, Takano H, Igarashi 2geneusingadirectidentificationofrepeatexpansionandcloningtechnique, DIRECT. Nat Genet 1996: 14:277-284.

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13. Gudmundsson K. The prevalence and occurenceof some rare neurological diseases in Iceland. Acta Neurol Scand 1969; 45:114-118. 14. Weatherall DJ. The New Genetics and Clinical Practice. Oxford: Oxford University Press,1984. 15. Polo JM, Calleja J, Combanos0, Berciano J. Hereditary ataxias and paraplegias in Cantabria, Spain, An epidemiological and clinical study. Brain 1991; 114:855-866. 16. Riess 0, Laccone FA, Gispert S, et al. SCA2 trinucleotide expansion in German SCA patients. Neurogenetics 1997; 1:59-64. 17. PrattRTC.TheGeneticsofNeurologicalDisorders.Oxford:OxfordUniversity Press,1967. 18. Cancel G, DurrA, Didierjean 0, et al. Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families. Hum Mol Genet 1997; 6:709-715. a Tunisian of fam19. Belal S, Cancel G, Stevanin G, et al. Clinical and genetic analysis ily with autosomal dominant cerebellar ataxia type l linked to the SCA2 locus. Neurology 1994; 44: 1423-1426. 20. Durr A, Smadja D, Cancel G, et al. Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families. Brain 1995; 118:1573-1581. 21. Durr A, Brice A,Lepage Lezin A,et al.Autosomal dominant cerebellar ataxia type I linked to chromosome 12q (SCA2: spinocerebellar ataxia type 2). Clin Neurosci 1995; 3~12-16. 22. Filla A, De Michele G, Banfi S, et al. Has spinocerebellar ataxia type 2 a distinct phenotype? Genetic and clinical study an ofItalian family. Neurology 1995; 45:793796. 23. Lopes Cendes I, Andermann E, AttigE, et al. Confirmation of the SCA-2 locus as an alternative locus for dominantly inherited spinocerebellar ataxias and refinement of the candidate region. Am J Hum Genet 1994; 54:774-781. 24. OrozcoDiazG,NodarseFleites A, CordovesSagaz R, AuburgerG.Autosomal dominant cerebellar ataxia: clinical analysis of 263 patients from a homogeneous population in Holguin, Cuba. Neurology 1990; 40: 1369-1375. 25. Burk K, Stevanin G, Didierjean0, et al. Clinical and genetic analysis of three German kindreds with autosomal dominant cerebellar ataxia type I linked to the SCA2 locus. J Neurol 1997; 244:256-261. 26. Wadia NH. A common variety of hereditary ataxia in India. In: Lechtenberg R, ed. Handbook of Cerebellar Diseases. New York: Marcel Dekker, 1993:373-388. 27. Lopes Cendes I, Teive HG, Calcagnotto ME, et al. Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA)ain large group of Brazilian patients. Arq Neuropsiquiatr 1997; 55:519-529. 28. Tang B, Wang D, Xia J. SCA1, SCA2, MJD/SCA3 (CAG)n mutation detection and analysis in patients with hereditary spinocerebellar ataxia from Chinese families. Chung Hua I Hsueh Tsa Chih 1997; 77:819-822. 29. Zhou YX, Wang GX, Tang BS, et al. Spinocerebellar ataxia type 2 in China: molecular analysis and genotype-phenotype correlation in nine families. Neurology 1998; 51:595-598. 30. Adams C, Starkman S, Pulst SM. Clinical and molecular analysis of a pedigree of

382

Burk and Dichgans

southernItalianancestrywithspinocerebellarataxiatype2.Neurology1997; 49~1163-1166. 31. Lorenzetti D, BohlegaS, Zoghbi HY. The expansion of the CAG repeat in ataxin-2 is a frequent causeof autosomal dominant spinocerebellar ataxia. Neurology 1997; 49~1009-1013. 32. Schols L, Gispert S, Vorgerd M, et al. Spinocerebellar ataxia type2. Genotype and phenotype in German kindreds. Arch Neurol 1997; 54:1073-1080. 33. Cancel G, Dun A, Didierjean 0, et al. Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families. Hum Mol Genet 1997; 6:709-715. 34. Geschwind DH, Perlman S, Figueroa CP, Treiman LJ, Pulst SM. The prevalence and wide clinical spectrumof the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia. Am J Hum Genet 1997; 60:842850.

35. Sasakj H, Fukazawa T, Wakisaka A, et al. Central phenotype and related varietiesof spinocerebellar ataxia 2 (SCA2):a clinical and genetic study with a pedigree in the Japanese. J Neurol Sci 1996; 144: 176-181. 36. Mizushima K, Watanabe M, Abe K, et al. Analysis of spinocerebellar ataxia type 2 in Gunma Prefecturein Japan: CAG trinucleotide expansion and clinical characteristics. J Neurol Sci 1998; 156:180-185. 37. Giunti P, Sabbadini G, Sweeney MG, et al. The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates. Brain 1998; 121:459-467. 38. Leggo J, Dalton A, Morrison PJ, et al. Analysisof spinocerebellar ataxia types l, 2, 3, and 6, dentatorubral-pallidoluysian atrophy, and Friedreich’s ataxia genes in spinocerebellar ataxia patients in the UK. J Med Genet 1997; 34:982-985. 39. Silveira I, Coutinho P, Masciel P, et al. Analysisof SCA1, DRPLA, MJD, SCA2, and SCA6GAG repeatsin48Portugueseataxiafamilies. AmJMedGenet1998; 81:134-138. 40. Gispert S, Lunkes A, Santos N, et al. Localization of the candidate gene D-amino acid oxidase outside the refined l-CMregion of spinocerebellar ataxia 2 [letter].Am J Hum Genet 1995; 57:972-975. 41. Burk K, Abele M, Fetter M, etal. Autosomal dominant cerebellar ataxia type1clinicalfeaturesandMRIinfamilieswith SCAl, SCA2andSCA3.Brain1996; 119:1497-1505. 42. Nechiporuk T, Nechiporuk A, Sahba S, et al. A high-resolution PAC and BAC map of the SCA2 region. Genomics 1997; 44:321-329. 43. Didierjean 0, Cancel G, Stevanin G, et al. Linkage disequilibrium at the SCA2 locus. J Med Genet 1999; 36:415-417. 44. Gacy AM, Goellner G, Juranic N, Macura S, McMurray CT. Trinucleotide repeats that expand in human disease form stable hairpin structures in vitro. Cell 1995; 81 :533--540. 45. Pulst SM, Nechiporuk A, Starhan S. Anticipation in spinocerebellar ataxia type 2 [letter]. Nat Genet 1993; 5:8-30. 46. Sahba S, Nechiporuk A, Figueroa KP, Nechiporuk T, Pulst SM. Genomic structure ofthehumangeneforspinocerebellarataxiatype2(SCA2)onchromosome 12q24.1. Genomics 1998; 47:359-364.

Ataxia Spinocerebellar

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48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64.

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383

Nechiporuk T, Huynh DP, Figueroa K, Sahba S, Nechiporuk A, Pulst SM. The mouse SCA2 gene: cDNA sequence, alternative splicing and protein expression. Hum Mol Genet 1998; 7:1301-1309. Huynh DP, Del Bigio MR,H0 DH, Pulst SM. Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer’s disease and spinocerebellar ataxia 2. Ann Neurol 1999; 45:232-241. Davies SW, Turmaine M, Cozens BA, et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997; 90:537-548. Paulson HL, Perez MK, Trottier U, et al. Intranuclear inclusionsof expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 1997; 19:333-344. Cummings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr HT, Zoghbi HY. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 1998; 19:148-154. Kawaguchi Y, Okamoto T, Taniwaki M, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 1994; 8:221-228. Matilla A, Koshy BT, Cummings CJ, Isobe T, Orr HT? Zoghbi HY. The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-l. Nature 1997; 389:974978. Wadia NH. A variety of olivopontocerebellar atrophy distinguished by slow eye movements and peripheral neuropathy. Adv Neurol 1984; 41 :149-177. of Buettner-Ennever JA, Wadia NH, Sakai H, Schwendemann G. Neuroanatomy oculomotor structures in olivopontocerebellar atrophy (OPCA) patients with slow saccades [abstr]. J Neurol 1985; 232 (suppl):285. Luschei ES, Fuchs AF. Activity of brainstem neurons during eye movements of alert monkeys. J Neurophysiol 1972; 35:445-461. Keller E. Participation of the medial reticular formation in eye movement generation in monkey. J Neurophysiol 1974; 37:316-332. Abele M, Burk K, Andres F, et al. Autosomal dominant cerebellar ataxia type 1. Nerve conduction and evoked potential studies in families with SCA1, SCA2, and SCA3. Brain 1997; 120:2141-2148. Filla A, De Michele G, Campanella G, et al. Autosomal dominant cerebellar ataxia type I. Clinical and molecular study in 36 Italian families including a comparison between SCAl and SCA2 phenotypes. J Neurol Sci 1996; 142:140-147. Perretti A, Santoro L, Lanzillo B, et al. Autosomal dominant cerebellar ataxia type I: multimodal electrophysiological study and comparison between SCAl and SCA2 patients. J Neurol Sci 1996; 142:45-53. Papp MI, Kahn JE, Lantos PL. Glial cytoplasmatic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 1989; 94:74-100. Gilrndn S, Sima AA, JunckL, et al. Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions. Ann Neurol 1996; 39:241-255. Klockgether T, Ludtke R, Kramer B, al. et The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain 1998; 121:589-600. Burk K, Fetter M, Skalej M, et al. Saccade velocity in idiopathic and autosomal dominant cerebellar ataxia. J Neurol Neurosurg Psychiatry 1997; 62:662-664.

384

Burk and Dichgans

65. Burk K, Fetter M, AbeleM, et al. Autosomal dominant cerebellar ataxia type I: oculomotorabnormalitiesinfamilieswithSCA1,SCA2andSCA3.JNeurol1999; 246:789-797. 66. BurkK,GlobasC,Bosch S, et al. Cognitive deficits in spinocerebellar ataxia 2 (SCA2). Brain 1999; 122:769-777. 67. Sequeiros J, Coutinho P. Epidemiology and clinical aspectsof Machado-Joseph disease. Adv Neurol 1993; 61:139-153. 68. Gardner K, AldersonK, Galster B, et al.Autosomal dominant spinocerebellar ataxia: clinical description of a distinct hereditary ataxia and genetic localization to chromosome 16 (SCA4) in a Utah kindred. Neurology 1994; 44:A 361. 69. Ceschwind DH, PerlmanS, Figueroa KP, Karrim J, Baloh RW, Pulst SM. Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype correlations [see comments]. Neurology 1997; 49: 1247-1251. 70. Ikeuchi T, Takano H, Koide R, et al. Spinocerebellar ataxia type 6: CAG repeat expansion in alpha,, voltage-dependent calcium channel gene and clinical variations in Japanese population. Ann Neurol 1997;42:879--884. 71. Matsumura R, Futamura N, Fujimoto Y, et al. Spinocerebellar ataxia type 6. Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology 1997; 49:1238-1243. 72. Sasaki H, Kojima H, Yabe1, et al. Neuropathological and molecular studies of spinocerebellar ataxia type 6 (SCA6). Acta Neuropath01 (Berl) 1998; 95:199-204. 73. Schols L, Kruger R, Amoiridis G, PrzuntekH, Epplen .TT,Riess 0. Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds. J Neurol Neurosurg Psychiatry 1998; 6457-73. 74. Watanabe H, Tanaka F, MatsumotoM, et al.Frequency analysisof autosomal dominant cerebellar ataxias in Japanese patients and clinical characterization of spinocerebellar ataxia type 6. Clin Genet 1998; 53:13-19. 75. Stevanin G,Dun A,David G, et al. Clinical and molecular features of spinocerebellar ataxia type 6. Neurology 1997; 49:1243-1246. 76. Johansson J, Forsgren L, Sandgren 0, Brice A, Holmgren G, HolmbergM.Expanded CAG repeats in Swedish spinocerebellar ataxia type 7 (SCA7) patients: effect ofCAG repeat length on the clinical manifestation. Hum Mol Genet 1998; 7:171-176. 77. a1 Din AS, a1 Kurdi A, a1 Salem MK, et al. Autosomal recessive ataxia, slow eye movements, dementia and extrapyramidal disturbances. J Neurol Sci 1990; 96: 191205. 78. Najim a1 Din AS, a1Kurdi A,Dasouki M,et al. Autosomal recessive ataxia, slow eye movements and psychomotor retardation. J Neurol Sci 1994; 124:61-66. 79. Klockgether T, Skalej M, Wedekind D, et al. Autosomal dominant cerebellar ataxia type I. MRI-based volumetry of posterior fossa structures and basal ganglia in spinocerebellar ataxia types l, 2 and 3. Brain 1998; 121:1687-1693.

Spinocerebellar Ataxia Type3 Machado-Joseph Disease Ludger Schols St. Josef Hospital, Bochum, Germany

Henry Paulson University of Iowa College of ~edicine,Iowa Citx Iowa

Olaf Riess University of Rostock, Rostock, Germany INTRODUCTION I,

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11. EPIDEMIOLOGY

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111. MOLECULAR PATHOGENESIS A. ChromosomalMappingandCloningthe MJDl/SCA3 Gene B. Instability of the Expanded CAG Repeat, Anticipation, and Mosaicism of the CAG C. Gender Effects and Transmission Distortion Repeat D. NuclearInclusionBodies E. TheMJDl GeneProduct E Expanded Glutamine: A Dominant Cytotoxic Domain of SCA3NJD G.TransgenicModels

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IV. NEUROPATHOLOGY

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V.

CLINICAL FEiATURES A. GeneralRemarks B. ClinicalSubphenotypes C. PhenotypicSpectrum D.Genotype-PhenotypeRelation E. Course of theDisease

387 390 390 39 l 392 394 396

398 398 398 402 406 407 385

VI.ANCILLARYTESTS A. Neuroimaging Electrophysiology B. C.MolecularGeneticDiagnosisandGeneticCounseling VII. MANAGEMENT

408 408 410 411 414 416

Machado-Joseph diseasewasoriginallydescribedinthreelargefamilies of Azorean-Portugueseancestry.In1972,Nakanoandco-workersdescribeda dominantly inherited disease in the““Machado family” characterized by progressive cerebellar symptoms and distal peripheral neuropathy, and beginning in the fifth decade (l). In the same year, Woods and Schaumburg reported autosomal dominant nigrospinodentatal degeneration in the ““Thomas family,” characterized by gait ataxia, external ophthalmoplegia, facial and lingual fasciculations, spasticity and rigidity, and beginning between the third and fifth decade (2). In 19’76, Rosenberg et al. described dominantly inherited striatonigral degeneration in the “Joseph family,” manifesting with gait ataxia, dystonia, parkinsonism, spasticity, and oculomotor disturbance, beginning in the second or third decade (3). Romanul and co-workers (4) as well as Coutinho and Andrade (5) observed families in whom phenotypic features from all three families were found within one family, supporting the conceptof a single genetic entityof Azorean disease, varying in its clinical and neuropathological expression. Azorean disease has since been described in families from Portugal, Spain, Brazil, Japan, China, and India. In considerationof these non-Azorean families and with respectto two of the original families, the disease has been referred toMachado-Joseph as disease

(MJD). Because MJD was later shown to be caused by the same mutation as spinocerebellar ataxia type 3 (SCA3), the abbreviation SCA3IMJD isnow used for the disease.

SCA3IMJD was first described in families of Portuguese-Azorean origin. The hypothesis that its current worldwide distribution resulted from the spread of an original founder mutation has been raised. Previous studies have suggested that the original mutation may have occurred more than five centuries ago in a

7 SephardicJewishsettlementintheisolatednortheasternregion of Portugal, Later, the disease might have spread to the Azores and from there to the United States, Canada, Brazil, Japan, China, and India (6). This possibility can be tested by analysis of closely linked DNA markers and shared haplotypes. These studies provided tentative evidence for at least two haplotypes at the SCA3 gene locus in the Azores, suggesting two or more ancestral mutations for SCA3/MJD and disproving the “Portuguese Navigator” hypothesis(7-9). In addition, several different haplotypes were found in patients from various geographic origins, indicating that multiple ancestral mutations account for the worldwide distribution of SCA3MJD (7). Interestingly, haplotype analysis also revealed that expansion mutations occurred on specific “disease chromosomes,” with relatively large normal CAG repeats of more than 33 units that tend to expand during parental transmission. Evidence supporting this view is that populations with the highest prevalence of SCA31MJD also appear to have the highest prevalence of large normal alleles (10). Although a single founder mutation clearly didnot give rise to the worldwide distribution of SCA3/MJD, these studies suggest that a founder effect does underly different frequencies of the SCA3MJD mutation in geographically distinct populations. Comparing the published frequencies of the SCA3/MJD mutation, one has to be cautious, because these studies used different criteria for the selection of the patients (e.g., some used all spinocerebellar ataxia pedigrees with autosomal dominant inheritance, whereas others restricted inclusion to ADCA type I families, according to the nomenclatureof Harding ( l 1). Moreover, there may be significant regional differences within each country, as has been shown for Germany and Japan. For instance, SCA3MJD frequencies in Germany var(18%), central (36%), and middle-west (North ied between centers from the north Rhine Westfalia) (45%) regions of the country (Table 1) (12). For immigrants of Portuguese ancestry, epidemiological data are available in Massachusetts, Rhode Island, and California. In this subpopulation, the prevalence of SCA3MJD is calculated as 1 :4000 and the frequency of heterozygous gene carriers is estimated as 1:1500. The highest prevalence known is, as expected, on the small Azorean island of Flores, where prevalence is 1 :140 and gene carriers are as frequent asl :48. In these populations strong founder effects areobserved,leadingtogenefrequenciessubstantiallyhigherthaninlessisolated regions (6).

nin MJD was first assigned to the long armof chromosome 14 (14q24.3-q32)by genetic linkage analysis in Japanese families (13), which was later confirmed for

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Table 1 Frequency of the SCA3 Mutation in Different Populations (%)

Frequency Population British Isles French Germany Germany Eastern Europe Northwest European Portuguese Japan Japan North African African American

S 30 39 36

0

l1 84 34

39

17 7s

Total number of tested Ref. individuals 38 87 28

66 6

28 38 101 64 12 12

101 60

101 12 101 101 102

103

104 60

101

Azorean pedigrees (14). Subsequently, a third locus for spinocerebellar ataxia (SCA3) was mapped to the same chromosomal region in French families (15). As MJD presented clinically with anticipation, Kalsizuka and colleagues specifically searched for cDNAs containing CAG repeats, They identified one cDNA, MJD1, that mapped to human chromosome 14q32.1, the same region containing theMJD locus (16).One of the cDNAs,MJDla, consists of 1776 base pairs (bp) and encodes a novel protein of 359 amino acids. Screening of a human genomic phage library identified three related genes, MJD2, MJD3, and MJD4, which mapped to 8923, 14q21, and Xp22.1, respectively (16). Of these, only MJD2 contains CAGCCG hexad repeats. Analyzing the CAG repeatin 12 MJD patients Kawaguchi and co-workers (16) identified expansions between 68 and 79 repeats. In control individuals the repeat sizes ranged from 13 to 36 units (Fig. 1). The expanded repeats clearly segregated with disease in affected families, indicating that the expanded CAG repeats of the MJD1 gene were causative for MJD. Subsequently, CAG expansions in the MJD1 gene were identified in SCA3 patients (17,18) demonstrating that MJD andSCA3 are allelic disorders.The smallest expanded repeat published thus far consists of 56 CAGs and the longest is 84 CAG (19). TheCAGrepeatharborstwovariantsequences,CAAandAAG,at three positions and is predicted to be translated into a polyglutamine tract in theCOOH-terminalportion of theopen-readingframe(Fig. 2). Patientsand controls contained the two variants at precisely the first and the second position. The third CAA-CAG substitutionwasfoundinabout10% of healthy individuals (1 6).

389 Normal CAG repeat size

500

Expanded CAG repeat size

450

Q00 350 300 250

200 l50

14 12 10

100

8 6 4 2

50

1:3 15 17 19

21 23 252729

31 33 35 37 57 59

61 63 65 67 69

71 73 75 77 79

81 83 85

Figure 1 Allele distribution in the MJDl gene: 1534 normal and 106 expanded CAG repeats of a white population were included. Note that different scales are used for allele frequency (y-axis) in normal and expanded alleles.

m

Figure 2 The MJDl geneproduct,ataxin-3:Ataxin-3isasmallhydrophilicprotein with a polymorphic glutamine repeat (Q) near the COOH-terminus. The published sequence is 359 amino acids, assuming 26 glutamine residues in the repeat. A predicted coiled-coil domain lies upstream from the glutamine repeat. Thearrow indicates a polymorphism (l l 18 A+C )that alters the published stop codon, extending the protein 16 by amino acids (black segment). A different COOH-terminus (dark gray) generated by alternative splicing is indicated below the open-reading frame (light gray).

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Instability of theexpandedpolyglutaminetractduringcelldivisionleadsto changes in repeat length. These can be either contractionsof expansions, but on average, there is a net gain in repeat length in younger generations. Clinically, successive generations tend to develop earlier and more severe symptoms than their affected parents. This phenomenon has been described as anticipation. All of of the expanded alleles seem to have a (CAG)nC polymorphism at the 3’ end the repeat, whereas both (CAG)nC and (CAG)nG were seen in normal alleles. Furthemore, innormalalleles,theCAGrepeattractwassignificantly longer in (CAG)nC than in (CAG)nG, suggesting that the (CAG)nC configuration is related to repeat instabilityof the MJDl gene (20,21). Most interestingly, intergenerational instability of the expanded CAG repeat is strongly affected by the genotype of the normal CAG repeat of the MJDl gene (22). For disease alleles of paternal origin, when the 3’ polymorphism is (CAG)n-CGG on the expanded allele and (CAG)n-GGG on the normal allele, there is a 75-fold increase in intergenerational instabilityof the repeat, often leading to a large intergenerational change in the number of CAG repeats during paternal transmission (22). Instability, however, can also occur in different cells withinan individual, leading to mosaicism of the CAG repeat in different tissues. Discussing the influence of CAG repeats on the age at onset one should always keep in mind that GAG repeats are generally estimated by the analysis of blood samples. Mosaicism has also been observed for the brain (23).

In SCA3/MJD, a gender-specific effect on the age at onset has been described, with brothers developing first symptoms about10 years earlier than sisters, even with the same expanded CAG length. Furthermore, dosage effects of the expanded CAG repeat might influence the age of onset, as homozygosity of the mutationexhibitsadditiveeffects(24,25).Additionalstudies of SCA3/MJD, however, suggest that gender and gene dosage may not have a significant effect on the age of onset (26,27). It has been proposed that the expanded CAG repeat accounts for approximately 60% of the variance in the age at onset (26-28). Clearly, age at onset in SCA3MJD is influenced by other genetic or environmental factors independent of CAG repeat length (29).In contrast to Huntington’s disease, sexof the transmitting parent appears to have only a weals influence in SCA31MJD (29,30). A gender effectof the transmitting parent is evident, however, in transmission distortion of the mendelian l :l segregation of affected versus unaffected

offsprings in SCA3MJD families. In Geman families, a gender effect has been found, with preferential transmission of the expanded allele in maternal transmittance (30), whereas in Japanese NIJD families a distortion has been observed in paternal transmittance (31). The biological nature of this phenomenon remains uncertain. A selective advantage of germ cells harboring the elongated protein during maturation is one of several possible reasons. Interestingly, even for the normal CAG repeats, the smaller CAG allele was inherited preferentially in female meiosis (32).

ies Until recently there were no distinguishing pathological hallmarks of SCA3/ MJD. Now, however, it is clear that the disease protein ataxin-3f o m s spherical inclusion bodies within the nuclei of neurons (Fig. 3) (33,34). These neuronal intranuclear inclusions (NI) are preferentially found in neurons from susceptible brain regions. In SCA3MJD they are particularly abundant in pontine neurons, a known target of disease, but they are also observed less frequently in other affectedregions,suchascranialnervemotornuclei,substantianigra,dentate nucleus, and anterior horn cells. They have not been observed in unaffected regions, such as cerebral and cerebellar cortex. The presence of NI in susceptible

Figure 3 Immunohistochemical analysis of nuclear inclusions (NI) in SCA3MJD: NI (B) ubiquitin, in pontine neurons from SCA3/MJD brain stain positively for (A) ataxin-3, and (C) the proteasome. NI vary in size (up to half the diameter of the nucleus) and number (one to three per cell). Arrows indicate NI, and arrowheads indicate nucleoli. Tissue section shown in a was lightly counterstained with hematoxylin; those in b and c were not.

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brain regions implies thatthey may contribute to the disease process. The subcellular localizationof NI suggests that the nucleus is a primaryofsite pathogenesis, a view supported by recent studies of other glutamine-repeat diseases (35,36) NI appear to be a common pathological hallmarkof glutamine-repeat diseases, having now been observed in at least six diseases and many transgenic Allavailable evidence suggests that the mutant models (reviewed in Refs. 37,38). protein in NI is misfolded and aggregated into essentially insoluble complexes. Components of the cellular machinery that recognizes and eliminates misfolded polypeptide redistribute into NI, including ubiquitin, the proteasome complex, and certain heat-shock proteins or chaperonins (39,40). Studies of ataxin-3 further indicate that even normal glutamine-repeat-containing proteins may be recruitedinto NI (41).Forexample,theubiquitoustranscriptionfactor TATAbinding protein, which has its own glutamine tract, is sequestered in NI in SCA3/ MJD brain (41). Given findings such as these, it is tempting to speculate that NI are central to the pathogenesis of glutamine-repeat diseases. At this point, however, it is still unclear whether NI are pathogenic entities, neutral bystanders in the disease process, or even, perhaps, a result of the neuron’s attempt to “package” potentially harmful protein into inert, nontoxic aggregates (for discussion see Ref. 42). Similar ataxin-3 inclusions have been observed in cell-based modmodel of SCA3/MJD (33,43,44). Studiesof these models els and in Drosophila a may help determine whether NI contribute to pathogenesis (see animal models). Even before the discovery of NI, abnormal ubiquitin staining had already been noted inSCA31MJD. In 1993, Suenaga and colleagues (45) noted skein-like ubiquitin-positive deposits in the cytoplasmof anterior horn cells and brain stem motor neurons. This is an important point, as it suggests that aggregatesof mutant protein are not limited to the nucleus.A systematic search for ubiquitin abnormalities in neuronal processes may provide insight into whether cytoplasmic aggregation contributes to the axonal neuropathy of SCA3/NIJD.

The protein encoded by the MJD1 gene is, with 359 amino acids, the smallest of 2). Called ataxin-3 or NIJDlp, this the glutamine-repeat disease proteins (see Fig. approximately 42-kDa protein is less than one-eighth theofsize the Huntington’s disease protein huntingtin, making it particularly amenable to studies employing a variety of experimental techniques.The size of ataxin-3 varies depending on at least three factors: the length of the glutamine repeat, a single nucleotide polymorphism situated within the stop codon, and an alternative COOH-terminus generated by differential splicing. The polymorphism (nucleotide I1 18 A-C) changes the originally published stop codon to a tyrosine residue, extending the protein by 16 amino acids (16). In rat and human, alternative splicing has been ’exon identified that replaces the last 17 amino acids with a 3 that encodes a novel COOH-terminus of 30 amino acids (34,46).

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Type 3

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Currently, it is unknown whether the polymorphic or splice variants alter the properties of the protein significantly. Both the A and C polymorphisms areassociatedwithdisease,andtheCOOH-terminalsplicevariantclearlyis present in NI of diseased brain (34). Whether the COOH-terminal splice variant is preferentiallyexpressedindiseasedneuronsis an important,unanswered 5' splice variants of the question. Although there is evidence for other more ataxin-3 protein (16,47), the predominant brain isoform of ataxin-3 is the fulllength protein. Very little is known about ataxin-3 and its function. It is a ubiquitous intracellular protein found in every tissue and cell line examined (47-49). A hydrophilic protein, ataxin-3 does not have significant homology with other proteins of knownfunction.Apredicted coiled-coil domainliesbeforethe glutaminerepeatinataxin-3. Coiled-coil structuresoftenmediate proteinprotein interactions, but whether it serves this purpose in ataxin-3 is unknown. Although ataxin-3 is highly conserved between rat and human, with an overall sequence identity of 88%, the rat protein lacks a pure glutamine repeat; instead it has only five glutamine residues interrupted by a histidine residue. This suggests that a homopolymeric glutamine repeat may be dispensible for ataxin-3 function. Mutant ataxin-3 is widely expressed in human brain, both in regions affected by disease and in regions that are typically spared [Fig. 4; also (34, 47)]. Asinotherglutamine-repeatdiseases,theremustbecell-specificfactorsin

Figure 4 Expression of Ataxin-3 in diseased brain: The immunoblot of various brain regions stained with antiataxin-3 antiserum shows wide expression of both normal and expanded ataxin-3, including regions typically affected (pallidurn and pons) and unaffected (cortex and putamen). Controls are an SCA3MJD lymphoblastoid cell line with alleles of (left) 28 and 68 repeats, and (right) the human neuronal cell line NT2. The glutamine repeat causes ataxin-3 to electrophorese anomalously through the gel,anwith apparent molecular weight greater than its actual molecular weight.

SCA31MJD that help determine the selective vulnerabiliy of certain brain regions despite widespread brain expression of the disease protein. The subcellular localization of ataxin-3 is complex and somewhat controversial. Several studies have shownp r e d o ~ n a n t l ycytoplasmic staining in most neuronsandcelllines,whereasotherstudieshaverevealednuclearstaining (33,34,48,49). The best interpretation of all available data is that this relatively small protein is capable of transport into the nucleus, and that its subcellular localization (nuclear, cytoplasmic, or both) is regulated by still unknown cellular mechanisms. Nuclear localization is likely to be critical to disease pathogenesis, and thus it will be important to identify the factors regulating ataxin-3’s nuclear versus cytoplasmic localization.

Several unifying featuresof glutamine-repeat diseases offer clues to the molecular basis of disease. First, they are dominantly inherited disorders except SBMA a dominant (an X-linked condition in which disease still probably occurs through mechanism). Second, each disease causes degeneration of select neurons, despite widespread expression of the disease protein in brain and elsewhere. Third, the neurodegenerative process is similar among these diseases, even though the disease proteins are entirely unrelated outside of their glutamine repeats, Finally, longerglutaminerepeatsareincreasinglydeleterioustocells,althoughthe threshold repeat length to cause disease differs for the various disease proteins. Taken together, these features indicate that expansionof the glutamine repeat confers on the disease protein a novel, dominant toxic property. Mounting evidencesuggeststhattheglutaminerepeatisitselftheneurotoxicelement. Unique structural featuresof expanded polyglutamine (50,5l ) presumably cause misfolding of the disease protein, leading to altered protein-protein interactions a and self-aggregation. Although polyglutamine misfolding and aggregation is self-driven process (52), it must be influenced by the particular protein in which theglutaminetractresides. The surroundingproteincontext may determine where in the brain, and what to degree, the toxic propertiesof expanded polyglutamine are manifested. The first evidence that expanded polyglutamine is itself the toxic element came from studiesof ataxin-3. Ikeda and colleagues(43) demonstrated that a truncated, expanded polyglutamine fragment of ataxin-3 causes Purkinje cell degeneration in transgenic mice, whereas full-length ataxin-3 protein with an expanded repeat had no effect. Additional results in transfected cells indicated that expanded polyglutamine forms insoluble aggregates that are toxic to cells (Fig. 5). Subsequent studies with ataxin-3 (33,41) and other glutaminerepeat disease proteins have confirmed that expanded polyglutamine fragments are potent cytotoxic and aggregation-prone factors, and that the full-length protein may mask the inherent toxicity of the polyglutamine domain.

39

Figure 5 An ataxin-3 fragment with expanded polyglutamine forms aggregates in transfected cells: In cos-7 cells, an ataxin-3 protein fragment containing a repeat of 78 glutamine residues forms (left) intranuclear aggregates, whereas (right) a nonpathogenic fragment with 27 residues does not.

A possible unifying disease mechanism for glutamine-repeat diseases is polyglutamine-containing limitedproteolysis of thediseaseprotein,yielding fragments that are more prone to misfold and aggregate than are the full-length proteins. Experimental evidence is consistent with this view: isolated, expanded polyglutamine fragments-whether from ataxin-3 or other proteins-are prone to aggregate, whereas the full-length protein is much less likely to do so. In vitro studies with ataxin-3 further suggest that a pathological polyglutamine fragment may serve as the seed or catalyst for glutamine-mediated aggregationof the full protein (33,41). However, we stress that there isno direct evidence that ataxin-3 proteolysis occurs in human disease. Proteolytic fragments of ataxin-3 have not yet been identified in disease tissue. Moreover, recent evidence suggests that full-lengthataxin-3canaggregate,providedthatithasbeentargeted to the nucleus (40). Whatfactorsdetermineselectivevulnerabilityinglutamine-repeatdiseases? One obvious factor is the expression level of the disease protein. Neurons expressing the highest levels may be predisposedto neurodegeneration. Ataxin-3, for example, seems to be more abundant in brain stem neurons, a major target of disease,thaninstriatalneurons,whicharerelativelysparedindisease.Cell

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specificity may also be determined by interacting proteins that modify or modulate the behaviorof the disease protein. Such interacting proteins have been identified for huntingtin andataxin-l, but not yet for ataxin-3. A third factor may that underly cell specificityis differing propensities for the disease protein to misfold and aggregate in different neuronal populations. In susceptible neurons, aggregation could be promoted by specific proteolytic events that release a polyglutamine fragment or by increased targeting of ataxin-3 to the nucleus. The best evidence that misfolding and aggregation underly polyglutaminemediatedneurodegenerationisthediscovery of NIin SCA3MJD andother glutamine-repeat diseases. It is still unclear whether the central toxic event in disease is misfolding of the disease protein, the resultant aggregation, or acornbination of the two. Still, it is easy to imagine ways in which intracellular aggregates, and in particular NI, might perturb cellular processes such as transcription, RNA processing, protein folding, or protein degradation. The availability of cellbased and transgenic animal models of SCA3MJD will aid scientists in determiningtherole of intranuclearmisfoldingandaggregationinglutaminemediated neurodegeneration. Whatever the mechanism ultimately proves to be, SCA3/MJD and other glutamine-repeat diseases can now be added to the growing list of neurodegenerative “proteinopathies,” including Alzheimer’s, Parkinson’s, and prion diseases, in which accumulation of misfolded or aggregated protein leads to neuronal damage.

Expansions of CAG t~nucleotiderepeats encoding glutamine residues are causative of neurodegeneration exclusively in humans. Although studies have indicated that the genes associated with these diseases are widely expressed, the neuronallossseenwitheachdisorderisquitedisease-specific.Thisobservation raises the question of how selective populations of neurons are affected in each of the disorders. The determinants of cell specificity and death in these diseases have been difficult to study. Pathological examination of patient tissue samples obtained at autopsy has revealed little relative to the progressive changes occurring during the course of the disease. Therefore, a promising approach for the study of these diseases is the generation of transgenic animals expressing the gene with the mutation. For SCA3/NLJD, transgenic mice expressing the full-length and truncated MJDla proteins with 79 glutamine residues (MJD79 and Q79C, respectively) were generated (43). Furthermore, truncated MJDla protein with 35 glutamine residues(Q35C)aswellasatransgenicmouseexpressingexclusivelya79age only the glutamine-residue tract (Q79) were produced. Whereas, at 4 of weeks Q79C and the Q79 mice developed ataxic postures and gait disturbances, of none the animals containing the full-length MJD79 were ataxic at 23 weeks of age.

This suggests that proteolytic or processed products of the protein with the expanded polyglutamines are involved in neurodegeneration. The Q35C mice did notdevelopsymptomsat32weeks of age.Histologicalexamination ofan 8-week-old Q79C mouse showed significant atrophy of the cerebellum. All three The Purkinje cells were shrunken and had layers of the cerebellum were affected. attenuated dendrites. This is due to the promoter used to drive the expressionof the transgene. Ikeda and colleagues (43) used the murine Purkinje-cell-specific promoter PCP-2 (L7) to generate the transgenic mice and, therefore, limited the transgene expression to cerebellar Purkinje cells, which are usuallynot affected in SCA3IMJD patients (33,34). The granule cell layer showed a significant reduction in granule cell number, with many of the remaining cells having an altered, shrunken morphology. Given that the molecular and granule cell layers were not targeted, the observed morphologies in the two layers are likely to reloss. The cerebrum of the Q79C flect the successive changes to the Purkinje cell animals was normal. Together with other findings, Ikeda and colleagues (43) conclude that expanded polyglutamines are indeed causative for neuronal cell loss and degeneration. This conclusion is further supported by targeted expression of the MJDl protein, with an expanded polyglutamine in Drosophila (44). Similar to the human brain of affected SCA3MJD patients (34,47) nuclear inclusions were found in neuronal cells of Drosophila. Most importantly, these experiments provided evidence that not all cells appear equally susceptible to the deleterious actionof expanded polyglutamines, despite the formation of nuclear inclusions. Furthermore, the glutamine-repeat-induced degeneration could be partially mitigated by concomitant expressionof the antiapoptotic geneP35 (44). However, this finding has not been confirmed in a similar Drosophila model for Huntington’s disease (53), another polyglutamine-repeat disease.

IV. Pathological findings vary greatly in SCA3/MJD, in keeping with the highly variable clinical featuresof disease. Nevertheless, some generalizations can be made based on a growing number of reports (54-61). First, the pathological changes are degenerative, involving neuronalloss and gliosis. Second, certain subcortical and brain stem regions are typically affected, although the pattern may differ depending on the patient’s ethnicity, ageof onset, and age of death. Commonly affected regions include, rostral to caudal: globus pallidus (particularly the internal segment), subthalamic nucleus, substantia nigra, dentate nucleus, pontine nuclei, cranial motor nerve nuclei, anterior horn cells, and Clarke’s column. Third, the pathological changes are particularly prominent in certain pathways, especially thepallidothalamic,dentatorubral,pontocerebellar,andspinocerebellartracts.

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Fourth, peripheral neuropathy is common, especially in late-onset cases, although it is highly variable. The neuropathy is usually symmetrical, involves sensory and motor neurons (unmyelinated and myelinated fibers), and may represent axonal degenerationsecondarytoneuronaldamage.Unaffectedregionstypically include cerebral cortex, striatum, cerebellar cortex (including Purkinje and granule cell layers), and the inferior olives. Changes in cerebellar cortex and the inferior olives have been noted in some European kindreds, but the degreeof degeneration is less than in SCA1.

The clinical presentation of SCA3MJD is highly pleomorphic. Figure 6 illusa populatrates clinical signs associated with SCA3/MJD and their frequency in tion of 80 German SCA3MJD patients. Lima and Coutinho (62) first established clinical criteria for the diagnosis of MJD. The characteristic featuresof this spinocerebellar degeneration were the following: autosomal dominant inheritance, progressive cerebellar ataxia, and a dystonic-rigid syndrome or peripheral pyramidal signs associated variably with amyotrophy. Several minor features were thought to be relatively specific signs of MJD, including progressive external ophthalmoplegia, dystonia, facial and lingual fasciculations, and bulging eyes (Fig. 7). Although these features can help make the diagnosis of SCA3/MJD, they are neither limited to SCA3MJD nor present in all SCA3/MJD families. This partly explains why the diagnosis of MJD was missed in the German families 1994, even withataxiabeforegenetictestingforMJDbecameavailablein though SCA3NJD has since been shown tobe the most frequent formof dominant ataxia in Germany (17).

linical ~ ~ b ~ ~ e n o t y ~ e s CoutinhoandAndrade (5) describedthreesubphenotypes of SCA3/MJD (Table 2). Subphenotype I is characterized by early onset (10-30 years of age), rapid progression, and prominent extrapyramidal and pyramidal abnormalities, with varying degrees of cerebellar dysfunction. In particular, orofacial and limb dystonia and rigidity are features that suggest type I SCA3MJD (see Fig. 7). Patients with subphenotype I1 have an intermediate age of onset (20-50 years) and progression. They present witha prominent cerebellar syndrome and ~ y r a ~ i dsigns, a ~ but without significant extrapyramidal deficits. A spastic gait component, hyperactive reflexes and clonus, extensor plantar responses, and spinal automatism are frequent signs.

399

Figure 6 Clinical features in SCA3MJD: Frequency of clinical signs in80 German patients with SCA3MJD.

ure 7 Phenotypic characteristics of SCA3MJD: (A) Limb dystonia

1

Figure 7 (B) “bulging eyes” caused by lid retraction in a 49-year-old patient with subphenotype I and onset at 15 years of age. (C) Severe atrophy of the interosseus dorsalis I muscle in a subphenotype 111 patient at ’71 years of age.

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Table 2 Characteristics of SubphenotypesinSCA31MJD

Characteristics Subphenotype Subphenotype I Age at onset Disease progression Cerebellar ataxia Dystonia, rigidity Spasticity Peripheral neuropathy CAG repeat size +,mild;

I1 10-30 yr Rapid +to

+++ +++ +++ +

++to ++to 0 to 275

20-50 yr Intermediate +to

+++ + +++

0 to ++to 0 to + 272

Subphenotype111 40-75 yr Slow +to 0 to + 0 to + 0 to +++ 573

+++

++, moderate; +++,severe.

Subphenotype I11 is defined by later onset (40-70 years) and relatively slow progression, allowing some patients to live into their eighth decade. Distal symmetrical peripheral ne~ropathyaccompanied by cerebellar findings is the hallmark of thissubtype.Fasciculations,muscleatrophy,footdrop,cramps, numbness, or dysesthesias are typical findings (see Fig. 7). “Pure” cerebellar syndrome has been suggested as a distinct phenotype (63) consisting of cerebellar dysarthria, cerebellar oculomotor signs, and ataxia of gait, stance, and limbs. Indeed some patients present with pure cerebellar symptoms, and only much later develop mild peripheral or pyramidal deficits. par~insonianfeaA fourth phenotype has been proposed, with prominent tures including bradykinesia, rigidity, resting tremor, impaired postural reflexes, and a beneficial response to levodopa. In contrast with subphenotype1, onset is later (30 and SS years of age), the course is more benign, and cerebellar, oculomotor, and pyramidal signs are typically minimal early in the course of disease (64). Spastic paraparesishas been described as another manifestation of SCA3/ MJD in Japanese kindreds (6S,66) and can present as the major symptom, especially in the beginning of the disease, leading to the misdiagnosis of spastic paraplegia.

~ e ~ o t y pSpectru ic Several symptoms can occur independently of subphenotypes. iplopia or blurred vision is a common complaint in SCA3MJD patients. Diplopia is frequently provoked or worsenedby rapid head or body movements and is exacerbatedby fatigue. It can severely interfere with reading and substantially reduce the quality of life. Diplopia or blurred vision in SCA3/MJD results from complex oculomotor dysfunction involving a combination of cerebellar mismatch in conjugation, gazepalsy, and nuclear ocular motor nerve deficits owing to brain stem involvement. Interestingly, diplopia is frequently reduced when saccadic velocity decreases or gaze palsy increases later in the disease.

ce in SCA3MJD frequently includes gaze-evoked nystagmus, saccadic dysmetria, impaired optokinetic nystagmus, and impaired visual suppression of the vestibulo-ocular reflex. Some patients display reduced saccadicvelocitandgaze palsy. can be disturbed in SCA3/MJD, as demonstratedby studtion and contrast sensitivity. Achromatic contrast sensitivity is reduced and color discrimination is significantly impaired in both the redgreenandthe blue-yellow axis. Visual dysfunctionworsenswithdisease duration and is similar to that seen in other forms of ADCA type 1(67,68),Apart from the observation of disc pallor in 17% of SCA3MJD patients (69), neuropathological studies of the retina or the afferent visual pathways are missing in SCA3MJD. Therefore, the anatomical correlate of the complex visual dysfunction in SCA3MJD remains speculative. agia is a common problem in later stages of the disease. Patients reased gag reflex and pseudobulbar paralysis have particular difficulty with certain kinds of food, such as carbonated drinks, crunchy food, and spices. loss is a common problem that may occur, in part owing to 1s because of swallowing problems. However,many patients lose weight despite a normal appetite and caloric intake and before the onsetof e and urinary urgency are rarely reported in SCA3/MJD, but t 20% of patients (70). Other autonomic disturbances, such as

tence, orthostatic hypotension, and constipation have been described (19),

SCA3/MJD, but until recently, were missed as symptoms of disease because most of German patients do not report these problems spontaneously (71). In a cohort SCA3MJD patients 45% experienced RLS with dysesthesias that occur primarily in the evening and are temporarily relievedby moving the limbs. Many such patients have difficulty falling asleep or wake repeatedly during the night. In many cases polysomnography can document periodic leg movements in sleep (PLMS) (Figs. 8 and 9). Even in the absence of RLS, SCA3MJD patients can suffer from insomnia for other reasons. Impaired sleep is associated with clinical signs of brain stem involvement, and RLS is associated with peripheral neuropathy. However, RLS and impaired sleep are not restricted to patients with neuropathy or brain stem affection. The foregoingdescription of thediversesubphenotypesandadditional symptomsdemonstratesthetremendousclinicalvariabilityinSCA3/MJD. Even within a family the age of onset, the symptoms, and the course of the disease may vary substantially. The autosomaldominantinheritancepattern trait may even be missed owing to different clinical features in membersof one family (70,72).

Schols et al.

404 right eye left eye 01-A1 02-Al

masseter m

EKG left tib.ant.m right tib.ant.m Nasal Thorax

Abdomen Sound Sa02

Figure 8 Restless legs and periodic leg movements in sleep (PLMS) in SCA3MJD: Polysomnographic recording: EEG (channel 3 and 4) initially shows sleep stage 2; then leg movements start in the left tibial anterior muscle (channel 8) and spread to the right side (channel 7), followed by an arousal reaction [K-complex in EEG and moderate increase in heart rate (channel6) with consecutive alpha activity in the EEG].

At present the full phenotypic spectrum of SCA31MJD may not even be 50s may present known. In particular, individuals with repeat lengths in the lower with unusual phenotypes. In a Dutch SCA3MJD family, Heutink observed patients with an “intermediate” repeat length of 53 CAG in the MJD1 gene, who developed late-onset peripheral neuropathy and restless legs without ataxia and without cerebellar or brain stem atrophy on MRI (Heutink, personal communica(’73) developed severe asymtion). Another patient from a separate Dutch family of 54. Further investigametrical proximal neuropathy with a CAG repeat length tions are underway to determine whether peripheral neuropathy and restless legs are a forme fruste of SCA3MJD.

405 A

AWK

EM 1

2 3

4

igure 9 Sleep profile and L-dopa response in SGA3NJD: Polysomnography reveals (A) predominantly superficial sleep stages or awakenings (AWK) and only short REMsleep periods,as well as marked EMG activity of the tibialis anterior muscle over all night before treatment. After2 months treatment with LOO mg L-dopa sleep profile is markedly improved with longer periods of undisturbed stage 2 and 3 sleepas well as REM sleep and reduced arousal reactions (B). EMG activity of the tibialis anterior muscle is decreased significantly by the L-dopa therapy.

C Q ~ n i t ifunctiQn: ~e Clinical studies found that the intellect of SCA3/NIJD patients is normal (3,5,6). In general, it seems that disabling dementia, global cognitive impairment, or psychosis are no more frequent in SCA3MJD than in of cognitive the general population(17). However, detailed and extensive studies function in SCA3MJD have yet to be performed. Maruff and co-workers (74)

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found specific deficits in visual attention function that they think reflects disruption of frontosubcortical pathways. Tests of learning and visual memory were normal.

enotype-Phenotype Relation The repeat length of the expanded allele has significant influence on the phenotype, whereas no influence of the CAG repeat in the normal allele could be established.

l. Determinants of Age at Onset and Progression Rate The size of the expanded CAG repeat in theMJDl gene significantly influences the age of symptom onset. Larger repeats cause earlier onset, with the repeat 60% of the variability in the age at onset length being responsible for about (Fig. 10). However, this is a statistical correlation, and age at onset can vary 20

4

A

10 0

l

60

65

l

l

70

75

I

I

Pwrl

l

l

80

Figure 10 Influence of CAG repeat length on age at onset and phenotype in SCA3I MJD: Linear regression analysis reveals inverse correlation of age at onset and number of CAG repeats (r = -0.80; p <0.0001; slope: -2.25 yrICAG repeat; n = 80). Characteristics of subphenotypes are given in Table 2. (A) Patients with subphenotype 1 had onset before 20 yearsof age. Most patients with(U)subphenotype 2 harbored73 or more CAG repeats, whereas (0) in subphenotype 3 patients 73 or fewer CAG motifs were found.No determining factor could be disclosed for the development of (+)subphenotype 4.

Ataxia Spinocerebellar

Type 3

407

years or more with identical repeat lengths. Thus, in the counseling of gene carriers, individual repeat length is of limited prognostic use. Homozygosity for the mutation is reported to cause earlier onset and a more severe course of the disease compared with heterozygous family members with similar repeat lengths. This suggests a dosage effect of the mutant protein (75,76). In addition to influencing the age at onset, CAG repeat length is a significant risk factor for the rate of progression in SCA3MJD: patients with larger repeats tend to have a more rapid course of disease (77,78). Independentof repeat length, female gender increased the riskof becoming dependent on walking aids or a wheelchair, but did not influence survivalSCA3MJD. in Thereason for this sex difference is currently unkown.

2. Determinants of Subphenotypes Repeat length also has a significant influence on the subphenotype of SCA3MJD (60,70,79). In the study of Schols and co-workers (70) subtype I patients with prominent pyramidal and extrapyramidal features had 77-80 CAG repeats. Interestingly, onset in subtype I patients was before age 20. In contrast, onset in all subtypes I1 and I11 patients was older than age 20, suggesting onset age as a major factor associated with the development of subtype 1. In subtype I1 patients with spasticity and ataxia, but without prominent extrapyramidal signs, repeat length varied between 72 and 82 CAG repeats, whereas in subtype I11 patients with peripheral neuropathy apart from ataxia, repeat length was 75 CAGunits or fewer (Fig. 10).

E. Course of theDisease The age of onset is highly variable, ranging from early childhood to the eighth of relative stabildecade. The course is progressive in all cases, although periods ity can last for several years, especially in patients with late onset. Some patients experience remitting phasesof double vision or gait unsteadiness years before the disease manifests with permanent deficits. Gait disorder is the most frequent complaint at the onset of disease (90%), Diplopia is the second most common manifesting symptom (- 9% of patients) and may precede ataxia by as much as 10 years in some patients. Rarely, cramps, dysesthesias, or sleep disturbances are noticed as the first symptom. There is no strict chronologyof symptoms as the disease progresses. Even within the previously decribed subphenotypes, there is no strict timing or sequence of progression. Therefore, a reliable prognostic statement for individual patients cannot be made. (78) investigatedthenaturalhistory of diseasein Klockgetheretal. 120 SCA3MJD patients. Median latency to confinement to a wheelchair was

408

Figure 11 ME1 in a 43-year-old patient with SCA3/MJD 3 years after onset of symptoms: (A)Mediosagital plane (1.5 tesla, TR 600, TE 1 S ms).

similarinSCA1,SCA2,andSCA3;itwasapproximately 17 yearsforthe whole group. Life expectancy forSCA3MJD was not separately mentioned, but was reported to be longer than in SCAl (mean 56 years). In other reports of SCA3/MJD age of death ranged from 35 to7 l years (mean 49 years) and disease duration until death varied from 7 to 29 years (mean 15 years) (6,57,60). However, we personally knowof patients who are only mildly disabled in their eighth decade. The exact cause of death is rarely reported, but aspiration pneumonia appears to be the most common terminal illness.

1. MagneticResonance imaging Magneticresonanceimaging(MRI)abnormalitiesin SCA3/MJP patientsare consistent with the variable pathological findings described in the foregoing.

Spinocerebellar Ataxia Type 3

409

Figure 11 Continued (B) axial image at the level of t h e middle cerebellar peduncles (1.5 tesla, TR 2700, TE 90 ms).

ThereisnosingleradiologicfeaturethatisconsistentlyobservedinSCA3/ MJI) (28,69,80,81). The mostcommonabnormality may bemarkeddilation of thefourthventricle.Thisprobablyreflectsatrophy of thesuperiorand middlecerebellarpeduncles,thepontinebase,andthecerebellarvermis, whereas the cerebellar hemispheres are less affected (see Fig. 11). Klockgether andcolleagues(82)performedaMRI-basedvolumetricstudyandfound putamina1 andcaudateatrophy in SCA3/MJD,but not in SCAl orSCA2. of themidbrain, Otherfrequentlynoted MRI abnormalitiesincludeatrophy medullaoblongata,andcervicalspinalcord.Althoughthecerebralcortexis relativelysparedinSCA3/MJD,frontalandtemporalatrophyhavebeen described. The severity of MRI abnormalities correlates significantly with both CAGrepeat length and age. In other words, young patients with larger repeats can present with atrophy similar to old patients with shorter repeats. The atrophic process does not start with onsetof symptoms, but has its onset in the presymptomatic stage (8 1,83). Deterrnining whether atrophy progresses linearly from of birth, or develops with a long latency period, will require follow-up studies presyrnptomatic gene carriers.

2.

Single Photon Emission Computed Tomography(SPECT)

In ['231]iomazenil SPECT studies, benzodiazepine receptor binding was noted to be decreased in SCA3NJD in the cerebellum, striatum, thalamus, and cerebral cortex, even though no cortical cerebral atrophy was evident on MRI, and cerebral blood flow was largely normal (84). Therefore, SPECT abnormalities are thought to demonstrate a subclinical impairment of the cerebral cortex.

mission Tomography Positronemissiontomography(PET)studieswith ['8F]fluorodeoxyglucose (FDG) also demonstrated reduced cerebral glucose metabolism in the cerebral cortex, cerebellum, brain stem, and striatum of SCA3IMJD patients. A similar pattern of regional brain hypometabolism has been described in asymptomatic gene carriers of SCA3/MJD, demonstrating subclinical disease (85-87). PET investigations of dopaminergic pathways with 'C 'Clraclopride and ['~F]6-fluoro-~-dopa found that striatal D2 receptors are normal and that impairment of the presynaptic nigrostriatal dopaminergic system is variable, correlating with neither repeat size nor with phenotype (8S,88).

y (EMG) reveal an axonal neuropathy in most SCA3 patients, with sural nerve potentials and EMG of distal muscles being the most sensitive tests (28,89). CAG-repeat length influences the sensory nerve action potential of the sural nerve as a landmark of peripheral neuropathy. If age is not taken into account, sensory nerve action potemtial of the sural nerve appears to be inversely correlated with repeat length, suggestingaparadoxprotectiveeffect of largerrepeatsinconsistentwithall pathogenic concepts (Fig. 12). However, if one corrects for the age at which the study is performed, CAG repeat length turns out be to an independent risk factor for peripheral neuropathy.If patients with subphenotype I or I1 and larger repeats were to reach the same age as type TI1 patients, neuropathy in type I and I1 would 111 (in which peripheral neuropathy is be even more severe than in subphenotype a hallmark of the disease) (90). Anatomicalstudies of peripheralnervesrevealedasubstantialloss of alpha- and gamma-motoneurons in the anterior roots.The sensory system is less involved at the root level; however, large myelinated fibers may show a predominantly distal degeneration with a relative preservation of unmyelinated fibers in the su se (SSR) revealed impairmentof the sympathetic sudomotoric pathways with abnormal SSR amplitudes in about SO% of SCA3/ MJD patients. SSR abnormalities correlate with sleep disturbances, but not with other vegetative symptoms (92).

he rityin

ting

EP) show normal or near norrnal peripheral c and of SCA3/MJD patients. MEP are frequently normal even in patients with severe spasticity pointing to the axCA3/NIJD (89,93). (SEP) demonstrate disturbed conducory pathways. Abele et al. (89) found cortical potentials tobe missing in 27% and to be delayed in 60%of SCA3/MJD not patients. As only cortical potentials were recorded the anatomical level could be determined in this study. In our experience, lumbar potentials are frequently delayed, and cervical potentials often absent, consistent with a combination of peripheral neuropathy and degeneration of the posterior columns as confirmed by autopsy studies. AEP) are abnormal in about 60% of the cochlear nerve, were foundin 38% of patients. In addition, pathological latencies of wave 111 and ‘V and prolonged interpeak latencies suggested widespread inways within the brain stem (89). S (VEP) revealedreducedP100amplitudesin about 50% and mildly prolonged P100 latency in up to 25% of SCA3 patients reviously mentioned clinical deficits in visual function. :Smooth pursuit gain (peak eye velocity over peals targetvelocity)wasdecreasedin81% of SCA3MJD patients (94). ‘Visually guidedsaccades had normallatency,butmildlyreducedvelocityin 30% of SCA3MJD patients and appear to be better preserved than in SCAl or SCA2 (69). Centrifugal saccades were hypometric in 56% and hypermetric in 18% of patients. In addition, the percentage of antisaccades were increased, suggesting frontal inhibitory deficits. Sixty-three percent of the patients presented with gaze-evoked nystagmus at an early stage of the disease. In comparison of different types of ataxia, the combination of gaze-evoked nystagmus and saccade hypornetria with normal saccade velocity is suggestiveof SCA3 and can help differentiate SCA3 patients clinically from SCAl and SCA2 patients. *

Although symptomatic treatment can substantially help ease some of the symptoms, SCA3/MJD is still incurable and leads to death after suffering from the disease for about15-30 years. Therefore, special care is warranted in differential diagnosisandinpresymptomatictesting.Layorganizations,clinicians,and geneticists support guidelines for testing SCA3/MJD patients and at-risk persons similar to those of other late-onset neurodegenerative disorders, as Huntington’s disease (95,96). The most important precondition before drawing blood for responsibly genetic analysis is to obtain a signed, informed consent, which means

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412

15

10

4

+

+ + +

5

o ! 65

A T

I

lI

70

'75

80

(CAG)n

I

I

0

20

l

I

l

I

40

60

*

T

+

80

Figure 12 Determinants of peripheral neuropathy in SCA3MJD: Plotting of CAG repeat length versus sural nerve sensory action potential (SNAP) reveals (A) an apparently protective effect with larger CAG repeats, whereas (B) age showeda strong negative correlation with SNAP. If correction for age is performed, CAG repeat length (C) turns out as an independent risk factor for peripheral neuropathy. Degree of atrophy (50 -SNAP) per year is more severe in patients with larger alleles.

Type

Spinocerebellar Ataxia

0

r:

413

3

I)

I)

75

3 (ct S2 70

65 ! 0.50 (C)

l

I

l.oo

l

l

1.50

Degree of atrophy per year of age [VVlyear]

Figure l2 Continued

thatthepatienthastobeinformedabouttheconsequences of thepossible results. It has to be solely the decision of the patient, or the person at risk, to undergogenetictesting.DNAanalysisin an autosomaldominantdisease affectsnotonlythepatient,butalsopossibleoffspringandotherrelatives. Even for a differential diagnosis for which DNA analysis is “only confirmative”onehastokeepinmindthat SCA3MJD is a life-threateningdisease. Therefore,thepatientmustbetoldthattheoutcome of thetestwillnot necessarily influence symptomatic treatment. Furthermore, although insurance companies should not receive any information on test results, they might learn thatagenetictesthasbeenperformed,whichinturn,mightinfluencea contract for the patient and his or her children. For presymptomatic testing, this point might even be more important. Furthermore, it will be necessary to discuss with the person at risk her or his reasons for requesting a genetic test. Predictive testing should not be undertaken in healthy children. In general, a friend or spouse should accompany the counseling sessions. Besides genetic counseling by a trained person, psychological or psychotherapeutic sessions are also recornmended by the guidelines, and only after repeated counseling should blood be drawn for DNA analysis. At each stage of the test, even after blood sampling, the person at risk can withdraw from the test. as a contact address Finally, the counseling team has to make sure to function even after the result has been given.

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In Germany, Switzerland, and Austria two blood samples (about 2 times 5 mL EDTA blood) should be taken that will be independently processed in the laboratory. Both analysis have to reveal the same result.The laboratory may rea short report quest a copy of the informed consent and for differential diagnosis on the clinical statusof the patient. There isan open debate whether the exact repeat length should be provided to the requesting party (97). We feel, however, that patients and persons at risk have the right to know this information. This necessitates standardization and professional counseling to prevent wrong conclusions by the persons at risk who might misinterpret the significance of the repeat length to predict the age at onset.

As the pathogenic mechanism of neurodegeneration in SCA3/MJD is still not fully understood, preventive therapies forSCA3MJD are still lacking. However, optimal symptomatic treatment can significantly improve several complaints. Parkinsonian features can successfully be treated many for years with levodopa or dopaminergic agonists. Sleep disturbances inSCA3/MJD are diverse. If sleep history or polysomnography reveals restless legs or periodic leg movements in sleep, levodopa or dopaminergic agonists are likely to improve sleep efficiency. Tilidin and sedating antidepressants, such amitriptyline, may be used alternatively in case of intolerance or wearing-off effects. Melatonin and cannabinol are reported to improve sleep in some patients, albeit with mostly short-term effects. Benzodiazepines can help with sleep disturbance in some patients, but can aggravate ataxia. Spasticity, spinal automatisms, and clonus are frequent complains of subphenotype I and I1 patients and can successfully be treated with antispasmodic of disease, spasdrugs such as baclofen, memantine, or tizanidine. In later stages ticity can become a major problem that interferes with mobility and prevents apor cause unpropriate nursing care.If classic antispasmodic drugs are ineffective toward side effects, cannabinol or botulinum toxin injections in severely affected muscles (e.g., the adductor magnus) have been effective in the few severely ill patients treated so far. blephaBotulinum toxin can also be used to treat dystonic features, as such rospasm, torticollis, and jaw-opening or jaw-closing dystonia. However, botulinum toxin must be used with great caution and in lower doses than normal because of potentially severe and long-lasting side effects, such as dysphagia(98). The increased sensitivity to botulinum toxin in SCA3/MJDmay be due to pathological involvement of cranial nerve motor neurons.

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Cramps can become a nagging complaint, especially in older patients, and can be successfully suppressed with magnesium or quinine. Dysesthesias are difficult to treatif they are not partof a restless legs syndrome. Most patients react to one of the following drugs: a-lipoic acid, antidepressants, tilidine, or pentoxifylline. Urinary dysfunciton requires careful urological assessment to identify uria hypernary tract infections, urinary retention, detrusor sphincter dyssynergy, or active or atonic bladder. Differential therapy is prescribed according to urodynamic findings (99). Physostigmine is reported to be effective for speech problems or ataxia. Similarly, oxitriptan and buspironemay improve ataxia, speech, or general wellbeing in some patients, although no consistent benefit has been established for either drug. The role of vitamin E or other potentially neuroprotective drugs such as selegelineorriluzoleinSCA3/MJDisstillspeculative, as controlled studies haveyetto be performed. Trimethoprim-sulfamethoxazole (TMS)hasbeen reported in several studies to be effective in SCA3/MJD, but these reports included very fewpatients,investigatedonlyshort-termeffects,anddescribed positive effects on various symptoms including spasticity, bradykinesia, gait performance, dystonia, swallowing, or contrast sensitivity.We performed a doubleblind, placebo-controlled, crossover trialof TMS in 22 SCA31MJD patients over l3 months and could not establish a short or long-term effect on the foregoing symptoms (100). Althoughphysiotherapycannotaltertheneurodegenerativeprocess,it canreduce or slowtherate of physicaldisabilityinpatients.Physiotherapy a physiological helps train balance, minimize gait instability, and to maintain gait pattern as long as possible. Furthermore, spasticity can be reduced with physiotherapeutic techniques. Appropriate technical aids (e.g., canes, walkers, wheelchairs,orthoticdevicesforfootdrop)willalsoreducethedegree of disability. Dysarthria should be treated with speech therapy to prevent major problems in communication. Many speech therapists offer special training programs a hyperactivegagreflexassociatedwith toreduceswallowdifficulties.For dysphagia, sucking of ice before meals can reduce the problem. Blurred vision that can be improved by closing one eye suggests a rather mild form of diplopia that may respond to correction with prism glasses. Double vision is a common and quite disabling problem in SCA3/MJD patientsas it interfereswithreadingorwatchingtelevisionor may causeheadaches;prism glasses can alleviate these problems substantially. Strabismus surgery in SCA31 MJD has only short-term effects, because eye positions tend to vary during the course of the disease owing to progressive brain stem affection.

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Progressivedisabilityfrequentlyleadstodepressionandoccasionally suicideattempts.Psychotherapycanhelpexplorecopingstrategiesorsolutionsforphysicaldisabilitiesthatarefrequentlythecause of emotionaldecompensation. In the future, there is hope that better understanding of the molecular pathogenesis of SCA3MJD will aid in the developmentof therapies that slow or halt the course of the disease.

REFERENCES 1. Nakano KK, DawsonDM,SpenceA.Machadodisease:ahereditaryataxiain Portuguese imigrants to Massachusetts. Neurology 1972; 22:49--55. 2. Woods BI, Schaumburg HH. Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia: a unique and partially treatable clinicopathological entity. J Neurol Sci 1972; 17: 149-166. 3. Rosenberg RN, Nyhan WL, Bay C, Shore P. Autosomal dominant striatonigral degeneration. A clinical, pathologic, and biochemical study of a new genetic disorder. Neurology 1976; 26:703-714. 4. Romanul FCA, Fowler HL, Radvany J, Feldman RC, Feingold M. Azorean disease of the nervous system. N Engl J Med 1977; 296:1505-1508. 5. Coutinho P, Andrade C. Autosomal dominant system degeneration in Portuguese families of the Azores Islands. A new genetic disorder involving cerebellar, pyramidal, extrapyramidal and spinal cord motor functions. Neurology 1978; 28:703709. 6. Sequeiros J, Coutinho P. Epidemiology and clinical aspects of Machado-Joseph disease. In: Harding A, Deufel T, eds. Advances in Neurology. Vol61. Raven Press: NewYork,1993:139-153. 7. Stevanin G, Cancel G, Didierjean0, Durr A, Abbas N, Cassa E, Feingold J, Agid Y,Brice A. Linkage disequilibrium at the Machado-Joseph diseasekpinal cerebellar ataxia 3 locus: evidence for a common founder ineffect French and PortugueseBrazilian families as well as a second ancestral Portuguese-Azorean mutation. Am J Hum Genet 1995; 57:1247-1250. I, DeStefanoAL,Maciel P, Silveira I, Coutinho P, 8. GasparC,Lopes-Cendes MacLeod P, Sequeiros J, Farrer LA, Rouleau GA. Linkage disequilibrium analysis in Machado-Joseph disease patients of different ethnic origins.Hum Genet 1996; 981620-624. 9. Iughetti P, Zatz M, Bueno MRP, Marie SIC. Different origins of mutations at the Machado-Joseph locus (MJD1). J Med Genet 1996; 333439440. 10. Takano H, Cancel G, IkeuchiT, Lorenzetti D, Maward R, Stevanin G, Didierjean 0 , Durr A, Oyake M, Shimohata T, Sasaki R, Koide R, Igarashi S, Hayashi S, Takiyama Y,Nishizawa M, TanakaH, Zoghbi H, Brice A, Tsuji S. Close association between prevalence of dominantly inherited spinocerebellar ataxias with CAGrepeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations. Am J Hum Genet 1998; 63:1060-1066.

Type

Spinocerebellar Ataxia

3

417

11. Harding A E . Classification of the hereditary ataxias and paraplegias. Lancet 1983; 1:1151-1155. 12. Riess 0, Schols L, Bottger H, Nolte D, Vieira-Saecker AMM, Schimming C, Kreuz F, Macek M Jr, Krebsovii A, Macek M, Klockgether T, Ziihlke C, Laccone FA. SCA6 is caused by moderate CAG expansion in the a,,-voltage-dependent calcium channel gene. Hum Mol Genet 1997; 6:1289-1293. S, SakamotoH,Karube Y, 13. Takiyama Y, NishizawaM,TanakaH,Kawashima Shimazaki H, ?Soutome M, Endo K, Ohta S, Kagawa Y, Kanazawa I, Mizuno Y, YoshidaM,Yuasa T, Horikawa Y, Oyanagi K,Nagai H, Kondo T, Inuzuka T, Onodera 0, Tsuji S. The gene for Machado-Joseph disease maps to human chromosome 14q. Nat Genet 1993; 4:300-304. 14. George-Hyslop PS, Rogaeva E, HutererJ, Tsuda T, Santos J, Haines JL, Schlumpf K, Rogaev EI, Liang Y, Crapper McLachlan DR, Kennedy J, Weissenbach J, Billingsley GD, Cox DW, Lang AE, Wherrett JR. Machado-Joseph disease in pedigrees of Azorean descent is linked to chromosome 14. Am J Hum Genet 1994; 55~120-125. 15. Stevanin G, LeGuern E, Ravis N, Chneiweiss H, Diirr A, Cancel G, Vignal A, Boch AL, Ruberg M, Penet C, Pothin Y, Lagroua I, Haguenau M, Rancurel G, Weissenbach J, Agid Y, Brice A. A third locus for autosomal dominant cerebellar ataxia type I maps to chromosome 14q24.3-qter: evidence for the existence of a fourth locus. Am J Hum Genet 1994; 54: 11-20. S, 16. Kawaguchi Y, Okamoto T, TaniwakiM,AizawaM,InoueM,Katayama KawakamiH,Nakamura S, NishimuraM,Akiguchi I, Kimura J, Narumiya S, Kakizuka A. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 1994; 8:221-228. M M , Schols S, PrzuntekH,EpplenJT,Riess 17. ScholsL,Vieira-Saecker 0. Trinucleotide expansion within the MJDl gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients. Hum Mol Genet 1995; 4:1001-1005. 18. HigginsJJ,NeeLE,Vasconcelos 0, IdeSE,LavedanC,GoldfarbLG, Polymeropoulos MH. Mutations in American families with spinocerebellar ataxia (SCA)type 3: SCA3isallelictoMachado-Josephdisease.Neurology1996; 461208-213. 19. Takiyama Y, SakoeK,NakanoI,NishizawaM.Machado-Josephdisease: cerebellar ataxia and autonomic dysfunction in a patient with the shortest known expandedallele(56CAGrepeatunits)ofthe MJDl gene.Neurology1997; 49~604-606. S. Relation20. Matsumura R, TakayanagiT, Murata K, Futamura N, Hirano M, Ueno ship of (CAG)nC configuration to repeat instability of the Machado-Joseph disease gene. Hum Genet 1996; 98:643-645. 21. LimprasertP, Nouri N, Heyman RA, Nopparatana C, Kamonsilp M, Deininger PL, Keats BJB. Analysis of CAG repeat of the Machado-Joseph gene in human, chimpanzee and monkey populations: a variant nucleotide is associated with the number of CAG repeats. Hum Mol Genet 1996; 5:207-213. 22. Igarashi S, Takiyama Y, Cancel G, et al. Intergenerational instabilityof the CAG

repeat of the gene for Machado-Joseph disease (MJDI) is affected by the genotype of the normal chromosome: implications for the molecular mechanisms of the instability of the CAG repeat. Hum Mol Genet 1996; 5:923-932. 23. Maciel P, Lopes-Cendes I, Kish S, Sequeiros J, Rouleau GA. Mosaicism of the GAG repeat in CNS tissue in relation to the age at death in spinocerebellar ataxia type I and Machado-Joseph disease patients. Am J Hum Genet 1997; 60:993-996. 24. Kawakami H, Maruyama H, Nakamura S, Kawaguchi U, Kakizuka A, Doyu M, Sobue G. Unique features of the CAG repeats in Nlachado-Joseph disease. Nature Genet 1995; 9:344-345. 25. Takiyama Y, Igarashi S, Rogaeva EA, et al. Evidence for inter-generational instability in the CAG repeat in the MJDI gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease. H u Mol ~ Genet 1995; 4: 1137-1146. 26. Diirr A, Stevanin G, Cancel G, Abbas N, Chneiweiss H, Agid U, Feingold J, Brice A. Gender equality in Machado-Joseph disease. Nat Genet 1995; 11:138. 27. DeStefano AL, Farrer LA, Maciel P, Gaspar C, Rouleau GA, Coutinho P, Sequeiros J. Gender equality in Machado-Joseph disease. Nat Genet 1995; I1 :l18-119. 28. Schols L, Amoiridis G, Butter T, Przuntek H, Epplen JT,0 Riess . Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol 1997a; 42:924-932. 29. DeStefano AL, Cupples LA, MacielP, Gaspar C, Radvany J, Dawson DM, Sudarsky L, Corwin L, Coutinho P, MacLeod P, Sequeiros J, Rouleau GA, Farrer LA. A familialfactorindependentofCAGrepeatlengthinfluencesageatonsetof Machado-Joseph disease. Am J Hum Genet 1996; 59:319--127. 30. Riess 0 , Epplen JT, Amoiridis G, Przuntek H, Schols L. Transmission distortion of the mutant alleles in spinocerebellar ataxia. Hum Genet 1997; 99:282--284. 31. Ikeuchi T, Igarashi S, Takiyama Y, Onodera 0 , Oyake M, Takano H, Koide R, Tanaka H, TsujiS. Non-Mendelian transmission indentatorubral-pallidoluysianatrophy and Machado-Joseph disease: the mutant allele is preferentially transmitted in male meiosis. Am J Hum Genet 1996; 58:730-733. Mac~~do-Joseph 32. Rubinsztein DC, Leggo J. Non-Mendelian transmission at the disease locusin normal females: preferentially transmission of alleles with smaller CAG repeats. J Med Genet 1997; 34:234-236. 33. PaulsonHL,PerezMK,Trottier U, TrojanowskiJQ,Subramony SW, Das SS, Vig P, Mandel JL, Fischbeck KH, Pittman RN. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type3.Neuron 1997; 19:333-344. 34. Schmidt T,LandwehrmeyerB,Schrnitt I, Trottier Y, AuburgerG,Laccone F, Klockgether T, Volpel M, Epplen JT, Schols L, Riess 0 . An isoform .of ataxin-3 accumulates in the nucleusof neuronal cells in affected brain regions of SCA3 patients. Brain Pathol 1998; 8:669-679. Yi H, Hersch SM, Clark HB, ZoghbiHY, Orr 35. Klement IA, Skinner PJ, Kaytor MD, HT. Ataxin- I nuclear localization and aggregation: role in polyglutamine-induced disease in SCAl transgenic mice. Cell 1998; 95:41-53. 36. Saudou F, Fi~beinerS, Devys D, Greenberg ME. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998: 9555-66.-

37. Davies SW, Beardsall K, Turmaine M, DiFiglia M, AroninN, Bates GP. Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansion? Lancet 1998; 351: 131-133. 38. Ross C. Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases? Neuron 1997; 19: 1147-1 150. HAT,ZoghbiHY. 39. Cumnnings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr Chaperone suppression of ataxin-1 aggregation and altered subcellular proteosome localization imply protein misfolding in SCAl. Nat Genet 1998; 19:148--154. 40. Chai U,Koppenhafer SL, Shoesmith SJ, et al. Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3MJD and suppression of polyglutamine aggregation in vitro. Hum Mol Genet 1999; 8:673-682. 41. Perez M, Paulson H, Pendse S, Saionz SJ, Bonini NM, Pittman RN. Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol 1998; 143: 1457-1470. 42. Kim TW, Tanzi RE. Neuronal intranuclear inclusions in polyglutamine diseases: nuclear weapons or nuclear fallout? Neuron 1998; 21:657-659. 43. Ikeda H,Ymaguchi M, Sugai S, Aze U,Narumiya S, Kakizuka A. Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet 1996; 13:196-202. 44. Warrick JM, Paulson HL, Gray-Board GL, Bui QT, Fischbeck RH, Pittman RN, Bonini NM. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 1998; 93:939-949. 45. Suenaga T, Matsushima H, Nakamura S, Akiguchi I, Kimura J. (1993) Ubiquitinimmunoreactive inclusions in anterior horn cells and hypoglossal neurons in a case with Joseph’s disease. Acta Neuropath01 85:341-344. 46. Nakamoto M, Ikeda H, Kakizuka A. Genetic and molecular studies of MachadoJoseph disease. In: Wells RD, Warren ST eds. Genetic Instabilities and Hereditary Neurological Diseases. Academic Press: San Diego, CA. 1998:283-294. 47. Paulson H, Das SS, Crino P, Perez MK, Pate1 SC, Gotsdiner D, Fishbeck KH, Pittman RN. Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain. Ann Neurol 1997; 41:453-462. 48. Wang,G,Ide,K,Nukina, N, Goto,J,Ichikawa, Y, Uchida,K,Sakamoto, T, Kanazawa, I. Machado-Joseph disease gene product identified in lymphocytes and brain. Biochem Biophys Res Commun 1997; 233:476-479. S, Ognibene A, Maraldi NM, 49. Tait D, Riccio M, Sittler A, Scherzinger E, Santi Lehrach H, Wanker EE. Ataxin-3 is transported into the nucleus and associates with the nuclear matrix. Hum Mol Genet 1998; 7:991-997. 50. Perutz MF. Glutamine repeats and inherited neurodegenerative diseases: molecular aspects. Curr Opin Struct Biol 1996; 6:848-858. 51. Trottier Y,Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G, Saudou F, Weber C, David G, Tora L. Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature 1995; 378:403-406. 52. Scherzinger E, Lurz R, Turmaine M, Mangiarini L, Hollenbach B, Hasenbank R, Bates GB, Davies SW, Lehrach H, Wanker EE. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 1997; 90:549-558.

Schols et al.

420

53, Jackson GR, Salecker I, DongX, Yao X, Arnheim N, Faber PW, MacDonald ME, Zipursky SL. Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 1998; 21 533-642. 54. Sachdev HS, Forno LS, Kane CA. Joseph disease: a multisystem degenerative disorder of the nervous system. Neurology 1982; 32:192-195. 55. Coutinho P, Guimaraes A, Melo Oires M, Scaravilli F. The peripheral neuropathy in Machado-Joseph disease. Acta Neuropath01 1986; 7 :1119-124. 56. Yuasa T, OhamaE, HarayamaH, Yamada M, KawaseY, Wakabayshi M, Atsumi T, Miyatake T. Joseph's disease: clinical and pathological studies in a Japanese family. Ann Neurol 1986; 19:152-157. 57. Takiyama Y, Oyanagi S, Kawashirna S, Sakamoto H, Saito K, Yoshida M, TsujiS, Mizuno Y, Nishizawa M. A clinical and pathological study of a large Japanese family with Machado-Joseph disease tightly linked to the DNA markers on chromosome 14q. Neurology 1994; 44:1302-1308. 58. Cancel G, Abbas N, Stevanin G, Dun A, Chneiweiss H, Neri C, Duyckaerts C, Penet C, Cann HM, AgidY. Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3Machado Joseph disease locus. Am J Hum Genet 1995; 57:809-816. 59. Kinoshita A, Hayashi M, Oda M, TanabeH. Clinicopathological studyof the peripheral nervous system in Machado-Joseph disease. J Neurol Sci 1995; 130:4858.

60. Dun A, Stevanin G, Cancel G, Duyckaerts C, Abbas N, Didierjean 0, Chneiweiss H, Benomar A, Lyon-Vaen 0, Julien J, Serdaru M, Penet C, Agid Y, Brice A. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol 1996; 39:490"499. 61 Lopes-Cendes I, Silveira I, Maciel P, Gaspar C, Radvany J, Chitayat D, Babul R, Stewart J, Dolliver M, Robitaille Y, Rouleau GA, SequeirosJ. Limits of clinical assessment in the accurate diagnosis of Machado-Joseph disease. Arch Neurol 1996; 53:1168-1174. of Machado-Joseph disease: re62. Lima L, CoutinhoP. Clinical criteria for diagnosis port of a non-Azorean Portuguese family. Neurology 1980; 30:319-322. 63. Ishikawa K, Mizusawa H, IgarashiS, Takiyama Y, Tanaka H, Ohkoshi N, ShojiS, Tsuji S. Pure cerebellar ataxia phenotype in Machado-Joseph disease. Neurology 1996; 46:1776-1777. 64. Tuite PJ, Rogaeva EA, George-Hyslop PHs, Lang AE. Dopa-responsive parkinsonism phenotype of Machado-Joseph disease: confirmation of 14q CAG expansion. Ann Neurol 1995; 38:684"87. 65. Sakai T, Kawakami W.Machado-Joseph disease: a proposal of spastic paraplegic subtype. Neurology 1996; 465346-847. 66. Kaneko A, Narabayashi Y, Itokawa K, Nakazato Y, Hosokawa T, IwasakiS, Ohno R, Hamaguchi K, Ikeda M, Nomura M. A case of Machado-Joseph disease presenting with spastic paraparesis. J Neurol Neurosurg Psychiatry 1997; 63542-543. 67. Azulay JP,Blin 0, Mestre D, Sangla I, Serratrice G. Contrast sensitivity improvement with sulfamethoxazole and trimethoprim in a patient with Machado-Joseph disease without spasticity. J Neurol Sci 1994; 123:95-99.

Ataxia Spinocerebellar

3

421

68. Schols L, Buttner T, ProphetY, Lack B, Przuntek H. Visual impairment in cerebellar degeneration. Mov Disord 1996; ll(supp1 1):37. J,SkalejM,Laccone F, Didierjean 0, 69. BurkK,AbeleM,FetterM,Dichgans BriceA,KlockgetherT.Autosomaldominantcerebellarataxiatype I. Clinical featuresand MRI infamilieswithSCA1,SCA2andSCA3.Brain1996;119: 1497-1505. 70. Schols L, Amoiridis G, Epplen JT, Langkafel M, Przuntek H, Riess 0. Relations between genotype and phenotype in German patients with the Machado-Joseph disease mutation. J Neurol Neurosurg Psychiatry 1996; 61:466-470. 71. Schols L, Haan J, Riess 0, Amoiridis G, Przuntek H. Sleep disturbance in spinocerebellar ataxias. Is the SCA3 mutation a cause of restless legs syndrome? Neurology 1998; 51:1603-1607. 72. Subramony SH, Currier RD. Intrafamilial variability in Machado-Joseph disease. Mov Disord 1996; 11:741-743. 73. vanSchaikIN,JobsisGJ,VermeulenM,KeizersH,BohuisPA,deVisserM. Machado-Joseph disease presenting as severe asymmetric proximal neuropathy. J Neurol Neurosurg Psychiatry 1997; 63534-536. 74. Maruff P, v i e r P, Burt T, Currie, BurnsC, Currie J. Cognitive deficits in MachadoJoseph disease. Ann Neurol 1996; 40:421-427. 75. Lerer I, Merims D, Abeliovich D, Zlotogora J, Gadoth N. Machado-Joseph disease: correlation between the clinical features, the CAG repeat length and homozygosity for the mutation. Eur J Hum Genet 1996; 4:3-7. 76. Sobue G, Doyu M, Nakao N, Shimada N, Mitsuma TT, Maruyama H, Kawakami H, NakamuraS. Homozygosity for Machado-Joseph disease gene enhances phenotype severity. J Neurol Neurosurg Psychiatry 1996; 60:354-356. 77 Klockgether T, Garner B, Ludtke R, Schols L, Laccone F. Repeat length and disease progression in spinocerebellar ataxia type 3. Lancet 1996; 348:830. 78. Klockgether T, Ludtke R, Kramer B, Abele M, Burk K, Schols L, Riess 0, 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. P, Radvany J, Dawson DM, 79. Maciel P, Gaspar C, SeStefano AL, Silveira I, Coutinho Sudarsky L, GuirnaraesJ, Loureiro JE, Nezarati MM, Corwin LI, Lopes-Cendes I, Rooke K, Rosenberg R, MacLeod P, Farrer LA, Sequeiros J, Rouleau GA. Correlation between CAG repeat length and clinical features in Machado-Joseph disease. Am J Hum Genet 199.5; 57:54-61. 80. Murata Y, Yarnaguchi S, Kawakami H, Imon Y, Maruyama H, Sakai T, Kazuta T, Ohtake T, Nishjmura M, Saida T, Chiba S, Oh-i T,Nakamura S. Characteristic magneticresonanceimagingfindingsinMachado-Josephdisease.ArchNeurol 1998; 55:33-37. 81 Onodera 0, Idezuka J, Igarashi S, Takiyama Y, EndoK,TakanoH,OyakeM, Tanaka H, Inuzuka T, Hayashi T, Yuasa T, It0J, Miyatake T, Tsuji S. Progressive atrophy of cerebellum and brainstem as a function of age and size of the expanded CAG repeats in the MJD1 gene in Machado-Joseph disease. Ann Neurol 1998; 43: 1-9. *

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Schols et al.

82. Klockgether T, Skalej M, Wedekind D, Luft AR, Welte D, Schulz JB, Abele M, Burk K, Laccone F, Brice A, Dichgans J. Autosomal dominant cerebellar ataxia type I. MRI-based volumetry of posteriorfossa structures and basal ganglia in spinocerebellar ataxia type 1,2 and 3. Brain 1998; 121:1687-1693. 83. Abe U, Tanaka, MatsumotoM, Doyu M, Hirayama M, Kachi T, Sobue G. CAG repeatnumbercorrelateswiththerate ofbrainstemandcerebellaratrophyin Machado-Joseph disease. Neurology 1998; 5 l :882-884. 84. Ishibashi M, Sakai T, Matsuishi T, Yonekura Y, Yamashita Y, Abe T, Ohnishi Y, Hayabuchi N. Decreased benzodiazepine receptor binding in Nlachado-Joseph disease. J Nucl Med 1998; 39:1518-1520. 85. Taniwaki T, Sakai T, Kobayashi T, Kuwabara Y, Otsuka M, Ichiya Y, Masuda K, Goto I. Positron emission tomography (PET) in Machado-Joseph disease. J Neurol Sci1997;145:63-67. 86. Soong SW, Cheng CH, Liu RS, Shan DE. Machado-Joseph disease: clinical, molecular,andmetaboliccharacterizationinChinesekindreds.AnnNeurol1997; 41:446-452. 87. Soong BW, Liu RS. Positron emission tomography in asymptomatic gene carriers of Machado-Joseph disease. J Neurol Neurosurg Psychiatry 1998; 64:499-504. 88. Shinotoh H, Thiessen B, Snow BJ, Hashimoto S, MacLeod P, Silveira I, Rouleau GA, Schulzer M, Calne DB. Fluorodopa and raclopride PET analysis of patients with Machado-Joseph disease. Neurology 1997; 49: 1133-1 136. 89. Abele M, Burk K, Andres F,Topka H, Laccone F, Bosch S, Brice A, Cancel G, Dichgans J, Klockgether T, Autosomal dominant cerebellar ataxia type I. Nerve conduction and evoked potentials in families with SCAl, SCA2 and SCA3. Brain 1997;120:2141-2148. 90. Klockgether T, Schols L, Abele M, Burk K, Topka H, Andres F, Amoiridis G, Ludtke R, Riess 0, Laccone F, Dichgans J. Age related axonal neuropathy in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). J Neurol Neurosurg Psychiatry; 1999; 66:222-224. 91. Kanda T, Isozaki E, Kato S, Tanabe H, Oda M. Type I11 Machado-Joseph disease in a Japanese family:a clinicopathological study with special reference to the peripheral nervous system. Clin Neuropath01 1988: 134-141. 92. Schols L, Amoiridis G, Bornke C, Przuntek H. Sympathetic skin response in cerebellar ataxias. Electroencephalogr Clin Neurophysiol 1997; 102:53P. 93. Schols L, Amoiridis G, Langkafel M, ScholsS, Przuntek H. Motor evoked potentials in the spinocerebellar ataxias type l and type 3. Muscle Nerve 1997; 20:226228. 94. Rivaud-Pechoux S, Durr A, Gaymard B, Cancel G, Ploner CJ, Agid Y, Brice A, Pierrot-Deseilligny C. Eye movement abnormalities correlate with genotype in autosomal dominant cerebellar ataxia typeI. A m Neurol 1998; 43:297-302. 95. World Federation of Neurology. Research Committee. Research Group on Huntington’s chorea. Ethical issues policy statement on Huntington’s disease molecular genetics predictive test. J Neurol Sci 1989; 27:327-332. 96. Van den Kerchove M, Evers-Kiebooms G, Kreuz F, Kroebel D, Legius E, Morgan M. Predictive and prenatal testing in hereditary ataxias. Genet Counc 1996; 7:325327.

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*

98. 99. 100.

101.

102. 103.

104.

Burgess MM, Hayden M. Patient’s rights to laboratory data: trinucleotide repeat length in Huntington disease. Am J Hum Genet 1996; 62:6-9. Tuite PJ,Lang AE. Severe and prolonged dysphagia complicating botulinum toxin A injections for dystonia in Machado-Jospeh disease. Neurology 1996; 46:846. Salsakibara R, Hattori T, Kita K, Arai K, Yamanishi T, Yasuda K. Stress induced urinary incontinence in patients with spinocerebellar degeneration. J Neurol Neurosurg Psychiatry 1998; 64:389-391. ScholsL,SchulteT,Mattern R, Berger K, Kraus P, Szymanski S, Przuntek H. Double-blind, placebo-controlled crossover study of trimethoprime sulfarnethoxazole in spinocerebellar ataxia type 3. Mov Disord 1998; 13(suppl 2):216. S, Aita J, Bird TT), GoRanurn LPW, Lundgren JK, Schut LJ, Ahrens MJ, Perlman mez C, Orr HT. Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAGexpansions among adult-onset ataxia patients from 3 11 families with dominant, recessive, or sporadic ataxia. Am J Hum Genet 1995; 57:603-608. Silveira I, Lopes-Cendes I, Kish S, et al. Frequency of spinocerebellar ataxia type 1, dentato~bropallidoluysianatrophy, and Machado-Joseph disease mutations ina large group of spinocerebellar ataxia patients. Neurology 1996; 46:2 14-2 18. Watanabe H, Tanaka F, Matsumoto M, Doyu M, Ando T, Mitsuma T, Sobue G. Frequency analysis of autosomal dominant cerebellar ataxias in Japanese patients and clinical characterization ofspinocerebellarataxiatype6.ClinGenet1998; 53:13-19. Matsumura R, Futamura N, FujirnotoY, Yanagimoto S, Horikawa H, Suzumura A, Takayanagi T. Spinocerebellar ataxia type 6: molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology1997;49:1238-1243.

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20 Spinocerebellar Ataxia Type4 Ying-Hui Fu and Louis J. PtaEek

University of Utah, Salt Lake Citg Utah

Michael Abele University of Bonn, Bonn, Germany

INTRODUCTION

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INTRODUCTION

The autosomal dominant cerebellar ataxias (ADCAs) area heterogeneous group of dominantly inherited disorders that have been divided into several types with different predominant clinical features (ADCA 1-111) (1). ADCA-I is character

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ized by supranuclear ophthalmoplegia, optic atrophy, basal ganglia symptoms, dementia, and amyotrophy;ADCA-I1 is distinct by having the additional feature of retinal degeneration; and ADCA-I11 is characterized by a purely cerebellar syndrome. More recent molecular genetic research established genetic heterogeneity of ADCA. Disease loci were assigned to chromosomes 6p (SCA1) (2), 12 q (SCA2) (3), 14q (SCA3) (4), 16q (SCA4) (5,6), llcen(SCA5) (7), 19p (SCA6) (8), 3p (SCA7) (9,10), 10q24 (SCA8) (11), and 22q13 (12) (SCA10). It was the cloningof the fragile-X mental retardation and myotonic dystrophy genes that led to the recognition that expanded trinucleotide repeats are the molecular basis of these diseases (13,14). Furthermore, the dynamic nature of these mutations-they may expand or contracton passage through meiosis-can lead to a worsening of phenotype as these disorders are transmitted through families. Individuals in subsequent generations are affected at earlier ages and with more severe disease. Anticipation was also noted in some of spinocerebellar ataxas ias (most notably SCA7). It was insight into the trinucleotide repeat expansion a mechanism of neurological disease with anticipation that allowed efficient cloning of the SCA1-3, 6, and 7 genes. The disease-causinggenesforSCA1,SCA2,SCA3,SCA6,andSCA7 have been cloned, and the mutations are unstable trinucleotide (CAC) repeat expansions within coding regions of the respective genes (8,15--21). The different SCA mutations cause distinct phenotypes with more or less characteristic clini(MRI) features cal,electrophysiological,andmagneticresonanceimaging (5-7,9,22-28). However, thereis considerable overlapof these syndromes and reliable diagnosison the basis of clinical featuresis possible only for SCA7(9,212). SCA1-3 and SCA5-7 are described in detail in the other chapters of this book. The description of the SCA4 locus as a distinct genotype dates back to a five-generation 1994 when wereportedlinkagetochromosomel6q22.1in family, with an autosomal dominant, late-onset spinocerebellar ataxia associated with sensory axonal neuropathy (5). This large family had been followed for many years and were said to have an autosomal dominant form of Friedreich’s ataxia because of the prominent posterior column findings on clinical examination. However, these patients do not have other findings that are characteristic of FA (see Chap. 6). Subsequent evaluation of additional branches of the family led to more precise mappingof the SCA4 locus(6). There have been several reports in the past about families with similar clinical features (29-35). Since Biernond reported clinical and neuropathological features in 1954, this type of ataxia is as ““Biemond’s ataxia”or“familialposteriorcolumn sometimesreferredto ataxia” (29). Because neuropathy canbe seen in allof the SCAs, it is impossible to classify patients as SCA4 without performing linkage analysis. However, we believe that SCA families in whom a very prominent sensory axonal neuropathy is present in all affected individuals are likely to have SCA4.

427

SCA4 seems to be an extremely rare disorder. Up to now, the Utah-Wyoming pedigree of Scandinavian origin reported by us is the only SCA4 family confirmed by linkage analysis (6). However, a definite statement on the prevalence is difficult because the gene has not been isolated yet; therefore, routine screening of patients with degenerative cerebellar ataxia is not possible. We have identified several additional families that clinically look very similar to our large SCA4 family. The ethnic backgrounds of these additional small families include Scandinavian, Spanish, and Italian origins. These additional familiesofare insufficient size to prove linkage to theSCA4 locus, but they may provide a valuable resource in our attempts to clone this gene.

The SCA4gene was mapped to chromosome 16q22.1 (6), with a maximum LOD score of 5-93 (0 = 0) at marker D16S397. The definite flanking markers from D 12 on the obligate recombinants areI) 16S514 at the centromeric side and 16S5 telomeric side.The genetic distance between these two markers is approximately 6 CM based on available genetic maps. We have used the information from the Genethon chromosome 16 map and have screened the CEPH YAC library with new markers to identify YAC clones to build a physical representation for the region. A totalof 36 YAC clones have been identified in the region. Thirty-two markers from this general region have been used to screen these YACs and to begin ordering them in a physical map. Deleted YACs and those containing short inserts were not characterized further. Fifteen YACs were selected for further characterization and more precise mapping. Eleven of these 15 clones have now been ordered into a contig with approximately 1X to 3X coverage (Fig. 1). We are currently identifying additional YACs from the region and obtaining end sequence to identify chimeric clones. Based on our minimum tiling setof YACs, the distance between the two flanking markers D16S514 and D16S512 is estimated to be 7-12 Mb.

IV. There are no neuropathological data for the SCA4 family that we reported (6). Neuropathological abnormalities in the families clinically resembling SCA4 include degeneration of the posterior columns and roots as well as demyelination of the trigeminal roots.In addition, mild atrophyof the cerebral cortex and severe

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A preliminary physical map of the SCA4 region: Screening of the CEPH YAC library with markers spanning the SCA4 locus has allowed identification of l l YAC clones that form a contiguous physical map across the region. Recoveryof the YAC ends is underway and will allow testing for whether these clones are chimeric. Identificationof additional YACs from the region are being isolated to give denser coverage of this region. The physical distance between the two flanking markers D16S514 and D16S512 is estimated to be 7-12 Mb.

atrophy of the cerebellar hemispheres with slight Purkinje cell loss is reported (29,35). Sural nerve biopsy revealed a severe loss of myelinated fibers (31,32).

The following descriptionof clinical features refers to our previous report (6). Of the 38 individuals examined, 20 were clinically affected. Although disease onset was most frequent in the fourth or fifth decade, age of onset ranged from 19 to 59 years. The median age of onset was 39.3 years. The first symptom noted by the patients was usually gait disturbance, followed by clumsiness of hands and often dysarthria. At presentation, most patients did not complain of neuropathic symptoms, although evidenceof a length-dependent neuropathy could invariably be demonstrated on examination: all had vibratory and joint position sense loss, and 95% had at least a minimal pinprick sensation The loss.course of the disease Loss is slowly progressive over decades, often leading to wheelchair dependence.

of proprioception and absent ankle-jerk reflexes were found in all patients. Pinprick sensation was impaired in all but one, and dysarthria was present in 50% of the patients. Less frequent findings were extensor plantar response (20%) and distal limb weakness (20%). Oculomotor disturbances were present in only15% of the patients, including sacchadic smooth pursuit and occasional square wave jerks. Two patients denied any neurological symptoms in spiteof clear evidence of clinical and electrophysiological affection. Similar to other dominantly inherited spinocerebellar ataxias, there is also evidence for anticipation in SCA4, at least in some branches of the family (6). The clinical findings are summarizedin Table 1. Anticipation in disease onset has been described in several neurodegenerativediseases,includingotherforms of dominantlyinheritedataxias.Several members of the fifth generation of our pedigree denied neurological symptoms, but had clear signs of neuropathy and ataxia or dysmetria on examination. The of the fourth generation; age of symptom onset was self-reported in all members le 1 ClinicalandElectrophysiological Characteristics of 20 SCA4 Patients

Median age of onset Fourth generation Fifth generation Gait ataxia Limb dysmetria Decreased sensation Vibration/joint position Pinprick Reflex abnormalities Absent ankle jerks Absent knee jerks Complete areflexia Dysarthria Limb weakness Distal Proximal and distal Extensor plantar response Oculomotor signs Sacchadic visual pursuit Square wave jerks Abnormal SNAP (13 patients) Absent sural nerve response Absent radial nerve response SNAP, sensory nerve action potential.

39.3 yr 41.9 yr 36.7 yr 95%

95% 100% 100% 95% 100%

100% 85%

25% 50% 20% 10% 20% 15% 10% 5%

100% 92% 23%

Fu et al.

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therefore, intergenerational comparisons of reported age of onset are not ideal. Reliable ages of onset could be ascertained for nine individuals in each of the fourth and fifth generations. For this data set, the median age of onset was 41.9 years for the fourth generation, and 36.7 years for the fifth generation. Anticipation is suggested within some individual branches. One woman first noted gait difficulty at age 62, whereas her children noted gait difficulty at age 25 and 45 years. Similarly, one individual noted symptoms at age 45, whereas reported age of symptom onset in his children ranged from 1939toyears. In contrast, another individual reported symptoms at age 35, whereas his children denied symptoms, but had demonstrable signs at ages 46 and 49 years. It remains tobe seen whether a trinucleotide repeat SCA4, similar to the other cloned SCA genes, results from expansion. In the families resembling SCA4, some additional clinical features have been reported. These include vertical gaze-evoked nystagmus, sensory loss in the distribution of the trigeminal nerve, and hearing loss (29,32,35).

Sensory nerve conduction studies in the reportedSCA4 family revealed sensory axonal neuropathy in all 13 patients examined (6). Sensory nerve action potentials of the sural nerve were absent in l 2 out of 13 patients; the 1 patient with preserved sural nerve response had a decreased amplitude of the radial sensory nerve action potential (see Table l).In spite of clinical and electrophysiological evidence of sensory neuropathy inall patients, most of them did not complainof symptoms of neuropathy. In the families resembling SCA4, possible electrophysiological features included abnormal somatosensory, visual or brain stem auditory-evoked potentials (3 1,32,35).The reported computed tomography or magnetic resonance imaging (CTMRI) scans in these families were normal (31,32). SCA4 can be supposed if patients present with ataxia and predominant sensory axonal neuropathy, which might be confirmed by nerve conduction studies. However, diagnosis of definite SCA4 is possible only by means of linkage analysis.

VII.

AGEMENT

The metabolic defect underlying SCA4is unknown. This iswhy there is no ratioa pronal treatment for the disease aside from supportive care. All patients with gressive hereditary ataxia should receive physiotherapy and, if necessary, speech therapy. Adaptation and adjustment can markedly attenuate the limitations in daily

431 life. Therefore, patients must be encouraged to train and extend their remaining capabilities. In addition, patients should be informed and counseled concerning the hereditary characterof the disease and possible implications for family planning.

l. Harding AE. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A studyl loffamilies, including descendants of the “the Drew family of Walworth.” Brain 1982; 1OS:l-28. 2. Zoghbi HY, Jodice C, Sandkuijl LA, et al. The gene for autosomal dominant spinocerebellar ataxia (SCA1) maps telomeric to the HLA complex and is closely linked to the D6S89 locus in three large kindreds. Am J Hum Genet 1991; 49:23-30. 3. Gispert S, Twells R, Orozco G, et al. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23-24.l. Nat Genet 1993; 4:295-299. 4. Stevanin G, Le GuernE, Ravise N, et al. A third locus for autosomal dominant cerebellar ataxia type I maps to chromosome 14q24.3-qter: evidence for the existence of a fourth locus. Am J Hum Genet 1994; S4:ll-20. S. Gardner K, Alderson K, Galster B, Kaplan C, Leppert M, Pt6cek LJ. Autosomal dominant spinocerebellar ataxia: clinical description of a distinct hereditary ataxia and genetic localization to chromosome 16 (SCA4) in a Utah kindred. Neurology 1994; 44:A361. 6. Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, LeppertMF, Kaplan C, Pthcek LJ. Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 1996; S9:392-399. 7. Ranum LP, Schut LJ, Lundgren JK, Orr HT, Livingston DM. Spinocerebellar ataxia type S in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet 1994; 8:280-284. 8. Zhuchenko 0, Bailey J, Bonnen P,Ashizawa T, Stockton DW, Amos C, Dobyns WE, Subramony SH, Zoghbi HY, Lee CC. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha l A-voltage-dependent calcium channel. Nat Genet 1997; 1S:62-69. 9. Gouw LC, Digre KB, Harris CP, Haines JH, Pt6cek LJ. Autosomal dominant cerebellar ataxia with retinal degeneration: clinical, neuropathologic, and genetic analysis of a large kindred. Neurology 1994; 44:1441-1447. 10. Benomar A,c o l s L, Stevanin G, et al. The gene for autosomal dominant cerebellar ataxia with pigmentary macular dystrophy maps to chromosome 3p12-p21.1. Nat Genet 1995; 10:84-88. 11. Nikali K, Isosomppi J, Lonnqvist T, Mao JI, Suomalainen A, Peltonen L. Toward cloning of a novel ataxia gene: refined assignment and physical map of the IOSCA locus (SCA8) on 10q24. Genomics 1997; 39:185-191. 12. Zu L, FigueroaKP, Grewal R, Pulst SM. Mapping of a new autosomal dominant spinocerebellar ataxia to chromosome 22. Am J Hum Genet 1999; 64:594--599.

43

U

et al.

13. Fu YH, Kuhl DP, Pizzuti A,et al. Variation of the CGG repeat at the fragile X site resultsingeneticinstability:resolution oftheShermanparadox.Cell1991; 67:1047-1058. 14. Fu YH, Pizzuti A, FenwickRC Jr, et al. An unstable triplet repeat ina gene related to myotonic muscular dystrophy. Science 1992; 255:1256-1258. l S. Orr HT, Chung MY, Banfi S, Kwiatkowski TJ Jr, Servadio A, Beaudet AL, McCall AE,DuvickLA,RanumLP,ZoghbiHY.Expansionofanunstabletrinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 1993; 4:221-226. 16. Imbert G, SaudouF, Yvert G, Devys D, Trottier Y, Garnier JM, Weber C, Mandel JL, Cancel G, Abbas N, Durr A, Didierjean0 , Stevanin G, AgidY, Brice A.Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats [see comments]. Nat Genet 1996; 14:285-291. 17. PulstSM,Nechiporuk A, Nechiporuk T, Gispert S, ChenXN,Lopes-CendesI, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, DeJong P, Rouleau CA, Auburger G, Korenberg JR, Figueroa C, Sahba S. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2 [see comments]. Nat Genet 1996; 14:269-276. 18. Sanpei K, Takano H, Igarashi S, et al. Identification of the spinocerebellar ataxia type 2 geneusingadirectidentification of repeatexpansionandcloningtechnique, DIRECT [see comments]. Nat Genet 1996; 14:277-284. 19. Kawaguchi Y, Okamoto T, TaniwakiM, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1 [see comments]. Nat Genet 1994; 8:221-228. 20. David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, Weber C, Imbert Sau- G, dou F, Antoniou E, Drabkin H, GemmillR, Giunti P, Benomar A, Wood N, Ruberg M, AgidY, Mandel JL, Brice A. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 1997; 17:65--70. 21 Gouw LG, Castaneda MA, McKenna CK, Digre KB, Pulst SM, Perlrnan S, Lee MS, Gomez C, Fischbeck K, Gagnon D, Storey E, Bird T, Jeri FR, Ptlicek LJ. Analysis of the dynamic mutation in the SCA7 gene shows marked parental effects on CAG repeat transmission. Hum Mol Genet 1998; 7525-532. 22. Ptlicek LJ. Autosomal dominant spinocerebellar atrophy with retinal degeneration. Clin Neurosci 1995; 3:28-32. M, Burk 23. KlockgetherT,Skalej M, Wedekind D, LuftAR, Welte D, Schulz JB, Abele K, Laccone F, Brice A, Dichgans J. Autosomal dominant cerebellar ataxia type I. MR1-based volumetry of posterior fossa structures and basal ganglia in spinocerebellar ataxia types I , 2 and 3. Brain 1998; 121:1687-1693. 24. Stevanin G, DurrA,David G, Didierjean 0, Cancel G, RivaudS, Tourbah A, Warter JM, Agid U, Brice A. Clinical and molecular features of spinocerebellar ataxia type 6 [see comments]. Neurology 1997; 49:1243-1246. 2s. Burk K, Stevanin G, Didierjean 0 , Cancel G, Trottier U, Skalej M, Abele M, Brice A,Dichgans J, Klockgether T. Clinical andgeneticanalysis of threeGerman kindreds with autosomal dominant cerebellar ataxia type I linked to the SCA2 locus. J Neurol 1997; 244:256-26 1. S, Brice A, Cancel G, 26.Abele M, BurkK,AndresF,TopkaH,LacconeF,Bosch *

27. 28. 29. 30. 31. 32. 33. 34. 35.

Dichgans J, Klockgether T. Autosomal dominant cerebellar ataxia type I. Nerve conductionandevokedpotentialstudiesinfamilieswithSCA1,SCA2,andSCA3. Brain1997;120:2141-2148. Schols L, Amoiridis G, Buttner T, Przuntek H, Epplen JT, Riess0.Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol 1997; 42:924-932. Burk K, Abele M, Fetter M, Dichgans J, Skalej M, Laccone F, Didierjean 0, Brice A, Klockgether T. Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCAI, SCA2 and SCA3. Brain 1996; 119: 1497-1505. Biemond A.La forme radiculo-cordonnale postdrieure des ddgdn6rescences spinocdrdbelleuses. Rev Neurol 1954; 91:2-21. Bennett RH, Ludvigson P, DeLeon G, BerryG. Large-fiber sensory neuronopathy in autosomal dominant spinocerebellar degeneration. Arch Neurol 1984; 41: 175-178. van Dijk GW, Wo&e JH, Oey PL, Franssen H, Ippel PF, Veldrnan H. A new variant of sensory ataxic neuropathy with autosomal dominant inheritance [see comments]. Brain 1995; 118: 1557-1563. Gemignani F, Pavesi G, Marbini A.A new variant of sensory ataxic neuropathy with autosomal dominant inheritance [letter; comment]. Brain 1997; 120:379-380. Marbini A, Pavesi G, Cenacchi G, Mazzucchi A,Preda P, Gemignani F. Hereditary sensory and autonomic neuropathy with ataxia and late onset. Clin Neurol Neurosurg 1994; 961191-196. Singh N, Mehta M, RoyS. Familial posterior column ataxia (Biernond’s) with scoliosis. Eur Neurol 1973; 10:160-167. Nachmanoff DB, Segal RA, Dawson DM, Brown RB, De Girolarni U. Hereditary ataxia with sensory neuronopathy: Biemond’s ataxia. Neurology 1997; 48:273-275.

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21 Spinocerebellar Ataxia Type 5 Lawrence J. Schut CentraCare, St. Cloud, Minnesota

John W. Day, H. Brent Clark, Michael D. Koob, and Laura P. W. Ranum University of Minnesota, Minnea~olis,Minnesota

INTRODUCTION I.

436

11. MOLECULAR PATHOGENESIS Anticipation A. B, GeneticandPhysicalMapping C. RepeatExpansionDetectionandRAPIDCloning Analysis

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In 1992 we identified a ten-generation family with a clinically mild autosomal dominant formof spinocerebellar ataxia (1). This Caucasian kindred has two major branches that both trace their ancestries to the paternal grandparents of President Lincoln (Fig. 1). We have collected blood samples from 202 members (58 affected) of this kindred. Abbreviated versionsof the two branchesof the family are shown in Fig, 2. After excluding linkage to the known ataxia loci, we performed a genome-wide screen and mapped the disease locus, spinocerebellar ataxia type 5 (SCAS) to chromosome 11 (1). The SCAS form of ataxia is clinically distinct from SCA1-3, and SCA7 (2,3), in that SCAS is more benign, primarily affecting the cerebellum (1). In general, the adult-onset cases appear similar to patients with SCA6 (4) and to previously described families with relatively “pure” forms of cerebellar ataxia (596). Disease onset is typically in the third or fourth decade, but can range from 10 to 68 years, beginning with a mild disturbance of gait, incoordinationof upper extremities, and slurred speech. Signs and symptoms progress over several decades. Although adult-onsetSCAS is disabling, the most striking clinical distinctions from SCAl-3 and SCA7 are that SCAS progresses more slowly and generally does not shorten life (1). This clinical diEerence is likely due to the lack of bulbar paralysis in all of the adult-onset SCAS patients examined. For other forms of dominant ataxia, bulbar paralysis often leads to a weakened ability to combat recurrent pneumonia(7). Two of the juvenile-onset SCAS cases, who are still young, have some bulbar involvement that may shorten their life span.

Eilathsheba I

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President Abraham Lincoln

Figure 1 The cornrnon ancestryof the two branches of the family: The solid square and circle indicate President Lincoln’ S uncle Josiah and aunt Mary who passed the ataxia gene to their descendants. (From Ref. l .)

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MOLECULARPATHOGENESIS

A. Anticipation Because anticipation resulting from trinucleotide expansions has been found in families with other formsof spinocerebellar ataxia (8,9), we examined the SCAS family for evidence of earlier ages of onset in progressive generations. Table 1 shows the ages of onset for parent-offspring pairs for maternally and paternally inherited SCAS. The mean ages at onset for the older (43.3 years) versus younger 0.001).Although the av(29.9 years) generations are significantly different (p (- 15.7 years) and paternally(- 9.3 erage decrease in age at onset for maternally years) inherited ataxiado not significantly differ from one another, the most dramatic examples of decreasing ages at onset that we have observed are for materof nal transmissions. For instance, there are several three-generation examples anticipation in which grandmothers have onsets 10-20 years later in life than their daughters, who in turn, have onsets10-20 years later in life than their children. Furthermore, allfive cases of juvenile-onset ( l 0-1 8 years) SCAS were maternally inherited. Although anticipation causedby an unstable trinucleotide repeat expansion is an attractive explanation for these data, the decrease in age at onset among the parent-offspring pairs could also be explainedby an ascertainment bias. For example, the age at onset difference for the older versus the younger generations will be lessened when affected offspring, who do not currently exhibit signs of the disease, are included in the calculation in future years as they become symptomatic,

B. GeneticandPhysicalMapping After mapping the SCAS gene to the centromeric region of chromosome 11 (l), we constructed a high-resolution genetic mapof the region, positioningSCA.5 to summary of the pairwiseLOD scores the long armof chromosome 11 (1 lq13). A for selected markers is presented inTable 2. Haplotype analyses using 27 microsatellite markers from the region positions SCAS to within an approximately 3-CM region. As a first step toward physically isolating and characterizing the SCAS gene, we constructed a yeast artifical chromosome(YAC) clone contig covering approximately 90% of the SCAS region. Because of the marked anticipationobserved for this kindred, clones from this contig have been used to identify and isolatetrinucleotiderepeats.FivecandidateCAGrepeatsandcorresponding flanking sequence were isolated from YACs in the region and, by subsequent polymerase chain reaction (PCR) analyses, were shown not be to involved in the SCAS disease process.We continue to use a positional cloning strategy to isolate the gene.

Spinocerebellar Ataxia Type5

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al.

et

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Schut

Table 1 Age at Onset for Maternal Versus Paternal Transmission

ge AgeChild Father change AgeChild Mother 68 68 68 40 22 59 59 36 55 26 39 39 29 29 28 28 Average change

28 40 30 25 20 36 18 33 25 30 28 32

50

24

13 10

-18 -40 20 -28 4210 +3 29 -39 -23 38 -18 28 22 50 -2 -14 -9 -1 +3 -15 -18 -15.7 yr

-18

50 32 50 37 50 40 40 50 30 27 38 45 Average change

-13

-30 +2 -11 -20

+l1

-10 +5 -9.3 yr

Source: Ref. 1

C.

RepeatExpansionDetectionandRAPID Cloning Analysis

Because the marked anticipation observed for this family would be consistent with the possible involvement of a trinucleotide repeat expansion, we have performed experiments to determine whether or not a CAGKTG repeat expansion is involved in the disease. Repeat expansion detection (RED) assays (10) were performed on genomic DNA from affected members of the SCAS family. The RED assay is an elegant technique that detects potentially pathological trinucleotide repeat expansions without knowledge of chromosomal location (10). Human genomic DNA is used as a template for a two-step ligation-cycling process that generates sequence-specific [(CAG)nJ oligonucleotide multimers when exTable 2 Painvise Lod Scores Lod Scores at 0 =

0.05

0.01

0.00 Marker DllS905 DllS913 INT2

" M )

14.66 "CO

11.02 14.39 12.60

12.26 13.28 14.40

11.94 11.85 14.07

10.04 8.83 11.66

7.26 5.64 8.18

3.77 2.48 4.05

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panded trinucleotide sequences are present in the genome. We have painstakingly optimized the RED assay in our laboratory using genomic DNA from SCA1, SCA3, HD, and DM patients withCAGKTG repeat expansions of known sizes. The RED products from control samples areof the predicted size and the results are highly reproducible. We have applied this technology to analyze DNA from members of the SCA5 family with juvenile-onset ataxia. To further investigate whether or not the CAG repeat expansions that were detected by RED analysis in the SCA5 family were pathogenic,we developed a procedure that isolates flanking sequence surrounding specific CAG repeat expansions that are detectedby RED analysis. Our method is called repeat analysis pooled isolation and detection (RAPID) of expanded trinucleotide repeats 1). (1 In general,thisprocessusesanoptimizedREDprotocoltofollowtherepeat through a seriesof enrichment steps until a single, isolated clone is obtained. The nucleotide sequence flanking the repeat is then determined and used to design a PCR assay to determine if a particular repeat cosegregates with a given disease. We demonstrated the power of RAPID cloning by independently isolating the expanded CAG repeat involved in SCA7(1 1)and, most recently,by isolating an untranslated CTG expansion that causes another a novel formof ataxia (SCA8) (12). Our RED and RAPID analyses indicate that SCAS is not causedby a CAG expansion of approximately 40 repeats or more. Although there is no evidence that a trinucleotide repeat underlies SCA5, a short CAGKTG tract (<40 repeats) or another trinucleotide motif may cause this disease.

111.

CLINICAL FEATURES

Progressive ataxiaof gait with truncal instability is the core clinical feature of the disease in this family. The mean age of onset was 33.0 t 13 years. The clinical features of affected family members are summarized in Table 3. Of the 58 affected individuals examined, only 6 had normal gait. Patient complaints early in the disease process consist of unsteadiness with one-foot stand in a shower, uncertainty negotiating stairs, or excessive stumbling. There is a gradual progression over many years, only sometimes progressing to wheelchair dependence. Ataxia of the upper limbs occurred in more than90% of individuals diagnosed with the disease.The coordination disturbances of the upper limbs arenot as marked as those affecting the lower limbs. In fact, the upper limb incoordination may be detectable only in performanceof finger-to-nose testing or rhythmic supination-pronation of one hand in the palm of the other. Most patients complain of deterioration in handwriting or other activities requiringfine finger dexterity. Only four individuals in their seventh to ninth decades of life were severely disabled by their upper extremity ataxia. Over 75% of affected individuals had cerebellar dysarthria with no evidence of bulbar or spastic components. Communication posed only minor prob-

Schut et al.

442 Table 3 ClinicalFeatures of SCAS

Limb ataxia Gait ataxia Truncal ataxia Abnormal eye movements Abnormal romberg Sensory Dysarthria Abnormal 3-cough sequence Muscle weakness and atrophy Bulbar abnormalities Hypoactive tendon reflexes Hyperactive tendon reflexes Babinski sign

++++ ++++ +++ +++ +++ ++ +++ +/-

-

+/-

+ ++

-

++++,2 9 0 % ; +++,S0 to 89%; ++,25 to 49%; +, 10% to 24%; +/-, 2 to 9%; -, <2%

lems for most individuals and only interfered with verbal communication in one individual. No one in the family had dysarthria as the sole abnormal finding. Mild sensory deficits were found in approximately one third of the individuals. Eye movement abnormalities found in approximatelyhalf of the affected individuals included mild gaze-evoked nystagmus, square wave jerks, and saccadic intrusions during smooth pursuit. None of the affected subjects had tongue atrophy, although two individuals may have shown fasciculations, one of whom developed symptoms of the disease at age10. Brisk reflexes suggested pyramidal tract of the affected individuals, with only one involvement in approximately one third individual having extensor plantar reflexes. Five family members had early onsetof disease, with initial symptoms developing before age20. In addition to the usual cerebellar findings these patients also demonstrated signs of mild bulbar or pyramidal tract involvement. It is not yet clear whether family members with early onset will eventually develop a more severe life-threatening disease due to bulbar atrophy, pyramidal tract degeneration or basal ganglia disease. Although brainstem involvement and respiratory difficulties often lead to premature death for the more severe forms of ataxia such as SCA1, SCA2, SCA3, and SCA7, we have not seen this severe clinical picture for adult-onset SCAS.

IV. NEUROIMAGING Computedtomography(CT)andMRIbrainscanshavebeenperformed on twelveindividualsaffectedwith SCAS. Minimallyaffectedsubjectshaveno

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definite abnormalities. In more markedly affected family members, atrophy of the cerebellar vermis andof the cerebellar hemispheres is evident. Nonspecific white matter lesions with increased TZsignal intensity are seen in the cerebral hemispheres of some affected individuals, and minimal cerebral atrophy is evident in a minority of subjects. Brain stem atrophy has not been evident in the imaging studies done to date.

V.

NEUROPATHOLOGY

The brain of one affected SCAS individual, an 89-year-old woman, has been examined neuropathologically. This woman had been evaluated clinically S years before her death, at which time she had slight ataxia in the upper extremities, moderate ataxia in the lower extremities, and minimal dysarthria. Her sensory examination was normal, and there was no abnormality of tone or movement other than the ataxia. The combination of her ataxia and severe arthritis made her unable to walk for the last 10 years of her life. Atypical for SCAS, this woman was also demented due to superimposed, pathologically confirmed Alzheimer’S disease. The brain weighed 940 g with frontal and temporal atrophy. The cerebellum was grossly shrunken(88 g), most notably in the anterior vermis. There was severe loss of Purkinje cells in most areas of the cortex, with shrinkage of the molecular layer, milder loss of granular neurons, and frequent empty basket fibers. Cortical pathology in the cerebellum was most pronounced in the vermis, where there was more evidence of loss of granular neurons.The cerebellar hemispheres were more severely involved in the superior portions, with mild loss of granular neurons, and least involved in the tonsillar cortex. The deep cerebellar loss. The inferior olivary nuclei had nuclei were gliotic, without obvious neuronal mild to moderate neuronal loss, more severe dorsally. The basis pontis, red nuclei, cranial nerve nuclei, dorsal columns, Clarke’s nuclei, and spinocerebellar tracts were intact. Severe changes of Alzheimer’s disease and mild amyloid angiopathy were also present. Pathologically, in contrast with most dominantly inherited spinocerebellar ataxias, SCAS appears to be principally a cerebellar cortical degeneration with predominant effects on Purkinje cells.

VI.

~AN~GE~ENT

Once a diagnosisof ataxia is made, there remains much to be done in the care of the patient. Patients want to learn what ataxia is, what causes it, and what influence it will have on their lives. A simply understood explanation is that the cerebellum and its connections provide coordination or smooth movements in walking,use of hands,andspeech. Any disorderaffectingthesenervoussystem structures leads to staggering, tripping, falling, clumsiness, and slurred speech.

444

The major disabilityin SCAS is impaired mobility, but that need not significantly curtail one’s lifestyle. Skilled physical therapists can evaluate a patient’s mobility,andadviseappropriateassistivedevices,includingcanes,crutches, walkers, and wheelchairs. Using proper-training techniques the patient with ataxia generally becomes more independent and mobile. Exercise builds stamina and strength that are needed in transfers, as well as in walking and standing. Normal individuals perform activities of daily living effortlessly. When ataxia sets in, it causes lossof dexterity; simple tasks become major challenges. Occupational therapists can evaluate the disability and recommend special aides for eating, personal hygiene, and dressing. The goal is to maximize independence. Slurred speech interferes with communication to varying degrees. Occasionally, swallowingis also affected.A speech pathologist provides a critical service in assessing the potential for aspiration and choking. Also, speech therapy may improve a patient’s communication skills. The emotionaleffect of havingadisablingdisease,suchashereditary ataxia, can be devastating. When SCAS is diagnosed in patients with ataxia by their neurologist the prognosis given is often excessively pessimistic and inconsistent with the rather benign disease course that is usually observed. Direct gene testing and education should provide patients with various types of ataxia more accurate prognostic information in the future. Often there is denial of disability during the early stagesof stumbling and clumsiness.As the losses become undeniable to afflicted individuals, they begin to grieve the losses and may require counseling and antidepressant medications. There are no neuroactive drugs that will control the symptoms of ataxia.

In summary, SCAS is clinically milder than SCA1, SCA2, SCA3, and SCA7. In contrast to many of the SCAs, SCAS primarily affects the cerebellum.Althoug~ marked anticipation has been observed, we have not detected a CAG/CTG repeat expansion by REDRAPID analysis. The eventual characterization of the SCAS ataxia gene will lead to a better understandingof the interdependence and functioning of the neuronal systems that degenerate during the SCA processes.

1.RanumLPW,SchutLJ,Lundgren JK, O n HT, Livingston DM. Spinocerebellar ataxia type5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet 1994: 8:280-284.

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2. Yagishita S, Inoue M. Clinicopathology of spinocerebellar degeneration-its correlation to the unstable CAG repeat of the affected gene. Pathol Int 1997; 47: 1-15. 3. Gouw LC, Digre KB, Harris CP, Kaplan CD, Haines JH, Ptacek LJ. Autosomal dominant cerebellar ataxia with retinal degeneration: clinical, neuropathologic and genetic analysis of a large kindred. Neurology 1994; 44:1441-1447. 4. Zhuchenko 0,Bailey J, BonnenP, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC. Autosomal dominant cerebellar ataxia (SCA6) lA-voltage-dependent associated with small polyglutamine expansions in the alphacalcium channel. Nat Genet 1997; 15:62-69. 5. Holmes G. A form of familial degenerationof the cerebellum. Brain 1907; 30:466489. 6. Harding A. Classification of the hereditary ataxias and paraplegias. Lancet 1983; 111151-1155. 7. Zoghbi HY. The spinocerebellar degenerations. Curr Neurol 199 1;11:121-144. 8. Klockgether T, Evert B. Genes involved in hereditary ataxias. Trends Neurosci 1998; 21:413-418. 9. BriceA.Unstablemutationsandneurodegenerativedisorders.JNeurol1998; 2451505-510. 10. Schalling NI, Hudson TJ, Buetow KH, Housrnan DE. Direct detection of novel expanded trinucleotide repeats in the human genome. Nat Genet 1993; 4:135-139. 11. Koob MD, Benzow KA, Bird TD, Day JW, Moseley NIL, Ranurn LPW. Rapid cloningofexpandedtrinucleotiderepeatsequencesfromgenomicDNA.NatGenet 1998;18:72-75. 12. Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW, Ranum LPW. AnuntranslatedCTGexpansioncausesanovelformofspinocerebellarataxia (SCAS). Nat Genet 1999; 21:379-384.

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Episodic Ataxia Type2 and Spinocerebellar Ataxia Type6 Robert W. Baioh and Joanna C. Jen UCLA School of Medicine,Los Angeles, California

INTRODUCTION I.

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11. EPIDEMIOLOGY

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111. MOLECULAR PATHOGENESIS A. CACNAl A-Encoded a,,-Subunit of Voltage-Dependent Calcium Channel B. SCAG EA-2 C. D. OtherAllelicDisorders of Symptoms and Signs E. Molecular Mechanism with Mutations in CACNAlA F. Responsiveness to Acetazolamide

449

IV. NEUROPATHOLOGY A. SCAG B. EA-2

456 456 456

V.

CLINICAL FEATURES A. SCAG B. EA-2

VI.ANCILLARYTESTS VII. MANAGEMENT REFERENCES

450 45 1 454 454 455 456

457 457 457 46 1 46 1 464

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I. INTRODUCTION Episodic ataxia type 2 (EA-2) is an autosomal dominant disorder characterized by episodes of ataxia lasting hours to days with interictal eye movement abnormalities. Exertion and stress commonly precipitate the episodes. Acetazolamide often dramatically stops the spells.Some individuals develop a slow progressive baseline ataxia with evidenceof cerebellar atrophy later in life. Affected patients may have migraine; some have basilar migraine. In 1995, the disease locus for EA-2 was localized to a region on chromosome 19p previously shown to be the disease locus for familial hemiplegic migraine (FHM) (1-3). FHM is a dominantly inherited subtype to migraine with aura, characterized by recurrent attacks of headache with ictal hemiparesis. Recovery between attacks is usually complete but, in some families, there is an associated slowly progressive baseline ataxia not unlike that seen in EA-2. Symptoms of EA-2, FHM, and basilar migraine overlap, suggesting that EA-2 and FHM may be forms of basilar migraine (4). A calcium channel subunit gene mapped to the EA-2 and FHM locus on chromosome 19p and, in 1996, Ophoff and colleaguesdefined the complex structure of this gene CACNAlA which spans 300,000 base pairs (bp) and consists of 47 exons that encodes the a,,-subunit with 2261 amino acids (5). These investigators went on to analyze the exons and flanking introns of CACNAlA and identified point mutations that resulted in premature stop, or that interfered with splicing, in two families with EA-2 and identified missense mutations in four families with FHM. Thus EA-2 and FHM are allelic disorders. Later in 1996, Zhucbenko and colleagues were searching for CAG repeat expansions that mightbe associated with cerebellar ataxia syndromeswhen they found a CAG repeat expansion in CACNAlA located on chromosome 19p (6). They then proceeded to screen their ataxia population for expansions of the CAG repeat. They found eight unrelated patients with late-onset ataxia who had alleles of repeats (4-16) seen in 475 with repeat numbers(21-27) larger than the number nonataxia persons. The expanded CAG repeats segregated with the phenotype in every family. This CAG repeat was in the open-reading frame of the gene and predicted ap o l y g l u t ~ i n tract e in the COOH-terminus.The families with the expanded CAG repeat exhibited a late-onset, slowly progressive cerebellar ataxia syndrome. Subsequently, there have been numerous reportsof large numbers of families around the world with the expandedCAC repeat in CACNAlA, called spinocerebellar ataxia-6 (SCA6).Some of these families have exhibited episodic symptoms overlapping with EA-2. Subsequently, Yue and colleagues (7) identified a family with severe progressive ataxia who exhibited a missense mutation in the critical pore regionof CACNAlA. Some members had episodesof ataxia typical of EA-2.Finallymutationsinthegeneencodingforthesame a,,-calcium channel subunit in mice have been identified in two recessive mu-

449 tants with ataxia (8). Homozygous point mutations cause epilepsy and ataxia in the mutant mouse tottering (tg) and mutations that produce novel sequences in the intracellular COOH-terminus cause ataxia and epilepsy in the mutant mouse leaner (tgLA). Because a great deal is already known about the function of calcium channels and their distribution within the nervous system, the range of mutations in CACNAl Aprovides a unique model with which to begin the process of explaining clinical symptoms and signs on the basis of specific mutations.

The prevalence of inherited spinocerebellar ataxiasin the general population has notbeenwellstudiedalthoughitisprobably no more than 1 :100,000to 2 :100,000 in unselected populations (9). In some isolated populations, however, the prevalence can beas high as 20:100,000 to25 :100,000. Abouta third of the inherited spinocerebellar ataxia syndromes are inherited in an autosomal dominant fashion (ADCA). Preliminary studies of the percentage of cases of ADCA a low of 1% in France to a high of 3 1% in Japan with SCA6 range from (Table 1) (10-13). Familial episodic ataxia type 2 (EA-2) is a rare disease, representing less than 1% of the inherited ataxia syndromes.So far there have been only a few reported families either linked to the region on chromosome 19p whereCACNAl A is located or mutations have been identified in CACNAlA (1,2,3,S,14,1S).

Both SCA6 and EA-2 result from mutations in the calcium channel CACNAlA thatcodesforthemaintransmembranecomponent of a calciumchannel expressed throughout the brain, but expressed particularly heavily in the cerebellum (16-18). Table l'

Epidemiology Age Families Families with

(31) 20 Japan France (22)Germany17 USA

of (%)

SCA6 ADCA with Country 64 74 77 7s

1 (1)

9 (12)

(range) onset 52 tr: 13 (28-73) 45 tr: 14 (24-67) 11 11 S3 tr(30-71) 13 51 tr: 6

Ref.

l0 12

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A.

and

CACNAIA-Encoded a,,-Subunit Calcium Channel

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of Voltage-Dependent

Voltage-dependent calcium channels are heteromeric complexes with a selective calcium permeability in response to membrane depolarization. The influx as a ubiquitous of calcium ions into the cell through calcium channels serves second messenger, critical in many cellular functions, ranging from membrane excitability,neurotransmitterreleaseandexcitation-contractioncoupling,to alAmigration,generegulation,andcelldeath. CACNAlA encodesthe subunit, which likely forms the endogenous P/Q channels most abundant in the cerebellum. Each of the four homologous domains in the a,,-calcium channel (S 1-S6) (19) subunit has six putative a-helical membrane-spanning segments (Fig. 1A). The central pore is lined by four P regions (pore loops) interconS5 andS6 of eachdomain. nectingputativemembrane-spanningsegments Calciumselectivityisachieved by interactionbetweencalciumionsand

OUTSIDE

INSIDE

Figure 1 (A)Schematic drawing of the a,,-subunit of a voltage-gated calcium channel coded for by CACNAlA.Each of the four domains (I-IV)has six transmembrane segments (1-6). The pore-forming regions (pore loops) are between segments 5 and 6. (B) Illustration of a three-dimensional model and how the central ofpore the channel is thought to be formed by pore loops from the four domains.

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high-affinity-binding sitesinthe P regions.Studiesusingmutagenesisto change specific amino acids in the pore region have shown that the selectivity filterisformed by theporeloops,whicharerelativelyshortpolypeptide segments that extend into the aqueous pore from one side of the membrane (20,21). The large portion of the pore loop is near the extracellular face of the channel, and only a small segment extends into the membrane to produce the selectivity filter. Theloopsextendingintotheporeallowtheionchannelto placeproperfunctionalgroupsatthecorrectpositionsinspacetoachieve selective ion binding. The calcium channels are believed to be composedof the integral membrane subunits (S1-S6) arranged in a ring, similar to the staves of a barrel, around the central pore (see Fig. 1B) (22). The four pore loops reach into the barrel and confer the ion conduction properties. Channel gating arises fromconformationalchangesinthetransmembranebarrelstaves of the subunits. Several other subunits interact with the a,,-subunit to modify its calcium permeability in response to membrane depolarization (19). Several isoforms of the alAcalcium subunit have been identified including a short form about half the size of the standard alA subunit (23). Furthermore, numerous factors modulate the calcium channel activities, including differential, but overlapping, expression of subunitisoforms,differentialsubcellulardistribution,association with G proteins, and differential phosphorylation (24).

B. SCAG The CAG-repeatexpansion CACNAlA responsiblefor SCAG iswithinthe open-reading frame and is predicted to encode a polyglutamine tract in a subset of isoforms of a,,-expressed in the cerebellum (Fig. 2; Table 2) (6). Unlike the otherCAGrepeatexpansionataxiasyndromes, SCAG resultsfromaslight expansion from an upper normal range of 19 to a disease-causing range of 20 and higher. Also unlike the other CAG repeat expansion syndromes, the CAG repeatexpansioncausing SCAG ismostlystablewhentransmittedfromone generation to another (anticipation has not been seen in clinical pedigrees). An exception to this general rule was a family reported by Jodice et al. (25) in whom a father with a 20-CAG repeat expansion passed on a 25-CAG repeat expansion to one of his five children. Three of the five children received the 20-CAGrepeatexpansion of thefather. The offspringwhoreceivedthe 25-CAGrepeatexpansionpasseditonunchangedtohistwochildren.Remarkably the phenotypes varied with the length of the CAG repeat expansion inthisunusualfamily.Familymemberswitha20-CAGrepeatexpansion exhibitedepisodicsymptoms,withminimalinterictalfindings,whereasthe memberswiththe25-CAGrepeatexpansionexhibitedaprogressiveataxia

452

DOM

Figure 2 Location of predicted mutations in the a,A-subunit in families with episodic spinocerebellar ataxia type6 ataxia, type 2 (EA-2), familial hemiplegic migraine(FHM), (SCAG), and episodic/progressive ataxia(EPA). See Table 2 for descriptionof the mutations in CACNA1A.

without episodic features. So far only one other intergeneration expansion in a CAG repeat with SCAG has been reported in about 100 meioses reported in familieswithSCA6.Thus,althoughtheexpandedCAGrepeatalleleswith SCAG appear to be much more stable than that of the more typical CAG repeat 35 repeats,moreinstability may beidentifiedas expansionswithmorethan larger numbers of families are studied. Although the great majority of patients with SCAG have only one allele with an expanded CAG repeat, persons homozygous for an expanded CAG re(10,13,26) found that individuals hopeat have been reported. Several groups mozygous for the CAG repeat hadan earlier age of onset and more severe clinicalmanifestationsthanotherfamilymemberswho had onenormalandone (2’7) identified three indiexpanded allele. On the other hand, Takiyama et al. viduals homozygous for the expanded CAG repeat (21121 ), only two of whom were symptomatic, and noted no apparent differences in the clinical phenotype between the persons who were homozygous and those who were heterozygous for the expanded GAG repeat. Differences in the sizeof the CAG repeat expansion might explain the difference in findings. Patients homozygous for larger repeat sizes (e.g.,>21) probably have a more severe clinical course tban heterozygous family members.

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EA-2

Ophoff et al. (5) initially reported two mutations disrupting the reading frame and thus predicting truncated al,-subunits in two families with EA-2 (see Fig. 2 and Table 2). Yue and colleagues (7) then identified a missense mutation in a family of with a severe progressive ataxia in some members and superimposed episodes vertigo and ataxia in others. This mutation predicted a glycine to arginine substitution at codon 293, a highly conserved amino acid in the critical pore loop region of the al, transmembrane subunit. These same researchers also identified a patient with acetazolamide-responsive episodic ataxia(EA-2) and no family history that showed a de novo mutation in exon 23 that predicted a premature stop code and a truncated protein (15). More recently, a nonsense mutation was identified in a large pedigree with episodic ataxia and interictal nystagmus previously linked to chromosome19p (family 3 in Ref.4; Table 2). Two (both female)of the 14 mutation carriers(8 female, 6 male) among 21 individuals (12 female, 9 male) spanningthreegenerationsareasymptomatic,demonstratingincompletepenetrance. Indeed, 1 of the asymptomatic mutation carriers has 2 children with episodic ataxia and interictal nystagmus.

D. Other Allelic Disorders In their initial report of the mutations in families with EA-2, Ophoff et al. also reported four different missense mutations in conserved functional domains in four families with familial hemiplegic migraine (FHM) (see Fig. 2 and Table 2) (5). In two of these families, there were interictal symptoms and signs of progressive cerebellar ataxia(FHIWPCA), whereas the other two families exhibited onlyhemiplegicmigraineepisodeswithoutinterictalfindings.Subsequently, Ducros et al. (29) studied 16 families with FHM and found missense mutations in 10 of them. Nine of 10 had the T666M mutation previously identified by Ophoff et al., and only 1 had anew missense mutation D715E. These mutations were not found in 12 probands from families with pure FHM. Mutations in genes encoding various calcium channel subunits have been identified in several recessive mouse mutants. Homozygous point mutations in the alAgene (P1802L, domain 2 P region) causes epilepsy and ataxia in the mu(8). NovelsequencesintheintercellularCOOHtantmousetottering(tg) terminus of the a,,-subunit also results in a mutant mouse phenotype leaner (tgLA) with ataxia and epilepsy(8). Burgess and colleagues (30) reported a mutation of a calcium channel gene with a predicted deletion of the highly conserved a,-binding motif in the @,-subunit in the mutant mouse lethargic, exhibitingbothataxiaandseizures.Characterization of thegeneticdefectsinthe stargazer and waggler mutants led to the identificationof a new neuronal calcium channel subunit-y (31).

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E. Molecular Mechanism of Symptoms and Signs with Mutations in CACNAI A Phenotypic variability among different pedigrees indicate that the location and type of mutation are important, whereas phenotypic variability among individuals with identical mutations suggest that other factors, including environmental, metabolic, gender, and other genetic factors, likely contribute to the phenotypic expression of these mutations. For example, in the large pedigree with episodic ataxia 3 in Ref.4; see Table 2), male members appreviously described in detail (family pear to be more severely affected than female members. Furthermore, all affected individuals except the most severely affected male member responded well to acetazolamide, with decreased frequency and severity of their ataxic spells. Individuals with mutations in CACNAlA demonstrate overlapping clinical features, suggesting that missense mutations, nonsense mutations, and CAG repeat expansions may affect channel and cellular function through similar mechanisms. A simple working hypothesis to explain the clinical syndromes associated with mutations inCACNAlA is that episodes are due to transient impairment of channel activation or to deactivation, whereas progressive interictal signs are due to chronic excess entry of calcium into the cell or release of intercellular calcium, leading to abnormal activation of intercellular signals and, ultimately, to cell death (apoptosis) ('7). Both mechanisms seem to occur with most mutations, although some mutations are relatively specific for episodic symptoms (e.g., families with pure FHM), whereas others produce predominantly progressive symptoms(e.g.,familieswithSCA6).Althoughinterrelated,thesetwodifferent pathophysiological mechanisms can be relatively independent, even among family members with the same mutation. Whether the relatively modest and stable GAG repeat expansion in SCA6 causes progressive ataxia through mechanisms similar to the larger, unstable CAG repeat expansions of the other SCA syndromes is unknown. Kraus et al. (32) introduced the four missense mutations, reported in families with FHM by Ophoff et al., into Xenopus laevis oocytes and investigated possible changes in channel function after functional expression of mutant subunits. Changes in channel gating were observed in three out of four of the mutants, but the time courseof recovery from channel inactivationwas accelerated in two and slower in the third compared with the wild-type. Although their data demonstrated that these missense mutations could alter inactivation gating of the calcium channel, they did not provide a clear explanation for how they cause clinical Symptoms becausetheywereassociatedwithbothincreasedand decreased calcium channel availability. Lau and colleagues(33) studied the expressionof alAmRNA and( x l A protein in the cerebella from 20-day-old homozygous leaner mice and control mice using in situ hybridization histochemistry and immunocytochemist~.They found

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no difference in the mRNA or protein expressionof the mutated , a subunit in the leaner mice, when compared with controls. Thus, they showed that thealAsubunit splice donor consensus sequence mutation carried by leaner mice does not result in any significant quantitative changes in either the mRNA or protein expression. Their data suggest that the leaner phenotype results from abnormal calcium channels that contain the altered a,,-subunits.

F. Responsivenessto Acetazolamide Calcium channels, such as CACNAl A, are exquisitely sensitive to changes in the concentration of pH and potassium(34). The decreasing pH (increasing the number of free protons) strongly inhibits ion permeation through open calcium channels. Recently, it has been shown that the protonation site in the L-type voltageregulated calcium channel lies with the pore(35). It is formed by a combination of conserved pore region glutamates, the amino acids shownbetokey to calcium selectivity of these channels (20). This mechanism is a simple molecular explanation for the modulatory effect of H+ ions on open channel flux and for the competition between H' ions and divalent cations.By increasing the extracellu(36), acetazolamide presumably stabilar proton concentration in the cerebellum lizes mutant channels that fail to properly inactivate.

IV. NEUROPATHOLOGY SCA6 A. The most prominent and consistent pathology associated withSCA6 is a degeneration of Purkinje cells in the cerebellar cortex(Table 3) (37). Granular neurons are relatively spared, and afferents to the cerebellum are uninvolved, with the exception of the inferior olives. Gliosis, identified in the inferior olives, the deep cerebellar nuclei, and vestibular nuclei, is probably secondary to loss of Purkinje cell efferents, because there is little evidence of neuronal degeneration in these structures. One patient with SCA6 showed axonal degeneration in the corticospinal tracts below the level off the medullary pyramids. This correlates with the clinical findingsof hyperreflexia and extensor plantar responses in some patients with SCA6, although these are infrequent findings. More patients with SCA6 will need to be studied beforewe can be sure that the corticospinal tract involvement is part of the SCA6 syndrome.

B. EA-2 There have been no studies reported mented EA-2.

of the pathology in a patient with docu-

457

The typical patient with SCA6 presents with a slowly progressive truncal ataxia beginning in the late 40s to early 50s (10-13,26). Dysarthria is the next most common symptom, followed by dysphagia, vertigo, and hypophonia. The mean age of onset of SAC6 has been remarkably consistent in the late 40s to early 50s, with a range of between 24 and 73 years of age. As with the other CAG repeat syndromes, there is an inverse relation between the ageof onset and the number of CAG repeats of CACNA1A (Fig. 3). A few cases with an expanded CAG repeat segment in CACNAl A have been reported without clinical symptoms or signs, but these patients rnay develop the disorder with longer follow-up. There does not appear to be any difference in the penetrance in men and women. Although the hallmark of SCA6 is a slowly progressive ataxia, episodic features are not uncommon. Patients often report fluctuations in the severity of A small subataxia related to stress and fatigue, and other environmental factors. set will have discrete episodes indistinguishable from the episodes associated with EA-2. Jen et al. (38) reported two families with SCA6 who experienced episodes of positional vertigo more than 20 years before the onset of progressive ataxia. The episodes of positional vertigo were associated with a central typeof positional nystagmus (downbeat). After late onset, the ataxia has an indolent course, rarely progressing to severe disability within the first l0 years. Many patients remained ambulatory even 20 years after onset. Because of its late onset and slow course, some cases of SCA6 rnay appear to be sporadic On neurologicalexamination,gaitataxiaandnystagmusarethemost prominentfindings.Horizontalgaze-evokednystagmusisalmostuniversally present, whereas spontaneous vertical nystagmus (usually downbeat) is seen in more than half of cases, Other cerebellar oculomotor findings are also common, such as impaired smooth pursuit and dysmetric saccades. Corticospinal tract findings such as hyperreflexia and extensor plantar responses occur in a minorityof patients, probably less than 20%. Mild sensory disturbances also occur in a small percentage of patients.

Episodic ataxia type2 is characterized by episodes of ataxia lasting hours and interictal nystagmus (1-4). The episodes vary from pure ataxia to combinationsof symptoms suggesting involvement of the cerebellum and brain stem and even occasionally the cortex. Vertigo, nausea, and vomiting are the most common as50% of patients. The episodes are sociated symptoms, being present in more than typically triggered by exercise and emotional stress and often relieved by acetazolamide. Other known triggers include alcohol, phenytoin, and caffeine.ofAge

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onset within genetically defined families with EA-2 range from age 2 to age 30 with several instancesof nonpenetrance, Whether the typeof missense mutation affects the age of onset or degree of penetrance awaits future studiesof families with many different mutations. About half of the patients report headaches that meet the IHS criteria for migraine (4). Later in life, some patients develop a slowly progressive truncal ataxia not unlike that seen with SCA6. On examination during an acute episode, patients typically show severe truncal ataxia, dysarthria, and even extremity ataxia. They may exhibit a spontaneous vertical nystagmus not seen during the interictal examination. When ex-

Ataxia Episodic

Type 2 and SCAG

461

amined in between episodes, the most common finding is a gaze-evoked nystagmus with features typical of rebound nystagmus. Spontaneous vertical nystagmus, particularly downbeat nystagmus, is seen in about a third of cases. This may begin with a positional downbeat nystagmus in the head-hanging position that gradually over time becomes a spontaneous downbeat nystagmus (38). Laterinthecourse,amildtruncalataxia may beseenalongwithimpaired smooth pursuit and saccade dysmetria, similar to that seen with SCA6.

VI. ANCILLARYTESTS The MRI scans of the brain often show atrophy particularlyof the midline both with SCAG and EA-2, particularly in patients with long-standing symptoms and signs (Fig. 4). Unlike the other SCA syndromes, however, the cortex, brain stem, and spinal cord are completely normal onMRI with these disorders. The family with the critical point mutation in the pore region of CACNAlA also exhibited atrophy of the cerebellum on MRI (7). Repetitive bursts of high-voltage 4- to 6-Hz generalized activity on EEG have been reported in two different families with EA-2 (39,40). A positron emission tomography (PET) study performed in a patient with EA-2 in between spells of ataxia demonstrated a decrease of glucose metabolism in the whole cerebellum, the inferior part of the temporal lobes, and the thalami (41). Eye movement recordings have demonstrated a unique, consistent oculomotor pattern in patients with SCAG (42). Saccade velocity remains normal but saccade dysmetria is common. Smooth pursuit and optokinetic responses are severely impaired and suppressionof vestibular-induced nystagmus is severely impaired. On the other hand, the vestibulo-ocular reflex gain is either high normal or increased. A similar, although less pronounced, oculomotor pattern is seen with eye movement recordings in patients with EA-2 The (4).finding of this oculomotor pattern in a patient with dominantly inherited, slowly progressive ataxia will effectively separate SCA6 from the other SCA syndromes (Fig. 5).

VII. MANAGEMENT Acetazolamide often has a dramatic effect on controlling the episodes of ataxia with EA-2 (4,43). There can be a variable response to acetazolamide, however, even within a single family with a known mutation.The family with a missense mutation in the pore region and severely progressive ataxia did not respond to acetazolamide (7). Acetazolamide presumably works by altering the pH within the cerebellum, thus stabilizing the mutated calcium channel (36).One typically begins with a low dose (125 mg/day) and then works upto an average effective

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Figure 4 MRIs (TI-weighted) showing the midline cerebellar atrophy in patients with (A) episodic ataxia type 2. (B) spinocerebellar ataxia type 6.

Episodic Ataxia Type 2 and SCA6

463

Figure 4 C~ntinued (C) episodic/progressiveataxia.Sagittalsectionsthroughthe cerebellar vermis.

dose between 500 and 750 mg/day. Most patients will experience paresthesiasof the extremities after taking the drug, but these symptoms typically decrease over time. The main long-term side effect is the development of kidney stones, which can be markedly decreased if the patient regularly drinks citrus juices. Patients with SCA6 who have episodic features may also respond to acetazolamide (38). It is unknown whether the long-term, slowly progressive ataxia is affected by the regular use of acetazolamide. Patients with known allergies to sulfa-containing drugs may have an allergic reaction to acetazolamide. There is relatively little experience with the other carbonic anhydrase inhibitors, but these drugs are probably as effective as acetazolamide. Unfortunately, patients allergic to acetazolamide are also often allergic to the other carbonic anhydrase inhibitors. Two children with EA-2 were reported to respond to the centrally active calcium channel blocker flunarizine (44). We have tried another centrally active calcium channel blocker nimodipine and other peripheral calcium channel blockers, including verapamil, with little success. Because emotional stress is often a trigger for attacks with both EA-2 and SCA6, stress management techniques such as biofeedback and meditation be can

464

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Figure 5 Summary of quantitative oculomotor findings in patients with different spinocerebellar ataxia syndromes (types 1, 2, 3, 6, and 7) caused by CAG repeat expansions. Patients with SCA6 have a characteristic patternof (l)normal saccade velocity, (2) high normid vestibulo-ocular reflex (VOR) gain, and (3) very low smooth pursuit and optokinetic (OKN) gain. (From Ref. 42.)

helpful controlling symptoms in some patients. Alcohol and caffeine should be avoided, and regular but modest exercise should be encouraged.

REFERENCES 1. Vahedi K, Joutel A, Van Bogaert P, Ducros A, Maciazeck J, Bach JF, Bousser MC, Tournier-Lasserve E. A gene for hereditary paroxysmal cerebellar ataxia maps to chromosome 19p. Ann Neurol 1995; 37289-293.

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2. Teh BT, Silburn P, Lindblad K, Betz R, Boyle R, Schalling M, Larsson C. Familial periodic cerebellar ataxia with myokymia maps to a 19-CM region19~13. on Am J Hum Genet 1995; 56: 1143-1449. 3. Kramer PL, Yue Q, Gancher ST, Nutt JG, Baloh R, Smith E, Browne D, Bussey K, Lovrien E, NelsonS. A locus for the nystagmus-associated form of episodic ataxia mapstoan1 1-CM regiononchromosome19p[letter].AmJHumGenet 1995;57:182-185. 4. Baloh RW, Yue Q, Furman JM, Nelson SF. Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. Ann Neurol 199’7; 41:8--16. 5. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SMG, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR. Familial hemiplegic migraine and episodicataxiatype-2arecaused bymutationsinthe Ca2+ channelgene CACNAlA. Cell 1996; 87:543-552. 6. Zhuchenko 0,Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, ZoghbiHY, Lee CC. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the a,,-voltage-dependent calcium channel. Nat Genet 1997; 15:62-69. 7. Yue Q, Jen JC, Nelson SF, Baloh RW. Progressive ataxia due to a missense mutation in a calcium-channel gene. Am J Hum Genet 1997; 61:1078-1087. 8. Fletcher CF, Lutz CM, O’Sullivan TN, Shaughnessy JD Jr, Hawkes R, Frankel WN, Copeland NG, Jenkins NA. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell 1996; 87:607-617. 9. Kurtzke JF, Kurland LT. The epidemiology of neurologic disease. In: Joynt RD, ed. Cinical Neurology. Philadelphia: JB Lippincott. 199l :66-67. 10. Matsumura R, Futamura N, Fujirnoto Y, Yanagimoto S, Horikawa H, Suzumura A, Takayanagi T. Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology 1997; 39:1238-1243. 11. Stevanin G, Diirr A, David G, Didierjean 0, Cancel G, RivaudS, Tourbah A, Warter J-M, Agid U,Brice A. Clinical and molecular features of spinocerebellar ataxia type 6. Neurology 1997; 49:1243-1246. Riess 12. Schols L, Amoiridis G, Biittner T, Przuntek H, Epplen JT, 0. Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes. Ann Neurol 1997; 42:924-932. 13. Geschwind DH, PerlmanS, Figueroa KP, Karrim J, Baloh RW, Pulst SM. Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype correlations. Neurology 1997; 49: 1247-125 l. 14. von Brederlow B, Hahn AF, Kooperman WJ, Ebers GC, Bulman DE. Mapping the gene for acetazolamide responsive hereditary paroxysmal cerebellar ataxia to chromosome 19p. Hum Mole Genet 1995; 4:2’79-284. 15. Yue Q, Jen JC, Thwe MM, Nelson SF, Baloh RW. De novo mutation in CACNAlA caused acetazolamide-responsive episodic ataxia. Am J Med Genet 1998; 77:298301. 16. Mori Y, Friedrich T, Kim M-S, et al. Primary structure and functional expression from complementary DNAof a brain calcium channel. Nature 1991; 350:398-4.02.

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Baloh and Jen

17. Volsen SG, Day NC, McCormack AL, et al. The expression of neuronal voltagedependent calcium channels in the human cerebellum. Mol Brain Res 1995; 34:271282. 18. Ludwig A, Flockerzi V, Hofman F. Regional expression and cellular localization of the a1 and p subunit of high voltage-activated calcium channels in the rat brain. J Neurosci 1997; 17:1339-1349. 19. Catterall WA. Structure and functionof voltage-gated ion channels. Annu Rev Biochem 1995; 64:493-531. 20. lkinemann SH, Terlau H, Stuhmer W, Imoto K, Numa S. Calcium channel characteristicsconferred on thesodiumchannel by singlemutations.Nature1992; 356:441-443. 21. yang J,Ellinor P, Sather WA, Zhang JF, TsienRW.Molecular determinants of Ca2+ selectivity and ion permeation in L-type Ca2+. Nature 1993; 366:158-161. 22. MacKinnon R. Poreloops:anemergingtheme in ionchannelstructure.Neuron 1995;14:889-892. 23. Scott VES, Felix R, Arikakth J, Campbell KP. Evidence for a 95m a short form of the alAsubunit associated with the w-conotoxin MVIIC receptor of the P/Q-type Ca2+ channels. J Neurosci 1998; 18:641-647. 24. Zamponi GW, Snutch TP. Modulations of voltage-dependent calcium channels by G proteins. Curr Opin Neurol 1998; 8:351-356. 25. Jodice C, MantuanoE, Veneziano L, TrettelF, Sabbadini G, Calandriello L, Francia A,Spadaro M, Pierreli F,Salvi F, Ophoff RA, Frants RR, Frontali M. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNAlA gene on chromosome 19p. Hum Mol Genet 1997; 6:19731978. 26. Ikecuhi T, T&ano H, Koide R, HorikawaU, Honma U,Onishi U, Igarashi S, Tanaka H, Nakao N, Sahashi K, Tsukagoshi H, Inoue K, Tsuji S. Spinocerebellar ataxia type alAvoltage-dependent calcium channel gene and clini6: CAG repeat expansion in cal variations in Japanese population. Ann Neurol 1997; 42:879-884. 27 Takiyama Y, Sakoe K, Namekawa M, SoutomeM, Esumi E, Ogawa T, IshkawaK, Mizusawa H, NakanoI, Nishizawa M, A Japanese with a spinocerebellar ataxia type in the 6 which includes three individuals homozygous for an expanded CAG repeat SCA6/CACNLlA4 gene. J Neurol Sci 1998; 158:141-147. tal28. Baloh RW,Ye' Q, Jen J, Nelson SF. Phenotype variability with mutations in the Cium channel gene CACNAlA. Abstr SOC Neurosci 1998; 24 (Part 2):1266. K, MichelA,Darcel F,MadigandM, 29. DucrosA,DenierC,JoutelA,Vahedi Guerouaou D, TisonF, JulienJ,Hirsch E, ChedruF,Bisgiird c , LucotteG, DesprCsp,Bi11ard C, Barthez MA, Ponsot G, BousSer MC, T'OUrnier-Lasserne E. Recurrence of the T666M calcium channel CACNAlA gene mutation in familial hemiplegicmigrainewithprogressivecerebellarataxia.Am J Genet1999; 64:89-98. 30. Burgess DL, Jones JM, Meisler MH, Noebels JL. Mutation in the Ca2' Channel beta is associated with ataxia and seizures in the lethargic n(1h) ~~se. subunit gene Cchb4 Cell 1997: 88: 185-392. 3 1. Letts VA, Felix R, Biddlecome GH, Arikkath, Mahaffey CL, Valezuela A, Barlett FS

Episodic Ataxia Type 2 and SCA6

32. 33. 34. 35

(I

36. 37.

38. 39. 40. 41. 42. 43

*

44. 45.

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11, Mori U, Campbell W,Frankel WN. The mouse stargazer gene encodes a neuronal Ca2'-channel y subunit. Nat Genet 1998; 19:340-347. Qaus RL, Sinneger MJ, Glossmann H, Hering S, Striessnig J. Familial hemiplegic migrainemutationschange aalA Ca2+-channelkinetics.JBiolChem1998; 273:5586-5590. Lau FC, Abbott LC, Rhyu IJ, Kim DS, Chin H. Expression of calcium channel alA niRNA and protein in the leaner mouse (tg"/tg'" cerebellum. Mol Brain Res 1998; 59:93-99. Hille B. Ionic Channelsof Excitable Membranes. 2d ed. Sunderland, MA: Sinauer, 1992. Chen X-H, Bezprozvanny I, Tsien RW. Molecular basis of proton block of L-type Ca2+ channels. J Gen Physiol 1996; 108:363-374. Bain PG, O'Brien MD, Keevil SF, Porter DA. Familial periodic cerebellar ataxia: a problem of molecular pH homeostasis. Ann Neurol 1992; 31:146-154. Gomez CM, Thompaon RM, Gamack JT, Perlman SL, Dobyns WB, Truwit CL, Zee DS, Clark HB, Anderson JH. Spinocerebellar ataxia type 6: gaze-evoked and vertical nystagmus, Purkinje cell degeneration and variable age of onset. Ann Neurol 1997; 42:933-950. Jen JC, Yue Q, Karrim J, Nelson SF, Baloh RW. Spinocerebellar ataxia type6 with positional vertigo and acetazolamide-responsive episodic ataxia. J Neurol Neurosurg Psychaitry 1998; 65:565-568. Zasorin NL, Baloh RW, Myers LB. Acetazolamide-responsive episodic ataxia syndrome. Neurology 1983; 33:1214. FeeneyGFX,BoyleRS.Paroxysmalcerebellarataxia.AustNZJMed1989; 19:113-117. VanBogaertP,VanNechel C,Goldman S, SzliwowskiHB.Acetazolamideresponsive hereditary paroxysmal ataxia: report of a new family. Acta Neurol Belg 1993; 93:268-275. Buttner N, Geschwind D, Jen JC, PerlmanS, Pulst S, Baloh RW. Oculomotor phenotypes in autosomal dominant ataxias. Arch Neurol 1998; 55:1353-1357. Griggs RC, Moxley RT, Lafrance RA, McQuillen J. Hereditary paroxysmal ataxia: response to acetazolamide. Neurology 1978; 28: 1259-1264. Boel M, Casaer P. Familial periodic ataxia responsive to flunarizine. Neuropediatrics 1988;19:218-220. Takeshi I, et al. Spinocerebellar ataxia type 6: CAG repeat expansion of alAvoltagedependent calcium channel gene and clinical variations in Japanese population. Am Neurol 1997; 42:879-884.

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23 Spinocerebellar Ataxia Type 7 Giovanni Stevanin, Alexandra Durr, and Alexis Brice Hdpital de la Salpdtriere,Paris, France

INTRODUCTION I.

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11. EPIDEMIOLOGY A.Frequency of the SCA7 Mutation B. De Novo Mutations from Intermediate Alleles

47 1 47 1 47 1

111. MOLECULAR PATHOGENESIS A.Instability of theCAGRepeat B. Cloning of the SCA7 cDNA and Analysis of Its Expression C. Toward thePathophysiology of SCA7

47 1 47 1

IV. NEUROPATHOLOGY

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V.

VI.

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CLINICAL FEATURES A.VisualImpairment B. NeurologicalSigns C. Genotype-PhenotypeCorrelations

476 476 477 478

ANCILLARYTESTS

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VII. MANAGEMENT REFERENCES

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INTRODUCTION

Autosomaldominantcerebellarataxia(ADCAs)associatedwithprogressive macular degeneration, also designated olivopontocerebellar atrophy type 111 (1) or ADCA type TI (2,3), was initiallydescribed by Fromentetal.(4)andis characterized by a very heterogeneousclinicalpresentation,diseaseseverity, and age at onset (5,6). Because of the retinopathy observed in most patients, this form of ADCA was considered to be a separate entity (OMIM database entry:164500). Threeindependentgroupsmappedtheresponsiblegene,designatedas SCA7 (spinocerebellar ataxia 7), to chromosome 3p (7-9). The initial candidate interval,a13.4-CMregionbetweenmarkersD3S1300andD3S1217, was furtherreduced by analyses of additionalfamilieswith new microsatellites

(10,lS). Several authors postulated, on the basis of three different observations, that a trinucleotide CAG repeat expansion might be involved in this disease. First,anticipation,aphenomenonresultinginotherneurodegenerativedisorders from unstable sequences, is particularly marked in SCA7 (-20 years per generation)(6,10,12).Second,the1C2monoclonalantibody,thatspecifically recognizes long polyglutamine stretches on Western blots, detected a specific 130-kDaproteininlymphoblasts(13)andcerebralcortex(12)fromSCA7 patientswithpredominantlyearlyonset(12).Thisbandwas not foundin controls and patients with other ADCAs. Finally, Lindblad et al. (14), using the (15), demonstratedthatlong repeatexpansiondetection(RED)technique I1 stretches of CAG repeats cosegregated with the disease in several ADCA pedigrees. Two independentgroupsidentifiedaclonecontaininganuninterrupted (CAG),, repeat that was isolated from YAC882-d-9 (16,17) and mapped to the 2.5-CM region flankedby markers D3S1600 and D3S1287 (17). This clone, used as a probe, detected on Southern blots a 1.33-kb MboUEcoRI fragment that was present in all individuals and an additional larger fragment, resulting from the expansion of the CAG repeat tract, specific to SCA7 patients (16). A third group isolated a clone containing 53 CAG repeats from an SCA7 patient by subcloningandenrichment of CAG-positivefractions by optimizedtwodimensional RED (18). Polymerase chain reaction (PCR) analysis with primers flankingtheCAGrepeatconfirmedthepresence of an expansioninSCA7 patients (16-1 8). Large series of controls and patients havenow been analyzed and revealed that the SCA7 CAG repeat is polymorphic, with sizes ranging from to4 35 units SCA7 andat-riskcarrierchromosomes incontrols,andfrom36to306in (17-24). The largest expansions, reported in four juvenile cases, carried at least 114, 130, 230, and 306 CAG repeats (19,20,23).

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II. EPIDEMIOLOGY A.

Frequency of the SCAT Mutation

The relative frequency of the SCA7 mutation in three large seriesof ADCA kinThe dreds of different origins was5% (18), 9% (unpublished data), and 12% (23). frequency can vary greatly, however, according to geographic origin, from 4% in French ADCA kindreds to 35% in those from North Africa (unpublished data). In our sample of families ( n = 40), as well as in published series, most families were either North African or European (France, Belgium, Sweden, Italy, Portugal), and several were Latin American (Ecuador, Peru), African American, Asian (Korea), Middle Eastern, and North American. One single family each originated from Australia, Israel, and Liberia. Preliminary results of haplotyping with flanking and intragenic markers show that different ancestral mutations probably account for the SCA7 kindreds. Regional founder effects are suspected in some populations, however (24a).

B. De Novo Mutations from Intermediate Alleles The strong anticipation in SCA7 and the rarity of contractions should have led to its eradication in a few generations. However,de novo mutations occur (21). Alleles of intermediate sizes (IAs) with28-35 repeats, are rare(
Ill. MOLECULARPATHOGENESIS

A.

instability of the CAG Repeat

Somatic mosaicism is detected in patient DNA extracted from leukocytes, not but from lymphoblastoid cell lines (16). Although normal alleles are always visualized as a single electrophoretic band, expanded alleles give rise to a major band flanked by numerous bands of higher and lower apparent molecular weights. The mean size of the expansion and the degree of gonadal instability in SCA7 are greater than those observed in any of the other neurodegenerative

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Figure 1 Partial pedigree ofanSCA7familyshowingadenovomutation(21):The number of CAG repeats carried by each chromosome is indicated in bold-face type. Haplotypes for seven microsatellite markers, flanking the SCA7 gene and spanning10 CM, are shown. A pathogenic SCA7 expansion occurred on a normal, 35-CAG repeat carried by individual 14901, resulting in 57 repeats and expression of the SCA7 phenotype in the grandson (14898). (From Ref. 21.)

0.9

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7

diseases known to be caused by translated CAG repeat expansions (Table 1). In 82% of the parent-child transmissions, the number of CAG repeats on the pathological chromosome increases. Contractions are very rare (8%). The mean 12, ranging from -13 to t-263 CAG repeats, by combining variation was the reported series of patients (1’7-24). The largest increases of CAG repeat size,whichresultedinjuvenilecases,werealwaystransmitted by affected fathers and were correlated with the size of the repeat in the parent (19,20). < 0.001)inpaternal (t-21 2 45, n = 53)thanin Instabilitywasgreater(p maternal tr~smissions (+63. 9, n = 84) and remained significantly different of (p < 0.05) if juvenilecaseswereomitted,resultinginameanvariation + 9 -I- 10 CAG in paternal transmissions (n = 48). Gonadal mosaicism, estimated on sperm DNA from a father who transmitted a large expansion (19), is even greater than in leukocytes. This marked instability of the SCA7 mutation compared with other polyglutamine diseases suggests that other factors such as up- or down-stream sequences in cis or trans (33), location relative to the origin of replication (34) or genetic background may affect the stabilityof CAG repeats. to test the Intragenic polymorphisms in theSCA7 gene would be interesting tools effect of flanking sequences. The SCA7 region is characterized by a large discrepancy between the estimated genetic and physical distances (16), although its significance relative to gonadal instability of the expanded repeat remains to be determined.

+

Table 1 Instability of CAG Repeats During Transmission as a Function of the Sex of

the Transmitting Parent Disease SCAl SCA2 SCA3MJD SCA7 DRPLA SBMA HD

Ref. +2.2 (0 @ +8, n = 16) (-8 @ +17,

FZ

(-3 0 +5,

~1

= 33) = 26)

(-6 @ t-263, ~1 53) +7.0 (0 @ +28, n = 33)

+

1.8 (-2 @ +S, n = 11)

+6.1 59,60 (-4 @ +74, TZ = 156)

Unpublished +0.4 data

(0 @ +4, n = 10)

53,54 + 1.7 (-4 @ +8, ~1 = 23) +0.6 (-8 0 +3, ~1 = 34) +6.0 (-13 @ +56, TZ = 84) +0.3 (-4 0 1-4, n = 9) +0.2

(-4 @ +2, YE = 20) +0.6 (-4 @ +16, n 160)

Unpublished data 17-20,22-24 55,56 57,58

MJD, Machado-Joseph disease; DRPLA,dentorubropallidolysian atrophy, SBMA, spinal and bulbar muscular atrophy; HD, Huntington’s disease.

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B. Cloning of the SCA7 cDNA and Analysis of Its Expression Overlapping cDNA clones obtained by screening a lymphoblast cDNA library (16) or by a combination of exon-trapping and reverse transcription (RT)-PCR (17),establishedconsensussequences of 3969bpor3465bp,containinga 2727-bp open-reading frame, encoding a protein of 892 amino acids designated ataxin-7. It contains anNH,-terminal polyglutamine tract at codons30-39 and a putative nuclear localization signal at amino acids 378-394. Apart from the polyglutamine region, there is no significant homology with known gene or protein sequences except for a small proline repeat, downstream from the polyglutamine, which is alsoobservedinhuntingtin,atrophin,andseveralhomeodomaincontaining proteins and other transcription factors (35). The polyglutamine reof gion is preceded by an alanine-rich region. Polymorphisms in the number GCN and CCG repeats, upstream and downstream from the CAG repeat, respectively, have also been observed (21). A single7.5-kbtranscriptisdetected by Northernblotanalysisandis expressed ubiquitously in adult and fetal tissues (16,17). The level of expression is higher in heart, placenta, skeletal muscle, and pancreas, than in brain, liver,andkidney,butsimilarintheretina(unpublisheddata),andallother centralnervoussystemstructurestested,exceptforthecerebellumwhere expressionishigher.Homologousgenesarealsopresentin monkey, mouse, rat, and cow.

C. Toward the Pathophysiology

of SCAT

The normal and pathological functionsof ataxin-7 remain unknown. However, in agreement with Trottier et al. (13), who detected the pathological protein in the cell nuclei, Holmberg et al. (36) reported intranuclear inclusions in neurons of several brain regions in a juvenile SCA7 patient, including the cerebellum and the inferior olive, which severely degenerate (Fig. 2), as well as in the cerebral cortex, which is much less affected. These aggregates were labeled with lC2 as well as with an antibody directed against ubiquitin. The degree of ubiquitination varied according to the structure (ranging from < l % in cerebral cortex to 60% in the inferior olive) and might be related to the progression of the disease in each structure at the timeof death. In addition, the 1C2 antibody stained the cytoplasm of neurons in the supramarginal gyrus, hippocampus, thalamus, lateral geniculate body, and pontine nuclei. Similar nuclear inclusions, restricted to neurons, were detected in patients and in animal and cellular models of other polyglutamine diseases (37,38), and appear to constitute a common feature of these disorders. Whether they are the cause, or a consequence,of the degenerative process remains, however, a matter

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Figure 2 Intranuclear inclusions (NIs) in the inferior olive of a SCA7 patient carrying 85-CAGrepeats (X250). The inclusion (mow) has been labeled with the lC2 antibody (13) and revealed by the peroxidase-antiperoxidase technique, with diaminobenzidine as the chromogen. Staining of the nucleus by Harris hematoxylin. These NIs are also detected with an anti-ubiquitine antibody (data not shown).

of debate. They are predominantly found in affected tissues and can be detected before the phenotype in a mouse model of HD (39,40), suggesting that theymay be deleterious. They are also present in epithelial cells of a Drosophila model of SCA3 showing no phenotype or degeneration (41), and in unaffected tissues in patients (36), arguing that their presence is not sufficient for the degenerative process. More recently, Klement et al. (42) demonstrated that although nuclear translocation of mutated ataxin-l is necessary, as also shown in cellular models with HD constructs (43), aggregation is not required to initiate pathogenesis. The inclusions, therefore may represent only a hallmark of the diseases or a cellular defense mechanism. If they are not responsible for the initiation of the disease, they may be implicated in disease progression and severity.

IV. NEUROPATHOLOGY The neuropathology differs from olivopontocerebellar atrophy, however, because pontocerebellar pathways are spared on postmortem neuropathological analyses (5,44,45). Spinocerebellar, olivocerebellar, and efferent cerebellar tracts are severely affected. In the cerebellum, the vermis is more affected than hemispheres, where Purkinje cells and, to a lesser extend, granule cells, degenerate. Mild cell

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loss also occurs in the dentate nucleus which, as the resultof Purkinje cell degeneration, presents with a reduced mantel. Extensive neuronal loss is observed in the inferior olive, with marked astrocytic gliosis. Mild cell loss is also observed in the substantia nigra and the basis pontis, whereas the thalamus and the striatum are spared. The distinctive neuropat~ologicalfeatures of ADCA I1 are degeneration of optic pathways and the retina. The pregeniculate visual pathways and the optic nerve are affected, probably as a consequence of retinal degeneration. In juvenilecasespresentingwithblindness,thosesystems may not be altered, probably due to the rapid course of the disease. Pathological examination of the retina shows early degeneration of photoreceptors and of bipolar and granloss ular cells, particularly in the foveal and parafoveal regions. Later, patchy of epithelial pigment cells and their ectopic migration into the retinal layers are observed (45).

.

Visual l m ~ a i r m e ~ t

SCA7 is distinguished from other ADCAs by a progressive macular degeneration that can be visualized in most patientsas a pigmented central core at the macula (Fig. 3) that can extend, in latter stages, into periphery.

Figure 3 Fundus color picture/fluorescein angiography of the right eye of a SCA7 patient presenting with a reduced and bilateral visual acuity (MO).Note the abnormal aspect of the macula and the presence of a pigmented central core. (Courtesy of Drs. Husson and Fardeau.)

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Visual failure, first of central vision, is progressive, bilateral, and symmetrical, leading to irreversible blindness (5,44). Peripheral vision is preserved at early stages, explaining why patients do not complain of symptoms until failure is well advanced, andwhy night visionis not impaired. Interestingly, dyschromatopsia in theblue-yellow axis is found years before visual failure becomes symptomatic (44). In contrast, fundoscopic abnormalities, consisting of a loss of the foveal reflex and progressive molting of pigment at the macula, are often delayed. Secondary optic atrophy can often be detected in later stages.

B. NeurologicalSigns The neurological signs clearly overlap between ADCAs. Studiesof large groups of patients have, however, revealed a constellation of signs that are frequently found in SCA7 patients (Table 2). Cerebellar ataxia is always associated with dysarthria, but patients present variably with pyrarnidal signs (increased reflexes, extensor plantar reflexes, lower limb spasticity, or some combination thereof),

Table 2 MajorPhenotypicCharacteristics of 69 SCA7 Patients (unpublished data) with a Mean Age at Onset of 29 rrt: 16 yr (1-70) and Carrying 51 tr 13 CAG Repeats (38-130).

Clinical Cerebellar ataxia Dysarthria Decreased visual acuity Brisk reflexes Diminished or abolished reflexes Babinski's sign Ophthalmoplegia Slow saccades Deep sensory loss Sphincter disturbances Amyotrophy Auditory impairment Axond neuropathy Facial myokimia Dementia Extrapyramidal rigidity Dystonia Bulging eyes Nystagmus

%

100 98.5 81 80 3 55 54 63 60 55 25 24 18 13 12 14

9 6 2

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decreased vibration sense, dysphagia, sphincter disturbances, and oculomotor abnormalities (supranuclear ophthalmoplegia). Extrapyramidal features (dystonia), myokymia, neuropathy, and mental impairment are rare.The frequency of swallowing and sphincter disturbances significantly increases with disease duration (19). The association of cerebellar ataxia and dysarthria with pyramidal signs, supranuclearophthalmoplegia,slowsaccades,anddecreasedvisualacuity is highly suggestive of SCA7.

C.Genotype-PhenotypeCorrelations 1. First Sign atOnset Cerebellar ataxia is usually the presenting symptom in adults with onset after the age of 30. In patients with earlier onset, however, decreased visualacuity, alone or associated with cerebellar ataxia, is the initial symptom (5,6). More than 45 years can elapse between the appearanceof cerebellar symptoms and visual failure, whereas, in the reverse situation, the latency never exceeds9 years (19). In some patients with late onset, visual acuity may never decrease.

2. Age at Onset, Anticipation, and Disease

Duration

The clinical manifestations typically begin in the third or fourth decade, with mean age at onset close to 30, but a range of 3 months or less to over 70 years (9,19,22,23,45,46).Analysis of parent-child couples have revealed striking anticipation(-20yearspergeneration).Previousstudiesreportedsignificantly greater anticipation in paternal than in maternal transmissions (6,7,10). This was not confirmed by recent reports(17,19,20,23),although all juvenile cases are paternally transmitted. In SCA7, anticipation is characterizedby both earlier onset and more rapid disease progression in successive generations. Disease duration until death is negatively correlated with the number of CAG repeats on the expanded allele (Pearson r = -0.70; p <0.05) and is limited to a few months or years in early-onset patients (19). Longer disease durations, up to 30 years or more, are observed only in late-onset patients (47). Anticipation is also associated with increasing severity of symptoms in successive generations. The frequency of decreased visual acuity, ophthalmoplegia, scoliosis, and extensor plantar reflexes significantly increases with the size of the expansion (19). The SCA7 phenotype of a given patient partly depends on both the size of the mutation and the disease duration at examination. In some infantile cases with very large repeat expansions, progression is extremely rapid, and the heart can be affected (23,47). It is surprising that the retinamay be affected in juvenile SCA2 patients (48). It may be that the retina and the cardiac muscle are sensitive only to large and very large expansions, respectively. The pathological threshold of a trinucleotide expansion may, therefore, be tissue-dependent.

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There is a strong negative correlation between the size of the CAG expansion and age at onset. The former accounts for approximately 75% of the variability of the latter, suggesting that other genetic or environmental factors play only a minor role in determining the SCA7 phenotype, unlike other disorders involving polyglutamine expansions (19,22). The CAG length-age at onset correlation, together with the increase in expansion size in successive generations, is consistent with the marked anticipation observed in ADCA I1 families.

VI. ANCILLARYTESTS Brain imaging shows marked atrophy in the cerebellum, particularly in the superior part of the vermis and in the brain stem, which may be associated with moderate atrophy of the cerebral cortex: (Fig. 4). Abnormal fundoscopy is not constant and is often difficult to visualize at an early stage, whereas dyschromatopsia in the blue-yellow axis is an early finding. Electroretinograms show abnormal photopic responses, but scotopic responses are preserved, even at late stages. Visual-evoked potentials are not discriminative for diagnostic purposes (5). Somatosensory-evoked potential are often abnormal. An infraclinical sensory or motor neuropathy on electromyography (EMG) and nerve conduction studies is found in a minority of patients. Direct detection of the mutation is now possible with routine laboratory tests. Individuals carrying 35 (18) and 34 (22) CAG repeats have been reported, but their onset ages and clinical status have not been described. Should they prove to be true patients, these intermediate-sized alleles may result in incomplete penetrance, as occurs for small expansions carrying 36-41 repeats at the HD locus (49,50). Care should also be taken to detect alleles with more than 100 repeats that are difficult to amplify, but are always associated with juvenile or infantile forms of the disease (19,20,23). Isolated cases with a phenotype compatiblewithSCA7shouldsystematicallybetestedforthemutation, because of the possible de novo mutation (21) or because anticipation can result in much earlier onset in the affected child than in the transmitting parent, usually the father. Presymptornatic testing in SCA7 families is possible for adult at-risk individuals but should follow the guidelines established for Huntington’s disease (52).

W. MANAGEMENT There is no specific drug therapy for this neurodegenerative disorder. Therapy remains purely symptomatic (physiotherapy for gait and balance disturbances). Ap-

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Figure 4 Cephalic MRI of a SCA7 patient: (a)Sagittal, Tl-weighted sequence (TR = 450 ms, TE = 11 ms) showing obvious atrophy of the cerebellar vermis associated with mild atrophy of the pons.

propriate measures can reduce diplopia, swallowing or sphincter disturbances. Dementia can be present (12%) and needs specific care.

ACKNOWLEDGMENTS The authors’ studies on SCA7 were financially supported by the Association FranCaise contre les Myopathies, the VER’LTM Foundation, the Association pour le Ddveloppement dela Recherche sur les Maladies Gknktiques Neurologiques et Psychiatriques,andtheAssociation FranCaise RetinitisPigmentosaRetina France. We are gratefulto Nacer Abbas, Geraldine Cancel, Gilles David, Charles Duyckaerts,PaolaGiunti,MonicaHolmberg, Anne-Sophie Lebre,Merle Ruberg, Nicholaus Wood, Cecilia Zander, and Jean-Louis Mandel’s group for their contribution to this study.

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Figure 4 (b) axial, T2-weighted image (TR= 3300 ms, TE = 85 ms) showing cerebell a cortical atrophy associated with atrophy of the pons. Note the absence of major change in the middle cerebellar peduncle. (From Ref. 61.)

1. Konigsmark SW, WeinerLP. The olivopontocerebellar atrophies: a review. Medicine 1970; 491227-241. 2. Hading AE.Theclinicalfeaturesandclassification of thelateonsetautosomal dominant cerebellar ataxias. A study11offamilies, including descendents of the “the Drew family of Walworth.” Brain 1982; 1OS:l-28. 3. Hading AE.Clinicalfeaturesandclassificationofinheritedataxias.AdvNeurol 1993; 61 11-14. 4. Froment J, Bonnet P,Colrat A. Heredo-dkgknkrations rktinienne et spinockrkbelle-

482

5.

6.

7.

8.

9. 10.

11.

12.

13.

14.

15.

16.

Stevanin et al.

uses: variantes ophtalmoscopiques et neurologiques prksentkes par trois gknkrations successives. J Med Lyon 1937; 22:153-163. Enevoldson TP, Sanders MD, Harding AE. Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy. A clinical and genetic study of eight families. Brain 1994; 1 17:445-460. Benomar A,Le Guern E, Durr A, Ouhabi H, Stevanin G, Yahyaoui M, Chkili T, Agid Y, Brice A. Autosomal-dominant cerebellar ataxia with retinal degeneration (ADCA type 11) is genetically different from ADCA typeI. Ann Neurol 1994; 35:439-444. Benomar A, Krols L, Stevanin G, Cancel G, Le Guern E, David G, Ouhabi H, Martin JJ, Dun: A, Zaim A, Ravise N, Busque C, Penet C, Van Regemorter N, Weissenbach J, Yahyaoui M, Chkili T, AgidY, Van Broeckhoven C, Brice A. The gene for autosomal dominant cerebellar ataxia with pigmentary macular dystrophy maps to chromosome 3p12-p21.1. Nat Genet 1995; 10:84-88. Gouw LG, Kaplan CD, Haines JH, Digre KB, Rutledge SL, Matilla A, Leppert M, Zoghbi HY, Ptacek LJ, Retinal degeneration characterizes a spinocerebellar ataxia mapping to chromosome 3p. Nat Genet 1995; 10:89-93. Holmberg M, Johansson J, Forsgren L, Heijbel J, Sandgren0, Holmgren G. Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome3pl2- p21.1. Hum Mol Genet 1995;4: 1441-1445. David G, GiuntiP, Abbas N, Coullin P, Stevanin G, Horta W, Gemmill R, Weissenbach J, Wood N, Cunha S, Drabkin H, Harding AE, Agid Y, Brice A. The gene for autosomal dominant cerebellar ataxia type I1 is located in a 5-CM region in 3p12p13: genetic and physical mapping of theSCA7locus.AmJHumGenet1996; 59:1328-1336. Krols L, Martin JJ, David G,Van Regemorter N, Benomar A, Lofgren A, Stevanin G, Dun A, Brice A, Van Broeckhoven C. Refinement of the locus for autosomal dominant cerebellar ataxia type I1 to Chromosome 3~21.1-14.1.Hum Genet 1997; 99:225-232. 0, Biirk K, Imbert G, Stevanin G, TrottierY, Cancel G, Diirr A, David G, Didierjean Saudou F, Abada-Bendib M, Gourfinkel-An I, Benomar A, Abbas N, Klockgether T, Grid D, AgidY, Mandel J-L, Brice A.Screening for proteins with polyglutamine expansionsinautosomaldominantcerebellarataxias.HumMolGenet1996; 5:1887-1 892. Trottier Y, Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G, SaudouF,Weber C, David G, Laszlo T, Agid Y, Brice A, Mandel J-L. Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature 1995; 378:403-406. K, Zander C, Ehrsson Lindblad K, Savontaus ML, Stevanin G, Holmberg M, Digre H, David G, Benomar A, Nikoskelainen E, Trottier Y, Holmgren G, Ptacek LJ, Anttinen A, Brice A, Schalling M. An expanded CAG repeat sequencein spinocerebellar ataxia type 7. Genome Res 1996; 6:965-971. Schalling M, Hudson TJ, Buetow KH, Housman DE. Direct detection of novel expanded trinucleotide repeats in the human genome. Nat Genet 1993; 4: 135-139. David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, Weber C, Imbert G, SaudouF,AntoniouE,DrabkinH, G e m i l l R, Giunti P,BenomarA,WoodN,

Ataxia Spinocerebellar

7

483

Ruberg M, AgidY, Mandel J-L, Brice A. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 1997; 17:65-70. 17. Del-Favero J, Krols L, Michalik A, Theuns J, Lofgren A, Goossens D, Wehnert A, van den Bossche D, van Zand K, Backhovens H, Van Regenmorter N, Martin JJ, Van Broeckhoven C. Molecular genetic analysis of autosomal dominant cerebellar ataxia with retinal degeneration (ADCA type IT) caused by CAG triplet repeat expansion. Hum Mol Genet 1998; 7:177-186. 18. Koob MD, Benzow KA, Bird TD, Day JW, Moseley ML, Ranum LPW. Rapid cloning ofexpandedtrinucleotiderepeatsequencesfromgenomicDNA.NatGenet 1998;18172-75. Lebre A-S, 19. David G, Durr A, Stevanin G, Cancel G, Abbas N, Benomar A,S,Belal Abada-Bendib M, Grid D, Holmberg M, Yahyaoui M, Hentati F, Chkili T, Agid Y, Brice A. Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCAT).Hum Mol Genet 1998; 7:165-170. 20. Johansson J, ForsgrenL,Sandgren 0, BriceA,HolmgrenG,HolmbergM.Expanded CAG repeat in Swedish spinocerebellar ataxia type 7 (SCA7) patients: effect of CAG repeat length on the clinical manifestation. Hum Mol Genet 1998; 7: 171176. Brice A. De novo ex21. Stevanin G, GiuntiP, Belal GDS,Dum A, Ruberg M, Wood N, pansion of intermediate alleles in spinocerebellar ataxia 7. Hum Mol Genet 1998; 7~1809-1813. S, Lee MS, 22. Gouw LG, Castaneda MA, McKenna CK, Digre KB, Pulst SM, Perlman Gomez C, Fischbeck K, Gagnon D, Storey E, Bird T, Jeri FR, Ptacek LJ. Analysis of the dynamic mutation in the SCA7 gene shows marked parental effectson CAG repeat transmission.Hum Mol Genet 1998; 7:525-532. 23. Benton CS, de Silva R, Rutledge SL, Bohlega S, Ashizawa T, Zoghbi HY. Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype. Neurology 1998; 51:1081-1086. 24. Lyoo CH, Hun K, Choi YC, Lee SC, Stevanin G, David G, Brice A, Lee MS. CAG repeat expansion in the SCA7 gene in Korean families presenting with ADCA type 11. J Korean Neurol Assoc 1998; 16:341-352. P, Benomar A, Abada-Bendib M, Lee MS, Agid 24a. Stevanin G, David G, Durr A, Giunti Y, Brice A. Multiple origins of the spinocerebellar ataxia 7 (SCA7) mutation revealed by linkage disequilibrium studies with closely flanking markers, including an intragenic polymorphism (G314sTG/A314sTG). Eur J Hum Genet 1999;7:889-896. V, Reutenauer L, Moutou C, Mandel JL, Koenig 25. Cossee M, Schmitt M, Campuzano M. Evolutionof the Friedreich’s ataxia trinucleotide repeat expansion: founder effect and premutations. Proc Natl Acad Sci ‘USA 1997; 94:7452-7457. 26. Myers RH, MacDonald ME, Koroshetz WJ, Duyao MP, Ambrose CM, Taylor SA, Barnes G, SrinidhiJ, Lin CS, Whaley WL, Lazzarini AM, Schwarz M, Wolff G, Bird ED, Vonsattel JP, Gusella JF. De novo expansion of a (CAG)n repeat in sporadic Huntington’s disease. Nat Genet 1993; 5:168-173. 27. Squitieri F, Andrew SE, Goldberg YP, Kremer B, Spence N, Zeisler J, Nichol K, Theilmann J, Greenberg J, Goto J, Kanazawa I, Vesa J, Peltonen L, Almqvist E, Anvret M, Telenius H, Lin B, Napolitano G, Morgan K, Hayden MR. DNA haplo-

484

28.

29.

30.

31.

32. 33.

34. 35. 36.

37. 38.

39.

Stevanin et al.

type analysis of Huntington disease reveals clues to the origins and mechanisms of CAGexpansionandreasonsforgeographicvariationsofprevalence.HumMol Genet 1994; 3:2103-2114. Almqvist E, Spence N, Nichol K, AndrewSE, Vesa J, Peltonen L, Anvret M, Goto J, Kanazawa I, Goldberg UP, Hayden MR. Ancestral differences in the distribution of the delta 2642 glutamic acid polymorphism is associated with varying CAG repeat lengths on normal chromosomes: insights into the genetic evolution of Huntington disease. Hum Mol Genet 1995; 4:207-214. Goldberg YP, McMurray CT, Zeisler J, Almqvist E, Sillence D, Richards F, Gacy AM, Buchanan J, Telenius H, Hayden MR. Increased instability of intermediate alleles in families with sporadic Huntington disease compared with similar sized intermediate alleles in the general population. Hurn Mol Genet 1995; 4:1911-1918. Rubinsztein DC, LeggoJ, Goodburn S, Barton DE, Ferguson-Smith MA. Haplotype analysis of the delta 2642 and (CAG)n polymorphisms in the Huntington’s disease (HD) gene provides an explanation for an apparent “founder” HD haplotype. Hum Mol Genet 1995; 4:203-206. Stevanin G, Lebre AS, Mathieux C, Cancel G, Abbas N, Didierjean0,Durr A, Trottier Y, Agid Y, Brice A. Linkage disequilibrium between the spinocerebellar ataxia 3IMachado-Josephdiseasemutationandtwointragenicpolymorphisms,oneof which, X359Y, aff‘ects the stop codon. Am J Hum Genet 1997; 60:1548-1552. Yanagisawa H, FujiiK, Nagafuchi S, et al.A unique origin and multistep process for the generation of expanded DRPLA triplet repeats. Hurn Mol Genet 1996; 5:373-379. Igarashi S, Talsiyama Y, Cancel G,et al. Intergenerational instabilityof the CAG repeat of the Machado-Joseph disease(MJDl) is affected by the genotype of the normal chromosome: implications for the molecular mechanisms of the instability of the CAG repeat. Hum Mol Genet 1996; 5:923-932. Kang S, Jaworski A, OhshimaK, Wells RD. Expansion and deletionof CTG repeats from human disease genes are determined by the directionof replication inE. coli. Nat Genet 1995; 10:213-218. Gerber HP, Seipel K, Georgiev 0, Hoff’erer M, Hug M, Rusconi S, Schaffner W. Transcriptionalactivationmodulatedbyhomopolymericglutamineandproline stretches. Science 1994; 263:808-811. Holmberg M, Duyckaerts C, Dun A, Cancel G, Gourfinkel-An I, Damier P, Faucheux B, Trottier Y, Hirsch EC, Agid Y, Brice A. Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet 1998; 7:913-918. Lunkes A, Mandel J-L. Polyglutamines, nuclear inclusions and neurodegeneration. Nat Med 1997; 3:1201-1202. Kim TW, Tanzi RE. Neuronal intranuclear inclusions in polyglutamine diseases: nuclear weapons or nuclear fallout? Neuron 1998; 21:657-659. Mangiarini L, SathasivamK, Seller M, Cozens B, Harper A, HetheringtonC, Lawton M, TrottierY, Lehrach H, DaviesSW, Bates GP. Exon 1 of theHD gene with an expanded CAG repeat is sufficient to causea progressive neurological phenotype in transgenic mice. Cell 1996; 87:493-506.

Ataxia Spinocerebellar

7

485

40. Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP. Formation of neuronal intranuclear inclusions (NII) underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997; 90:537-548. R N , Bo41. Warrick JM, Paulson HL, Gray-Board GL, Bui QT, Fischbeck KH, Pittman nini NM. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 1998; 93:939-949. Yi H, Hersch SM, Clark HB, Zoghbi HY, Orr 42. Klement IA, Skinner PJ, Kaytor MD, HT. Ataxin- l nuclear localization and aggregation: role in polyglutamine-induced disease in SCAl transgenic mice. Cell 1998; 95:41-53. 43. Saudou F, Finkbeiner S, Devys D, Greenberg ME. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998; 95:55[6]6. 44. Gouw LG, Digre KB, Harris CP, Haines JH, Ptacek LJ. Autosomal dominant cerebellar ataxia with retinal degeneration: clinical, neuropathologic, and genetic analysis of a large kindred. Neurology 1994; 44:1441[1]447. 45. Martin JJ, VanRegemorter N, Krols L, Brucher JM, deBarsy T,SzliwowskiH, Evrard P, Ceuterick C, Tassignon MJ, Smet-Dieleman H, Hayez-Delatte F, Willerns PJ, Van Broeckhoven C. On an autosomal dominant form of retinal-cerebellar degeneration: an autopsy study of five patients in one family. Acta Neuropath01 (Berl) 1994; 88:277-286. 46. Jobsis GJ, Weber JW, Barth PG, Keizers H, Baas F,van Schooneveld MJ, van Hilten JJ, Troost D, Geesink HH, Bolhuis PA. Autosomal dominant cerebellar ataxia with retinal degeneration (ADCA11): clinical and neuropathological findings in two pedigreesandgeneticlinkageto3p12-p21.1.JNeurolNeurosurgPsychiatry1997; 621367-37 l. 47. NeetensA,MartinJJ,Libert J, VanDenEndeP.AutosomaldominantConedystrophy-cerebellaratrophy(ADCoCA)(modifiedADCA Hading 11).Neuroophthalmology1990;10:261-275. 48. Babovic-Vuksanovic D, Snow K, Patterson MC, Michels VV. Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion. Am J Med Genet 1998; 79~383-387. 49. Rubinsztein DC, Leggo J, Coles R, et al. Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet 1996; 59:16-22. 50. Andrew SE, Goldberg YP, Hayden MR. Rethinking genotype and phenotype correlationsinpolyglutamineexpansiondisorders.HumMolGenet1997;6:20052010. J, Agid Y,Brice A. 51. Dun A, Chneiweiss H, Khati C, Stevanin G, Cancel G, Feingold Phenotypic variability in autosomal dominant cerebellar ataxia type I is unrelated to genetic heterogeneity. Brain 1993; 116: 1497-1508. 52. World Federation of Neurology Research Group on Huntington’s Chorea. International Huntington Association and the World Federation of Neurology Research

al. 486

53.

54. 55.

56.

57. 58.

59. 60.

61.

et

Stevanin

Group on Huntington’s Chorea. Guidelines for the molecular genetics predictive test in H~~ntington’s disease. J Med Genet 1994; 31:555-559. Sanpei K, Takano H, Igarashi S, et al. Identification of the spinocerebellar ataxia type 2geneusingadirectidentificationofrepeatexpansionandcloningtechnique, DIRECT. Nat Genet 1996; 14:277-284. Cancel G, Dum A, Didierjean 0, et al. Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families. Hum Mol Genet 1997; 6:709-715. S, DentatorubralpallidolIkeuchi T, Onodera0, Oyake M, Koide R, Tanaka H, Tsuji uysian atrophy (DRPLA): close correlation of CAG repeat expansions with the wide spectrum of clinical presentations and prominent anticipation. Semin Cell Biol 1995; 637-44. Komure 0, San0 A, Nishino N, Yamauchi N, Ueno S, Kondoh K, San0 N, Takahashi M, Murayama N, KondoI, Nagafuchi S, Yamada M, Kanazawa I. DNA analysis in hereditary dentato~bral-pallidoluysianatrophy:correlationbetweenCAGrepeat length and phenotypic variation and the molecular basis of anticipation. Neurology 1995; 451143-149. Biancalana V,Serville F, Pommier J, Julien J, Hanauer A, MandelJL.Moderate instability of the trinucleotide repeat in spino bulbar muscular atrophy. Hum Mol Genet 1992; 1:255-258. Watanabe M, Abe K, Aoki M, Yasuo K, Itoyama Y, Shoji M, Ikeda Y, Iizuka T, Ikeda M, Shizuka M, Mizushima K, HiraiS. Mitotic and meiotic stabilityof the CAG repeat in the X-linked spinal and bulbar muscular atrophy gene. Clin Genet 1996; 50~133-137. Duyao M, Ambrose C, Myers R,al. et Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 1993; 4:387-392. Kremer B, Alrnqvist E, TheilmannJ, Spence N, Telenius H, Goldberg YP, Hayden MR. Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes. Am J Hum Genet 1995; 57:343-350. David G, Abbas N, Durr A, Stevanin G, Cancel G, Yvert G, Imbert G, Saudou F, Mandel J-L, Agid Y, Brice A. Autosomal dominant cerebellar ataxia with macular dystrophy (SCA7) is caused by a highly unstable CAG repeat expansion. In: Wells RD, Warren ST, eds. Genetic Instabilities and Hereditary Neurological Diseases. San Diego: Academic Press, 1998:273-282.

Episodic AtaxiaType 1 Evvout R. Brunt University Hospital Groningen, Groningen, The Netherlands

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11. EPIDEMIOLOGY

489

III. MOLECULAR PATHOGENESIS Mutation A. B. KCNAl Gene of Shaker-RelatedChannels C.PhysiologicalFunction D. KCNAl Channel Dysfunction. E.Hyperexcitability of PeripheralAxons F. Pathophysiology of CentralSymptoms

489 489 489 490 492 494 495

IV. NEUROPATHOLOGY

496

V. CLINICAL FEATUREiS A. GeneralFeatures B. Resting Muscle Activity and Interictal Manifestations C. Attacks of Ataxia, Subjective Sensations, and Impairment D. Onset,Frequency,andProvocation E.Phenomenology of Attacks VI.

ANCILLARYTESTS A. DifferentialDiagnosis B. EMG C.DNAAnalysis

VII. MANAGEMENT

497 497 497 501 504 505 506 506 507 511 511

ADDENDUM

512

REFERENCES

512

487

488

Brunt

I. INTRODUCTION Episodic ataxia type 1 (EAl) is a rare, disabling, autosomal dominant-inherited disorder. It combines attacks of ataxia and tremor with resting motor unit activity. Onset of clinicalmanifestationsisusuallyinchildhood. Itis uncertain whether EA1 patients were included in thefirst report on familial periodic ataxia by Parker in 1946, and the disorder was first clearly described by Van Dyke and colleagues in 1975 (1,2). Following this report, clinical data of 11 other families withEA1 have been published (3-12). There is considerable clinical variability in these families that is reflected by the diverse labels given to them in the past(Table 1). The resting muscle activity may be described clinically as myokymia, but has electromyographic (EMG) characteristics comparable with neuromyotonia. The clinical classification has not always been clear, and the relationof EA1 to familial paroxysmal kinesigenic choreoathetosis, syndromesof continuous motor unit activity, and familial periodic ataxia, has repeatedly been discussed in the first papers (2-5). After identification of the gene, the disorder is designated episodic ataxia type 1 (EAl), MIM 1601 20 (1 3).The main clinical differences to EA2 (MIM 108500) and periodic vestibulocerebellar ataxia (no MIM number) consider both the interictal state and the characteristicsof the attacks. In EA1, continuous motor unit activity is present, and nystagmus is absent interictally. The attacks in EA1 are characterized by kinesigenic provocation, short duration, the combination of ataxia and rhythmic movements, and the absence of nystagmus and vertigo (14,15).The genetic identificationof EA1 and EA2 has confirmed their clinical distinction.

Table 1 Designations for EA1 Used in the Past

Designation Hereditary myokymia and periodic ataxia Continuous muscle discharges and titubation Kinesigenic paroxysmal ataxia and episodic ataxia and neuromyotonia Familial paroxysmal kinesigenic ataxia and continuous myokymia Hereditary paroxysmal ataxia with neuromyotonia Familial paroxysmal ataxia Hereditary myokymia and paroxysmal ataxia Episodic ataxia and myokymia Familial periodic ataxia with myokymia

Ref. 2

3 4 5 6 7

8 9 l1

Episodic Ataxia Type 1

II.

489

EP~~E~IOLOGY

The prevalence of EA1 can be estimated only roughly. At present, 19 families have been described. Of these, 7 are from the United States, 5 from the United Kingdom, 3 from The Netherlands, and 2 each from Spain and Russia. Demonstration of two different mutations in the state of Oregon, with apThe Netherproximately 2.5 million inhabitants, and three different mutations in lands, with approximately 16 million inhabitants, suggests a mutational prevaof approximately lence of 1 :5 millionpeopleandadiseaseprevalence 1:500,000.The actual prevalence may well be considerably higher, as the disorder may remain unrecognized in many families.

111.

~ O L E ~ ~ PATHOGE~ESIS L A R

A.

~utatio~

In 1994, Litt and colleagues found a strong linkage between 4 unrelated EA1 families and chromosome 12pl3, in the vicinity of a cluster of K+-channel candidate genes. They found no locus heterogeneity, and excluded linkage to this locus in a large Family with EA2 (16). In the same year, this group demonstrated a heterogeneous missense mutation in highly conserved regions of the KCNAI gene in all affected members of each of these families, establishing EA1 as the first human potassium channelopathy(17). These mutations were absent in unaffected members, indicating full penetrationof the gene mutation. Since thisfirst report, eight other point mutations and one mutation leading to truncation of part of the intracellular COOH-terminal have been reported EA1 in families (Table2) (9,12,18-21).

6. The KCNAl gene is an intronless gene of 1488 bp, which encodes an a-subunit of a voltage-dependent potassium ion channel. The KCNAl channel is the human homologue of the shaker channel inDrosophila melanogastel; and of the Kvl .1 channel in animals (22,23).The shaker channel is named after a drosophila phenotype, which exhibits violent leg jerking when anesthetized with ether (24). In this phenotype, nerve fibers show broadened action potentials and multiple firing, (25). The and at the neuromuscular junction transmitter release is prolonged shaker channel is the prototype of a familyof about eight delayed rectifier potasso on, in husium ion channels, which are designated KCNA1, KCNA2, and mans, and Kv1.1, Kv1.2, and so on, in animals. The shaker-related channels belong toasuperfamily of voltage-dependentpotassiumchannelsindicatedas

Brunt

490 Table 2 Mutations ofthe KCNA1 Gene in EA1 DNA analysis

Browne et a1 (17) Family 1 Family 2 Family 3 Family 4

DNA Protein mut. Clin. descript. mut,express. Mut. G 122214

G715T C520A A745T

Val408Ala Arg239Ser Val 174Phe Phe249Ile

No No Yes (5) Yes, kindred VI (4)

Yes (4345,47) Yes (43,44,46) Yes (43,44,46) Yes (43,44,46)

C520A

Vall74Phe

Yes (43,46)

Family 7 Family 8 Cornu et a1 (9) Scheffer et a1 (19) Family 1 Family 2 Family 3 Zen et a1 (20) Kullmann et a1 (21)

G975C T551G C677T

Glu325Asp Phe 184Cys Thr226Met

Yes, kindred v (4) Yes (8) Yes (2). Yes (9)

Yes (4446) Yes (43,44,46,4: Yes (20,46)

A676G T530A G1210A

No

Yes (20)

Zuberi et a1 (12)

C677G

Thr226Ala Ile 177Arg Va1404Ile Gly311Ser Arg417stop Va140411e Thr226Arg

Browne et a1 (18) Family 6

No

Yes (7) No No No

Yes (12)

Yes (21,46) Yes (20) Yes (21) Yes (2 l,46) Yes (12)

No mutation has been reported in the families described by Wanson et al. (3), Vaamonde et al. (6), Silbu~ et al. (lo), and Gomez-Gosalvez et al. (11)

Kvl.x, Kv2.x, and so on. The a-subunits of these channels are also evolutionarily related to subunits of voltage-dependent sodium and calcium channels (26). KCNA channels consistof a tetramerof four a-subunits (27). Each a-subunit has six transmembrane domains, numbered Sl-S6 from NH,-terminal (Fig. 1). In broad lines, the S5 and S6 transmembrane domains are part of the ion pore, and S4 acts as the voltage sensor (25,28,29). The kinetics of the channel may be modified by one or more P-subunits at the cytosol face.

C.PhysiologicalFunction

of Shaker-RelatedChannels

Shaker-related channels are widely expressed in the rodent nervous system, with an overlapping, regional-specific expression of each channel (30,31). On a subcellular level, these channels are concentrated in synaptic terminals and in paranodal regions(34-36). The study of functional differences between these delayed rectifying channels hasbeen complicated by the formation of heteromultimers of

491

Episodic Ataxia Type 1 S1

S2

S3

S4

S5

H5

S6

Figure 1 Putative transmembrane structure of the a-subunit of a shaker-related channel, with six transmembrane segments (S1-S6) and a pore segment H5 between S5 and S6. The approximate positions of the EA1 mutations are shown. (From Ref. 18.)

different a-subunits in addition to homomultimers, and by the functional overlap between these channels (33). Delayed rectifier channels play an important role in action potential generation, membrane repolarization, impulse conduction, and transmitter release. More specifically, their function includes stabilizationof resting transmembrane potential, preventionof hyperexcitability, terminationof the action potential, frequency modulation during repetitive depolarization, and maintenance of cell volume (33,377. At opening, a gradient-driven outward flux of potassium ions produces a rectifying outward A-current, that is terminated by inactivation of the channel. Two mechanisms of inactivation can be distinguished, a more rapid is voltageN-typeandamoreslowC-typeinactivation.N-typeinactivation dependent, and in the shaker K-channel, involves a tethered particle region near the NH,-terminal of the a-subunit that can block the internal mouth of the channel (ball-and-chain). In mammalian Kvl.1 channels, N-type inactivation is conferred by a P-subunit, and in a heteromer, an inactivation particle can also be donated by Kvl.4 subunit(31,38).C-typeinactivationistime-related,and influenced by external monovalent cation concentration, whereas it is largely independent of transmembrane potential. C-type inactivation can accumulate during intense neuronal activity. It probably does not involve cytoplasmic domains neartheCOOH-terminal,anditissuggestedtooperate by conformational changes near the external pore (25,37,39,40). Depending on their nature and position, mutationsmay affect voltage-gating or inactivation characteristics, or give rise to nonfunctional channels (37,41,42).

Brunt

492

D. KCNAI ChannelDysfunction Adelman and colleagues, expressed nine humanEA1 mutations in Xenopus Zaevis oocytes, and studied their characteristics(20,4345). When expressed as homomers,eightmutations(V408A,F184C, V174F, F2491, E325D,T226A, T226N1, and G3 11S) resulted in functional channels, and one (R239S) was nonfunctional. In homomeric channels, the mutations caused significant changes in current amplitude, voltage dependency, activation and deactivation kinetics, and C-type inactivation. For example, V408A channels showed accelerated activation and deactivation kinetics and increased C-type inactivation. When coassembled with wild-type subunits in an 1:1 fashion, all mutations resulted in functioning channels with altered properties, which were mostly intermediate between those of wild-type channels and channels composed of four mutated subunits (Figs. 2 and 3). From their studies, Adelman and colleagues argue the presence of both a dominant negative effect and haplotype insufficiency in EA1 (44). Recently, three other reports have been published on expression of EA1 mutations. Kullmann and colleagues studied the oocyte expression of three other human EA1 mutations (T226R, V4041, and R417Stop) (21). These mutations also resulted in altered channel functions, with a variable combinationof reduced current amplitude, increased activation threshold, slowed activation, and accelKCNAl confirmed erated deactivation. Coexpression of a mutation with wild-type the previous findingsof a proportional alteration. Boland and colleagues studied seven EA1 mutations in corresponding conserved residues of the shakerK' channel (V234F, F244C, T284M, R297S, F3071, E395D, and V478A) expressed in oocytes, using both a shaker NW,-terminal deletion mutant and shakerH4 (46).

C

B

A

-80 -60 -40 -20

rnV

0

20 40 60

-80 -60 -40 -20 0

20 40 60

-80 -60 -40 -20 0 rnV

20

40 60

Figure 2 Time constantsof activation (filled symbols) and deactivation (open symbols) of Kvl.1 with three different human EA1 mutations, expressed in Xenopus oocytes: for comparison,wild-typevaluesareshownincircles. (A)V174F (triangles); (B) F2491 (squares); and (C) E325D (diamonds); data are from single representative experiments. Activation of currents was best described with a sum of two exponentials, and the time constant of the fast component is represented here. (From Ref. 44.)

493

Episodic Ataxia Type1

B

A

V408A WT-V40%A

5’ I

3 ’ 1

3

-

~

WT-V408A V408A

10 ms

1( P 4

E

-60 -40 -20

0, 20 Vm (mv)

40

60

-60 -40 -20 0 20 Vm (mV)

40

60

-60 -40 -20

0

20

40

60

Vm (mV)

H t15

0 20 40 60 -80 -60 -40-20 Vm (mv)

WT

-80 -60 -40-20 0 20 40 60 Vm (mv)

V408A

T

-80 -60 -40-20 0 20 40 60 Vm (mv)

WT-V408A

Figure 3 Kinetics of activationandinactivationforwild-type(WT),V408A,and WT-V408A channels:(A) Schematic representationof WT-V408A dimeric construct; (B) superimposed and normalized current traces from WT, V408A, and WT-V408A channels expressed inXenopus oocytes; (C-E) Peak tail currents, plotted as a function of membrane prepulse potential; (F-H)Time constants of activation (filled symbols) and deactivation (open symbols). Activation and deactivation currents were fitted with double and single exponential functions, respectively. Bottom panels: Kinetics of C-type inactivation. Representative current families were recorded from oocytes expressing WT,V408A,and WT-V408A channels. The membrane was held at -80 mV and stepped from t-40 to -20 mV, every 10 mV for 10 S. (From Ref. 45.)

494

Brunt

All mutations produced functional channels with reduced current amplitudes, and variably changed activation gating and N-inactivation kinetics. Their findings suggest that both reduced expression and altered-gating characteristics are responsible for EA1 manifestations. Brettschneider and colleagues expressed two human EA1 mutations (F184C and V408A) in mammalian cells. They found reduced expression and confirmed and extended earlier data on channel characteristics of these mutations (47). The channel characteristics were not changed by acetazolamide, rendering a direct effect of this drug on KCNAI channels unlikely. Although the studies with human mutations indicate EA1 asa phenotype of reduced or ablated of KCNAl channel function, studies in knockout animals support the idea of relative redundancy of Kvl .l channels, and their functional overlap with other related channels. Complete absence of Kvl .lchannels in mice resulted in a phenotype with spontaneous seizures and increased hippocampal excitability, and a subtle prolonged depolarization of peripheral nerves, with increased refractory period at double stimulation, but without change in resting membrane potential (33).

E. Hyperexcitability of Peripheral Axons The idea that the manifestations in EA1, might be related to hyperexcitability of the nervous system, was already expressed before to the genetic identification and studies on mutations(3-5). From the findingsof alterations of channel properties by mutationsinthe Kv1.1 gene, a reducedoutwardrectifyingcurrent caused by human mutations in the KCiVAl gene, and hyperexcitability in Kvl.l knockout in mice, itmay be suggested that, in EA1,a slowed repolarization, hyof the central perexcitability, and increased transmitter release in certain areas and peripheral nervous system are responsible for the manifestations. Although the still unexplained pathophysiology of the central nervous manifestation in EA1 does not provide support for this hypothesis, studies on the etiology of the resting muscle activity do suggest the presence of axonal hyperexcitability and slowed repolarization. In severalEA1 families, a peripheral origin of myokymic activity has been demonstrated by its persistence during peripheral nerve block (3,5,6). Adispersegeneration of spontaneousactionpotentialsalong the unbranched motor axon is indicated by the relation between the number of disappearing myokymic discharges and the localization of the nerve block, and by the individual reactivityof each myokymic discharge during proximally and distally applied regional ischemia of the arm. Based on the findings that frequency and durationof myokymic bursts change independently during ischemia, and that the rhythm of a myokymic discharge in both EA1 patients and a myokymia model can be resetby proximal electrical stimulation beyonda refractory period,

Episodic Ataxia Type 1

495

Brunt and vanWeerden suggested that the burst frequencyof myokymic activity reflects the repetitive spontaneous axonal depolarization, whereas the burst dura(5,48). A delayed or slowed repotion reflects a localized, delayed repolarization larization has also been demonstrated in potassium channelopathies, which cause a disturbance of heart rhythm, known as the long QT syndrome (49). In EA1, hyperexcitabilityof peripheral motor axons is further indicated by the recruitment of myokymic activity following regional ischemia and exercise, and hyperexcitabilityof both peripheral sensory and motor axons is suggested by the early occurrence of paraesthesias and increase of myokymia following administration of carbonic anhydrase-inhibiting drugs, as reported in two families (578).

F. Pathophysiolo~yof CentralSymptoms The opposite effects of carbonic anhydrase drugs, with a reductionof attacks of ataxia and increase in myokymia, are not readily explained. Among possible contributing factors are different expression and function of the KCNA1 channels between brain and peripheral nerves, and metabolic changes by these drugs. Both lowering of pH and loweringof extracellular potassium concentration accelerate C-type inactivation kineticsof Kvl channels, but loweringof extracellular potassium concentration may also reduce the numberof channels opening on depolarization (37).An effect of acetazolamide on brain intracellular pH, as has been reported for EA2, is not known for EA1 (50). Whereas myokymia can be related to altered axonal excitability and delayed repolarization, attacks of ataxia and shaking may be related to excessive transmitter release in certain brain regions by delayed terminal axonal repolarization and increased calcium influx (45). In EA1, precipitants of attacks, such as kinesigenic provocation and startle, possibly cause a critical depolarization, and factors such as illness and emotional upset that increase susceptibility for attacks, may act by changing extracellular homeostasis and further slowing inactivation kinetics. The hypothesis that somatic afferent stimuli may be involved in the precipitation of attacks in EA1 has not been confirmed (7). Dysfunction of KCNA1 channels may also be responsible for an increased occurrence of epilepsy in EA1, as recently suggested by Zuberi and colleagues (12). The molecular pathogenesis of mild, persistent cerebellar symptoms, which are present in someof the elderly EA1 patients, is unclear.The relation between these signs and EA1 needs confirmation, as a slight loss of motor coordination and the appearance of action tremor are not uncommon in normal ageing, and their presence has been mentioned in only twoEA1 families (33). However, the occurrence of mild, persistent uncoordination in EA1 is not unexpected, as a combination of episodic manifestations with progressive symptoms is also seen

496

Brunt

in EA2 and disorders of muscle ion channels (14,51), Similarly, mutations in an inward rectifier Kt channel cause progressive ataxia in mice (52). Within a family, affected members may show considerable variation in clinical manifestations, and the two families with the same mutation show, for instance, a difference for the presence of dystonia (Table 3: kindred V described by Gancher and Nutt, and the family described by Brunt and van Weerden). Because of this variation in clinical manifestation from a single mutation, different alterations in channel properties, which result from the individual mutations are not easily related to clinical differences in EAI. The occurrence, however, of pronounced carpopedal spasm and apparently different responses to drugs in some families, suggest the possibility to partly relate clinical manifestations to individual mutations in EA1.

IV. NEUROPATHOLOGY With the possible exceptionof findings in muscle biopsies, neuropathological investigations inEA1 have failed to show clear abnormalities, and progressive cerebellar atrophy, as occurs in EA2, is not observed in EA1. Macroscopic and microscopic examination of the brain of one patient did not show relevant changes(5). This patient, indicated as111-39, showed minimal upper limb incoordination at examination between attacks, and died at the of age 52 from a pontine hemorrhage. Considering the causeof her death and the limited immunohistochemical analysis, the normal appearance of cerebellum and basal ganglia does not exclude the presence of subtle changes at the neuronal level. Threereportsmentionmicroscopicexamination of peripheralnerves (2,4,5). Moderate loss of axons and myelin sheaths consistent with peripheral neuropathy was found in one sural nerve biopsy, but another sural nerve biopsy and a femoral nerve examined postmortem, showed no abnormalities. Microscopic muscle examination has been reported for seven biopsies, and one postmortem examination (2-6). In four biopsies, small, intensely staining fibers of both types were seen (Fig. 4).In three biopsies, fiber-type grouping was present, 1 and type 2 fiber enlargement. and in two biopsies, histography showed type Type 1 predominance, type 1 fiber atrophy, and focal atrophy, each were seen in one biopsy. Electron microscopy was reported normal in one case. The small intensely staining fibers in about half of the muscle biopsies, may be related to myokymia. A study of myokymia in single motor unit, suggested that high frequency axonal firing, that may continue for many weeks, can only partlybe followed by individual muscle fibersof a motor unit, putting a high demand on muscle fiber metabolism (48).

Episodic Ataxia Type 1

V.

CLINICALFEATURES

A.

GeneralFeatures

497

From the reports on 12 families with EA1, the following global pattern of clinical manifestations emerges (see Table 3). The main characteristics are brief attacks of dysarthria and incoordination, which commence in childhood and are variably associated with tremor or shaking. These attacks are often heralded by usua special sensation, and kinesigenic provocation and predisposing factors are ally obvious. Between these attacks, persistent muscle activity, which varies over time, can be discerned mostly in face and hand muscles. Basically, EA1 isa nonprogressive disorder, and cerebellar symptoms are absent during intervals, but some elderly patients show slight permanent ataxia and posturaltremor. The severity of the clinical manifestationsmay vary considerably inany individual, and affected members of the same family may show differences in character and severity of attacksandintheamount of continuousmuscleactivity.Recently, Zuberi and colleagues focused attention on the increased occurrenceof epilepsy in EA1 (12). EA1 does not limit longevity.

B. Resting Muscle Activity and lnterictal Manifestations Myokymia is the foremost interictal manifestation in EA1, and is manifest in most patients. It is less conspicuous in young children, but may also be absent in adults (2,5). In some families, it was initially not recognized at all (4,7). Myokymia may be visibleasfinesemirhythmicaltwitchinginhand muscles and sometimes the tongue, and as rippling of the skin about the eye and mouth. Subtle myokymic activity may be recognized from small rhythmical lat(3,5). More pronounced eral finger movements in the relaxed prone pending hand activity may cause “piano playing” fingers, or cause intermittent, unpredictable small jerky finger movements (23). When present in larger muscles, it may apTO K V ~ C Xi.e., , pear as truly undulating muscle (myokymia stems from Greek “wave7’), ormay be detected by palpation (2). Myokymia is frequently accentuated during attacks of ataxia, and varies over time. It is often increased following sustained muscle activity, but may also be increased without apparent reason. Patients may experience stiffness in hands or cramps in cold weather, and examination may show persistent thumb 5), adduction-opposition (a “priest’s hand”), comparable with carpal spasm (Fig. or increased firmess of calves. When pronounced, myokymia may cause clasped hands and abnormal foot position during the first months of life with delay in motormilestones,and may leadtoAchillestendon-lengtheningprocedures (3,4912).

Brunt Table 3 ClinicalFeatures of EA1 Families VanDyke (1975) al. et Hanson Number Reported Examined Affected Attacks Age at onset (yr) Attenuation (yr) Frequencylday Duration Subjective sensations

3

7 11 (3/11 epilepsy) 1-12 ?

Description of attacks (ataxia, tremorljerking, muscle stiffening)

Provocation of attacks, promoting circumstances

Prevention possibleby avoiding stimuli Neurol. examination CNS during interval Myokymia, contractures

0-10 -3 min Sensory aura: + Vertigo, dizziness, blurred vision, diplopia Generalized ataxia, unsteadyness, jerking extremities, nodding head, increased myokymia, carpal spasm Kinesigenic: Caloric stimulation: Hunger, fatigue, excitement, distress, viral infection Yes

+

Gancher and Nutt V (1986)

et (1977) al. kindred 3 3 4

2

4-8 ? 0-1

4-6

3 6

10-15 min Sensory aura weakness legs, eyes drawn backward

+

Shaking, titubation, loss of balance, slurred voice, increased tremor, stiffness

+

>30 0-2 -15 min, <3 h Sensory aura ? Swollen tongue, vertigo, headache Generalized ataxia, Dysarthria Tremor?

+

Kinesigenic: Caloric stimulation: illness, perimenstrual,

Kinesigenic: Exercise, startle, postural changes, head movernents,

?

?

Nystagmus -ataxia -

Nystagmus: -ataxia -

>12 yr Face twitching, moving fingers, carpal spasm, calf hypertrophy

At birth: clenched hands and feet Children: contractions Adult: resting tremor, rippling, carp. spasm CMUA, repetitive normallpolyphasic discharges duplets, multiplets

Nystagmus: ataxia: Not noticed

+

EMG

CMUA

Medical therapy Phenytoin Acetazolamide

ataxia: 4, myok.: = n.d.

ataxia: 4, myok.: = n.d.

Ataxia: 4, t myok.: (carbmz:ataxia: =) n.d.

Investigations: Laboratory, C T N R Muscle biopsy Nerve biopsy Brain microscopy

Normal Type 1 predominance Axon and myelin loss ad.

CK slightly elevated Small type 1,2 fibers n.d. n.d.

n.d. n.d. n.d.

+,

Myokymia later confirmed by EMG

?

present; CMIJA, continued motor unit activity; n.d., not done;=,no change; Legend: -, absent; decrease; 1', increase.

L,

Episodic Ataxia Type 1

Gancher and Nutt kindred VI (1986)

Brunt and van Weerden (1990)

3

22 22 28 (3/22 epilepsy) 2-15 20-50 0-1s 10 S-10 min; <6 h Sensory aura: t limp, stiffness, heaviness, blurred vision, diplopia Generalized ataxia, dysarthria, postural tremor of head/arms: + Sometimes stiffeningof the hands Kinesigenic: Caloric stimulation: ? Startle, anxiousness, fatigue, illness, perimenstrual t Yes

2 l 3

3 3 3

6

3

Nystagmus: Ataxia: 2, few elderly Most adults: muscle twitching in hands and face, few spasm Children: t,pending finger movements Myokymic activity, repetitive irregular/regular repeated singlets/multiplets

Nystagmus: Ataxia: Muscle rippling, undulatory twitching face, hands, thumb abduction

Nystagmus: Ataxia: Later information: Carpal spasm t

Neuromyotonia, recurrent grouped discharges: duplets, triplets, multiplets

n.d.

7

15 6-15 >20 0-2 -2 min Sensory aura ? Weightlessness Sensation of falling Generalized ataxia, dysarthria Tremor? Muscle twitching, puckering mouth Kinesigenic: ? Exercise, stress, trauma, fatigue, excitement ?

Nystagmus:

-ataxia: -

Intermittent muscle twitching, facial and carpopedal spasm foot deformities, shortened tendons Neuromyotonia; repetitive grouped discharges, rhythmic singlets

+

Vaamonde et al. (1991)

Averyanov et al. (1995)

?

?

0-2 Few min Sensory aura: ? Blurred vision

0-4

Dysarthria, ataxia ? unsteadyness, jerking movements of head limbs, exaggerated hand and foot flexion

+

Kinesigenic: Caloric stimulation: ? Fatigue, emotional stress, fever , hyperventilation ?

Ataxia: t,myok.: Ataxia: =,myok.: ?

Ataxia: =($) myok.: = Ataxia: 1,myok.: t

(flunarizine: atax.: -1) Ataxia: $?, myok.: ? Ataxia: =,myok.: ?

Normal fiber type grouping Normal n.d.

Normal Normal (H-E stain) Normal Normal

Normal Normal n.d. n.d.

4-S min, <2 h Sensory aura: ?

Diplopia Visualizations Anxiety Dysarthria, gait instability, limb incoordination, shaking

+

Kinesigenic: Caloric stimulation: ? Fatigue, fever Emotional upset Refractory period t: ?

?

Ataxia: 4, myok.: ? SEP: abnormal Normal n.d. n.d. n.d.

Brunt Table 3 Continued (1996) al. (1995) Cornu Lubbers al. et et Number Reported Examined Affected Attacks Age at onset (yr) Attenuation (yr) Frequency/day Duration Subjective sensations

Description of attacks (ataxia, Wemodjerking, muscle stiffening) Provocation of attacks, promoting circumstances

Prevention possible by avoiding stimuli Neurol. examination CNS during interval Myokymia, contractures

EMG

Medical therapy Phenytoin Acetazolamide Investigations: Laboratory, CTMR Muscle biopsy Nerve biopsy Brain microscopy Legend: -, absent; +,present; 4, decrease; 1', increase.

6 6

6 5

9

6

4-6

2-4 Yes

16-20 0-10 1-5 min, <3 h Sensory aura: +?Weakness, stiffness, diplopia, oscillopsia, nausea, dizziness Generalized ataxia, dysarthria, shaking, trembling, stiffening bands +Kinesigenic: + Caloric stimulation: ? Emotional stress, illness, startle Perimenstrual period Yes

?

Few min-h Sensory aura: ? Light-headedness, dizziness, trembling blurred vision Generalized ataxia, dysarthria, shaking, tremulousness Slowing movements stiffening hands I: Kinesigenic: + Caloric stimulation: ? Emotional stress, exercise Yes

Nystagmus: Ataxia: Muscle rippling, regdadjerky finger movements

Nystagmus: Ataxia: Rippling movements, face, hands

Reguladirregular repetitive singlets, multiplets (postischemic)

Regular, repetitive, multiplets

n.d. Ataxia: L,myok.: ?

Ataxia: =; myok.: ? ataxia: 4, unsustained

Normal n.d. n.d. n.d.

n.d. n.d. n.d.

?

CMUA,continued motor unit activity; n.d., not done;=,no change;

Apart from myokymia, neurological examination between attacks is basically normal. An important difference to EA2 is absence of oculomotor disturbances. In the elderly patients a slight to moderate loss of coordination may be found, or a minor postural tremorof the head or arms, and sometimes a mild intention tremor in the finger-to-nose test (33).

501

Episodic Ataxia Type 1

Gomez-Gosalvez (1996) Zuberi al. (1997)etSilburn

(1999) et al.

1s 1s 1s

1 1 4

1,5 Yes

5

5

5 S

(215 epilepsy) 2-10 ?

&S0

? ?

Min-h Sensory aura: ? Dizziness

Few min Sensory aura: ? Dizziness, diplopia

Dysarthria, shaking of head, arms, and legs

Gait imbalance, dysarthria

Generalized ataxia, dysarthria, buckling knees

Kinesigenic: Caloric stimulation: ? Emotional stress, fever, exercise

Physical exercise

Kinesigenic: Startle, anxiety Exercise

?

Yes

?

?

Myokymia

Nystagmus: Ataxia: Myokymia, hands

?

Regular, repetitive, multiplets

Nystagmus: Ataxia: Infancy: clenched hands, flexed thumb, equinovarus feet Adult: myokymia: periorbital, fingers CMUA regular, repetitive multiplets, singlets

+

?

Ataxia: L,myok.: ? Normal n.d. n.d. n.d.

0-? Few min Sensory aura: ?

+

(carbzp: ataxia: L) ataxia: L,unsustained Normal

n.d. n.d. n.d.

C. Attacks of Ataxia, Subjective Sensations, and Impairment The first awareness of an attackmay be a short click or a shock in the head, neck, or body, which within seconds is followed by a diffuse emerging or spreading sensation of stiffness, slackness, or weakness in hands, face, tongue, and legs.If the onset of an attack is less sudden, the accompanying sensation usually shortly precedes the incoordination and oscillating movements, and gives awareness of

5

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ure 4 Muscle biopsy of a 12-year-old boy with EA1 who presented with marked spontaneous muscle activity in early life: Small fibers located at the junction of several muscle fibers stain intensely with oxidative enzymes (myosin ATPase with acid preincubation: X250).(From Ref. 3.) an attack without actually moving. Similarly, minor attacks may pass unnoticed by others. The accompanying sensation has also been described as eyes being driven backward, fly-aways, weightlessness, lightheadedness, or the impression of falling, dizziness, and tremulousness. Following and accompanying these sensations, dysarthria, imbalance, and limb incoordination arise, in combination with more or less pronounced tremor, nodding, and jerking movements. The impaired speech has been described as if drunken and as speech with a swollen tongue. Although vertigo has sometimes been used to describe unsteadiness, a rotatory sensation is not mentioned, and nausea or vomiting are absent. Consciousness is always retained, and patients who also suffer from epilepsy easily discriminate the two kinds of attacks. Vision may be blurred, and sometimes diplopia has been mentioned. In one report all

igure 5 Fixed hand postures resembling carpal spasm: The postures are exaggerated during attacks. (From Ref. 2.)

3

504

Brunt

Family members experienced unnatural visualizations which, however, also occurred between the attacks (7).A few patients mentioned vegetative signs, such as a feeling of warmth or increased perspiration, and in case of a prolonged attack, a bluish discoloration of the skin and increased ~ c t u r i t i o nafter recovery have been noticed.The intensity of the sensation reaches a maximum within seconds and subsequently declines gradually, Usually, the durationof the attacks is in the orderof seconds to minutes, but in some instances, attacks may last up to 6 hr, and sometimes, recovery following an attack may extend over several hours. Seldom, attacks are followed by headache. Depending on the severityof the ataxia and the oscillating movements, patients stand still or sit down during an attack, whereas some continue walking. Eating, writing, and manipulating are usually interrupted during an attack. Patients who were surprised by an attack while cycling, were usually able to dismount from their bike, but sometimes patients hadto let themselves fall to prevent an accident. Indeed, several traffic accidents and a near drowning have been caused by an attack. To alleviate or shorten an attack, most patients sit or lie down and avoid movements, but in the event of an attack with violent rocking, some prefer to stand. More prolonged attacks can sometimes be terminated by taking some food or having a short sleep. Perhapsof a more ritualistic nature are measures such as application of a cold flannel to the faceor hands, or keeping one’s hands in cold running water.

D. Onset,Frequency,andProvocation The age at which the attacks are first recognized is usually 4between and 7 years, a early age with a rangeof 2-15 years. It is not unlikely that attacks start at very but, initially, remain unnoticed. Indeed, attacks have been recognized in infants from a sudden slowing of movements, diffuse tremulousness, and a scared appearance (9). Some young children have reported attacks as “funny legs.” 20 in one day to less than once The attack frequency ranges from more than in a month, with a rather large inter- and intraindividual variation. It tends to be highest in the first and second decade, and often shows a decline following puberty or a gradual diminution with aging. Sometimes an occurrence in clustersis reported (4). Attacks may occur spontaneously, but typically follow a kinesigenic provocation, which may be of an instantaneous or of a more sustained character. Precipitation usually involves a sudden, rapid axial movement, typically following a short rest. The sudden movement may be either a volitionally controlled and planned one, or a more automatic, unexpected one. Planned quick movements, which may precipitate an attack involve rising from a chair when asked to appear in front of the schoolclass, or when invited to enter a physician’s office, rising to

Episodic Ataxia Type 1

505

descend from a bus, or getting up to answer the telephone. One woman described how she repeatedly hadan attack some seconds after starting in a running match at school. Sudden unexpected movements thatmay precipitate an attack include falling, stumbling, sliding, turning, or startling. In startling, the emotion also contributes as a precipitant. One male patient reported that, while riding his motorbike when he was startledby a car blowing its horn behind him, he experienced an attack. Kinesigenic provocation of a more sustained character includes running, cycling, dancing, performing gymnastics or sport, and running up a staircase. At school, children are seldom exempted from gymnastics and sport. Obviously, many of the kinesigenic precipitants include vestibular stimulation. Some situations, such as sitting in a merry-go-round, sudden positional head change, or the occurrenceof an attack following caloric stimulation, support the idea of genuine vestibulogenic provocation. Anxiety, excitement, and emotional upset increase the susceptibility for an attack, as do fatigue, hyperventilation, and notably fever. One mother reported that for several years, her child had attacks exclusively when febrile, and often had an attack as a first signof an upcoming fever. Hormonal changes also influence proneness for an attack, with an increased premenstrual susceptibility and a decrease during pregnancy. In contrast to EA2, lack of sleep, hunger, and the use of alcohol or coffee do not increase the susceptibility for an attack. Following an attack, an apparent refractory period is sometimes mentioned, and attacks axe uncommonly repeated within 1 hr. Inpatientswithobviouskinesigenicprovocation,prevention of attacks may first of all be achievedby moving slowly and consciously, and by avoidance of sudden abrupt movements and exercise. Patients may, for instance, wait, standing next to the physician’s door, so that not to rise in a hurry.

E. Phenomenology of Attacks Many reports describe successfully provoked attacks(2-6,8,9,12). These attacks have been provoked by caloric stimulation, with or without change in head POsition, by quickly rising from a chair, after a loud handclap, sometimes in combination with a quick turn-around or following sleep deprivation, by repeated knee bends, by hopping, and by quickly running up a stair. Only a few of the attempts that used a single abrupt movement were successful. Provocations with a more sustained exercise, allowing a gradual build up, more often seemed to be effective. With a successful abrupt provocation, the disturbance of coordination and the tremor usually starts a few seconds after the provocation, reaches a peak after 10-30 S, and then gradually declines over several minutes. Often, renewed orcontinuedprovocationcanenhanceanongoingabortiveorminorattack shortly after its onset, but a second attempt followingan attack is usually futile.

Brunt

506

Repeated provocation of attacks is limited by the uncomfortable feeling of patients during both the provocation and the actual attack. On examination during the attacks, tendon reflexes are normal or moderately increased, pathological reflexes are absent, and muscle strength is normal. Some patients breathe with their mouth open, giving an appearance of slightly hyperventilating. Dysarthria, limb and gait ataxia, and oscillating movements are present in a variable degree, and often the involuntary resting muscle activity is increased. The presence of ataxia may be obscuredby marked shaking or jerking movements (6). However, ataxia can be recognized mostly by signs such as a broad-based gait, reduced balance with impaired tandem gait, uncoordinated and dysmetric limb movements,or slowing of rapid-alternating movements.The dysarthria is characterized by a reduced wordfluency and an obstructed appearance, as if with stiff and cold facial muscles, Restriction of eye movements, as suggested by the history from some patients, has not been found on examination, and is absent. The rhythmic,oscillating spontaneous,orgaze-evokednystagmus movements range from a small lateral tremorof the mandible and nodding head or rocking of the body. Oscillating movement,togrossshaking,staggering, movements may occur simultaneously in different body parts with distinct frequencies, depending on the body part involved. The shaking and rocking axial movements have an estimated frequency of three to five per second. The rhythmic movements resemble a postural tremor in their diminution or disappearance during relaxation, but an additional kinetic, intentional, increase can sometimes be distinguished with the finger-to-nose test. During pronounced shaking, a characteristic posture is sometimes present, with a widened stance, and arms extended downward from shoulders (2). Dystonia and chorea are absent; however, dystonic attacks occur in few paEA1. The dystonic attacks in one patient tients as a separate manifestation in whom I observed, were well-comparable with attacks of paroxysmal kinesigenic choreoathetosis (8). During attacks, about half of the patients show increased myokymia in facial and hand muscles, manifesting as mouth puckering, increased adductionopposition of the thumb, or carpal spasm.

VI. ANCILLARY TESTS A.

DifferentialDiagnosis

Dependent on the probability of the clinical diagnosis, ancillary investigations may be chosen to confirm the diagnosis or differentiate between other disorders. In a patient, who presents with sudden, short-lasting attacks of incoordination and dysarthria, with kinesigenic provocation, and who shows resting muscle activity in absenceof a nystagmus, a diagnosisof EA1 can be considered as almost

Episodic Ataxia Type 1

507

certain. To confirm a diagnosisof EA1, EMG and DNA analysis are required. A negative family history argues against EA1, as nonfamilial EA1 has not yet been described. If a clinical diagnosis of EA1 is less obvious, and myokymia is not found with EMG, differential diagnosis may include partial epilepsy, a metabolic disorder causing intermittent ataxia, or a structural brain stem lesion(53-57). Incidently, differentiation from paroxysmal kinesigenic choreoathetosis or disorders with continuous motor unit activity may be relevant (58-61). Laboratory investigations, which have yielded normal results in EA1 patients, include blood chemistry,CSF analysis, venous pyruvate/lactate levels, serum copper, vitamin B,,, immunoglobulins, carotene, and urinary excretion of amino acids. Neurophysiological investigations with normal results include EEG, both at rest and during attacks, motor and nerve conduction velocity, muscle fiber conduction velocity, contingent negative variation, and muscle accommodation. Brain imaging by magnetic resonance (MRI) and computed tomography (CT), reported in four patients, including the oldest known affected patient and the patientwiththemostmarkedinterictalataxia,havenotshownabnormalities (5,6,11).Results of electrocardiography (ECG) have also been normal. Investigations, apart fromEMG and DNA analysis, which have shown abnormal results in some EA1 patients are serumCK, vestibulo-ocular reflex and posturography, and somatosensory-evoked potentials (SEP), Serum CK levels have been slightly in(2,3,6).An abnormal gain of creased in some patients, but were normal in others vestibulo-ocular reflex has been reported in one patient with attacks of both ataxia and dystonia (4.). Changes in SEP latency and waveform have been reported in three affected members of one Family(7). The abnormal posturography and SEP findings in EA1 need confirmation. Resultsof nerve and muscle biopsy have been discussed in a previous section.

B. EMG For a clinical diagnosis of EA1, three aspects of EMG may be applied; the registration of resting motor unit activity, the provocationof myokymic activity by regional ischemia, and the study of reactivity of individual myokymic discharges during ischemia (5,8). Changes in hyperexcitability, whichmay be demonstrated by motor nerve stimulation, are not of primary clinical relevance (5). The search and registration of resting motor unit activity is best achieved by using surface electrodes. Surface electrodes are preferred to concentric needle electrodes, because of their relatively large area of detection. If characteristic myokymic activity is found, needle examinationis not necessary. In EA1, spontaneous myokymic activity is usually most pronounced in the hand muscles, and can almost always be demonstrated there, also in patients, who lack visible symptoms of myokymia.

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Figure 6 (a) Spontaneous muscle activity:A and B depict four different multiplets occurring rhythmically and independently. Surface recording from first dorsal interosseus muscle. C and D depict rhythmically occurring singlet-duplet with burst interval dependent on the number of spikes. Concentric needle recording from first dorsal interosseus muscle. (From Ref. 5.)

Characteristically, myokymic activity in EA1 consists of independently occurring, regularly repeated duplets or triplets, but single spikes and multiplets are also frequently seen (Fig. 6a)(3-6,8,9,11,12). In addition to rhythmic activity, irregularly repeated single potentials and complex bursts of about 50-100 ms; with varying shape, may occur in EA1 (see Fig. 6b). The intensity of resting activity may reachintermediateinterferencepattern. The basicfrequency(“burst frequency”) of rhythmic activity is fairly constant, and usually between 2 and5 Hz, with a range of 0.5-8 Hz. The burst duration ranges from about5 ms for a single spike, to more than 25 ms for multiplets. The spike frequency within a burst of 20-250 Hz. The period during is usually betweenl00 and 200 Hz, with a range

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Figure 6 C o ~ ~ ~ (b) f l Spontaneous ~ ~ d muscle activity: A depicts different multiplets occurring s ~ ~ ~ ~ h(surface ~ t ~recording ~ i c from ~ l the l abductor ~ pollicis brevis muscle). B depicts ~~~t~~~~~~~~ ~ c c u ~ . ~doublet, i n g provoked by 3 min of local ischemia (concentric needle recording f f ~ m the? ~ ~ ~di u quinti ~ muscle). t ~ rC depicts irregularly occurringburstswithrelativehigh ~ m ~ ~ i t ~low d efrequency,causingsmalljerkyfinger movements, and regular small myakymic activity marked by arrowheads(A)(surface recording from first dorsal interosseus muscle), (From

510

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which an individual myokymic discharge continues, ranges from a few seconds to many hours, and probably many weeks. Apart from the first spike of each burst, the amplitude of the myokymic potentials is rather low (up to 600pV) in comparison with voluntary recruited action potentials. This is explained by partial involvement of the motor unit in successive spikes of a burst (48). In addition to spontaneous occurrence, duplets and multiplets may also be seen during voluntary contraction. Strong voluntary contraction during about 10 S , typically suppresses myokymic activity for2-S S . On reappearance, the frequency of the spontaneous activity is markedly reduced, and gradually recovers over 10-20 S . If no spontaneous myokymic activity is found after a careful search, ischemic provocationmay be attempted. This procedure was introduced by Brunt and van Weerden based on the original work of Kugelberg and Cobb (62). In EA1, regional ischemia by cuff inflation recruits new myokymic activity. Following 3 rninof ischemia, new myokymic activity appears within Y2-l min, reaches a maximum at 2-S min., and gradually disappears over 10-15 min. In addition to recruitment of new myokymic activity, existing myokymic complexes may be temporarily enlarged by extra spikes. Reactivity of individual myokymic discharges during regional ischemia, may provide an additional characteristic feature of myokymia in EA1, and may serve to differentiate this activity from continuous motor unit activityof central origin, During!h”min of ischemia applied at the upper arm, the burst frequency of some myokymic discharges in the hand gradually rises to about 2 - 2 s times 7). This reaction is individually constant, and implies that of its original level (Fig. the originof the myokymic dischargeis within the ischemic region. In this sense, this test provides information comparable with blocking of a peripheral nerve.

Figure 7 Influence of ischemia: Different reaction following upper and lower m application of the sphygmomanometer cuff. Rhythmically occurring duplet, burst interval plotted against time. Hatched area indicates absolute values; drawn line indicates mean values (surface recording from abductor digiti minirni). (From Ref,5.)

Episodic Ataxia Type 1

C.

511

DNA Analysis

As in other hereditary ataxias, the definite diagnosis of EA1 is made by moleculargeneticanalysis. Thus far,allmutationsin EA1 havebeenfoundinthe KCNAl gene on chromosome 12p 13. The genetic diagnosis consistsof two steps. The first step is the demonstration of linkage to the KCNAl gene. The markers that may be usedtoestablishlinkageareD12S100,D12S372,D12S99, D12S1088, KCNA5, and D12S93 (18,19). The second step is the demonstration of a mutation in a conserved region, by sequencing the gene’s single exon.

VII. ~ A N A ~ E ~ E N T An important issue in the management of EA1 patient is establishing a definite diagnosis and explaining that the disorder not psychogenic is nor epileptic and that attacks of shaking and ataxia are not in themselves harmful. If medical treatment isrequested, I wouldsuggestthatoneproceedsfromacarbonicanhydraseinhibiting (CAI) drug such as sulthiame or acetazolamide, to carbamazepine, and finally phenytoin. The effect of drugs seems to differ both between and within families. Because of the irregular occurrence of attacks in most patients, evaluation of a drug’S efficacy inan individual withEA1 isoften complicated, andmay require a patient’s diary and a sufficiently long treatment period (e.g.,1 month). Although effective in most cases (see Table 3), the effect of acetazolamide in EA1 is less reliable than in EA2 (63,64). The daily dosage is often restricted by the early occurrenceof paresthesias and, to a lesser extent, alsoby increase in muscle stiffness or myokymia, and easy fatigability. Sulthiame, which has also been used in EA2,is often preferred to acetazolamide, as it causes fewer side effects (65). Sulthiame is less potent than acetazolamide, but its favorable pharmacokinetic profile, with relative high uptake in the central nervous system, implies less paresthesias and allows the use of a higher dosage. In both acetazolamide and sulthiame, paresthesias may be reduced by oral potassium supplementation. The maintenance dosage of acetazolamide in our patients is usually between62 and 375 mg/day; thatof sulthiame is between 100 and 300 mg/day. The suppressive effectof CAI drugs is strongest during thefirst weeks and stabilizes at about half its initial efficacy in long-term treatment. Becauseof their good immediate effect, small dosages of CAI drugs, are well-suited for incidental use (e.g., 1-2 hr) before sporting activities. Both carbamazepine and phenytoin seem less effective than CAI drugs. Results of trials with carbamazepine have been reported in only a few EA1 patients, and these reports do not suggest efficacy. However, a good long-term efficacy of carbamazepine has been observed in several members of one Dutch EA1 Family. Becauseof its potential efficacy and less complex pharmacokinetics

512

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compared with phenytoin, a trial with carbamazepine may be worth while before turning to phenytoin. Treatment with phenytoin effectively reduced the occurrence of attacks in about half of the treated patients. Information on therapeutic levels and on long-term efficacy is not available. Other drugs that have been given inEA1 include phenobarbitone, betahistin, cinnarizin, flunarizin, clomipramin, and clonazepam. A good long-termefficacy of flunarizin has been reported in one patient (6). The mode of action of the various drugsis unclear. Obviously, allof these drugs have antiepileptic, membrane-stabilizing effects. However, the suppressive effect on attacks of ataxia seems to be unrelated to antiepileptic effects, as suggested by two patients, in whom phenobarbitone and phenytoin prevented epileptic seizures, but not attacks of ataxia.

ADDENDUM A further EA1 kindred has since been brought to my attention (E. Storey, M. A. Knight, P. Hand, S. M. Forrest, R, J. M. Gardner,personalcommunication, 1999). This is a large Australian kindred, and 14 affected family members in 3 generations were personally studied, with 6 actual attacks video-recorded in 4 subjects. The clinical picture is essentially consistent with the broad phenotypic range described in this chapter; interictal myokymia was observed3 of in the 14, and carbarnazepine had proven to provide effective prophylaxis in each of the 6 in whom it had been tried. A conservative KCNAl leu329ile missense mutation cosegregated with disease in the family.

REFERENCES 1. Parker HL. Periodic ataxia. Col1 Papers Mayo Clin 1946; 38:642-645. 2. Van Dyke DH, Griggs RC, Murphy MJ, Goldstein MN. Hereditary myokymia and periodic ataxia. J Neurol Sci 1975; 25:109-118. 3. Hanson PA, Martinez LB, Cassidy R. Contractures, continuous muscle discharges, and titubation. Ann Neurol 1977; 1:120-124. 4. Gancher ST,Nutt JG. Autosomal dominant episodic ataxia: a heterogeneous syndrome. Mov Disord 1986; 1 :239-253. 5. Brunt ER,van WeerdenTW. Familial paroxysmal kinesigenic ataxia and continuous myokymia. Brain 1990; 113:1361-1382. 6. Vaarnonde J, Artieda J, Obeso JA. Hereditary paroxysmal ataxia with neuromyotonia. Mov Disord 1991; 6:180-182. 7. Aver’ianov I, Zenkov LR, Nechkina NP, Toropina GG, Klishevskaia LA, [Familial paroxysmal ataxia]. Zh Nevropatol Psikhiatr Im S S Korsakova 1995; 95:94-97. 8. Lubbers WJ, Brunt ER, Scheffer H, et al. Hereditary myokymia and paroxysmal

Episodic Ataxia Type 1

9. 10. 11.

12. 13. 14. 15.

16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

513

ataxia linked to chromosome 12 is responsive to acetazolamide. J Neurol Neurosurg Psychiatry 1995; 59:400-405. (3omu S , Giuliani M, NarayananV. Episodic ataxia and myokymia syndrome: a new mutation of potassium channel gene Kv1.1C. Ann Neurol 1996; 40:684-687. Silburn PA, Li F-Y, Teh BT, Wright GDS. Familial kinesigenic cerebellar ataxia with myokymia, clinical and genetic studies. Mov Disord 1996; ll(supp1 1):35. Gomez-GosalvezF, Smeyers P, Escriva P, et al. Ataxiapericidicafamiliarcon mioquimia sensible a acetazolamida: presentacicin de una familia. Rev Neurol 1997; 25~1925-1927. Zuberi SM, Eunson LH, Spauschus A, et al. A novel mutation in the human voltagegated potassium channel gene (KvI.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. Brain 1999; 122:817-825. OMIM.OnlineMendelianInheritanceinMan.Baltimore,MD:OMIM,John’s Hopkins University, 1999; [Internet communication]. Brandt T, Strupp M. Episodic ataxia type1 and 2 (familial periodic ataxidvertigo). Audio1 Neurootol 1997; 2:373-383. Damji KF, Allingham RR, Pollock SC,et al. Periodic vestibulocerebellar ataxia, an autosomaldominantataxiawithdefectivesmoothpursuit,isgeneticallydistinct from other autosomal dominant ataxias. Arch Neurol 1996; 53:338-344. Litt M, Kramer PL, Browne DL, Brunt ER, Root D. A gene for episodic ataxid myokymia maps to chromosome 12~13. Am J Hum Genet 1994; 55:709. Browne DL, Gancher ST, Nutt JG, et al. Episodic ataxidmyokymia syndrome is associated with point mutations in the human potassium channel gene KCNAI. Nat Genet 1994; 8: 136-140. Browne DL, Brunt ER, Griggs RC, et al. Identification of two new KCNA1 mutations in episodic ataxia myokymia families. Hum Mol Genet 1995; 4:1671-1672. Scheffer H, Brunt ER, Mol GJ, et al. Three novel KCNA1 mutations in episodic ataxia typeI families [published erratum in Hum Genet 1998; 102:713]. Hum Genet 1998; 102:464-466. Zerr P, Adelman JP, MaylieJ. Characterizationof three episodic ataxia mutations in the human Kvl.l potassium channel. FEBS Lett 1998; 431:461-464. Kullmann DM, Spauschus A, Eunson LH, Rea R, Wood NW, Hanna MC. Novel Mutations of KCNAl in episodic ataxia type 1:functional analysis. Neurology 1999; ~ ~ ( S U2):A553-A553. PP~ Papazian DM, Schwarz TL, Tempel BL, Jan YN, Jan LY. Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila. Science 1987; 237:749-753. Chandy KG, Gutman CA. Nomenclature for mammalian potassium channel genes. Trends Phmacol Sci 1993; 14:434. Kaplan WD, Trout WE. The behavior of four neurological mutants of Drosophila. Genetics 1969; 61:399-409. Pongs 0. Molecular biology of voltage-dependent potassium channels. Physiol Rev 1992; 72 (Suppl4):S69-S88. Pthcek LJ. Ion channel shake-down [editorial]. Nat Genet 1994; 8:111-1 12. Scott VE, Muniz ZM, Sewing S, et al. Antibodies specific for distinct Kv subunits

514

28. 29. 30. 31. 32. 33. 34. 35.

36. 37. 38. 39. 40. 41. 42. 43 44. 45.

Erunt

unveilaheterooligomericbasisforsubtypes of alpha-dendrotoxin-sensitiveK' channels in bovine brain. Biochemistry 1994; 33:1617-1623. Slesinger PA, Jan YN, Jan LY. The S4-S5 loop contributes to the ion-selective pore of potassium channels. Neuron 1993; 11:739-749. Smith-Maxwell CJ, Ledwell JL, Aldrich RW. Role of the S4 in cooperativity of l :399-420. voltage-dependent potassium channel activation. J Gen Physiol 1998; 11 Beckh S. Differential expressionof sodium channel W A S in rat peripheral nervous system and innervated tissues. FEBS Lett 1990; 262:317-322. Rettig J, Heinemann SH, Wunder F, et al. Inactivation properties of voltage-gated K' channels altered by presence of beta-subunit. Nature 1994; 369:289-294. Verma-Kurvari S, Border B, Joho RH. Regional and cellular expression patterns of four K+ channel W A S in the adult rat brain. Brain Res Mol Brain Res 1997; 46~54-62. Smart SL, LopantsevV, Zhang CL, etal. Deletionof the K(V)1.1 potassium channel causes epilepsy in mice. Neuron 1998; 20:809-819. Chiu SY, Ritchie JM. Evidence for the presence of potassium channels in the paranodalregion ofacutelydemyelinatedmammaliansinglenervefibres.JPhysiol (Lond) 1981; 313:415-437. Veh RW, Lichtinghagen R, Sewing S, Wunder F, Grumbach IM, Pongs0. Immunohistochemical localizationof five members of the Kvl channel subunits: contrasting subcellular locations and neuron-specific co-localizations in rat brain. Eur J Neurosci 1995; 7:2189-2205. Mi H, Deerinck TJ, Ellisman MH, Schwarz TL. Differential distribution of closely related potassium channels in rat Schwann cells. J Neurosci 1995; 15:3761-3774. Lopez-Barneo J, Hoshi T, Heinemann SH, Aldrich RW. Effects of external cations and mutations in the pore region on C-type inactivationof Shaker potassium channels. Receptors Channels 1993; 1:61-71, Nakahira K, ShiG,Rhodes KJ, TrimmerJS.Selectiveinteractionofvoltagegated K' channel beta-subunits with alpha-subunits. J Biol Chem 1996; 271:70847089. Hoshi T, Zagotta WN. Recent advances in the understanding of potassium channel function. Curr Opin Neurobiol 1993; 3:283-290. Panyi G, ShengZ, Deutsch C. C-type inactivation of a voltage-gated K' channel occurs by a cooperative mechanism. Biophys J 1995; 69:896-903. Molina A, Ortega-Saenz P, Lopez-Barneo J. Pore mutations alter closing and opening kinetics in Shaker K' channels. J Physiol (Lond) 1998; 509:327-337. Smith-Maxwell CJ, Ledwell JL, AldrichRW. Uncharged S4 residues and cooperativityinvoltage-dependentpotassiumchannelactivation.JGenPhysiol1998; 111:421-439. AdelmanJP,BondCT,PessiaM,Maylie J.Episodicataxiaresultsfromvoltage-dependent potassium channels with altered functions. Neuron 1995; 15: 14491454. Zerr P, Adelman JP, Maylie J. Episodic ataxia mutations in Kvl. 1 alter potassium channelfunctionbydominantnegativeeffectsorhaploinsufficiency.JNeurosci 1998;18:2842-2848. D'Adamo MC, LiuZ, Adelman JP, MaylieJ, Pessia M. Episodic ataxia type-lmu-

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46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60.

61.

62. 63. 64. 65.

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tations in thehKvl .l cytoplasmic pore region alter the gating properties of the channel. EMBO J 1998; 17:1200-1207. Boland LM, Price DL, JacksonKA. Episodic ataxidmyokymia mutations functionally expressed in the Shaker potassium channel. Neuroscience 1999; 91:1557-1564. BretschneiderF, Wrisch A, Lehmann-Horn F,Grissmer S. Expression in mammalian cells and electrophysiological characterization of two mutant Kvl. 1 channels causing episodic ataxia type 1 (EA-l). Eur J Neurosci 1999; 11:2403-2412. Brunt ER, van Weerden TW. Distal axonal origin and motor unit involvement in myokymia. Neurology 1994; 44(suppl 2):A411. Sanguinetti MC, Spector PS. Potassium channelopathies. Neuropharmacology 1997; 36~755-762. Bain PG, O’Brien MD, Keevil SF, Porter DA. Familial periodic cerebellar ataxia: a problem of cerebellar intracellular pH homeostasis. Ann Neurol 1992; 31:147-154. Ptricek LJ. Channelopathies: ion channel disorders of muscle as a paradigm for paroxysmal disordersof the nervous system. Neuromusc Disord 1997; 7:250-255. Goldowitz D, Smeyne RJ. Tune into the weaver channel [editorial]. Nat Genet 1995; 11~107-109. Blass JP, AviganJ, Uhlendorf BW. A defect in pyruvate decarboxylase in a child with an intermittent movement disorder. J Clin Invest 1970; 49:423-432. Salam M. Metabolic ataxias.In: Vinken PJ, Bruijn GW, De Jong JMBV, eds. Handbook of Clinical Neurology. Vol. 2 1, System Disorders and Atrophies. 1. Amsterv01 dam: North-Holland Publishing, 1975:573-585. Sander JE, Malamud N, Cowan MJ, Packman S, Amman AJ, Wara DW.Intermittent ataxiaandimmunodeficiencywithmultiplecarboxylasedeficiencies:abiotinresponsive disorder. Ann Neurol 1980; 8:544-547. Glotzner FL. Hirnstammanfalle. Fortschr Neurol Psychiatr Grenzgeb 1979; 47:538549. Twomey JA, Espir ML. Paroxysmal symptoms as the first manifestations of multiple sclerosis. J Neurol Neurosurg Psychiatry 1980; 43:296-304. Kertesz A. Paroxysmal kinesigenic choreoathetosis. An entity within the paroxysmal choreoathetosis syndrome. Description of 10 cases, including l autopsied. Neurology1967;17:680-690. Y, Roongta SM. A dominantly inherited syndrome with Ashizawa T, Butler IJ, Harati continuous motor neuron discharges. Ann Neurol 1983; 13:285-290. AugerRG,DaubeJR,GomezMR,LambertEH.Hereditaryformofsustained muscle activity of peripheral nerve origin causing generalized myokymia and muscle stiffness. Ann Neurol 1984; 15:13-21. Byrne E, White 0, Cook M. Familial dystonic choreoathetosis with myokymia; a sleep responsive disorder. J Neurol Neurosurg Psychiatry 199 1;54: 1090-1092. Kugelberg E, Cobb W. Repetitive discharges in human motor nerve fibres during the post-ischaemic state. J Neurol Neurosurg Psychiatry 1951; 14:88-94. Griggs RC, Moxley RT, Lafrance RA, McQuillen J. Hereditary paroxysmal ataxia: response to acetazolamide. Neurology 1978; 28: 1259-1264. Griggs RC, Nutt JG. Episodic ataxias as channelopathies. Ann Neurol 1995; 37:285287. WolfP. Familiiire episodische Ataxie. Nervenarzt 1980; 51:355-358.

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Spinocerebellar Ataxia Type 10 Stefan-NI. Pulst UCLA School of Medicine, Los Angeles, California

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I. INTRODUCTION Despite the ever-increasing numberof dominant ataxia mutations and ataxia loci that have been identified over the last 10 years, 30-50% of dominant ataxias have not yet been assigned (1). One of the most recent additions is the locus for spinocerebellar ataxia type 10 (SCAlO) (2). This form of ataxia combines features of a chronic progressive degenerative ataxia with the presence of epileptic seizures in some individuals. At this time, only two pedigrees with SCAlO have been described (Fig. 1) (3,4). 517

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Both SCAlO families are of Mexican extraction. It is unknown whether SCAlO occurs predominantly in this ethnic group.

ENESIS111.

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In 1999, Zu et al. (2) mapped SCAlO to the distal long arm of chromosome 22. This location was independently confirmed in a second pedigree (4). Combining the mapping data from both groups theSCAlO candidate region has been limited to a 6-CM region between D22S 1140 and D22S1160. Anticipation of the age of onset is a prominent feature in both pedigrees. In the pedigree reported by Grewal et al. (3) the average age of onset in generation I11 was 34 years and in generation IV, it was 16 years. Furthermore, in five

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parent-child pairs, the onset of disease was significantly earlier in the offspring, ranging from 18 to 23 years. In the pedigree reportedby Matsuura (4) the average age at onset was 35.6 -t- 5.7 years, ranging from 26 to 45 years. In eight informative father-child pairs, the mean anticipation of age at onset was 9.9 +- 3.9 years, ranging from 3 to 16 years.

No pathology has been reported in patients with SCA10.

In the pedigree reported by Grewal et al. (3), 11 individuals were affected. Neurological signs were limited to ataxia and nystagmus. Long tract or basal ganglia signs were not observed. Optokinetic nystagmus was absent or greatly reduced. Two individuals reported the occurrence of seizures. In the second pedigree, 12 individuals were considered affected and l was possibly affected (4). Eight of the affected individuals had a history of generalized motor seizures that started in the third to fifth decade. Two of these patients also had apparent episodes of complex partial seizures, with or without secondary generalization.The presenting sign in6 of 8 individuals was an unsteady gait in the third to fifth decade of life. Two patients had onset with seizures. On examination, patients in both pedigrees had gait and limb ataxia, dysarthria, and gaze nystagmus in all directions and impaired smooth pursuit. Many patients also complained of dysphagia. Based on the observations in two pedigrees, SCA10 is notable for the absenceof ophthalmoplegia, decreased saccadic velocity, retinopathy, optic neuropathy, deafness, pyramidal or extrapyramidal signs, sensory loss, neuropathy, or dementia.

Examination of SCAlO patients in both pedigrees has been almost entirely clinical. A cranial magnetic resonance imaging (MRI) examination of one patient showed cerebellar atrophy, with relative preservationof the brain stem (Fig. 2). The intericatal electroencephalogram (EEG) in a patient with seizures was normal. Electromyographic and nerve conduction studies of two patients were normal (2).

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Figure 2 T2-weighted MRI of individual 111-2 at age 43, l0 years after onset of &t@tia (TR: 400 TE: 18). Note atrophy of the cerebellum with relative~~~~~~~t~~~of the bwib

stem. (From Ref. 3.)

VII. MANAGEMENT Management is supportive, andmany patients remaina m b u l a t o ~for a prolonged time period. No detailed study of seizure management in SCA10 k t l ~been reported.

This work was supported by grants from the Drown Foundation and FRIENDS of Neurology.

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REFERENCES

Pulst SM, PerlmanS. In: Pulst SM, ed., Hereditary Ataxias, in “Neurogenetics.” New York; Oxford Press, 2000. Zu L, Figueroa KP, Grewal R, Pulst SM. Mapping of a new autosomal dominant spinocerebellar ataxia to chromosome 22. Am J Hum Genet 1999; 64:594-599. Grewal R, Tayag E, Figueroa KP, Zu L, Durazo A, Nunez C, Pulst SM. Clinical and genetic analysis of a distinct autosomal dominant spinocerebellar ataxia. Neurology 1998; 51~1423-1426. Matsuura T, Achari M, Khajavi M, BachinskiLL, Zoghbi HY, Ashizawa T. Mapping of the gene for a novel spinocerebellar ataxia with pure cerebellar signs and epilepsy. Ann Neurol 1999; 45:407-411.

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26 Ataxia in the Transmissible Spongiform Encephalopathies Lev G. Goldfarb, Cathrin NI. Butefisch, and Paul Brown

National Instituteof Neurological Disorders and Stroke, National ~nstitutesof Health, Bethesda, ~aryland

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INTRODUCTION

A group of chronic, progressive, and fatal neurological disorders, human transmissible spongiform encephalopathies (TSE), or prion diseases, include kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease 523

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(GSS),fatalfamilialinsomnia (€TI), and a recentlydescribed new variant Creutzfeldt-Jakob disease (nvCJD). Kuru was the first human chronic noninflammatory neurodegenerative disorder proved to be transmissible to chimpanzees after incubation periodsof 18-24 months (1). CJD,GSS, and FFI were subsequently found to be experimentally transmissible to nonhuman primates to and rodents, with similarly long incubation times (2-4). Related neurodegenerative transmissible disorders naturally affecting animals have also been extensively studied, among them scrapie in sheep and goats, transmissible mink encephalopathy, feline spongiform encephalopathy, chronic wasting disease of mule deer and elk(S), and bovine spongiform encephalopathy (BSE) (6). The interrelations between the human and animal diseases may be closer than currently appreciated. Studies of nvCJD (7) suggest that this human disease may be associated with consumptionof contaminated meat from animals affected with l3SE. Recent advances in cellular and molecular biology have yielded increasingly strong evidence that TSE results from the accumulation in the brain of an abnormal isoform of prion protein (PrP), a posttranslational modification of a normal host protein encoded by the PRNP gene located on human chromosome 20 (for review, see Ref.8). This abnormal isofom and its toxic fragments gradually accumulate in neurons, resulting in neuronal death and other pathogenic effects responsible for the TSE phenotypes.

In 1957 Gajdusek and Zigas (9) described kuru, a prototype TSE characterized as a progressive fatal ataxia that spread among the Fore peopleof New Guinea by serial transmission of the causative agent through ritual cannibalism.The origin of kuru in this community remains unknown, but the disease frequency grew dramatically from the beginning of the 20th century to reach epidemic proportions in the 1950s (10). More than 3000 cases of kuru were recorded in 169 villages of the Eastern Highlands of New Guinea (5). Kuru has since been disappearing gradually as a result of the cessation of cannibalism in the late 1950s(S, 10). Bea significant number of cause the incubation time may exceed three decades, cases were recorded in the 1970s and 1980s, and single-digit numbers are still being recorded in the 1990s. In 1921 Jakob described several cases of a chronic neurological disease that has since become knownas CJD. The discovery in 1968 (2) that CJD can be of experimentally transmitted provided a diagnostic basis for the assessment population frequency and patterns of world distribution. Approximately 90% of CJD cases are sporadic (i.e., having no detectable cause); sporadic CJD is evenly distributed throughout the world, with a frequency of 0.5 :million to 1:million

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per year (11). In some families, cases of CJD accumulate showing a pattern of autosomal dominant inheritance. Familial (inherited) forms account 5-15% for of CJD cases (11,12), which are associated with multiple missense and insertional mutations in the PRNP gene (13; Table 1). The PRNP gene has five repeating sequences between codons 5 1 and 91, that may expand to include one to nine additional repeats. Repeat expansion is associated with a distinct form of familial CJD. At the time of this report, 21 repeat-expansion families have been characterized (14). The two most frequent point mutations are located at codons 178 and 200. Phenotypic manifestations of the D178N mutation are determined by a valine-methionine polymorphism at codon 129 (15). The D178N/129V haplotype is responsible for a CJD-like syndrome, whereas the D178N/129NI haplotype has been associated with FFI. To date, 10 families of the CJD D178N type are known. The E200K mutation has been associated with three large geographic clusters of CJD. These clusters occur a population group in Central Chile in rural Slovakia, Libyan-born Jews, and (16). The same mutation has also been identified in the Tunisian and Greek Jewish populations and Italian, Spanish, British, North American, German, Austrian, Argentinean, and Japanese non-Jewish populations (17). A small number of cases of iatrogenic CJD has resulted from medical interventions. CJD associated with human-to-human transmission,first reported in the 1970s, involved a contaminated corneal graft taken from a donor with neuropatbologically confirmed CJD. Neurosurgical procedures, involving contaminated instruments, EEG needles, and contaminated dura mater grafts, were later found to be significant causesof CJD transmission. In1985, the first case in what has become a tragic outbreak of CJD among the recipientsof human growth hormone replacement therapy was reported (for review, see Ref. 18). To date, there have been over400 growth hormone-associated deaths, witha few new cases occurring each year after increasingly long incubation periods ranging up to 30 years (19). It is expected that in the future the number of iatrogenic CJD cases will decrease as a result of recombinant pituitary hormones having completely replaced cadaveric hormones, and new highly efficient procedures having been introduced to sterilize dura mater grafts. Gerstmann in 1928 and Gerstmann, Straussler, and Scheinker in 1936 characterized membersof the “H” family witha unique syndromeof progressive limb and truncal ataxia, dysarthria, personality change and decline in cognitive function (for review, see Ref. 20). Approximately 40 other GSS families have been as an autosomal dominant disorder described over the years, all characterized caused by mutations in the PRNP gene. The set of PRNP mutations responsible Table l), suggesting that hefor GSS differs from those seen in familial CJD (see reditary CJD and GSS are allelic disorders. GSS typically differs from CJD by more prominent cerebellar ataxia, longer durationof illness, and the presenceof morphologically distinct multicentric amyloid plaques in the cerebellum.

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In 1986 Lugaresi and collaborators (21) described a unique hereditary disease characterized by insomnia, dysautonomia, and motor deficits. Twenty-one kindreds have been diagnosed with FFI making it the third most common inherited humanTSE (22). This unique syndrome is associated with the D178N/129M haplotype (see Table 1). In 1996 ten cases of CJD with distinctive clinical presentationsand neuropathological features were reported in British adolescents and young adults (7). The report suggested that this was a new CJD variant related to the BSE epidemic. Nearly three dozen casesof nvCJD have so far occurred in Great Britain, and a single case in France.The epidemic of BSE in Britain started in 1986 and spread throughout the country to involve over 170,000 animals. It resulted from changes in rendering ovine and bovine carcasses for the production of animal food pellets, which permitted at least partial survival of the infectivity. Although the input of infectious carcasses ceased after a 1988 banof the use of ruminantderived protein to feed cattle, the peak of the BSE epidemic was reachedonly in late 1992, and a significant number of new BSE cases are still being reported. Recent studies of biological characteristics of PrP extracted from the nvCJD brain tissue suggested similarities to BSE, but not sporadic CJD, strengthening the connection between nvCJD and BSE (23,24).

111.

MOLECULARPATHOGENESIS

The predominant view of TSE pathogenesis is based on the “protein only” hypothesis. According to this hypothesis, the critical event is a change of conformation in the normal host-encoded PrP molecule transforming it intoan abnormal pathogenic isoform (8). The normal prion protein (PrP-sen) is a 35-kDa glycoprotein that has four a-helical domains. Its normal function is unknown. By an as yet unexplained mechanism, in disease-affected individuals the PrP a-helical domains are transformed into P-sheet configuration, resulting in an insoluble P-pleated amyloid-type molecule that is partially resistant to proteases (PrP-res). Proteases completely digest PrP-sen, whereas the partially protease-resistant PrPres is reduced to core a protein with molecular weightof 27-30 kDa (PrP27-30). PrP27-30 exhibits remarkable resistance to physical and chemical agents, its turnover is extremely slow, and it tends to forrn insoluble fibrillar aggregates in cell compartments. After cell death PrP accumulates in the extracellular space forming amyloid plaques. Although the levelof PrP-sen is constant throughout the disease, PrP-res accumulates in the brain with disease progression. PrP-res alone, or in association with another as yet unidentified molecule (25), has the capacity to transmit the disease if inoculated into a susceptible animal by converting the recipient’s PrP-sen into an abnormally folded PrP-res. The level of PrP-res correlates with infectivity. PrP-sen and PrP-res are encoded by the same

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PRNP gene and have the same amino acid sequence and, therefore, are antigenically indistinguishable by the infected host, thus accounting for the absence of immunological and inflammatory changes in the TSE. Mutations in thePRNP gene alter the protein’s secondary structure predisposing the PrP molecule to acquire a P-sheet configuration. Transgenic mice expressing mutant PrP analogous to the human P102L mutation spontaneously develop a neurological illness characterized by ataxia, lethargy, and rigidity, and show vacuolar degeneration in the neocortex and PrP deposits in the cerebrum and cerebellum (26). A specific association of mutant PrP with ataxia and neuronal death in the granular layer of the cerebellum has recently been observed in mice expressing PrP with deleted 32-121 and 32-134 residues (27). The PrP methionine-valine polymorphism at position 129 has been the subject of intensive research. Accumulated evidence has shown that although the substitution does not by itself cause disease, it influences the phenotypic effects of other mutations (15) or predisposes to other forms of disease: homozygous carriers of the 129M allele are overrepresented among patients with both sporadic and iatrogenic CJD (28,29).

W. CLINICALANDNEUROPATHOLOGICALFEATURES The clinical and neuropathological spectrumof the human TSEsis extremely diverse. The phenotype of the inherited forms depends on the causative mutation, whereas the route of infection determines, to a significant extent, the featuresof the infectious forms. Cerebellar ataxia is partof the clinical spectrum in eachof the TSE forms. In some forms (kuru, several variants of GSS, iatrogenic CJD with peripheral routeof infection) ataxia is the presenting symptom that tends to dominate the clinical picture, whereas cognitive decline, psychiatric symptoms, or insomnia are more prominent in others (sporadic SJD, nvCJD, FFI). Spongiform change and astrocytic gliosis are found in most, but not all, forms of TSE. The presence and morphology of PrP amyloid plaques and PrPimmunoreactive deposits is variable. Lesion topography has also become an important basis for classification: cerebral cortex and subcortical ganglia are predominantly affected in all forms of CJD, the cerebellum is primarily affected in kuru and GSS, and the thalamus is the major site of degeneration in FFI.

A. SporadicCreutzfeldt-JakobDisease The onset of recognizable neurological disease in sporadic CJD is gradual, occurring over a period of weeks or even months. The average age at onset is 60 years and the duration of illness is 7 months (see Table 1). The disease usually starts with mental deterioration manifested by memory loss, confusion, or behav-

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Figure 1 Electroencephalogramsof two patients with sporadic Creutzfeldt-Jakob disease:Uppertracingshowsasuggestivebutnonspecific“burst-suppression”pattern. Lower tracing shows the pathognomonic l- to 2-cycles/s triphasic periodic sharp wave discharge (PSD)pattern.

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ioral changes. Cerebellar symptoms, eye movement abnormalities, or visual impairment may appear before, during,or after the onsetof mental signs.As the illnessevolves,mostpatientsdevelopdeficits of highercorticalfunctions, cerebellar and oculomotor dysfunction, tremors, myoclonus, choreiform or athetoid movements, and pyramidal tract signs(30). Periodic sharp wave discharge ontheelectroencephalogram(PSD)ishighlycharacteristic of sporadicCJD (Fig. 1). The clinical course is relentlessly progressive. Within a year all patients are globally demented, often mute and physically incapacitated by severe ataxia, myoclonus, rigidity, pseudobulbar dysphagia, cortical blindness, and seizures. Some important diagnostic features such as myoclonus and PSD may not be eviof CJD ismade by hisdent until very late in the illness. The definitive diagnosis tological examinationof brain tissue obtained at biopsy or autopsy. The predominant findings are spongiform degeneration and loss of neurons in the cerebral cortex, striatum, and the molecular layer of the cerebellum. Reactive astrocytic gliosis is a very prominent accompanying feature. An overt inflammatory response is not found, and the reaction of microglia and macrophages is minimal. In 5 1 0 % of cases amyloid plaques may be seen in the cerebral cortex and cerebellum (Fig. 2).

B. HorizontallyTransmitted(Infectious)Spongiform Encephalopathies 1. Kuru The clinical course of kuru is remarkably uniform. During a prodrome, the patient shows transient unsteadiness and minor changes in personality and in mood. Limb and truncal ataxia, dysarthria, and what has been described as “shivering tremor” progress to the pointof inability to walk and sit or to perform any activity. Myoclonus,choreiformandathetoidmovementsdevelopasthedisease progresses. Overt dementia may not be present until a late stage of illness (10). Death ensues 6-18 months after the onsetof clinical illness. The most consistent features of kuru neuropathology are diffuse astrocytic proliferation and gliosis with significant neuronal loss and the presence of characteristic (“kuru-type”) amyloid plaques (see Fig. 2) scattered throughout the brain, but most prominent in the dentate nucleus of the cerebellum(31). Spongiform degeneration is present in some cases. 2. NewVariantCreutzfeldt-Jakob

Disease

Distinctive features of nvCJD include a remarkably early age of onset (average 29 years) and a consistent phenotype of early psychiatric symptoms, including behavioral and personality change, depression, and memory loss. Ataxia is an early clinical feature in almost all patients. Dementia and myoclonus develop as

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Figure 2 Representative sections of the cerebellum in patients with various forms of transmissible spongiform encephalopathies: (a) Kuru; characteristic amyloid plaque with fine radiating fibrillar corona (PAS,X 100); (b) Gerstrnann-Straussler-Scheinker disease; characteristic multicentric amyloid plaque (PAS, X 100).

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Figure 2 Continued (c)sporadicCreutzfeldt-Jakobdisease;Kuru-likeamyloid plaques (H&E, X60).(d) new variant Creutzfeldt-Jakob disease; “daisy” plaques (H&E, X60).(Courtesy of Dr. James Ironside.)

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the disease progress (7). There areno periodic complexes on EEG. The average duration of illness is 14 months. At autopsy, the defining diagnostic feature is a kuru-type amyloid plaque encircled by a ring of severe spongiosis (“daisy” or “florid” plaques). The plaques are widespread in the cerebral cortex and cerebellum. In addition, astrocytosis and neuronal loss characteristic of other CJD forms are also present (7).

3. Iatrogenic Creutzfeldt-Jakob Disease The length of incubation time and clinical features are determined to a significant extent by the route of infection. When the infectious agentis directly introduced into the brain, as with neurosurgical instruments or stereotactic EEG electrodes, the incubation time is 16-28 months, and the predominant clinical feature is a rapidly progressing dementia (19). However, when the contaminated tissue is applied to the surfaceof the brain as with dura mater grafts, the incubation is on average 6 years and the clinical presentationmay be either mental deterioration or cerebellar dysfunction. With peripheral routes of infection, as in hormone re15 years, and the placement therapy, the average incubation time increases to clinical presentation is invariably a cerebellar syndrome with limb and truncal ataxia, dysarthria, and nystagmus (see Table l). Mental deterioration evolving into mutism appears comparatively late in the illness (29). Neuropathological examination reveals widespread spongiform change, marked astrocytic gliosis, and neuronal loss.

C. FamilialTransmissibleSpongiformEncephalopathies 1. Familial Creutzfeldt-Jakob Disease In patients with the 24-bp repeat expansion, the average age at onset is significantly earlier than in patients with other types of familial CJD; in contrast, the duration of illness in repeat-expansion patients is unusually long (see Ref. 14 and Table l). A premorbid personality disorder marked by excessive mood swings, irritability, learning disability, and a history of long-time psychiatric care are observed in most patients. Complaints of clumsiness, poor coordination, and slurred speech are early signs marking the disease onset, in combination with progressive intellectual slowing. Signs and symptoms of the fully developed encephalopathy: progressive dementia, ataxia, spasticity, seizures, myoclonus, and EEG periodic Complexes are similar to those in patients with the sporadic disease (14). Brain atrophy, predominantly in the frontal and occipital cortex, diffuse spongiform change, and astrogliosis are observed in many patients. In addition, PrP depositions have been found in 50% of the studied patients. A PRNP allele with theDl78N mutation and valine at polymorphic codon of 129 (D 178N/129V haplotype) is responsible for a similar dementing form

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CJD, with an average age of onset of 46 years and duration of illness of 23 months (see Table 1). The 1781129V type of CJD only rarely shows periodic sharp wave discharges on EEG. Diffuse spongiform change, neuronal loss, and gliosis are the pathological features of this variant (32). The E200K mutation in the PSNP gene is the most common mutation associatedwithfamilialCJD,accountingformorethan 70% of CJD families worldwide, and is similar in many respects to sporadic CJD. The average age at onset is 55 years. The illness starts with cognitive impairment and altered behavioral patterns that are rapidly progressing. Limb and truncal ataxia and dysarthria 50% of patients that may or may be present at the disease onset in approximately may not be accompanied by mental deterioration. Incoordination gradually becomesdisabling,andcorticalblindness,startle-inducedorspontaneousmyoclonic jerks, and muscle rigidity of an extrapyramidal or frontal type develop during the courseof illness. Periodic sharp wave discharges on EEG isvery characteristic of this form (33) (see Table 1). The duration of illness is, on average, 8 months. Neuropathologically, severe spongiform degeneration with,diffuse loss of neurons in the cerebral cortex, Striatum, and the molecular layer of the cerebellum, and astrocytic gliosis are observed (33). The very rare V1801 and M232R mutations are associated with dementia, tremor, and rigidity of relatively late onset and rapid progression. 2. Gerstmann-Straussler-Scheinker Disease The P102L mutation in thePSNP gene is the most frequent GSS mutation, caus80% of all known GSS families (20). In P102L mutationing the disease in about associated GSS, the age of onset is on average 48 years, and the duration of illness is on average 6 years. The clinical course of GSS is characterized by early development and slow progressionof ataxia and dysarthria associated with pyramidal and extrapyramidal signs and pseudobulbar symptoms. Mental impairment is infrequent at the disease onset, but develops later in the course of illness manifesting as personality disorder and dementia (see Table1). Cerebellar atrophy is documented by MRI (Fig. 3). Myoclonic movements and periodic sharp wave discharges onEEG are rarely observed.The distinctive neuropathological feature is the presence of multicentric PrP amyloid plaques in the cerebellum and, to a lesser extent, in the cerebral cortex. The plaques present as amorphous aggregates of spheroid bodies sometimes consisting of a centrally located larger core encircled by numerous satellite cores (see Fig. 2). The unicentric plaques have the appearance of kuru-type plaques. Spongiform degeneration varies from severe to absent (34). The P105L mutation is the causeof GSS in several Japanese families (35). This form exhibits distinctive features of severe spasticity and the presence of multicentric amyloid plaques in the cerebral cortex rather than the cerebellum.

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Figure 3 Tl-weighted magnetic resonance image of the brain in a 38-year-old patient with Gerstmann-Straussler-Scheinker disease: Note marked diffuse cerebellar atrophy and enlargement of the fourth ventricle.

The A1 17V variant of GSS is characterized by an even earlier ageof onset (average 38 years) and a high frequency of pseudobulbar signs, with comparatively less frequent ataxia. The neuropathology shows prominent PrP deposits throughout the cerebral-cortex, but not in the cerebellum. The Indiana kindred segregating GSS with the F198S mutation, and two familieswith GSS associated with the Q217R mutation are distinct in that uni- and multicentric PrP plaques characteristic of GSS colocalize with plaques having a rich neuritic component, similar to that seen in Alzheimer’s disease (20). Both types of plaques reacted with anti-PrP antibodies. Widespread Alzheimer’s type neurofibrillary tangles were seen in the cerebral cortex and subcortical nuclei.

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Fatal Familial Insomnia

Fatal familial insomnia is an inherited disease characterized by a subacute progression of intractable insomnia and autonomic, endocrine, and motor abnormalities. The average age at onset is 49 years, and the duration of illness is 15 months (see Table 1). The highly characteristic feature of W1 is the disturbance of sleep, leading to severe progressive reductionof sleep time. Rapid eye movement (REM) sleep and spindle activity during non-REM sleep are reduced and eventually disappear (for review, see Ref. 36). Ataxia, dysarthria, and dysphagia, are among the early signs, whereas the cognitive functions remain relatively of illness. It has been noted that in patients having spared until late in the course 129M on both mutated and nonmutated alleles, insomnia and dysautonomia are more severe and dominating at the onset of illness, whereas patients heterozygous for the same allele show ataxia and dysarthria at the onset and tend to have more prominent cognitive impairment and seizures. PET studies disclose severe thalamic and cortical hypometabolism (37). The histopathological hallmark of FFI is the lossof neurons and astrogliosis in the thalamus. The mediodorsal and anterior thalamic nuclei are invariably andseverelyaffected,whereasinvolvement of otherthalamicnucleivaries. Spongiosis and astrogliosis in the cerebral cortex vary in proportion to the disease duration and are rarely prominent (36).

V.

DIAGNOSIS AND ANCILLARY TESTS

Electroencephalography is routinely used in patients with CJD. The typical EEG abnormality in advanced disease consists of1-2 cycleh triphasic sharp waves superimposed on a depressed background. They are usually asymmetrical, may occur in synchrony with myoclonic jerks, and tend to become slower with the disease progression. Serial tracings reveal the characteristic triphasic sharp wave pattern in up to 80% of patients with sporadicCJD at some time during the course of illness (19). PSD is rare in some other TSEs. An important new assay that detects proteins 130 and 13 1of a family of 14-3-3 brain protease inhibitors released from damaged neurons has proved extremely useful in the diagnosis of difficult cases (38). The sensitivity and specificity of this test in sporadic CJD exceeds 90%.The diagnostic validity of other tests, such as neuron-specific enolase, tau protein, and S-l00 protein, has not been fully investigated. Magnetic resonance imaging (MRI) reveals enlargement of the ventricles and wideningof the cortical sulci, and in some patients, a symmetrical hyperintense signal in the basal ganglia. In GSS, significant cerebellar atrophy may be apparent (see Fig. 2). In patients with inheritedTSE (and some-

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times in seemingly sporadic CJD patients), pathogenic PRNP mutations can be identified, establishing the diagnosis of hereditary TSE. A new range of neuropathological techniques, such as scrapie-associated fibrils (SAF) detection by electron microscopy, PrP immunocytochemist~, PrP detection by the immunoblot or histoblot, in situ polymerase chain reaction, and determination of PrP “gly~otypes~~ are coming into use as additions to the traditionalassessment of structuralchangesandtransmissibility(for review, see Ref. 39).

VI.

MANAGEMENT

Precautions should be taken in the general care and managementof hospitalized TSE patients. The infectious agent is not present in any external secretion, but it may be present in cerebrospinal fiuid (CSF) and blood; therefore, gloves should be worn when handling patient’s CSF and blood. Penetrating injuries from potentially contaminated instruments should be avoided. Accidental contamination of intact skin should be treated with the applicationof fresh undiluted bleach or 1 N sodium hydroxide to the area for about 1 min, followedby thorough washing with soap and water. Disposable instruments and other materials shouldbe used whenever possible; if retained, instruments should be disinfected by immersion in fresh undiluted bleach or 1 N sodium hydroxide for 1 h at room temperature followed by steam autoclaving for 1 h at 132°C. Special precautions should also be taken while handling pathological samples (40). No effective treatment yet exists for TSE, but prospective therapiesmay be directed toward interruptionof the conversion from normal to abnormal PrP. The identification of mutations in the PRNP gene opens a possibilityof genetic counseling, as prenatal genetic testing can be done at the family’s request (41).

REFERENCES 1. Gajdusek DC, Gibbs CJ Jr, Alpers M. Experimental transmission of kuru-like syn-

drome to chimpanzees. Nature 1966; 209:794”796. Gibbs CJ Jr, Gajdusek DC, Asher DM, Alpers MP, Beck E, Daniel PM, Matthews WB.Creutzfeldt-Jakobdisease(subacutespongiformencephalopathy):transmission to the chimpanzee. Science 1968; 161:388-389. 3, Masters C, Gajdusek D, Gibbs C Jr. Creutzfeldt-Jakob disease virus isolations from the Gerstmann-Straussler syndrome. Brain 1981; 104:559-588. 4. Tateishi J, Brown P, Kitamoto T, Hoque ZM, Roos R, Wollman R, Cervenakova L, Gajdusek DC. First experimental transmission of fatal familial insomnia. Nature 1995; 376:434“435.

2.

with Associated Diseases Prion

541

5. Gajdusek DC. Subacute spongiform encephalopathies: transmissible cerebral amy-

6. 7. 8.

9. 10. 11. 12. 13. 14.

15.

16. 17.

18. 19.

loidoses caused by unconventional viruses. In: Fields BN, ed. Virology, 2nd ed. New York: Raven Press, 1990. Wells GA, Scott AC, Johnson CT, Gunning W, Hancock RD, Jeffrey M, Dawson M, Bradley R. A novel progressive spongiform encephalopathy in cattle. Vet Res 1987; 121:419-420. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, Poser S, Pocchiari M, Hofman A, Smith PG. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996; 347:921-925. Prusiner SB. The prion diseases. Brain Path01 1998; 8:499-513. Gajdusek DC, Zigas V. Degenerative disease of the central nervous system in New Guinea: the epidemic occurrenceof “kuru” in the native population. N EnglMed J 1957; 257:974-978. Gajdusek DC. Unconventional viruses and the origin and disappearance of kuru. Science1977;197:943-960. Brown P, Cathala F, Castaigne P, Gajdusek DC. Creutzfeldt-Jakob disease: clinical analysis of .a consecutive seriesof 230 neuropathologically verified cases. Ann Neurol 1986; 20597-602. MastersCL,HarrisJO,GajdusekDC,GibbsCJJr,BernoulliC,AsherDM. Creutzfeldt-Jakob disease: patternsof worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol 1979; 5:177-188. Goldfarb LG, BrownP. The transmissible spongiform encephalopathies. Annu Rev Med 1995; 4657-65. Goldfarb LG, Cervenakova L, BrownP, Gajdusek DC. Genotype-phenotype correlations in familial spongiform encephalopathies associated with insert mutations. In: Court L, Dodet B, eds. Transmissible Subacute Spongiform Encephalopathies: Prion Diseases. Paris: Elsevier, 199642543 l. Goldfarb LC, Petersen RB, Tabaton M, Brown P, LeBlanc AC, Montagna P, Cortelli P, Julien J, Vital C, Pendelbury WW, Haltia M, Wills PR, Hauw JJ, McKeever PE, Monari L, Schrank B, Swergold CD, Autilio-Gambetti L, Gajdusek DC, Lugaresi E, Gambetti P. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science 1992; 258:806-808. GoldfarbLC,Brown P. CervenakovaL,GajdusekDC.Geneticanalysisof Creutzfeldt-Jakob disease and related disorders. Philos TransR SOC London Ser B 1994; 343~379-384. S, Qi H-Y, Lee HS, Sambuughin N, Cervenrikovri L, Chapman J, Pocchiari M, Litvak Budka H, del Ser T, Furukawa H, Brown P, Gajdusek DC, Korczyn A, Goldfarb LC. Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt-Jakob disease. Amer J Human Genetics 1999; 64: 1063-1070. Brown P, Preece MA, Will RG. “Friendly fire” in medicine: hormones, homografts, and Creutzfeldt-Jakob disease. Lancet 1992; 340:24-27. BrownP.Transmissiblehumanspongiformencephalopathy(infectiouscerebral amyloidosis):Creutzfeldt-Jakobdisease, Gerstmann-Straussler-Scheinker syndrome, and kuru. In: Calne DB, ed. Neurodegenerative Diseases. Philadelphia: WB Saunders,1994:839-876.

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Goldfarb et al.

20. Ghetti B, Dlouhy SR, Giaccone G, Bugiani 0, Frangione B, Farlow MR, Tagliavini E Gerstmann-Straussler-Scheinker’s disease and the Indiana kindred. Brain Pathol 1995; 5161-75. 21. Lugaresi E, Medori R, Montagna P, Baruzzi A, Cortelli P, Lugaresi A, Tinuper P, Zucconi M, Gambetti P. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 1986; 27412079-2082. 22. Gambetti P, Lugaresi E. Conclusions of the symposium. Brain Pathol 1998; 8:571575. 23. Collinge J, Sidle KC, Meads J, Ironside Hi11J,AF. Molecularanalysis of prion strain variation and the aetiology of “new variant” CJD. Nature 1996; 3831685-690. 24. Bruce ME, Will RG, Ironside JW, McConnellI, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock CJ. Transmissions to mice indicate that “new variant” CJD is caused by the BSE agent. Nature 1997; 3891498-501. 25. Telling GC, Scott M, Mastriani J, Gabizon R, Torchia M, CohenFE, DeArmond SJ, Prusiner SB. Prion propagation in mice expressing human and chimeric PrP transgenesimplicatestheinteractionofcellularPrPwithanotherprotein.Cell1995; 53179-90. 26. Hsiao KK, Groth D, Scott M, Yang S-L, Serban H, Rapp D, Foster D, Torchia M, DeArmond SJ, Prusiner SB. Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proc Natl Acad Sci USA 1994; 91:9126-9130. 27. Shmerling D, Hegyi I, Fischer M, Blattler T, Brandner S, Gotz J, Rulicke T, Flechsig E, Cozzio A, von Mering C, Hangartner C, Aguzzi A, Weissmdnn C. Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions. Cell 1998; 93:203-214. 28. Palmer MS, Dryden AJ, HughesT, Collinge J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 1991; 3521340-342. 29. Brown P, Cervenakova L, Goldfarb LC, McCombie WR, Rubenstein R, Will RG, PocchiariM,Martinez-LageJF,ScaliciC,MasulloC,GrauperaG,Ligan J, Gajdusek DC. Iatrogenic Creutzfeldt-Jakob disease: an example of the interplay between ancient genes and modern medicine. Neurology 1994; 44291-293. 30. Brown P, Gibbs CJ Jr, Rodgers-Johnson P, Asher DM, Sulima MP, Bacote A, Goldfarb LG, Gajdusek DC. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 1994; 351513-529. 31. Klatzo I, Gajdusek DC, Zigas V. Pathology of kuru. Lab Invest 1959; 8:799-847. 32. BrownP, Goldfarb LG, Kovanen J, Haltia M, Cathala F, Sulima M, Gibbs CJ Jr, Gajdusek DC. Phenotypic characteristics of familial Creutzfeldt-Jakob disease associated with the codon 178*”” PRNP mutation. Ann Neurol 1992; 31:282-285. 33. Brown P, Goldfarb LG, Gibbs CJ Jr, Gajdusek DC. The phenotypic expression of different mutations in transmissible familial Creutzfeldt-Jakob disease. Eur J Epidemiol 199l ;7:469-476. 34. Piccardo P, Dlouhy SR, Lievens PMJ, Young K, Bird TD, Nochlin D, Dickson DW, Vinters HV,Zimmerman TR,MackenzieIRA,KishSJ,AngL-C,DeCarliC,

Prion Associated Diseases

35. 36.

37.

38.

39. 40.

41.

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Pocchiari M, BrownP, Gibbs CJ Jr, Gajdusek DC, Bugiani0, Ironside J, Tagliavini F, Ghetti B. Phenotypic variability of Gerstmann-Straussler-Scheinker disease is associated with prion protein heterogeneity. J Neuropath01 Exp Neurol 1998; 979-988. Kitamoto T, TateishiJ. Human prion diseases with variant prion protein. Philos Trans R SOC London Ser B, 1994; 343:391-398. Gambetti P, Parchi P, Petersen RB, Chen SG, Lugaresi E. Fatal familial insomnia and familialCreutzfeldt-Jakobdisease:clinical,pathologicalandmolecularfeatures. Brain Pathol 1995; 5:43-51. Montagna P, Cortelli P, Avoni P, Tinuper P, Plazzi G, GalassiR, Portaluppi F, Julien J, Vital C, Delise MB, GambettiP, Lugaresi E. Clinical featuresof fatal familial insomnia: phenotypic variability in relation to a polymorphism at codon 129 of the prion protein gene. Brain Pathol 1998; 8:515-520. Hsich G, KenneyK, Gibbs CJ Jr, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med 1996;335:924-930. Ironside JW. Neuropathological diagnosis of human prion disease. In: Baker HF, Ridley RM, eds. Methods in Molecular Medicine: Prion Diseases. Totowa, NJ: Humans Press, 1996:35-57. Budka H, Aguzzi A, Brown P, Brucher JM, Bugiani 0, Collinge J, Diringer H, Gullotta F, Haltia M, Hauw JJ. Tissue handling in suspected Creutzfeldt-Jakob disease (GJD) and other human spongiform encephalopathies. Brain Pathol 1995; 5:319322. Brown P, Cervenakova L, Goldfarb LG, Gajdusek DC, Horwitz J, Creacy SD, Bever RA, Wexler P, Sujansky E, Bjork RJ. Molecular genetic testing of a fetus at risk of Gerstmann-Straussler-Scheinker’s syndrome. Lancet 343: 18 1-182, 1994.

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Idiopathic Cerebellar Degeneration Multiple System Atrophy Jorg 6. Schulz and Johannes Dichgans University of Tubingen, Tubingen, Germany

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 EATURES A. DiagnosticCriteria B. ClinicalDomains C.RedFlags D. ExclusionCriteria E.NaturalHistory

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ANCILLARYTESTS A.AutonomicTests B. Neuroendocrine Tests C.MagneticResonanceImaging D. PET and SPECTScanning E.SphincterEMG F. Electrophysiology

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VII. MANAGEMENT REFERENCES

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I. I ~ T R O D U C T I O ~ Adult-onset idiopathic cerebellar ataxia is characterized by a progressive cerebellar ataxia without evidenceof a focal or nonfocal symptomatic originof the disorder, absence of any neurodegenerative disorders in relatives, and no evidence of consanguinity of parents. Some patients initially suffer from a seemingly pure idiopathic cerebellar ataxia (IDCA-C); however, in the course of the disease, many of thesepatientsdevelopanonresponsiveorpoorly L-doparesponsive parkinsonism (IDCA-P) and/or severe symptomatic autonomic failure, thus leading to the diagnosis of probable multiple system atrophy (MSA). Multiple system atrophy (MSA) is a term introduced in 1969 by Graham and Oppenheimer. MSA is a sporadic disease, with onset after the age of 30 years, which encompasses the pathologies of striatonigral degeneration (SND), Shy-Drager syndrome, and olivopontocerebellar atrophy. In the absence of distinctive clinical markers, a definitive diagnosisof MSA can be achieved onlyby neuropathological confirmation.The pathological changes consistof cell loss and gliosis in a selection of sites, principally striatum and substantia nigra, but optionally the inferior olives, pons, cerebellum, and the intermediolateral cell columns and Onuf‘s nucleus in the spinal cord. Oligodendroglial cytoplasmic inclusions are characteristically present, but Lewy bodies are absent unless incidental. The most frequent motor symptoms are ataxia and parkinsonism with akinesia and rigor (1,2). Usually, the response toL-dopa treatment in MSA is either poor or less prominent than in Parkinson’s disease. In MSA, the substantia nigra almost always shows a lossof dopaminergic pars compacta neurons that can be as severe as that in Parkinson’s disease. Until recently, it has been questioned whether all patients with a “sporadic olivopontocerebellar atrophy,” for which the clinical diagnosis of IDCA-P would be appropriate, will develop MSA during life. Although no longitudinal studies are available, two recent positron-emission tomography (PET) studies(3,4) provided in vivo neurochemical evidence for the unityof these syndromes. Gilman and colleagues (3) showed that patients with sporadic olivopontocerebellar atrophy had deficits in forebrain glucose utilization that could not be separated from (4) showed that most,if not all, patients with those in MSA. Rinne and colleagues sporadic olivopontocerebellar atrophy have a subclinical striatonigral degeneration,makingthemcases of MSA.Althoughpuresporadiccerebellarataxia (IDGA-C) with noma1 life expectancy exists (3,here, we will concentrate on a review of MSA.

II.

EPIDEMIOLOGY

The prevalence of MSA is unknown, butmay be higher than previously thought. Investigations suggest that MSA could account for anything from 3.6 to 22%

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(1,6,7) of incident cases of parkinsonism. A mean figure of this series is 8.2% (68/833) of all patients with parkinsonism. Because the prevalenceof parkinso100:100,000to 200 :100,000inhibitants.(8), nian syndromes overall ranges from the prevalence of MSA may be as high as 10: 100,000 to 20: 100,000. MSA affects both sexes equally, usually beginning in middle age and progressing over intervals of 0.5-24 years, with a median survivalof 6 years from the first symptom (9,lO).

Ill. MOLECULARPATHOGENESIS The molecular pathogenesis of MSA remains to be elucidated. PathOlOgiCallY, there is widespread neuronal loss and gliosis, preferentially involving striatum, substantia nigra, locus caeruleus, inferior olive, pons, cerebellum, and i n t m ~ ~ e diolateral cell columns, as well as Onuf‘s nucleusof the spinal CO@. As .a result patients suffer from a combination of symptoms, including parkinsonism, cerebellarorpyramidalsigns,andautonomicfailure.Althoughthespectrum of symptoms varies from patientto patient, the brainsof all affected individuals exhibit abundant oligodendroglial and scattered neuronal intracytoplasmic argyrophilic inclusions(11). The glial cytoplasmic inclusions (GCIs) found in MSA can be stained with antibodies directed against ubiquitin (12). Recently, it was shown that a-synuclein accumulates as insoluble aggregates in white matter oligodendrocytesof MSA brains as GCIs (13,14), suggesting that a selective reduction in the solubility of a-synuclein in oligodendrocytes may result in the precipitation of. this protein into tubular or filamentous structures and the formationof GCIs. Although a-synuclein deposits occur in several neurodegenerative diseases, it still is not an ubiquitous phenomenon following neuronaldamage;brains of patientswithmulti-infarctdementiahaveno synucleininclusions (13, andthetau-positiveneuronalinclusionbodiesin Pick’s disease have no synuclein associated with” them (15). Thus, synuclein is not an obligatory componentof protein bodies, butis confined toa group of neurodegenerative diseases that may be termed “syn~cleinopathies.’~ The abundance of a-synuclein in the GCIs is surprising because a-synuclein is expressed primarily in neurons in the normal brain. Hence, the accumulation~of a-synuclein in GCIs may be due to a selective up-regulationof its expression in oligodendrocytes in MSA, or to an impairment in the ability of these cells to degrade it, which theymay produce at very low levels. These findings indicate that a reduction in the solubility of a-synuclein may induce this protein to form filaments that aggregate into cytoplasmic inclusions, which contribute to the dysfunction or death of glial cells.The degeneration of neurons may occur as a secondary event. Missense mutations in the a-synuclein geneof kindreds with familial Parkinson’s disease (PARK 1) provide evidence that autosomal, dominantly inher-

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ited Parkinson’s diseasemay result from mutant forms of a-synuclein. Moreover, the detections of extensive Lewy bodiesand related Lewy neurites with antibodies to a-synucleinin idiopathic Parkinson’s disease (IPD), dementia with Lewy bodies, and the Lewy body variant of Alzheimer’s disease(16-21) provide strong support for the notion that wild-type a-synuclein contributes to the pathogenesis of these disorders. Although a-synuclein is a highly soluble synaptic protein in the normal human brain, it accumulates as insoluble aggregates in white matter oligodendrocytes of MSA brains as GCIs (13,14), suggesting thata selective reduction in its solubility in oligodendrocytes may result in the precipitationof this protein into tubularor filamentous structuresand the formationof GCIs. Because the solubilityof a-synuclein may be due to abundant negatively charged glutamic acid residues in the COOH-terminal half of this protein (22), abnormal modifications of this region may be an early step in its aggregation into neuronal and glial inclusions. Although MSA is considered to be a sporadic disease, one case-control study conductedin MSA patients found evidence suggesting a possible contributory genetic component in the pathogenesisof this disorder (23). In the absence of sevof families or an efficient numberof siblings with MSA, the polymorphism eral candidate genes was investigated. An association between a polymorphism in exon 6 of the debrisoquine (CYP2D6) geneand MSA was reported ina small series of Japanese patients (24), but has not been confirmed in a large series of white patients with MSA (25). Furthermore, there is no association between the CYP2D6 poor metabolizer phenotype and MSA (26). In a study of 80 MSA patients, no pathological changes were detected in a series of possible candidate 1 and 3 genes (SCA1and SCA3), genes, including the spinocerebellar ataxia type the human homologue of the weaver mouse gene, the IGF-1 receptor gene, the ciliary neurotrophic factor gene (CNTF), and HLA-A32 association (27). A specific deficiencyof mitochondrial complexI activity has been found in IPD. The contribution of this biochemical defect to the cause of dopaminergic cell death in IPD is enhancedby the finding that, within the brain, complex I deficiency is confined to the substantia nigra and is not present in the caudate nucleus, putamen, globus pallidus, cerebral cortex, or cerebellum review, (for see Ref. 28). Although an approximately 30% complex I deficiency inskeletal muscle from five patients with MSA was reported (29), complex I-IV function appears unaffected in substantia nigra (a site of major pathological change in MSA) in pathologically proved cases of MSA (30), casting doubt on the relwith a clinical diagnoevance of any defect observed in other tissues in patients sis of MSA. In addition, and in contrast with IPD, there is no evidence for oxidative stress in MSA (31). When analyzing the gene expression profile in brains with MSA by a highdensity cDNA filter method,a novel gene, ZNF 23 l , was identified, the expression of which was elevated in cerebella of patients with MSA (32). The expres-

Degeneration Idiopathic Cerebellar

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sion of this gene is specific for the brain and apparently restricted to neurons. The gene encodes a double zinc-finger protein containing two nuclear-targeting signals and a leucine-zipper motif, suggesting that the gene encodes a nuclear protein or transcription regulator. However, its functional role in the pathogenesis of MSA remains to be elucidated.

IV.

NEUROPATHOLOGY

The characteristic neuropathology of MSA is the presence of many glial Cytoplasmic inclusions (GCIs) and the absence of Lewy bodies (33). There have been descriptions of distinctive neuropathological featuresof MSA, consisting of oligodendroglial (11,12,34-37) and neuronal (34,38,39) intracytoplasmic and intranuclear argyrophilic inclusions containing accumulations of tubular structures. However, of these, only the GCIs occur consistently and in a great enough density to be the significant hallmark lesion of MSA. GCIs are not randomly distributed in the central nervous system, but are system-related (35). Structures with high GC1 density (more than 300/mm2) include the supplementary motor and primary motor cortical areas, with their subjacent white matter, the putamen, the caudate nucleus, the globus pallidus, the internal and external capsules, the reticular formation, the basis pontis, the middle cerebellar peduncles, the cerebellar white matter, and the spinal cord (35). In contrast, the visual and auditory pathways, olfactory structures, somatosensory systems, associations and limibic cortical areas, and subcortical limbic structures contain none or only few GCIs. of whether the patient’s The GCIsare present in all MSA brains, regardless diagnosis in life wasMSA-P, MSA-C,or a Shy-Drager syndrome (11,34,3S). In contrast, GCIs were not initially found in a large number of neurological controls, including patients with Parkinson’S disease, progressive supranucle~palsy, and Machado-Joseph disease ( l 1). However, following the initial reports of GCIs, various glia1 inclusions have been described in both astrocytes and oligodendrosuglialcellsinvariousneurodegenerativediseases,includingprogressive pranuclear palsy, corticobasal degeneration, Pick’s and Alzheimer’s diseases, and in chromosome 17-linked dementia. Although the significance of these inclusions remains to be established, these recent findings have apparently challenged the diagnostic valueof specificity inMSA. However, both morphological and immunohistochemical evidence indicates that the CGIs in MSA are different from the oligodendroglial inclusions of other neurodegenerative diseases, including those found in progressive supranuclear palsy and corticobasal degeneration. Even if CGIs were not specific, their density and distribution in MSA is unique. The European BrainBank Network, considering the need of standardized neuropathological criteria for various neurodegenerative diseases, has accepted that demonstration of GCIs by immunohistochemistry or silver impregnation in the frontal

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cortex, lentiform nucleus, pons, cerebellum, midbrain, medulla oblongata, or in the spinal cord provides a reliable and consistent neurohistological criterion for the diagnosis of MSA (40). The GCIs stain positive for ubiquitin. This unequivocal ubiquitin-positivity is an important distinguishing feature from other oligodendroglial inclusions, which are tau-positive, but usually ubiquitin-negative. GCIs may represent a cytoskeletal alteration in glial cells that results in neuronal degeneration. Thus, it is tempting to speculate that these glial cytoplasmic inclusions are relevant to the pathogenesis of MSA. The functional significance of GCIs and glial synuclein aggregates in the pathogenesis of MSA and the neuronal cell death therein remains unclear. One could speculate that MSA isa disease with primary glial pathology and that neuronal death occurs secondary to impaired function or lossof glial supporting elements, as in multiple sclerosis. Alternatively, it also could abeglial response to neuronal damage. Orthostatic hypotension in MSA is due to absent autonomic and neuroendocrine reflexes as a result of afferent and central neuronal loss. In a small, but elegant, study of patients with MSA and well-documented premortem evidence of autonomic failure, Benarroch and colleagues (41) reported depletion of catecholaminergic neurons in the rostral (Cl group) and caudal (A1 group) ventroof sympathetic cardiolateral medulla. These neurons are involved in the control vascular outflow, cardiorespiratory interactions, andreflex control of vasopressin release, thereby providinga neuropathological basis for the abnormal blood pressure control of MSA patients (42). Experimentally, a region homologous with the human medullary arcuate nucleus is involved in the autonomic cardiorespiratory regulation. Recently, it was shown that the neuronal density of the arcuate nucleus in patients with MSA was markedly depleted in comparison with controls and patients with idiopathic Parksinson’s syndrome and amyotrphic lateral sclerosis (43).

V.

CLINICALFEATURES

A.

DiagnosticCriteria

According to a recently released consensus statement (44), MSA is clinically characterized by (a) sporadic progressive cerebellar ataxia or a sporadic adultonset,nonresponsiveorpoorlylevodopa-responsiveparkinsonism;(b)severe symptomatic autonomic failure, with at least postural syncope or presyncope or pronounced urinary incontinence or retention not due to other causes; (c) absence of dementia according toDSM-III R criteria, and the absenceof generalized tendon areflexia, or predominant downgaze supranuclear palsy (Table 1). From their clinical presentation and theirfirst motor symptom, patientsmay subdivided into

rebellar

Idiopathic Table 1 Clinical Domains, Features, and Criteria Used in the Diagnosis

551

ofMSA"

I. Autonomic and urinary dysfunction

A. Autonomic and urinary features 1. Orthostatic hypotension (by 20-mmHg systolic or 10-mmHg diastolic) 2. Urinary incontinence or incomplete bladder emptying B. Criterion of autonomic failure or urinary dysfunction in MSA Orthostatic fall in blood pressure (by 30-mHg systolic or 15-mmHg diastolic) or urinary incontinence (persistent, involuntary partial, or total bladder emptying, accompanied by erectile dysfunction in men) or both 11. Parkinsonism A. Parkinsonian features l. Bradykinesia 2. Rigidity 3. Postural instability (not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction) 4. Tremor (postural, resting, or both) B. Criterion for parkinsonism in MSA Bradykinesia plus at least one of items 2-4 111. Cerebellar dysfunction A. Cerebellar features l . Gait ataxia (wide-based stance with steps of irregular length and direction) 2.Ataxicdysarthria 3.Limbataxia 4. Sustained gaze-evoked nystagmus B. Criterion of cerebellar dysfunction in MSA Gait ataxia plus at least one of items 2-4 IV. Corticospinal tract dysfunction A. Corticospinal tract features 1. Extensor plantar responses with hyperreflexia B. Criterion for corticospinal tract dysfunction in MSA Corticospinal tract dysfunction in M S A (no corticospinal tract features are used in defining the diagnosis of MSA) "Afeature (A) is characteristicof the disease.A criterion (B) is a defining feature or composite of features required for diagnosis Source: Ref. 44.

two groups, one with predominant parkinsonism (MSA-P) and another with predominant ataxia (MSA-C). Depending on the combination of symptoms the clinical diagnosisof MSA may be called possibleor probable, the definitive diagnosis can only be confirmed postmortem (Table 2). The initial presentation and progression of symptoms vary. MSA can be diagnosed (see Table 2) by using criteria or features of clinical domains (see

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Table 2 DiagnosticCategoriesof MSA" Possible MSA: one criterion plus two features from separate other domains. When the criterion is parkinsonism, a poor levodopa response qualifies as one feature (hence, only one additional feature is required). Probable MSA: criterion for autonomic failure or urinary dysfunction plus poorly levodopa-responsive parkinsonism or cerebellar dysfunction. Definitive MSA: pathologically confirmed by the presence of a high density of glial cytoplasmic inclusions in association with a combination of degenerative changes in the nigrostriatal and olivopontocerebellar pathways. "The features and criteria for each clinical domain are shown

Source: Ref. 44.

in Table 1

Table 1).Clinical domains are(I) autonomic and urinary dysfunction,(11)parkinsonism, (111) cerebellar dysfunction, and (IV) corticospinal tract dysfunction.

B. ClinicalDomains l,

1. AutonomicandUrinaryDysfunction Male erectile dysfunction is an early and almost obligatory symptom; however, the symptom has low specificity. Urinary frequency, urgency, incontinence, or incompletebladderemptyingoccurearlyandcommonlyduringthedisease. Orthostatic hypotension may indicate autonomic failure and can be asymptomatic or symptomatic. When symptomatic, it typically occurs after the onset of male erectile dysfunciton and urinary symptoms (44). Symptoms of orthostatic hypotension result from cerebral hypoperfusion, and syncope may occur. The consensus conference determined that the clinical diagnosis of probable MSA requires a reduction of systolic pressure by at least 30 mmHg or of diastolic blood pressure by at least 15 mmHg within 3 min of standing from the recumbant position (44). Frequently, this is accompanied by an inadequate increase in heart rate (fewer than 10 beats per minute). Further patients may suffer from respiratorystridorowingtovocalcordabductorparalysis,which may occur early in disease. Moreover,many MSA patients suffer from REM sleep behavior disorder (RBD) (45).

2.

Parkinsonism

Most MSA patients develop parkinsonian features at some stageof the disorder. In a metanalysis of 203 published cases of pathologically proved MSA, 87% of patients showed parkinsonism(46). All these patients had bradykinesia. Rigidity, postural instability, and tremor also often occur (4'7). The tremor is usually irregular and postural, often incorporating myoclonus. A classic pillrolling parkin-

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sonian rest tremor is uncommon. The parkinsonism in MSA is frequently more symmetrical than in idiopathic Parkinson’s disease; however, it can be asymmetrical. The dysarthria is mainly hypokinetic, often mixed with other components (48). The parkinsonian features usually respond poorly to prolonged levodopa therapy. However,up to 30% of patientsshowaclinicallysignificant response to levodopa therapy at some time in the course. But the response is usually sustained for less than 5 years (9,49,50). These are the most challenging patientsforaccuratediagnosis. We recommenddesignatingpatientsashaving MSA-P if parkinsonian features predominate (2,51,512). 3. CerebellarDysfunction Cerebellar ataxia occurs in more than 50% of patients with MSA (46). Ataxiaof gait, the most common cerebellar featureof MSA, often occurs accompaniedby dysarthria, limb ataxia, gaze-evoked nystagmus, cogwheeled smooth pursuit, and saccadic dysmetria (2). Cogwheeled saccadic pursuit movements come with abnormal vestibulo-ocular reflex cancellation(53-56). We recommend designating patients as having MSA-Cif cerebellar features predominate (2,5 1,52). The dysarthria in patients with MSA-C is mainly ataxic, often mixed with other components (48).

4. CorticospinalTractDysfunction Extensor plantar responses with hyperreflexia occur in about 50% of MSA patients (46). Corticospinal signs can contribute to the diagnosis, but they are less important than abnormalities in other domains.

C. RedFlags Apart from the clinical domains considered in the foregoing, other “soft” clinical features, always considered as only partof an overall picture,may help point to(1) (Table 3). ward MSA ormay suggest that a patient’s parkinsonism is atypical Among these are early instability and falls, rapid progression, severe hypophonic dysarthria, pain unrelievedby levodopa (577, disproportionate antecollis (46,58), absent or atypical levodopa-induced abnormal involuntary movements (46), especially in the face and neck (59)-often elicited by a very small levodopa dose, a recent past historyof hypertension giving way to erect normo-or hypotension, the presence of contractures, pseudobulbar crying or laughing, and dusky discoloration or coldness of the extremities not caused by drugs (60), or Raynaud’s phenomenon (61), which may be provoked by ergot drugs. Excessive snoring at night, and vocal cord abductor palsy (62-66) leading to nocturnal and sometimes daytime stridor may occur. The latter is highly suggestiveof MSA. We have followed patients in whom a vocal cord paralysis requiring tracheostomyor an ap-

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Table 3 Clinical Pointers for MSA (and Against Idiopathic PD) in Parkinsonism Clinical donnains Cerebellar dysfunction Corticospinal tract dysfunction Autonomic dysfunction Soft signs Partial or absent response toa sufficient dose of L-dopa (800-1000 mg/day, if tolerated) ~, ., Rapid progression Permanently wheelchair-bound despite therapy Early instability and falls Irregular jerky tremor or myoclonus Absent or atypical L-dopa-induced abnormal involuntary movements, especially in the face and neck, often elicited by a very small L-dopa dose Marked dysarthria Marked dysphagia Disproportionate antecollis Respiratory stridor, sighs, increased snoring Sleep apnea Cold dusky hands, Raynaud’s phenomenon provoked by ergot drugs Contractures Abnormal eye movements I

nea syndrome was the first symptom of MSA (66). Occasional deep involuntary sighs may also occur. A recently recognized feature of MSA is REM sleep behavior disorder to dreams. (RBD). RBI) consists of nocturnal motor paroxysmal episodes related RBD is common in MSA (90% in Plazzi’s recent series), and can precede ap- the pearance of other symptoms (45). Other polysomnographic findings include nonclinical obstructive sleep apnea, laryngeal stridor, and periodic limb movements during sleep. The frequency of mood disorders is no higher in MSA than in idiopathic may be less common Parkinson’s disease (67). In fact, mood affective symptoms (68). In addition, ideomotor apraxia may occur in patients with idiopathic Parkinson’s disease (27%) or with progressive supranuclear palsy (75%), but patients with MSA do not show any disturbance of praxic functions (69).

.

ExclusionCriteria

The exclusion criteria for a diagnosis of MSA are summarized in Table4. They include early onset of the disease, a family history, symptomatic origins of the

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Table 4 Exclusion Criteria for the Diagnosis of MSA

l . History Symptomatic onset younger than 30 years of age Family history of a similar disorder Systemic diseases or other identifiable causes for features listed in Table 1 Hallucinations unrelated to medication 2. Physicalexamination DSM criteria for dementia Prominent slowing of vertical saccades or vertical supranuclear gaze palsy Evidence for focal cortical dysfunction, such as aphasia, alien limb syndrome, and parietal dysfunction 3. Laboratoryinvestigation Metabolic, molecular, genetic, or imaging evidence for an alternative cause of features listed in Table 1

disease, dementia, and signs of progressive supranuclear palsy and corticobasal ganglionic degeneration.

E. Natural History Life expectancy in MSA is shorter than in IPD. a metanalysis In of 433 published cases of pathologically proved MSA cases over a 100-year period, the mean age of onset was 54 years (range 31-78) and median survival was 6 years (range 0.5-24). Survival was unaffectedby gender, parkinsonsian or pyramidal features, or whether the patient was classified as MSA-P or MSA-C (10). Survival analysis showeda secular trend froma median durationof 5 years for publications between 1887 and 1970, to 7 years between 1991 and 1994; these figures may reflect improved symptomatic treatments of autonomic dysfunction.

VI. ANCILLARY TESTS Autonomic and neuroendocrine tests, magnetic resonance imaging (MRI)of the brain, imaging of D, receptors or dopamine transporters, and sphincter electromyography (EMG), can be used as confirmatory tests to aid clinical diagnosis.

A. Autonomic Tests Numerous studies have described abnormal cardiovascular reflexes in MSA patients (70-73). Assessment of autonomic function can be assisted by a comprehensive battery that evaluates the distribution and severity of sudomotor, cardio-

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vagal,andsympatheticadrenergicdeficits.Itisourexperiencethat,forthe diagnosis of autonomic dysfunction, a careful history of erectile impotence, urinary frequency, urgency, and incontinence; a tilt table test for orthostatic hypotension; and a bedside test for incomplete bladder emptying, are sufficient. Only undercertaincircumstancesmoresophisticatedinvestigations(laryngoscopy, manometric study of swallowing, 24-h registration of blood pressure and heart rate, and polysomnography) may be necessary.

.

NeuroendocrineTests

A characteristic of MSA is that afferent and central autonomic and neuroendocrine refex pathwaysareselectivelyaffected,whereaspostganglionicautonomic fibers are spared (41,74). Intravenous injection of clonidine, a centrally active a,-adrenoreceptor agonist that stimulates growth hormone secretion, can be used to test the function of hypothalamic-pituitary pathways in MSA (75). Clonidine raises serum growth hormone in patients with idiopathic Parkinson’s disease and patients with pure autonomic failure, but does not in those with MSA. These findings suggest that the growth hormone responses to intravenous clonidine can differentiate MSA from idiopathic Parkinson’s disease and pure autonomic failure and point toa specific a,-adrenoreceptor-hypotha1amic deficit in MSA. The use of positron-emission tomography (PET), with the norepinephrine to the sympathetic postganglionic innervaprecursor [’*F~fluorodopa~ine, study tion of the heart on MSA patients showed normal cardiac sympathetic innervation (76). This finding further confirmed the hypothesis that the autonomic dysfunction of MSA patients is caused mainly by central nervous system lesions that result in failure to engage peripheral postganglionic autonomic neurons.

C. MagneticResonanceImaging Modern-imaging methods, such as MRI, single-photon emission CT (SPECT), and PET are increasingly used in IPD and related disorders to study their morphological and functional characteristics (2,52,77-84). MRI of the brain can detect abnormalitiesof striatum, cerebellum, and brain stem (2,52,85-87). Infratentorial abnormalities that are seen on MRI in patients with MSA include atrophy in the pons, cerebellar vermis, and hemispheres, and signal change in the pons and middle cerebellar peduncle. Of those, abnormal signal intensities on T2weighted imagesmay be most important for practical purposes aonroutine basis (Figs. 1 and 2). In the pons and the middle cerebellar peduncle, high-signal intensity may be detectable on T2-weighted images, suggesting degeneration and demyelination of pontocerebellar fibers (see Fig.1). Shrinkage of pons as well as middle cerebellar peduncles differentiates MSA-C from IDCA-C (2,s).

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Figure 1 NIRI of upper pons (A, C) and middle cerebellar peduncles (B, D): The upper panel shows images (A, B) of a healthy control. The lower panel (C, D) shows hyperintensities of the transverse pontine fibers between tegmentum and the base of the pons (C) and in the middle cerebellar peduncles (D) in a patient with NISA-C.

Striatal abnormalities in MSA include atrophy of caudate nucleus and putamen (52) and putamina1 hypointensity on T2-weighted images, as well as slitlike signal change at the posterolateral putamina1 margin (2,87,88) (see Fig. 2). This striking signal change in the lateral putamen corresponds to the area showing the most pronounced microgliosis and astrogliosis, as well as the highest (87). This abnormal intensity is frequently amount of ferric iron at necropsy asymmetrical. In contrast with pontocerebellar atrophy, which often can be recognized on MRI at first glance (2,89), more sophisticated methods are necessary to deter-

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Figure 2 Hypointensities of basal ganglia in MRI (T2-weighted spin-echo images 1.5 T, TR = 2100 ms, TE = 45 90 ms, slice thickness = 4 mm): (A) Healthy control; normal distributionof hypointensities: absenceof hypointensities in the putamen, normal hypointensity in the pallidum. (B-D) Hypointensitiesof the basal ganglia inMSA patients. The hypointensity extends (B) into the dorsolateral margin of the putamen, (C) through part of the body of putamen, or (D) throughout the entire putamen, with an intensity exceeding that in globus pallidus. Note the slit-like hyperintensity at the lateral putamina1 border (D).

+

mine the atrophy of basal ganglia by three-dimensional volume measurements as well as infratentorial (52). These investigations (2,52) show that basal ganglia, MSA-Por MSA-C,respectively. There are pachanges, are not confined to either tients without obvious parkinsonian signs who have pronounced putamina1 hypointensities or atrophy; on the other hand, infratentorial atrophyor hyperinten-

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sities of pontocerebellar fibers occur in almost all patients with MSA-C, also but in several patients with MSA-P. The lack of high sensitivity or specificity for MSA of these parameters does not allow one to make a diagnosis by the evaluation of one parameter alone. However, the combination of several parameters [e.g., atrophy of .basal ganglia and atrophy of posterior fossa structures (52), or cerebellar atrophy together with signal abnormalities (2), or clinical signs and signal abnormalities in MRI ('73)] allows ax~~muah better separation of patients with MSA from IPD or pure cerebellar cortical atrophy. Magnetic resonance spectroscopy (MRS) has demonstrated a reduction of of MSA but notof IPD patients N-acetylaspartate signal in the lentiform nucleus (90).However,similarabnormalitieshavebeenobservedinprogressive supranuclear palsy, indicating that MRS may be helpful to distinguishIPD from atypical parkinsonian patients, but that it fails to differentiate atypical parkinsonian syndromes (91).

D. PETandSPECTScanning Single-photon (SPECT) or positron emission tomography (PET) studies of MSA patientshavedemonstratedsimultaneousabnormalitiesinthenigrostriatal a pathway as well as postsynapticabnormalitiesinthestriatum,indicating combined nigra1 and striatal pathology. Investigations of the striatal dopamine of dopaminetransporterwith storagecapacitywith[18F]fluorodopaPETor [ ' 'CC]nomifensine PET or [1231]2-~-carbomethoxy-3-~-(4-iodophenyl)-tropane (P-CIT) SPECT show a severely reduced integrityof the presynaptic striatal dopaminergic system comparable with the situation in patients with IPD (92-95). Compared with healthy controls and untreated (de novo) IPD patients, MSA patients additionally demonstratea loss of postsynaptic D, receptors in the striatum, as shown by [1231] iodobenzamide SPECT (2,81,82) and [llC]raclopride (95) or ["Cldiprenorphin (4,96) PET. However, because treated IPD patients with treatment fluctuations also show reduced D, receptor densities, MSA patients cannot be differentiated from L-dopa-treated IPD patients by raclopride PET, and the loss of D, receptors may not be the only reason for failure of L-dopa treatment in MSA patients (95). The poor L-dopa response may, in addition, be related to a deficiency of striatal dopamine D, receptors, as shown by PET studies in clinically diagnosed MSA patients using the ligand ["C]Sch-23390 (97). Widespread functional abnormalities in NISA-C have been demonstrated using [18F]fluorodeoxyglucose PET (3). Reduced metabolism was most marked as putamen, caudate nucleus, in brain stem and cerebellum, but other areas, such also involved, in contrast to autosomal domithalamus, and cerebral cortex, were of striatalpathology nantcerebellarataxias(ADCAs).Subclinicalevidence usin MSA-C, in the absenceof extrapyramidal features, has been demonstrated ing the nonselective opioid receptor ligand diprenorphine and PET (4). Differ-

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encesincerebellarbenzodiazepinereceptor-bindingdensitieshave also been shown in MSA-C, pure cortical cerebellar ataxia, and ADCA using ["Clflumazenil PET (98).

The striated muscles of the external anal and urethral sphincter are partly innervated by fibers that originate in Onuf's nucleus in the segments S2-S4 of the spinal cord. The nucleus is particularly vulnerable in patients with MSA, but not in those with IPD. In patients with MSA, involvement of Onuf's nucleus is much more frequent than thatof anterior horn cells in the restof the cord. Interestingly,thereverseoccursinpatientswithamyotrophiclateralsclerosisin whom Onuf's nucleus is selectively spared. Neuronal loss in Onuf's nucleus is reflected by signs of denervation and chronic reinnervation onEMG of anal and urethral sphincter muscles. Abnormal sphincter EMGs are found in 82-93% of MSA patients (99,100). Although it was suggested that abnormal spontaneous activity on EMC may be the most useful criterion to differentiate IPD from MSA (loo), we do not think that a sphincter EMG should be done on every patient in whom the diagnosis of MSA is suspected, because (a) abnormal spontaneous sphincter activitymay be difficultto detect and requires specific expertise; (b) sphincter EMGs are unpleasant for the patient; (c) abnormal spontaneous also occurs in 42% of patients Sphincter activity is not specific for MSA, but with progressive supranuclearpalsy, although these patientsdo not normally exhibit clinical signs of autonomic dysfunction (101); and (d) in our hands, the combination of the clinical syndrome together witha detailed history of autonomous dysfunction and MRI imaging of the brain gives an excellent certainty of the clinical diagnosis.

Electrophysiology Motor-evoked potentials are,normal inMSA patients, whereas 40% of MSA patients demonstrate abnormalities in visual- and somatosensory-evoked potentials (102). Because motor-evoked potentials are abnormal in almost all SCAl patients, but only in a few SCA2 and SCA3 patients, they cannot be used to separate MSA from SCA.

of the There is no specific treatment for the cerebellar and pyramidal features of MSA padisease. In contrast with patients with IPD, more than two-thirds tientsfail to respondusefullytotreatmentwith L-dopa. Insome of these, a

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modest beneficial effect is sometimes evident only when they deteriorate after L-dopa has been withdrawn. The remaining 25-30% experience a moderate to good response to L-dopa, and 10% even report an initially excellent improvement of symptoms as iswitnessedin IPD (49,50).Inmostpatients,benefit from L-dopa wanes over the course of 1-2 years, so that in advanced MSA only 13% of patients experience a good response to L-dopa. In about 25% of patientswithMSA-Ptreatedwith L-dopa, end-of-doseakinesia, on-off phenomenon, dyskinesia, and painless or painful dystonia are observed. Dyskinesias in MSA predominate in, or are largely restricted to, the neck; face, or tongue, and often take the form of more sustained dystonic spasm. Unilateral L-dopainduced facial dystonic spasms are particularly suggestive of MSA (103). In a small proportion of patients with MSA-P, these atypical dyskinesias ordystonia may reach a dramatic degree and intensity following a dose as small as 50 mg of L-dopa. Because one-third of patients responds toL-dopa, a therapeutic trial with a sufficient dose (800-1000 mg/day) is justified, if toletated. In occasional cases, MSA patients can tolerate and benefit from dopamine agonists, although they have previously failed to tolerate or benefit from L-dopa. Therefore, a subsequent trial of dopamine agonists may be justified. In patients who do not respond to L-dopa or dopamine agonists,we recommend therapy with amantadine, although no convincing treatment trials are available. L-Dopa and dopamine agonists influenceautonomicfunction,which may already be subclinicallyaffected in MSA. A worseningof autonomic dysfunction (e.g.,of postural hypotension)may limit a further increase in dosage. Patients with MSA benefit from symptomatic treatmentof autonomic dysfunction. Postural hypotensive symptoms can be treated by elastic support stockings or tights, a high salt diet, a head-up tilt of the bed at night, and by rising slowly from a sitting to a standing position. If these measures fail, the mineralocorticoid fludrocortisone (104) 0.05-0.3 mg nightly may be given. Treatments with ephedrine, midodrine (105,106), octreotide (107), yohimbine (lOS), and inof domethacin (109) have given inconsistent results. L-Threo-DOPS, a precursor norepinephrine, currently registered only in Japan, has been claimed to substantially improve orthostatic hypotension (104). For most patients with MSA, the bladder symptoms pose a substantial problem. Frequency and urge incontinence are often helped by oxybutynin, but this peripherally acting anticholinergicmay instead precipitate urinary retention. A substantial postmicturation residue of more than 150 mL is an indication for clean intermittent self-catheterization. In advanced stages of MSA, a urethral or suprapubic catheter may become necessary. Inspiratory stridor develops in about 30% of patients. The management of respiratory stridor in MSA poses particular practical and ethical problems. Few would question considering the use of tracheostomy to relieve distressing day-

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time stridor, if it occurs early in the disease. Indeedit may even be the presenting feature (66,110). However, it is atleastdebatablewhetherpreventingsudden death at night is necessarily a kindness if the patient is otherwise severely affected by MSA.

REFERENCES 1. Quinn N. Multiple system atrophy. In: Marsden CD, Fahn S, eds. Movement Dis-

orders 3. Oxford: Butterwo~h-Heinemann, 1994:262-28 1. 2. Schulz JB, Klockgether T, Petersen D, Jauch M, Muller-SchauenburgW, Spieker S, Voigt K, DichgansJ. Multiple system atrophy: natural history, MRI morphology, and dopamine receptor imaging with 1231BZM-SPECT. J Neurol Neurosurg Psychiatry 1994; 57:1047-1056. 3. Gilman S, Koeppe RA, Junck L, Kluin KJ, Lohman M,St Laurent RT. Patterns of cerebral glucose metabolism detected with positron emission tomography differ in multiplesystematrophyandolivopontocerebellaratrophy.AnnNeurol1994; 36:166-175. 4. Rinne JO, Burn DJ, Mathias CJ, Quinn NP, Marsden CD, Brooks DJ. Positron emission tomography studieson the dopaminergic system and striatal opioid binding in the olivopontocerebellar atrophy variant of multiple system atrophy, Ann Neurol 1995; 37568-573. 5. Klockgether T, Schroth G, Diener HC, Dichgans J. Idiopathic cerebellar ataxiaof late onset: natural history and MRI morphology. J Neurol Neurosurg Psychiatry 1990; 53:297-305. A clinicopathologicalstudy. 6. FearnleyJM,LeesAJ.Striatonigraldegeneration. Brain1990;113:1823-1842. 7. Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism-a prospective study. Can J Neurol Sci 1991; 18:275-278. 8. Tanner CM.Epidemiological clues to the cause of Parkinson’s disease. In: Marsden CD, Fahn S, eds. Movement Disorders 3. Oxford: Butterwo~h-Heinemann, 19941124-146. Y, Magalhaes M, DanielSE, Quinn NP.Clinical features 9. Wenning GK, Ben Shlomo and natural history of multiple system atrophy. An analysis of 100 cases. Brain 1994;117:835-845. 10. Ben ShlomoY, Wenning GK, Tison F, Quinn NP. Survival of patients with pathologicallyprovenmultiplesystematrophy:arneta-analysis.Neurology1997; 48:384--393. of patients 11. Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 1989; 94:79-100. 12. Nakazato U,Yamazaki H, Hirato J, Ishida Y, Yamaguchi H. Oligodendroglial microtubulartanglesinolivopontocerebellaratrophy. J Neuropath01ExpNeurol 1990; 49:521-530. lzJ. ? Tu PH, Calvin JE, Baba M, Giasson B, Tornita T, LeightS, Nakajo S, Iwatsubo T,

ebellar

Idiopathic

14. 15. 16.

17. 18. 19. 20. 21. 22. 23. 24.

25. 26. 27.

563

Trojanowski JQ, Lee VM. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 1998; 44:415-422. Mezey E, Dehejia A, HartaG, Papp MI, Polymeropoulos MH, Brownstein MJ. Alpha synuclein in neurodegenerative disorders: murderer or accomplice? Nat Med 1998; 41755-757. Mezey E, Dehejia AM, Harta G, Suchy SF, Nussbaum RL, Brownstein MJ, Polymeropoulos MH. alpha Synuclein is present in Lewy bodies in sporadic Parkinson’s disease. Mol Psychiatry 1998; 3:493-499. Irizarry MC, GrowdonW, Gomez-Isla T, Newell K, George JM, Clayton DF, Hyman BT. Nigra1 and cortical Lewy bodies and dystrophic nigra1 neurites in Parkinson’s disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity. J Neuropath01 Exp Neurol 1998; 57:334-337. Takeda A, Mallory M, Sundsmo M, Honer W, Hansen L, Masliah E. Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am J Pathol 1998;152:367-372. Wakabayashi K, Matsumoto K, Takayama K, Yoshimoto M, Takahashi H. NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson’s disease. Neurosci Lett 1997; 239:45-48. SpillantiniMG,SchmidtML,LeeVM,TrojanowskiJQ,JakesR,GoedertM. alpha-Synuclein in Lewy bodies. Nature 1997; 388:839--840. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 1998; 95:6469-6473. Baba M, Nakajo S, Tu pH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 1998; 152:879--884. Jakes R, Spillantini MG, Goedert M. Identification of two distinct synucleins from human brain. FEBS Lett 1994; 345:27-32. Nee LE, Gomez MR, DambrosiaJ, Bale S, Eldridge R, Polinsky RJ. Environmental-occupational risk factors and familial associations in multiple system atrophy: a preliminary investigation. Clin Auton Res 199 ;11:9-13. Iwahashi K, Miyatake R, Tsuneoka Y, Matsuo Y, IchikawaY, Hosokawa K, Sat0 K, Hayabara T. A novel cytochrome P-450IID6 (CYPIID6) mutant gene associated withmultiplesystematrophyletter].JNeurolNeurosurgPsychiatry1995; 58~263-264. Bandmann 0, Wenning GI(, Quinn NP, Harding AE. Arg296 to Cys296 polymorphism in exon 6 of cytochrome P-450-2D6 (CYP2D6) is not associated with multiple system atrophy. J Neurol Neurosurg Psychiatry 1995; 59:557. Plante Bordeneuve V, Bandmann 0, Wenning G, Quinn NP, Daniel SE, Harding AE. CYP2D6-debrisoquine hydroxylase gene polymorphism in multiple system atrophy. Mov Disord 1995; 10:277-278. Bandmann 0, Sweeney MG, Daniel SE, Wenning GK, Quinn N, Marsden CD, Wood NW. Multiple-system atrophy is genetically distinct from identified inherited causes of spinocerebellar degeneration. Neurology 1997; 49: 1598-1604.

564

Dichgans

Schulz and

28. Schulz JB, Beal MF. Mitochondrial dysfunction in movement disorders. Curr Opin Neurol 1994; 7:333-339. 29. Blin 0 , Desnuelle C, Rascol 0 , et al. Mitochondrial respiratory failure in skeletal muscle from patients with Parkinson’s disease and multiple system atrophy. J Neurol Sci 1994; 125:95-101. 30. Gu M, Gash MT, Cooper JM, Wenning GK, Daniel SE, Quinn NP, Marsden CD, Schapira AH. Mitochondrial respiratory chain function in multiple system atrophy. Mov Disord 1997; 12:418-422. 31. Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD. Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 1994; 36:348-355. I, Sakaki Y. Cloning 32. Hashida H, Goto J, Zhao N, Takahashi N, Hirai M, Kanazawa and mapping of ZNF231, a novel brain-specific gene encoding neuronal double zinc finger protein whose expression is enhanced in a neurodegenerative disorder, multiple system atrophy (MSA). Genomics 1998; 54:50-58. 33. Lantos PL. Multiple system atrophy. Brain Pathol 1997; 7:1293-1297. 34. Lantos PL, Papp MI. Cellular pathology of multiple system atrophy: a review. J Neurol Neurosurg Psychiatry 1994; 57:129-133. 35. Papp MI, Lantos PL. The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 1994; 117:235243. 36. Kato S, Nakarnura H, Hirano A, Ito H, Llena JF, Yen SH. Argyrophilic ubiquitinated cytoplasmic inclusionsof Leu-7-positive glial cells in olivopontocerebellar atrophy (multiple system atrophy). Acta Neuropathol 1991; 82:488-493. 37. Abe H, Yagishita S, Amano N, Iwabuchi K, Hasegawa K, Kowa K. Argyrophilic glial intracytoplasmic inclusions in multiple system atrophy: immunocytochemical and ultrastructural study. Acta Neuropathol 1992; 84:273-277. 38. Kato S, Nakarnura H. Cytoplasmic argyrophilic inclusions in neurons of pontine nuclei in patients with olivopontocerebellar atrophy: immunohistoche~cal and ultrastructural studies. Acta Neuropathol (Berl) 1990; 79:584-594. 39. Papp MI, Lantos PL. Accumulation of tubular structures in oligodendroglial and neuronal cellsas the basic alteration in multiple system atrophy. J Neurol Sci 1992; 1071172-182. 40. Lantos PL. Neuropathological diagnostic criteria of multiple system atrophy. In: Cruz-Sanchez FF, Ravid R, Cuzner ML, eds. Neuropathological Diagnostic Criteria for Brain Banking. Amsterdam: IOS Press, 1995:116-121. 41. Benarroch EE, Smithson IL, Low PA, Parisi JE. Depletion of catecholaminergic neurons of the rostral ventrolateral medulla in multiple systems atrophy with autonomic failure. Ann Neurol 1998; 43:156-163. of orthostatic hypotension in multiple sys42. Saper CB. All fall down: the mechanism tem atrophy and Parkinson’s disease [editorial]. 1998; 43:149-151. Y, Nakarnura S. Decrease of neurons 43. Noda K, Katayama S, Watanabe C, Yamamura in the medullary arcuate nucleus of multiple system atrophy: quantitative comparison with Parkinson’s disease and amyotrophic lateral sclerosis. J Neurol Sci 1997; 151~89-91.

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44. Gilman S, Low PA, Quinn N, Albanese A, Ben-Shlomo U,Fowler CJ, Kaufmann H, Klockgether T, Lang AE, Lantos PL, Litvan I, Mathias CJ, Oliver E, Robertson D, Schatz I, Wenning GK. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 1999; 163:94-98. 45. Plazzi G, CorsiniR, Provini F, Pierangeli G, MartinelliP, Montagna P, Lugaresi E, Cortelli P.REM sleep behavior disorders in multiple system atrophy. Neurology 1997; 48:1094-1097. 46. Wenning GK, Tison F, Ben Shlomo U,Daniel SE, Quinn NP. Multiple system atrophy: a review of 203 pathologically proven cases. Nlov Disord 1997; 12:133147. 47. Quinn NP, Marsden CD. The motor disorder of multiple system atrophy.J Neurol Neurosurg Psychiatry 1993; 56: 1239-1242. of mul48. Kluin KJ, GilmanS, Lohman M, Junck L. Characteristics of the dysarthria tiple system atrophy. Arch Neurol 1996; 53:545-548. 49. Hughes AJ, Colosimo C, Kleedorfer B, Daniel SE, Lees AJ. The dopaminergic reJ Neurol Neurosurg Psychiatry 1992; 55: 1009sponse in multiple system atrophy. 1013. 50. Parati EA, FetoniV, Geminiani GC, SoliveriP, Giovannini P, Testa D, GenitriniS, Caraceni T, Girotti F, Response to L-DOPA in multiple system atrophy. Clin Neuropharmacol1993;16:139-144. 51. Mathias CJ. Autonomic dysfunction. Br J Hosp Med 1987; 38:238-243. J, Klock52. Schulz JB, Skalej M, Wedekind D, Luft AR, Abele M, Voigt K, Dichgans getherT.MRI-basedvolumetrydifferentiatesidiopathicParkinson’ S syndrome from MSA and PSP. Ann Neurol 1999; 45:65-74. 53. Rottach KG, Riley DE, DiScenna AO, Zivotofsky AZ, Leigh RJ. Dynamic propertiesofhorizontalandverticaleyemovementsinparkinsoniansyndromes.Ann Neurol 1996; 39:368-377. 54. Rascol 0, Sabatini U, Simonetta Moreau M, Montastruc JL, Rascol A, Clanet M. Squarewavejerksinparkinsoniansyndromes.JNeurolNeurosurgPsychiatry 1991; 54~599-602. 55. Rascol OJ, Clanet M, Senard JM, Montastruc JL, Rascol A. Vestibulo-ocular reflex in Parkinson’s disease and multiple system atrophy. Adv Neurol 1993; 60: 395-397. 56. Rascol 0, Sabatini U, Fabre N, Senard JM, Simonetta Moreau M, Montastruc JL, Clanet M, Rascol A. Abnormal vestibuloocular reflex cancellation in multiple system atrophy and progressive supranuclear palsy but not in Parkinson’s disease. NlovDisord 1995; 10:163-170. 57. Tison F, Wenning GK, Volonte MA, Poewe WR, Henry P, Quinn NP. Pain in multiple system atrophy. J Neurol 1996; 243:153-156. 58. Rivest J, Quinn N, Marsden CD. Dystonia in Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Neurology 1990; 40: 157 1-1578. 59. Blunt SB, Khalil NM, Perkin GD. Facial myokymia in multiple system atrophy. Mov Disord 1997; 12:235-238. 60. Klein C, Brown R, Wenning G, Quinn N. The “cold hands sign” in multiple system atrophy. Mov Disord 1997; 12:514-518.

Dichgans 566

and

Schulz

61. Santens P, Crevits L,Van der Linden C. Raynaud’s phenomenon in a case of multiple system atrophy. Mov Disord 1996; 11:586-588. 62. Isozaki E, Shimizu T, Takamoto K, HoriguchiS, Hayashida T, Oda M, Tanabe H. Vocalcordabductorparalysis(VCAP)inParkinson’sdisease:differencefrom VCAP in multiple system atrophy. J Neurol Sci 1995; 130:197-202. 63. Isozaki E, Osanai R, Horiguchi S, Hayashida T, Hirose K, Tanabe H. Laryngeal electromyography with separated surface electrodes in patients with multiple system atrophy presenting with vocal cord paralysis. J Neurol 1994; 241:551-556. 64. Isozaki E, Naito A, Horiguchi S, Kawamura R, Hayashida T, Tanabe H. Early diagnosis and stage classification of vocal cord abductor paralysis in patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 1996; 60:399-402. 65. Wu YR, Chen CM, R0 LS, Chen ST, Tang LM. Vocal cord paralysis as an initial sign of multiple system atrophy in the central nervous system. J Formosan Med Assoc 1996; 95:804-806. 66. Schulz JB, Klockgether T, Dichgans J. Beidseitige Stimbandlahmung als Symptom einer Multisystematrophie (MSA). Aktuel Neurol 1993; 20: 170-1 73. 67. Pilo L, Ring H, Quinn N, Trimble M. Depression in multiple system atrophy and in idiopathic Parkinson’s disease:a pilot comparative study. Biol Psychiatry 1996; 39:803--807, 68. Fetoni V, Soliveri P, Monza D, Testa D, Girotti F. Affective symptoms in multiple system atrophy and Parkinson’s disease: response to levodopa therapy. J Neurol Neurosurg Psychiatry 1999; 66:541-544. 69. Leiguarda RC, Pramstaller PP, Merello M, Starkstein S, Lees AJ, Marsden CD. Apraxia in Parkinson’s disease, progressive supranuclear palsy, multiple system atrophy and neuroleptic-induced parkinsonism. Brain 1997; 120:75-90. 70. Smith CD, Mathias CJ. Differences in cardiovascular responses to supine exercise and to standing after exercise in two clinical subgroups of Shy-Drager syndrome (multiple system atrophy). J Neurol Neurosurg Psychiatry 1996; 61:297-303. 71. Plaschke M, SchwarzJ, Dahlheim H, Backmund H, Trenkwalder C. Cardiovascular and renin responses to head-up tilt tests in parkinsonism. Acta Neurol Scand 1997; 96:206-210. 72. Frongillo D, Stocchi F, Buccolini P, Stecconi P, Viselli F, Ruggieri S, Cannata D. Ambulatory blood pressure monitoring and cardiovascular function tests in multiple system atrophy. Fundam Clin Pharmacol 1995; 9:187-196. 73. Albanese A, Colosimo C, Bentivoglio AR, Fenici R, Melillo G, Colosimo C, Tonali P. Multiple system atrophy presenting as parkinsonism: clinical features and diagnostic criteria. J Neurol Neurosurg Psychiatry 1995; 59: 144-151. 74. Kaufmann H, Oribe E, MillerM,Knott P,Wiltshire-ClementM,YahrMD. Hypotension-inducedvasopressinreleasedistinguishesbetweenpureautonomic failureandmultiplesystematrophywithautonomicfailure. Ann Neurol1992; 42:590-593. 75. Kimber JR, Watson L, Mathias CJ. Distinction of idiopathic Parhnson’s disease frommultiple-systematrophy bystimulationofgrowth-hormonereleasewith clonidine. Lancet 1997; 349: 1877-188 1. 76. Goldstein DS, Holmes C, Cannon R 0 3rd, Eisenhofer G, Kopin IJ. Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 1997; 336:696-702.

ebellar

Idiopathic

567

77. Burn DJ, Sawle CV, Brooks DJ. Differential diagnosis of Parkinson's disease, multiplesystematrophy,and Steele-Richardson-Olszewski syndrome:discriminant analysisofstriatal"F-dopaPETdata.JNeurolNeurosurgPsychiatry1994; 57:278-284. 78. Brooks DJ. Functional imaging of movement disorders. In: Marsden CD, FahnS, eds. Movement Disorders 3. Oxford: Butterworth-Heinemann, 1994:65-87. 79. Leenders KL, Frackowiak RS, Lees AJ. Steele-Richardson-Olszewski syndrome. Brain energy metabolism, blood flow and fluorodopa uptake measured by positron emission tomography. Brain 1988; 111:615-630. 80. Brooks DJ, Ibanez V, Sawle GV, Playford ED, Quinn N, Mathias CJ, Lees AJ, Marsden CD, Bannister R, Frackowiak RSJ. StriatalD, receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with "C-raclopride and positron emission tomography. Ann Neurol 1992; 31:184-192. 81. van Royen E, Verhoeff NFLG, Speelman JD, Wolters EC, Kuiper MA, Janssen AGM. Multiplesystematrophyandprogressivesupranuclearpalsy:diminshed striatal D, dopamine receptor activity demonstrated by '231-IBZM single photon emission computed tomography. Arch Neurol 1993; 50:5 13-516. 82. Schwarz J, TatschK, Arnold G, Gasser T, Trenkwalder C, Kirsch CM, Oertel WH. "31-iodobenzamide-SPECT predicts dopaminergic responsiveness in patients with de novo parkinsonism. Neurology 1992; 42:556-561. 83. Brucke T, Podreka I, Angelberger P, Wenger S, Topitz A, Kufferle B, Muller C, Deeke L. Dopamine D, receptor imaging with SPECT: studies in different neuropsychiatric disorders. J Cereb Blood Flow Metab 1991; 11:220-228. 84. Davie CA, Wenning GK, Barker GJ, Tofts PS, Kendall BE, Quinn N, McDonald WI, Marsden CD, Miller DH. Differentiation of multiple system atrophy from idiopathic Parkinson's disease using proton magnetic resonance spectroscopy.Ann Neurol 1995; 37:204-210. 85. SavoiardoM, Strada L, Girotti F, Zirnmermann RA, GrisoliM, Testa D, Petrillo R. Olivopontocerebellar atrophy: MR diagnosis and relationship to multisystem atrophy. Radiology 1990; 174:693-696. 86. Schrag A, Kingsley D, Phatouros C, Mathias CJ, Lees AJ, Daniel SE, Quinn NP. Clinicalusefulness of magneticresonanceimaginginmultiplesystematrophy. J Neurol Neurosurg Psychiatry 1998; 65:65-71. 87. Schwarz J, Weis S, Kraft E, Tatsch K, Bandrnann 0, Mehraein P, Vogl T, Oertel WH. Signal changes on MRI and increases in reactive microgliosis, astrogliosis, and iron in the putamen of two patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 1996; 60:98-101. 88. Konagaya M, KonagayaY, Iida M. Clinical and magnetic resonance imaging study of extrapyramidal symptoms in multiple system atrophy. J Neurol Neurosurg Psychiatry 1994; 57:1528-1531. 89. Testa D, Savoiardo M, Fetoni V, Strada L, Palazzini E, Bertulezzi G, Girotti F. Multiple system atrophy. Clinical and MR observationson 42 cases. Ita1 J Neurol Sci1993;14:211-216. 90. Davie CA, Wenning GK, Barker GJ, Tofts PS, Kendall BE, Quinn N, McDonald WI, Marsden CD, Miller DH. Differentiationof multiple system atrophy from id-

568

91. 92.

93.

94.

95.

96.

97

I)

98. 99. 100.

101.

102.

Dichgans

Schulz and

iopathic Parkinson’s disease using proton magnetic resonance spectroscopy. Ann Neurol 1995; 37:204-210. Davie CA, Barker GJ, Machado C, Miller DH, Lees AJ. Proton magnetic resonance spectroscopyin Steele-Richardson-Olszewski syndrome.MovDisord1997; 12:767-771. Burn DJ, Sawle CV, Brooks DJ. Differential diagnosis of Parkinson’s disease, multiplesystematrophy,and Steele-Richardson-Olszewski syndrome:discriminant analysis of striatal“F-dopaPETdata.JNeurolNeurosurgPsychiatry1994; 57:278-284. Brooks DJ, Ibanez V, Sawle GV,QuinnN, Lees AJ, Mathias CJ, Bannister R, Marsden CD, Frackowiak RS. Differing patterns of striatal “F-dopa uptake in Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990; 28:547-555. Brucke T, Asenbaum S, Pirker W, Djamshidian S, Wenger S, Wober C, Muller C, Podreka I. Measurement of the dopaminergic degeneration in Parkinson’s disease withbeta-CITandSPECT.Correlationwithclinicalfindingsandcomparison with multiple system atrophy and progressive supranuclear palsy. J Neural Transm SUPPI199’7;50:9-24. Brooks DJ, Salmon EP, Mathias CJ, Quinn N, Leenders K L , Bannister R, Marsden CD,Frackowiak RS. Therelationshipbetweenlocomotordisability,autonomic dysfunction, and the integrityof the striatal dopaminergic system in patients with multiple system atrophy, pure autonomic failure, and Parkinson’s disease, studied with PET. Brain 1990; 113:1539-1552. Burn DJ, Rime JO, Quinn NP, Lees AJ, Marsden CD, Brooks DJ. Striatal opioid receptorbindinginParkinson’ S disease, striatonigral degeneration and SteeleRichardson-Olszewski syndrome, A [“Cldiprenorphine PET study. Brain 1995; 118:951-958. Shinotoh H, Inoue 0, Hirayama K, Aotsuka A, Asahina M, SuharaT, Yamazaki T, Tateno Y. Dopamine D, receptors in Parkinson’s disease and striatonigral degeneration: a positronemissiontomographystudy.JNeurolNeurosurgPsychiatry 1993; 56:46’7-472. Gilman S, Koeppe RA, Junck L, Kluin KJ, Lohman M, St Laurent RT. Benzodiazepine receptor binding in cerebellar degenerations studied with positron emission tomography. Ann Neurol 1995; 38:176-185. Wenning GK, Kraft E, Beck R, Fowler CJ, Mathias CJ, Quinn NP, Hading AE. Cerebellar presentationof multiple system atrophy. Mov Disord 1997;115-117. 12: Schwarz J, Komhuber M, Bischoff C, Straube A. Electromyography of the external anal sphincter in patients with Parkinson’s disease and multiple system atrophy: frequency of abnormal spontaneous activity and polyphasic motor unit potentials. Muscle Nerve 1997; 20:1167-1 172. Valldeoriola F, Valls-Sole J, Tolosa ES, Marti MJ. Striated anal sphincter denervation in patients with progressive supranuclear palsy. Mov Disord 1995; 10:550555. Abele M, Schulz JB, Biirk K, Topka H, Dichgans J, Klockgether T. Evoked potentials in multiple system atrophy (MSA). Acta Neurol Scand 2000; 101:111-115.

ebellar

Idiopathic

569

103. Wenning GK, Quinn NP, Daniel SE, Garratt H, Marsden CD. Facial dystonia in pathologically proven multiple system atrophy: a video report. Mov Disord 1996; 11: 107-109. 104. Matsubara S, Sawa Y, Yokoji H, Takamori M. Shy-Drager syndrome. Effect of fludrocortisone and ~-threo-3,4-dihydroxyphenylserine on the blood pressure and regional cerebral blood flow. J Neurol Neurosurg Psychiatry 1990; 53:994-997. 105. Wright RA, Kaufmann HC, Perera R, Opfer-Gehrking TL, McElligott MA, Sheng KN, Low PA. A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51:120-124. 106. Robertson D, Davis TL. Recent advances in the treatment of orthostatic hypotension. Neurology 1995; 45:S26-S32. of or107. Bordet R, Benhadjali J, Libersa C, Destee A. Octreotide in the management thostatic hypotension in multiple system atrophy: pilot trial of chronic administration. Clin Neurophannacol 1994; 17:380-383. 108. Senard JM, Rascol 0, Durrieu G, Tran MA, Berlan M, Rascol A, Montastruc JL. Effects of yohimbineon plasma catecholamine levels in orthostatic hypotension related to Parkinson disease or multiple system atrophy. Clin Neuropharmacol 1993; 16~70-76. 109. Tsuda Y, Kimura K, YonedaS, Asai T, Handa N, TanouchiJ, Inoue M, Abe H. Hemodynamics in Shy-Drager syndrome and treatment with indomethacin. Eur Neurol 1983; 22:421"427. 110. Kew J, Gross M, Chapman P. Shy-Drager syndrome presenting as isolated paralysis of vocal cord abductors, Br Med J 1990; 300: 1441.

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28 Alcoholic Cerebellar Degeneration (including Ataxias That Are Due to Other Toxic Causes) Dagmar Timmann-Braun and Hans-Christoph Diener University of Essen, Essen, Germany

I.ALCOHOLICCEREBELLAR Introduction A. Epidemiology B. C. Pathogenesis Neuropathology D. E.ClinicalFeatures F. Ancillary Tests Management G.

DEGENERATION

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I. ALCOHOLICCEREBELLARDEGENERATION A.

Introduction

“Alcoholic” cerebellar degeneration or cortical cerebellar degeneration in alcoholic patients refers toa common and uniform typeof cerebellar degeneration in 5?1

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alcoholics. In their thorough and guiding review of the available literature at that time and reportof 50 patients, Victor et al. (1,2) proposed the following definition of the condition: “Sporadic cases(of cerebellar cortical degeneration) beginning in adult life, on a background of prolonged alcoholism, characterized clinically by a chronic course, usually with long periodsof stability, and pathologicallyby a predominance of the degenerative changes in the anterior superior vermis and hemispheres.” This syndrome isCharacterized by an ataxia of gait and legs, with relatively little involvement of the arms, speech, and ocular motility. Historically, alcohol intoxication has been related to lesions in the cerebellum since 1905, when Thomas (3) reported the appearance of cerebellar ataxia in a chronic alcoholic patient and described changes in the cerebellar cortex, particularly of the rostral vermis. Alcoholism as the etiological factor in cerebellar degeneration was subsequently suggestedby several other observers(4-13). The a relations of cerebellar cortical degeneration to chronic alcoholism had been controversial matter. One objection to the existence of this entity was that such cases may simply be examplesof late cortical cerebellar atrophy occurring in alcoholics (14). The cerebellar syndrome in chronic alcoholics highly corresponds with that in casesof sporadic and familial late cortical atrophy initially described by Holmes (15) and Marie et al. (16) (present nomenclature: idiopathic cerebellar degeneration; spinocerebellar ataxia type 5 and 6). However, the large series of pathologically verified cases by Victor et al. (1,2) led to the definitionof cortical cerebellar degeneration in the alcoholicas a distinct clinical and pathological entity. Additional cases have since been reported (17-23).

Cerebellar degeneration resulting from alcoholism is probably the most common form of chronic cerebellar ataxia. The prevalence, however, can only be estimated. Based on the available clinical, autopsy, and radiologic data, approximately one-third of all severe alcoholics have cerebellar degeneration. The onset in most cases is before the ageof 50, most commonly in the fifth decade of life, and after many years of chronic alcoholism. This disorder is about twiceas fremeninthan quent as Wernicke’s disease, but, unlike the latter, it is more frequent in women. Scholz et al. (23) found clinical signsof cerebellar ataxia in 33% of 78 alcoholic patients, who were consecutively hospitalized for alcohol withdrawal therapy, and recorded posturographic measurements of increased sway in 69%. a 5-year period in Oslo (=29% of Among 9735 autopsies performed during deaths in Oslo) there werel52 cases of alcoholic cerebellar atrophy (1.7%) (24). Similarly, Stork (21) found 31 cases among 1830 autopsies from Geneva (1.7%). Torvik et al. (24) found cerebellar atrophy in 26.8% of all examined alcoholics (567 cases). Only 3 of the cases with cerebellar atrophy were diagnosed clinically. However, clinical datawas sparse and the degree of cerebellar involvement

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that is needed to produce obvious cerebellar symptoms is unknown. The percentage of alcoholics and the frequencyof alcoholic cerebellar atrophy were similar in a 5-year follow-up study in Oslo (27.6%; 25).many As as 13cerebellar degenerations (42%) were reported in autopsies of 31 consecutively selected chronic alcoholics (26). Cerebellar atrophy has been described in 10-81% of patients with chronic alcoholismby computed tomography (CT) scans(27-32; for further discussion see Sec. 1.F). In their large series,Victor et al. (1,2) described that the earliest age of onset was 31 years; the latest63 years; the average age was 46.3 years. Two-thirds of the patients acquired their disease before the age of 50. Other authors reported similar ages of disease onset (9,12,18). Onsetof cerebellar symptoms have been 5 (18) and 10 (2) yearsof alcohol addiction.Vicreported not to occur until after tor et al. (2) reported a malelfemale ratioof 11:1 (46 men, 4 women). However, their cases were not consecutively selected. Torvik et al. (24) and Lindboe and Lgberg (25) in their 5-year follow-up studies described male/female ratios of 6.2 :1 and 5.6:1. The ratios corrected for sex distribution among alcoholics were 1.4: 1 and 1.3: 1. Insummary,alcoholiccerebellardegenerationoccursinapproximately 25% of chronic alcoholics after the age of 40 years and appears to be more frequent in men than in women.

C. P a t h o ~ e ~ e s i s The exactpathogenesis of alcoholiccerebellardegenerationstillremains unknown. Malnutrition, alcoholic neurotoxicity, and individual factors may contribute. Based on their influential work, Victor and Adams advocate the view that alcoholiccerebellardegeneration is duetovitamin B, (thiamine)deficiency (33,34). However, although a large amountof data supports this notion, the evidence remains indirect. Usually a prolonged and serious degree of malnutrition precedes the illness (9,18,35). In their large series, Victor et al. (2) found in 38/50 alcoholics a history of poor nutrition for many months or years. In9 cases, a particularly severe degree of weight loss had occurred within a short period before the onset of cerebellar symptoms.At the same time, there was no indication that the intake of alcoholhadbeensignificantlyincreased.Infact,6patientshadactuallybeen abstinent for varying periods of time before to the onset of their cerebellar symptoms in the course of hospitalization. Malnutrition,reducedintestinaluptake,andanincreasedmetabolic demand can cause vitamin deficiencies in chronic alcoholics. Thiamine deficiencyiswelldescribed,amongotherBvitamins (22,36-38). Although Langohr et al. (38) reported a correlation of vitamin B, and B, deficiency and signs of “cerebellar and/or brainstem lesions,” other authors did not find a consistent relation between thiamine deficits and occurrence of cerebellar degenera-

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tion (23,39). However, current laboratory determinations rnay not reflect past status, and thiamine may intermittently have been administered. The most common manifestation of thiamine deficiency in the Western world is Wernicke’s encephalopathy. It is commonly seen in alcoholic patients, as but may also occur in patientswith impaired nutrition from other causes, such gastrointestinal disease or acquired immunodeficiency syndrome (AIDS) (40). Alcoholic cerebellar degeneration is frequently associated with Wernicke’s encephalopathy, although the latter may be unsuspected during life. Neuropathological changes of Wernicke’s disease were found in 4/11 (2) and 6/7 autopsied cases (20) of alcoholic cerebellar degeneration. Moreover, cerebellar ataxiais common in Wernicke’s encephalopathy, and the histopathological changes in the cerebellum are precisely those that characterize alcoholic cerebellar degeneration (33,41,42). The clinical signs in alcoholic cerebellar degeneration, particularly in the form that is restricted to ataxia of stance and gait and in the acute and transient form, cannot be distinguished from the cerebellar manifestationsof Wernicke’s disease. InVictor et al.’s large series (33), cerebellar ataxia was present in 87% of 245 cases of Wernicke’s disease, a cerebellar lesion was found and of 82 patients who were examined postmortem, in 55%. Similar frequencies of cerebellar degeneration in Wernicke’s disease have been reported by others [(42), 44%; (24), 38.6%]. In one-third of patients with Wernicke’s disease, the ataxia resolved under the influence of thiamine alone. The remainder recovered partially ornot at all and had a residual gait disorder similar to that of alcoholic cerebellar degeneration (33). Therefore, it has been proposed by Victor and co-workers that alcoholic cerebellar degeneration, similar to Wernicke’s disease, is probably due to thiamine deficiency. They advocate that Wernicke’s disease and alcoholic cerebellar degeneration “represent the same disease process, the former term being used when the cerebellar abnormalities are associated with ocular and mental signs and the latter, when the cerebellar syndrome dominates the clinical picture.” Lesions resembling those in Wernicke’s disease have been produced by thiamine-deficient diets in several mammalian species, as well as in birds (33). For example, in thiamine-deficient rhesus monkeys, Rinehart et al. (43), found lesions of the central nervous system that corresponded in a general way to the findings in Wernicke’s encephalopathy. Cortical degeneration of the cerebellar vemis was present in4/7 cases. However, a thiamine-deficient animal model resembling alcoholic cerebellar degeneration without Wernicke’s encephalopathy is still lacking. Thiamine plays an important role in the metabolism of the cerebellum (44,45). However, how biochemical abnormalities caused by thiamine deficits may relate to cerebellar degeneration remains unknown. Thiamine levels are reduced in degenerative forms of cerebellar ataxia (38,46); however, thiamine has no beneficial effect in these cerebellar disorders, and decreased thiamine levels rnay well be a secondary phenomenon. Furthermore, isolated thiamine deficiency

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(beriberi) (47) does not cause chronic cerebellar degeneration in humans. Rather, in infantile beriberi, acute cardiac symptoms dominate the picture and polyneuropathy dominates in adults (40,48). Thus, it remains unclear why a lack of thiamine may cause beriberi in some patients and Wernicke’s disease or a selective lesion of parts of the cerebellum in others. There is increasing evidence, that the chronic cerebellar syndrome observed in alcoholics, at least partly, may be caused by toxicity from alcohol itself. The acute effects of alcohol on cerebellar function are well known. The clinical findings are supported by recent experimental evidence. Ethanol, for example, decreases the firing rate of cerebellar Purkinje neurons through a y-aminobutyric acidtype A (GABA,) mechanism (49-51). Interestingly,results of a recent positron emission tomography (PET) study suggest that severe chronic alcoholism damages neurons containing GABA,-benzodiazepine receptors in the superior cerebellar vermis in patients with cerebellar degeneration (52). Degeneration of cerebellar cortex has been producedby chronic alcoholic intoxication in animals(53-56). In Purkinje cellsof alcohol-fed rats, progressive morphological changes in neuronal cytoplasm have been demonstrated;namely, an increase of lipofuscin granules and structural changes of their mitochondria (57). Later studies revealeda significant decrease in the numberof dendritic microtubules of Purkinje cells (58). The depletion of the microtubule cytoskeleton in Purkinje cells may lead to the degenerationof the Purkinje cell dendritic tree. These changesmay be linked witha transsynaptic degenerative process, for it has been demonstrated that degeneration of granule cell soma and their neurites occur before the degeneration of the Purkinje cells after prolonged alcohol consumption (59,60). There are several possible ways alcohol and its metabolites may affect nervous tissue. Alcohol is oxidized by hepatic alcohol dehydrogenase to acetaldehyde, a metabolite that is highly cytotoxic. Acetaldehyde hasbeen implicated in the pathogenesis of alcohol-related liver damage through various mechanisms (e.g., adduct formation with proteins that makes them immunologically foreign, reduces enzyme activity, and damages the microtubular system, and formation of cytotoxic free radicals) (61). These mechanisms may also havea role in alcoholic brain damage (62). Changes in some pro- and antioxidants have been shown in rat cerebellum after alcohol intake (63). For example, prolonged alcohol intake increase the cytosolic iron concentration in the cerebellum, which may contribute to the generationof free radicals (64,65).A decrease of the main antioxidants in the cerebellum is another likely contributor to cerebellar oxidative stress. Continued alcohol consumption decreased the cerebellar vitamin E, copper, and selenium levels in the rat; however, adaptive processes resulted in enhanced activity of other antioxidant systems (65). Further studies are needed to confirm the hypothesis that an ethanol-induced oxidative stress is involved in the pathogenesis of cerebellar degeneration in alcoholic patients. Idiosyncratic sensitivity to alcohol may be an additional factor. For example, Setta et al. (66) reported ona

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patient who showedhigh vulnerability to small doses of alcohol. Small quantities of alcohol induced a cerebellar syndrome that resembled that of a cerebellar cortical degeneration. Furthermore, alcoholic patients exhibiting cerebellar ataxia do not have higher alcohol consumption than nonataxic alcoholic patients (39). The strong association between nutritional deficiencies, especially B vitamins, and chronic alcoholism points to possible aggravationby metabolic interactions at various levels between, for example, acetaldehyde and t~iamineor other B vitamins. Selective regionalvulne~abilitymay reflect differences in ease of acetaldehyde access or to metabolic differences (62). Likewise, Zimitat et al. (67) examined the clinicaland neuropathological consequences of either ethanol consumption or thiamine deficiency, or both, in rats. Rats with the latter two diets developed loss of coat condition, ataxia,opi~thotonus,and ultimat~ly,death. The onset and progression of the disease was significantly faster in the thiaminedeficient rats that received ethanol. ~ u t ~ t i o nfactors al other than vitamin B, deficiency may be of additional importance [e.g., cell loss in the cerebellumof adults rats has been demonstrated after long-term low-protein diet (6S)l. Chronic liver failure, as well as mechanisms implicating electrolyte imbalance have also been considered. For example, alcoholic (l7/30 Kri1 and Butterworth (69) found cerebellar degeneratio~ in both cases) and nonalcoholic(3/6 cases) patients, with autopsy-proved cirrhosis, who died while in hepatic coma, In conclusion, mal~utrition,particularly thiaminedeficiency, is now seen as A direct toxic acbut one of several factors that adversely affect the cerebellum, tion of alcohol and its metabolites on central nervous system tissue has become i ~ c r ~ a s ~ n suggested. gly Why the cerebellar vermis should be s~lect~vely vulnerable in alcoholic patients is unclear.

Victor et al.’s (2) fundamental work of l1 autopsied cases remains the foundation for the neuropatholo~icaldescription of alcoholic cerebellar degenerati~n. The essential pathological change isa degeneration of all ne~rocellular elements of the cerebellar cortex, particularly of the Purkinje cells, which is restricted to the anterior and superior aspects of the vermis and the hemispheres (Fig. l).

Figure 1 (A)Superior aspect of the cerebellum, showing slight shrinkage of folia and widening of sulci of superior vermis, extending into most anterior portions of anterior lobes. (B) Midsagittal sectionof vermis: shrinkageof folia and separationof superior vermis (lingula, central lobe, culmen, and portion of declive bordering on primary fissure). Inferior vermis appears grossly normal. (From Ref. 2.)

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In the most extreme case, the molecular layer is markedly reduced in width, with loss of all the nerve cell and fiber elements and fibrous gliosis throughout the cortex. In the least severely affected portions, only the Purkinje cells appear to be lost. The olivary nuclei are almost always involved; the fastigial, globose, emboliform, and vestibular nuclei are less constantly affected. These changesareconsideredtoberetrogradedegenerationfollowingtheinvolvement of the cerebellar cortex. The dentate nuclei, cerebellar white matter and peduncles,thespinocerebellartracts,andotherbrainstemnucleiareessentially unaltered. Most of the lesion is located in the anterior lobe of Larsell (i.e., anterior to the primary fissure); therefore, the characteristic clinical state is generally considered to be “anterior lobe syndrome.” Nevertheless, lesions are not confined precisely to this territory, or to what has been designated as the spino- or paleocerebellum or the medial longitudinal zone (vermis) (70). The involvement of any given part is often incomplete or unequal, with the convexity of thefoliabeingmoreseverelyaffectedthanthedepth of the sulci. Subsequent neuropathologica~ observations (20,24,26,42) were very similar to the findings of Victor et al. (2). Quantitative histological measurements confirmed Victor et al.’s macroscopic observations that the small rostral lobes havethegreatestreduction of tissuecontent(26,71).Similarly,inanimal studies the midrostrocaudally located lobes have shown the greatest Purkinje cell loss in chronic, alcohol-fed mice(55) and rats (54). Phillips etal. (71) found a mean Purkinje cell loss of 21% in the cerebellar vermis of alcoholics comparedwithcontrols. The molecularlayer of thevermisshowedthelargest 11 degree of shrinkage compared with the granular and medullary layer (from to 39%). Likewise,asignificantreduction of arborization of Purkinjecells wasshowninchronicalcohol-fedratsandhumancases of alcoholiccerebellardegeneration(57,72).Ameanreduction of Purkinjecellsalsooccurs (73). Torvik and Torp (26) rewith age, most apparent at about the 60th year ported that one-third of nonalcoholic controls older than the age of 70 years showed atrophy of the anterior vemis, presumably as a consequence of physiological aging. Although the cerebellar degeneration affects all three layers of the cerebellar cortex, the Purkinje cell loss is commonly most easily seen(2,24). However, in Neubuerger’s (74) studyof alcoholic brains, the main finding was granule cell (20) concluded loss. From autopsy reportsof seven alcoholics, Allsop and Turner that granule cell loss was the earliest histological change, followed by Purkinje cell degeneration in chronic alcoholism. This hypothesis is supported by findings of Tavares et al. (56) in chronic alcohol-fed rats. In a follow-up study, granule cell and molecular layer interneurons were the earliest and most severely affected populations. A decrease in the numberof Purkinje cells was observed after only 18 months of alcohol consumption.

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E. ClinicalFeatures Alcoholiccerebellardegenerationresemblestheso-calledanteriorlobesyndrome in humans.The cerebellar syndrome is remarkably uniform (1,2,9,12,20). It is characterized by an ataxia of stance and gait, with varying degreesof instability of the trunk and ataxia of the legs. The arms are affected to a much lesser extent, and nystagmus and dysarthria are infrequent signs.The relation between the clinical and pathological findings is most meaningful in the lightof somatotopic localization in the cerebellum (2). The parts consistently involved in the pathological process correspond to the “leg area” within the anterior lobe (75,76). The lateral extensions into the posterior folia of the anterior lobe are usually spared; thus muchof the “arm area” is uninvolved. It should be emphasized that not all symptoms that occur after ablation of the anterior lobe in animals are present in alcoholic cerebellar degeneration (i.e., increased tendon reflexes, pronounced lengthening and shortening reactions, and gross exaggeration of positive supporting reactions) (77). The initial difficulty complained of by the patients is in walking. The abnormality of gait is described as “weak legs,” “rubber legs,” “slowing up,” staggering, stumbling, unsteadiness, or lossof balance, and remains the major complaint throughout the illness(2). Characteristically, the patient stands with his or her feet placed far apart, the trunk shifted forward slightly, and arms held stiffly a to-and-fro instabilityof the trunk, and away from sides. Most the patients show and there may be also a titubation of the head. This form of postural tremor consists of a specific 3-Hz rhythmic swaying in the anteroposterior direction (78-80). Visual stabilization of posture is preserved and the tremor is provoked by eye closure (presence of Romberg’s sign). Patients rarely fall because the tremor is opposite in phase in head, trunk, and legs, resulting ina minimal shift of the center of gravity. Postural abnormalities are accentuated during ambulation. Patients walk with a wide-based, staggering gait (“drunken” or “reeling” gait). Symptoms are more pronounced during tandem walking and under circumstances that require rapid postural adjustments, suchas the initiation of walking, turning, avoiding obstacles, or coming to a halt and sitting down. Patients may compensate by shortening their steps and shuffling. Patients are usually capable of getting about, many require a walking aid. The slightest, nonweight-bearing contact has a remarkably steadying effect. The legs are affected in most patients, best demonstrated on the heel-toshin test. In contrast to the legs, the arms are little affected with only slight slowness and clumsinessof rapidly alternating movements and mild terminal dysmetria on the finger-to-nose test (81). A moderate or severe degreeof cerebellar incoordination or intention tremor is rare. Handwriting might be impaired. Yet, the clinical abnormalities may be limited to an instability of stance and gait (34). Speech is not consistently affected and is characterized more by slowing and

slurring than by scanning. A horizontal nystagmus can be present, but is frequently absent. ~ e n d u l ajerks r and the “rebound” phenomenon rnay be observed. Hypotonia usually cannotbe demonstrated. Abouthalf of the patients have signs of accompanying polyneuropathy, which is usually mild (2,123). In some patients, there is evidence of a previous attackof Wernicke’s encephalopathy or nutritional optic neuropathy (“tobacco-alcohol amblyopia”) (2). Victor et al. (1,2) described four categories of the evolution and progression of thedisease.Inthefirst,andlargestgroup(23/46cases),thedisease evolved rapidly, the maximurn deficit being attained in a period of weeks or months. Thereafter, the cerebellar symptoms remain essentially unchanged for a slow, many years.In a secondgroup (16146 cases),theillnessevolvedin gradual fashion over a period of several years. Aftera period of steady progression, the clinical conditionof some of these patients might also stabilize. A third group (7/46 cases) was characterizedby the presence of mild stationary cerebellar signs for many years, followed by a rapid worsening in weeks or months, to be followed by a period of stabilization. Worsening rnay occur in relation toa severe intercurrent disease, such as infections or alcoholic delirium. Another particular type is acute and transient. The cerebellar symptoms are identical with the ones that characterize the chronic formof the disease. Followinga severe drink“ ing excess, cerebellar signs usually last for several days or weeks and are always reversible. Stabilization of the chronic disease process is usually accompanied with abstinence and with improvement in nutrition. Conversely, progression of the illness is said to be associated with continued excessive drinking and poor nutrition (2). Once the cerebellar signs become fully established, they remain to a greater or less extent. There are few reports that ataxia may improve after continued abstinencefromalcohol (l 8,20),butparametricdocumentationandsystematic follow-up studies are sparse. Diener et al. (22) performed posturography in quantifying postural ataxia in follow-up studies and were able to confirm that abstinence from alcohol improves ataxia almost invariably and even in severe cases. However, the relation between the improvement in abstinent patients and the administration of high-calorie, high-protein diets and vitamin supplements remains unclear. Both CT and MRI studies have shown that alcohol-induced enlargement of the ventricular system and the subarachnoid spaces are reversible within a few weeks (82,83). Alcohol-induced reversible brain atrophy has been attribute to deand rehydration of the brain, a rise in protein synthesis after alcohol withdrawal, and a subsequent increase in dentritial growth (84). These studies comment on cerebral changes, and there is little information on the gross anatomical changes of the human cerebellum following abstinence, Brain glucose metabolism increased significantly during detoxification, predominantly within 16-30 days and in the frontal lobes(85). No significant difference was found within the cerebel-

1

lum during detoxification. However, studies in alcohol-fed animals maintained on a nutritionally complete diet revealed plastic changes of the granule cells following prolonged alcohol uptake (86,87). S

1. Imaging Computed tomography or MRI scans may show vermian atrophy, and less frequently, atrophy of the cerebellar hemispheres (Figs. 2 and 3). Hemispheric atrophy occurs only in the presence of vermian atrophy (28,29). When cerebellar atrophy is present, widening of the space between the vemian sulci, prominent cisterns surrounding the brain stem, especially cisterna ambiens, and visible sulci MRI findings correspond to the laterally over the cerebellar hemispheres are seen. topographic distribution of cerebellar atrophy in autopsiesof chronic alcoholics. Cerebellar atrophy has been described10-8 in 1% of patients with chronic alcoholism onCT scans (27-32). The different frequencies most likely reflect differences in patients’ age and mean duration of alcoholism [e.g.,28% in Haubeck and Lee’s study (28), which examined patients younger than the of 35 ageyears]. About onethird to one-halfof patients with cerebellar atrophy CT on had no cerebellar signs,

Figure 2 Cerebellaratrophyon CT of apatientwithchronicalcoholism,showing (A)vermal atrophy and (B) enlargement of the superior cistern. (FromRef. 29.)

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Figure 3 Cerebellar atrophy onMRI (Tl-weighted image) of a patient with chronic alcoholism: midsagittal section shows anterior superior verrnian atrophy (white arrows), (From Ref. 200.)

which is in keeping with the frequent observation of asymptomatic cerebellar degeneration in alcohol-dependent patients at autopsy. However, not all chronic alcoholics with cerebellar ataxia show cerebellar atrophy on CT scans (39). The MRI findings in chronic cerebellar degeneration have not been sysis a commonsymptomin tematicallystudied.Inaddition,althoughataxia Wernicke’s disease, involvement of the cerebellum has rarely been commented on in MRI studies (88,89). Data of a recent PET study indicate that hypometabolism in the anterior superior cerebellar vermis closely follows clinical symptomatology in patients with

3

Degeneration Alcoholic Cerebellar

alcoholic cerebellar degeneration, and does not occur in alcohol-dependent patients without clinical evidence of cerebellar dysfunction (90).

2.

Electrophysiology

Sensory- and magnetic-evoked potentials, electroencephalography (EEG), electroneurography, and electromyography, (EMG) ,we normal in alcoholic cerebellar degeneration. Abnormal findings indicate additional pathology (e.g., polyneuropathy). Posturography is used to quantify postural sway. Simple platforms record sway during quiet stance (static posturography). A moving platform can also be used to elicit postural reflexes, which can be recorded by means of surface electrodes from leg muscles (dynamic posturography). Mean amplitudeof sway and sway length are greatly increased. Patients with anterior lobe atrophy show a predominant anteroposterior sway, often with a spontaneous high-frequency body tremor of about 3 Hz (78-80,91) that is most easily visualized in the Fourier power spectrum and histogramsof sway direction and sway position. Less characteristic and smaller in amplitude is a mainly lateral sway component with an by eye closure and average frequencyof 0.5 Hz (78). Postural tremor is provoked by a rapid push to the trunk or platform tilt. In the toe-up paradigm, patients with anterior lobe atrophy exhibit normal latencies of all EMG responses, but an increase in duration and amplitude of the long-latency response (92). Delayed or absentposturalreflexesindicateadditionalpathology, (e.g., polyneuropathy). Postural tremor is interpreted as the consequence of hyperexcitability of postural reflexes (22, 78, 80). The finding of increased postural sway in the anteroposterior directionofis limited diagnostic value because the tremor is frequently visible at bedside. However, posturography is more sensitive than clinical investigations and, therefore, is able to identify incipient cases of cerebellar ataxia(23; see Sec.1.B). Posturography may also be helpful for follow-up during therapy or to follow the natural course of the disease (22).

3.

LaboratoryTests

The blood counts, urinalysis, and blood chemistry determinations are abnormal only in patients with associated medical disease, particularly those with liver disease and intercurrent infections (2,39). Likewise, cerebrospinal fluid (CSF) is normal or shows only a modest elevationof protein content (2,9,12,18,20). Proof a tein values higher than 100 mg/dL or a pleocytosis suggest the presence complicating illness. Amine metabolites in the CSF of patients with alcoholic ataxias were no different from those of controls (93). Vitamins B,, B,, and B, deficiencies are common(22,38). Plasma concentration reflects current intake, rather than tissue stores. The measurement of red blood cell activity, with and without coenzyme activators, is a more accurate

method. For example, blood transketolase activity requires thiamine pyrophosB, phatase as a cofactor. Erythrocyte transketolase activity is reduced in vitamin deficiency because of lack of this coenzyme (36,37).

G. Management The most important therapeutic step is a cessation of alcohol consumption. Assuming that thiamine deficiency is a major pathogenetic factor, thiamine and other B vitamin Supplements are commonly recommended, according to the protocol for the treatment of Wernicke’s disease: initially,50 mg of thiamine is given intravenously and 50 mg intramuscularly. On each following day an additional intramuscular shot of 50 mg thiamine is given until the patient is able to eat normal food (34,94,95). In addition to thiamine, a multivitamin preparation should be given because the patient is usually deficient in more than thiamine The alone. further management involves the use of a balanced diet and all the B vitamins. Thiamine shouldbe given until the transketolase level is normalized. These measures should be accompanied by physiotherapy. Walking aids are helpful in cerebellarataxia,perhapsthroughproprioceptivecuesfromthehands.Padded clothing, knee and hip pads, and elbow guards, can prevent injuries. Occupational counseling may be helpful (e.g., floor covering, lighting, grab bars). With abstinence from alcohol and nutritional supplements, improvement in cerebellar symptoms occurs slowly and is often incomplete. There are no studies comparing the effects of abstinence alone, thiamine alone, or abstinence plus thiamine treatment. Therefore, it cannot be decided if vitamin B, or abstinence, or both, contribute to clinical improvement.

A The cerebellum is affected by a variety of drugs, heavy metals, solvents, and other industrial toxins. Toxic cerebellar degeneration is usually part of diffuse toxic encephalopathy, and cerebellar ataxia, therefore, is accompanied by various cognitive and neurological symptoms. Some toxins, however, predominantly affect the cerebellum [i.e., phenytoin, lithium, cytarabine (cytosine arabinoside), 5-flourouracil, methylmercury, bismuth, and toluene).

1. Phenytoin a. Introduction. In high doses all antiepileptic drugs, including the newer ones, can cause transient cerebellar signs. However, unlike phenytoin, they appear to lack permanent cerebellar toxicity (e.g., carbamazepine, phenobarbital, gabapen-

tine, lamotrigine, tiagabine, topiramate, vigabatrin, felbamate, and oxcarbazepin) (96,97). Interestingly, Specht et al. (98) reported that cerebellar atrophy increases the susceptibility for cerebellar adverse effects of carbamazepine. Since its introduction in 1938, the occurrence of transient cerebellar symptoms during anticonvulsant treatment with phenytoin is well known (99). Nysu g L ) and is followed tagmus is thefirst sign (at a blood level between 20 and 30 by ataxia of gait (at levelsof 30 u g L and higher) and then incoordinationof the extremities. Great individual variation exists and elevated blood levels are not universally associated with clinical neurotoxicity (100,101). In1958,Utterback’sclinicalfindings of persistentcerebellarataxiain two epileptic patients receiving large doses of phenytoin and his pathological findings of widespread destruction of the cerebellar cortex in one epileptic patientandphenytoin-treatedrats,suggested an organiccerebellardamageinduced by thedrug(102,103).Subsequently,similarclinicalandpathological findings were described in human case studies (104-107). However, pathological changes in the cerebellum in epileptic patients were noted before phenytoin was introduced (108-110). To the present day, the cause of cerebellar atrophy in epileptic patients remains controversial because it is unclear whether the cerebellar atrophy results from phenytoin toxicity or from the effects of recurrent seizures. b. ~ p i ~ e ~ i o Z oCerebellar ~y. atrophyhasbeendescribedin 10-64%of cases with phenytoin-treated epilepsy (1 11-1 15). However, the exact frequency of phenytoin-inducedcerebellaratrophyremainsunknownforvariousreasons. First, large epidemiological studies in phenytoin-treated patients are rare and most of them examined mentally retarded patients with possible underlying cerebellar abnormalities. Second, the majority of patients treated with phenytoin suffer from recurrent seizures that,by themselves, may cause cerebellar atrophy. Third, patients are rarely treated with phenytoin alone. Finally, cerebellar atrophy noted radiologically or in autopsies is frequently not associated with clinical manifestations of cerebellar ataxia. Margerison and Corsellis( l 16) reported cerebellar atrophy in 25/55 (45%) autopsiedcasesininstitutionalizedepilepticpatients.Medicaltreatmentand clinical signs of cerebellar ataxia were not commented on. Darn (117) described a reduced number of Purkinje cells in 10/32 institutionalized epileptic patients. All except two had been treated with phenytoin. Iivanainen et al. (111) investigated 131 mentally retarded epileptics whohad been treated with phenytoin, collected from a total of 338 cases. Pneumencephalography revealed atrophyof the cerebellum or brain stem, or both, in 36 patients (28%). The same percentage, however, was found for the total series of cases. Phenytoin intoxication was diagnosed retrospectivelyin 73/13 1 cases, of whom 18 had persistent lossof locomotion. Young et al. (115) reported that 54% of 41 chronically institutionalized

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adultpatientswithepilepsyhadataxia of gait.Allpatientshadbeentaking phenytoin for some years. Ballenger et al. (1 18) studied CT scans of 70 patients with seizures and 48 patients with headachesand found no significant incidence of probable cerebellar atrophy in either group. However, these negative findings have been challenged of 106 in later CT studies. Botez et al. (112) found cerebellar atrophy in 64% phenytoin-treated epileptics, with clinical signs of chronic cerebellar ataxia in only 6 cases. Theodore etal. (1 19) described that in 42 phenytoin-treated patients with complex. partial seizures only 4 patients had cerebellar atrophy on CT or MRI. Luef etal. (1 13) examined11 patients who had episodesof abnormally increased phenytoin serum levels. MRI scans revealed cerebellar atrophy in 6/11 cases. None of them had permanent signs of cerebellar dysfunction. Ney et al. ( l 14) undertook an MRI-study ina group of 36 nonretarded patients with partial epilepsy and long-term phenytoin exposure.Of their patient group, 21/36 (58%) had signs of cerebellar atrophy. It should be noted, however, that MRI scans revealed cerebellar atrophy in 35% of patients with focal epilepsy and carbamazepine monotherapy (98). Durationanddose of phenytoinmedicationbeforeonset of cerebellar symptomsvariedconsiderably.Mostcasestudiesreportpersistentcerebellar ataxia after many months or several yearsof phenytoin intake (range 1 month to 28 years) (106,107,111,120-123). However, persistent cerebellar ataxia has been reported after severe acute phenytoin intoxication (124,125). Casesof pontocerebellar hypoplasia have rarely been reported in neonates following intrauterine exposure to anticonvulsants, including phenytoin (126-128).

c. Pathogenesis. The cause of cerebellar atrophy in phenytoin-treated epileptic patients remains controversial because it is difficult to separate effects resulting from phenytoin toxicity and effects of recurrent seizures. Although findings are somewhat contradictory, human and animal studies provide evidence for both causes, which may well be synergistic (114,120). Phenytoin as the single cause of cerebellar atrophy in humans has been questioned because the occurrence of irreversible neuronal damage in the cerebellum of patients with epilepsyhad been demonstrated before the introduction of phenytoin (109). However, cerebellar degeneration has been demonstrated in patients treated prophylactically with phenytoin who had never had a seizure (122,129). Hypoxic damageof the cerebellum is accompaniedby changes in the hippocampus because the most vulnerable cells to hypoxia are in the hippocampalpyramidallayer.Therefore,neuropathologicalchangesinthecerebellum alone in phenytoin-treated epileptic patients suggest a toxic effect of the drug (107,129). Furthermore, it has been argued that cerebellar degeneration in phenytoinexposed patients with partial seizures could not be related to the cumulative ef-

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fect of systemichypoxiaresultingfromrepeatedgeneralizedconvulsions (114,120). However, although not denying that cerebral hypoxia on a circulatory or ventilatory basis can play a significant role, local metabolic requirements as the causeof seizure-susceptible nerve cells have been emphasized (130,13 1). For example, Salcman et al.(130) demonstrated marked degeneration in the Purkinje cell layer in biopsies of the cerebellar cortex in epileptic patients who never experienced a generalized convulsion. The authors suggested that the permanent neurological damage in epilepsywas related to the effectsof the seizure disorder, but drug-related effects werenot discussed. Savic andThorell(13 l)investigated whetherPETmeasurements of benzodiazepinereceptordensitycanshow seizure-related cerebellar changes in patients with partial seizures.The benzodiazepine receptor antagonist flumazil tagged with carbon11 is a sensitive marker of Purkinje cells. The main finding was that the cerebellar benzodiazepine density was locally reduced and that the siteof this reduction was spatially directly related to the epileptogenic region. This phenomenon may not be accounted for entirely by the antiepileptic medication, rather, it seems to be related to the partial seizures through cerebrocerebellar connections. Studies relating the occurrenceof cerebellar atrophy, phenytoin treatment, and seizure activity have been inconclusive. Although some studies suggested a relationbetweenphenytointreatmentandoccurrence of cerebellaratrophy (l 11,112), others found a relation to severe grand mal epilepsy, rather than to medication with phenytoin (117). Most recent studies, however, did not find a statistically significant correlation between cerebellar atrophy and variables reflective of seizure severity (i.e., duration and frequencyof partial or generalized seizures; occurrence of status epilepticus) or degree of phenytoin exposure (i.e., periods of intoxication;durationanddose of phenytointreatment;plasma levels) (113-1 15,132). A PET study showed that patients with partial seizures (119). The correlation have bilateral decreased cerebellar glucose metabolism between length of seizure history and cerebellar metabolisms was weak and a tendency of phenytoin to lower cerebellar glucose metabolism was not statistically significant. Animal data strongly suggest a phenytoin toxic effect on the cerebellum, despite some contradictory findings. Early observations showed in phenytointreated cats and rats widespread destructionof the cerebellar cortex, particularly of the Purkinje cells (102,104,105,133). These findings were questioned by a large experimental series by Dam et al. (11’7): The main result was that the density of Purkinje cells in monkeys, pigs, and rats treated with phenytoin was within the range of variation in untreated animals. Dam concluded that there is by no realloss of Purkinje cells in phenytoin-treated animals. More recent studies Volk and co-workers(134-1 36), however, showed that chronic phenytoin administration in mice causes distal axonopathy of cerebellar neurons with the accurnulation of smooth membranes. Purkinje cells were nearly exclusively affected.

588

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Furthermore, neurotoxicityof phenytoin administered to newborn mice on developing cerebellum has been shown (137). A discrete binding site for phenytoin in the vicinityof cerebellar Purkinje and granule cells has been demonstrated (138). However, how phenytoin may lead to degeneration of the cerebellar cortex is far from being understood. Volk et al. (135) proposed that phenytoin-related Purkinje cell damage may be produced by an induction of Purkinje cell microsomes with proliferation of the smooth endoplasmatic reticulum which causes a swelling and enlargement of presynaptic segments of Purkinje cell axons in deepCerebellar nuclei. Phenytoin is known to reduce the GABA content and change the metabolismsof biogenic amines in Purkinje cells (136). Administration of phenytoin also changes the discharge rateof the Purkinje cell. In fact, the cerebellum has been proposed as possessing an inhibitory influence over cortical excitability (139) and, therefore, to be involved in processes of epileptogenesis and anticonvulsant therapy (140,141). However, studies in different species and different phenytoin dosages showed both increases (142,143) and decreases (144) in Purkinje cell discharge rate. Yan et al. (145) demonstrated that exposure of cultured cerebellar granule neurons to pharmacologically relevant concentrationof phenytoin results ina delayed type of neurotoxicity characterized by the biochemical and morphological features of apoptosis. d. Neuropathology. Spielmeyer(109)firstdescribeddiffuseloss of Purkinje cells and proliferationof Bergmann astroglia in the cerebellar cortex of epileptic patients. Similar neuropathological findings have been observed in phenytointreated epileptic patients. These consist of marked reduction of Purkinje cells with Bergmann’s gliosis throughout the entire cerebellum and a mild degree of diffuse loss of the granule cell layer. No changes are commonly detected in the cerebellar white matter and nuclei and cerebellar connections with the brain stem (102,104,107,129). The Purkinje cells at the crests and the depth of the foliae are almost equally affected (117). Reduced Purkinje cell densities and gliosis have also been demonstrated in biopsies of the cerebellar cortex in patients with pharmacologically intractable epilepsy at the timeof cerebellar electrode installation (130,146).

e. Clinical Features. Cerebellardegenerationobservedinphenytoin-treated patients is diffuse. Clinical presentation, therefore, includes nystagmus, dysarthria, truncal, stance, and gait ataxia, as well as ataxia of the limbs and may be disabling (120-122). Symptoms are usually slowly progressive and showa slow and slight improvement when phenytoin is reduced or discontinued. Cerebellar symptoms commonly remain to various extent. Worsening of symptoms has been reported by increases in phenytoin doses and relapses may occur when phenytoin medication is resumed (121). Additional signs of polyneuropathy may be present. In cases of cerebellar degeneration after acute and severe phenytoin intoxication,

Degeneration Alcoholic Cerebellar

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signs of cerebellar dysfunction subsided very slowly and incompletely over the course of several months (124,125).

J: Ancillary Tests. ComputedtomographyandMRIscansrevealdiffusecerebellar atrophy in phenytoin-treated epileptic patients (112-114). In CT scans, Koller et al. (29) reported a specific pattern of enlargement of the cisterna magna, cerebellopontine angle, and superior cerebellar cisterns. Both the vermis (121) and the cerebellar hemispheres(112,113) have been reported to be slightly more frequentlyaffected.However,mostcommonly,thevermisandcerebellarhemispheres are affected to similar extends. PET studies showed bilaterally reduced cerebellar glucose and oxygen metabolism in patients with focal and generalized seizures treated with phenytoin, with and without cerebellar atrophy CT or on MRI scans (119,147,148). Cerebrospinal fluid (CSF) has been reported to be unaffected (120,121), and thiamine levels may be decreased in blood and CSF (149). g. Management. Asageneralrule,chronictreatmentwithphenytoinshould be avoided, particularly in patients with cerebellar signs or cerebellar atrophy on CT or MRI, and seizure frequency should be optimally controlled. Cerebellar atrophy is frequently observed, whereas the patients are asymptomatic, and raises the issue thatCT or MRImay be helpful in the preclinical detection of phenytoininduced cerebellar degeneration (29).The use of various new antiepileptic drugs may be helpful to avoid long-term phenytoin treatment. A beneficial role of thiamine therapy has been discussed; however, the recovery might well be related to spontaneous recovery following the withdrawal of the drug (123).

2. Antineoplastic Drugs

a. Cytarabine (CytosineArabinoside;Ara-C). Ara-C is widelyusedinthe treatment of leukemia and lymphoma. Neurotoxicityis a very rare complication of conventional cytarabine regimens (e.g., 100-200 mg/m2 every day for 5-7 consecutive days). Since 1979, high-dose intravenous Ara-C regimens have becomepopularforpatientswhoarerefractorytoconventionaltherapy(e.g., 3 g/m2 every 12 h for 12 doses per course). Subsequently, reversible cerebellar 1).The frequency of reataxia and cerebellar degeneration were reported (150,15 ported CNS side effects of high-dose cytarabine ranges from 6 to 47% 1). (15The cerebellar syndrome is characterized by acute onset of dysarthria, nystagmus, ataxia of trunk, stance, gait, and extremities. The first symptoms of CNS dysfunction are usually noted between 3 and 8 days after the first dose was administered. Symptoms often resolve within 2 days or a few weeks of completing chemotherapy; however, irreversible toxicity has also been reported (e.g., in 16.7% of cases) (152). CT and lumbar puncture are nearly always normal except for an elevated protein content in the CSF. Postmortem examination has shown loss of Purkinje cells in the depth of the cortical sulci, with relative preservation of those

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in the most posterior and inferior parts of the cerebellum (152-154). It is unknown whether CNS toxicity is causedby the active pyrimidine antimetabolites or by toxicity of the inactive metabolites. Several risk factors have been described, including past history of neurological dysfunction, hepatic dysfunction, be renal insufficiency, and age (150). In some studies CNS toxicity proved to dose-related (153). However, a safe dosage regimen has not yet been defined. b. 5-Fluorouracil (5-FU). Neurotoxicitycaused by 5-FTJ is a rarelyreported phenomenon. About 5%of patients receiving 5-FU alone have neurotoxic symptoms (150,151). The primary manifestation is an acute pancerebellar syndrome. Symptoms evolve suddenly during maintenance therapy after periods of weeks to several months (155). The cerebellar toxicity is reversibleon drug withdrawal or dose reduction, and the symptoms usually resolve completely within 1-6 weeks. CT is normal. The biochemical basis for 5-FU neurotoxicity is unknown.

c. Others. Cerebellarataxia rnay beone of thepresentingsymptoms of encephalopathy caused by various antineoplastic drugs (e.g., methotrexate, ifosamide, and interleukin-2) (151,156). 3. Lithium Lithium is a drug commonly used for acute mania, manic-depressive disorders, and cluster headache. Lithium has a narrow therapeutic and safety range, with toxicity occurringjust above therapeutic levelsof about 0.6-1.2 &q/L for maintenance therapy (157,1SS). Less commonly, neurotoxicity occurs at therapeutic levels. Although transient toxicity attributed to lithium is common, persistent neurological symptoms are infrequent. Maintenance therapy with lithium usually produces minor neurological side effects, such as mild tremor. Acute toxicity is characterized by confusion, decreased level of consciousness and coma, muscular irritability, seizures, and a variety of motor signs, including tremor, ataxia, dyskinesia, and rigidity. Cerebellar symptoms, however, are not prominent in the acute stage. Mostpatientswithlithiumintoxicationhavenopersistentneurological dysfunction, Nagaraja et al. (159) described persistent neurological sequelae in 1.2% with manic-depressive illness receiving continuous lithium therapy. In another study, 10% of patients with lithium intoxication had persisting aftereffects, and 14% died (157). Persistent neurological deficits usually develop following a pancerebellar syndrome (i.e., trunthe acute intoxication and typically resemble cal, stance, gait ataxia, nystagmus, limb ataxia, and dysarthria) (160). Initially, cerebellar ataxia may be disabling. Choreoathetosis, parKinsonism, corticospinal tract signs, and peripheral neuropathy rnay be present. Lithium-induced neurotoxicity usually occurs because of high serum levels following accidental or suicidal overdose or during maintenance therapy. Pos-

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sibleprecipitatingcircumstancesaresomaticillnesswithfever,low-saltdiet and diuretics, dehydration and kidney disease, and combination therapy with nonsteroidal anti-in~ammatorydrugs (NSAIDs). Increased sensitivity of the elderly and combination therapy (e.g., with neuroleptics), have been discussed as possible risk factors. The mechanisms for the cerebellar degeneration in lithium intoxication remain uncertain. Lithiummay influence electrolyte balance, neurotransmitter systems, and carbohydrate metabolism, andmay play a role in membrane stabilization (161). D’Mello et al. ( l 62) reported that treatment of i m a turegranulecellsinculturewithlithiumresultedinprograrnrnedcelldeath (apoptosis); however, lithium prevented deathof mature neurons caused by low potassium levels. Postmortem neuropathological examination revealed Purkinje and granule cell loss and gliosis in the cerebellar cortex and dentate nuclei; the cerebellar whitematterexhibitedprominentspongychange.Changesweremorepronounced in the superior vermis than in the hemisphere (161,163). Cerebellar atrophy may be present in CT and MRI. CSF is normal (164). Discontinuing the administrationof lithium in the intoxicated patient does not result in immediate disappearance of toxic symptoms (34). This may be delayed by l or 2 weeks, presumably because brain levels drop more slowly. Fluids, sodium chloride, aminophylline, and acetazolamide promote theexcretion of lithium. Lithium coma may require hemodialysis. Lithium therapy has been restarted in patients without lowering lithium tolerance or aggravation of neurological symptoms (1 56).

4. OtherDrugs

A condition termed worm wobbleis a reversible cerebellar syndrome that occurs in children taking piperazine for threadworm infestations (165,166). Among others, ataxia may be one of the presenting adverse effects of isoniazid overdose (167), bromide(168), disulfiram (169), amiodarone (170), and glutethimide (171). 6. HeavyMetals

1. Mercury Human exposure to mercury vapor is from dental amalgam and industries using mercury. To date, methylmercury compounds are found exclusively in seafood a triad of and freshwater fish. Severe exposure to inorganic mercury results in symptoms: erethrism, tremor, and gingivitis. Methylmercury intoxication results in focal brain darnage affecting the cerebellum and the visual cortex (172). In the early 20th century the potent fungicidal properties of organic mercury led to the widespread use in industry and agriculture (e.g.,on seed grains). The Iraq outbreak was causedby the consumption of homemade bread prepared

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from grain treated with a methylmercury fungicide (173) and, as a result, a worldwide ban was initiated against the use of alkylmercurials as fungicides. In the Japan outbreaks of the 1950s and 196Os, methylmercury itself had been produced as an unknown byproduct in the manufacture of acetaldehyde. Methylmercury compounds were discharged in the nearby ocean bay of Miniinata (Minimata disease) (174). Bioaccumulation occurred in the aquatic food chain to an extent that fishermen who consumed the fish were poisoned. The acetaldehyde process has since been discontinued in Japan and elsewhere. In the late 1960s a third source of human exposure was discovered. This was the natural methylation of inorganic mercury by microorganism in sediments of bodies of fresh- and ocean water and bioaccumulation up the aquatic food chain. It is not known if the current dietary supply of methylmercury in fish and seafood offers a significant health risk. A WHO Expert Group concluded that there may be a low risk of poisoning at hair levels of about 50 ppm and blood levels of about 200 ppm (172). A characteristic of methylmercury poisoning is the selective damage to the CNS. Extensive loss of neuronal cells is seen in the granular layer of the cerebellum, whereas the Purkinje cells are in general spared, in the visual cortex, and other focal areas (175). The biochemical basis appears to be the selective action of methylmercury on inicrotubules in the cytoskeleton of the neuronal cell. The effect that appears first is paresthesia in the extremities of the hand and feet and circumorally and is followed by pancerebellar ataxia and constricted visual fields. A latent period of 1 month or more may ensue between the start of ingestion of methylmercury and the first appearance of paresthesia. The chelating agent 2.3-dimercapto- 1-propanesulfonate (DMPS) was the most effective agent to reduce methylmercury in blood in a study testing the efficacy of different antidotes (176). 2.

Lead

In the past, inorganic lead poisoning was a serious concern in industrial and in occupational situations. Because of preventive legislation, lead poisoning is now mainly a nonindustrial problem. The greatest concerns are exhaust fumes from automobiles still using lead-containing gasoline. water supplies through lead pipes, and lead paint (177). Occupational hazards are due to inhalation of lead fumes or physical contact with lead in processes that require remelting of lead, such as lead smelting, pottery glazing, and storage battery manufacture. Lead intoxication most often occurs in 1- to 3-year-old children because of their chewing of lead paint in old housing. Acute encephalopathy is a serious complication in children. Lead toxicity is much less common in adults. The usual manifestations of lead poisoning in adults are colic, anemia, and peripheral motor neuropathy. Acute encephalopathy is rare (178). Most of the limited number

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of cases reported since 1930 were the results of consumption of illicit liquor contaminated by lead (moonshine whiskey) (179). Acute lead encephalopathy is characterized by apathy, lethargy, intense and persisting headaches, vomiting, cerebellar ataxia, and seizures.The disease may progress to papilledema, coma, and death.CT and MRI reveal widespread calcifications, particularly in the cerebellar hemispheres, basal ganglia, and thalamus, with increased signal densities on the T2-weighted images of the periventricular white matter, basal ganglia, and pons. The toxic action of lead is due to blockade of the synthesis of porphyrins. Impaired heme synthesis results in an increased excretion of urinary coproporphyrin and of 8-aminolevulinic acid. In most textbooks 2,3-dimercaptopropanol (BAL) and CaNa, EDTA, followed by a course of penicillamine, are mentioned as the chelators of choice (34). DMPS is recommended by others (179).

3. Thallium Thallium is a heavy metal, the saltsof which are used in the manufactureof optical lenses, green-colored fireworks, and imitation jewelry, and thallium isotopes areusedincardiacscanning.Thalliumcompoundswereusedastherapeutic agents in the late 19th century and early 20th century (e.g., as a depilatory agent). In 1930, thallium sulfate was introduced as a potent rodenticide (rat poison) and insecticide (180-1 82). Commonmanifestationsarepolyneuropathy,alopecia,gastrointestinal symptoms,encephalopathy,andcranialnervepalsies.Whenlargedosesare taken, the first symptoms are gastrointestinal symptoms and headaches, followed by delirium, hallucinations, seizures, coma, and death. When smaller doses are ingested, ataxia, paresthesia, and pain may be the outstanding symptoms. Tremor, chorea, athetosis, myoclonus, mental changes, and changesof consciousness are commonly noted (1 83,184). Reed et al. (1 83) described persistent abnormalities in 54% of the cases, mainly mental changes, but also abnormal reflexes, ataxia, and tremor. Ataxiaandtremorresultingfromthalliumintoxicationarecommonly thought to reflect widespread cerebellar disorder (1 85). Likewise, an electron microscopic studyof the effectsof thallium poisoning on the rat cerebellum showed mitochondrial abnormalities and multilamellar cytoplasmic bodies in most neurons of the cerebellar cortex (186). However, neuropathological studies of patients with fatal thallium intoxication reported changes in motor cortex, basal ganglia, brain stem, spinal cord, and peripheral nerves, but not in the cerebellum (183,187). Severe sensory polyneuropathyis a common finding andmay at least in part cause ataxia. The currenttreatmentforthalliumpoisoningisPrussianblue[ferric hexacyanoferrate (II)] and potassium chloride (1 80,182).

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Bismuth 4. Bismuth subsalicylate preparations are over-the-counter products for gastrointestinal complaints. Prolonged consumption of oral preparationsmay cause bismuth encephalopathy (188,189). Salient features include subacute onset of intention tremor, gait ataxia, myoclonus, and poor concentration. Delirium, psychosis, and seizures have been described. Purkinje cell loss is described in one autopsy case. Symptoms are reversible over several weeks or months, when bismuth intake is stopped.

5. Manganese Manganese poisoning results from prolonged inhalation and ingestion of manganese particles; it occurs in minersof manganese ore. The initial stages of intoxication may be marked by a prolonged confusional-hallucinatory state. Later, the symptoms are predominantly parkinsonian. Cerebellar ataxia is not a characteristic feature (190,191).

C. Solvents 1. Mixed Solvents The term organic solvents indicates a group of liquid, volatile compounds containing, at least, carbon and hydrogen (192,193). The use of solvents is widespread, with numerousof specific substances and different mixtures, of which no more than a few dozen have been tested for neurotoxicity. The most frequently investigated solvents have been carbon disulfide, tri- and tetrachloroethylene, toluene,xylene,styrene,andtheirmixtures.Carbondisulfide,n-hexane,and some ketones (toluene and trichloroethylene) are proved neurotoxicants. Longtern exposure to n-hexane is associated with the development of polyneuropathy, whereas prolonged abuse of toluene and chlorinated solvents can cause permanent damage to the central nervous system, including the cerebellum.

2. Toluene Toluene (methyl benzene) is used in industry as an organic solvent aand dilutent of lacquers and inks. Toluene has been especially popular among solvent sniffers because of its availability in the form of glue, contact cement, and other adhesives (194). Cerebellar degeneration in toluene sniffers has been known since 1961 (195). Neurological signs including cognitive, pyramidal, cerebellar, and cranial nerve findings are common in chronic solvent abusers. Pancerebellar signs are particularly prominent and have been reported in 45% of solvent abusers (primarily toluene) (196,197). A neuropathological case study showed dif%use cere-

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bra1 and cerebellar atrophy and peripheral axonopathy. CT scans reveal diffuse cerebral and cerebellar atrophy (197). During abstinence cerebellar symptoms improve; however, permanent cerebellar deficits occur (196,197). 3. Others Acrylarnide poisoningmay give rise to ataxia(198) and sodium azide has caused cerebellarcorticaldegeneration(199).Organochlorideinsecticidescancause tremor (168).

REFERENCES 1. Victor M, Adams RD, Mancall EL. Alcoholic cerebellar degeneration. Trans Am Neurol Assoc 1958; June: 95-99. 2. Victor M, Adams RD, Mancall EL. A restricted form of cerebellar cortical degeneration occurring in alcoholic patients. Arch Neurol 19.59; 1579-688. 3. Thomas A. Atrophie lamellaire des cellules de Purkinje. Rev Neurol 1905; 13:917924. 4. Jakob A. Zur Klinik und pathologischen Anatomie des chronischen Alkoholismus. Zugleich ein Beitrag zu Erkrankungen des Kleinhirns. Z Gesamte Neurol Psychiatr 1912;13:132-152. S. Stender A, Luthy F. Uber Spatatrophie der Kleinhirnrinde bei chronischem Alkoholismus. Dtsch Z Nervenheilkd 1931; 119:604-622. Med 1934; 28:379-390. 6. Lhermitte J. Cortical cerebellar degeneration. Proc R SOC 7. De Haene A. Contribution a l’ktude clinique et anatomique de l’atrophie cerebelleuse tardiveB predominance corticale. J Belg Neurol Psychiatr 1937; 37:427-454. 8. Guillian G, Bertrand I, Guillian J. Etude anatomo-clinique cas d’atrophie cerebelleuse corticale progressive. Bull SOCMkd Paris 1939; 55:218-219. 9. Romano J, Michael M, Merritt HH. Alcoholic cerebellar degeneration. Arch Neurol 1940; 44:1230-1236. 10. Santha von K. Lokalisierte Atrophie der Kleinhiminde bei chronischem Alkoholismus. Monatsschr Psychiat Neurol 1948; 116:346-363. 11. Zulch KJ. La pathogenie des atrophies ckrebelleuses. Rev Neurol 1952; 86:798800. 12. Skillicorn SA. Presenile cerebellar ataxias in chronic alcoholics. Neurology 1955; 5527-533. 13. Chodoff P, Auth T, Toupin H. Parenchymatous cortical cerebellar atrophy. J Nerv Ment Dis 1956; 123:376-381. 14. Greenfield JD. The Spinocerebellar Degenerations. Oxford: Blackwell Scientific, 1954. 15. Holmes G. A form of familial degeneration of the cerebellum. Brain 1907; 30:466488. 16. Marie P, Foix C, Alajouanine T. De l’atrophie cerebelleuse tardive B predominance corticale. Rev Neurol 1922; 29:849-885.

596

Diener Timmann-6raun and

17. Alajouanine T, Castagaigne F, Contamin F, Le Bourges J. Sur six cas d’atrophie ckrkbelleuse du type cortical tardif (Pierre Marie-Foix-Alajouanine) observks chez des alcooliques chroniques. Rev Neurol 1959; 100:411-429. 18. Decker JB, Wells CE, McDowell F. Cerebellar dysfunction associated with chronic alcoholism. Neurology 1959; 9:361-366. 19. AmesF.Six cases of cerebellar degeneration associated with chronic alcoholism. S Afr Med J 1961; 35:152-154. 20.Allsop J, TurnerB.Cerebellardegenerationassociatedwithchronicalcoholism. J Neurol Sci 1966; 3:238-258. 1. 2Stork J. Kleinhirnwurma~ophie und chronischer Alkoholismus-~linischanatomische Studie iiber 44 Falle. Schweiz Arch J Neurol Neurochir Psychiatry 1967; 99:40-82. 22.DienerHC,DichgansJ,BacherM,GuschlbauerB.Improvementofataxiain alcoholiccerebellaratrophythroughalcoholabstinence.JNeurol1984;231: 2.58-262. 23. Scholz E, Diener HC, Dichgans J, Langohr HD, Schied W, Schupmann A. Incidence of peripheral neuropathy and cerebellar ataxiain chronic alcoholics. J Neurol 1986; 233:212-217. 24. Torvik A, Lindboe CF, Rogde S. Brain lesions in alcoholics. J Neurol Sci 1982; 56:233-248. 25. Lindboe CF, Lgberg EM. The frequency of brain lesions in alcoholics. Comparison between the 5-year periods 1975-1979 and 1983-1987. J Neurol Sci 1988; 88:107113. 26. Torvik A, Torp S. The prevalence of alcoholic cerebellar atrophy. A morphometric and histological study of an autopsy material. J Neurol Sci 1986; 75:43-52. 27.AllenJH,MartinJT,McLain LW. Computedtomographyincerebellaratrophic processes. Radiology 1979; 1330:379-382. 28. Haubeck A, Lee K. Computed tomography in alcoholic cerebellar atrophy. Neuroradiology 1979; 18:77-79. 29. Koller WC, Glatt SL, Perlik S, Huckman MS, Fox JH. Cerebellar atrophy demonstrated by computed tomography. Neurology 198l ;3 1 :405-4 12. 30.RonMA,Acker W, ShawGH,LishmanWA.Computerizedtomographyofthe brain in chronic alcoholism. A survey and follow-up study. Brain 1982; 10.5:4975 14. 3l . Hillbom M, Muuronen A, Holm L, Hindmarsh T. The clinical versus radiological diagnosis of alcoholic cerebellar degeneration. J Neurol Sci 1986; 73:45”3. 32. Melgraad B, Ahlgren P. Ataxia and cerebellar atrophyin chronic alcoholics. J Neurol 1986; 233:13-15. 33. Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff Syndrome. A Clinical and Pathological Studyof 24.5 Patients, 82 with Post-mortem Examinations. Philadelphia: FA Davis, 1971. 34.AdamsRD,Victor M, RopperAH.PrinciplesofNeurology.6thed.NewYork: McGraw-Hill,1997. 35. Thomson AD, Jeyasingham MD, Pratt OE, Shaw GK. Nutrition and alcoholic encephalopathies. ActaMed Scand Suppl 1987; 717:55-65.

ebellar

Alcoholic

597

36. DasteurDK,SanthadeviN,QuadrosEV,AvariFCR,WadiaNH,DesaiMM, Bharucha EP. The B-vitamins in malnutrition with alcoholism. A model of intervitamin relationships. Br J Nutr 1976; 36:143-159. 37. Bottoni A, Piatti M, Patrini C, Caramella C, Casirola G. Content of thiamine and its phosphoesters in red blood cells of alcoholics with and without liver injury. Acta Vitamin01 Enzymol 1987; 8:9-13. 38. Langohr HD, Petruch F, Schroth G. Vitamin B,, B, and B, deficiency in neurological disorders. J Neurol 1981; 225:95--108. 39. Estrin WJ. Alcoholic cerebellar degeneration is not a dose-dependent phenomenon. Alcohol Clin Exp Res 198’7; 11:372-375. 40. E 1 JJ. Neuropathology of thiamine deficiency disorders. Metab Brain Dis 1996; 11:9-17. 41. Victor M, Ferrendelli JA. The nutritional and metabolic diseases of the cerebellum. Clinical and pathological aspects. In: FieldsWS, Willis WD, eds. The Cerebellum in Health and Disease. St Louis, MO: Warren H Green, 1970:412-449. 42. HarperC.Theincidence ofWernicke’sencephalopathyinAustralia-aneuropathological studyof 131 cases. J Neurol Neurosurg Psychiatry 1983; 46593-598. 43. Rinehart JF, Friedman M, Greenberg LD. Effects of experimental thiamine deficiency on the nervous system of the rhesus monkey. Arch Pathol 1949; 48:129-139. 44. Plaitakis A,Nicklas WJ, Berl S. Thiamine deficiency: selective impairmentof the cerebellar serotonergic system. Neurology 1978; 28591-698. 45. Nauti A, Patrini C, Reggiani C, Merighi A, Bellazi R, Rindi G. In vivo study of the kinetics of thiamine and its phosphoesters in the deafferented rat cerebellum. Metab Brain Dis 1997; 12:145-160. 46. Poloni M, MazzarelloP, Laforenza U, Caramella C, Patrini C. Thiamin contents of cerebrospinal fluid, plasma and erythrocytes in cerebellar ataxia. Eur Neurol 1992; 32:154-158. 47. Eijhan C. Antineuritisches Vitamin und Beriberi. In: Les Prix Nobel en 1929. Stockholm: Imprimerie Royal, 1930:1-10. 48. Hahn JS, BerquistW, Alcorn DM, Chamberlain L, Bass D. Wernicke encephalopathy and beriberi during total parenteral nutrition attributable to multivitamin infusion shortage. Pediatrics 1998; 101:elO. 49. Palmer MR, Hoffer BJ. GABAergic mechanisms in the electrophysiological actions of ethanol on cerebellar neurons. Neurochem Res 1990; 15:145-15 1, 50. Lin AM-Y, Freund RK, Hoffer BJ, Palmer MR. Ethanol-induced depressions of cerebellarPurkinjeneuronsarepotentiatedbyP-adrenergicmechanismsinrat brain. J Pharmacol Exp Ther 1994; 271:1175-1180. 51. Pearson BJ, Donatelli DP, Freund RK, Palmer MR. Differential development and characterizationof rapid acute neuronal tolerance to the depressant effects of ethanol on cerebellarPurkinjeneurons of low-alcohol-sensitiveandhigh-alcoholsensitive rats. J Pharmacol Exp Ther 1997; 280:739-746. 52. Gilman S, Koeppe RA, Adams K, Johnson-Greene D, Junck L, Kluin KJ, Brunberg J, Martorello S, Lohman M. Positron emission tomographic studies of cerebral benzodiazepine-receptor binding in chronic alcoholics. Ann Neurol 1996; 16340: 171.

598

Timmann-Braun and Diener

53. Lhermitte J, DeAjuriaguerra J, Garnier.Les Mons dusystkmenerveuxdans

l’intoxication alcoolique expkrimentale. R SOC Biol 1938; 128:386-388. 54. Barnes DE, Walker DW Morphological alteration of hippocampus and cerebellum resulting from prolonged ethanol consumption in rats. Alcohol 1979; 3:168. 55. Phillips SC, Cragg BG. Alcohol withdrawal causes a loss of Purkinje cells in mice. J Stud Alcohol 1984; 45:475480. 56. Tavares MA, Paula-Barbosa MM, Cadete-Leite A. Chronic alcohol consumption reduces the cortical layer volumes and the number of neurons of the rat cerebellar cortex. Alcohol Clin Exp Res 1987; 11:315--319. 57. Tavares MA, Paula-Barbosa MM, Gray EG. A morphometric Golgi analysis of the Purkinje cell dendritic tree after long-term alcohol consumption in the adult rat. J Neurocytol 1983; 12:939-948. 58. Paula-Barbosa MM, Tavares MA. Long term alcohol consumption induces microtubular changes in the adult rat cerebellar cortex. Brain Res 1985; 339:195-199. 59. Tavares MA, Paula-Barbosa MM. Alcohol-induced granule cell loss in the cerebellar cortex of the adult rat. Exp Neurol 1982; 78574-582. 60. Tavares MA, Paula-Barbossa MM, Verwer RW. Synapses of the cerebellar cortex molecular layer after chronic alcohol consumption. Alcohol 1987; 4: 109-1 16. 61. Kitson KE. Ethanol and acetaldehyde metabolism: past, present, and future. Alcohol Clin Exp Res 1996; 20(suppl):82A-92A. 62. Pratt OE, Rooprai HK, Shaw GK, Thomson AD. The genesis of alcoholic brain tissue injury. Alcohol Alcohol 1990; 25:217-230. 63. Nordmann R. Alcohol and antioxidant systems. Invited review. Alcohol Alcohol 1994; 29~513-522. 64. Nordmann R, Ribikre C, Rouach H. Ethanol-induced lipid peroxidation and oxidative stress in extrahepatic tissues. Alcohol Alcohol 1990; 25:231-237. 65. Rouach H, HouzeP, Gentil M, OrfanelliMT, Nordmann R. Changes in some proand antioxidants in rat cerebellum after chronic alcohol intake. Biochem Pharmac01 1997; 531539-545. 66. Setta F, Jacquy J, Hildebrand J, Manto M-U. Ataxia induced by small amounts of alcohol. J Neurol Neurosurg Psychiatry 1998; 65:370-373. 67. Zirnitat C, Kril J, Harper CG, Nixon PE Progression of neurological disease in thiamin-deficient rats is enhanced by alcohol. Alcohol 1990; 7:493-501. FP, CamoesI,VolkB, 68. Paula-BarbosaMM,AndradeJP,CastedoJL,Azevedo Tavares MA. Cell loss in the cerebellum and hippocampal formation of adult rats after long-term low-protein diet. Exp Neurol 1989; 103:186-193. 69. Kril JJ, Butterworth RF. Diencephalic and cerebellar pathology in alcoholic and nonalcoholic patients with end-stage liver disease. Hepatology 1997; 26:837-841. of the cerebellum. 70. Jansen J, Brodal A. Experimental studies on the intrinsic fibers 11. The corticonuclear projection. J Comp Neurol 1940; 73:267-321. 71. Philipps SC, Harper CG, Kril J. A quantitative histological study of the cerebellar vermis in alcoholic patients. Brain 1987; 110:301-314. 72. Ferrer I, Fabregues I, Pineda M, GraciaI, RibaltaT. AGolgi studyof cerebellar atrophy in human chronic alcoholism. Neuropath01 Appl Neurobiol 1984; 10:245253.

ebellar

Alcoholic

599

73. Hall TC, Miller AKH, Corsellis JAN. Variations in the human Purkinje cell population according to age and sex. Neuropath01 Appl Neurobiol 1975; 1:267-292. 74. Neubuerger KT. The changing neuropathologic picture of chronic alcoholism. Arch Pathol 1957; 63: 1-6. 75. Snider RS, Stowell A. Receiving areas of the tactile, auditory, and visual systems in the Cerebellum. J Neurophysiol 1944; 7:331-357. 76. Nitschke MF, Kleinschmidt A, Wessel K, Frahm J. Somatotopic motor representation in the human anterior cerebellum. A high-resolution functional MRI study. Brain 1996; 119: 1023-1029. 77 Fulton JF? Connor G. The physiological basis of three major cerebellar syndromes. Trans Am Neurol Assoc 1939; 65:53-57. of stance in late cor78. Mauritz KH, Dichgans J, Hufschmidt A. Quantitative analysis tical cerebellar atrophy of the anterior lobe and other forms of cerebellar ataxia. Brain 1979; 102:461-482. a specific disor79. Silfverskiold BP. Cortical cerebellar degeneration associated with der of standing and locomotion. Acta Neurol Scand 1977; 55:257-272. 80. Diener HC, Dichgans J, Bacher M, Gompf B. Quantification of postural sway in normals and patients with cerebellar diseases. Electroencephalol Clin Neurophysiol 1984: 57~134-142. 81. Johnson-Greene D, Adarns K M , Gilman S, Kluin KJ, Junck L, MartorelloS, Heumann M. Impaired upper limb coordination in alcoholic cerebellar degeneration. Arch Neurol 1997; 54:436-439. 82. Carlen PL, Wortzmann G, Holgate RC, Wilkinson DA, Rankin JG. Reversible cerebral atrophy in recently abstinent alcoholics measured by computed tomography scans. Science 1978; 200: 1076-1078. 83. Schroth G, Naegele T, Klose U, Mann K, Petersen D. Reversible brain shrinkage in abstinent alcoholics, measured by MRI. Neuroradiology 1988; 30:385-389. 84. Carlen PL, Wilkinson DA. Reversibility of alcohol-related brain damage: clinical and experimental observations. Acta Med Scan Suppl 1987; 717:19-26. 85. Volkow ND, Wang G-J, Hitzernann R, Fowler JS, Overall JE, Burr G, Wolf AP. Recovery of brain glucose metabolism in detoxified alcoholics. Am J Psychiatry 1994; 1511178-183. 86. Phillips SC. Qualitative and quantitative changes of mouse cerebellar synapses after chronic alcohol consumption and withdrawal. Exp Neurol 1985; 88:748-756. 87. Tavares MA, Paula-Barbosa MM, Volk B. Chronic alcohol consumption induces plastic changes in granule cell synaptic boutonsof the rat cerebellar cortex. J Submicrosc Cytol 1986; 18:725-730. 88. AntunezE,EstruchR,CardenalC,NicolasJM,Fernandez-SolaJ,UrbanoMarquez A. Usefulness of CT and MR imaging in the diagnosis of acute Wernicke’s encephalopathy. AJR Am J Roentgen01 1998; 171:1131-1137. 89. Bitsch A, Seipelt M, Rustenbeck HH, Haug B, Nau R. MRI findings in Wernicke encephalopathy. Nervenarzt 1998; 69:707-7 11. 90. Gilman S, Adams K, Koeppe RA, Berent S, Kluin KJ, Modell JK, Io011 P, Brunberg JA. Cerebellar and frontal hypometabolism in alcoholic degeneration studied with positron emission tomography. Ann Neurol 1990; 28:775-785. *

600

and

Timmann-Braun

Diener

91. Dichgans J, Mauritz KH, Allurn JHJ, Brandt T. Postural sway in normals and ataxic patients. Aggressologie 1976; 17C: 15-24. 92. Diener HC, Dichgans J, Bacher M, Guschlbauer B. Characteristic alterations of long-loop “reflexes” in patients with Friedreich’s ataxia and late atrophy of the cerebellar anterior lobe. J Neurol Neurosurg Psychiatry 1984; 47579-685. 93 Kaakkola S, Tuomainen P, Mannisto PT, PaloJ. Biogenic amine metabolites in the CSF of patients with late onset and alcoholic ataxias. Acta Neurol Scand 1993; 87~309-311. 94. Graham JR, Woodhouse D, Read FH. Massive thiamine dosage an alcoholic with in cerebellar cortical degeneration. Lancet 197;2:1 107. 95. Thier P.Acuteand chronic alcohol-related disorders. In: Brandt T, Caplan LR, Dichgans J, Diener HC, Kennard C, eds. Neurological Disorders. Course and Treatment. San Diego: Academic Press, 1996:677-693. 96. Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 1997; 38:859-880. 97. Bourgeois BFD. New antiepileptic drugs. Arch Neurol 1998; 55:1181-1183. V, Schmidt RC, Schiitz M, Wolf P. Cerebel98. Specht U, May TW, Rohde M, Wagner laratrophydecreasesthethresholdofcarbamazepinetoxicityinpatientswith chronic focal epilepsy. Arch Neurol 1997; 54:427-431. 99. Merritt HH, Putnam TJ. Sodium diphenyl hydantoinate in treatment of convulsive seizures.Toxicsymptomsandtheirprevention.ArchNeurolPsychiatry1939; 42: 1053-1058. 100. Gallagher BB, Baume1 IP, Mattson RH, Woodbury SG. Primidone, diphenylhydantoin and phenobarbital. Aspects of acute and chronic toxicity. Neurology 1973; 23: 145-149. 101. Ziegler DK. Toxicity to the nervous system of diphenylhydantoin:a review. Int, J Neurol 1978; 11:383-400. 102. Utterback RA, Ojeman R, Malek J. Parenchymatous cerebellar degeneration with Dilantin intoxication. J Neuropath01 Exp Neurol 1958; 17:516--519. 103. Utterback R A . Parenchymatous cerebellar degeneration complicating diphenylhydantoin (Dilantin) therapy.AMA Arch Neurol Psychiatry 1958;80:180-1 8l. 104. Hofmann WW. Cerebellar lesions after parenteral Dilantin administration. Neurology1958;81210-214. 105. Kokenge K, Kutt H, McDowell F. Neurological sequelae following Dilantin overdose in a patient and in experimental animals. Neurology 1965; 15:823--829. 106. Selhorst JB, Kaufman B, Horwitz SJ. Diphenylhydantoin-induced cerebellar degeneration. Arch Neurol 1972; 27:453-455. 107. Ghatak NR, Santoso RA, McKinney WM. Cerebellar degeneration following longterm phenytoin therapy. Neurology 1976; 26:8 18-820. 108. Liebers M. uber Kleinhi~atrophienbei Epilepsy nach epileptischen Krampfanfallen. Z Neurol Psychiatr 1928; 113:739-756. 109. SpielmeyerW. The anatomic substratumof the convulsive state. Arch Neurol Psychiatry 1930; 23:869--875. 110. Zimerrnan HM. The histopatology of convulsive disorders in children. J Pediatr 1938;13:859-880; *

Degeneration Alcoholic Cerebellar

601

E-P. Cerebellar atrophy in phenytoin-treated men111. Iivanainen M, Viukari M, Helle tally retarded epileptics. Epilepsia 1977; 18:375-386. 112. Botez MI, Attig E, Vezina JL. Cerebellar atrophy in epileptic patients. Can J Neurol Sci1988;15:299-303. 113. Luef G, Chemelli A, Birbamer G, Aichner F, Bauer G. Phenytoin overdosage and cerebellar atrophy in epileptic patients: clinical and MRI findings. Eur Neurol 1994; 34:79-8 1. 114. Ney GC, Lantos G, Barr WB, Schaul N. Cerebellar atrophy in patients with longterm phenytoin exposure and epilepsy. Arch Neurol 1994; 5 1 :767-77 l. 115. Young GB, Oppenheimer SR, Gordon BA, Wells GA, Assis LPA, Kreeft JH, Lohuis NA, Blume WT. Ataxia in institutionalized patients with epilepsy. Can J Neurol Sci 1994; 21:252-258. 116. Margerison JH, Corsellis JAN. Epilepsy and the temporal lobes: a clinical, electroencephalographic and neuropathological studyof the brain in epilepsy, with particular reference to the temporal lobes. Brain 1966; 89:499-530. 117. Dam M. The density and ultrastructureof the Purkinje cells following diphenylhydantoin treatment in animals and man. Acta Neurol Scand 1972; 48 (suppl 49): 1-65. 118. Ballenger CE, Lucke JF, King DW, Gamma1 TE, Brooks BS, Green JB. Cerebellar atrophy in epilepsy and headache: lack of relationship to phenytoin. Neurology 1982; 32:910-912. 119. Theodore WH, Fishbein D, Deitz M, Baldwin P. Complex partial seizures: cerebellar metabolism. Epilepsia 1987; 28:319-323. 120. Mclain LW, Martin JT, Allen JH. Cerebellar degeneration due to chronic phenytoin therapy. Ann Neurol 1980; 7: 18-23. 121. Baier WK, BeckU, Doose H. Cerebellar atrophy following diphenylhydantoin intoxication. Neuropediatrics 1984;15:76-8 1. 122. Lindvall 0, Nilsson B. Cerebellar atrophy following phenytoin intoxication. Ann Neurol1984;16:258-260. 123. Botez MI, Grave1J, Attig E, Vezina J-L. Reversible chronic cerebellar ataxia after phenytoin intoxication: possible role of cerebellum in cognitive thought. Neurology 1985; 35~1152-1157. 124. Masur H, Elger CE, Ludolph AC, GalanskiM. Cerebellar atrophy following acute intoxication with phenytoin. Neurology 1989; 39:432-433. 125. Kuruvilla T, Bharucha NE. Cerebellar atrophy after acute phenytoin intoxication. Epilepsia 1997; 38:500-502. 126. Gadisseaux JF, Rodrigues J, Lyon J. Pontoneocerebellar hypoplasia-a probable consequence of prenatal destruction of the pontine nuclei and a possible role of phenytpin intoxication. Clin Neuropath01 1984; 3: 160-167. 127. Mallow DW, Herrick MK, Gathman G. Fetal exposuretoanticonvulsant drugs-detailedpathologicstudyofacase.ArchPath01LabMed1980;104: 215-218. 128. Squier W, Hope PL, Lindenbaum RH. Neocerebellar hypoplasia in a neonate followingintra-uterineexposuretoanticonvulsants.DevMedChildNeurol1990; 32:737-742.

602

Diener

and

Timmann-Braun

129. Rapport RL, Shaw C-M. Phenytoin-related cerebellar degeneration without seizures. Ann Neurol 1977; 2:437-439. 130. Salcman M, Defendini R, Correll J, GilmanS. Neuropathological changes in cerebellar biopsies of epileptic patients. Ann Neurol 1978; 3:10-19. 131. Savic I, Thorell JO. Localized cerebellar reductions in benzodiazepine receptor density in human partial epilepsy. Arch Neurol 1996; 53:656-662. 132. Luef G, Burtscher J, Kremser C, Birbamer G, Aichner F, Bauer G, FelberS. Magnetic resonance volumetry of the cerebellum in epileptic patients after phenytoin overdosages. Eur Neurol 1996; 36:273-277. 133. Del Cerro PM, Snider RS. Studies on Dilantin intoxication. I. Ultrastructural analogies with lipoidoses. Neurology 1967; 17:452-466. 134. Volk B, KrchgassnerN. Damage of Purkinje cell axons following chronic phenytoin administration: an animal model of distal axonopathy. Acta Neuropathol 1985; 67:67-74. 135. VolkB,KirchgassnerN,Detmar M. Degenerationofgranulecellsfollowing chronicphenytoinadministration:anelectronmicroscopicinvestigationofthe mouse cerebellum. Exp Neurol 1986; 91:60-70. 136. Kiefer R, Knoth R, Anagnostopoulos J, Volk B. Cerebellar injury due to phenytoin. Identification and evolution of Purkinje cell axonal swellings in deep cerebellar nuclei of mice. Acta Neuropathol 1989; 77:289-298. 137. Ohmori H, Yamashita K, Hatta T, Yamasaki S, Kawanura M, Higashi Y,Yata N, Yasuda M. Effects of low-dose phenytoin administered to newborn mice on developing cerebellum. Neurotoxic01 Teratol 1997; 19:205-211, 138. Hanxnond EJ, Wilder BJ. Immunofluorescent evidence for a specific binding site for phenytoin in the cerebellum. Epilepsia 1983; 24:269-274. E. The influenceof the cerebellumon ex139. Dow RS, Fernandez-Guardiola A, Manni perimental epilepsy. Electroencephalogr Clin Neurophysiol 1962; 14:382-398. 140. Grabow JD, Ebersold MJ, Albers JW, Schima EM. Cerebellar stimulation for the control of seizures [subject review]. Mayo Clin Proc 1974; 49:759-774. 141. Laxer KD, Robertson LT, Julien RM, Dow RS. Antiepileptic drugs. Phenytoin: relationshipbetweencerebellarfunctionandepilepticdischarges.In:GlaserGH, Penry JK, Woodbury DM, eds. Antiepileptic Drugs: Mechanisms of Actions. New York: Raven Press, 1980:415-427. 142. Halpern LM, Julien RM. Augmentation of cerebellar Purkinje cell discharge rate after diphenylhydantoin. Epilepsia 1972; 13:377-385. 143. Mameli 0, Tolu E, PireddaS, Monaco F, Mutani R. Cerebellar impairment following acute nontoxic administration of phenytoin in rat. Epilepsia 1982; 23:683-691. 144. Latham A, Paul DH. Combined study of the pattern of spontaneous activityof cerebellarPurkinjecellsandphenytoinserumlevelsintherat.Epilepsia1980; 21:597-610. 145. Yan G-M, Irwin RP, Lin S-2, Weller M, Wood KA, Paul SM. Diphenylhydantoin induces apoptotic cell death of cultured cerebellar granule neurons. J Pbarmacol Exp Ther 1995; 274:983-990. 146. Rajjoub RK, Wood JH, Van Buren JM. Significance of Purkinje cell density in seizure suppression by chronic cerebellar stimulation. Neurology 1976; 26:645-650.

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Alcoholic

603

147. Bernadi S, Trimble MR, Frackowiak RSJ, Wise RJS, Jones T. An interictal study of partial epilepsy using positron emission tomography and the oxygen-15 inhalation technique. J Neurol Neurosurg Psychiatry 1983; 46:473-477. 148. Kamo H, Purves SJ, McGeer PL, Pate BD, Martin WRW, Li DKB, Wada JA. MRI andPETstudies on epileptic patients treated with phenytoin. Neurology 1986; 36(suppl 1):86. 149. Botez MI, Joyal C, MaagU, Bachevalier J. Cerebrospinal fluid and blood thiamine concentrations in phenytoin-treated epileptics. Can J Neurol Sci 1982; 9:37-39. 150. Shapiro WR,Young DF.Neurological complications of antineoplastic therapy. Acta Neurol Scand 1984; 70(suppl 100):125-132. 151. Tuxen MK, Hansen SW. Complications of treatment. Neurotoxicity secondary to antineoplastic drugs. Cancer Treat Rev 1994; 20:191-214. 152. Winkelman MD, Hines JD. Cerebellar degeneration caused by high-dose cytosine arabinoside: a clinicopathological study.Ann Neurol 1983; 14:520-527. U, Fishman DJ. 153. LazarusHM,HerzigRH,HerzigGP,PhillipsGL,Roessmann Central nervous system toxicity of high-dose systemic cytosine arabinoside. Cancer 1981;48:2577-2582. 154. Salinsky MC, Levine RL, Aubuchon JP, Schutta HS. Acute cerebellar dysfunction with high-dose &a-C therapy. Cancer 1983; 51:426-429. 155. RiehlJL,BrownWJ.Acutecerebellarsyndromesecondaryto5-fluorouracil therapy. Neurology 1964; 14:961-967. 156. Karp BI, Yang JC, Khorsand M, Wood R, Merigan TC. Multiple cerebral lesions complicating therapy with interleukin-2. Neurology 1996; 47:417-424. 157. Schou M. Long-lasting neurological sequelae after lithium intoxication. Acta Psychiatr Scand 1984; 70:594-602. 158. Kores B, Lader MH. Irreversible lithium neurotoxicity:an overview. Clin Neuropharmacol 1997; 20:283-299. 159. Nagaraja D, Taly AB, Sahu RN, Channabasavanna S, Narayanan H. Permanent neurologic sequelae due to lithium toxicity. Clin Neurol Neurosurg 1987; 89:31-34. 160. Apte SN, Langston JW. Permanent neurological deficits due to lithium toxicity. Ann Neurol 1983; 13:453-455. 161. Schneider JA, Mirra SS. Neuropathologic correlates of persisting neurologic deficits in lithium intoxication. Ann Neurol 1994; 36:928-931. 162. D’Mello SR, Anelli R, Calissano P. Lithium induces apoptosis in immature cerebellar granule cells but promotes survival ofmature cells. Exp Cell Res 1994; 211:332-338. 163. Mangano WE, Montine TJ, Hulette CM. Pathologic assessment of cerebellar atrophy following acute lithium intoxication. Clin Neuropath01 1997; 16:30-33. 164. Donaldson IM, Cuningham J. Persisting neurologic sequelaeof lithium carbonate therapy. Arch Neurol 1983; 40:747-751. 165. Parson AC. Piperazine neurotoxicity: “worm wobble.” Br Med J 1971; 4:792. 166. Conners GP. Piperazine neurotoxicity: worm wobble revisited. J Emerg Treat 1995; 131341-343. 167. Alvarez FG, GuntupalliKK. Isoniazid overdose: four case reports and review of the literature. Intensive CareMed 1995; 21 :641-644.

604

Diener

and

Timmann-6raun

168. Johnson LM, Hubble JP, Koller WC. Effect of medications and toxins on cerebellar function. In: Lechtenberg L, ed.HandbookofCerebellarDiseases.New York Marcel Dekker. 1993:537-546. 169. Hotson JR, Langston SW. Disulfiram-induced encephalopathy. Arch Neurol 1976; 33:141-142. 170. Hilleman D, Miller MA, Parker R, Doering P, Pieper JA. Optimal management of amiodarone therapy: efficacy and side effects. Phm,acotherapy 1998; 18:138S145s. 171. Valsamis MP, Mancall E. Toxic cerebellar degeneration. Hum Pathol 1973;4513520. 172. Clarkson TW. The toxicology of mercury. Crit Rev Clin Lab Sci 1997; 34:369-403. 173. Bakir F, Damluji SF, Amin-Zaki L, Murtadha M, Khalidi A, Al-Rawi NY, Tikriti S, Dhahir HI, Clarkson TW, Smith JC, Doherty RA. Methylmercury poisoning in Iraq. Science 1973; 181:230-241. 174. Ninomiya T, Ohmori W, Hashimoto K, Tsuruta K, Ekino S. Expansion of methylmercury poisoning outside of Minimata: an epidemiological on study chronic methylmercury poisoning outside of Minimata. Environ Res 1995; 70:47-50. 175. Hunter D, Russel DS. Focal cerebral and cerebellar atrophy in a human subject due to organic mercury compounds. J Neurol Neurosurg Psychiatry 1954; 17:235-241. 176. Clarkson W ,Magos L, Cox C, Greenwood MR, Amin-Zaki L, Majeed MA, AIDamluji SF. Tests of efficacy of antidotes for removal of methylmercury in human poisoning during the Iraq outbreak. J Pharmacol Exp Ther 198 1; 218:74-83. 17'7. Chang LW, Guo CL. Neurotoxicology of metals. In: Sipes IC, McQueen CA, Gandolfi AJ, eds. Comprehensive Toxicology. Oxford: Pergamon. 1997:495-506. 178. Mani J, Chaudhary N, Kanjalkar M, Shah PU. Cerebellar ataxia due to lead encephalopathy in an adult. J Neurol Neurosurg Psychiatry 1998; 65:797-806. 179. Bmyn GW, Wolff de FA. Plumbism. In:Wolff FA, ed. Handbook of Clinical Neurology, v01 20: Intoxications of the Nervous System, Part I. Amsterdam: Elsevier Science, 1994:431442. 180. Saddique A, Peterson CD. Thallium poisoning: a review. VetHumToxicol 1983; 25:16-22. 181. Van Kesteren RG. Thallium. In: Wolff FA, ed. Handbook of Clinical Neurology, v01 20: Intoxications oftheNervousSystem,Part I. Amsterdam:ElsevierScience, 1994~323-329. 182. Galvan-Arzate S, Santarnaria A. Thallium toxicity. Toxicol Lett 1998; 99:1-13. 183. Reed D, Crawley J, Faro SN, Pieper SJ, Kurland LT. Thallotoxicosis.J M A 1963; 183:516-522. 184.Bank WJ, PleasureDE,Suzuki R, NigroM,Katz R. Thalliumpoisoning.Arch Neurol 1972; 26:456-464. 185. Gilman S, Bloedel JR, Lechtenberg R. Disorders of the Cerebellum. Philadelphia: FA Davis, 1981. 186. Hasan M, AshrafI, Ajpai VK. Electron microscopic study of the effects of thallium poisoning on the rat cerebellum. Forensic Sci 1978; 11:139-146. 187. Munch JC, Ginsberg HM, Nixon CE. The 1932 thallotoxicosis outbreak in California. JAMA 1933: 10:1315-1319.

rebellar

Alcoholic

605

188. Jungreis AC, Schaumburg HH. Encephalopathy from abuse of bismuth subsalicylate (Pepto-Bismol). Neurology 1993; 43: 1265. 189. Gordon MF, Abrams RI, Rubin DB, Barr WB, Correa DD. Bismuth subsalicylate toxicityasacause ofprolongedencephalopathywithmyoclonus.MovDisord 1995;10:220-2. 190. Feldman RG, Manganese. In: Wolff FA, ed. Handbook of Clinical Neurology, v01 20: Intoxications oftheNervousSystem,Part I. Amsterdam:ElsevierScience, 1994~303-322. 191. Huang C-C, Chu N-S,Lu C-S, Wang J-C, Tsai J-L, Tzeng J-L, Wolters EC, Calne DB. Chronic manganese intoxication. Arch Neurol 1989; 46: 1104-1 106. 192. Flanagan RJ, Ruprah M, Meredith TJ, Ramsey JD. An introduction to the clinical toxicology of volatile substances. Drug Safety 1990; 5:359-383. 193. Cassitto MG. Organic solvents and the nervous system. In: Wolff FA, ed. Handbook of Clinical Neurology,v01 20: Intoxicationsof the Nervous System, Part I. Amsterdam: Elsevier Science. 1994:39-61. 194. Boor JW, Hurtig HI. Persistent cerebellar ataxia after exposure to toluene. Ann Neurol 1977; 2:440“442. 195. Grabski DA. Toluene sniffing producing cerebellar degeneration. Am J Psychiatry 1961; 118:461-462. 196. Fornazzari L,Wilkinson DA, Kapur BM, Carlen PL. Cerebellar, cortical and functional impairment in toluene abusers. Acta Neurol Scand 1983; 67:319-329. 197. Hormes JT, Filley CM, Rosenberg NL. Neurologic sequelae of chronic solvent vapor abuse. Neurology 1986; 36:698”702. 198. Kulig BM. Acrylamide. In: Wolff FA, ed. Handbook of Clinical Neurology, v01 20: Intoxications of theNervousSystem,Part I. Amsterdam:ElsevierScience, 1994:63-80. 199. Mettler FA, Sax DS. Cerebellar cortical degeneration due to acute azide poisoning. Brain 1972; 95:505-516. 200. Greenberg JO. Neuroimaging. A Companion to Adams and Victor’s Principles of Neurology. New York: McGraw-Hill, 1995.

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Paraneoplastic Cerebellar Degeneration Josep 0. Dalmau and Jerome B. Posner Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, New York

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CLINICAL FEATURES A. PCD Associated with Anti-Yo Antibodies B. PCD and SCLC (with and Without Anti-Hu Antibodies) C.PCD andAnti-RiAntibodies D.PCDandAnti-TrAntibodies E. PCD Associated with Other Paraneoplastic Markers F. PCD with No Identified Paraneoplastic Markers

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In patients with cancer, cerebellar symptoms areusually caused by metastasis to the cerebellum, the brain stem, or the posterior fossa leptomeninges (1). Other cancer-related complications thatmay result in cerebellar symptoms are shown in Table 1. Cerebellar dysfunction is considered paraneoplastic when none of the 1 can be identified,or when well-characterized other mechanisms shown in Table immunological responses against Purkinje cells of the cerebellumand the tumor are detected in the serum or spinal fluid of the patient, The cortical cerebellar syndromes associated with cancer (paraneoplastic cerebellar degeneration; PCD) were first described, but not recognized as such, by Brouwer in 1919 (2). Finally, in 1938 Brouwer et al. (3) postulated that a “toxicosis” generated by the presence of a tumor was the cause of the cerebellar degeneration. Several other theories about the etiology of these “remote effects of cancer on the nervous system” (4) have been postulated. Greenfield reported in in 1934 (5) two patientswith “subacute spinocerebellar degeneration occurring the elderly”; one of the patients had bronchial carcinoma. In both patients, pain in the limbs was a prominent early symptom; this was succeeded by weakness, ataxia, dysarthria, and mental dysfunction. The spinal fluid revealed significant pleocytosis. At autopsy, both patients had degeneration of the long tracts of the spinal cord, especially the dorsal columns and cerebellar tracts, loss of Purkinje cells, and conspicuous infiltratesof lymphocytes (and some plasma cells) involving multiple levelsof the neuraxis, including dorsalnerve roots, spinal cord, leptomeninges, brain stem, white matter and dentate nucleusof the cerebellum, subthalamic nuclei, pallidum, and hippocampus. Greenfield did not recognize the association with cancer, but suggested that the cerebellar degeneration resulted from a degenerative process, and the inflammatory infiltrates were secondary to Table 1 Cause of Cerebellar Symptoms in Patients with Cancer

Metastatic mechanisms Cerebellum Brain stem Leptomeningeal metastases Spinal cord compression Nonmetastatic mechanisms Cerebellar infarct or hemorrhage (cancer-related coagulopathy) Metabolic and nutritional deficits Infections Side effects of therapy (i.e., chemotherapy with 5-FU and Ara-C) Paraneoplastic syndromes

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this process. The severity of the inflammatory infiltrates led Russell (6) to postulate that they were a manifestation of an immunological reaction against the nervous system. The cerebellum and cerebellar tracts are involved in several paraneoplastic syndromes of the central nervous system. Someof the early reports of spinocerebellar degeneration (such as the two patients reported by Greenfield) probably correspond to the syndrome currently known as paraneoplastic encephalomyeliby Henson tishensory neuronopathy (PEWSN). This syndrome, reported in 1965 and colleagues (7)) affects multiple areas of the central nervous system, dorsal root ganglia, and autonomic nerves. In 20% of the patients with PEMISN the presenting symptoms are a cerebellar dysfunction, sometimes difficult to distinguish from other syndromes that remain confined to the cerebellum (8). In 1976, Trotter et al. (9) identified, in the serum of a 21-year-old woman S lymphoma, antibodies that with subacute cerebellar degeneration and Hodgkin’ reacted with cerebellar Purkinje cells. This study and the discoveryof other antineuronal antibodies in the seraof patients with paraneoplastic sensory neurop[a syndrome reported in 1948 athy and dorsal root ganglia degeneration (10) (1 l)] supported the concept that PCD could be an immune-mediated disorder. Since then, other paraneoplastic antibodies have been discovered and the target antigens cloned and sequenced. ~

11.

EPIDEMIOLOGY

Almost every type of tumor has been reported in association with PCD.The tumors most frequently involved are cancer of the lung, ovary, breast, and lymphoma. In about 60% of the patients, the neurological symptoms precede the detection of the tumor. In infants, the development of opsoclonus and myoclonus, sometimes associated with hypotonia and cerebellar ataxia,may precede the detection of a neuroblastoma (1). It isunknown why certain tumors are more frequently associated with PCD than others.The frequent association with lung cancer is partly related to the high prevalence of this tumor. However, although small-cell lung cancer (SCLC) represents only 20% of all the histological types of lung cancer, this tumor is associated with PCD more frequently than the other types of lung cancer combined (12,13), perhaps because of the neuroendocrine properties of SCLC and the frequent expressionof neuronal proteinsby the neoplastic cells. Similarly, although breast cancer is much more common than ovarian cancer, the latter tumor associates more frequently with PCD than does breast cancer (14). There are two distinct pathological findings in most tumorsof patients with PCD: (a) the tumors usually express Purkinje cell proteins (15,16); and (b) they

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Figure 1 Inflammatory infiltrates in the tumor of a patient with anti-Yo-associated cerebellar degeneration: Note the neoplastic cells (adenocarcinoma of the ovary) surrounded by extensive infiltrates of lymphocytes and plasma cells.

frequently show extensive infiltrates of lymphocytes and plasma cells (Fig. 1) ( 1 7 3 ) . In addition, SCLCs associated with PCD and anti-Hu antibodies show expression of major histocompatibility proteins (MHC class I and 11) more frequently than similar tumors not associated with paraneoplastic symptoms (19). That some tumors associate withPCD more frequently than others should be taken into consideration when a patient with a tumor that infrequently associates with PCD (i.e., prostate cancer), develops symptomsof PCD. In this situation the search for another neoplasm (i.e., SCLC) is reasonable. The detection of antineuronal antibodies may provide additional help in uncovering a second malignancy.

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A. Antibodies and Target Antigens Some patients withPCD harbor antibodies in serum andCSF that react with antigens expressedby the nervous system and the tumor (Table 2). The detection of

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Table 2 Paraneoplastic Antibodies and Antigens in PCD

Antibody Anti-Tr Anti-Yo

Cytoplasm of neurons (mainly Purkinje cells) and molecular layer of cerebellum 34, 52, and 62 kDa (cytoplasm of Purkinje cells and large neurons of brain stem) 35-40 kDa (nuclei of neurons of the central’ and peripheral nervous system) 55 and 80 kDa (nuclei of neurons of the central nervous system) 37 and 40 kDa (nuclei and cytoplasm of neurons of the central and peripheral nervous system) 40 kDa (nuclei and cytoplasm of neurons of the central nervous system) 66 kDa (cytoplasm of oligodendrocytes) ii

1

Anti-Hu Anti-Ri Anti-Ma Anti-Ta Anti-CV2

Unknown cdr24, cdr62-l, cdr62-l HuD, HuC/ple21, Hel-Nl Nova- 1, Nova-2 Mal-5 Ma2 c-22 (Unc-33 j

a paraneoplastic these antibodies indicates that the cerebellar dysfunction has origin and directs the search for the tumor to one or a few organs. Several antineuronal antibodies have been identified, some more specific for Purkinje cells than others. The target antigens of most of these antibodies have been cloned and sequenced:

1, Anti-Tr In 1976, Trotter et al. (9) discovered that the serum of a patient with PCD and Hodgkin’s lymphoma contained antibodies that reacted with the cytoplasm of Purkinje cells. Subsequently, the distribution and location of the target antigen has been well characterized (Fig. 2), but the identity of the antigen is unknown (20,21). The antibodies contained in the serum and spinalfluid of these patients are called anti-Tr, and react in a dot-like pattern with the cytoplasm of Purkinje cells and the molecular layerof the Cerebellum. Neurons from other areasof the nervoussystem,includingneocortex,entorrhinalcortex,hippocampus,basal ganglia, and brain stem are also immunoreactive, but the expression of the Tr antigens is not as intenseas in the Purkinje cells. Using confocal and immunoelectron microscopy, theTr antigen was found expressed in the cytosol and outer surface of the endoplasmic reticulum of the perikarya of neurons of the molecular of Purkinje cells. The distribution of this layer and the cell body and in dendrites reactivity is characteristicof molecules involved in the modulationof intracellular ea2+ stores, but none of these currently known molecules matches perfectly the neuronal distribution of Tr reactivity (22).

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Figure 2 Reactivity of anti-Tr antibody with cerebellum: (a) Rat cerebellum incubated with serum from a patient with Hodgkin’s lymphoma and anti-Tr-associated paraneoplastic cerebellar degeneration. Note the selective reactivity with the Purkinje cells and molecular layer.

2. Anti-Yo In 1983, and in 1985, antineuronal antibodies were identified in the serum and spinal fluid of patients with ovarian cancer and PCD (24,25). These antibodies (called anti-Yo) react with the cytoplasm of Purkinje cells and identify two proteins of 34 and 62 kDa in Western blot analysis of proteins extracted from Purkinje cells (25). Subsequently, an intermediate band of about 52 kDa has also been discovered. The exact function of these proteins remains unknown, but in normal tissues, their expression is highly restricted to Purkinje cells, neurons of the molecular layer, and large neurons of the brain stem. The genes encoding the 34- and 62-kDa antigens (cdr-34 and cdr-62) have been cloned and sequenced (26-29). The cdr-62 protein contains a zinc-finger domain and a leucine-zipper motif that is typical of proteins that bind to DNA as hetero- or homodimers (29). The cdr-34 antigen is unusual in that it consists al-

Paraneoplastic Cerebellar Degeneration

Figure 2 Continued (b) the characteristic dot-like immunolabeling involving the cytoplasm of the Purkinje cells and the molecular layer of the cerebellum.

mostentirely of tandemhexapeptiderepeats of theamino acid sequence LFLEDVE that gives rise to a number of single Leu-Leu zipper elements. The anti-Yo antibodies recognize an epitope within the leucine-zipper domainof the cdr-62 protein (30). Recent studies have demonstrated two cdr-62 proteins: cdr-62-1 and cdr62-2. Analysisof tumors from patients withanti-Yo-associated PCD showed that these tumors express Yo antigens (13, specifically cdr34 and cdr62- 1, but not cdr62-2 (31). The cdr62-1 antigen binds toC-myc, and it is postulated that it exerts its activity by inhibiting the activity of the C-myc gene (32). No other functional analysis of the cdr proteins is available, but their structure suggests a role in the regulation of gene expression, perhaps by acting as transcription factors.

3. Anti-Hu In 1965, an antineuronal antibody was reported (10) in the sera of patients with SCLC and paraneoplastic sensory neuronopathy. Several years later, the antibody

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and the targetantigens-a set of proteins of 3 5 4 0 kDa expressed mainly by the nuclei of neurons of theperipheralandcentralnervoussystem,including Purkinje cells-were characterized (16). Subsequently, the anti-Hu antibodywas found to be a marker of PEM/SN, which in about 20% of the patients presents with a subacute cerebellar dysfunction (8). Four human genes encodingHu antigens recognizedby anti-Hu antibodies have been cloned: HuD, HuC/ple21, HelN-l, and HelN-2. A fifth component (HuR) of the same human gene family has recently been cloned (33), but is not Drorecognized by most anti-Hu sera.The Hu proteins are homologous with the sophila proteins Elav (34), Rbp9 ( 3 3 , and Sex-lethal (36). These proteins contain three copies of the RNA recognition motif (RRM) that forms the core of functionalRNA-bindingdomains(37).ProteinscontainingtheRRMare involved in many aspects of RNA processing, including splicing, transport, and translation (38,39). In the Hu antigens, the first two RRMs are tandemly located and connected to the third RRM by a highly basic region (40). In Drosophila, Elav is essential for the development and maintenance of the nervous system (41). Mutationsof the elav gene result in a lethal phenotype characterized by the abnormal proliferationof immature neuroblasts, a failure of neuronal differentiation, and inappropriate neuroblast migration (42). Transcription of elav starts early infly embryogenesis and is restricted to cells destined to become neurons (41,43). Similarly, theHu proteins are expressed earlyin neurogenesis and may first be detected in neurogenic precursor cells that have exited the ventricular zone of the spinal cord (44,45). In chicken embryos the Hu proteins are expressed by cells in the sensory and sympathetic ganglia and in the of early neuronal development and neural tube, supportinga role in the regulation differentiation (45). The Hu proteins bind to AU-rich elements in the 3’-untranslated regionsof several growth-related mRNAs including c-nzyc, c-fos, and GM-CSF (46), and p21 (wafl) (47). This sequence is involved in regulating mRNA stability, localization, and translation. The homology to Elav, the very early expression during mammalian neua role of the Hu ronal development, and the RNA-binding properties, support proteins in neural growth and differentiation. In the neuronal nucleus, based on homology with theDrosophila gene sex-lethal, the Hu antigens could function to regulate alternative splicing of neuronal pre-RNAs (48). In the cytoplasm, they may modulate RNA processing by binding to mRNA 3’ UTRs (46,49,50). Epitope mapping reveals two immunodominant regions, contained within (5 1).It isnot known if the bindingof antibody the first two RNA-binding regions affects the RNA-binding function of the protein.

4. Anti-Ri The target antigens of anti-Ri antibodies are two sets of neuronal proteins of 55 and 80 kDa (52,53). By immunohistochemistry, the antigens are expressed by all

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neurons of the central nervous system, butnot by neurons of the dorsal root ganglia or myenteric plexus (54). Patients with anti-Ri antibodies usually develop ataxia and abnormal eye movements such as opsoclonus (52). A gene coding a 55-kDa protein, named Nova-l, was cloned using the serum of a patient with anti-Ri antibodies (55).The Nova-l antigen is a nuclear protein that is highly conservedbetweenhumansandrodents. The predictedproteinsequencehas three putative RNA-binding motifs that are homologous with the KH motifs found in hnRNP-K protein (56). RNA-binding proteins that contain KH domains have been found to be involved with regulation of alternative-splicing events and possibly RNA targeting (57,58). Nova-l appears to bind two neuronal pre-mRNAs, one encoding the inhibitory glycine receptora2and the second encoding Nova-l itself (SS).Expression of Nova-l is restricted to structures in the (56). Anti-Ri antibodventral diencephalon, midbrain, cerebellum, and hindbrain ies from patients with paraneoplastic ataxia and opsoclonus recognize the third (55).A secondprotein,called KHdomainandblockNova-lRNAbinding Nova-2, has been cloned using sera from patients with anti-Ri antibodies. Nova-2 is closely related to Nova-l, and has a pattern of expression that is reciprocal with Nova-l, including high levels of Nova-2 expression in the neocortex and hippocampus (59).

5. Anti-MaandAnti-TaAntibodies Anti-Ma antibodies have been identified in the serum and spinal fluid of some patientswithparaneoplasticcerebellar and brainstemdysfunctionassociated with several types of tumors (lung, breast, parotid gland, and colon). These anof testibodies react with proteins expressed in neurons and spermatogenic cells tis. There are at least five Ma proteins;Mal and Ma2 are the best characterized. In immunoblotsof neuronal proteins, the anti-Ma antibodies recognize two bands of 37 and 40 kDa that correspond to Mal and Ma2 (60). The anti-Ta antibodies are present in the serum and spinal fluid of patients with paraneoplastic limbic and brain stem encephalitis associated with testicular cancer, About 30% of these patients develop cerebellar symptoms, which are usually mild and always associatedwithbrainstemdysfunction(61).Theseantibodiesrecognizemainly epitopes contained in Ma2 (40-kDa neuronal protein). The Ma proteins are expressed by the tumorsof patients with paraneoplastic syndromes, but by notsimilar tumors from patients without paraneoplastic syndromes.

6. Other Antibodies and Antigens That May Be Related to PCD P/Q-type voltage-gated calcium channels are the target of antibodies associated with theLambert-Eaton myasthenic syndrome (LEMS).The antibodies cause the clinical, neurophysiological and pathological abnormalities of LEMS. Several authors have founda higher-than-expected association betweenPCD and LEMS

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(62). Mason et al. (63) found that at least 16% of SCLC patients with PEM/SN anti-P/Q-type, VGCC antibodypresenting as PCD also have LEMS and are positive. These findings and that Purkinje cells are rich in P/Q-type VGCC suggest that in some patients an immune response directed against these calcium channels may cause cerebellar dysfunction.

7 . Anti-CV2 Some patients with multifocal encephalitis and associated symptoms of PCD, develop an immune response (anti-CV:! antibodies) against a protein called c-22 (64), which is homologous with the unc-33 gene of Caenor~ab~itis eEegans (65). Mutations of unc-33 leads to defects in neuritic outgrowth and axonal guidance resulting in uncoordinated movements of the nematode (66).

Despite the identificationof several antibodies against proteins expressedby the tumor and nervous system, these antibodies have not been shown to cause PCD. The anti-Yo antibodies react with antigens expressed mainly in Purkinje cells and large neuronsof the brain stem, which are the neurons that undergo degeneration in PCD. This, and the finding of anti-Yo antibodies in only 1% of patients with ovarian cancer without PCD, suggest that the immune response against the Yo antigens is probably pathogenic, but that other mechanisms (i.e., cytotoxic T cells) are also involved. A recent study suggests that a cytotoxic T-cell response against cdr-:! causes the more indolent behavior of the tumor of these patients (67). Whether this immune responsealso affects the Purkinje cells remains to be proved.Furthermore,theearlypresence of cerebrospinal fluid pleocytosisin most patients with theanti-Yo syndrome also suggests that cell-mediated mechanisms play a pathogenic role (14). The anti-Hu antibodies react with all types of neurons; therefore, the target antigens are less restricted to the cerebellum than are the Yo antigens. The role of cytotoxic T cells in the pathogenesis of anti-Hu-associated PEM/SN has been examined in several studies (68-70). Strong, but still circumstantial, by the folevidence for a cytotoxic T-cell mediated mechanism is provided lowing: 1. Autopsies of patients with anti-Hu-associated PEM/SN show intense inflammatory infiltrates of mononuclear cells, including CD4 and CD8, which predominate in the areas of the nervous system that are symptomatic. The infiltrates of T cells almost always affect the brain stem, and in patients with cerebellar symptoms, they usually involve the deep cerebellar nuclei (7,8,12,63,71). Only in rare instances do the inflammatory infiltrates involve the cerebellar cortex (63). One of our patients had clusters of T cells specifically located in the Purkinje cell layer, associated with extensive loss of Purkinje cells (8).

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The mechanism whereby CD4 or CD8 cytotoxic T cells recognize antigens expressed in neurons (which in normal circumstances lack expression of the antigen-presenting molecules MHC class I and 11) is unknown. It is possible that these inflammatory infiltrates are not the primary cause of the neuronal damage, but are a consequence of a primary unknown mechanism (i.e., cytokines, antibodies) that causes neuronal dysfunction. Because neuronal damage can result in expression of MHC molecules (72), theT-cell infiltrates would be a “second hit,” resulting in neuronal loss. 2. A study of the T-cell receptor usage in the inflammatory infiltrates of the nervous system of patients with anti-Hu-associated PEWSN showed a limited V p T-cell receptor repertoire.An overrepresentation (> 10% of total CD3+) of certain Vp families was identified in three patients (up to of45% total CD3 +), which consisted mainly of CD8+ cells. Furthermore, the CDR3 sequences obtained from one patient revealed an in situ expansion of a restricted number of clones in the brain and tumor. the This study indicates that the infiltrates of T cells in the brain and tumorof patients with anti-Hu-associated PEM/SN are specifically directed to neuronal and tumor antigens (68). 3. Extensive infiltrates of T cells have also been demonstrated in thenervous system of patients with anti-Ri (73), anti-Ma(8,60), and anti-Ta antibodies

(61).

IV. NEUROPATHOLOGY The pathological hallmark of PCD is diffuse loss of Purkinje cells, usually accompanied by thinning of the molecular and granular layers, and degeneration of the dentate, olivary nuclei, and long tracts of the spinal cord (Fig. 3) (74). As pointed out by Henson and Urich in 1982 (12), the cortical cerebellar degeneration associated with cancer(now called PCD) can be pathologically divided into those with absent or mild inflammation and those with prominent inflammation. To explain these findings, these authors outlined three possibilities: (a) the two groups are morphologically and pathogenetically separate entities; (b) the second group represents the coexistence of two seemingly independent processes, one degenerative, the other inflammatory; and (c) both groups are variants of a single entity with active inflammationin some cases, burned out in others. Henson and Urich considered that the evidence was insufficient to support any three of their views; therefore, they preferred “to keep an open mind and adhere to strictly morphologicalclassification.”However,theoccurrenceinsomepatients of Purkinje cell degeneration independently of encephalomyelitis, or the reverse situation, led Vick et al. (75) to suggest that encephalomyelitis and degeneration of Purkinje cells develop by different and independent mechanisms. These observations and comments remain valid today. Furthermore, our current knowledge of the different subsets of PCD suggests that most patients

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Figure 3 Cerebellum from a patient with anti-Hu-associated cerebellar degeneration: There is absence of Purkinje cells and Bergmann gliosis. In addition, the patient had inflammatory infiltrates involving the dentate nucleus and cortex of the cerebellum (not shown).

with prominent inflammatory infiltrates suffered from PEM with cerebellar involvement. In fact, a review of the literature shows that many patients reported as having “cerebellar symptoms associated with cancer” also had sensory neuronopathy, brain stem dysfunction, limbic dysfunction, or autonomic dysfunction, and the tumor is frequently SCLC (5,74,76). In contrast, the pathological cases without inflammation probably correspond to the other subgroups of PCP) in which the disease usually remains restricted to the cerebellum.Yet, the absence of inflammatory infiltrates in the autopsy of these patients doesnot rule out that the disorder is immune-mediated by a cytotoxic T-cell response. As suggested by Henson and Urich, the absence of inflammation at autopsy may represent the “burned out” stage of an inflammatory process.The observation that most patients with PCD have spinal fluid pleocytosis during the initial stages of the disease supports this concept (75,77).

V.

CLINICALFEATURES

The presenting symptoms of PCD are dizziness, nausea, blurry or double vision, (1,63).In some patients sometimes associated with oscillopsia, and gait instability

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these symptoms are precededby a flu-like illness. Subsequently, these symptoms are followedby a variable degreeof ataxia involving upper and lower extremities. In addition, patients develop dysarthria and mild to severe dysphagia. In general, the presenting symptoms are similar for most types of PCD (Table 3), regardlessof the type of cancer or antibody association, but the course of the disease may be different depending,o*n* this immunological response. For Sec. the all typesof PCD, except the associated with anti-Tr antibodies (see VD), neurological syndrome usually develops before the tumor is identified.

A.

PCD Associated with Anti-Yo Antibodies

Patients with anti-Yo antibodies are almost always postmenopausal women with (5%) ovarian cancer (65% of the patients), breast cancer (30%), or other cancers (14,78). A few patients with lung cancer, and two male patients, have been reported (79,80). The development of symptoms is subacute (days or weeks) with stabilization in about 2 or 3 months; by that time most patients have severe difficulties walking, feeding themselves, writing, reading, or watchingTV. The examination usually demonstrates nystagmus, frequently downbeating. Some patientsdevelopsignsandsymptoms of brainstemdysfunction, mild distal symmetrical neuropathy, and extensor plantar responses. These extracerebellar symptoms are usually mild and do not become a major disabling problem.

B. PCD and SCLC (with and Without Anti-Hu Antibodies) Patients with SCLC and PCD develop LEMS more frequently than expected (62). About 2-3% of patients with SCLC develop LEMS, but in patients with PCD the frequency of LEMS is 16% (63,81). Because the development of both disorders is highly disabling and because LEMS usually responds to treatment (82), all those patients with SCLC who develop PCD should be examined for LEMS. The detection of anti-Hu antibodies ina patient with PCD indicates that the underlying tumor is SCLC (although rare exceptions have been reported), and that the disorder is PEM that initially presents with cerebellar symptoms. Most of these patients have involvementof other areas of the nervous system (mainly sensory neuronopathy and severe brain stem dysfunction), or they will eventually develop these symptoms. However, if anti-Hu antibodies are absent, symptoms usually remain restricted to the cerebellum and, if other symptoms develop,they are usually mild (63)

C.PCDandAnti-RiAntibodies A distinctive clinical finding in patients with anti-Ri antibodies is the frequent presence of opsoclonus, ocular flutter, and ocular dysmetria (53); the latter two usually develop when opsoclonus subsides. Opsoclonus is present in 75% of the

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patients (83). Patients without opsoclonus may have other oculomotor abnormalities, including nystagmus, abnormal visual tracking, blepharospasm, and abnormal vestibulo-ocular reflexes. Ataxia predominates in the trunkmay andcause severe gait difficulty and frequent falls.The number of anti-Ri patients reported in the literature is too small to clearly delineate other differences between this syndrome and other types of PCD. One patient developed axial rigidity with spasms (84), and two of our patients had multifocal involvement of the central The tumors more nervous system, oneof them with intestinal pseudo-obstruction. frequently associated with anti-Ri antibodies are cancer of the breast or lung, and gynecological cancers. One of our patients had a bladder cancer that expressed antigens recognized by anti-Ri antibodies. A postmortem study reported perivascular and interstitial inflammatory infiltrates involving the tegmentum of the pons and mesencephalon, and extensive degenerationof the Purkinje cells of the cerebellum (73).

D.PCDandAnti-TrAntibodies These patients are usually younger than the patients with other types of PCD. usually afThis reflects the fact that the associated tumor, Hodgkin’s lymphoma, fects young individuals. Different also from other types of PCD, this disorder predominates in men. One of our patients with anti-Tr antibodies had non-Hodgkin’ S lymphoma.

E. PCD Associated with Other Paraneoplastic Markers The number of patients reported with PCD and anti-Ma or anti-CV2 antibodies is too small to identify distinctive clinical symptoms. However, three patients reported with anti-Ma antibodies have severe brain stem and cerebellar dysfuncof inflammation, and the pathological studies demonstrated extensive infiltrates tory cells and neuronal loss in the brain stem, and severe loss of Purkinje cells of the cerebellum (60). Patients with anti-CV2 antibodies usually develop a clinical picture resembling PEM with cerebellar symptoms (64).

F. PCD with No Identified Paraneoplastic Markers A numberof patients develop symptomsof PCD without distinctive paraneoplastic markers. In general, the clinical pictureof these patients is similar to that described at the beginningof this section.The tumors more frequently involved are non-Hodgkin’ S lymphoma and non-SCLC. The detection of some paraneoplastic markersmay predict a worse prognosis than others. For example, most patients with PCD and anti-Hu antibodies de-

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Dalmau

velop severe multifocal neurological symptoms and frequently dieas a result of the neurological disease (63). Patients with anti-Yo and anti-Ri antibodies usually do not die as a result of the neurological disease, but remain disabled for years, and the cause of death is usually the tumor.

VI. ANCILLARY TESTS The diagnostic approach varies, depending on whether or not the presence of a cancer is known( l ,SS). In patients with known cancer, the subacute development of cerebellar symptoms usually representsa metastatic complication, and neuroimaging studies should be obtained. Other nonmetastatic complications associated with cancer thatmay result in cerebellar symptoms are shown inTable 1. If PCD is suspected, the serum and CSF should be examined for antineuronal antibodies. The detection of a paraneoplastic antibody (seeTable 3) establishes that a paraneoplastic origin. Other spinal fluid findings, the cerebellar dysfunction has a positive IgG insuch as pleocytosis, increased proteins, oligoclonal bands, and dex, although nonspecific, are suggestiveof an immune-mediated disorder. Irrespective of the presence or absence of antineuronal antibodies, the serum of these patients should also be studied for cancer markers (CA125, CA15.3, and CEA), which may direct the search of the tumor to a few organs. In patients without known cancer, cerebellar dysfunction should be considered paraneoplastic when symptoms develop subacutely and no other causes 50, (mainly stroke) are identified. Suspicion is higher when patients are older than there is family historyof cancer (breast or ovarian cancer), when the patient is a smoker, or there are other symptoms suggesting the possibility of a neoplasm (i.e., unexpected lossof weight). The detection of paraneoplastic antibodies represents an important shortcut in making the diagnosis of PCD and guides the clinician to uncover the neoplasm. Although not pathognomonic, other spinal fluid findings (see foregoing) may also be supportive of a paraneoplastic disorder. In the initial stages of PCD, the CT and MRI of the head are usually normal, although exceptions occur (Fig. 4). Studies obtained several months after symptom development often reveal global cerebellar atrophy. If the patient has limbicdysfunctionassociatedwithPCD,theMRIcandemonstratebilateral mesial-temporal abnormalities in the T2-weighted sequences (63). The absence of antineuronal antibodies does not rule out that a cerebellar of the lung, ovary, breast, and lymdysfunction is paraneoplastic. Because cancer cerphoma are the most common neoplasms involved in PCD, all patients awith ebellar disorder of unknown cause should be examined for these tumors. If no cause is identified, physical and neuroimaging studies (chest and abdomen CT, mammogram, and pelvic examination) shouldbe obtained every 6 months for at least 3 years. After the third year of symptom development, the likelihood of

Paraneoplastic Cerebellar Degeneration

623

Figure 4 MRI of a patient with non-Hodgkin’s lymphoma and anti-Tr-associ~ted paraneoplastic cerebellar degeneration: There is enhancement of the cerebellar cortex after ad~in~stration of contrast. Spinal fluid studies revealed increased proteins, absence of neoplastic cells, and high titersof anti-Tr antibodies.

identifying a tumor related to the cerebellar dysfunction decreases signi~cantly, of patients with~ a r ~ e o p l a s tcerebellar ic sympBecause there are several reports toms and cancer of the testis and colon (61,86,87), the search for a neoplasm in these organs should also be considered. A note of caution: not all patients with cerebellar symptom who develop antibodies against the nervous system or ~erebellumhave a paraneoplastic disorder. Patients with cerebellar symptoms may have anti-CAD antibodie~(88,89).

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These antibodies are not markers of a paraneoplastic disorder; therefore, the search for a neoplasm is not needed. Patients with anti-GAD antibodies usually develop late-onset insulin-dependent diabetes mellitus, and may have several types of organ-specific antibodies. Some of these patients develop autoimmune thyroiditis and pernicious anemia. Only antibodies previously characterized as markers of paraneoplastic disorders should be considered as indicators of PCD.

VII.

MANAGEMENT

Most patients with PCD do not improve with treatment of the tumor or immunosuppressants, including steroids, plasma exchange, or intravenous gamma globulin (14,90,91). However, a number of isolated case reports describe patients who improved with some of these treatments (92-100). Although plasma exchange and intravenous immunoglobulin do not usually improve PCD, these treatments should be considered in patients who develop PCD associated with LEMS, because the latter improves with antibody removal and immune modulation (10 1,102). This differential response to treatment of PCD and LEMS has been reported by several authors (103-107). Patients with anti-Tr antibodies may also improve after treatment of the tumor, or spontaneously (21). There is no specific treatment for PCD, but efforts should be directed to a prompt identification of the disorder and treatment of the tumor. Recent studies suggest that in patients with anti-Hu antibodies, which is the type of PCD with a worse prognosis, the best chance to stabilize the disorder is with a prompt identification and treatment of the tumor (108).

REFERENCES I . Posner JB. Neurologic Complications of Cancer. Philadelphia: FA Davis. 1995. 2. Brouwer B. Beitrag zur Kenntnis der chronischen diffusen Kleinhirnerkrankungen. Neurol Zentralbl 1919; 38:674-682. 3. Brouwer B. Biemond A. Les affections parenchymateuses du cervelet et leur signification du point de vue de l’anatomie et la physiologie de cet organe. J Belg Neurol Psychiatr 1938: 38:691-757. 4. Brain WR, Noiris FH. The Remote Effects of Cancer on the Nervous System. New York: Grune & Stratton, 1965. 5. Greenfield JG. Subacute spino-cerebellar degeneration occurring in elderly patients. Brain 1934; 57: 161-178. 6. Russell DS. Encephalomyelitis and carcinomatous neuropathy. In: van Bogaert L, Radermecker J, Hozay J, Lowenthal A, eds. The Encephalitides. Amsterdam: Elsevier. 1961:131-135.

neration Cerebellar Paraneoplastic

625

7. Henson RA, HoffmanHL,UrichH.Encephalomyelitiswithcarcinoma.Brain 1965; 88:449-464. 8. Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 7 1 patients. Medicine 1992; 7 1:59-72. 9. Trotter JL, Hendin BA, Osterland K. Cerebellar degeneration with Hodgkin’s disease. An immunological study. Arch Neurol 1976; 33:660-661. 10. Wilkinson PC, ZeromskiJ. Immunofluorescent detection of antibodies against neurons in sensory carcinomatous neuropathy. Brain 1965; 88:529-538. 11. Denny-Brown D. Primary sensory neuropathy with muscular changes associated with carcinoma. J Neurol Neurosurg Psychiatry 1948; 11:73-87. 12. Henson RA, Urich H. Cortical cerebellar degeneration. In: Henson RA, Urich H, eds. Cancer and the Nervous System. Oxford: Blackwell Scientific, 1982:314-345. 1991; 13. Posner JB. Paraneoplastic cerebellar degeneration. Princ Pract Oncol5:1-13. 14. Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology 1992; 42:1931-1937. 15. Furneaux HM, Rosenblum MK, Dalmau J, Wong E, Woodruff P, Graus F, Posner JB. Selective expression of Purkinje-cell antigens in tumor tissue from patients with paraneoplastic cerebellar degeneration. N Engl J Med 1990; 322: 1844-1851. 16. Graus F,Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology 1985; 35:538-543. 17. Verschuuren J, Chuang L, Rosenblum MK, Lieberman F, Pryor A, Posner JB, Dalrnau J. Inflammatory infiltrates and complete absence of Purkinje cells in anti-Yoassociated paraneoplastic cerebellar degeneration. Acta Neuropathol 1996; 91 :5 19525. 18. Hetzel DJ, Stanhope CR, O’Neill BP, Lennon VA. Gynecologic cancer in patients with subacute cerebellar degeneration predicted by anti-Purkinje cell antibodies and limited in metastatic volume. Mayo Clin Proc 1990; 65:1558--1563. 19. Dalmau J, Graus F, Cheung NK, Rosenblum MK, Ho A, Caiiete A, Delattre JY, Thompson SJ, Posner JB. Major histocompatibility proteins, anti-Hu antibodies, and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer. Cancer 1995; 75:99-109. 20. Hammack J, Kotanides H, Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration:11. Clinical and immunologic findings in 21 patients with Hodgkin’s disease. Neurology 1992; 42:1938-1943. 21. Graus F, Dalmau J, ValldeoriolaF, Ferrer I,Refid R, Marin C, Vecht CJ, Arbizu T, Targa C, Moll JWB. Immunological characterization of a neuronal antibody (antiTr) associated with paraneoplastic cerebellar degeneration and Hodgkin’s disease, J Neuroimmunol 1997; 74:55-61. 22. Graus F, Gultekin SH, Ferrer I, Reiriz J, Alberch J, Dalmau J. Localizationof the neuronal antigen recognized by anti-Tr antibodies from patients with paraneoplastic cerebellar degeneration and Hodgkin’s disease in the rat nervous system. Acta Neuropathol 1998; 96: 1-7. 23. Greenlee JE, Brashear HR. Antibodies to cerebellar Purkinje cells in patients with

626

Dalmau and Posner

paraneoplastic cerebellar degeneration and ovarian carcinoma.Ann Neurol 1983; 14:609-613. 24. Jaeckle KA, Graus F, Houghton A, Cardon-Cardo C, Nielsen SL, Posner JB. Autoimmune response of patients with paraneoplastic cerebellar degeneration to a Purkinje cell cytoplasmic protein antigen. Ann Neurol 1985; 18:592-600. 25. Cunningham J, Graus F, Anderson N, Posner JB. Partial characterization of the Purkinje cell antigens in paraneoplastic cerebellar degeneration. Neurology 1986; 36:1163-1 168. 26. Dropcho EJ, Chen YT, Posner JB, Old LJ. Cloning ofa brain protein identified by autoantibodiesfrom a patientwithparaneoplasticcerebellardegeneration.Proc Natl Acad Sci USA 1987; 84:4552-4556. 27. Furneaux HM, Dropcho EJ, Barbut D, Chen YT, RosenblumMK,Old LJ, Posner JB. Characterizationof a cDNA encodinga 34-kDa Purkinje neuron protein recognized by sera from patients with paraneoplastic cerebellar degeneration. Proc Natl Acad Sci USA 1989; 86:2873-2877. 28. Sakai K, Mitchell DJ, Tsukamoto T, Steinman L. Isolation of a complementary DNA clone encoding an autoantigen recognized by an anti-neuronal cell antibody from a patientwithparaneoplasticcerebellardegeneration.AnnNeurol1990; 28~692-698. 29. Fathallah-Shaykh H, Wolf S, Wong E, Posner JB, Furneaux HM. Cloning of a leucine-zipper protein recognized by the seraof patients with antibody-associated paraneoplastic cerebellar degeneration. Proc Natl Acad Sci USA 1991; 88:34513454. 30. Sakai K, Ogasawara T, Hirose G, Jaeckle K A , Greenlee JE. Analysisof autoantibody binding to 52-kd paraneoplastic cerebellar degeneration-associated antigen expressed in recombinant proteins. Ann Neurol 1993; 33:373-380. 31. Corradi JP,YangCW, Darnell JC, Dalrnau J, Darnell RB. A posttranscriptional regulatorymechanismrestrictsexpressionoftheparaneoplasticcerebellardegenerationantigencdr2toimmuneprivilegedtissues.JNeurosci1997;17: 1406-1415. 32. Darnell RB. Onconeural antigens and the paraneoplastic neurologic disorders: at the intersectionof cancer, immunity, and the brain. Proc Natl Acad Sci USA 1996; 93:4529-4536. 33. Ma WJ, Cheng S, Campbell C, Wright A, Furneaux H. Cloning and characterizationofHuR a ubiquitouslyexpressedElav-likeprotein. J BiolChem1996; 2711814443151. 34. Robinow S, White K. The locus elav of Drosophila nzelanogaster is expressed in neurons at all developmental stages. Dev Biol 1988; 126294-303. 35. Kim YJ, Baker BS. TheDrosophila gene rbp9 encodes a protein that isa member of a conserved group of putative RNA binding proteins that are nervous systernspecific in both flies and humans. J Neurosci 1993; 13:1045-1056. 36. Bell LR, Maine EM, SchedlP, Cline TW. Sex-lethal, aDrosophila sex determination switch gene, exhibits sex-specific RNA splicing and sequence similarity to RNA binding proteins. Cell 1988; 55:1037-1046. 37. Query CC, Bentley RC, Keene JD. A c o m o n FtNA recognition motif identified

eneration Cerebellar Paraneoplastic

38. 39. 40. 41. 42. 43

I)

44. 45. 46. 47. 48.

49. 50. 51.

52. 53.

627

within a defined U1 RNA binding domain of the 70K U1 snRNP protein. Cell 1989; 57:89-101. Kenan DJ, Query CC, Keene JD. RNA recognition: towards identifying determinants of specificity. Trends Biochem Sci 1991; 16:214-220. Birney E, Kumar S, Krainer AR. Analysis of the RNA-recognition motif and RS and RGG domains: conservation in metazoan pre-mRNA splicing factors. Nucleic Acids Res 1993; 21:5803-5816. Szabo A, Dalmau J, Manley G, Rosenfeld M, Wong E, Henson J, Posner JB, FurneauxHM.HuD,aparaneoplasticencephalomyelitisantigen,containsRNAbinding domains and is homologous to Elav and Sex-lethal. Cell 1991; 67:325-333. Robinow S, Campos AR, YaoK M , White K. The elav gene product ofDrosophila, required in neurons, has three RNP consensus motifs. Science 1988; 242:15701572. Campos AR, Grossman D, White K. Mutant alleles at the locus elav in Drosophila melanogaster lead to nervous system defects. A developmental-genetic analysis. J Neurogenet 1985; 2:197-218. Robinow S, White K. Characterization and spatial distribution of the ELAV protein during Drosophila melanogaster development. J Neurobiol 1991; 22:443-461. Marusich MF, Weston JA. Identification of early neurogenic cells in the neural crest lineage. Dev Biol 1992; 149:295-306. Marusich MF, Furneaux HM, Henion PD, Weston JA. Hu neuronal proteins are expressed in proliferating neurogenic cells. J Neurobiol 1994; 25:143-155. Liu J, Dalmau J, Szabo A, RosenfeldM?Huber J, Furneaux H. Paraneoplastic encephalomyelitis antigens bind to the AU-rich elements of mRNA. Neurology 1995; 45:544-550. Joseph B, Orlian M, Furneaux H. p21 (wafl) mRNA contains a conserved element in its 3"untranslated region that is bound by the Elav-like mRNA-stabilizing proteins. J Biol Chem 1998; 273:20511-20516. Valcarcel J, Singh R, Zamore PD, Green MR. The protein Sex-lethal antagonizes the splicing factor U2AF to regulate alternative splicing of transformer pre-mRNA. Nature 1993; 362:171-175. Gao FB, Carson CC, Levine T, Keene JD. Selection of a subset of mRNAs from combinatorial 3' untranslated region libraries using neuronal RNA-binding protein Hel-N1.Proc Natl Acad Sci USA 1994; 19:11207-1 12l 1. King PH, Levine TD, Frerneau RT Jr, Keene JD. Mammalian homologs of Drosophila ELAV localized to a neuronal subset can bind in vitro to the 3' UTR of mRNA encoding the Id transcriptional repressor. J Neurosci 1994; 14: 1943-1952. Manley GT, Smitt PS, Dalmau J, Posner JB. Hu antigens: reactivity with Hu antibodies,tumorexpression,andmajorimmunogenicsites.AnnNeurol1995; 38:102-110. Budde-Steffen C, Anderson NE, Rosenblurn MK, Graus F, Ford D, Synek BJ, Posner JB. An antineuronal autoantibody in paraneoplastic opsoclonus. Ann Neurol 1988; 23~528-531. Luque FA, Furneaux HM, Ferziger R, Rosenblum MK, Wray SH, Schold SC Jr, Glantz MJ, Jaeckle K A , Biran H, Lesser M, Paulsen WA, River ME, Posner JB.

628

54. 55.

56. 57, 58. 59. 60.

61.

62. 63.

64.

65.

66.

Dalmau and Posner

Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 1991; 29241-251. Graus F, Rowe G, Fueyo J, Darnell RB, Dalmau J. The neuronal nuclear antigen recognized by the human anti-Ri autoantibody is expressed in central but not peripheral nervous system neurons. Neurosci Lett 1993; 150:212-214. BuckanovichRJ,Yang YY, DarnellRE.TheonconeuralantigenNova-1is a neuron-specific RNA-binding protein, the activity of which is inhibited by paraneoplastic antibodies. J Neurosci 1996; 16:l114-1 122, Buckanovich RJ, Posner JB, Darnell RB. Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system. Neuron 1993; 11:657-672. Gibson TJ, Thompson JD, Heringa J. The €U3domain occurs in a diverse set of RNA-binding proteins that include the antiterminator NusA and is probably involved in binding to nucleic acid. FEBS Lett 1993; 324:361-366. Nandabalan K, Roeder GS. Binding of a cell-type-specific RNA splicing factor to its target regulatory sequence. Mol Cell Biol 1995; 15:1953-1960. Yang YY, Yin GL, Darnell RB. The neuronal RNA-binding protein Nova-2 is implicated as the autoantigen targeted in POMA patients with dementia. Proc Natl Acad Sci USA 1998; 95:13254-13259. Dalmau J, Gultekin SH, Voltz R, Hoard R, Deschamps T, Balrnaceda C, Batchelor T, Gerstner E, EichenJ, Frennier J, Posner JB, Rosenfeld MR.Mal, a novel neuronal and testis specific protein, is recognized by the serum of patients with paraneoplastic neurologic disorders. Brain 1999; 122:27-39. Voltz R, Gultekin SH, Posner JB, Rosenfeld MR, Dalmau J. Seraof patients with testicular cancer and paraneoplastic limbic/brainstem encephalomyelitis harbor an antineuronal antibody (anti-Ta) that recognizesa novel neuronal protein. J Neurol 1998; 245:412 Clouston PD, Saper CB, Arbizu T, JohnstonI, Lang E, Newsom-Davis J, Posner 111. Cerebellar degeneration, cancer and JB. Paraneoplastic cerebellar degeneration. the Lambert-Eaton myasthenic syndrome. Neurology 1992; 42: 1944-1950. Mason WP, GrausF, Lang B, HonnoratJ, Delattre J-Y, ValldeoriolaF, Antoine JC, Rosenblum MK, Rosenfeld MR, Newsom-Davis J, Posner JB, Dalmau J. Smallcell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome. Brain 1997; 120:1279-1300. Honnorat J, Antoine JC, Derrington E, Aguera M, Belin MF. Antibodies to a subpopulation of glial cells anda 66 kDa developmental protein in patients with paraneoplastic neurological syndromes.J Neurol Neurosurg Psychiatry 1996; 61 :270278. Quach TT, RongY, Belin MF, Duchemin AM, AkaokaH, Ding S, Baudry M, KOlattukudy PE, Honnorat J. Molecular cloning of a new unc-33-like cDNA from rat brain and its relation to paraneoplastic neurological syndromes. Brain Res Mol Brain Res 1997; 46:329-332. Hedgecock EM, Culotti JG, Thomson JN, Perkins LA. Axonal guidance mutants of Caenorhabditiselegans identified by filling sensory neurons with fluorescein dyes. Dev Biol 1985; 111:158-170.

neration Cerebellar Paraneoplastic

629

67. Albert ML, Darnell JC, Bender A, Francisco LM, Bhardwaj N, Darnell RB. Tumorspecifickillercellsinparaneoplasticcerebellardegeneration.NatMed1998; 11:1321-1324. 68. Voltz R, Dalmau J, Posner JB, Rosenfeld MR. T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis. Neurology 1998;5 l :1146-1 150. 69. Jean WC, Dalmau J, H0 A, Posner JB. Analysis of the IgG subclass distribution and inflammatory infiltrates in patients with anti-Hu-associated paraneoplastic encephalomyelitis. Neurology 1994; 44: 140- 147. 70. Benyahia B, Liblau R, Merle-Bkral H, Tourani JM, Dalmau J, DelattreJ-Y. Cellmediated auto-immunity in paraneoplastic neurologic syndromes with anti-Hu antibodies. Ann Neurol 1999; 45: 162-167. 71. Graus F, Ribalta T, Campo E, Monforte R, Urbano A, Rozman C. Immunohistochemical analysis of the immune reaction in the nervous system in paraneoplastic encephalomyelitis. Neurology 1990; 40:2 19-222. I genes in 72. Neurnann H, Cavalie A, Jenne DE, Wekerle H. Induction of MHC class neurons. Science 1995; 269549-552. 73. Hormigo A, Dalmau J, Rosenblum M, River ME, Posner JR. Immunological and pathological study ofa patient with anti-Ri-associated encephalopathy [abstr]. Ann Neurol 1993; 34:278-278. 74. Brain WR, Wilkinson M. Subacute cerebellar degeneration associated with neoplasms. Brain 1965; 88:465-478. 75. Vick N, Schulman S, Dau P. Carcinomatous cerebellar degeneration, encephalornyelitis, and sensory neuropathy (radiculitis). Report of a case incorporating both purely degenerative and intense inflammatory changes, with special prominence of the latter in the putamen. Neurology 1969; 19:425-441. 76. Brain WR, Daniel PM, Greenfield JG. Subacute cortical cerebellar degeneration and its relation to carcinoma. J Neurol Neurosurg Psychiatry 195;1459-75. 1 77. Munch-Petersen CJ. Ataxia subacuta atrophia cerebelli primaria. Acta Psychiatr Neurol 1947; 21 3-225. 78. Anderson NE, Rosenblum MI(, Posner JB. Paraneoplastic cerebellar degeneration: clinical-immunological correlations. Ann Neurol 1988; 24559-567. 79. Krawaker J, BalmacedaCM,TorresGluckT,PosnerJB,FetellMR,Dalmau J. Anti-Yo paraneoplastic cerebellar degeneration ainman with adenocarcinoma of unknown origin. Neurology 1996; 46: 1486-1489. 80. Felician 0 , Renard JL, Vega F, Creange A, Chen QM, Bequet D, Delattre JY. Paraneoplasticcerebellardegenerationwithanti-Yoantibodyin a man.Neurology 1995; 4511226-1227. 81. Elrington GM, Murray NM, Spiro SG, Newsom-Davis J. Neurological paraneoplastic syndromes in patients with small cell lung cancer. A prospective survey of 150 patients. J Neurol Neurosurg Psychiatry 1991; 54:764-767. 82. O’Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 1988; 111:577-596. 83. Escudero D, Barnadas A, Codina M, Fueyo J, Graus F. Anti-Ri-associated paraneoplastic neurologic disorder without opsoclonus ina patient with breast cancer. Neurology 1993; 43:1605-1608,

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84. Casado JL, Gil-Peralta A, Graus F. Arenas C, Lopez JM, Alberca R. Anti-Ri antibodies associated with opsoclonus and progressive encephalomyelitis with rigidity. Neurology 1994; 44:1521-1522. 85. Dalmau J. Paraneoplastic syndromes of the nervous system: general pathogeneic mechanisms and diagnostic approaches. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. Amsterdam: Elsevier, 1997:319-328. 86. Bennett JL, Galetta SL, Frohman LP, Mourelatos Z, Gultekin SH. Dalmau JO, Posner JB. Neuro-ophthalmologic manifestations of a novel paraneoplastic syndrome associated with testicular carcinoma. Neurology 1999: 52864-867. 87. Tsukamoto T, Mochizuki R, Mochizuki H, Noguchi M, Kayama H, Hiwatashi M, Yamanioto T. Paraneoplastic cerebellar degeneration and limbic encephalitis in a patient with adenocarcinoma of the colon. J Neurol Neurosurg Psychiatry 1993: 56 :7 13-7 16. 88. Honnorat J, Trouillas P, Thivolet C, Aguera M, Belin ME Autoantibodies to glutamate decarboxylase in a patient with cerebellar cortical atrophy, peripheral neuropathy, and slow eye movements. Arch Neurol 1995; 52:462468. 89. Saiz A. Arpa J, Sagasta A, Casamitjana R, Zarranz JJ, Tolosa E, Graus F. Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus, and polyendocrine autoimmunity. Neurology 1997; 49: 1026-1 030. 90. Uchuya M, Graus F, Vega F, Re% R, Delattre JY. Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies. J Neurol Neurosurg Psychiatry 1996; 60:388-392. 91. Graus F, Vega F, Delattre JY, Bonaventura I, ReGe R. Arbaiza D, Tolosa E. Plasmapheresis and antineoplastic treatment in CNS paraneoplastic syndromes with antineuronal autoantibodies. Neurology 1992; 42:536-540. 92. Paone JF, Jeyasingham K. Remission of cerebellar dysfunction after pneumonectomy for bronchogenic carcinoma. N Engl J Med 1980; 302:156-156. 93. Cocconi G, Ceci G. Juvarra G. Successful treatment of subacute cerebellar degeneration in ovarian carcinoma with plasmapheresis. A case report. Cancer 1985; S6:23 18-2320. 94. Batson OA, Fantle DM, Stewart JA. Paraneoplastic encephalomyelitis. Dramatic response to chemotherapy alone. Cancer 1992; 69: 1291-1293. 95. Counsel1 CE, McLeod M, Grant R. Reversal of subacute paraneoplastic cerebellar syndrome with intravenous immunoglobulin. Neurology 1994: 44: I 1841185. 96. Cher LM, Hochberg FH, Teruya J, Nitschke M. Valeiizuela RF, Schmahmann JD, Herbert M, Rosas HD, Stowell C. Therapy for paraneoplastic neurologic syndromes in six patients with protein A column immunoadsorption. Cancer 1995; 75: 1678-1683. 97. Stark E, Wurster U, Patzold U, Sailer M, Haas J. Immunological and clinical response to immunosuppressive treatment in paraneoplastic cerebellar degeneration. Arch Neurol 1995; 52814-818. 98. David YB, Warner E, Levitan M, Sutton DM, Malkin MG. Dalmau JO. Autoimmune paraneoplastic cerebellar degeneration in ovarian carcinoma patients treated

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with plasmapheresis and immunoglobulin. A case report. Cancer 1996; 78:21532156. Nitschke M, HochbergF, Dropcho E. Improvement of paraneoplastic opsoclonusmyoclonus after protein A column therapy. N Engl J Med 1995; 332:192-192. de la SayetteV, Bertran F, Honnorat J, Schaeffer S, Iglesias S, Defer G. Paraneoplastic cerebellar syndrome and optic neuritis with anti-CV2 antibodies: clinical response to excision of the primary tumor. Arch Neurol 1998; 55:405-408. Newsom-Davis J, MurrayNM.Plasmaexchangeandimmunosuppressivedrug treatment in the Lambert-Eaton myasthenic syndrome. Neurology 1984; 34:480485. Chalk CH, Murray NM, Newsom-DavisJ, O’Neill JH, Spiro SG. Response of the Lambert-Eaton myasthenic syndrome to treatment of associated small-cell lung carcinoma. Neurology 1990; 40: 1552-1556, Blumenfeld AM, Recht LD, Chad DA, DeGirolami IT, Griffin T,Jaeckle KA. Coexistence of Lambert-Eaton myasthenic syndrome and subacute cerebellar degeneration: differential effectsof treatment. Neurology 199I ;41:1682-1685. Bain PG, Motomura M, Newsom-DavisJ, Misbah SA, Chapel HM, Lee ML, Vincent A, Lang B. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology 1996; 47:678-683. Fueyo J, Gomez-Manzano C, PascualJ, Pou A. Paraneoplastic syndromes. Neurology 1993; 43:236-236. Goldstein JM, Waxman SG, Vollmer TL, Lang B, Johnston I, Newsom-Davis J. Subacute cerebellar degeneration and Lambert-Eaton myasthenic syndrome associated with antibodies to voltage-gated calcium channels: differential effect of immunosuppressive therapy on central and peripheral defects. J Neurol Neurosurg Psychiatry 1994; 57:1138--1139. Satoyoshi E, Kowa H, Fukunaga N. Subacute cerebellar degeneration and EatonLambert syndrome with bronchogenic carcinoma. Neurology 1973; 23:764-768. Keime-GuibertF,Refit5 R,Graus F, Delattre J-Y.Evolutionof paraneoplastic/ sensory neuronopathy syndrome (PEM/SN) with anti-Hu antibodies according to the response of the tumor to antineoplastic treatment. Neurology 1998; 50:423.

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30 Ataxia Caused by ~cquiredWitamin DeficiencyoretabolicDisorders Peter Thier University of Tubingen, Tubingen, Germany

I. VITAMIN B I DEFICIENCY-WERNICm’S ENCEPHALOPATHY A. Introduction Pathogenesis B. C. Neuropathology D. ClinicalFeatures E. Management

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TI. VITAMIN E DEFICIENCY A. GeneralRemarks B.CeliacDisease C. Short-Bowel Syndrome Cholestasis D. E.ChronicPancreatitisandPancreaticExocrineInsufficiency

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111. VITAMIN B 12 DEFICIENCY Introduction A. B. Pathogenesis Neuropathology C. D.ClinicalFeatures E. Diagnosis F, Management

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VITAMIN B, DEFICIENCY WERNICKE’S ENCEPHALOPATHY Introduction

Wernicke’s encephalopathy (WE) is a neurological disorder caused by vitamin B, (thiamine) deficiency, affecting oculomotor and cognitive systems as well as the cerebellum. The most frequent cause of vitamin B, deficiency is alcohol frequently missed during apaabuse. If mild and uncharacteristic formsof M, tient’s lifetime and revealed only by postmortem investigation of the brain, are considered, WE may be estimated to affect at least 20% of alcoholics and 0.5% of the general population. Similar to WE, Korsakow psychosis(W, amnesic, or amnestic-confabulatorypsychosis)isusuallyaconsequence of alcoholismrelated thiamine deficiency. In such cases it represents the common denominator for the memory disturbances and related cognitive symptoms of M E .

B. Pathogenesis The cause of WE isalways thiamine deficiency, which is possibly especially del(l).Although alcoholism-related maleterious in genetically predisposed persons nutrition is by far the most frequent cause of thiamine deficiency, there are also other causes. Thiamine deficiency may result from malnutrition of other kinds, including excessive fasting, inadequate parenteral nutrition (excessive intake of carbohydrates),hemodialysis,uremia,repeatedvomiting(forinstanceduring pregnancy), disseminated tuberculosis, carcinomas of the upper gastrointestinal tract, and disseminated tumors of the hemopoietic system. Thiamine contributes to the metabolismof carbohydrates. Its pyrophosphate is a coenzyme involved in glycolysis, in the tricarboxylic acid cycle, and in the hexose monophospate shunt. It is unclear if thiamine deficiency affects brain function by way of a disturbed carbohydrate metabolism, or indirectly,by way of alterations of the metabolism of various central nervous system (CNS) transmitters, such as serotonin, glutamate, or aspartate. Similar to WE, KP is usually a consequence of alcoholismrelated thiamine deficiency. However, typical isolatedKP may also be observed following lesions of the diencephalon or the temporal lobes of other origin, for instance herpes simplex encephalitis or tumors.

C. Neuropathology The structuralchangescharacteristicfor WE aresymmetrical,hemorrhagic, spongiform lesions, located in the thalamus and hypothalamus in the vicinityof the ventricles, lesions close to the aqueduct, or on theoffloor the fourth ventricle. In addition, cerebellar pathology may occur. The chronic form of WE seems to result from a sequenceof mild or clinically inapparent lesions that are frequently

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missed (2). The characteristic lesions are found in 0.6-4.7% of unselected autopsy cases and about 20% of the brains of alcoholics. In only 20% of the neuropathologicalcaseswithsigns of WE, thisdiagnosiswasmadeonclincial grounds during their lifetimes (3-5).

R. ClinicalFeatures WEi is characterized by eye muscle paresis, gaze paresis and nystagmus, pupillary dysfunction, autonomic dysregulation, including hypotension and hypothermia, and seizures. Accompanying mental disturbances may include confusion, disorientation, apathy, and varying degrees of clouding of consciousness, from drowsiness to coma. Cerebellar symptoms are characterized by severe ataxia of stance and gait, with conspicuous intersegmental instability with two to four forward-backward oscillations of the pelvis. These disturbances are accentuated by eye closure. Although theknee-heel test is ataxic, coordinationof hands and arms is not, or isonly mildly disturbed. Cog-wheel pursuit, impaired suppression of the vestibulo-ocular reflex, and gaze-evoked nystagmus are much rarer. Symptoms may occur in various combinations and they may be accompanied by the signs of alcoholic polyneuropathy.The onset of symptoms is usually quite acute. The ocular symptoms of WE and also the milder mental symptoms, such as 2-24 h) if drowsiness or impaired concentration, will improve rapidly (within thiamine is substituted. Nystagmus and ataxia, however, may last much longer, albeit with reduced intensity. The good response to thiamine suggests that at this stage of the disease, the aforementioned symptoms result mainly from functional and not from structural alterations. Korsakow psychosis (W,amnesic, or amnestic-confabulatory psychosis) is characterized by a profound loss of shortand long-term memory (retrograde amnesia) and an impaired ability to acquire new information (anterograde amnesia). Other cognitive functions are spared or only mildly impaired. Confabulations, a term referring to the fabrication of stories and accounts of events, are typically observed in the early phase of the psychosis and during recovery.The amnestic-confabulatory psychosis, if present, is usually not much affectedby substitution of thiamine. Only about20% of all patients suffering from KP show satisfactory recovery. These facts indicate that the amnestic-confabulatory psychosis is mainly due to irreversible structural alterations. In other words, it is obviously of utmost importance to substitute thiamine as early as possible, before the symptoms of W have developed.

E. Management Parenteral application of high-dose thiamine is necessary.The doses usually applied by far exceed the amounts of thiamine needed tofill up the tissue stores and tocoverthedailyrequirements of healthysubjects.Dependingonthe

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author, daily doses ranging from 50 to 300 mg have been recommended.The application of such large doses frequently exceeds the actual requirements. This does not pose a problem, though, because even higher dosesof thiamine have to be given to provoke toxic side effects. Even long-term application of 150 mg/day will be tolerated without signs of toxicity. The real problem of thiamine substitution therapy is not toxicity, but intolerance, independentof dose. Both the frequency and the severity of these allergic reactions, which may end lethally, are usually underestimated. Reliable numbers on the incidence of thiamine intolerance are unavailable. It does not seem to be unconceivable that thiamine application and not the underlying disease itself may be blamed for some fatal outcomes of Wernicke’sdisease.Thisissuggested by thefactthatWernicke’s disease and thiamine intolerance share symptoms suchas seizures, clouded consciousness, including coma and severe autonomic dysregulation, with tachycardia, hypotension, difficulty in breathing, and finally, full-fledged shock. Other symptoms include erythema, urticaria, precordial and epigastric pain, vomiting, and others. Contrary to parenteral thiamine, oral thiamine seems tobe relatively safe. An effective treatmentof the memory deficitsof patients with persisting€LP is not yet available.

II.

VITAMIN E DEFICIENCY

A. GeneralRemarks Vitamin E (tocopherol), a lipid-soluble vitamin with antioxidant properties, is widely distributed in food.Vitamin E is taken up from the intestineby a mechanism similar to that of other fat-soluble vitamins (A, D, E, and K), incorporated a process that involves the a-tocopherol-transfer prointo lipoproteins in the liver, tein, and secreted by the liver. The plasma level of vitamin E closely correlates with plasma lipid levels. There are eight naturally occurring tocopherols with vitamin E activity. a-Tocopherol is the most widely distributed and the most ofactive these tocopherols. Because vitamin E is stored in alltissues, vitamin deficiency develops over long periods. Vitamin E deficiencymay result from various conditions or underlying malabsorption, including hepatobiliary disorders, either congenital acquired in childhood; abetalipoproteinemia (Bassen-Kornzweig syndrome; see Chap, 9), short-bowel syndrome, chronic inflammatory bowel disease, and oth5 years of deficiency in adults before neurological damage ers. It takes more than i s measurable (6). On the other hand,an isolated vitamin E-deficiency syndrome, without any indication of fat malabsorption, may result from various types of mutations of the a-tocopherol-transfer protein (a-TTP), a cytosolic liver protein that supports the intracellular transportof a-tocopherol, the most active form of vitamin E (see Chap. 10). In healthy subjects, a daily intake of about 10-30 mg of a-tocopherol is usually recommended to obtain optimal plasma a-tocopherol

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levels of 30 pM or higher ('7). Vitamin E-deficient neurons and other cells generate increased numbers of oxygen radicals, causing an increase in peroxidation of mitochondrial membranes and a progressive decrease in respiration-dependent axonal transport, finally resulting in cell death(8). The cardinal sites affected are the central axonsof dorsal root ganglion cells and the retina, with minor involvement of the peripheral sensory nerve, optic nerve, and pyramidal tract. Ataxia resulting from prolonged vitamin E deficiency is the only human neurodegenerative disorder that can be led back to insufficient levels of an essential antioxidant. Large doses of vitamin E are usually tolerated without causing harm. However, excessive doses of vitamin E will antagonize vitamin K, thereby inhibiting prothrombin time, an action that may potentiate the effect of oral anticoagulants. Furthermore, a toxic action has been observed in premature infants who may develop hepatosplenomegaly, with ascites and thrombocytopenia, in response to inadequate doses of parenteral vitamin E. The following sections will present some of the pecularities of specific causes of vitamin E deficiency. A full accountof the neurological sequelaeof vitamin E deficiency and the managementof such deficiency will be given within the framework of the discussion of celiac disease.

1. Introduction Celiac disease (see also Chap. 31) is a gluten-induced enteropathy affecting both children and adults. It is characterized by abnormal small-bowel structure with villous atrophy and crypt cell hyperplasia. It is more frequent in women, has a tight association with HLA-DG alleles andan overall prevalence estimated to be on the order of l:200-1 :l000 (9). The mucosal lesions seem to result from T-cell-mediated inflammation triggered by gluten, a protein found in wheat and wheat-based products. Adult-onset celiac disease has recently been shown to be much more common than hitherto assumed and to have a surprisingly wide spectrum of manifestations, including gastrointestinal disturbances, cardiac arrhythmia, anemia, endocrine disturbances, dermatitis herpetiformis, pemanent tooth in enamel defects(10,l l), and avariety of neurological deficits, further discussed the following. Moreover, a rangeof other autoimmune diseases, such as insulindependent diabetes mellitus andan increased riskof intestinal lymphomamay be associated with celiac disease.

2. Clinical Features of Neurological ~anifestations The neurological disturbances that have been associated with celiac disease are protean. Probably most common is the basic pattern of deficits common to longlasting vitamin E deficiency, with slowly progressing ataxia, hypotonia, dysme-

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tria of thelimbs,dysarthricspeech,muscleweakness,visualdisturbances, Babinski’s sign, and signs of peripheral neuropathy with areflexia. Much rarer, celiac disease may result in relapsing, progressive symptoms suggesting brain stemandcerebellarpathology.Afewpatientswithceliacdiseasedevelop manifestations corresponding to the syndrome of Ramsay Hunt (dyssynergia cerebellaris myoclonica), characterized by progressive ataxia in combination with action- and stimulus-sensitive myoclonus of cerebrocortical origin and infrequent seizures (12-14). Further adding to the wide spectrum of neurological manifestations of celiac disease are reports of neuromuscular disorders, including various types of neuropathies, neuromyotonia, and inclusion body myositis (15). Anotherrareneurologicalassociation of manifestorlatentceliacdiseaseare cerebrocortical calcifications with epilepsy and mental deterioration reminiscent of Sturge-Weber syndrome (16-19). It now seems very likely that the listof neurological manifestations of celiac disease is still incomplete, because antigliadin antibodies (see later) can alsobe found in subjects with normal small-bowel mucosa, and their incidence is increased in patients with neurological diseaseof unknown cause (20).

3. Pathogenesis The intestinal atrophy may lead to malabsorption and to severe vitamin E deficiency. Parenteral application of vitamin E is able to normalize serum vitaminE levels, with at times a significant improvement of function. However, there are reports of patients suffering from neurological disturbances associated with celiac disease, without any indication of gluten intolerance and malabsorption or nutritional deficiency, but with the presence of antigliadin antibodies (gliadin is the alcohol-soluble fraction of gluten) in the serum and the cerebrospinal fluid (CSF), in whom neithera gluten-free diet nor vitamin supplements improved the neurological deficits. The variable efficacy of vitamin E replacement therapy as well as the wide range of neurological disturbances associated with celiac disease strongly suggest that vitamin E deficiency is not the only pathogenetic principle involved. Although close at hand, no convincing evidence for a neuroimmunological basisof neurological manifestationsof celiac disease has asyet been provided, and the few attempts to treat patients who do not benefit from vitamin E replacement therapy have failed.

4.

Diagnosis

Diagnosis is based on the demonstration of serum antibodies to endomysia1 reticulin and gliadin antigens and the demonstration of atrophy on intestinal biopsy when the patient is receiving a gluten-containing diet. Moreover, the intestinal lesions should disappear once gluten is excluded from the diet. In malabsorption, vitamin E levels (normal 5-30 pg/mL) will be reduced or not rise after oral ad-

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ministration of 2 g of vitamin E. Nerve conduction measurements may reveal slowed conduction, and tests of somatosensory-, visual-, and auditory-evoked potentials may reveal central conduction delays or reduction of response amplitudes. With involvementof peripheral nerves, a biopsy will show nerve fiber loss and lipofuscin deposits, whichmay also be found in skin and muscle. After treatment, lipofuscin storage disappears in a skin biopsy (21). Fundoscopic investigation may reveal pigment retinopathy. Brain scans may show symmetrical atrophy of the cerebellar hemispheres and, occasionally, also mild cerebrocortical atrophy. Rarely, multiple large and partially enhancing lesions of the cerebellum, reminiscent of inflammatory lesions, have been observed (22). In patients suffering from seizures associated with celiac disease, cerebrocortical calcifications have been described.In case of a lack of vitamin E deficiency or insufficient response to vitamin E supplements, the frataxin gene expansion underlying Friedreich’s ataxia should be ruled out if the clinical picture resembles Friedreich’s ataxia.

5. Management A lifelong, strict gluten-free diet is mandatory. However, it is not sufficient to set the patient on a gluten-free diet, because the vitamin deficiency, E if present, will persist for a long time. Rather, vitamin E therapy has to be initiated early on (23,24).Mostauthorsrecommendintramuscularapplication of a-tocopherol with doses of 100-200 mg/day. However, also megadoses of up to 900 mglday and, alternatively, applications only every 3-4 days have been used with success. In view of these uncertainties, serum vitamin E levels (normal 5-30 pg/mL,) should be controlled and the dose adapted accordingly. Attempts have been made to use water-soluble formsof vitamin E, such as tocopheryl succinate polyethylene glycol as oral vitamin E supplement. Althoughfirst observations suggest that these water-soluble forms of vitamin E will be taken up in sufficient amounts in patients with severe fat malabsorption owingto short-bowel syndrome (see Sec. 1I.C) and to stop the progressionof neurological deficits (25), it would be premature to recommend them as alternatives to parenteral a-tocopherol. Even if adequate, replacement therapy may fail to alleviate the neurological deficits or to stop their progression. Attempts to resort to immunosuppressive drugs or plasmapheresis in such cases have as yet been unsuccessful.

C. Short-BowelSyndrome Extensive small-bowel resectionmay be necessary in children becauseof necrotizing enterocolitis, atresias, long-segment Hirschsprung’s disease, midgut volvulus, or gastroschisis, and becauseof mesenteric thrombosis or Crohn’s disease in adults. It leads to malabsorption, fluid and electrolyte loss, lactic acidosis, di-

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arrhea and steatorrhea, weight loss, and deficiencies of the fat-soluble vitaminsA, D,E,and K with,amongothers,development of thefull-fledgedvitamin E-deficiency syndrome as described earlier (see Sec. I1.A; 26-29). Vitamin B,, and folic acid levels are usually normal. Nevertheless, macrocytic anemia may be found. The amount of malabsorption and the amount of vitamin deficiencies directly reflect the extentof distal small-bowel resection(30). In casesof extensive small-bowel resection, home total parenteral nutrition may be inevitable.

.

Cholestasis

Vitamin E deficiency is found in most children suffering from congenital forms of intrahepatic cholestasis or extrahepatic biliary atresia. Before 1 year of age, neurological function is usually normal. However, at the ageof 3, abnormalities are present in about 50% of the vitamin E-deficient children and, after 3 years, all of themshow first signs of spinocerebellardegenerationwithareflexia, ataxia, dysmetria, diminished vibratory position sense, and occasionally also pigmentary retinopathy, which further progress in the following years (31,32). Even massive oral dosesof vitamin E are not able to correct the deficiency 50-100 and mg of vitamin E have to be administered intramuscularly every 3-7 days. This (33). Also, arrests clinical progressionof the degeneration and the clinical deficits improvement has often been documented. On the other hand, early long-term correction of vitamin E deficiency in children suffering from chronic cholestasis is able to prevent the developmentof neurological symptoms. Chronic cholestasis in adults may result from extrahepatic biliary obstruction caused by stones, as primary biliary cirrhosis and, tumors,orfromintrahepaticdisorders,such among others, will lead to typical deficiencies in fat-soluble vitamins, including vitamin E.

.

ChronicPancreatitisandPancreatic Exocrine insufficiency

If more than 90% of the exocrine functionof the pancreas is lost, malabsorption with weight loss, steatorrhea, and deficiencies in fat-soluble vitamins (A, D, E, and K) result. Frequently, the absorption of vitamin E is more affected than absorption of the other fat-soluble vitamins(34). A vitamin E deficiency syndrome with ataxia, as described earlier, will result (e.g., 35,36). In adults, the most frequent cause of pancreatic exocrine insufficiency is alcoholism. In children and young adults, cysticjbrosis, an autosomal recessive disease, characterizedby the presence of mucosal plugs in the excretory ducts of the exocrine glands, is the usual cause of pancreatic exocrine insufficiency. In addition to pancreatic exocrine insufficiency, cystic fibrosis will also lead to cholestasis, which likewise will contribute to the malabsorption of vitamin E (see Sec. 1I.D).

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111. VITAMIN 6,,,DEFICIENCY A.

Introduction

Vitamin B,, (cynanocobalamin) is a cofactor of enzymatic reactions that transfermethylgroups,exclusivelysynthesized by microorganisms,andtakenup with meat and dairy products. Vitamin B,, binds to the intrinsic factor, a glycoprotein produced by the parietal cells of the stomach. This complex attaches tospecificmucosareceptorsinthedistalileumthatmediatethetransfer of vitamin B,, to the capillary circulation, where it binds to several serum transport proteins (the transcobalamins). About 2 mg of vitamin B,, is stored in the liver and another 2 mg in the remainder of the body. Because about 2.5 kg of vitaminBisneededdaily,ittakesseveralyearstodevelopvitaminBdeficiency if thesupplyisstoppedabruptly. Vitamin B,,isconvertedintothe active forms methylcobalamin and adenosylcobalamin in the tissue. Both are importantforthesynthesis of normalneuronallipids. ~ethylcobalamin is needed in the conversion of homocysteine to methionine, the latter required for the production of choline-containing phospholipids and the methylation of myelin basic protein. Adenosylcobalamin is involved in the conversion of methymalonyl coenzyme A (CoA) to succinyl CoA. In the absence of adequate levels of adenosylcobalamin, the access of methyrnalonyl GOA will lead to the synthesis of nonphysiolgicalneuronallipids.Unliketheneurologicalsequelae, thehematologicalconsequences of vitaminB,,deficiencyaresecondaryto as an acceptor an interferencewithfolatemetabolism:cobalaminisneeded of themethylgroupsplit off frommethyltetrahydrofolate,theinactiveform of folate,thatistakenupfromtheblood on conversiontotheactiveform tetrahydrofolate (37).

6. Pathogenesis The most frequent cause of vitamin B deficiency is pernicious anemia, an autoimmune disease with antibodies against parietal cells, causing lack of intrinsic factor (38). Lack of intrinsic factor may also result from gastric atrophy or as a consequence of gastrectomy. Vitamin B deficiency may also follow disorders compromising the absorptive capacityof the distal ileum or a strictly vegetarian diet. Borderline vitamin B,, deficiency may become overt as a consequence of anesthesia with nitrous oxide (N,O) owing to inactivation of the cobalt atom in vitamin B,, by oxidation (39,40). Clinical syndromes resembling vitamin B,, deficiency rnay result from disturbances of the enzymatic reactions to which cobolamin contributes. One example is folate deficiency. Because methyltetrahydrofolate is needed for the formation of methylcobolamin andfinally methionine, folate deficiency rnay cause not only hematological and mucosal changes, but also the peripheral neuropathy and combined subacute combined myelopathy

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typical of vitamin B deficiency (41). Although low serum vitamin B 12 levels are the common cause of B ,,-related subacute combined degeneration of the spinal cord, there have been occasional reports of subacute combined degeneration with high serum levels of vitamin B,, and folate. In such cases the uptake of vitamin B,, into the cells seemed to be inhibited by, as yet unidentified, plasma factors (42). Disturbances of transmethylation, possibly secondary to disturbances of vitamin B I Z metabolism may also underly the demyelinating myelopathy in acquired immunodeficiency syndrome (AIDS) (43).

C. Neuropathology The specific spinal cord lesion caused by vitamin B13 deficiency is known as subacute combined degeneration (SCD). It is characterized by demyelination of the dorsal and lateral columns of the spinal cord, involving the corticospinal and spinocerebellar tracts, manifesting as high-intensity lesions on T2-weighted images. Although, the demyelination for unknown reasons emphasizes the cervical and thoracic parts of the spinal cord, the pathology may involve the peripheral nervous system and other parts of the central nervous system, the latter with patterns of deinyelination reminiscent of multiple sclerosis (44,45). The multiple focal and confluent white matter hyperintensities occasionally seen on T2-weighted magnetic resonance imaging (MRI) studies are the morphological basis of the variable supraspinal symptoms found in vitamin B deficiency.

,

D. Clinical Features

,

Vitamin B deficiency causes a niacrocytic anemia, mucosal atrophy, and neurological complications that may involve a sensorimotor polyneuropathy, a subacute combined degeneration of the spinal cord, and an encephalopathy. On neurological examination, diminished vibratory sensation and proprioception in the lower extremities are the most common findings. Other neurological symptoms involve ataxia of stance and gait, dysmetria of the legs, loss of cutaneous sensation, muscle weakness, diminished or hyperactive reflexes, spasticity, urinary or fecal incontinence, orthostatic hypotension. loss of vision, dementia, psychoses, and disturbances of mood (38). It is important to note that about 20% of patients may not present with major hematological disturbances, such as elevated corpuscular volume or reduced hematocrit. Even in anemic patients, neutropenia or thrombocytopenia are unusual.

E. Diagnosis A vitamin B,, deficiency may be suggested if vitamin B12in serum is below the normal range of 200-900 pg/mL. The Schilling test, measuring the absorption of

oral vitamin B,,, with or without intrinsic factor, has traditionally been applied to determine if the deficiency is a consequence of intrinsic factor depletion orof ileal disease. Newer approaches involve the analysisof methylmalonic acid, homocyst(e)ine,thetranscobalamins,andanti-intrinsicfactorantibodies.Note, however, that inmany cases of significant neurological deficits, the serum cobalamin concentration may not be or only moderately be decreased (see Sec. I1I.B for an explanation). On electrophysiological examination of central fiber tracts, slowing of sensory and motor conduction may be found (44,46). The electrophysiogical examinationof peripheral nerves may reveal signs of a primarily demyelinating polyneuropathy.

If neurological deficits are present, higher doses than those needed for the treatment of anemia are considered necessary. Until improvement of the neurological deficits, 1000 pglday of hydroxycobalaminaregivenintramuscularly.Subsequently, the interval between applications is expanded to two each week for a year, followed by lifelong application of 1000 pglrnonth. Most patients will benefit considerably from replacementtherapy. In a studyby Healton and colleagues (38), almost half of the sample showed complete recovery and another 40% showed at least a significant improvement of the deficits. Not unexpectedly, more of deficits predict a poorer outsevere pretreatment deficits and a longer duration come. In accordance with the good clinical responses, follow-up MRIs usually show a decrease of the high-intensity zones in the dorsal columns of the spinal cord on T2-weighted images (47).

Hypothyroidism results from insufficient synthesis of thyroid hormone causedby a variety of structural and functional abnormalitiesof the thyroid glandor, much rarer, of the suprathyroid (pituary or hypothalamic) circuits controlling the thyroid gland. Myxedema is the term for severe hypothyroidism, leading to the thickening of the skin owing to accumulation of hydrophilic mucopolysaccarides. Hypothyroidism typically leads to cold intolerance, hoarseness, dry skin, constipation, delayed relaxation phase of deep tendon reflexes, and bradycardia. Rarely, psychiatric symptoms, including depression, apathy, or frank psychosis (usually with paranoid symptoms), and neurological disturbances including myopathy, dementia, or cerebellar ataxia, may dominate the clinical picture (48-51). Most patients showan ataxia of gait. In addition, some of them may present with ataxia of the arms, dysarthria or nystagmus. Long-term replacement therapy usually leads to a regressionof the Symptoms, including the psychiatric and neurological

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disturbances.However,therearealsooccasionalreports of a failure of replacement therapy to improve ataxia, raising doubts about the etiological relation of cerebellarsymptomsandhypothyroidism(52,53). The scarceneuropathological data do not help clarify the pathogenesis of ataxia associated with (54) havedescribedunusualglycogenhypothyroidism.PriceandNetsky containing bodies (“myxedema bodies”) throughout the brain of two patients with myxedema, but only one of the two patients had shown ataxia during life. The brain of the one with ataxia showed Purkinje cell loss and gliosis of the MOlecular layer, in addition to the presence of myxedema bodies. However, the relevance of this finding has been doubted (55) because this patient had been a serious alcoholic.

V.

HYPOPARATHYROIDISM

Hypoparathyroidism, whether acquired or idiopathic,may result in extrapyramidal as well as cerebellar dysfunction. Acquired hypothyroidism usually results from the inadvertent surgical removal of the parathyroid glands during thyroidectomy (56). Idiopathic hypoparathyroidism can occur isolated or as part of a morecomplexautoimmunepolyglandulardeficiency,Idiopathichypoparathyroidism is usually hereditary (57) and becomes manifest in the first decade, but may occur much later in adult life. Laboratory findings reveal severe hypocalcemia and hyperphosphatemia, with low levels of parathyroid hormone. The normal response to injected parathyroid hormone distinguishes hypoparathyroidism as fromotherconditionswithhypocalcemiaandhyperphosphatemia,such pseudohypoparathyroidism, in which the action of parathyroid hormone is ineffective and, consequently, the secretionof parathyroid hormone is excessive. Patients may exhibitextraosseuscalcifications,includingcalcifications of basal ganglia, dendate nucleus, and even cerebellar cortex.The clinical picture of hypoparathyroidism and pseudohypoparathyroidism is characterized by the consequences of hypocalcemia, with muscle cramps, seizures, paresthesias, and dementia, and the consequences of basal ganglia or cerebellar dysfunction with various combinations of choreoathetotic movements, dystonia, tremor, rigidity, (58-60). Rarely, flexedposture,ataxia of limbsand of gait,anddysarthria pseudotumor cerebri with papilledema and progressive deterioration of visual function may result from hypoparathyroidism (61). Treatment of hypoparathyroidism with subcutaneous applications of human parathyroid hormone is effective (62). However, usually, the effective and safe long-term treatmentwith oral la-hydroxyvitamin D, (a-D3) incombination A mean daily doseof 1 pg (range 0.5-2.5 with calcium supplements is preferred. pg), to which 2-3 g of elemental calcium should be added, is usually sufficient a marked improvement to compensate the endocrinological deficit and to achieve

Ataxia from Vitamin

45

of neurological function (63). At any rate, the dosesof a-D,and calcium have to be adjusted according to the serum calcium level. The doses of a-D,and calcium required for the treatment of pseudohypoparathyroidism are usually lower, reflecting incomplete resistence to the action of parathyroid hormone.

1. Adams A. Nutritional cerebellar degeneration. In: Vinken PJ, Bruyn GW, eds. Metabolic and Deficiency Diseases of the Nervous System. Handbook of Clinical Neurology. v01 28. Amsterdam: Elsevier. 1976:271-283. 2. Lishman WA. Alcohol and the brain. Br J Psychiatry 1990; 156:635-644. 3. HarperC,GoldJ,RodriguezN,PerdicesN.TheprevalenceoftheWernickeKorsakoff syndrome in Sydney, Australia: a prospective necropsy study. J Neurol Neurosurg Psychiatry 1989; 52:282-285. 4. Harper C. The incidence of Wernicke’s encephalopathy in Australia-a neuropathological study of 131 cases. J Neurol Neurosurg Psychiatry 1983; 46:593-598. 5. Riethdorf L, Warzok R, Schwesinger GT. [Alcoholic encephalopathies in autopsy material]. Zentralbl Patholl991;137:48-56. 6. Satya-Murti S, Howard L, Krohel G, Wolf B. The spectrum of neurologic disorder from vitamin E deficiency. Neurology 1986; 36:917-921. 7. Traber MG, Sies H. Vitamin E in humans: demand and delivery. Annu Rev Nutr 1996;16:321-347. 8. Fryer MJ. The possible role of nitric oxide and impaired mitochondrial function in ataxia due to severe vitamin E deficiency. Med Hypotheses 1998; 50:353-354. 9. Troncone R, Greco L, AuricchioS. Gluten-sensitive enteropathy. Pediatr Clin North Am 1996; 43:355-373. 10. Aine L. Coeliac-type permanent-tooth enamel defects. Ann Med 1996; 28:9-12. 11. Egan CA, O’LoughlinS, Gormally S, Powell FC. Dermatitis herpetiformis: a review of fifty-four patients. Ir J Med Sci 1997; 166:241-244. 12. Lu CS, Thompson PD, Quinn NP, Parkes JD, Marsden CD. Ramsay Hunt syndrome and coeliac disease: a new association? Mov Disord 1986; 1:209-219. 13. Bhatia KP, Brown P, Gregory R, Lennox GG, Manji H, Thompson PD, Ellison DW, Marsden CD. Progressive myoclonic ataxia associated with coeliac disease. The myoclonus is of cortical origin, but the pathology is in the cerebellum. Brain 1995; 118:1087-1093. D, Turnbull DM. CSF anti14. Chinnery PF, Reading PJ, Milne D, Gardner-Medwin gliadin antibodies and the Ramsay Hunt syndrome. Neurology 1997; 49: 1131-1 133. 15. Hadjivassiliou M, Chattopadhyay AI(, Davies-Jones GA, Gibson A, Grunewald RA, Lobo AJ. Neuromuscular disorderas a presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry 1997; 63:770-775. 16. Gobbi G, Bouquet F, Greco L, Lambertini A, Ttssinari CA, Ventura A, Zaniboni MC.Coeliacdisease,epilepsy,andcerebralcalcifications.TheItalianWorking Group on Coeliac Disease and Epilepsy [see comments]. 1992 17. Magaudda A,Dah-Bernardina B, De Marc0P, et al. Bilateral occipital calcification,

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epilepsy and coeliac disease: clinical and neuroimaging featuresa new of syndrome. J Neurol Neurosurg Psychiatry 1993; 56:885-889. 18. Cuvellier JC, Vallee L, Nuyts JP. [Celiac disease, cerebral calcifications and epilepsy syndrome]. Arch Pediatr 1996; 3:1013-1019. 19.DugganJM.Recentdevelopmentsinourunderstandingofadultcoeliacdisease. Med J Aust 1997; 166:312-315. 20. Hadjivassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, MilfordWard A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996; 347:369-37 1. 21. Battisti C, Dotti NIT, Formichi P, BonuccelliU,Malandrini A, CarraiM, Tripodi SA, Federico A. Disappearance of skin lipofuscin storage and marked clinical improvement in adult onset coeliac disease and severe vitamin E deficiency after chronic vitamin E megatherapy. J Subrnicrosc Cytol Pathol 1996; 28:339-344. 22. Ghezzi A, Filippi M, Falini A, Zaffaroni M. Cerebral involvement in celiac disease: a serial MRI study ina patient with brainstem and cerebellar symptoms. Neurology 1997; 49: 1447-1450. 23. Mauro A, Orsi L, Mortara P, Costa P, Schiffer D. Cerebellar syndrome in adult celiac disease with vitamin E deficiency. Acta Neurol Scand 1991; 84: 167-170. 24. Martinello F, Fardin P, Ottina M, Ricchieri GL, Koenig M, Cavalier L, Trevisan CP. Supplemental therapy in isolated vitamin E deficiency improves the peripheral neuropathy and prevents the progression of ataxia. J Neurol Sci 1998; 156:177-179. 25.TraberMG,SchianoTD,SteephenAC,KaydenHJ,ShikeM.Efficacyofwatersoluble vitamin E in the treatmentof vitamin E malabsorption in short-bowel syndrome. Am J Clin Nutr 1994; 59:1270-1274. 26. Bertoni JM, Abraham FA, Falls HF, Itabashi HH. Small bowel resection with vitaminEdeficiencyandprogressivespinocerebellarsyndrome.Neurology1984; 34:1046-1052. 27. Edes TE, Walk BE, Thornton WH Jr, Fritsche KL. Essential fatty acid sufficiency does not preclude fat-soluble-vitamin deficiency in short-bowel syndrome. Am J Clin Nutr 1991; 53:499-502. 28. Miura S, Shikata J, Hasebe M, Kobayashi K. Long-term outcome of massive small bowel resection. Am J Gastroenterol 1991; 86:454-459. 29.SelznerM,IsenbergJ,KellerHW.[Currentstatus of surgicaltreatmentofshort bowel syndrome]. Zentralbl Chir 1996; 121 :1-7. 30. Leichtmann GA, Bengoa JM, Bolt MJ, Sitrin MD. Intestinal absorption of cholecalciferol and 25-hydroxycholecalciferol in patients with both Crohn's disease and intestinal resection. Am J Clin Nutr 1991; 54548-552. 3 l. Sokol RJ, Guggenheim MA, Heubi JE, IannacconeST, Butler-Simon N,Jackson V, Miller C, Cheney M, Balistreri WF, Silverman A. Frequency and clinical progression of the vitamin E deficiency neurologic disorder in children with prolonged neonatal cholestasis. Am J Dis Child 1985; 139:1211-1215. 32. Perlmutter DH, Gross P, Jones HR, Fulton A, Grand RJ. Intramuscular vitamin E repletion in children with chronic cholestasis.Am J Dis Child 1987; 141:170-174. 33. Sokol RJ, Guggenheim MA, Iannaccone ST, Barhaus PE, Miller C, Silverman A, Balistreri WF, Heubi JE. Improved neurologic function after long-term correction of

Ataxia

34. 35

1)

36.

37

I

38.

39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51.

52. 53.

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1985; vitaminEdeficiencyinchildrenwithchroniccholestasis.NEnglJMed 313:1580-1586. Nakamura T, Takebe K, ImamuraK, Tando Y, Yamada N, AraiY, Terada A, Ishii M, Kikuchi H, Suda T. Fat-soluble vitamins in patients with chronic pancreatitis (pancreatic insufficiency). Acta Gastroenterol Belg 1996; 59:10-14. Davidai G, Zakaria T, Goldstein R, Gilai A, Freier S. Hypovitaminosis E induced neuropathy in exocrine pancreatic failure. Arch Dis Child 1986; 61:901-903. Sitrin MD, Lieberman F, Jensen WE, Noronha A, Milburn C, Addington W. Vitamin E deficiency and neurologic disease in adults with cystic fibrosis. Ann Intern Med 1987;107:51-54. Lehninger AL, Nelson DL, Cox MM. Principles of Biochemistry. 2nd ed Worth Publishing, 1994. of Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaurn J. Neurologic aspects cobalamin deficiency. Medicine 1991;70:229-245. Flippo TS, Holder WD Jr. Neurologic degeneration associated with nitrous oxide anesthesia in patients with vitamin B,, deficiency. Arch Surg 1993; 128:1391-1395. Pema PJ, Horak HA, Wyatt RH. Myelopathy caused by nitrous oxide toxicity. Am J Neuroradiol 1998; 19:894-896. Parry TE. Folate responsive neuropathy. Presse Med 1994; 23:131-137. Reynolds EH, Bottiglieri T, Laundy M, Stern J, Payan J, Linnell J, Faludy J. Subacute combined degeneration with high serum vitamin B and abnormal vitamin 12 level B, binding protein. New cause of an old syndrome. Arch Neurol 1993; 50:739-742. Kieburtz m, Giang DW, Schiffer RB, Vakil N. Abnormal vitamin B,, metabolism in human immunodeficiency virus infection. Association with neurological dysfunction. Arch Neurol 1991; 48:312-314. Haan J, Haupts M, Uhlenbrock D. Magnetic resonance imaging (MRI), cranial computerizedtomography(CCT),evokedpotentialsandcerebrospinalfluid(CSF) analysis in five patients with funicular myelosis. Neurosurg Rev 1987; 10:209-211. Stojsavljevic N,Levic Z, Drulovic J, Dragutinovic G. A 44-month clinical-brain MRI follow-up in a patient with B,, deficiency. Neurology 1997; 49:878--881. Yamada K, Shrier DA, Tanaka H, NumaguchiY. A case of subacute combined degeneration: MRI findings. Neuroradiology 1998; 40:398-400. Timms SR, Cure JK, Kurent JE.Subacute combined degeneration of the spinal cord: NIR findings. AJNR Am J Neuroradiol 1993; 14:1224-1227. Jellinek EH, Kelly RE. Cerebellar syndrome in myxedema. Lancet 1960; 2:225. Cremer GM, Goldstein NP, Paris J. Myxedema and ataxia. Neurology 1969, 19:37-46. McGaffee J, Barnes MA, LippmannS. Psychiatric presentationsof hypothyroidism. Am Fam Physician 1981; 23:129-133. Gentilini M, Palmieri M. [Myxedematous cerebellar ataxia. Descriptionof a case]. Riv Patol Nerv Ment 1984; 105:75-80. Bonuccelli U, Nuti A, Monzani F, De Negri F, Muratorio A. Familial occurrenceof hypothyroidism and cerebellar ataxia. Funct Neurol 1991 ;6: 17 1-175. Quinn N, Barnard RO, Kelly RE. Cerebellar syndrome in myxoedema revisited: a published case with carcinomatosis and multiple system atrophy at necropsy. J Neurol Neurosurg Psychiatry 1992; 55:616-618.

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54. Price TR, Netsky MG. Myxedema and ataxia: cerebellar alternations and “neural myxedema bodies.” Neurology 1966; 16:957. 55. Adams RD, Victor M, Ropper AH. Principles of Neurology. McGraw-Hill, 1997. 56. Bergamaschi R, Becouarn G, Ronceray J, Arnaud JP, Morbidity of thyroid surgery, Am J Surg 1998; 1765‘1-75. 57. Baron J, Winer KK, Yanovski JA, CunninghamAW, Laue L, Zimmerman D, Cutler GB Jr. Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism. Hum Mol Genet 1996; 5:601-606. 58. Smits M,Gabreels F, Froeling P, Thijssen H, Colon E, ter Haar B, Ruland C, Lam R. Autosomal dominant idiopathic hypoparathyroidism and nervous system dysfunction: reportof three cases and reviewof the literature.J Neurol 1982; 228:13-122. 1 59. Abe S, Tojo K, Ichida K, Shigematsu T, Hasegawa T, Morita M, Sakai 0.Arare case of idiopathichypoparathyroidismwithvariedneurologicalmanifestations.Intern Med 1996; 35:129-134. 60. Stuerenburg HJ, Hansen HC, Thie A, Kunze K. Reversible dementia in idiopathic hypoparathyroidism associated with normocalcemia. Neurology 1996; 47:474“476. 61. Sheldon RS, Becker WJ, Hanky DA, Culver RL. Hypoparathyroidism and pseudotumor cerebri: an infrequent clinical association. Can J Neurol Sci 1987; 14:622625. 62. Winer KK, Yanovski JA, CutlerGB Jr. Synthetic human parathyroid hormone 1-34 vs calcitriolandcalciuminthetreatment of hypoparathyroidism.JAMA1996; 2761631-636. 63. Halabe A, Arie R, Miman D, Samuel R, Liberman UA. Hypoparathyroidism-a long-term follow-up experience with l alpha-vitamin D, therapy. Clin Endocrinol (0x0 1994; 40:303-307.

31 Cerebellar Encephalitis Marios Hadjivassiliou Royal Hallamshire Hospital, Sheffield, England

Richard A. ~ r u n e w a ~ d Royal Hallamshire Hospital, Sheffield, England

I. INTRODUCTION

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11. GLUTEN ATAXIA Introduction A. Epidemiology B. C.MolecularPathogenesis Neuropathology D. E.ClinicalFeatures F. Ancillary Tests G. Management

650 650 65 1 652 652 653 656 657

111. CEREBELLARENCEPHALITISININFECTIOUSDISEASE Introduction A. B. Epidemiology C. MolecularPathogenesis Neuropathology D. E. ClinicalFeatures F. AncillaryTests Management G.

657 657 657 658 659 659 660 660

IV. MILLERFISHERSYNDROME Introduction A. B. Epidemiology C.MolecularPathogenesis

660 660 660 660 649

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Neuropathology D. E.ClinicalFeatures F. AncillaryTests Management G.

V. CEREBELLAR ATAXIA AND ANTI-GAD ANTIBODIES A. Introduction Epidemiology B. C.MolecularPathogenesis D. ClinicalFeatures REFERENCES

66 l 66 l 662 662 662 662 662 663 663 663

The term cerebellar encephalitis in the context of this chapter is used to describe acuteorchronicprimarycerebellardysfunctionresultingfromtwopossible mechanisms: direct damageto the cerebellum by infection, or immune-mediated cerebellar degeneration of diverse etiology. Cerebellar dysfunctionis most commonly encountered in multiple sclerosis and probably has an immune-mediated pathogenesis. This diseaseis not primarily a disease of the cerebellum and inclusion in this chapter is beyond the scope of this book. Paraneoplastic cerebellar degeneration is a cause of cerebellar encephalitis, but is the subjectof a separate chapter (see Chap. 29) and is not discussed further here. This chapter will concentrate on gluten ataxia, infectious and parainfectious ataxia, Miller Fisher syndrome, and ataxia associated with anti-GAD antibodies.

In a lecture entitled On the Coeliac AJjcection (l), given at the Hospital for Sick Children, Great Ormond Street, London, in 1887, Gee described the condition we With clinical maninow refer to as celiac disease or gluten-sensitive enteropathy. festations largely confined to the gastrointestinal tract or attributable to malabsorption, it was logical to assume that the key to the pathogenesisof this disease resided in the gut. The first report of neurological dysfunction in patients with celiac disease was by Brown in 1908 (2). In hisbook, entitled Sprue and Its Treatment, he mentioned two patients with “sprue” whose illnesses were associated with peripheral neuritis localized to the legs. Elders (31, however, is credited with the first report,

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in 1925, of a patient with sprue and ataxia, plus anesthesia of both legs. He went on to comment that of the two neurologists who saw this patient, one thought there was [cerebellar] ataxia and the other thought there was pseudo 70 years later). This was one of [sensory] ataxia (a continuing problem even very few papers published on the topic of neurological dysfunction and sprue before the establishment of criteria for the diagnosis of celiac disease following the introduction of small-bowel biopsy in 1953. Authors of such reports could notverifythecause of steatorrhea,andneurologicaldetailswere scanty. In 1966, Marks and her colleagues demonstrated an enteropathy in 9 of 12 patients with dermatitis herpetiformis (4), which bore a striking similarity to that of celiac disease. Further studies by the same group demonstrated that both the enteropathy and the skin rash were gluten-dependant, but that skin involvement could occur even without histological evidenceof gut involvement. This discovery started to shift the emphasis away from the gut as the sole protagonist in this disease. The same year as Marks’ paper saw the publication of a landmark paperby Cooke and Thomas-Smith on neurological disorders associated with adult celiac disease (5). All of the patients they described had ataxia. Some also had severe peripheral neuropathy and myelopathy. Subsequently, at least 15 further case reports of ataxia, with or without myoclonus, and celiac disease have been published.

B. Epidemiology Most of the case reports in the literature are based on patients with overt celiac disease who then develop ataxia, implying that gut involvement is a prerequisit. However, neurological dysfunction can both precede and be the sole clinical manifestation of celiac disease (6).We have, therefore, approached the conditions associated with gluten sensitivity from a neurological angle. We recently reported a high prevalenceof circulating antigliadin antibodies in patients with neurological dysfunction of obscure etiology (7) (57 vs. 5% in a neurological disease control group and 12% in healthy control group). The most common neurological disorders associated with gluten sensitivity were ataxia and neuropathies. Only 35% of the antigliadin-positive patients had histological evidence of celiac disease on duodenal biopsy. The remaining 65% have gluten sensitivity in which the target organ is the brain (in particular the cerebellum) or the peripheral nerves, a situation analogous to that of the skin in dermatitis herpetiformis. The prevalence of antigliadin antibodies among these patients with apparently idiopathic ataxia was as high as 68%. These patients appear to have the same human lymphocyte antigen (HLA) as seen in patients with celiac disease presenting with gastrointestinal symptoms. The HLA association is one of the strongest observed in any immune-mediated disease (90% have HLA-DQ2, the remaining having DR4,DQ8).

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C. MolecularPathogenesis In 1982, Harding et al. (8) described two patients with ataxia associated with “chronic malabsorption” and vitamin E deficiency. One of these improved with vitamin E supplementation. Only one of our patients had bioche~icalevidence major etiological factor in the of vitamin E deficiency, and this is unlikely to abe causation of ataxia. An immune mechanism seemsa much more plausible explanation for the cerebellar damage associated with gluten sensitivity. It is apparent that an immune response triggeredby sensitivity to gluten can find its principal expressionin organs other than the gut. Both the central and peripheral nervous systems are susceptible. The presence of lymphocytic infiltration in the cerebellum and posterior columns as well as the peripheral nervous system found in our patients and others, implies immunologically mediated neural damage. The brunt of the damage to the nervous system in gluten ataxia may be borne by the cerebellum or the dorsal columns of the spinal cord, although clinical presentation can be identical. The end result of the insult to the cerebellum in gluten ataxiais Purkinje cell loss, a pathology commonly encountered in cerebellar degeneration from whatever reason. That peripheral nerves are also commonly affected is demonstrable neurophysiologically, and isit likely there is a significant neuropathic component to the ataxia in at least some patients. It is also apparent from the neuropathology of the cases who have come to autopsy (see later discussion). The immune response in gluten ataxia has both cell-mediated and humoral components, but it is uncertain which is principally responsible for the neuronal damage. We are currently investigating the high prevalence in our patients of antibodies that are directed against cerebellar tissue (anti-Purkinje cell antibodies). These antibodies are present in over one-third of our patients at presentation and disappeared in most within the first6 months of a gluten-free diet. We are in the process of characterizing these antibodies by immunoblotting. So far they seem to be distinct from anti-Yo and anti-Hu that have been described in association with paraneoplastic cerebellar degeneration. The presence of such antibodies is not specific for cerebellar damage. Such antibodies were present in some patients without cerebellar ataxia and were not present in all ataxic patients; therefore, it is unlikely that they are directly responsible for the neurological damage observed, which is perhaps more likely to beT-cell-mediated. It is possible, however, that they reflect ongoing damage to cerebellar tissue, and that their disappearance on gluten-free diet correlates with the arrest of degeneration.

D. ~ e u r o p a t ~ o ~ o g y Postmortemexaminationhasbeencarriedouton 2 of the 34 patients we havestudied. The first patientdied of bronchopneumonia.Examination of

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Figure 1 Loss of Purkinje cells in cerebellum of a 61-year-old man with a 5-yearhistory of progressive ataxia associated with gluten sensitivity.

loss of Purkinjecells(Fig. 1) thecentralnervoussystemrevealedpatchy throughoutthecerebellarcortex. The cerebellarwhitemattershowed an astrocytic gliosis, vacuolation of the neuropil, and a diffuse infiltrate of mainly 2), T lymphocytes. Marked perivascular cuffing, with inflammatory cells (Fig. mainlyTlymphocyteswithsmallernumbers of I3 lymphocytesandmacrophages, was presentwithinthecerebellarwhitematterandtheposterior columns of the spinal cord. The peripheral nerves showed a sparse lymphocytic infiltrate. The second patient diedas a consequence of intestinal obstruction. Central nervous system examination revealed a normal cerebellum, but marked degeneration of the posterior columnsof the spinal cord (Fig.3). There was no inflammatory cell infiltration of the central nervous system, but a sparse lymphocytic infiltrate was seen within the peripheral nerves.

E. Clinical Features Hardings seminal paper (9) on idiopathic late-onset ataxia divides patients into three groups.The first was characterized by mild upper limb ataxia, but moderate to severe ataxiaof gait, a mean age of onset at 55 years, and male predorninance.

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Figure 2 Perivascular cuffing mainly withT lymphocytes in cerebellar white matter in a patient with gluten ataxia ( s m e patient as Fig. 1).

Figure 3 Marked degeneration of the posterior columns of the thoracic cord in a 67year-old woman with myositis, ataxia, and neuropathy associated with celiac disease.

roportion

Cerebellar

The second group exhibited prominent resting or postural tremor, which became more marked on purposeful movement, and those in the third group were considered to be sporadic cases of olivopontocerebellar atrophy. The characteristics of our patients with gluten sensitivity and ataxia resemble most closely the first group, and we have proposed the term “gluten ataxia” (10) to describe them.So far we have identified 34 patients with gluten ataxia(Table 1). The mean age of these patients was 58 years (range 21-79). The mean age at onset of ataxia was 54 years (range 18-75). The male/female ratio was 3 :1. All 34 patients ‘had gait ataxia, In 12 patients the gait ataxia was severe (wheelchair-bound), in 10 it was moderate (used walking aids), and in the remaining 12 mild (walked without aid). Limb ataxia was present in all but 4 of the patients and was more marked in the lower limbs. Patients with moderate or severe ataxia had longer symptom duration than those with mild symptoms. Nystagmus was present in only 3 patients and was present on lateral gaze bi1 had extensor plantars. laterally. Seven patients had brisk reflexes, but only of pyramidal,extrapyramidal,orautonomicfeatureswas Nootherevidence found. Four patients developed a neuromuscular disorder before the developof periment of ataxia. In 10 patients there were clinical features suggestive pheral neuropathy at the time of assessment. These included absent deep tendon reflexes and distal sensory loss. Eight patients had evidence of impaired proprioception. That the clinical distinction between cerebellar and sensory ataxia can be very difficult is illustrated by the two cases with autopsy examinations. Their clinical features were identical, yet the findings at autopsy showed severe cerebellar involvement with Purkinje cell loss in one, but an intact cerebellum in the other. Both patients had posterior column damage, and in both, the peripheral nervous system showed sparse lymphocytic infiltrate.

Table 1 Summary of ClinicalCharacteristics of Gluten Ataxia

Feature IgA antigliadin antibody-positive IgG antigliadin antibody-positive Gastrointestinal symptoms Nystagmus on lateral gaze Limb ataxia Gait ataxia Coexistent neuropathy Histologically proven celiac disease DQ2 haplotype DR4,DQ8 haplotype

of patients

15/34 25/34 15/34 3/34 30134 34/34 22/29 13/34 29/34 5/34

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No patient had a family historyof spinocerebellar degeneration. Resultsof 2, 3, 6, 7, and Friedreich's ataxia genetic testing for spinocerebellar ataxia 1, were negative in all patients. Only one patient had low serum vitamin E levels. B,, (155 ngL, 138 ngL, normal range Two patients had a 'borderline low serum 160-900 ng/L). None of the 34 patients were anemic or had any other laboratory evidence of mal-i&xmption. Of the 34 patients, 25 were tested positive for IgG 6 for both. Fifteen paantigliadin antibody,15 for IgA antigliadin antibodies, and tients (44%) admitted to gastrointestinal symptoms after specific questioning (abdominal distention, abdominal pain, diarrhea). Twenty-nine patients (85%) had the HLA DQ2 genotype, the r e ~ a i n i n ghaving DR4DQS.

F. Ancillary Tests Distal duodenal biopsies showed mucosal changes in keeping with celiac disease in 13 patients. Two patients had lymphocytic infiltration in the lamina propria of the small bowel, but no villousatrophy. The remaining 17 patients hada normal mucosa. Threepatientswere not examinedneurophysiologically. Two patients were diabetic; one had an axonal and the other a demyelinating peripheral neuropathy. Of the remaining 30 patients,11 were members of a cohort being monitored for the effectof gluten-free diet and, therefore, had nerve conduction studies (NCS) only. Six had evidence of an axonal peripheral neuropathy and5 were normal, but the possibility that electromyography (EMG) might have disclosed a motor neuropathy cannotbe excluded. The other 18 patients had EMG and NCS; 2 were normal,5 had mononeuritis multiplex,8 had sensorimotor peripheral neuropathy (6 axonal, and 2 mixed axonal/demyelinating in type), and 3 had EMG evidence of motor neuropathy. One of the patients with axonal peripheral neuropathy also had evidence of myopathy (a muscle biopsy was compatible with polymyositis). Magnetic resonance imaging (MRI) studies were performed in 19 cases. Twelve of these showed incidental minor features, age-related global atrophy in 8, slight excess global atrophy in relation to age in 3, and evidence of previous asymptomatic ischemic events in 3 cases. Cerebellar atrophy, out of proportion to any evidence of atrophy in the cerebellar hemispheres, affecting both thevermis and the hemisphereswas noted in 6 cases. In 3 cases this was mild, in 2 cases moderate, and in 1 case was severe. The last case was also incidentally noted to have a Chiari 1 malformation. In noneof these 6 cases did any particular part of the cerebellum appear to be preferentially affected. The brain stem was not affected other than in the most severe case, in whom there was evidence of slight pontine atrophy. The mean time interval from onset of ataxia to the diagnosisof gluten sensitivity was 4.7 yews in the patients with mild atrophy, 7.5 years in those with moderate, and 23 years in the patient with severe atrophy.

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G. Management The duration of the immunological activity resulting in Purkinje cell damage may be important. Our series show a correlation between the duration of the ataxia and its severity as well as the presence of cerebellar atrophy on MRI. This may reflect chronic irreversible damage to the cerebellum, resulting in the loss of Purkinje cells, triggered by continuous ingestion of gluten in a gluten-sensitive individual. A study on the effect of a gluten-free diet on the ataxia and the peripheral neuropathy is currently taking place. Some of our patients in whom the diagnosis of gluten ataxia was prompt and the duration of the ataxia was short have experienced complete resolutionof their symptoms following strict adherence to a gluten-free diet. It is important to have a high indexof suspicion for gluten ataxia. It commonly occurs in patients in the absence of gastrointestinal symptoms and evidence of malabsorption. The use of antigliadin antibodies as a guide to diagnosis and a measureof adherence to the dietis promising, but antiendomysial antibodies may be less sensitive for a pathology the principal target of which is the nervous system.

111.

CEREBELLARENCEPHALITIS IN INFECTIOUS DISEASES

A.

Introduction

Wesphal(1 1) is credited with the first description of an acute cerebellar syndrome associated with an infectious illness in18’72.He reported four adult patients with acute ataxia related to smallpox and a fifth case associated with typhoid fever. The same syndrome occurring in childhood was described by Batten (12) in 1905 who reported five cases in whom the infective agent was measles, pertussus, or scarlet fever.

B. Epidemiology Postinfectious cerebellar encephalitis accounts for 0.4% of neurological presentations in children (13). There have been numerous reports of ataxia, predominantly in children, associated with specific infections, commonly viral illnesses, such as influenza, parainfluenza, mumps, measles, rubella, poliomyelitis, variola, cytomegalovirus, vaccinia, Echo, Coxsackie, varicella, herpes simplex, herpes zoster, Epstein-Barr virus (EBV), and epidemic encephalitis. Ataxia has also been associated with bacterial infections, such as pertussus, typhoid, scarlet fever, Q fever, diphtheria, leptospirosis, and mycoplasma (for reports on specific infections see Ref. 14). The same syndrome has also been described after falci-

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parum malaria parasitemia (15). Atypical pneumonias can also be associated with acute cerebellar dysfunction. Endtz et al. (16) highlighted this association in cases of mycoplasmal pneumonia in adults and Steele et al. (17) dealt specifically with pediatric cases. One of the authors of this chapter (MH) has seen a case of acute cerebellar encephalitis in a patient with Legionnaires’ disease. The clinical features of cerebellar encephalitis associated with bacterial infections are indistinguishable from those associated with viral infections. Cerebellar encephalitis makes up 50% of all neurological sequelae of varicella infection. It is estimated that 0.1% of patients with varicella infection will develop neurological dysfunction (1 8). One of the largest studies (73 patients) on the course and outcome of acute cerebellar ataxia in childhood is by Connolly et al. (1 3). The most common infective agent was varicella virus, which accounted for 26% of the cases. From the rest 2.6% were attributed to Epstein-Barr virus, 2.6% followed vaccination (one for smallpox and one for measles), and the remaining were presumed to be viral, but no positive serology was found. Cerebellar encephalitis in association with infection is less common in adults. The most common preceding infection is by EBV or Mycoplnsmn (1 9,20).

C. Molecular Pathogenesis Although results of viral cultures of the cerebrospinal fluid are seldom positive. the use of DNA amplification techniques has revealed evidence of viral infection in cerebellar encephalitis caused by varicella or niycoplasmal infections (19). Thus, the mechanism of cerebellar dysfunction in these cases could be related to direct infection of the CNS by the virus or bacterium, producing meningocerebellitis. The absence of any structural abnormality on the MRI scans is evidence against this being a result of a demyelinating process, such as acute disseminated encephalomyelitis (ADEM). ADEM is an immune-mediated monophasic demyelinating disease of the central nervous system characterized by perivenous inflammatory demyelination. MRI in ADEM usually reveals widespread white matter lesions, which can also be present in the cerebellum. ADEM tends to follow an infective illness with a latency of several days, sometimes even weeks. Although cerebellar dysfunction is frequently seen in ADEM, this is usually in combination with other focal neurological deficits, a situation analogous to multiple sclerosis. The absence of acute or chronic structural abnormalities on MRI in most patients is in favor of an alternative immune-mediated mechanism. Support to this contention comes from a study of De-Silva et al. (15). They described 12 patients with a self-limiting, delayed-onset cerebellar dysfunction following an attack of falciparum malaria that occurred 18-26 days previously. They found elevated concentrations of tumor necrosis factor (TNF), interleukin-6 (IL-6) and

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IL-2. These levels were much higher while the patients was ataxic than during the recovery phase from the parasitemia. Similar findings were observed in the patients’ cerebrospinal fluid. They concluded that iminunological mechanisms may play a role in delayed cerebellar dysfunction following falciparum malaria.

D. Neuropathology As the course of this illness is benign, there is very limited information from postmortem examination on the neuropathology of this condition. Isolated case reports of fatal encephalopathy in glandular fever are the only source of such information. Dolgopol et al. (21) found selective degeneration of the nerve cells in the nuclei of the third and fourth cranial nerves and the Purkinje cells of the cerebellum. There was also evidence of recent hemorrhages in the gray matter of the spinal cord. In a case described by Bergin (22) the changes were more widespread and consisted of cerebral edema. The cerebellum showed edema of the Purkinje layer. Both of these cases, however, presented with a much more fulminant illness unlike the cases with cerebellar encephalitis described earlier. In 2 of the 11 cases described by Klockgether et al. (20), MRI at follow-up did show cerebellar atrophy, implying that permanent damage may ensue in a few cases.

E. Clinical Features The clinical features of the patients described by Connoly et al. (13) showed remarkable uniformity and consisted of predominantly gait and lower limb ataxia. The peak incidence was at 3 years of age. Thirty-four percent of the children had severe ataxia, causing inability to walk. Nystagmus was present in 13.7% of the cases. The mean latency from onset of prodromal illness to onset of ataxia was 9.9 days (range 1 4 3 ) . The recovery period averaged at about 2 months, with the majority of the patients (88%) making a full recovery. Klockgether et al. (20) described 11 adult patients with acute cerebellar encephalitis identified over a period of 8 years. Ten patients were men and 1 was a woman (age range was 23-64 years, median 43 years). The clinical features were very similar to those encountered in children, with the addition of oculoniotor disturbances in 73% (impaired smooth pursuit being the most common, with a prevalence of 64%). The latency from onset of prodromal illness to development of ataxia was longer than that encountered in children at 3.5 weeks vs. 9.9 days. Serological testing was suggestive of Epstein-Barr virus infection in 4 and varicella infection in 2 patients. Complete recovery was observed in 9 of these patients and occurred within a mean of 12 weeks.

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F. Ancillary Tests Cerebrospinal fluid examination shows elevation of white cell count, predominantly lymphocytes, in 50% of patients, and high protein levels in about 30% of patients. Cerebrospinal fluid culture is usually sterile. Brain imaging with x-ray CT or MRI tend to be normal. In 3, of the 11 patients described by Klockgether et al.. for whom recovery was incomplete, there was cerebellar atrophy evident on MRI.

G. Management There is no evidence to suggest that treatment of the underlying infective agent (e.g., niycoplasma or varicella) alters the neurological sequelae. Management is supportive in the form of physiotherapy and occupational therapy during the symptomatic phase of the illness. The knowledge of a favorable prognosis is a source of reassurance for the patient.

IV. MILLER FISHER SYNDROME A.

Introduction

In 1932 Collier (23) descibed the triad of ataxia, areflexia, and ophthalmoplegia as a variant of the Guillain-Bad syndrome. In 1956 Miller Fisher (24j reported three patients with clinical features characterized by acute onset of ophthalmoplegia, ataxia, and areflexia suggesting that this was a distinct clinical entity. The disease is best considered to be a sensory ataxic neuropathy (ataxia being the dominant presenting feature) with associated ophthalmoplegia. 6 . Epidemiology The Miller Fisher syndrome is said to account for 5% of cases of acute inflammatory demyelinating polyneuropathy. The incidence, therefore, can be estimated to be 1 : 1 million per year.

C. Molecular Pathogenesis The association of sensory ataxic neuropathies with serum antibodies reactive against gangliosides is well-recognized. Gangliosides are membrane glycolipids present in nervous tissue, containing a ceramide moiety in the outer leaflet of the plasma membrane lipid bilayer and an oligosaccharide core exposed extracellularly. High titers of anti-GQ IgG antiganglioside antibodies have been observed in patients with Miller Fisher syndrome (25j, whereas this antibody is not usually elevated in patients with Guillian-Bad syndrome or chronic inflammatory demy-

,,

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elinating polyneuropathy in the absenceof ataxia and ophthalmoplegia, supporting a pathogenetic link between the antibodies and the neuropathy. A variantof Miller Fisher syndrome comprising ataxic areflexia with oropharyngeal palsy, but not ophthalmoplegia, exists with similar antibody profile (26). IgG anti-GO,, antij and, body has been reported to stain human cerebellar molecular layer (27 therefore, may be directly neurotoxic. The pathogenic effect of the antibody is likely to depend on many factors, including its specificity, integrityof the blood-nerve barrier, and the membrane microenvironment. Antibodies to Go,, cross-react with epitopes contained in the liposaccharide of Miller Fisher-associatedCampyZobacter jejuni strains, suggesting the possibility of molecular mimicry (28).

D. Neuropathology Autopsy findings have been reported as showing inflammatory lesions in the brain stem and demyelination of cranial nerves (29). There are no reports of inflammatory lesions in the cerebellum, although loss of Purkinje cells has been described (29). In the peripheral nervous system, dorsal root ganglion neurons are affected (30). Anti-GQ,, antibodies are associated with more severe damage to sensory, rather than motor nerves (the reverse scenario to that seen in GuillianBarr6 syndrome and anti-GM, antibodies) (30).The cerebellar pathology may be partly responsible for the ataxia seen in Miller Fisher syndrome, although the generally held view is that ataxia in Miller Fisher syndrome is peripheral in origin.

E. Clinical Features The mean age of onset is 44 years. The male/female ratio is approximately 2: 1 (31). A viral infection, commonly upper respiratory tract, precedes the neurological illness in 72% by an average of 10 days. The longest reported interval between prodromal illness and onset of symptoms is 5 weeks. The initial symptoms consist of diplopia in 39% of cases, gait ataxia in 21%, minor sensory symptoms, and often headache (29). The ophthalmoplegia usually evolves as a symmetrical failure of upgaze, followed by loss of lateral gaze, and last by downgaze, recovery occurring in the reverse order (31). The ataxia is often prominent and disabling. Deep tendon reflexes are depressed or absent in 82%of cases. Cranial nerves, other than the oculomotor nerves, are involved in more than half the cases, usually the facial, glossopharyngeal, and vagus nerves (31). Ophthalmoplegia may be complete or partial, and downgaze is sometimesspared.Disturbances of consciousness may occur, as may supranuclear oculomotor signs. Ptosis may be present, but may be asymmetrical, and near-light dissociation has been reported. Rarer manifestations of the condition include upper lid jerks, Parinaud’s syndrome, convergence spasm, internuclear ophthalmoplegia, and horizontal nystagmus.

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F. AncillaryTests Nerve conduction studiesmay be normal, although evidenceof peripheral demyelination level is often found, especially in sensory nerves. The cerebrospinal fluid protein level is often elevated. Evoked potential studies usually reveal no evidence of central demyelination, although a case associated with bilateral optic neuropathy has been reported (32). Electroencephalography may show generalized slowing. Enhancing lesions visible on MRI of the brain in the spinocerebel(33). These lesions lar tracts at the level of the lower medulla have been reported disappeared with resolution of the symptoms.

G. Management Prognosis is usually considered to be excellent, although itmay be slow, with recovery in a meanof 10 weeks. One-third of patients are left with residual symptoms and, in a few patients, recurrent episodes have been described. Mortality is a and usually selfless than 5%. Miller Fisher syndrome, therefore, is often mild limiting condition. There have been anecdotal reports of response to steroids, intravenous immunoglobulin treatment, and plasmapheresis.

V.

CEREBELLAR ATAXIAAND ANTI-GAD ANTIBODIES

A. Introduction Solimena et al. (34) were the first to report the presence of antibodies to glutamic acid decarboxylase (GAD; the enzyme responsible for the synthesis of y-aminobutyric acid) in the serumof a patient with stiff-man syndrome.The patient also had insulin-dependent diabetes mellitus (IDDM). Stiff-man syndrome is a rare disorderof the central nervous system characterizedby progressive and fluctuating axial muscle rigidity, with superimposed painful spasms. It is probably an autoimmune disorder and is associated with IDDM, thyroid disease, pernicious anemia, and vitiligo. Antibodies to glutamic acid decarboxylase (antiGAD) are found in 60% of patients with this condition. This enzyme is not confined to GABAergic neurons of the central nervous system, but it is also found in beta-cells of the endocrine pancreas. Seventy percent of patients with IDDM have anti-GAD antibodies. The association of anti-GAD antibodies and cerebellar ataxia is controversial.

B. Epidemiology The same authors that reported the presenceof anti-GAD in stiff-man syndrome published an abstract describing a patient with idiopathic late-onset ataxia and

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IDDM, who also had anti-GAD antibodies (35). A few isolated reports of antiGAD antibodies in idiopathic ataxia followed, but there has been no systematic estimation of the prevalence of these antibodies among patients with idiopathic ataxiaswithsuitablecontrolgroups.Furthermore,allbutone(36)cases described so far also hadIDDNI and, therefore, the presenceof the anti-GAD antibodies had an alternative explanation. Saiz et al. (37) described three patients with cerebellar ataxia, IDDM, and polyendocrine autoimmunity, who had antiGAD antibodies. The identification of these three patients was based on screening 67 patients with idiopathic cerebellar ataxia, giving this antibody a prevaThe authors do not provide an lence of 4% among patients with idiopathic ataxia. estimation of the prevalence in the normal population. Grimaldi et al. (38) provide a prevalence figure of anti-GAD in other neurological disorders at 3%. From currently available data there is no clear associationof anti-GAD antibodies and cerebellar ataxia.

C. MolecularPathogenesis We have seen two patients with stiff-man syndrome and anti-GAD antibodies, both of whom also had antigliadin antibodies and the HLA typing in keeping with gluten sensitivity. Oneof them went on to develop ataxia. Gluten sensitivity (discussed in Sec. 11) is an important cause of idiopathic late-onset ataxia and may well be the underlying mechanism of ataxia in such patients with anti-GAD antibodies.

D. ClinicalFeatures Given the limited number of cases described in the current literature, the clinicalexpressionisheterogeneous. Some of thecasesdescribedhadfeatures suggestive of late-onsetpurecerebellarataxia(35,37).However,one of the patients described showed clinical characteristics suggestive of paraneoplastic cerebellar degeneration (37) and another had early-onset (age 19) progressive ataxia with marked disturbanceof eye movements (36). Further large-scale studies looking at the prevalence of anti-GAD antibodies in the general population and patients with cerebellar ataxia without IDDNI or gluten sensitivity are necessary if a true association between ataxia and anti-GAD antibodies is to be established.

REFERENCES 1. Gee S. On the coeliac affection. St Bartholomew’s Hospital reports. 1888; 24:17-20. 2.Brown WC. Sprue and Its Treatment. London: Bale, 1908.

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3. Elders C. Tropical sprue and pernicious anaemia, aetiology and treatment. Lancet

1925;1:75-77. 4. Marks J, Shuster S, Watson AJ. Small bowel changes in dermatitis herpetiformis. Lancet 1966; 2: 1280-1282. 5. Cooke WT, Thomas-Smith W. Neurological disorders associated with adult coeliac disease. Brain 1966; 89:683-722. 6. Hadjivassiliou M, Chattopadhyay AK, Davies-Jones GAB, Gibson A, Grtinewald RA, Lobo AJ. Neurornuscular disorder as a presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry 1997; 63:770-775. 7. HadjivassiliouM,Gibson A, Davies-Jones GAB, Lobo A, Stephenson TJ, MilfordWard A. Is cryptic gluten sensitivity an important cause of neurological illness? Lancet 1996; 347: 369-371. 8. Harding AE, Muller PR, Thomas PK, Willison HJ. Spinocerebellar degeneration secondarytochronicintestinalmalabsorption:avitaminEdeficiencysyndrome. Ann Neurol 1982; 12:419424. 9. Harding AE. “Idiopathic” late onset cerebellar ataxia. A clinical and genetic study of 36 cases. J Neurol Sci 1981; 51:259-271. 10. Hadjivassiliou M, Grunewald RA, Chattopadhyay AK, Davies-Jones GAB, Gibson A, Jarratt JA, Kandler RH, Lobo A, Powell T, Smith CML. Clinical, radiological, neurophysiologicalandneuropathologicalcharacteristics of glutenataxia.Lancet 1998; 352:1582-3585. 11. Westbhal C. h e r eine Affection des Nervensystems nach Pocken und Typhus.Arch Psychiat Newenkr 1872; 3:376406. 12. Batten FE. Ataxia in childhood. Brain 1905; 87:141-152. RS. Course and outcome of acute cer13. Connolly AM, Dodson WE, Prensky AL, Rust ebellar ataxia Ann Neurol 1994; 35:673-679. 14. Weiss S, Guberman A. Acute cerebellar ataxia in infectious disease. In: Vinken PJ, BruynGW,KlawansHL,eds.HandbookofClinicalNeurology.Amsterdam: Elsevier Science, 1978:619-639. 15. De Silva HJ, Hoang P, Dalton H, De Silva NR, Jewel1 DP, Peiris JB. Immune activationduringcerebellardysfunctionfollowing Plasmodium ~alciparummalaria. Trans R SOC Trop Med Hyg 1992; 86:129-131. ~ycoplasmapneumoniae. 16. Endtz LJ, Hers JFP. Ataxie cdrdbelleuse aigui5 caus6e par Rev Neurol 1970; 122:52-54. S, Fleming PC. Acute cerebellar ataxia and 17. Steele JC, Gladstone RM, Thanasophon concomitant infection withMycoplasma pneumoniae. J Paediatr 1972; 80:467-469. 18. Kennedy PGE. Neurological complications of varicella zoster virus. In: Kennedy PGE, Johnson RT, eds. Infections of the Nervous System. London: Buttenvorths, 1987: 177-208. 19. Adams AD, Victor M, Ropper AH. Viral infections of the nervous system. In: Principles of Neurology. New York: McGraw-Hill, 1997:750. 20. Klockgether T, Doller G, WullnerU,Petersen D, Dichgans J. Cerebellar encephalitis in adults. J Neurol 1993; 240: 17-20. 21. Dolgopol VB, Husson GS. Infectious mononucleosis with neurologic complications. Arch Intern Med 1949; 83:179-196.

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22. Bergin JD. Fatal encephalopathy in glandular fever. J Neurol Neurosurg Psychiatry 1960; 23:69-73. 23. Collier J. Peripheral neuritis. Edin Med J 1932; 39:601-618. 24. Fisher CM. An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia). N Engl J Med 1956; 25557-65. 25. Chiba A, Kusonoki S, Shimizu T, Kanazawa I. Serum IgG antibody to ganglioside GQ,, is a possible marker of Miller Fisher syndrome. Ann Neurol 1992; 31:677679. 26. O’Leary CP, Veitch J, Durward WF, Thomas AM, Rees JH, Willison HJ. Acute oropharyngealpalsy is associatedwithantibodiestoGQ,,andGT,,gangliosides. J Neurol Neurosurg Psychiatry 1996; 61:649-5 l. 27. Kornberg AJ, Pestronk A, Blume GM, Lopate G, YueJ, Hahn A. Selective staining of the cerebellar molecular layer by serum IgG in Miller-Fisher and related syndromes. Neurology 1996; 47: 13 17-20. 28. Hahn AF. Guillain-Barre syndrome. Lancet 1998; 352:635-641. 29. Berlit P, Rakicky J. The Miller Fisher syndrome. Review of the literature. J Clin Neuroophthalmol1992;1257-63. 30. O’Leary CP, Willison HJ. Autoimmune ataxic neuropathies (sensory ganglionopathies). Curr Opin Neurol 1997; 10:366-370. 31. Al-Din SN, Anderson M, Eeg-Olofsson0,Trontelj JV. Neuro-ophthalmic manifestations of the syndrome of ophthalmoplegia, ataxia and areflexia: a review. Acta Neurol Scand 1994; 89(3): 157-63. 32. Toshniwal P. DemyelinatingopticneuropathywithMiller-Fishersyndrome.The caseforoverlapsyndromeswithcentralandperipheraldemyelination.JNeurol 1987; 234:353-358. 33. Urushitani M, Udaka F, Kameyama M. Miller Fisher Guillain-Barre overlap syndrome with enhancing lesions in the spinocerebellar tracts. J Neurol Neurosurg Psychiatry 1995; 58:241-243. 34. Solimena M, FolliF, Denis-Donini S, Comi GC, Pozza G, De Carnilli P, Vicari AM. Autoantibodies to glutamic acid decarboxylaseain patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med 1988; 318:1012-1020. 35. Solimena M, PiccoloG, Martino G, FolliF, Fratino P, De CamilliP. Autoantibodies directed against GABAergic nerve terminals in a patient with idiopathic late-onset cerebellar ataxia and type IB diabetes melitus. Clin Neuropath01 1988; 7:211. 36. Honnorat J, Trouillas P, Thivolet C, Aguera M, Belin M. Autoantibodies to glutamate decarboxylase in a patient with cerebellar cortical atrophy, peripheral neuropathy, and slow eye movements. Arch Neurol 1995; 52:462-468. 37. Saiz A, Arpa J, Sagasta A, Casarnitjana R, Zarranz JJ, Tolosa E, Graus F. Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, lateonset insulin dependent diabetes mellitus, and polyendocrine autoimmunity. Neurology 1997; 49:1026-1030. 38. Grimaldi LME, Martino G, Braghi S, Quattrini A, Furlan R, Bosi E, ComiG. Heterogeneitv of antibodies in stiff-man svndrome. Ann Neurol 1993: 3457-64.

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INTRODUCTION I.

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11. EPIDEMIOLOGY

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111. PATHOPHYSIOLOGY A.Heat-InducedCentralNervousSystemInjury B. Control of BodyTemperature C. Pathophysiology of Heat Stroke and Neuroleptic Malignant Syndrome

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CLINICAL FEATURES A.Heat-InducedCerebellarDeficits B. Clinical Features of Heat Stroke and Neuroleptic Malignant Syndrome

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VII. MANAGEMENT A. Management of Cerebellar Deficits Following Heat Injury B. Management of Acute Heat-Related Disorders REFERENCES

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INTRODUCTION

Hyperpyrexia with a body core temperature above 40°C can cause cerebellar damage with a subsequent cerebellar syndrome. The either transient or persistent heat-induced cerebellar deficits may be due to heat stroke (HS) (1-3), or to the neuroleptic malignant syndrome (NMS) (4-6). Other possible conditions associated with heat-induced cerebellar deficits are febrile illness, fever therapy (7-1 0), and postsurgical complications following thyroidectomy (1 1). Heat stroke is defined as a thermal insult to the cerebral thermoregulatory system and is characterized by a steady rise in body temperature (>4OoC), hot dry skin, and disturbances of consciousness, ranging from confusion to coma ( I 3). It is subdivided into “classic” and “exertional” HS. Although HS occurs in all age groups and under different environmental conditions, there are many predisposing factors for the disease. Environmental risk factors include high ambient temperatures and humidity, such as in heat waves or in certain industries ( 1,13-15). Classic HS often occurs epidemically during summer. Especially susceptible individuals are the elderly, alcoholics, infants, patients with chronic idiopathic anhydrosis. unacclimatized patients, and those with preexistent medical problems such as cardiovascular disease or diabetes mellitus who are taking diuretics or multiple medications (15-1 7). Other potentially hazardous drugs are antidepressants, neuroleptics and amphetamine (1 8-20). Exertional HS typically occurs in healthy young individuals in association with physical exertion (21). The iizaligimzt izeuroleptic syndroine is a rare, but often fatal, complication of antipsychotic medication. It is characterized by extrapyramidal rigidity, tremor, hyperpyrexia. altered mental status, autonomic dysfunction, and elevated levels of serum creatinine phosphokinase and white blood cell count (22). In spite of different etiology and clinical presentation, the described syndromes share the feature of hyperpyrexia as a possible cause of cerebellar ataxia.

II. EPIDEMIOLOGY Cerebellar ataxia caused by heat-induced central nervous system injury is a very rare disorder. Yaqub et al. (12) reported 2 out of 87 (2%) heat stroke patients seen at the Mecca Pilgrimage with a pancerebellar syndrome. In contrast, 2 out of 11 (1 8%) heat stroke patients developed persistent cerebellar deficits during the 1995 heat wave in Madison, Wisconsin (2 1). It remains unclear, if the difference between the two reports is only due to the small number of patients with distinct baseline characteristics in the latter. or if it is based on other factors such as geographic variations or different treatment modalities. Cerebellar ataxia caused by NMS, febrile illness, or postsurgical complications following thyroidectomy is reported for only single cases as a transient or persistent sequela (5,6,8-11.23).

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Incidence of heat stroke is not exactly known. During heat waves there is marked increase in heat-related deaths and hospital admissions. During the severe summer heat wave in the midwestern United States in 1995, admissions for heat stroke increased from0.2: 1000 casesin 1994 to2.3 :1000 cases in Madison, Wisconsin. In addition, 465 heat-related deaths were reported in Chicago, an 85% increase compared with 1994 (21). Sudden death in childhood from heat stroke was reported with an incidence of 0.3 :1 million (24). Annual incidence of heat 1 millionin one study (25). Mortalityof stroke in the army is estimated to be : 95 heat stroke is estimated to be 12% worldwide (26). The neuroleptic malignant syndrome occurs in 0.2-1.4% of patients treated with neuroleptics, with a fatality rate of 4-22% (22,27).

111.

PATHOPHYSIO~OGY

A.

Heat-InducedCentralNervousSystemInjury

The dimension of brain tissue damage in heat stroke depends on the duration and level of increased body core temperature. Heat stroke induces cerebral ischemia and neuronal damage as well as widespread involvement of other body tissues such as thoracic and abdominal visceral and parenchymal damage (28). However, pathological changes are most conspicuous in the central nervous system. The underlying mechanisms are not yet fully understood. Cerebral hemorrhages and most of the lesions outside the brain are probably dueto shock, with anoxia and circulatory failure. Hyperpyrexia may cause direct cell damage by denaturation of enzymes or liquefaction of membrane lipids. Metabolic changes in the brain duringhyperpyrexiaincludeincreasedconcentrations of neurotransmitters, such as dopamine, serotonin, norepinephrine, and of the cytokines interleukin-l (IL-l), IL-6, and tumor necrosis factor (TNF). Heat stroke-induced cerebral ischemia and neuronal damage in rats can be attenuated by depletion of dopamineserotonin andby blockade of IL-1 receptors (29).The proinflammatory cytokines IL-l and TNF induce nitric oxide (NO) production by activating nitric oxide synthase (NOS) (30). Nitric oxide can react with superoxide radical to form peroxynitrite and the hydroxyl radical, two oxidating agents that can induce tissue damage. The increased concentrations of monoamines at the onsetof heat stroke is possibly associated with NO production, because NO stimulates the release of dopamine and serotonin in the striatum and in the medial preoptic area (31,32). The basis of selective vulnerabilityof cerebellar Purkinje cells and neurons of the deep cerebellar nuclei to heat-induced CNS injuries is not completely understood.Onereasonmightbethattheheat-shockresponsewithexpression of anti-inflammatory heat-shock proteins (HSP) differs in spatial and temporal distribution in the brain (33,34). Accumulationof HSP mRNA in rabbits with wholebody hyperthermia is delayed in Purkinje cells, neurons of the deep cerebellar

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nuclei, and motor neuronsof the spinal cord. BecauseHSP inhibits NOS, failure to accumulate HSP might result in cellular damagein these parts of the nervous system. The rare complicaton of cerebellar deficits in neuroleptic malignant syndrome, febrile illness, fever therapy, and postsurgical complications following thyroidectomymostprobablyisalsoduetohyperpyrexia-inducedcerebellar damage.

ontrol of Body ~ e m ~ e r a t ~ r e Body core temperature in humans is maintained within a narrow range at about 37°C despite extreme changes in physical exertion and environmental conditions. Although moderate elevationof the body temperature canbe useful to initiate the acute-phase response in different diseases, hyperpyrexia above 40°C can cause damage to the brain and other tissues. The thermoregulatory centers controlling heat production and heat loss are located in the hypothalamus.The most important source for heat production is muscle activity. However, heat is also gained during digestion of food and from the environmentif the ambient temperatureis more than the body temperature (35). Heat loss can be achieved by convection, radiation, and evaporation.The principal method is to carry heat to the body surface by increasing the volume of blood circulating in the skin and subcutaneous loss, which tissues. In addition, sweat production and vaporization increases heat is particularly important if the ambient temperature exceeds thatof the body, or if physical exercise increases the body core temperature. The thermoregulatory system is a negative-feedback control system: Integrative structures gain informations about the existing central temperature through afferent pathwaysof the temperature sensors and initiate appropriate countermeasures by vasomotor, sudomotor, and metabolic effectors.

e and Neuro~e~tic Heat stroke may be induced by several mechanisms: (a) ineffective sweating caused by high ambienthumi~ity,slow air movements, or overcrowding; (b) cessation of sweating caused by exhausted sweat glands; (c) reduced sweating by cholinergic system dysfunction or anticholinergic drugs; or (d) interference of antidopaminergic drugs with hypothalamic thermoregulation (5,19). Heat stroke may occur if body core t ~ ~ ~ e rexceeds ~ t ~ 40°C r e (12). Temperatures of up to 44.4"C have been recorded in this disorder.A temperature higher than 455°C is probably incompatible with life (36)' The pathophysiology of NMS remainsspeculative. The mostprobable of dopamine receptors in both the basal ganglia mechanisms seem to be blockade and the hypothalamus. Affection of the basal ganglia leads to muscle rigidity and

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blockade of the dopaminergic tuberoinfundibular system to hyperpyrexia caused by cessation of subcutaneous vasodilation. However, the dopamine-deficiency hypothesis cannot sufficiently explain all aspects of the syndrome (37).

Acutefatalheatstrokeresultsinwidespreadpathologicalchangesindifferent body tissues. However, tissue injury by thermal cellular damage and circulatorychanges is mostconspicuousinthecentralnervoussystem(CNS). The most common pathological changes in the CNS include edema, petechial hemorrhages, and congestion, most pronounced in the region of the third ventricle, aqueduct, fourth ventricle, and white matter (7,28). These alterations are similar to those in shock without hyperpyrexia and, therefore, are most probably due to circulatory failure. Specific pathological changes caused by hyperpyrexia may be present in basal ganglia and cerebral cortex. However, changes are most striking, most consistent, and most rapid in development in the cerebellum. These include lossof Purkinje cells and, less pronounced, of deep nuclei neurons as well as a moderate proliferation of satellite oligodendroglia in molecularandgranularlayers.ProliferatingBergmann’sgliacellsreplacethe Purkinje cell layer. The severity of these alterations depends on the length of survival after occurrence of hyperthermia in fatal cases of heat stroke. Survival of more than 1 week leads to an almost entire loss of Purkinje cells. In shorter survival times, there is marked edema of the Purkinje layer, with reduction of Purkinje cells. The remaining Purkinje cells are swollen, pyknotic, or disintegrated (5,28). Pathological changes outside the CNS following heat stroke are present in thoracic and abdominal viscera. These include hemorrhages in lungs, subepicardial and subendocardial tissues, and in the region of His. Affectionof the coagulation systemmay lead to disseminated intravascular coagulation (38). Parenchyof more than 24h. Affected mal lesions are predominant in cases with a survival parenchyms include heart muscle, lungs, liver, and adrenal cortex (28).

V. ~ L I ~ I C A FL A.

Heat-l~d~ced Cerebellar Deficits

The rare cerebellar deficits in heat-induced CNS injury are nonspecific and range from isolated cerebellar dysarthria to a pancerebellar syndrome. Symptoms might include ataxia of stance, gait, and limbs, as well as dysarthria, tremor, and oculomotor disturbances. The natural clinical course of the deficits is unpredictable and ranges from complete recovery to a severe persistent wheelchair-bounding pancerebellar syndrome (2,3,5,6,10,12,39-43).

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.

Clinical Features of Heat Stroke and aligna ant Syndrome

Characteristic clinical features in heat stroke are sudden onset with collapse, changes in the levelof consciousness, ranging from restlessnessor confusion, to deep coma, hot dry skin, constricted pupils, anda rectal temperature of 40°C or more. Deep coma, with areflexia and absent brain stem reflexes, were reported in 29% in a series of 87 heat stroke patients. Plantar responses in comatose patients were usually extensor or equivocal, and automatic complex movements such as chewing or lip smacking, were present in 20% of the patients. Hemiplegia and treatment complications, such as body shivering during and convulsions after cooling, were reportedin less than 10%of the patients, as well as a pancerebellar syndrome (12). Other rare neurological deficits in single-case reports include isolated cerebellar dysarthria, parkinsonism, aphasia, flaccid paralysis, athetosis, sensory deficit with anosmia, and diplopia (2,4143). Excessive sweating is unusual, but has been reported in some heat stroke patients (28,43,44). Patients with exertional heat stroke have the additional features of rhabdomyolysis and renal failure (45,46).The mortality rate is nowadays estimated to be 12%, and full recovery can be expected in more than 80% of the patients (1,21,26), Clinical course and prognosis depend on initial presentation, core temperature, and cooling time. as well as with a temPrognosis is worse with sudden onset and prolonged coma perature of 42°C or more and a cooling time of 70 min or more (1,28,47). The neuroleptic malignant syndrome is a very rare side effect of antipsychotic medications. It is characterized by severe rigidity, tremor, high fever, altered mental status, autonomic dysfunction, with an elevated serum creatinine phosphokinase level and white blood cell count (22). Althoughmost the common drug involved is haloperidol, NNIS can virtually be induced by all neuroleptics, including the newer atypical antipsychotics (6,48). The typical syndrome evolves within days after initiation of treatment, dosage adjustment, or withdrawal of medication (27,37). Resolutionof symptoms after discontinuationof neuroleptics occurs within a mean duration of 13 days for nondepot and 26 days for depot neuroleptics (27). Severe complications appear to be secondary to the patients debilitated state and most commonly include pneumonia, renal failure, and cardiorespiratory arrest (27). Cognitive deficits, parkinsonian signs, and cerebellar deficits are extremely rare long-term complications of NMS (5,6,23).

VI. ANCILLARY TESTS Ancillary tests in the acute stages of the diseases focuson the metabolic changes and the possible complications described in the foregoing. Creatinine phosphokinase level is usually raised in heat stroke and neuroleptic malignant syndrome.

Physical Causes of Ataxia

673

Preserved brain stem auditory-evoked potentials might beof diagnostic value in comatose heat stroke patients with absent brain stem reflexes (12). Initial imaging of the brain is usually normal. However, irregular patchy areas may be present in the cerebral white matter on T2-weighted MRI of heat stroke patients (42). A progressive generalized cerebellar atrophy often evolves in patients with both NMS-and heat stroke-induced cerebellar syndrome. The neuroradiologic alterations, including enlargementof cerebellopontine angle, superior cerebellar cisterns, cerebellar sulci, and fourth ventricle, are visible after several months and might be progressive over several years (3,6,19,40,42). The progressive cerebellar atrophy reflects the particular vulnerability of cerebellar neurons in heat-inducedCNS injury and corresponds well to the neuropathological finding of Purkinje cell and deep cerebellar nuclei neuron loss.

VII.

A.

MANAGEMENT Management of CerebellarDeficits Following Heat injury

All patients with a persistent heat-induced cerebellar syndrome should receive physiotherapy and, if necessary, speech therapy. Adaptation and adjustment can markedly attenuate the limitiations in daily life. Patients should be informed about the nonprogressive character of the disorder and must be encouraged to train and extend their remaining capabilities.

B. Management of Acute Heat-Related Disorders The prognosis of heat stroke patients depends essentially on early diagnosis and prompt treatment. Close monitoring of temperature, blood pressure, heart rate, white blood cell count, electrolytes, and renal function is essential for adequate treatment. Rapid cooling of the patient, hydration with hypotonic crystalloidsolutions, and avoidance of heart failure, aspiration, and other possible complications, are most important. Rapid cooling can be achieved with the classic icewater bath or, less effective, with sponging, fans,or cooling blankets. If external cooling is insufficient, internal cooling can be achieved by gastric or peritoneal lavage with iced saline. If available, special body cooling units for evaporative cooling or special cooling beds should be used (12,47). Computed tomography or MRI scans of the brain should be done in an early stage of heat stroke to exclude edema or hemorrhage caused by disseminated intravascular coagulation. In neuroleptic malignant syndrome, neuroleptics should be stopped immediately and supportive medical treatment, suchas cooling and rehydration, must be initiated. Adjuvant drug therapy with amantadine, dantrolene, or bromocrip-

674

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tine might attenuate symptoms and shorten the course of the disease (37). Physostigmine is indicated in~yperthermiacaused by atricyclic antidepressant overdose (49). In febrile illness, specific therapy based on the differential diagnosis for a givenpatientismostimportant.However, for temperatures of 41°C ormore, physical cooling and treatment with antipyretics to reset the hypothalamic setpoint is clearly indicated (49).

1. Yaqub BA, Al-Harthi SS, Al-Orainey IO, Laajam MA, Obeid MT. Heat stroke at the Mekkah pilgrimage: clinical characteristics and course of 30 patients. Q J Med 1986; 59:523-530. 2. Stewart RM. Occurrenceof cerebellar syndrome following heat stroke. Rev Neurol Psychiat 1918; 16:78. 3. Albukrek D, Bakon M, Moran DS, Faibel M, Epstein Y.Heat-stroke-induced cerebellaratrophy:clinicalcourse,CTandMRIfindings.Neuroradiology1997; 39: 195-197. 4. La1 V, SardanaV, Thussu A, Sawhney IM, Prabhakar S. Cerebellar degeneration following neuroleptic malignant syndrome. Postgrad Med J 1997; 73:735-736. 5. Lee S, Merriam A, Kim TS, Liebling M, Dickson DW, Moore GR. Cerebellar degeneration in neuroleptic malignant syndrome: neuropathologic findings and review of the literature concerning heat-related nervous system injury. J Neurol Neurosurg Psychiatry 1989; 52:387-391. 6. Manto M, Goldman S, Hildebrand J. Cerebellar gait ataxia following neuroleptic malignant syndrome. J Neurol 1996; 243: 101-102. 7. Gore I, Isaacson NH. The pathology of hyperpyrexia: observation at autopsy in 17 cases of fever therapy. Am J Pathol 1949; 25:1029-1059. 8. Adamolekun B, Eniola A.Thidne-responsive acute cerebellar ataxia following febrile illness [see comments]. Cent Afr J Med 1993; 39:40-41. 9. Mohapatro AI(,Thomas M, Jain S, Mishra NK, Goulatia RK, Maheshwari MC. Pancerebellar syndrome in hyperpyrexia. Australas Radio1 1990; 34:320-322. 10. Manto MU, Topka H. Reversible cerebellar gait ataxia with postural tremor during episodes of high pyrexia. Clin Neurol Neurosurg 1996; 98:227-230. 11. Silverman JJ, Wilson JE. An unusual complication following thyroidectomy: heat stroke with permanent cerebellar damage. Ann Intern Med 1950; 33: 1036-1041. 12. Yaqub B, A1 Deeb S. Heat strokes: aetiopathogenesis, neurological characteristics, treatment and outcome. J Neurol Sci 1998; 156: 144-151. 13. Charatan FB. Hundreds die in US as temperatures reach 41 degrees C [news]. Br Med J 1995; 311:277. 14. Lim MK. Occupational heat stress. Ann Acad Med Singapore 1994; 23:719-724. 15. Kilbourne EM, Choi K, Jones TS, Thaclcer SB. Risk factors for heatstroke. A casecontrol study. JAMA 1982; 247:3332-3336.

16. Dann EJ, Berkman N. Chronic idiopathic anhydrosis-a rare cause of heat stroke. Postgrad Med J 1992; 68:750-752. P. Heatstroke in well-wrapped infants. Lancet 1979; l:42217. Bacon C, Scott D, Jones 425. 18. Epstein U,Albukrek D, Kalmovitc B, Moran DS, Shapiro Y. Heat intolerance induced by antidepressants. Ann NY Acad Sci 1997; 813:553-558. 19. Lefkowitz D, Ford CS, Rich C, Biller J, McHenry LC Jr. Cerebellar syndrome followingneurolepticinducedheatstroke.JNeurolNeurosurgPsychiatry1983; 46:183-185. 20. Watson JD, Ferguson C, Hinds CJ, Skinner R, Coakley JH. Exertional heat stroke inducedbyamphetamineanalogues.Doesdantrolenehaveaplace?Anaesthesia 1993; 48: 1057-1060. 21. Dixit SN, Bushara KO, Brooks BR. Epidemic heat stroke in a midwest community: risk factors, neurological complications and sequelae. WisMed J 1997; 96:39-41. 22. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am 1993; 77: 185-202. 23. Koponen H, Rep0 E, Lepola U. Long-term outcome after neuroleptic malignant syndrome. Acta Psychiatr Scand 199;184:550-55 1. 24. Niimura I, Maki T. Sudden cardiac death in childhood. Jpn Circ J 1989; 53:15711580. 25. Dickjnson JG. Heat illness in the services. J R Army Med Corps 1994; 140:7-12. 26. Faunt JD, Willsinson TJ, Aplin P, Henschke P, Webb M, Penhall RI(. The effete in the heat: heat-related hospital presentations during a ten day heat wave [see comments]. Aust NZ J Med 1995; 25:117-121. 27. Addonizio G, Susman VL, Roth SD. Neuroleptic malignant syndrome: review and analysis of115 cases. Biol Psychiatry 1987; 22:1004-1020. 28. Malamud N, HaymakerW, Custer RP. Heat stroke. A clinico-pathological studyof 125 fatal cases. Milit Surg 1946; 99:397-449. 29. Lin MT. Heatstroke-induced cerebral ischemia and neuronal damage. Involvement of cytokines and monoamines. Ann NY Acad Sci 1997; 813572-580. 30. Chao CC, Hu S, Ehrlich L, Peterson PI(. Interleukin-l and tumor necrosis factoralphasynergisticallymediateneurotoxicity:involvementofnitricoxideandof N-methyl-D-aspartate receptors. Brain Behav Immun 1995; 9:355-65. 31. LonartG,Cassels m,Johnson K M Nitricoxideinducescalcium-dependent ['Hldopamine release from striatal slices. J Neurosci Res 1993; 35:192-198. 32. Lorrain DS, Hull EM. Nitric oxide increases dopamine and serotonin release in the medial preoptic area. Neuroreport 1993; 5:87-89. 33. Manzerra P, Rush SJ, Brown IR. Temporal and spatial distribution of heat shock mR.NA and protein (hsp7O) in the rabbit cerebellum in response to hyperthermia. J Neurosci Res 1993; 36:480-490. 34. Higashi T, Nakai A, UemuraY, Kikuchi H, Nagata K. Activationof heat shock factor 1 in rat brain during cerebral ischemia or after heat shock. Brain Res Mol Brain Res 1995; 34:262-270. 35. Stolwijk JA, Nadel ER, Thermoregulation during positive and negative work exercise. Fed Proc 1973;32:1607-1613.

676

Abele

36. Petersdorf RC, Root RK. Disturbances of heat regulation. In: Braunwald E, Isselbacher KJ, Petersdorf RG, Wilson JD, Martin JB, Fauci AS, eds. Harrison’s Principles of Internal Medicine. 11 ed. New York McGraw-Hill 1987:43-50. 37. Weller M, KornhuberJ. Pathophysiology and management of neuroleptic malignant syndrome. Nervenarzt 1992; 63:645-655. 38. Lelis M, doCarno G, Caldeira L, Abreu J, Freitas L, Doroana M. (Febrile coma and disseminated intravascular coagulation following heat stroke]. Acta Med Port 1992; 5:215-218. 39. Freeman W, Dumoff E. Cerebellar syndrome following heat stroke. Arch Neurol Psychiatry 1944; 5l $37-72. 40. Yaqub BA, Daif AK, Panayiotopoulos CP. Pancerebellar syndrome in heat stroke: clinical course and CT scan findings. Neuroradiology 1987; 29:294-296. 41. Manto MU. Isolated cerebellar dysarthria associated with a heat stroke. Clin Neurol Neurosurg 1996; 98:55-56. 42. Biary N, Madkour MM, SharifH. Post-heatstroke parkinsonism and cerebellar dysfunction. Clin Neurol Neurosurg 1995; 97:55--57. 43. Willcox WH. The nature, prevention and treatment of heat hyperpyrexia: the clinical aspect. Br Med J 1920; 1:392. 44. Shibolet S, Col1 R, Gilat T, Sohar E. Heatstroke: its clinical picture and mechanism in 36 cases. Q J Med 1967; 36525-548. 45. Lazar AI. Acute renal failure in severe exertional rhabdomyolysis [letter; comment]. J Assoc Physicians India 1993; 41:57-59. 46. WangAY, Li PK, Lui SF, Lai KN. Renal failure and heatstroke. Ren Fail 1995; 17: 171-179. 47. Al-Aska AK, Abu-Aisha H, Yaqub B, AI-Harthi SS, Sallam A. Simplified cooling bed for heatstroke [letter]. Lancet 1987; 1:381. AK.Neuroleptic malignant syndrome: a re48. Pelonero AL, Levenson JL, Pandurangi view. Psychiatr Serv 1998; 49: 1163-1 172. E, Is49. Gelfand JA, Dinarello CA. Fever and hyperthermia. In: Fauci AS, Braunwald selbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL, eds.Warrison’s Principles of Internal Medicine. 14th ed. New York: McGraw Companies, 1998:84-89.

I

Aase-Smith syndrome, 127 Abetalipoproteinemia, 206-2 17 acanthocytosis, 214 clinical features, 10-2 2 13 electrophysiology, 2 13 lipoprotein profile, 2 15 MTP gene mutations, 207 Retinitis pigmentosa, 210 treatment, 215-217 Vitamin E deficiency, 207-208 Acanthocytosis, 206 Acetazolamide: in EA-1, 511 in SCA6 and EA-2,456,461-463 Acidurias, organic 285 Acrocallosal syndrome, 117 Acute disseminated encephalomyelitis (ADEM), 658 Addison only, 272 Adrenoleukodystrophy, 272-273 Adrenomyeloneuropathy, 198, 272 AFP levels in A-T, 177 Alcoholic cerebellar degeneration, 57 1-584 alcohol toxicity, 575-576 clinical features, 579-580

[Alcoholic cerebellar degeneration] course, 580, 584 definition, 572 neuroimaging, 580-583 neuropathology, 576-578 pathogenesis, 573-576 prevalence, 572-573 treatment, 584 vitamin deficiency, 573-576 a,,-subunit of voltage-dependent calcium channel, 450-451 (see also Episodic ataxia type 2 and Spinocerebellar ataxia type 6) Amino acid disorders, 285 Aniridia,133 Anosmia in Refsum’s disease, 236 Antiepileptic drugs and ataxia, 584-585 Anti-GAD antibodies and cerebellar ataxia, 623-624, 662-663 clinical features, 663 prevalence, 662-663 Anti-Gliadin antibodies, 65 1, 655 Anti-GQ,, ,IgG antiganglioside antibodies, 660-661 Antineoplastic drugs and ataxia, 589-590 677

Index

Antineuronal antibodies, 611-6 15 Aquaductal stenosis in Walker-Warburg syndrome,133 Arachnoid cysts in glutaric aciduria type l, 282 Argininosuccinate synthetase deficiency, 286 Arylsulfatase a in MLD, 273 Ataxia: classification,102 clinicogenetic classification (Harding), 89-94 definition, 55, 101-103 diagnostic approach, 103 (see also Diagnosis of ataxia) history of the tern, 77-78 pathological classification, 88-89 Ataxia and pigmentary retinopathy, 201 Ataxia due to toxic causes, 584-595 Ataxia, intermittent, in metabolic disorders, 285-288 Ataxia teleangiectasia, 90, 164-1 82 AFP levels, 177 ATM mutations, 167 clinical features, 171-177 diagnostic criteria, 171 molecular pathogenesis, 164-171 treatment and vaccination, 179-1 8 l Ataxia with isolated vitamin E deficiency (AVED), 223-23 I (see also Vitamin E deficiency) a-TTP gene mutations, 226 clinical features, 227-229 diagnosis, 229 neuronal lipofuscin accumulation, 227 treatment, 230 Ataxia with parkinsonism, 201 Ataxin-1,345 Ataxin-2, 365 Ataxin-3, 389, 392-394 Ataxin-7, 474 A-TFRESNOy 165 ATM gene, 164 Autism, 66

Autonomic and urinary dysfunction in MSA, 552 (see also Multiple system atrophy) treatment 56 1 Autosomal dominant cerebellar ataxias (ADCA), 90-93 Autosomal recessive cerebellar ataxias, 106 Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), 193, 3 11-322 ARSACS gene carrier frequency, 314 clinical features, 15-3 3 l8 counseling, 322 electrophysiology, 3 18 eye signs, 316-317 neuroimaging, 3I 8-3 19 neuropathology, 3 15 treatment, 3 19-322 Ballistic movements, 56 Basilar impression, in Chiari malformation type I, 127-1 29 Basket cells, 9 Behr's syndrome, 201 Biernond'S ataxia, 426 Bilateral periventricular nodular heterotopia-mental retardation (BPNHMR) syndrome, 139, 144 Bismuth, ataxia due to 594 Bone marrow transplantation in ALD, 273 Burst neurons of the parapontine reticular formation (PPRF), 369 CACNAIA gene, 448, 450 (see also Episodic ataxia type 2 and Spinocerebellar ataxia type 6) mutations, 453-454 Calcium channel dysfunction in CACNAl A mutations, 455(see also Episodic ataxia type 2 and Spinocerebellar ataxia type 6) Cancer and cerebellar symptoms, 608 Carbohydrate-deficient-glycoprotein (CDG) syndromes, 136-137, 284 type TA,284-285

Index

Cardiac conduction block in mitochondrial disorders, 33 1,333 Carnitine supplementation in glutaric aciduria type 1, 283 Celiac disease and ataxia, 637-639, 650-657 (see aEso Gluten ataxia) Cerebellar agyria in Walker-Warburg syndrome,132 Cerebellar circuitry, basic operation of, 62-64 Cerebellar dysfunction: cerebellar tremors, 60 dysarthria, 66 eye movements, 54 multi-joint studies, 56 single-joint studies, 55 symptoms,102 voluntary movement, 55 Cerebellar encephalitis, 649-663 in infectious diseases, 657-660 cerebrospinal fluid examination, 660 clinical features, 659-660 epidemiology, 657-658 molecular pathogenesis, 658-659 neuroimaging, 658, 659, 660 neuropathology, 659 treatment, 660 Cerebellar encephalocele in Chiari type 111 malformation, 130 Cerebellar hypoplasia, 138-144 causes and syndromes, 139 Cerebellar malformations, 115-144 anatomical classification, 117 midline or vermis malformations, 120 unilateral malformations, 117 Cerebellum: anatomy,1-3,31-33 attention shifting, 65 autism, 66 cognitive functions,64-66 ~ontributionto speech, 66-67 control of eye movements, 54 control of voluntary movement, 55 development,13-16,120-121 ~unctional compartmentalization, 54 long-term depression, 12

[Cerebellum] molecular compartments, 15 motor learning, 12, 61-62 receptors, 7-9 timing theory, 12 Cerebraocular dysplasia-muscular dystrophy (COD-MD) syndrome, 133 Cerebrotendinous xanthomatosis (CTX), 200, 257-263 cholestanolkholesterol accumulation, 257-260 clinical features, 261-262 diagnosis, 262-263 electrophysiology, 262 magnetic resonance imaging, 262 treatment, 263 27-hydroxylase gene mutations, 259 Chenodeoxycholic acid (CDCA) in CTX, 263 Chiari malformations, 122, 127-130 Chiari type IV, 137 Childhood ataxia with central hypomyelination (CACH), 274-275 Cholestanolkholesterol accumulation in cerebrotendinous xanthomatosis, 257-260 Cholestasis and vitamin E deficiency, 640 Cholesterol in SLO syndrome, 14 L Choreoathetosis in A-T, 172 Chronic progressive external . ophthalmoplegia (CPEO), 326, 33 1 mutations, 329 Climbing fibers, 5, 25 COACHsyndrome,122,132,133 Cockayne’s syndrome, 90, 110, 201 Coenzyme Q in mitochondrial disorders, 337 Cogan’s syndrome, 122, 130 Cold feet in ARSACS, treatment 321 Coloboma, choroideoretinal, 1 17 associated with Joubert’s syndrome, 132

680

Congenital blindness in Walker-Warburg syndrome,133 Cortical cerebellar atrophy, history of the term, 83 Cortical cerebellar degeneration in the alcoholic (see Alcoholic cerebellar degeneration) COS cells, 350-351 Cowden’s syndrome, 13 1 COX-negative fibers, 335 Creutzfeldt-Jakob disease (CJD), 523-540 clinical features, 531-533, 536-537 “daisy” plaques in new variant CJD, 533, 535 diagnosis, 539 EEG, 532-533, 539 familial, 536-537 14-3-3 brain protease inhibitors, 539 histology, 533 iatrogenic, 525, 536 kuru-like amyloid plaques, 533, 535 magnetic resonance imaging new variant, 533 precautions, 540 prevalence, 524-525, 530 PRNP genehutations, 524, 525, 527 sporadic, 531 Cyst, posterior fossa, in Dandy-Walker malformation,122 Cytarabine (Cytosine Arabinoside; Ara-C), ataxia due to, 589-590 Cytochrome c oxidase (COX) deficiency, 330 D-2-Hydroxiglutaric aciduria, 284 Dandy-Walker complex, 124 Dandy-Walker malformation, 122, 124-127 Dandy-Walker variant, 122, 127 Decomposition of movement, 55 Deep cerebellar nuclei, 31-33 Dejerine Thomas type, 89 Dekaban’ssyndrome,122,132 Dentatorubral-pallidoluysian atrophy (DRPLA), 93, 105, 109

Index

De Toni-Fanconi-Debr6 syndrome, 33 1 Diagnosis of ataxia: autosomal dominant inheritance, 105 autosomal recessive inheritance, 106 characteristic phenotypes, 104 early-onset sporadic disease, 107 focal cerebellar disorders, 103 late-onset sporadic disease, 107 myoclonus,109 rapid disease progression, 108 retinal degeneration, 110 symptomatic ataxias, 102 Diffuse hypertrophy of the cerebellar cortex, 13 1 Dorsal root atrophy: in infantile-onset spinocerebellar ataxia, 299 in Friedreich’s ataxia, 154 Down gaze impairment in Niemann-Pick disease, 277 Drugs, ataxia due to 584-591 Dysdiadochokinesis, 55 Dysequilibrium syndrome, 90 Dysmetria, 55 Dysplastic cerebellar gangliocytorna, 13 1 Dyssynergia, 55 Early onset cerebellar ataxia, 90, 191-201 clinical features, 194 differential diagnosis, 198, 201 electrophysiology,196-197 magnetic resonance imaging, 197 progression,196 Eighth cranial nerve and nuclei atrophy in IOSCA, 299 Episodic ataxia type 1 (EA-l), 487-512 age of onset, 504 attacks of ataxia, 501-502 clinical features, 497-506 diagnosis, 506-507, 5 l l duration of attacks, 504 electromyography, 507-5 10 epilepsy, 497, 502 frequency of attacks, 504 hyperexcitability of peripheral axons, 494-495

Index

[Episodic ataxia type 1 (EA-l)] KCNA1 channel dysfunction, 492-494 KCNAl gene/mutations, 489-490 long QT syndrome, 495 molecular pathogenesis, 489-496 myokymia, 497 neuropathology, 496 phenomenology of attacks, 505-506 prevalence, 489 treatment, 511-5 12 triggers, 504-505 unnatural visualizations, 504 Episodic ataxia type 2 (EA-2), 447-465 a,,-subunit of voltage-dependent calcium channel, 450-45 1 acetazolamide responsiveness, 456 calcium channel dysfunction, 455 clinical features, 457, 460-461 molecular pathogenesis, 449-456 mutations, 453-454 neuroimaging, 46 1 oculomotor pattern, 46 1 prevalence, 449 treatment, 46 1-463 triggers, 457 Episodic/progressive ataxia, 448 CACNAlA mutation, 453 neuroimaging, 46 1 Exercise intolerance in MELAS, 333 Familial hemiplegic migraine (FHM), 448 acetazolamide responsiveness, 456 CACNAlA mutations, 453 calcium channel dysfunction, 455 Familial posterior column ataxia, 426 Familial spastic paraplegia, 3 12 Fatal familial insomnia, 539 prevalence, 530 Fatal infantile olivopontocerebellar hypoplasia,137 Ferrochelatase in IOSCA, 302 5-Flourouracil (5-FU), ataxia due to, 590 Focal cerebellar disorders, 103

681

Friedreich’s ataxia, 151-158 diagnostic criteria, 155-156 GAA expansion, 152-153 history, 79, 151-152 mitochondrial dysfunction, 153-154 treatment,158 Fukuyama congenital muscular dystrophy (FCMD), 133 Galactocerebrosidase in GLD, 274 Gaze-evoked nystagmus, 54 Gerstmann-Straussler-Scheinkerdisease (GSS), 105, 523-540 clinical features, 537-538 diagnosis, 539-540 EEG, 537 magnetic resonance imaging, 537 precautions, 540 prevalence, 524-525 PRNP gene/mutations, 525, 528-529, 537 PrP amyloid plaques, 537 Gillespie syndrome, 90, 123, 133 Glial cytoplamic inclusions (GCIs), 549-550 (see also Multiple system atrophy) Globoid cell leukodystrophy (GLD, Krabbe’s disease), 106, 198, 274 Glutamine expansion and neurodegeneration, 394-396 Glutaric aciduria type 1, 280-283 Glutaryl-CoA-dehydrogenase (GDH) deficiency, 280 Gluten ataxia: clinical features, 653-656 diagnosis, 656 duodenal biopsy, 656 electrophysiology, 656 epidemiology 637, 65 1 molecular pathogenesis, 652 neuroimaging, 656 neuropathology, 652-654 treatment, 657 GM, gangliosidosis, 106, 198, 277-280 Golgi cells, 10 Granular layer, 10

Index

HARD rt E syndrome, 132 Hartnup disorder, 288 Headache and mtDNA, 333 Hearing loss: in FRDA, 301 in IOSCA, 303 in Refsum’s disease, 246 Heat-induced central nervous system injury, 667-674 epidemiology, 668-669 neuroimaging, 673 pathophysiology, 669-67 1 treatment, 673 Heat stroke, 668, 670, 672 ataxia due to, 671 incidence, 669 neuropathology, 67 1 treatment, 673 Heavy metals, ataxia due to, 591-594 Hepatic fibrosis in COACH syndrome, 132 Hereditary spastic ataxia, 312 Hereditary spastic paraplegia, 79, 91, 94 Heredopathia atactica polyneuritiformis (see Refsum’s disease) Herniation in Chiari malformation type I, 128 Hexosaminidase AA3 in GM, gangliosidosis, 277-278 Holmes’ type of cerebellar ataxia, 88, 201 Hydrocephalus: in Chiari type I1 malformation, 130 in Dandy-Walker malformation, 124 in Walker-Warburg syndrome, 132 Hyperpyrexia, 668 Hypogonadism, female 294 Hypoparathyroidism and ataxia, 644-645 Hypoplasia of frontal and temporal lobe in glutaric aciduria type l, 282 Hypothyroidism and ataxia, 643-644 IDCA-C/-P, 546 Idiopathic cerebellar ataxia (IDCNILOCA), 9 1, 94, 107-108, 546

Idiopathic cerebellar degeneration, 545-562 Immunodeficiency in A-T,171, 173-175 Incontinence treatment, in ARSACS, 321 Infantile-onset spinocerebellar ataxia (IOSCA),193,293-307 central nervous system pathology, 299 clinical features, 302-304 electrophysiology, 305-306 gene locus, 295 hormonal tests, 306 imaging, 304-305 peripheral nerve pathology, 297 treatment, 306-307 Infantile Refsum’s disease, 237 Infectious diseases, cerebellar encephalitis in, 657-660 Inferior olive: comparator hypothesis, 30 lamellar bodies, 28 morphology, 25 olivary glomeruli, 27 physiology, 28 rhythmic activity, 28 timing hypothesis, 3 1 Insulin-dependent diabetes mellitus (IDDM) and anti-GAD antibodies, 662 Iron homeostasis: in Friedreich’s ataxia, 154 in IOSCA, 302 Isovaleric acidemia, 285-286 Joubert’s syndrome, 90, 122, 132 KCNAl gene, 489-490 (see also Episodic ataxia type 1) Kearns-Sayre syndrome (KSS), 198,326 diagnostic criteria, 33 1 mutations, 329 Klippel-Feil syndrome, 129 Krabbe’s disease, 106 Kuf‘s disease (adult NCL), 276 Kuru, 526, 533 amyloid plaques, 533, 534 prevalence, 524

Index

L-2-Hydroxiglutaric aciduria, 283-284 Lactate analysis in mitochondrial disorders, 335 Lactic acidosis in MELAS, 333 Lafora disease, 109 Late onset cerebellar ataxia, 90 Lateral reticular nucleus, 22 Lead, ataxia due, to 592-593 Leber’s hereditary optic neuropathy, 326, 334 Leigh’s disease, 326, 330, 334 Leukemia in A-T, 168, 175 Leukodystrophies, unknown, 275 Lhermitte-Duclos disease, 122, 131 Lichtenstein-Knorr disease, 201 Lipoic (thioctacid) acid in mitochondrial disorders, 337 Lipomas in MERRF, 333 Lissencephaly in Walker-Warburg syndrome,132 Lithium, ataxia due to, 590-591 Lorenzo’s oil in ALD, 273 Louis-Bar syndrome (see Ataxia teleangiectasia) Lymphoma in A-T, 168, 175 Macrocephaly in glutaric aciduria type 1, 281 Macular degeneration in SCA7, 476-477 Magnetic resonance imaging in mitochondrial disorders, 335-336 Magnetic resonance spectroscopy in MLD, 273 Malabsorption syndrome in abetalipoproteinemia, 210 Malignancies in A-T, 175 Manganese, ataxia due to, 594 Maple syrup urine disease, 285 Marie’s ataxia, 83-85, 192 Marinesco-Sjogren syndrome, 90, 201 Maternal inheritance in mitochondrial disorders, 327 Meckel’s syndrome, 127 Medial vestibular nucleus, 23 Megacisterna magna, 122, 127

683

Megalencephaly in “van der Knaap leukoencephalopathy,’’ 275 Menzel type of cerebellar ataxia, 88 Mercury, ataxia due to, 591-592 Merosin M-chain expression, 133 MERRFNELAS overlapsyndrome, 333 Metachromatic leukodystrophy,106,273 Methylrnalonic acidemia, 285 Microlissencephaly,137 Migraine in EA-2, 448 Miller Fisher syndrome, 660-662 anti-GQ,, IgG antiganglioside antibodies, 660-66 l cerebrospinal fluid examination, 662 clinical features, 661 incidence, 660 neuroimaging, 662 neuropathology, 66l treatment, 662 Mitochondrial cytopathy, 326, 335 Mitochondrial disorders, 325-338 clinical features, 331-336 diagnosis, 335-336 electromyography, 335 gene therapy, 338 magnetic resonance imaging, 335-336 MERRFNELAS overlap syndrome, 333 molecular genetics, 328-330 muscle biopsy, 330 neuropathology, 330 threshold concept, 330 treatment, 337 Mitochondrial DNA diagram, 328 Mitochondrial encephalornyopathy, lacticacidosis,withstrokelike episodes (MELAS), 326,333-334 clinical features, 333 mutations, 329 neuropathology, 330 Mitochondrial neuropathy and gastrointestinal encephalomyopathy (MNGIE), 329 Mixed solvents, ataxia due to, 594 Mohr syndrome, 127 1

684

Morbus Madelung, 334-335 Mossy fibers, 10, 16 Multiple sclerosis, 104 Multiple symmetric lipomatosis (Morbus Madelung), 334-335 Multiple system atrophy (MSA), 546-562 a-synuclein, 547 autonomic and urinary dysfunction, 552 autonomic tests, 555-556 clinical features, 550-555 diagnostic criteria, 550-552 electrophysiology, 560 gene expression profile, 548 genetic component?, 548 glial cytoplasmic inclusions (GCIs), 549-550 L-dopa induced facial dystonic spasms, 56 1 median survival, 547, 555 neuroendocrine tests, 556 neuroimaging, 556-560 prevalence, 546-547 red flags, 553-554 sphincter EMG, 560 treatment, 560-562 Muscle biopsy in mitochondrial disorders, 330 Muscular dystrophy, 132-133 Myelomeningocele in Chiari type 11 malformation,130 Myoclonic epilepsy with ragged red fibers (MERRF), 198-200, 326, 332-333 mutations, 329 neuropathology, 330 Myoclonus and ataxia, 109 Myokymia in EA-1,497 Nageotte nodules in IOSCA, 299 NARP syndrome, 198-200, 326, 334 Neonatal adrenoleukodystrophy, 237 Neural tube defect in Chiari type II/TII malformation,130 Neuroleptic malignant syndrome, 668, 670, 672 ataxia due to, 671-672

Index

[Neuroleptic malignant syndrome] epidemiology, 669 treatment, 673-674 Neuronal ceroid lipofuscinosis, 109, 110, 275-277 biopsy, 277 subtypes, 276 Neuronal intranuclear inclusions, 350-35 1 Neuropathy, ataxia and retinitis pigmentosa (NARP), 198-200, 326, 334 mutation, 330 Niemann-Pick disease type C, 198-199, 277 Night blindness in Refsum’s disease, 236 Nijmegen breakage syndrome(NBS), 165 Nucleus reticularis tegmenti pontis, 2 1-22 eye movements, 22 Nystagmus, downbeat, in Chiari type I malformation,129 Ocular dysmetria, 54 Oculomotor apraxia: in A-T, 171 in Cogan’s syndrome, 130 Oligodendroglial cytoplasmic inclusions, 546 Olivopontocerebellar atrophy, history of the term, 81-83 Ophthalmoplegia: in CPEO, 331 in IOSCA, 294 in Miller Fisher syndrome, 660, 661 Ophthalmoplegia plus, 33 l Ornithine transcarbamylase deficiency, 286 Osteoporosis in CTX, 261 Pain therapy in ARSACS, 319 Paine syndrome, 90, 137 Pancreatic exocrine insufficency/chronic pancreatitis and vitamin E deficiency, 640 Parallel fibers, 5

Index

Paramedian pontine reticular formation, 23 Paramedian reticular nucleus, 22 Paraneoplastic cerebellar degeneration (PCD), 607-624 Anti-CV2, 6 16, 620-62 1 Anti-Hu, 613-614, 619-620 Anti-Ma, 615, 620-621 Anti-Ri, 6 14-6 l 5, 6 19-62 1 Anti-Ta, 615, 620 Anti-Tr, 6 1,1 620-62 l Anti-Yo, 612-613, 619-620 clinical features, 618-622 diagnosis, 622-624 epidemiology, 609 immune pathogenesis, 6 16 Lambert-Eaton myasthenic syndrome (LEMS) and PCD, 615-61 6 neuroimaging, 622-623 neuropathology, 6 17-6 18 treatment, 624 Paraneoplastic encephalomyelitis/ sensory neuropathy (PEM/SN), 609 Pearson syndrome, 326, 331 PEHO syndrome, 137 Perihypoglossal nuclei, 22 Phenytoin, ataxia due to, 584-589 clinical features, 588-589 epidemiology, 585-586 management, 589 neuroimaging, 586, 587, 589 neuropathology, 588 pathogenesis, 586-588 Phytanic acid in Refsum’s disease, 236, 23 8-242 Pigmentary retinopathy in KSS, 33 1 Pontine nuclei, 17-21 eye movements, 21 Pontocerebellar hypoplasia (PCH), 9 1, 136-138 Prion diseases (transmissible spongiform encephalopathies), 523-540 Prion protein (PrP), 530-531 Progressive myoclonus epilepsy (PME), 109

685

Prominent myelinated retinal nerve fibers in ARSACS, 316-317 Propionic acidemia, 285 “Protein only” hypothesis, 530 Ptosis in KSS, 331 Purkinje cell layer, 5-10 Pyruvate dehydrogenase deficiency, 286 Radical scavanger in mitochondrial disorders, 337 Radiosensitivity in A-T, 171 Ragged blue fibers, 330 Ragged red fibers, 330, 335 Rarnsay Hunt syndrome, 85-87 Raphe nuclei, 23 Refsum’s disease, 236-2.52 clinical features, 244-248 CSF protein, 239 diet, 25 1-252 electrophysiology, 248-249 phytanic acid 238-242 phytanoyl-CoA hydroxylase gene mutations, 238, 242-243 plasma exchange, 252 treatment, 249-252 Renal cysts, 132 Respiratory chain, 327 Restless legs syndrome in SCA3, 403-404 Retinal degeneration and ataxia, 110 Retinal degeneration in SCA7, 476-477 Retinal dysplasia in Walker-Warburg syndrome,132 Retinal dystrophy in Joubert’s syndrome,132 Retinitis pigmentosa: in abetalipoproteinemia, 206, 2 12 in neuronal ceroid lipofuscinosis, 110 in Refsum’s disease, 236 Rhombencephalosynapsis, 122, 13 1 Saccade slowing in SCA2, 369, 373 Sandhoff disease, 277 Saposin B in MLD, 273 Scrapie, 524

Index

686

Sensory axonal neuropathy: in IOSCA, 294 in SCA4,426, 428-430 Shaker-related channels,490-49 1 Short-bowel syndrome and vitaminE deficiency, 639-640 Shy-Drager syndrome, 546 Sialidosis type 1, 109, l10 Smith-Lemli-Opitz syndrome, 139, 141-144

Solvents, ataxia due to, 594-595 Spasticity treatment: in ARSACS, 319 in SCA3,414 Speech deficit inIOSCA, 303 Sphingomyelinase in Niemann-Pick disease, 277 Spinocerebellar ataxia type 1(SCAl), 343-357

anticipation, 345 C A G repeat length variation, 345 clinical features, 353-354 correlation of repeat length and age of onset, 345 electrophysiology, 354-355 molecular pathogenesis, 345-352 neuroimaging, 355 neuronal intranuclear inclusions, 350-35 l

neuropathology, 352 prevalence, 344 proximal axonal dilations (torpedoes), 348

transgenic mice, 346-350 treatment, 356-357 Spinocerebellar ataxia type2 (SCA2), 363-380

anticipation, 367 clinical features, 373-375 cognitive dysfunction, 374-375 correlation of repeat length and age of onset, 366, 368 diagnosis, 368 differential diagnosis, 376 electrophysiology, 377 molecular pathogenesis, 365-368

[Spinocerebellar ataxia type2 (SCAZ)] neuroimaging, 376-379 neuropathology, 369-373 overlap of normal and expanded alleles, 365 predictive testing, 368 prevalence, 364-365 saccade slowing, 369, 373 treatment, 377, 380 Spinocerebellar ataxia type3 / Machado-Joseph disease(SCA3 / MJD), 385-416 allele distribution, 389 anticipation, 390 ataxin-3, 389, 392-394 clinical features, 398-408 clinical subphenotypes, 398-402 cognitive function,405-406 course, 407 diagnosis, 411-414 diplopia, 402 electrophysiology, 410-411 founder effect, 387 gender effects, 390 genotype-phenotype relation,406-407 glutamine expansion and neurodegeneration,394-396 molecular pathogenesis, 387-397 mosaicism, 390 neuroimaging, 408-410 neuropathology, 397-398 nuclear inclusion bodies,391-392 presymptomatic testing, 413-414 prevalence, 387 restless legs syndrome, 403-404 transgenic mice, 396-397 treatment, 414-416 Spinocerebellar ataxia type4 (SCA4), 425-43 1

anticipation, 429-430 clinical features, 428-430 electrophysiology, 430 molecular pathogenesis, 427 neuroimaging, 430 neuropathology, 427-428 prevalence, 427

Index

[Spinocerebellar ataxia type 4 (SCA4)] sensory axonal neuropathy, 426, 428-430 treatment, 430-43 1 Spinocerebellar ataxia type 5 (SCAS), 435-444 anticipation, 437, 440 clinical features, 441-442 genetic and physical mapping, 437 molecular pathogenesis, 437-441 neuroirnaging, 442-443 neuropathology, 443 treatment, 443-444 Spinocerebellar ataxia type 6(SCAG), 447-465 acetazolamide responsiveness, 456 a,,-subunit of voltage-dependent calcium channel, 450-45 1 anticipation, 45 1-452 CAG-repeat expansion, 451 calcium channel dysfunction, 455 clinical features, 457 correlation of repeat length and age of onset, 460 molecular pathogenesis, 449-456 neuroimaging, 461 neuropathology, 456, 458-459 prevalence, 449 treatment, 461-463 unique oculomotor pattern, 46 1 Spinocerebellar ataxia type 7 (SCA7), 469-48 1 anticipation, 478 ataxin-7, 474 clinical features, 476-479 correlation of repeat length and age of onset, 479 degeneration of optic pathways and retina, 476 de novo mutations, 471 diagnosis, 479 dyschromatopsia in the blue-yellow axis, 477, 479 electrophysiology, 479 first sign at onset, 478 frequency, 47 1

687

[Spinocerebellar ataxia type 7 (SCA7)l gonadal instability, 472-473 molecular pathogenesis, 47 1-475 neuroimaging, 479 neuronal intranuclear inclusions, 474 neuropathology, 475-476 presymptornatic testing, 479 treatment, 479-480 ubiquitination, 474 visual impairmenthlindness, 476-477 Spinocerebellar ataxia type 10 (SCA IO), 5 17-520 anticipation, 518 clinical features, 5 19 neuroimaging, 5 19 seizures, 5 19 Spinocerebellar disorders (SCD), 312-313 Spinocerebellar tracts, 23, 26-27 properties, 24 receptive fields, 24 Spinopontine atrophy,87-88 Splenomegaly in Niernann-Pick disease, 277 Stellate cells, 9 Stiff-man syndrome, 662 Strabism in CDG syndrome, 136 Striatonigral degeneration (SND), 546 Stroke and stroke-like episodes in mitochondrial disorders,331,333 Succinic semialdehyde dehydrogenase deficiency (4-Hydroxybutyric aciduria), 285 Sulthiame in EA-l , 5 11 Synucleinopathies, 547 Syringohydromyelia, in Chiari malformation,128 Tapetoretinal degeneration, in CDG syndrome,136 Tau-positive neurofibrillar degeneration in ARSACS, 315 Tay-Sachs disease, 277 Tectocerebellar dysraphia, 122, 13l Teleangiectasies, oculocutaneous, 17 1, 173

Index

688

Thallium, ataxia due to, 593 Thiamine deficiency, 634-636 Threshold concept in mitochondrial disorders, 330 Toluene, ataxia due to 594-595 Transferrin isoelectric focusing in CDG syndrome type I, 138, 285 Transmissible spongiform encephalopathies, 523-540 bovine spongiform encephalopathy (BSE), 524 clinical and neuropathological features, 531-539 diagnosis, 539-540 precautions, 540 prevalence, 524-525 prion protein (PrP), 530 PRNP genelmutations, 524, 525 “protein only” hypothesis, 530 PrP amyloid plaques, 531 Tremor, 60 Troyer syndrome, 3 12-3 13 Unverricht-Lundborg type, progressive myoclonus epilepsy of, 109, 201 Urea cycle defects, 286 Van der Knaap leukoencephalopathy, 275 Vanishing white matter disease, 274-275 Varicella infection and ataxia, 658 Vermis agenesis, 132-1 35 in Dandy-Walker malforrgation, 124 Vermis aplasia,familial,133 with holoprosencephalie, 123, 133 Vermis dysgenesis, 130-131 Vestibulo-ocular reflex, 54 j

Visuospatial deterioration in ARSACS, 3 17 Vitamin B, deficiency (Wernicke’S encephalopathy), 634-636 clinical features, 635 treatment, 635-636 Vitamin B , , deficiency, 641-643 clinical features, 642 diagnosis, 642-643 neuropathology, 642 pathogenesis, 641-642 treatment, 643 Vitamin E, 224-225, 636-637 Vitamin E deficiency: in abetalipoproteinemia, 206 in ataxia with isolated vitamin E deficiency, 223-23 I in celiac disease, 637-639 in cholestasis, 640 in chronic pancreatitis and pancreatic exocrine insufficency, 640 clinical features, 637-638 in short bowel syndrome, 639-640 treatment, 639 Walker-Warburgsyndrome,123,132, 137 Wernicke’s encephalopathy, 574, 634-636 Wilson disease, 198, 200 Worm wobble, 591 Xanthomas in CTX, 261 Xeroderma pigmentosum, 90, 20 1 X-linked dominant cerebellar vermis aplasia, 123 Zellweger’s syndrome, 237

About the Editor

THOMAS KLOCKGETHER is Professorof Neurology and Directorof the Department of Neurology, University of Bonn, Germany. Heis the coauthor of numerous articles on disordersof the nervous system, focusing on ataxia disorders. A former Deputy Director of the Department of Neurology at the Universityof Tubingen, Germany, he is a Corresponding Fellow of the American Academyof Neurology and member of the Movement Disorder Society and the Deutsche Gesellschaft fur Neurologie. Dr. Klockgether received the M.D. degree (1980) from the University of Gottingen, Germany, and the Habilitation degree (1 99 1) from the University of Tubingen, Germany.

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