Huntington's disease [4 ed.] 9780199929153, 0199929157

Table of contents :
Cover
Huntington’s Disease
Series
Copyright
Contents
Contributors
Section one
Clinical Aspects of Huntington’s Disease
1 Huntington’s Disease in a Historical Context
2 Clinical Neurology
3 Neuropsychiatry and Neuropsychology
4 Juvenile Huntington’s Disease
5 Premanifest and Early Huntington’s Disease
Section two
Genetics of Huntington’s Disease
6 Genetic and Molecular Studies
7 Epidemiology
8 Genetic Counseling and Testing
Section three
Neurobiology of Huntington’s Disease
9 Neuropathology in the Human Brain
10 Altered Neuronal Circuitry
Section Four
Molecular Biology of Huntington’s Disease
11 Normal Function of Huntingtin
12 Structural Biology: Order, Disorder, and Conformational Flux
13 Pathogenic Mechanisms
14 Peripheral Pathology
Section five
Therapeutic Interventions in Huntington’s Disease
15 Comprehensive Care
16 Preclinical Experimental Therapeutics
17 Experimental Therapeutics: Moving Forward in Clinical Trials
Index

Citation preview

Huntington’s Disease

OXFORD MONOGRAPHS ON MEDICAL GENETICS General Editors: Judith G. Hall Peter S. Harper Louanne Hudgkins Evan Eichler Charles J. Epstein (deceased 2011) Arno G. Motulsky (resigned 2011) 1. R.B. McConnell: The genetics of gastrointestinal disorders 2. A.C. Kopéc: The distribution of the blood groups in the United Kingdom 3. E. Slater and V.A. Cowie: The genetics of mental disorders 4. C.O. Carter and T.J. Fairbank: The genetics of locomotor disorders 5. A.E. Mourant, A.C. Kopéc, and K. Domaniewska-Sobezak: The distribution of the human blood groups and other polymorphisms 6. A.E. Mourant, A.C. Kopéc, and K. Domaniewska-Sobezak: Blood groups and diseases 7. A.G. Steinbert and C.E. Cook: The distribution of the human immunoglobulin allotypes 8. D. Tills, A.C. Kopéc, and R.E. Tills: The ­distribution of the human blood groups and other polymorphisms: supplement I 10. D.Z. Loesch: Quantitative dermatoglyphics: ­classification, genetics, and pathology 11. D.J. Bond and A.C. Chandley: Aneuploidy 12. P.F. Benson and A.H. Fensom: Genetic biochemical disorders 13. G.R. Sutherland and F. Hecht: Fragile sites on human chromosomes 14. M. d’A Crawfurd: The genetics of renal tract disorders 16. C.R. Scriver and B. Child: Garrod’s inborn factors in disease 18. M. Baraitser: The genetics of neurological disorders 19. R.J. Gorlin, M.M. Cohen, Jr., and L.S. Levin: Syndromes of the head and neck, third edition 21. D. Warburton, J. Byrne, and N. Canki: Chromosome anomalies and prenatal development: an atlas 22. J.J. Nora, K. Berg, and A.H. Nora: Cardiovascular ­disease: genetics, epidemiology, and prevention 24. A.E.H. Emery: Duchenne muscular dystrophy, second edition 25. E.G.D. Tuddenham and D.N. Cooper: The molecular genetics of haemostasis and its inherited disorders 26. A. Boué: Foetal medicine 27. R.E. Stevenson, J.G. Hall, and R.M. Goodman: Human malformations 28. R.J. Gorlin, H.V. Toriello, and M.M. Cohen, Jr.: Hereditary hearing loss and its syndromes 29. R.J.M. Gardner and G.R. Sutherland: Chromosomes abnormalities and genetic counseling, second edition 30. A.S. Teebi and T.I. Farag: Genetic disorders among Arab populations 31. M.M. Cohen, Jr.: The child with multiple birth defects 32. W.W. Weber: Pharmacogenetics 33. V.P. Sybert: Genetic skin disorders 34. M. Baraitser: Genetics of neurological disorders, third edition 35. H. Ostrer: Non-Mendelian genetics in humans

36. E. Traboulsi: Genetic factors in human disease 37. G.L. Semenza: Transcription factors and human disease 38. L. Pinsky, R.P. Erickson, and R.N. Schimke: Genetic disorders of human sexual development 39. R.E. Stevenson, C.E. Schwartz, and R.J. Schroer: X-linked mental retardation 40. M.J. Khoury, W. Burke, and E. Thomson: Genetics and public health in the 21st century 41. J. Weil: Psychosocial genetic counseling 42. R.J. Gorlin, M.M. Cohen, Jr., and R.C.M. Hennekam: Syndromes of the head and neck, fourth edition 43. M.M. Cohen, Jr., G. Neri, and R. Weksberg: Overgrowth syndromes 44. R.A. King, J.I. Rotter, and A.G. Motulsky: The genetic basis of common diseases, second edition 45. G.P. Bates, P.S. Harper, and L. Jones: Huntington’s disease, third edition 46. R.J.M. Gardner and G.R. Sutherland: Chromosome abnormalities and genetic counseling, third edition 47. I.J. Holt: Genetics of mitochondrial disease 48. F. Flinter, E. Maher, and A. Saggar-Malik: The genetics of renal disease 49. C.J. Epstein, R.P. Erickson, and A. Wynshaw-Boris: Inborn errors of development: the molecular basis of clinical disorders of morphogenesis 50. H.V. Toriello, W. Reardon, and R.J. Gorlin: Hereditary hearing loss and its syndromes, second edition 51. P.S. Harper: Landmarks in medical genetics 52. R.E. Stevenson and J.G. Hall: Human malformations and related anomalies, second edition 53. D. Kumar and S.D. Weatherall: Genomics and clinical medicine 54. C.J. Epstein, R.P. Erickson, and A. Wynshaw-Boris: Inborn errors of development: the molecular basis of clinical disorders of morphogenesis, second edition 55. W. Weber: Pharmacogenetics, second edition 56. P.L. Beales, I.S. Farooqi, and S. O’Rahilly: The genetics of obesity syndromes 57. P.S. Harper: A short history of medical genetics 58. R.C.M. Hennekam, I.D. Krantz, and J.E. Allanson: Gorlin’s syndromes of the head and neck, fifth edition 59. D. Kumar and P. Elliot: Principles and practices of ­cardiovascular genetics 60. V.P. Sybert: Genetic skin disorders, second edition 61. R.J.M. Gardner, G.R. Sutherland, and L.C. Shaffer: Chromosome abnormalities and genetic counseling, fourth edition 62. D. Kumar: Genomics and health in the developing world 63. P.S. Harper: A short history of medical genetics, ­second edition (online) 64. G. Bates, S. Tabrizi, and L. Jones: Huntington’s Disease, fourth edition

Huntington’s Disease 4th edition

Ed i t e d b y G i l l i a n P. B at e s , S a r a h J .   Ta b r i z i and Lesley Jones

1

1 Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford New York Auckland  Cape Town  Dar es Salaam  Hong Kong  Karachi  Kuala Lumpur Madrid Melbourne Mexico City Nairobi  New Delhi Shanghai Taipei Toronto  With offices in Argentina Austria Brazil Chile Czech Republic France Greece  Guatemala Hungary Italy Japan Poland Portugal Singapore  South Korea Switzerland Thailand Turkey Ukraine Vietnam Oxford is a registered trademark of Oxford University Press in the UK and certain other countries. Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016

© Oxford University Press 2014 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above. You must not circulate this work in any other form and you must impose this same condition on any acquirer. Library of Congress Cataloging-in-Publication Data Huntington’s disease (2014) Huntington’s disease/edited by Gillian P. Bates, Sarah J. Tabrizi, Lesley Jones.—4th edition.   p. ; cm. Preceded by Huntington’s disease/[edited by] Gillian P. Bates, Peter S. Harper, Lesley Jones. 3rd ed. 2002. ISBN 978–0–19–992914–6 (alk. paper) I.  Bates, Gillian, editor of compilation.  II.  Tabrizi, Sarah, editor of compilation.  III.  Jones, Lesley, editor of compilation.  IV.  Title. [DNLM: 1.  Huntington Disease. WL 359.5] RC394.H85 616.85′1—dc23 2013035308

1 3 5 7 9 8 6 4 2 Printed in the United States of America on acid-free paper

Contents

Contributors  vii

Section 2: Genetics of Huntington’s Disease

Section 1: Clinical Aspects of Huntington’s Disease

6.  Genetic and Molecular Studies  109

1. Huntington’s Disease in a Historical Context  3

7. Epidemiology  131

Peter S. Harper

2.  Clinical Neurology  25 Raymund A. C. Roos

3. Neuropsychiatry and Neuropsychology  36

David Craufurd and Julie S. Snowden

4.  Juvenile Huntington’s Disease  66 Oliver W. J. Quarrell

5. Premanifest and Early Huntington’s Disease  86

Cécile Cazeneuve and Alexandra Durr Chris Kay, Emily Fisher, and Michael R. Hayden

8.  Genetic Counseling and Testing  165 Rhona MacLeod and Aad Tibben

Section 3: Neurobiology of Huntington’s Disease

9. Neuropathology in the Human Brain  185

Henry J. Waldvogel, Eric H. Kim, Lynette J. Tippett, Jean-Paul G. Vonsattel, and Richard L. M. Faull

Edward J. Wild and Sarah J. Tabrizi

  •  v

10.  Altered Neuronal Circuitry  218 Michael S. Levine, Elizabeth A. Wang, Jane Y. Chen, Carlos Cepeda, and Véronique M. André

Section 4: Molecular Biology of Huntington’s Disease

11. Normal Function of Huntingtin  243

Chiara Zuccato and Elena Cattaneo

12. Structural Biology: Order, Disorder, and Conformational Flux  274 Ronald Wetzel and Rakesh Mishra

13.  Pathogenic Mechanisms  323 Alis Hughes and Lesley Jones

14.  Peripheral Pathology  370

Jorien M. M. van der Burg, N. Ahmad Aziz, and Maria Björkqvist

vi  •  C ontents

Section 5: Therapeutic Interventions in Huntington’s Disease

15.  Comprehensive Care  393 Martha A. Nance

16. Preclinical Experimental Therapeutics  410

Gillian P. Bates and Christian Landles

17. Experimental Therapeutics: Moving Forward in Clinical Trials  462 Beth Borowsky and Cristina Sampaio

Index 485

Contributors

Véronique M. André, PhD Neurosciences TA Biology UCB Pharma SA Braine-L’Alleud, Belgium N. Ahmad Aziz, MD, PhD Department of Neurology Leiden University Medical Center Leiden, The Netherlands Gillian P. Bates, PhD Department of Medical and Molecular Genetics King’s College London London, United Kingdom Maria Björkqvist, PhD Department of Experimental Medical Science Wallenberg Neuroscience Center Lund University Lund, Sweden Beth Borowsky, PhD Director of Translational Medicine CHDI Foundation, Inc. Princeton, United States

Elena Cattaneo, PhD Department of BioSciences and Centre for Stem Cell Research Università degli Studi di Milano Milano, Italy David Craufurd, MB, BS, MSc, FRCPsych Manchester Academic Health Science Centre and Central Manchester University Hospitals NHS Foundation Trust University of Manchester Alexandra Durr, MD, PhD Hôpital de la Salpêtrière, Departement of Genetics Clinical Genetics Institut du Cerveau et de la Moelle Épinière UPMC, Inserm UMR_S1127, CNRS UMR 7225 Université Pierre et Marie Curie-Paris Paris, France

  •  vii

Cécile Cazeneuve, PharmD, PhD Hôpital de la Salpêtrière, Departement of Genetics and Cytogenetics Fonctional Unit of Molecular and Cellular Neurogenetics Paris, France Carlos Cepeda, PhD Intellectual and Developmental Disabilities Research Center Semel Institute for Neuroscience and Human Behavior and the Brain Research Institute David Geffen School of Medicine University of California Los Angeles Los Angeles, United States Jane Y. Chen, BA Intellectual and Developmental Disabilities Research Center Semel Institute for Neuroscience and Human Behavior and the Brain Research Institute David Geffen School of Medicine University of California Los Angeles Los Angeles, United States Richard L. M. Faull, MB, ChB, PhD, DSc Centre for Brain Research and Department of Anatomy with Radiology University of Auckland Auckland, New Zealand Emily Fisher, MSc, BSc Centre for Molecular Medicine and Therapeutics Child and Family Research Institute University of British Columbia Vancouver, Canada Peter S. Harper, MD Institute of Medical Genetics School of Medicine, Cardiff University Cardiff, United Kingdom Michael R. Hayden, MD, PhD Centre for Molecular Medicine and Therapeutics Child and Family Research Institute University of British Columbia Vancouver, Canada Alis Hughes, PhD MRC Centre for Neuropsychiatric Genetics and Genomics Institute of Psychological Medicine and Clinical Neurosciences School of Medicine Cardiff University Cardiff, United Kingdom

viii  •  C ontributors

Lesley Jones, PhD MRC Centre for Neuropsychiatric Genetics and Genomics Institute of Psychological Medicine and Clinical Neurosciences School of Medicine Cardiff University Cardiff, United Kingdom Chris Kay, BSc, BA Centre for Molecular Medicine and Therapeutics Child and Family Research Institute University of British Columbia Vancouver, Canada Eric H. Kim, PhD Centre for Brain Research and Department of Anatomy with Radiology University of Auckland Auckland, New Zealand Christian Landles, PhD Department of Medical and Molecular Genetics King’s College London London, United Kingdom Michael S. Levine, PhD Intellectual and Developmental Disabilities Research Center Semel Institute for Neuroscience and Human Behavior and the Brain Research Institute David Geffen School of Medicine University of California Los Angeles Los Angeles, United States Rhona MacLeod, PhD Manchester Centre for Genomic Medicine Central Manchester University Hospitals NHS Foundation Trust Manchester, United Kingdom Rakesh Mishra, PhD Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases University of Pittsburgh School of Medicine Pittsburgh, United States Martha A. Nance, MD Department of Neurology Hennepin County Medical Center and Park Nicollet Health Services Minneapolis, United States Oliver W. J. Quarrell, MD Department of Clinical Genetics Sheffield Children’s Hospital Sheffield, United Kingdom

Raymund A. C. Roos, MD, PhD Department of Neurology Leiden University Medical Center Leiden, The Netherlands Cristina Sampaio, MD, PhD CHDI Foundation, Inc. Princeton, United States Julie S. Snowden, PhD Manchester Academic Health Science Centre Cerebral Function Unit, Clinical Neurosciences Salford Royal Foundation Trust Salford, United Kingdom Sarah J. Tabrizi, MD, PhD Department of Neurodegenerative Disease University College London, Institute of Neurology London, United Kingdom Aad Tibben, PhD Department of Clinical Genetics Leiden University Medical Center Leiden, The Netherlands Lynette J. Tippett, PhD Centre for Brain Research and Department of Psychology University of Auckland Auckland, New Zealand Jorien M. M. van der Burg, MD, PhD Department of Experimental Medical Science Wallenberg Neuroscience Center Lund University Lund, Sweden

Henry J. Waldvogel, PhD Centre for Brain Research and Department of Anatomy with Radiology University of Auckland Auckland, New Zealand Elizabeth A. Wang, BA Intellectual and Developmental Disabilities Research Center Semel Institute for Neuroscience and Human Behavior and the Brain Research Institute David Geffen School of Medicine University of California Los Angeles Los Angeles, United States Ronald Wetzel, PhD Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases University of Pittsburgh School of Medicine Pittsburgh, United States Edward J. Wild, MD, PhD Department of Neurodegenerative Disease University College London, Institute of Neurology London, United Kingdom Chiara Zuccato, PhD Department of BioSciences and Centre for Stem Cell Research Università degli Studi di Milano Milano, Italy

Jean-Paul G. Vonsattel, MD Department of Pathology Presbyterian Hospital Columbia University New York, United States

Contributors  •  ix

Section one Clinical Aspects of Huntington’s Disease

1 Huntington’s Disease in a Historical Context Peter S. Harper

Introduction A historical approach to Huntington’s disease (HD) is worthwhile for two broad reasons. First, the successive steps in our new understanding of the disorder, together with the specific work underlying this and the people involved, not only are important for science and medicine but also are unusually fully and clearly documented, providing an unbroken chain of information and evidence over the past 140 years. Second, and of equal importance, HD provides in many ways a paradigm for genetic and neurodegenerative disorders in general, both in terms of how they have been approached and increasingly understood through research, and in terms of their wider effects on the families involved and on society as a whole. There are numerous important wider lessons that we can learn from HD by studying its history—while for the more specific group of late-onset degenerative brain disorders, there are close parallels, where our experience of HD has directly led the way for a greater understanding of these devastating conditions. This chapter looks first at the history of our knowledge of HD, and how it has developed; it then turns to the wider aspects, placing HD in the more general context of hereditary neurodegenerative disorders as a whole.

Early History Huntington’s disease has a particularly rich historical literature, stretching back well over a century and involving some of the most prominent

figures in medicine and neurology. When reading the early clinically based descriptions, it is often striking how relevant they remain today and how thorough they are, reflecting the fact that detailed and accurate clinical studies were for the most part all that could be undertaken at that time. Early neuropathology studies likewise often show both descriptive and illustrative material of considerable detail and high standards. By contrast, in current publications, particularly those on molecular and neurobiologic aspects, clinical descriptions are often inadequate compared with the more experimental aspects. As a starting point for outlining the origins and growth of our early knowledge on HD, there can be no better source than the original description that first clearly delineated the disorder and that has served ever since as the foundation for all subsequent work. The description by George Huntington in 1872 of the disease that has subsequently borne his name is one of the most remarkable in the history of medicine. Subsequent workers, from Osler to those of recent times, have remarked on its clarity, brevity, and comprehensiveness. It was not the first description of the disorder, as will be seen, but it stands out as the first full delineation of the condition as a specific disease entity, separate from other forms of chorea.

George Huntington and Hereditary Chorea Huntington’s paper was given before the Meigs and Mason Academy of Medicine in Middleport,   •  3

Ohio, on February 15, 1872, and was published only 2 months later in the Philadelphia journal, The Medical and Surgical Reporter (Figure  1.1). Although the first part deals with chorea in general and does not contain any particularly original information, the final part, occupying only a single page of printed text, is strikingly different in character; its vividness and authenticity of clinical detail come across as strongly today as they did to contemporary readers such as Osler. One can do no better than quote it in full here. And now I wish to draw your attention more particularly to a form of the disease which exists, so far as I know, almost exclusively on the east end of Long Island. It is peculiar in itself and seems to obey certain fixed laws. In the first place, let me remark that chorea, as it is commonly known to the profession, and a description of which I have already given, is of exceedingly rare occurrence there. I do not remember a single instance occurring in my father’s practice, and I have often heard him say that it was a rare disease and seldom met with by him. The hereditary chorea, as I shall call it, is confined to certain and fortunately a few families, and has been transmitted to

them, an heirloom from generations away back in the dim past. It is spoken of by those in whose veins the seeds of the disease are known to exist, with a kind of horror, and not at all alluded to except through dire necessity, when it is mentioned as “that disorder.” It is attended generally by all the symptoms of common chorea, only in an aggravated degree hardly ever manifesting itself until adult or middle life, and then coming on gradually but surely, increasing by degrees, and often occupying years in its development, until the hapless sufferer is but a quivering wreck of his former self. It is as common and is indeed, I  believe, more common among men than women, while I am not aware that season or complexion has any influence in the matter. There are three marked peculiarities in this disease:  1.  Its hereditary nature. 2.  A  tendency to insanity and suicide. 3. Its manifesting itself as a grave disease only in adult life. 1. Of its hereditary nature. When either or both the parents have shown manifestations of the disease, and more especially when these manifestations have been of

Figure 1.1  The title page of George Huntington’s 1872 paper in the Medical and Surgical Reporter. 4  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

a serious nature, one or more of the offspring almost invariably suffer from the disease, if they live to adult age. But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease. This you will perceive differs from the general laws of so-called hereditary diseases, as for instance in phthisis, or syphilis, when one generation may enjoy entire immunity from their dread ravages, and yet in another you find them cropping out in all their hideousness. Unstable and whimsical as the disease may be in other respects, in this it is firm, it never skips a generation to again manifest in another; once having yielded its claims, it never regains them. In all the families, or nearly all in which the choreic taint exists, the nervous temperament greatly preponderates, and in my grandfather’s and father’s experience, which conjointly cover a period of 78  years, nervous excitement in a marked degree almost invariably attends upon every disease these people may suffer from, although they may not when in health be over nervous. 2. The tendency to insanity, and sometimes that form of insanity which leads to suicide, is marked. I know of several instances of suicide of people suffering from this form of chorea; or who belonged to families in which the disease existed. As the disease progresses the mind becomes more or less impaired, in many amounting to insanity, while in others mind and body both gradually fail until death relieves them of their sufferings. At present I know of two married men, whose wives are living, and who are constantly making love to some young lady, not seeming to be aware that there is any impropriety in it. They are suffering from chorea to such an extent that they can hardly walk, and would be thought, by a stranger, to be intoxicated. They are men of about 50 years of age, but never let an opportunity to flirt with a girl go past unimproved. The effect is ridiculous in the extreme. 3. Its third peculiarity is its coming on, at least as a grave disease, only in adult life. I  do not know of a single case that has shown any marked signs of chorea before

the age of thirty or forty years, while those who pass the fortieth year without symptoms of the disease are seldom attacked. It begins as an ordinary chorea might begin, by the irregular and spasmodic action of certain muscles, as of the face, arms, etc. These movements gradually increase, when muscles hitherto unaffected take on the spasmodic action, until every muscle in the body becomes affected (excepting the involuntary ones), and the poor patient presents a spectacle which is anything but pleasing to witness. I have never known a recovery or even an amelioration of symptoms in this form of chorea; when once it begins it clings to the bitter end. No treatment seems to be of any avail, and indeed nowadays its end is so well-known to the sufferer and his friends that medical advice is seldom sought. It seems at least to be one of the incurables. Dr Wood, in his work on the practice of medicine, mentions the case of a man, in the Pennsylvania Hospital, suffering from aggravated chorea, which resisted all treatment. He finally left the hospital uncured. I strongly suspect that this man belonged to one of the families in which hereditary chorea existed. I know nothing of its pathology. I have drawn your attention to this form of chorea gentlemen, not that I  considered it of any great practical importance to you, but merely as a medical curiosity, and as such it may have some interest. It can be seen that all the cardinal features of HD are recognized in this description:  the adult onset, progressive course, and eventually fatal outcome; the choreic movements combined with mental impairment, and risk for suicide; even the pattern of inheritance, with “the thread broken” once a person had gone through life without developing it. A description of this nature could have been written only by one whose observations were based on direct and continued contact with affected patients. George Huntington’s role as a family doctor, following his father and grandfather to give a 78-year total period of observation, gave him this perspective to a unique degree. The active involvement of the two older generations of the family was acknowledged by George Huntington himself (1910) and is attested by the presence of pencil notes and corrections by his father on the

Huntington’s Disease in a Historical Context  •  5

original manuscript (Winfield, 1908; De Jong, 1937). The paper was prepared while George Huntington was working in his father’s practice before leaving for Ohio, so that it can indeed be regarded as a distillation of the observations of three generations of family doctors. Huntington was more fortunate than many authors who have given classic descriptions of a disease; his paper was widely appreciated from the outset and soon became internationally recognized. Browning (1908a) discussed the reasons why this was so. There were good reasons why his paper succeeded in drawing general attention to this disorder and in securing for it permanent recognition. Huntington was the first to give definitely the location of his cases and thus positively establish a verifiable record. The abstracting of his original article by Kussmaul and Nothnagel in Virchow-Hirsch’s “Jahrbuch” for 1872. Thanks to the work of Friedreich on hereditary ataxia, as well as the growing interest in heredity, the time was ripe for its appreciation. Only work of unusual, incisive and wide reaching interest could attract such a share of attention.

A further factor was the interest and appreciation of William Osler, Professor of Medicine at Philadelphia and then Johns Hopkins Hospital, Baltimore. Osler remarked that “there are few instances in the history of medicine in which a disease has been more accurately, more graphically or more briefly described” (Osler, 1894, 1908).

George Huntington’s Life The intimate connection between George Huntington’s description of HD and his background in family practice gives a particular interest to knowing more about his life. Fortunately, this had already become a subject of interest during his lifetime; the “Huntington’s number” of Neurographs, edited by William Browning (1908a–d), provides much detail, including portraits (Figure  1.2), with a valuable biographical sketch by Winfield (1908). Further information and accounts from family members have been collected by Durbach and Hayden (1993), whereas Alice Wexler, in her recent book, The Woman Who Walked Into the Sea (2008), has provided a valuable account of both the Huntington family and the original families with the disorder, in the social context of small-town America,

Figure 1.2  George Huntington as a young man (left) and in later life (right). (Reproduced from the “Huntington number” of Neurographs [Browning, 1908a]). 6  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

as discussed later in this chapter. It should also be noted that there has been confusion in some accounts with George Sumner Huntington, an apparently unrelated 19th century American anatomist (Van der Weiden, 1989, 1993). Huntington’s ancestors came, as did those of the families he studied, from the East Anglia region of England. Simon Huntington, of Norwich, is recorded as sailing to America in 1633 with his wife and children; he died on the voyage, but a son settled in Connecticut, from where Abel Huntington, grandfather of George, moved in 1797 to practice medicine in East Hampton, Long Island. Dr.  Abel Huntington was a distinguished physician and was the first on Long Island to perform the operation of lithotomy. He was also interested in infectious diseases and personally prepared and preserved the variola virus. His interests were not confined to medicine. He held several important public offices: in 1820, he was Presidential Elector; in 1821, he was elected New York City Senator; he was elected congressman for two terms; in 1845, he was appointed Collector of Customs for Sag Harbor; and in 1846, he was a member of the committee to revise the constitution of the State of New  York. Dr.  Abel Huntington’s son, George Lee Huntington, succeeded him in his practice, and George Huntington the younger was born at East Hampton in 1850. George Huntington’s upbringing would seem to have been a quiet and stable one, in a respectable small town in rural surroundings. He accompanied his father on his rounds and began his medical studies with him before graduating from Columbia University, New  York, in 1871. In present-day medical education, where originality is often stifled by an excessive number of facts, it is salutary to note that he qualified at 21  years of age and wrote his paper at the age of 22  years. Although George Huntington initially returned to East Hampton to practice, he soon moved to Pomeroy, Ohio, where he married, but apparently found Pomeroy “abundantly supplied with Physicians,” causing him to move again, first to Dutchess County, New York, and then to Asheville, North Carolina. He had serious health problems during this time, principally asthma, but by 1903 was able again to return to Dutchess County, where he remained in practice until 1915. In this year, he retired to live with his son not far away, dying in 1916 at the age of 65 years. George Huntington never published further papers after his 1872 description, either on chorea or on other topics. This would seem to

have been due not just to his health, nor to his practice commitments, but to his removal from the environment that had resulted in his single, but remarkable, contribution to medicine—the presence of the patients studied by three generations of his family, suffering from the disorder that has so appropriately preserved the name of Huntington. Durbach and Hayden (1993) have also shown how his devotion to country medical practice and his interests in rural pursuits, along with his poor health, would have been factors against him working in an urban academic setting. Perhaps the clearest insight into how George Huntington’s background affected his description of the disorder is seen in an address that he gave in 1909 to the New  York Medical Society. Over fifty years ago, in riding with my father on his professional rounds, I  saw my first cases of ‘that disorder’, which was the way in which the natives always referred to the dreaded disease. I recall it as vividly as though it had occurred but yesterday. It made a most enduring impression upon my boyish mind; an impression every detail of which I  recall today, an impression which was the very first impulse to my choosing chorea as my virgin contribution to medical lore. Driving with my father through a wooded road leading from East Hampton to Amagansett, we suddenly came upon two women, mother and daughter, both tall, thin, almost cadaverous, both bowing, twisting, grimacing. I stared in wonderment, almost in fear. What could it mean? My father paused to speak with them and we passed on. Then my Gamaliel-like instruction began; my medical education had its inception. From this point on my interest in the disease has never wholly ceased.

Descriptions Before 1872 There can be few diseases in medicine for which the description that has given the author’s name to the condition is truly the first. Huntington’s disease is no exception, and there is no doubt that others had recognized and to some extent described the condition before George Huntington published his 1872 paper. Not surprisingly, there have been a number of claims of such descriptions (De Jong, 1937; Bruyn, 1968; Stevens, 1972), but few stand up to critical examination. Thus Elliotson’s (1832) mention of chronic adult chorea, noting that “I have often

Huntington’s Disease in a Historical Context  •  7

seen it hereditary,” might or might not have referred to HD, whereas Husquinet’s interesting finding (1975) that the case described in 1873 by Landouzy could be traced to Belgium and linked to records from the previous century can hardly be regarded as a prior description. The first definite record of HD was in a letter by Charles Oscar Waters (1816–92) in 1841 and published by Dunglison in the first edition of his Practice of Medicine in 1842. It is worth reproducing this in detail because it gives such a clear picture of the clinical features and natural history. It consists essentially in a spasmodic action of all the voluntary muscles of the system, of involuntary and more or less irregular motions of the extremities, face and trunk. In these involuntary movements the upper part of the air passages occasionally participate as is witnessed by the ‘clucking’ sound in the glottis and in a manifest impediment to the powers of speech. The expression of the countenance and general appearance of the patients are very much such as are described as characteristic of chorea. The disease is markedly hereditary, and is most common among the lower classes, though cases of it are not infrequent among those who by industry and temperance have raised themselves to a respectable rank in society. These involuntary movements of the face, neck, extremities and body cease entirely during sleep. The singular disease rarely, very rarely indeed makes its appearance before adult life, and attacks after forty-five years of age are also very rare. When once it has appeared, however, it clings to its suffering victim with unrelenting tenacity until death comes to his relief. It very rarely or never ceases while life lasts. The first indications of its appearance are spasmodic twitching of the extremities generally of the fingers which gradually extend and involve all the voluntary muscles. This derangement of muscular action is by no means uniform; in some it exists to a greater, in others to a less extent, but in all cases it gradually induces a state of more or less perfect dementia. When speaking of the manifestly hereditary nature of the disease, I  should perhaps have remarked that I  have never known a case of it to occur in a patient, one or both of whose ancestors were not, within the third

generation at farthest, the subject of this distressing malady. In 1846, a further description occurred in the form of a thesis submitted to Jefferson Medical College, Philadelphia, by Dr.  Charles Gorman (1817–96) entitled, “On a Form of Chorea, Vulgarly Called Magrums.” Although the thesis is lost, it is mentioned in the third edition (1848) of Dunglison’s book: “an inaugural dissertation, presented before the Faculty of Jefferson Medical College of Philadelphia by Charles R, Gorman of Luzerne County, PA. The writer states that this affection prevails also in other portions of the country. According to him, it seems to be circumscribed by neighbourhood boundaries, and to be confined to sections of the country, the inhabitants of which are intimately connected in their Social or Business relations.” A valuable account of these early American descriptions of hereditary chorea is given by Browning (1908a–d) in the “Huntington number” of Neurographs, along with the location of the families and biographic details of Waters, Gorman, and other early workers. The other independent early description that undoubtedly represented HD is that of Johan Christian Lund, written in Norwegian and generally appreciated only since relevant parts were translated by Ørbeck (1959), although recognized in Scandinavia before that. Lund was public health physician in the region of Saetersdal, Norway, and wrote in his medical report for 1860: As recorded in the previous medical report, chorea St Vitus [which is Lund’s term for St Vitus’s dance] seems to recur as an hereditary disease in Saetersdal. It is commonly known as the ‘twitches’, occasionally as the ‘inherited disease’. It usually occurs between the ages of 50 and 60, generally starting with less obvious symptoms, which at times only progress slowly, without becoming violent, so that the patient’s normal activities are not particularly hindered:  but more often after a few years they increase to a considerable degree, so that any form of work becomes impossible and even eating becomes difficult and circuitous. The entire body, though chiefly the head, arms, and trunk, is in constant jerking and flinging motion, except during sleep, when the patient is usually motionless. A couple of the severely affected patients have during the last days of their lives become

8  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

Fatui [i.e. demented]. The disease occurs in two families which are registered below. Information is not as complete as could be desired though enough to start with, as long as doctors in Saetersdalen are mindful of the disease in future. [Lund, 1860; quoted by Ørbeck, 1959].

Lund gave further details on family members in later reports, and according to Ørbeck, descendants with HD still exist today. It seems that Lund was doubly unlucky in not gaining recognition because not only was the original source restricted in readership by being written in Norwegian, but also subsequent commentators on it confused the disorder with Parkinson’s disease. One further description of HD before 1872 is widely quoted, namely that of Lyon (1863), who reported three families from New York State with hereditary chorea under the title “Chronic Hereditary Chorea” in the American Medical Times. Lyon’s families do not seem to have been connected with those of Waters, but were also called “megrim families” locally. Browning (1908d) traced the localization of the families to Bedford, on the New  York–Connecticut border, but no subsequent clinical evaluation of the patients or their descendants has been carried out. However, a critical look at the description of these cases suggests that Lyon’s families 1 and 2 (family 3 was not described in detail) were far from typical for HD and much more suggestive of benign familial chorea. So that readers can decide for themselves, these cases are quoted here. CASE I. Mr A., residing in the town of ___, county of ___, NY, has well marked chorea, which is quite general; so that he is constantly, when awake, making irregular movements with the upper and lower extremities, facial muscles, and more or less with those of the body. This condition has existed for many years, but seems not to interfere materially with his general health, the vegetative functions being well performed. Mr A. has two brothers and three sisters; the two brothers have themselves never had choreal symptoms, but one of them has two children in whom well defined chorea has existed for many years; of the three sisters, two have had chorea for the most of their lives, being now past the middle age. The progenitors of Mr A., on the male side, were perfectly free from chorea, but not so on the maternal side; his mother had

well developed choreal manifestations from early life, which continued till her decease; she had also a brother who died during adult life from the severity of the disease; but to go still further, both the grandfather and great-grandfather of Mr A., on the maternal side, had the same disorder which we find in their children: whether collateral instances of the affection occurred in the families we are not advised. CASE II. Mrs K., of the town of ____, Ct and a descendant from a family which has long been known and designated as migrim, had chorea for the most of her life, being about seventy-five years old at the date of death. She had a family of two sons and three daughters:  of these one son and two daughters had chorea, with which disease they attained an advanced age; no satisfactory information can be readily obtained in relation to the offspring of the son and one of these daughters so affected; but the other daughter married, and had a son, who is now forty years of age, in whom chorea has exhibited itself from puberty. In particular, the fact that the proband of family 1 is stated to have had chorea for many years, but that the condition had not interfered with his general health, while his two affected sisters “had chorea for most of their lives” and their mother from early life, is most unlike HD. So is the fact that the grandson in family 2, then 40 years old, had had chorea since puberty. There is no mention of progression or of general deterioration apart from the one individual of family 1, who is stated to have “died during adult life from the severity of the disease.” Thus it would seem that Lyon’s families should not be accepted as having HD, but are rather characteristic of benign familial chorea.

William Osler The rapid spread and wide distribution of knowledge concerning HD was in no small measure due to the interest that William Osler (1849– 1919) took in it. Osler had a lifelong interest in chorea, and his monograph, On Chorea and Choreiform Affections (1904), contains a wealth of personally collected data on rheumatic (Sydenham’s) chorea. However, he included a separate chapter on hereditary chorea in this, as well as a brief section in his The Principles and Practice of Medicine (1892), and dealt specifically

Huntington’s Disease in a Historical Context  •  9

with Huntington’s chorea in several case reports and papers (1890, 1893, 1894). (Surprisingly and most atypically, he misspells the eponym as “Huntingdon” in some of these.) Osler made attempts to reassess Huntington’s original family during the summer of 1887, but Huntington wrote back indicating that they would not welcome this, although Osler was sent notes on these patients the following year. He was able to gain personal experience from patients seen at Johns Hopkins Hospital of both English and German origin; his case reports are a model of clarity and detailed observation, and ring as true today as a century ago. When sitting in a chair, at ease, the arms and hands are in more or less constant irregular motion. The fingers are extended and flexed alternately; sometimes the entire set. At other times the whole hand will be lifted, or there are constant movements of pronation and supination. For half a minute or so they may be perfectly motionless. The head and trunk present occasional slow movements; in the latter more of a swaying character. The legs jerk irregularly and the feet are flexed or extended; but the movements are not so frequent as in the arms. The face in repose is usually motionless, but the lips are occasionally brought together more tightly and the chin elevated or depressed. There is an occasional movement of the zygomatic and of the frontal muscles. He puts out the tongue, with tolerably active associated movements of the face, and it is usually quickly withdrawn or rolled from side to side. It is impossible for him to hold it out for any length of time. There are no irregular movements of the palate muscles. He walks with a curious irregular gait, displaying distinct incoordination, swaying as he goes, hesitating a moment in a step, keeping the arms out from the body and in constant motion. The legs are spread wide apart; the steps are unequal in length and he seems rather to drag the feet. He stands well with the heels close together and the eyes shut. [From Osler, 1894]

The Spread of Knowledge The rapid spread of awareness of George Huntington’s 1872 paper has already been mentioned, but from the work on hereditary chorea

that has been discussed so far, it could be imagined that most of the interest and activity was in America, not in Europe. Such an impression would be entirely wrong, for not only was the topic of chorea in general one of great interest among European physicians and neurologists, but also many of the early reports and studies of HD in the last quarter of the 19th century were European in origin. The monograph of Petit (1970) and the review of Bruyn (1968) are especially valuable in giving appropriate recognition to these early European workers. Table 1.1, based on the bibliography of Bruyn et al. (1974), gives a picture of how widely diffused information on HD soon became. Some of these reports (e.g., that of Landouzy in 1873) were described before being aware of Huntington’s description, but international communication seems to have been remarkably rapid at that time (perhaps because the number of investigators and volume of literature were limited). Medicine, neurology, and pathology had not yet become fully demarcated specialties, and in reading the early descriptions, one gains the impression of an actively communicating body of workers whose interests ranged over a wide variety of disorders. The names of some of these workers who published on HD, including Landouzy (1873), Bourneville (1874), Golgi (1874), Déjerine (1886), and Hoffmann (1888), are now better remembered in relation to other neurologic disorders than in connection with HD. It is also relevant to note that HD was described early in a number of countries, such as Cuba and Brazil, in which the disorder is not today recognized as being of frequent occurrence, reinforcing the impression, discussed further in c­ hapter 6, that HD has been a widespread condition for a considerable time.

Tracing the History and Origins in New England While the recognition of HD was spreading rapidly throughout the world during the last decades of the 19th century, laying the foundations of our detailed knowledge of the natural history of the disease, there was considerable activity also in tracing and attempting to connect the various families in the New England region that had been responsible for most of the original descriptions. Jelliffe (1908) and Davenport and Muncey (1916) were able to compile extensive pedigrees and to link them into groups that could be traced

10  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

Table 1.1. The Spread of Information on Huntington’s Disease: First Reports From Different Countries C o u n t ry

Dat e of Rep ort*

Au t hor *

United States Norway France Italy Germany United Kingdom Russia Cuba Netherlands Poland Brazil Denmark Argentina Czechoslovakia Yugoslavia Australia Canada

(1842), 1972 (1860) 1873 1874 1877 1880 1889 1890 1890 1890 1891 1892 1894 1895 1900 1902 1904

(Waters), Huntington (Lund) Landouzy Golgi Meynert Harbinson Kornilowa Arostegui Beukers Biernacki Couto Friis Costa Ganghofner Gutschy Hogg Mackay

* Entries in parentheses indicate a description before George Huntington’s 1872 report. Data based on Bruyn et al., 1974.

back to possible founding members. Most of these appeared to originate in the early 17th century from the East Anglia area of England (from which George Huntington’s ancestors had also come), and which had seen extensive migration to the United States. Unfortunately, the attempts to identify specific individuals as the source of the gene for HD all seem to have stretched the evidence far beyond what actually exists. Now that we know the nature of the HD mutation and that healthy individuals exist carrying intermediate alleles, we can recognize the futility of this approach, so for details of this work, readers are referred to previous editions of this book (Harper 1981, 1991). Regardless of the precise details, New England has clearly played a pivotal role in receiving HD genes from Europe and distributing them throughout the United States. It is possible also that it may have been responsible for a wider spread of the disorder because it seems likely that the HD gene in some Pacific Island communities may have been brought by visiting New England whaling ships in the early 19th

century (Scrimgeour, 1983). If this can be confirmed (a possibility now with molecular haplotypes), it will provide a particularly interesting example of how a genetic disorder may not only contribute to a chapter of history but also leave long-term effects that persist after the original events of the Pacific whaling industry are all but forgotten, except as literature.

Evolution of the Clinical Picture Compared with most original descriptions of a disease, that given by George Huntington in 1872 was remarkably complete, despite its brevity. This was largely a result of the all-around view that he was able to obtain as a general practitioner and the length of time over which his own family had observed the patients for whom they cared. Subsequent work over the next three decades thus served mainly to give more detail to the neurologic and psychiatric symptoms, to extend awareness of the range and variation seen in the disorder, and to attempt to analyze the pathologic and genetic aspects. The numerous Huntington’s Disease in a Historical Context  •  11

case and family reports following the original description have already been mentioned and, in the case of Osler, quoted. The existence of HD as a specific entity of chronic, progressive, hereditary chorea of adult onset soon became widely accepted. The detailed clinical picture that emerged will be described in ­chapters  2 and 3, but it is worth examining here some of the more important aspects that had not been fully appreciated in the initial descriptions already given. Psy c h iatr ic Sy ndrom es

Huntington in his original paper recognized that mental deterioration was one of the characteristic features of the disorder that was to bear his name; he noted “the tendency to insanity, and sometimes that form of insanity that leads to suicide.” Most of the subsequent case reports, however, concentrated on the chorea rather than the psychiatric manifestations of HD. Chapter 3 of this book describe the psychiatric aspects of HD in detail. One of the more systematic of the early studies on mental disorder in HD was conducted by Phelps (1892) in Rochester, Minnesota. He found five patients with HD, or 1 in 600 (out of the 3,000 admissions) who had been admitted to the Second Minnesota Hospital for the Insane. In addition, he wrote to the superintendents of 50 psychiatric institutions all over the United States asking for details on patients with HD. Thirteen cases were reported to him in replies from 24 hospitals, so that he had the largest series up to that time. He described many of the major forms of psychiatric disorder, including psychotic symptoms, “melancholia,” suicide, irritability, and “steady mental degeneration.” In the early literature on HD, there are clear descriptions of psychosis. Delusions of grandeur figure prominently in a number of clinical descriptions. One inpatient said that “God is my lawyer” (Phelps, 1892), whereas another called her mental hospital a “castle” (Eager & Perdrau, 1910). Delusions of royalty in HD have also been reported (Phelps, 1892; Eager & Perdrau, 1910). An interesting American case of delusions of special ability was described in a man who said he was getting “a million dollars for standing back and allowing Harrison to be President instead of himself” (Phelps, 1892). Some of these patients may have had concurrent general paresis due to syphilis, which is a well-known cause of grandiose delusions. Cognitive decline was described in the early reports (e.g., Osler, 1893), and indeed in the

opinion of Sinkler (quoted by Mitchell, 1895), “nearly all cases of Huntington’s chorea terminate in dementia.” Perhaps the most perceptive of the early accounts of impaired intellectual functioning was provided by Edward Mapother (1911) from Dublin. As the disease progresses the most marked noteworthy and constant feature comes to be a failure of the power of sustained attention. Often there is no marked deficit of memory. There is no disorientation either in regard to place or time. Comprehension of speech is good and the capacity for simple judgements and deduction is unimpaired. But if one gives the patient a somewhat complex order involving the performance of several successive actions or the observation of a series of phenomena, his capacity for sustained attention is immediately manifested. Bower and Mills (1890) also commented on higher mental functions in HD, especially abnormalities of speech and handwriting. Although dementia was thus well recognized in HD, early authors also observed that there were exceptions and that some patients remained “mentally clear” (Fisher, 1906). J uve n il e Dise as e an d the  Rigid Form

The paper of Lyon (1863) is commonly quoted as the first description of childhood HD, but as mentioned earlier, the lack of clear progression and the early onset in his families make it likely that he was dealing with a separate disorder such as benign familial chorea. A number of other early childhood cases are discussed by Bruyn (1968) in his review, but the most detailed of these is the report of Hoffmann (1888). In this three-generation family with HD, there were two daughters who had onset at 4 and 10 years; they showed rigidity, hypokinesia, and seizures, as well as choreic movements; and both had prolonged survival. This report showed clearly that not only could childhood onset occur within a typical HD family but also the clinical features might be strikingly different from those normally seen in the adult disorder. The recognition of juvenile HD was closely linked with the realization that chorea was not the only motor disorder in HD and that some patients showed a predominance of rigidity and hypokinesia. The term “Westphal variant”

12  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

has often been used for this clinical presentation, but in describing his 18-year-old patient with these features, Westphal (1883) attributed them to a separate cause rather than to HD. The family of Hoffmann (1888) already mentioned, together with the families reported by Curschmann (1908), Freund (1911), and many others, reinforced the existence of the rigid form of HD as an important clinical picture, usually in young adults or children, but occurring in the same families as cases with more typical chorea as the presenting feature, something puzzling at the time but now readily understandable in the light of the unstable nature of the HD mutation. See ­chapter 4 of this book for a full discussion of juvenile HD. Thus by the end of the 19th century, as a result of a very large number of careful and detailed descriptions, the clinical picture of HD was, if not complete, at least well established in terms of its main neurologic features, its psychiatric involvement, and its natural history. It was already quite clear that it was a specific disorder with well-defined, though variable, clinical features; the universal adoption of the title “Huntington’s chorea” or later “Huntington’s disease” reinforced the degree to which the disorder was accepted as an entity, as well as the contribution that George Huntington had made to its original description.

Understanding the Neuropathology The search for neuropathologic abnormalities in HD began early. Lewis (1876) was forced to conclude that “no definite portion of the cerebrospinal system can at present be chosen as the site of lesions peculiar to chorea.” However, Meynert (1877) was more successful in detecting the postmortem changes in HD. He proposed that chorea could be explained by lesions in the corpus striatum, but this remained contentious for many years. Osler (1893) found no specific changes, as already mentioned, and could give no clear explanation for the clinical features. Some workers thought that brain inflammation was a neuropathologic characteristic of HD (Oppenheim, 1887; Phelps, 1892; Sinkler, 1892), whereas others believed that the disorder was caused by a congenital malformation of the motor cortex (Stier, 1902; Muller, 1903). These reports were disputed by other investigators who thought that vascular sclerosis and the overgrowth of neuroglia were the pathologic changes in HD (see Mapother, 1911).

Perhaps the most influential of the early neuropathologic studies was that conducted by Jelgersma (1908). He described generalized shrinkage of the HD brain and atrophy of the caudate nucleus (reduced to one-third of its original volume). These findings were confirmed by later workers (Alzheimer, 1911; Pfeiffer, 1913), but it was not until the 1920s that there was general agreement that the brain changes in HD were primarily degenerative and atrophic and that the caudate nucleus was preferentially involved in the process. Neuropathologic studies have recently again become of central importance in HD research, (see Vonsattel et  al., 2011, and ­chapter 9 of this book for detailed reviews), first with the advent of detailed quantitative analyses, and now with the recognition of neuronal inclusions as a key element in the pathology of both human HD and the mouse models of this disorder, as discussed in later sections of the book.

Early Forms of Treatment At the time of Huntington’s report, there was little in the therapeutic armamentarium for most diseases. Nonetheless, several authors tried drug treatment for HD, and some animal trials were also conducted. In the 1890s, strychnia was injected into dogs until they were “violently choreic” (Wood, 1893). Quinine was found to “arrest these movements,” and in a clinical trial on a patient with pronounced chorea, the drug was reported to be effective (Wood, 1893). After administration of bromide of potassium, it was noted that “twitchings decreased remarkably” in another case report (McFaren, 1874). Other drugs were less successful, such as hyoscamine (Lewis, 1876)  and arsenic (Eager & Perdrau, 1910). MacFaren (1874) was probably the first investigator to recommend a nutritional diet for weight loss in HD. Nonetheless, admission to an asylum was the only significant intervention that could be offered. Now we are at last on the threshold of more definitive therapies, as indicated in ­chapters 16 and 17.

Inheritance Later parts of this book give a detailed description of the genetic and molecular basis of HD and the practical applications of this knowledge in genetic counseling and prediction (see ­chapters 6 and 8). The main features of the inheritance Huntington’s Disease in a Historical Context  •  13

pattern were already well recognized by George Huntington in his original description. When either or both parents have shown manifestations of the disease, and more especially when these manifestations have been of a serious nature, one or more of the offspring almost invariably suffers from the disease, if they live to adult age. But if by any chance these children go through life without it, the thread is broken, and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease. Unstable and whimsical as the disease may be in other respects, in this it is firm; it never skips a generation to manifest itself in another; once having yielded its claims, it never regains them. [From Huntington, 1872]

Reading this passage today, it is as clear a description of Mendelian dominant inheritance as one could wish. However, although Mendel had published his work in 1865, it was rediscovered only in 1900, so no theoretical basis could be provided for the pattern that had been observed until after this time. It did not take long, however, for workers looking for possible human examples of Mendelian inheritance to recognize that HD provided a likely instance. In February 1908, Punnett, a close colleague of Bateson, whose work was primarily on poultry, cited HD as likely to follow dominant inheritance, whereas later in the same year Jelliffe (who had read Punnett’s paper) also mentioned this. Neither was very definite, both preferring to cite brachydactyly as a more conclusive example. This is not surprising because the material in Bateson’s records (archived at John Innes Institute, Norwich), consists mainly of small and fragmented families. By 1911, Davenport was able to be much more confident in listing HD as an autosomal dominant disorder, along with other conditions illustrating autosomal recessive and sex-linked inheritance. Interestingly, he also cited other forms of chorea as being dominantly inherited. By the time of this later collection of material specifically on HD, containing large families (Davenport & Muncey, 1916), the mode of inheritance was beyond doubt, and detailed analysis could begin. In any discussion of the early development of our concepts of the genetics of HD, the work of Charles Davenport (Davenport, 1911; Davenport & Muncey, 1916)  requires special discussion.

Davenport’s prejudiced attitude to the disorder, his advocacy of radical eugenic views (Davenport, 1911), and his later political association with the German race-hygienists make it difficult to assess his work objectively, as does his tendency to overinterpret Mendelian principles, especially in relation to other disorders involving intelligence and mental characteristics. Despite this, though, and bearing in mind the early time at which he was working, he must be acknowledged not only as the person who made it clear beyond doubt that HD followed Mendelian dominant inheritance, but also for his documentation of such important aspects as age at onset, variation between families, possible anticipation and its biases, and the reasons for apparent skipped generations. Clinically, too, Davenport recognized the variability in degree and type of mental involvement and the variety of motor disturbance that might occur. His compilation of data on almost 1,000 affected individuals, mainly in the New England area and descended from a small number of original progenitors, provided the foundation for much of the work that was to come, and he should be recognized for this, even though many of the conclusions drawn may have been flawed. Alice Wexler (2008) gives a detailed description of the social background and consequences of Davenport and Muncey’s studies on HD.

Development of Research Until 20 years ago, the history of research on HD was one of gradual progress, rather than of sudden leaps. The main discoveries in the different fields of work are recorded in the specific chapters of this book and have been shared by many different disciplines in addition to the neurosciences, genetics having been a major contributor from the beginning to the present. When analyzing the patterns and development of HD research, modern information technology has greatly simplified the analysis and retrieval of published literature, but a valuable resource for earlier publications is the HD Centennial Bibliography (Bruyn et al., 1974), which lists all known publications on HD up to 1972, the 100th anniversary of George Huntington’s original publication, with a supplement extending the work to 1978. The critical approach taken, extensive cross-indexing, and informative comment accompanying the bibliography not only make this the definitive collection of

14  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

early material on HD but also give a clear picture of the patterns of research, its progress and evolution into different subjects, and the geographic distribution of work on the disorder. By 1890, up to 20 papers each year were being published on HD, with a peak just before World War I only reached again in the mid-1930s, falling during World War II, but rising sharply and continuously thereafter. Understandably, the main topics have changed over the years, with studies of neuropathology prominent in the earlier phases, whereas pharmacologic and biochemical topics were more abundant in the 1960s; clinical and genetic reports remained relatively constant, at least until 1972, the latter increasing dramatically in the later 1970s, after the conclusion of the bibliography. The importance of monographs in bringing together and synthesizing information on HD deserves recognition. In addition to the present work and its earlier editions (Harper 1991, 1996; Bates et  al., 2002), the monograph of Hayden (1981) contains many original data, whereas that of Folstein (1989) is especially important in being written from the perspective of the psychiatrist. An important focus and forum for discussion of new work on HD over the past 30 years has been the World Federation of Neurology Research Group on Huntington’s Disease. Founded by Dr. André Barbeau, this group first met in Montreal in 1967 and has since held a succession of valuable workshops at about 2-year intervals, which have evolved into the World Huntington’s Congress. It has helped to create a community of research workers involved with HD who have developed close and continuing links and collaborations spanning a number of different disciplines, as well as working closely with the international lay organizations, as described next.

the illness of Woody Guthrie, the American folk singer (Figure  1.3), who developed HD symptoms around 1952 and died in 1967 at the age of 55. The remarkable biography by Klein (1981) gives considerable insight into the interplay between personality, creativity, and disease in Guthrie’s life. His widow Marjorie devoted the later part of her life to promoting all aspects of HD, and in 1967 the Committee to Combat Huntington’s Disease (later the Huntington’s Disease Association) was formed with objectives to provide services for families and to promote education and research (Figure  1.4). Marjorie Guthrie was also largely responsible for the initiation of comparable organizations in other countries, resulting in 1978 in the International Huntington’s Association, a body that now involves more than 30 member countries. Close links with medical groups, such as the World Federation of Neurology Research Group, have ensured that the lay societies have played a constructive role in developing policies in such critical areas as predictive testing. An organization with different aims but of equal importance has been the Hereditary Disease Foundation, initiated by Dr.  Milton

Lay Groups and HD Research A striking feature of the medical scene during the past 30 years has been the development of support groups run by sufferers and their families. Fund-raising for research, improvement of services, and greater public awareness have all been major aims. In the case of HD, progress would undoubtedly have been much slower had such societies not been developed, and it is unlikely that the disorder would have the high public profile internationally that it does today. The initial development in this area arose from

Figure 1.3  Woody Guthrie, the American folk singer affected with HD, whose illness was the catalyst for the founding of the first lay society involved with HD, the Committee to Combat Huntington’s Disease. (Courtesy of Woody Guthrie Publications.)

Huntington’s Disease in a Historical Context  •  15

Figure 1.4  The initial newsletter of the Committee to Combat Huntington’s Disease.

Wexler after his wife developed the disorder, and continued by his daughter Nancy Wexler. The Foundation has been responsible for a long-running series of small workshops on all aspects of HD research, coordinated for many years by its scientific director Dr.  Allan Tobin. It was also instrumental in the collection and analysis of the large Venezuelan kindred that was so important in the cloning of the HD gene (see later), and in the funding of the Collaborative Research Group responsible for the discovery. A  fascinating account of some of these activities seen from the perspective of a family member has been written by Alice Wexler (1995).

The Venezuela Project The remarkable concentration of patients with HD living in the Zulia region of Venezuela, by the shores of Lake Maracaibo (Figure 1.5), represents the largest cluster of cases derived from a single ancestor that has remained geographically localized. This pedigree includes more than 10,000 members, with more than 100 living affected subjects. Some of the epidemiologic aspects of this concentration are described in c­hapter  7, but the wider significance of HD in Venezuela

for the development and understanding of the disease deserves a special mention here. The high frequency of the disorder in some of the small and isolated lakeside communities was first documented by Negrette (1963), and was brought to general attention by his colleague Avila-Giron (1973), who presented details at the 1972 Centennial Symposium on HD. Okun and Thommi (2004) and Moscovich et al. (2011) have given appreciations of Negrette’s contributions to our clinical understanding of HD. It was recognized that this isolate could be of special significance, particularly in studying possible homozygotes, because several families had both parents affected; visits by Dr.  André Barbeau and others confirmed this, but the key development was the decision of the Hereditary Disease Foundation to mount a systematic study of the population. After an initial visit in 1979, comprehensive studies were carried out by an annual visiting team beginning in 1981; detailed pedigrees were drawn up, allowing a full genealogy of the different branches to be pieced together, while accurate clinical assessment of both affected members and relatives at risk was carried out, concentrating on families with two affected parents containing possible homozygotes. Blood samples were taken for

16  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

Figure  1.5  Huntington’s disease in Venezuela. The concentration of the disorder in the villages around Lake Maracaibo and the occurrence there of probable homozygotes for the disorder have led to a major longitudinal study of the disease and to studies of the HD gene. (Courtesy of Nancy Wexler.)

DNA analysis and cell lines set up, allowing their long-term study. At the same time the workers tried to provide as much practical help as possible to these poor and deprived communities. The background to the work is well described in a number of general readership articles (Drake, 1984; Kolata, 1984; Pines, 1984; Steinmann, 1987); a full account of this remarkable project has yet to be written from a historical perspective, although it is touched on in the book of Alice Wexler (1995). The most spectacular result of the Venezuela project was its crucial role in locating and isolating the HD gene, as outlined later. Almost as important, however, have been the clinical studies, which provide a unique longitudinal documentation of HD in a population without access to medication for the disease, as well as clearly showing that the likely homozygotes for HD are no more severely affected than are those with a single copy of the gene.

Isolation of the Gene It may seem premature for an event as recent as 1993 to be classed as “history,” but there can be no doubt that isolation of the HD gene is already

perceived as a historical point in HD research. The scientific aspects and the consequences for our understanding of the disorder are described in many of the chapters in this book, but the background deserves to be noted here. The book by Alice Wexler (1995) gives a fuller account, from a different perspective, whereas Bates (2005) has given a detailed account as seen from the viewpoint of one of the principal scientists involved. The transcripts of recorded interviews by the author with a number of those involved in isolation of the HD gene are available at the Genetics and Medicine Historical Network website (www.genmedhist.org), including interviews with Gillian Bates, Michael Conneally, James Gusella and Marcy MacDonald, Russell Snell, and Allan Tobin. The Huntington’s Disease Collaborative Research Group was formed as a direct outcome of the Venezuela project described previously, following the realization that this extended kindred held great potential for mapping and isolating the gene. Supported again by the Hereditary Disease Foundation, it developed into a close collaboration of six teams in the United States and Britain. Central to the f­ unction—and ultimate success—of the group was an agreement Huntington’s Disease in a Historical Context  •  17

to share fully all resources and to share in any credit by publishing the paper reporting isolation of the gene under the name of the group, as indeed was done (Huntington’s Disease Collaborative Research Group, 1993). Equally important was the complementary nature of the teams involved, with all members able to offer some particular skill or resource, and to bring in the new techniques or ideas from basic molecular research or from work on other disorders. It can be imagined that maintaining such close collaboration over a prolonged period (it took 10  years from the initial localization to isolation of the gene itself) was a challenging task, and the Hereditary Disease Foundation deserves great credit for its role in this, as do the scientists involved, who in some cases invested many years of their career in this joint effort—with no guarantee that it would be the Collaborative Research Group itself that was ultimately successful. The historical nature of the isolation of the HD gene was reflected in the explosion of research that has followed the publication of the full gene sequence and nature of the mutation in the paper by the Collaborative Research Group. This publication allowed the world research community, including many not previously involved in HD research, to join in the field on equal terms, and thus inevitably brought to an end the Collaborative Research Group in its original closed form. Perhaps its best justification has been that its very success should result in its conclusion; happily, the close links formed during its existence, and the continuing support of the Hereditary Disease Foundation, have resulted in most of the teams involved continuing in HD research and maintaining and developing their productive collaborations. In this, as in many other ways, HD has provided an example for those working on other disorders.

late Dr.  Max Perutz, that the polyglutamine sequence in the HD protein, huntingtin, translated from the CAG repeat in the gene, might itself be the key to disease pathology. Perutz et al. (1994) suggested on the basis of molecular modeling that the protein molecules containing this expanded polyglutamine repeat could form a “polar zipper” structure (Figure 1.6), resulting in aggregates that might themselves produce neuronal damage. The detection of neuronal inclusions in HD brains and that of mouse models of HD, as

Research After Isolation of the Gene The isolation of the HD gene, while marking the end of an era, has provided the starting point for numerous new research approaches to the pathogenesis of the disorder, which are the subject of the later chapters of this book. One of these, however, deserves particular mention at this point; this is the hypothesis, now supported, though modified, by experimental data, of the

4.8Å

– Cα,

– C,

– N,

–O

Figure 1.6  The “polar zipper” model for polyglutamine repeats. (From Harper & Perutz, 2001; and Perutz, 1994, with permission.)

18  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

well as direct biochemical studies, indicate that expanded glutamine repeats in the huntingtin protein do indeed lead to aggregation. This concept has a particular historical resonance, linking directly with Perutz’s comparable studies on hemoglobin and other key molecules originating more than 50 years earlier. This also provides a striking example of how HD research has repeatedly attracted the interest and involvement of outstanding scientists whose main field of work has been in apparently unrelated areas, but whose insights into basic processes has thrown light on HD also. Klug (2002) gives an account of Perutz’s overall work and contributions. Now that we are starting to understand the key elements of the molecular pathology of HD and related trinucleotide repeat disorders, there is increasing need and opportunity for such lateral involvement, which has proved rewarding for all concerned.

Wider Aspects of Huntington’s Disease as a Historical Paradigm In tracing the history of our experience and understanding of HD, a remarkable number of aspects have strong parallels to what we see in other disorders, particularly other brain degenerations, but also late-onset inherited disorders generally. In many cases the situation for HD has been identified and documented well before these comparable problems in other disorders have been recognized, so that HD has become a paradigm from which we have learned much that is of general significance. Some of these wider aspects are noted here (Table  1.2), but before describing them further, it is worth asking why HD should have led the way, rather than following in the wake of some of these other conditions.

Table 1.2. Landmarks in the Study of Huntington’s Disease 1841 1872 1888 1908 1934 1958–59 1967 1967 1972 1983 1987 1993 1996 1997 2000 2001 2003 2006 2009 2012

First definite description of HD (Waters) George Huntington’s definitive description Juvenile HD clearly described (Hoffman) Mendelian dominant inheritance recognized Systematic study of inheritance (Bell) First detailed genetic-epidemiologic survey in specific region (Michigan) Committee to combat Huntington’s disease formed World Federation of Neurology research group formed Centennial Symposium, Columbus, Ohio Localization of HD gene on chromosome 4 First application of DNA markers in prediction Isolation of HD gene; identification of mutation as expanded CAG repeat Neurologic phenotype produced in transgenic mouse model with expanded CAG repeat Neuronal inclusions recognized in transgenic mouse and human HD brain Reversal of pathology and phenotype in mouse models through reducing HTT protein expression (Yamamoto) PREDICT-HD: to study healthy subjects at risk for HD Registry study: European observational study of HD >10,000 participants COHORT study: large-scale observational study of HD in United States and Australia, 3,500 participants TRACK-HD: observational biomarker study of premanifest and early-stage HD ENROLL study: worldwide observational study of HD, foundation for clinical trials in HD

Huntington’s Disease in a Historical Context  •  19

One contributing factor must be the long tradition, begun by George Huntington himself and continuing through later observers, as already noted, of accurate and broadly based descriptions of its clinical features, natural history, inheritance, and pathology. This has meant that, for the most part, investigators have been analyzing and reporting the details of a single specific disorder, rather than a heterogenous group of conditions that would have to be disentangled at a later date, rendering earlier studies of uncertain significance. A second relevant factor is that many of the features and consequences of the disorder, notably aspects of its inheritance and later the issues relating to genetic prediction, stand out in greater clarity than for other related disorders, demanding to be addressed and resolved. Only when this has been done for HD has it then become clear that these issues are in fact general ones, occurring for many other conditions, but less recognized until viewed in the light of our HD experience. In some instances, such as approaches to presymptomatic testing and the testing of children, this has led to the definition of overall principles, interacting with the broader concepts of ethicists and philosophers. A final reason that HD has led the way to such a significant extent is the willingness, now the accepted practice, of workers on HD collaborating, sharing their data, and more recently, being prepared to collect information in standardized, or at least comparable, ways. Thus the collective experience has been far greater than might have been expected for a relatively infrequent condition, about which individual investigators or centers inevitably have relatively limited material on which to base conclusions. This collaborative approach has been especially evident in the research leading to isolation of the HD gene, in the approaches to and consequences of presymptomatic detection, and now in the coordination and performance of therapeutic trials.

Wider Aspects of Inheritance Huntington’s disease, as described earlier, was not among the very first disorders to be recognized as following Mendelian inheritance, but it was certainly one of the first for which Mendel’s principles could be seen to apply to disorders of late onset, not just to conditions evident from birth. Equally, as anomalies in Mendelian disorders were recognized, HD paved the way with the recognition that the juvenile form occurred

within families in which the more typical phenotype predominated, and that it showed mainly paternal transmission. It was well more than 50 years before this parent-of-origin effect could be combined with the concept of genetic anticipation and explained in terms of DNA instability (as discussed in ­chapter 6). It is worth mentioning here that these aspects of HD would not have led the way in defining a new mechanism of mutation had it not been for the willingness of workers on HD, notably geneticists, to “look across” to comparable situations in other genetic conditions. In this case, it was the comparison with the muscle disorder myotonic dystrophy, in which both genetic anticipation and parent-of-origin effects were more striking than in HD, that forced the recognition that both disorders were part of a small family of genetic conditions showing a new and unique form of genetic mutation. Huntington’s disease was likewise a pioneer for the wider process of gene mapping and positional cloning, from the original suggestions of Fisher (1935) and Bell and Haldane (1937) that linked genetic markers might be used in the prediction of HD, to the identification of the first DNA polymorphism linked to a serious autosomal disease by Gusella et al. (1983), from which sprang the shared experience in presymptomatic testing referred to previously.

Wider Insights Into Neurobiology and Neuropathology Discovery of the HD mutation in 1993 not only provided the explanation of anticipation and related anomalies of inheritance through DNA instability but also gave a completely fresh neurobiologic approach to the pathogenesis of HD through the recognition that the expanded trinucleotide repeat coded for polyglutamine, which might itself be directly involved in neuronal pathology in HD and in other degenerative brain disorders. Launched by Max Perutz’s polar zipper hypothesis (see Figure 1.6) and extended and modified by numerous further studies, described in later chapters, this showed how an understanding of the basic molecular mechanism at the protein level underlying the HD mutation could be linked to the actual cellular pathology within the brain. Again, the importance of these findings was enhanced by the realization that the mechanisms were not unique to HD, or even to trinucleotide repeat disorders as a group, but

20  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

were likely relevant to neurodegeneration more generally. Bringing the wider history of HD even closer to the present, the development of mouse models for HD, bearing the expanded trinucleotide sequence, has, since the original report of Mangiarini et al. (1996), again opened up a new field for the study of human brain degenerations as a whole, not only vindicating the central role of the mutational defect itself in the brain pathology but also providing models for testing the effects of interventions that can then become the basis for clinical trials.

Social History The wider influence of HD described earlier has been principally on the new understanding of disease in a medical and scientific context, but HD has also made a profound contribution in our perception of how patients with a serious brain disorder interact with society more generally. This can be readily seen from the earliest literature concerned with HD onward, but it has only recently been the subject of serious analysis, notably in the papers of Alice Wexler (2002, 2010)  and in her 2008 book, The Woman Who Walked Into the Sea: Huntington’s and the Making of a Genetic Disease. Wexler’s study focuses on the New England study of East Hampton, New York home to the three generations of the Huntington family as physicians, and to the affected families for whom they provided medical care, and of whom George Huntington was to report in his original 1872 paper. Her description of their interactions, and of their setting in a small-town American community of the later 19th century, are not only sensitive and well grounded in the local records of the town but also show a much more complex picture than given by reports in the medical literature a few decades later and continuing into recent times. In particular, Wexler shows how the families, including some individuals later affected with HD, were often well integrated and playing prominent roles in the social fabric of the community—a contrast with the later medical and psychiatric literature in which they are stigmatized and at times close to demonized. Wexler’s analysis of the study of Davenport and Muncey (1916), also undertaken in New England, shows how this severely prejudiced attitude became closely associated with Davenport’s wider advocacy of eugenics, which itself became extremely influential across

America and internationally, finding its ultimate expression in Nazi Germany, where HD families were a prominent target. Returning to more positive aspects of the social history of HD, its role as an exemplar for the formation of lay societies related to specific disorders has already been described, as has its contribution to the social and psychological foundations of genetic counseling and presymptomatic testing. Perhaps the most important lesson to be learned in all these respects from HD is that it has shown how affected families themselves can and should be directly involved, alongside professionals, in developing patterns of practice and care and in the overall strategies of prevention and therapy for the disorder.

References Alzheimer A. Uber die anatomische Grundlage der Huntinton’schen Chorea und der choreatischen Bewegungen überhaupt. Zeitschrift für die gesamte Neurologie under Psychiatrie. 1911;3:566–567. Avila-Giron R. Medical and social aspects of Huntington’s chorea in the State of Zulia, Venezuela. In: Barbeau A, Chase TN, Paulson GW, eds. Advances in Neurology. New York: Raven Press; 1973:261–266. Barbeau A, Chase TN, Paulson GW. Huntington’s Chorea, 1872–1972. New York: Raven Press; 1973. Bates GP. History of genetic disease: the m ­ olecular genetics of Huntington disease—a history. Nature Reviews Genetics. 2005;6:766–773. Bates G, Harper PS, Jones L. 2002. Eds. Huntington’s Disease (3rd edition) New York, Oxford University Press. Bell J. Huntington’s chorea. In: Fisher RA, ed. Treasury of Human Inheritance. Vol. IV, Part 1. Cambridge: Cambridge University Press; 1934:1–67. Bell J, Haldane JBS. The linkage between the genes for colour-blindness and haemophilia in man. Proceedings of the Royal Society of London B. 1937;123:119–150. Bourneville DM. De l’ emploi thérapeutique du monobromure de camphre. Progrès Médical (Paris). 1874;2:456–459. Bower JL, Mills CK. Notes on some cases of c­ horea and tremor. Journal of Nervous and Mental Disease. 1890;15:131–142. Browning W. Huntington number. Neurographs. 1908a;1:1–64.

Huntington’s Disease in a Historical Context  •  21

Browning W. Rev Charles Oscar Waters MD. I. Biographic sketch. II. Location of his cases. Neurographs. 1908b;1:137–144. Browning W. Dr Charles Rollin Gorman. I. Personal sketch. II. His relation to the chorea question. Neurographs. 1908c;1:144–147. Browning W. Irving Whitehall Lyon MD. I. Personal sketch. II. Location of his cases. Neurographs. 1908d;1:147–149. Bruyn GW. Huntington’s chorea. Historical, clinical and laboratory synopsis. In: Vinken PJ, Bruyn GW, eds. Handbook of Neurology. Vol. 16. Amsterdam: Elsevier; 1968:298–378. Bruyn GW, Baro F, Myrianthopoulos NC. A ­centennial bibliography of Huntington’s chorea ­1872–1972. The Hague: Martinus Nijhoff; 1974. Curschmann H. Eine neue ChoreaHuntingtonfamilie. Deutsche Zeitschrift für Nervenheilkunde. 1908;35:293–305. Davenport CB. Heredity in relation to eugenics. New York: H. Holt; 1911 (reprinted by Arno Press, 1972). Davenport CB, Muncey EB. Huntington’s chorea in relation to heredity and eugenics. Eugenics Record Office Bulletin. 1916;17:195–222. Déjerine J. L’Hérédité dans les maladies du système nerveaux. Paris: Thèse Aggreg; 1886. De Jong RN. George Huntington and his relationship to the earlier descriptions of chronic hereditary chorea. Annals in Medical History. 1937;9:201–210. Drake DC. The curse of San Luis. Philadelphia Inquirer. August 26, 1984. Dunglison R. Practice of Medicine. 1st ed. Philadelphia: Lee and Blanchard; 1842. Dunglison R. Practice of Medicine. 3rd ed. Philadelphia: Lee and Blanchard; 1848. Durbach N, Hayden M. George Huntington: the man behind the eponym. Journal of Medical Genetics. 1993;30:406–409. Eager R, Perdrau JR. Notes on four cases of Huntington’s chorea. Journal of Mental Science. 1910;56:506–509. Elliotson J. St Vitus’s dance. Lancet. 1832;1:162–165. Fisher ED. A case of Huntington’s chorea. Journal of Nervous and Mental Disease. 1906;33:781. Fisher RA. Linkage studies and the prognosis of hereditary ailments. Transactions of the International Congress on Life Assurance Medicine (London). 1935:615–617. Folstein S. Huntington’s Disease: A Disorder of Families. Baltimore: Johns Hopkins University Press; 1989.

Freund CS. Zwei Brüder mit Huntingtonscher Chorea. Berliner klinische Wochenschrift. 1911;48:735. Golgi C. Sulla alterazioni deglia organi centrali ­nervosi in uno caso di corea gesticulatoria ­assoziata ad alienazione mentale. Rivista Clihnicale Bologna. 1874;4:361. Gorman CR. In: Dunglison R, ed. Practice of Medicine. 3rd ed., Vol. 2. Philadelphia: Lee and Blanchard; 1848:218. Gusella JF, Wexler NS, Conneally PM, et al., A polymorphic DNA marker genetically linked to Huntington’s disease. Nature. 1983;306:234–238. Harper PS, ed. Huntington’s Disease, 1st ed. London: WB Saunders; 1991. Harper PS, ed. Huntington’s Disease, 2nd ed. London: WB Saunders; 1996. Harper PS, Perutz MF, eds. Glutamine repeats and neurodegenerative diseases: molecular aspects. Oxford: Oxford University Press; 2001. Hayden MR. Huntington’s Chorea. Berlin: Springer; 1981. Hoffmann J. Uber Chorea chronic progressive (Huntingtonsche Chorea, Chorea hereditaria). Virchows Archiv für pathologische Anatomie. 1888;3:513–548. Huntington G. On chorea. Medical and Surgical Reporter. 1872;26:320–321. Huntington G. Recollections of Huntington’s chorea as I saw it at East Hampton, Long Island, during my boyhood. Journal of Nervous and Mental Disorders. 1910;37:255–257. Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable in Huntington’s disease chromosomes. Cell. 1993;72:971–983. Husquinet H. Premières descriptions de la chorée de Huntington en France et en Belgique. Clin Medica. 1975;10:197–204. Jelgersma G. Die abnatomische Veranderungen bei Paralysis agitans und chronischer Chorea. Verhandlung der Gesellschaft deutscher Naturforscher und Arzte. 1908;2(2):383–388. Jelliffe SE. A contribution to the history of Huntington’s chorea: a preliminary report. Neurographs. 1908;1:116–124. Klein J. Woodie Guthrie: A life. London: Faber and Faber; 1981. Klug A. Max Perutz (1914–2002). Structural biology and biochemistry: Retrospective. Science. 2002;295(5564):2382–2383. Kolata G. Closing in on a killer gene. Discover. 1984;March:83–87.

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Landouzy LTJ. Mouvements choréiques des members inférieurs. Gazette Médical de Paris. 1873;48:329–330. Lewis B. A case of chorea associated with mania, terminating fatally by cerebellar apoplexy. Medical Times and Gazette. 1876;2:280–282. Lund JC. Chorea St Vitus dance in Saetersdalen. Report of health and medicine and medical conditions in Norway in 1860, 1860:137 (quoted by Ørbeck, 1959). Lyon IW. Chronic hereditary chorea. American Medical Times. 1863;7:289–290. MacFaren J. A case of chorea. Journal of Mental Science. 1874;20:97–99. Mangiarini L, Sathasivam K, Seller M, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996;87:493–506. Mapother E. Mental symptoms in association with choreiform disorders. Journal of Mental Sciences. 1911;57:646–661. Mendel G. Versuche über Pflanzenhybriden. Proceedings of the Natural History of Brunn. 1865;4:3–47 (English translation reprinted 1965. Edinburgh: Oliver and Boyd). Meynert T. Discussion to Fritsch. Psychiatry. 1877;Clb 4:47. Mitchell JK. Huntington’s chorea. Journal of Nervous and Mental Disorders. 1895;22:395–397. Moscovich M, Munhoz RP, Becker N, et al. Americo Negrette and Huntington’s disease. Arquivos de Neuro-Psiquiatria. 2011;69:711–713. Müller LTR. Uber drei Falle von Chorea chronic progressive (Chorea hereditaria, Chorea Huntington). Deutsche Zeitschrift für Nervenheilkunde. 1903;23:315–335. Negrette A. Corea de Huntington (Estudio de una sola familial investigade, través de varias generaciones). Talleros Graticos. University of Zulia, Maracaibo, Venezuela, 1963. Okun MS, Thommi N. Americo Negrette (1924 to 2003): diagnosing Huntington disease in Venezuela. Neurology. 2004;63:340–334. Oppenheim H. Eine seltene Motilitatsneurose (chorea hereditaria)? Berliner klinische Wochenschrift. 1887;24:309–310. Ørbeck AL. An early description of Huntington’s chorea. Medical History. 1959;3:165–168. Osler W. Hereditary chorea. Johns Hopkins Hospital Bulletin. 1890;1:110. Osler W. The Principles and Practice of Medicine. Edinburgh: Young J Pentland; 1892: 944–945. Osler W. Remarks on the varieties of chronic chorea and a report upon two families of the hereditary

form with one autopsy. Journal of Nervous and Mental Disorders. 1893;18:97–111. Osler W. Case of hereditary chorea. Johns Hopkins Hospital Bulletin. 1894;5:119–129. Osler W. On chorea and choreiform affections. Philadelphia: Blakiston and Son; 1904:96–112. Osler W. Historical note on hereditary chorea. Neurographs. 1908;1:113–116. Perutz MF, Johnson T, Suzuki M, Finch JT. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proceedings of the National Academy of Sciences, U S A. 1994;9:3555–3787. Petit H. La maladie de Huntington. In: Warot P, ed. C.R. 67e. congress de Psychiatre et Neurologie. Langue Franc. Paris: Masson; 1970:901–1058. Pfeiffer JAF. A contribution to the pathology of chronic progressive chorea. Brain. 1913;35:276–292. Phelps RM. A new consideration of hereditary chorea. Journal of Nervous and Mental Disorders. 1892;19:765–776. Pines M. In the shadow of Huntington’s disease. Science. 1984;May:32–39. Punnett RC. Mendelian inheritance in man. Proceedings of the Royal Society of Medicine. 1908;1:135–168. Scrimgeour EM. Possible introduction of Huntington’s chorea into Pacific Islands by New England whalemen. American Journal of Medical Genetics. 1983;15:607–613. Sinkler W. On hereditary chorea with a report of three additional cases and details of an autopsy. Medical Record (NY). 1892;41:281–285. Steinmann M. In the shadow of Huntington’s disease. Columbia. 1987;13:14–19. Stevens DL. The history of Huntington’s chorea. Journal of the Royal College of Physicians. 1972;6:271–282. Stier E. Zur patholoogischen Anatomie der Huntington’schen Chorea. Münchener medizinische Wochenschrift. 1902;49:770. Van der Weiden RMF. George Huntington and George Sumner Huntington. A tale of two doctors. History and Philosophy of the Life Sciences. 1989;11:297–304. Van der Weiden RMF. George Huntington: the man behind the eponym. Journal of Medical Genetics. 1993;30:1042. Vonsattel JP, Keller C, Cortes Ramirez EP. Huntington’s disease—neuropathology. Handbook of Clinical Neurology. 2011;100:83–100. Waters CO. In: Dunglison R, ed. Practice of Medicine. Vol. 2. Philadelphia: Lee and Blanchard; 1842:312.

Huntington’s Disease in a Historical Context  •  23

Westphal C. Uber eine dem Bilde der cerebrospinalen grauen Degeneration-ähnliche Erkrankung des zentralen Nervensystems ohne anatomischen Befund, nebst einigen Bemerkungen über paradoxe Kontraktion. Archiv für Psychiatric und Nervenkrankheiten. 1883;14:87–96, 767–773. Wexler A. Mapping fate. New York: Times Books; 1995. Wexler AR. Chorea and community in a nineteenth-century town. Bulletin of the History of Medicine. 2002;76:495–527.

Wexler A. The Woman Who Walked Into the Sea: Huntington’s and the Making of a Genetic Disease. New Haven: Yale University Press; 2008. Wexler A. Stigma, history, and Huntington’s ­disease. Lancet. 2010;376(9734):18–19. Winfield JM. A biographical sketch of George Huntington, M.D. Neurographs. 1908;1:89–91. Wood HC. The choreic movements. Journal of Nervous and Mental Disorders. 1893;4:241.

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2 Clinical Neurology Ray m u n d A .   C .   Ro o s

The first description of a choreatic patient, which dates from 1841, was by Waters (Bruyn, 1968). With hindsight, we can tell that he had in fact painted a picture of the condition that we now call Huntington’s chorea. However, it was not until 1872 that George Huntington in his lecture “on chorea” described the clinical picture of this devastating disease. It is a neurodegenerative disorder that is inherited from generation to generation within families, with onset in middle age, and that is characterized clinically by unwanted choreatic movements, behavioral and psychiatric disturbances, and dementia (Bruyn, 1968). In the 1980s, with increased ­awareness of the extensive nonmotor symptoms and signs, the name was changed to Huntington’s disease (HD). In 1983, a genetically linked marker was mapped to chromosome 4, and in 1993, the mutation that causes HD was identified (Huntington’s Disease Collaborative Group, 1993). This was a true milestone because from then on it became possible to perform predictive diagnosis. Cell and animal models have been developed worldwide, and now, two decades later, we are on the brink of finding a rational treatment.

Clinical Symptoms and Signs A precisely taken family history remains the basis of the diagnosis of HD, which can nowadays be confirmed by DNA analysis. The presence of motor signs was until recently the gold standard for diagnosis, but we have learned from the systematic follow-up of premanifest

mutation carriers that cognitive as well as psychiatric symptoms or signs can also be the first manifestation of the disease. The motor signs, mainly unwanted movements, remain, however, the most characteristic and specific for a clinical diagnosis. This chapter will concentrate on the motor phenotype; the other main symptoms and signs such as neuropsychology and neuropsychiatry are described extensively in ­chapter 3.

Motor Behavior Signs Ch ore a

The most common and characteristic form of unwanted movements in HD is chorea, derived from the Greek term for “dance.” These rapid, elegant, short-lasting, unwanted movements can be seen in all muscles of the trunk, face, and extremities. They show a unique pattern that is unpredictable and that changes over time. The smooth muscles are not involved. Rapid, subtle movements of facial muscles can be seen, such as raising the eyebrows and closing the eyelids simultaneously or separately. Frequently observed movements are opening and closing the eyes, twitching around the mouth and cheek, pouting the lips, opening the mouth, and moving the tongue. Generally the extensor muscles of the neck and trunk prevail over the flexor muscles, leading to stretching the long muscles of the back. Fast, graceful, small movements of the fingers and hands, toes and feet can also be seen. Often in the early stage of the disease, unwanted movements are incorporated into deliberate movements, for example, passing a hand through the hair, or pointing to something in a distance. Choreatic

  •  25

movements are present when the patient is awake, although some patients, and more usually partners of patients, report unwanted movements at night while asleep. All unwanted movements are increased by unexpected situations, such as anxiety, stress, and positive as well as negative emotions. Many patients are not aware of the choreatic movements or at least not of the extent to which they are present, though the consequences of the unwanted initiation of muscle movement can catch their attention indirectly. H y p o kin e s ia

Although chorea remains the predominant sign in Huntington’s disease, all patients also show a more or less severely expressed hypokinetic motor pattern. Both juvenile and late-stage patients demonstrate so-called parkinsonian symptoms. Slowness in starting a movement (akinesia), slowness in executing a movement (bradykinesia), showing fewer spontaneous automatic movements, and a decrease in all motor activities (hypokinesia) can be seen. This leads to a combination of hypokinesia and hyperkinesia, which means that facial expressions can disappear while at the same time many small choreatic movements are present. The parkinsonian signs form part of the natural course of HD, but neuroleptic drugs, used to treat behavioral disturbances and hyperkinesias, certainly contribute to this. Dy s to n ia

The combination of unwanted movements and increased muscle tone can lead to dystonic, slowly twisting and turning movements in all voluntary muscles. This can result in abnormal posture, rotation of the trunk or limbs, and even torticollis, blepharospasm, and all other forms of typical focal or segmental forms of dystonia. Expression of dystonia in the fingers and hands can become more evident during other motor activities such as walking. Flexion or extension of the back is often present when sitting or during walking. Combinations of chorea and dystonia are often seen, the differentiation of which can be extremely difficult because there are no hard criteria. Dystonia can also be induced by the use of neuroleptic drugs. Tic

Tics are very rapid, stereotypic, suppressible movements, mainly occurring in the face and

the arms. They are sometimes present, usually in combination with one of the unwanted movements described previously. Patients are usually aware of these movements, and some learn to suppress them.

Course of the Motor Symptoms and Signs From P re man ife st to P rodromal P hase to Ea rly-Stage Man ife st Dise as e

Every individual has a specific pattern of motor behavior that is genetically and culturally determined (Bates et  al., 2002; Shannon, 2011). Huntington’s disease progresses gradually, so changes in behavior and changes in motor activities also develop slowly and may therefore remain unnoticed for a long time. Circumstances influence the presence or absence of the first subtle signs. The small changes over time are difficult to recognize, especially when the patient and family are not familiar with the disease. Initial changes are often not noticed by the patients; an awareness emerges later, for instance, when looking at a video recording of themselves. However, when the individuals at risk are familiar with the symptoms and signs from an affected parent, this can lead to a fixation on their own behavior. It can become even worse when their status changes from being “at risk” to being a proven gene carrier. Uncertainty can exert a tremendous influence, the carrier becoming obsessed with every unexpected movement, with every dropped glass, with feeling unsteady when walking, or with feeling unsafe on stairs. Restless legs when in bed often is a sign noticed by others. Careful observation during a visit to the outpatient clinic can detect incidental, unexpected movements in all muscles—provoked by the stress of the situation—so it is important for the clinician to have a good view of the legs, feet, and toes (often hidden behind the desk). The partner and family, once aware of the situation, are usually very reluctant to say anything about the changes they have noticed. Family and friends who have less frequent contact will often notice changes earlier. Activities of daily life, such as getting up in the morning, taking a shower, getting dressed, and eating, start to take longer. Remembering when and where the change in motor behavior started is extremely difficult, and the memory of this tends to become falsified over time. A fall down the stairs

26  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

is, therefore, often regarded as the start, and sometimes even the cause, of the disease. The date the disease started is often related to major life events or family events. It is very clear from clinical practice that in the transition phase from the pre(motor) manifest to the (motor) manifest disease, changes in motor behavior can be present but then disappear for some time. These symptoms and signs determine the prodromal stage (see c­ hapter 5 for an extensive description of the stages of the disease). Stressful events, physical as well as psychological, strongly influence motor behavior. Problems at work and workload reorganization, whether or not related to poorer functioning because of HD, have an enormous impact. This influence remains during the course of the disease, which makes interpretation and management of these signs difficult. For the gene carrier, the feelings of uncertainty are strong. The person at risk might raise the question: do I have HD? For the gene carrier, this has been replaced by: has the disease started yet? F ro m Ear ly-S tag e Manifest D is e ase to Lat e S tag e

Motor symptoms and signs increase over the months and years. Obvious motor changes at the beginning of the clinically manifest disease start to intrude into daily life. Walking becomes unsteady, with irregular steps, sometimes leading to a missed step and stumbling, but not to a fall. Unwanted choreatic movements in the face, trunk, arms, and legs are occasionally present. Focal dystonia, torticollis, can be the first sign, but this is uncommon. Eye movements will change, sometimes in the very early stages, before other signs are visible. Patients never complain about this, but on examination the movements are found to be disturbed (see later). All daily activities can be performed without help, but at a slower pace. With further progression, walking becomes more difficult, often leading to a near fall. Falls occur in more than 50% of the patients and are more frequent in patients who have a combination of motor and cognitive signs. The walking pattern is influenced by unwanted movements as well as by instability. The patient describes these sensations as comparable to walking in a drunken fashion. Walking distance decreases, and stairs become tricky. Those used to cycling become uncertain, need more space, and can no longer steer in a straight line. Also when driving a car, which requires many more other skills, changes become visible.

The way the steering wheel is handled leads to a swaying course, and a stuttering propulsion develops because of the unsteady use of the accelerator. Finally, walking alone, without support, becomes too dangerous, and wheelchair support becomes essential. The increase in unwanted movements causes problems with articulation resulting in slurred speech, and the development of severe dysarthria finally makes talking impossible. Swallowing leads more and more to choking. This often starts with choking during meals, but later it can happen at any time during the day. All activities of daily life need increasing support from family or professionals. In the late stage or end stage, walking becomes completely impossible, and the patient becomes wheelchair dependent and bedridden. The choreatic movements are often expressed less, and more hypokinetic elements become manifest. The final stage leads to a completely bedridden, mute patient adopting a fetal position, with flexion of arms, legs, and trunk with contractions. The patient becomes incontinent and needs the caregiver’s help with all daily life activities: dressing, showering, toileting, and eating. During the course of the disease, the movements can be influenced by the side effects of medication. Well-known examples are the orofacial dyskinesia and hypokinetic syndromes induced by the classic neuroleptic drugs. The process of progression is not determined by, and cannot be monitored by, a focus on a single sign. The combination of motor with psychological and psychiatric signs determines how the patient is functioning and the extent of help required. Hence the functional capacity, the independence of the patient, is of much greater importance than the degree of change of one of the three core symptoms alone (see later). The restriction placed on an individual by all contributing signs finally determines the quality of life of that person.

Patterns of Symptoms and Signs The clinical symptomatology of patients is not predictive. The way the parent, brother, or sister of that person experienced the disease gives no clue to the way the disease will manifest. Clinical studies have described that the presence of moderate to severe hypokinesia in motor symptomatic HD mutation carriers co-occurs with executive cognitive dysfunctioning and adversely affects global functioning (Reedeker

Clinical Neurology  •  27

et al., 2010). If the motor phenotype is predominantly choreatic, better global and cognitive functioning is evident compared with patients with a predominantly hypokinetic-rigid motor phenotype (Hart et al., 2013). Van Vugt et al. (1996) demonstrated that all patients show hypokinesia related to their level of functional activity. Hypokinesia increases with a lower level of functional activity and with an increase of neuroleptic drug use (Van Vugt et al., 2001). This decrease in movement is most probably caused by an impaired antagonistic inhibition before and during agonistic activity (Van Vugt et al., 2004). It was shown by Delval et al. (2006) that gait velocity and cadence were reduced, whereas the stride length was not affected. The motor pattern is also influenced by the age at onset. This will be described in detail in ­chapter  4, most juvenile cases with symptoms before the age of 10  years show a hypokinetic hypertonic pattern of movements (Quarrel et al., 2009). Choreatic signs usually develop in the second decade. Dependency due to motor limitations occurs quite early in the course of the disease, and behavioral changes precede motor changes in most cases.

Psychological Symptoms and Signs The very first symptom of HD can be thinking more slowly:  a disturbed balance between cognitive load and cognitive capacity leading to stressful situations, nowadays called burnout (see ­chapter 3). Follow-up of premotor manifest gene carriers has shown that these symptoms are very often present before any motor change can be seen. Later, it becomes more difficult to maintain a focused attention, leading to a reduction in memory function. Orientation to time and place is lost. Executive functioning becomes increasingly problematic. There can be a loss of insight into one’s own functioning. Planning becomes difficult. In later stages, a complete clinical picture of dementia develops, although the degree of dementia is often difficult to determine because of the loss of a capability to communicate (Lemiere et  al., 2004; Paulsen and Conybeare, 2005; Stout et al., 2012).

Psychiatric Symptoms and Signs Psychiatric symptoms were described by George Huntington in his publication and are discussed extensively in ­chapter 3. A review of the literature

shows that the reported prevalence of depressed mood, anxiety, irritability, and apathy varies from 33% to 76%, whereas obsessive-compulsive symptoms and psychosis occur less often, with prevalences of 10% to 52% and 3% to 11%, respectively (Van Duijn et  al., 2007). All major psychiatric symptoms and signs are described in patients with HD. Neuropsychiatric symptoms often precede the motor symptoms of HD. The presence of psychopathology in particular has an important negative impact on daily functioning and quality of life for patients and caregivers, and increases the risk for institutionalization and suicide (Craufurd et al., 2001; Van Duijn et al., 2008).

Secondary Signs Besides the three core symptoms and signs, HD is characterized by three secondary symptoms and signs:  loss of body weight, sleep disturbances, and autonomic disturbances. We ight Loss

Unintentional loss of body weight is a hallmark of HD leading to a general weakening and loss of quality of life. In most patients, a considerable weight loss occurs in the final stages of the disease (Kremer et  al., 1990, 1992). Other studies have, however, demonstrated that HD patients are either underweight or tend to lose weight earlier in the course of their illness and eventually become cachectic (Trejo A  et  al., 2005). Weight loss in HD is not associated with anorexia but rather with an increased appetite. Although there are indications of a higher sedentary energy expenditure because of unwanted movements (Pratley et al., 2000), these findings do not completely explain the lower body mass index found in certain groups of asymptomatic gene carriers and early-stage HD patients even without unwanted movements. Undernutrition is prevalent in HD patients and contributes to a higher mortality (Lanska et  al., 1988). Myers showed that a higher body mass index was associated with a slower rate of progression (Myers et  al., 1991). Aziz et  al. (2008) showed that patients with a higher CAG repeat number had a faster rate of bodyweight loss, probably resulting from a hypermetabolic state. Sl e e p Disturban ce s

Patients with Huntington’s disease have about twice the amount of nighttime sleep impairment

28  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

compared with control subjects. They show a delayed sleep-onset time and longer sleep duration, use more sleep medication, and experience more daytime dysfunction. The sleep-onset latency and the usual wake-up time are both significantly delayed in HD patients, suggesting a phase shift in the circadian sleep–wake cycle toward later hours. Interestingly, a delayed rise in melatonin concentration in the morning and an increased rate of early-morning cortisol production have been described, which may illustrate a manifestation of a delayed circadian rhythm in HD. Circadian rhythm disturbance is likely to be caused by pathology in the suprachiasmatic nucleus or its afferents. The time at which HD patients wake up is related to the level of functional impairment. The most important overall predictor of sleep impairment is depression (Aziz et al., 2010a). Au to n o m ic Dysreg u lat ion

Vegetative symptoms, indicative of autonomic nervous system dysfunction, have repeatedly been reported in patients with HD and include hyperhydrosis (±40%), heat and cold intolerance (±40%), sialorrhoea (±30%), micturition and swallowing difficulties (±71%), sexual dysfunction (±60%), and complaints suggestive of orthostatic intolerance. Other, less frequently reported symptoms are abdominal fullness, straining for defecation, fecal and urinary incontinence, urgency, incomplete bladder emptying, and lightheadedness. Although vegetative symptoms are most prominent in the advanced stages of the disease, autonomic complaints such as dizziness after standing up, excessive perspiration, and tachycardia can occur even in mildly disabled HD patients as well as in otherwise asymptomatic gene carriers. The degree of autonomic dysfunction is related, not to the Unified Huntington’s Disease Rating Scale (UHDRS) motor score, but rather to functional capacity, and also shows a positive relation to depressive symptoms and the use of antidepressant drugs. Several tests show that sympathetic (skin response test) as well as parasympathetic (pupillary light reflex response) dysfunction exists. Also, the regulation of the heartbeat shows a combination of dysfunction of both paths in the autonomic nervous system. The clinical manifestation of some of these signs is not well known because some of the signs are detected in the late stage when symptoms are often difficult to read (Aziz et al., 2010b).

Clinical Diagnosis The clinical diagnosis of HD is based on the history of the patient, the family history, the neurologic examination, and confirmation by DNA analysis.

History of Patient and Family Taking the history of a patient is the core activity of any doctor. Depending on the complaints of the person seeking advice, the questions should deal with all elements of the disease, including motor disturbances, behavior, cognition, and the impact of the disease on daily life. Enquiries should also be made about any secondary signs. The familial and social context, education and training, and kind of job the person has should also be discussed. It is also crucial to obtain information from the partner or from a very good friend. It is essential to outline the family history and draw a pedigree. Details about the affected parent, especially the age at onset, can be of use if these are available. If family members are not aware of the presence of HD in one of the parents, a very detailed description of the parents, their medical history, and their end-of-life circumstances can be very valuable. For instance, the presence of slightly demented, parkinsonian features may indicate the presence of HD.

Neurologic Examination The neurologic examination starts with observation of the patient from the moment the doctor calls them from the waiting room. Those first moments during the transition from “apparently not being observed” to “being observed” often provide a considerable amount of information about motor behavior: changing position, standing up from the chair, and walking are influenced by that moment of stress. During the history taking, facial expression and speech are automatically observed. Rapid subtle movements of all facial muscles may result in raising the eyebrows and opening the eyes very wide. The mouth may open, the lips pout, and sometimes the tongue protrudes. The routine neurologic examination then proceeds with measuring body weight. For the rest of the examination, it is useful to follow the motor part of the UHDRS, which can be extended as indicated by other elements of the neurologic examination. When walking in the office or in the corridor, the patient characteristically shows a hesitation in initiating movement Clinical Neurology  •  29

and an irregular, broad-based step. During walking and turning, the patient often stays on the forefoot, stretches the legs, and then continues to walk after a short hesitation. This resembles the walk of someone who is drunk. Later in the course of the disease, walking requires support. Unsupported line walking is a good test of balance. Difficulty in line walking for at least 10 steps starts with many compensatory movements of the arms and trunk, leading to sidestepping or the need to seek support from a desk or wall. Postural stability must be tested in a standardized way, by holding the patient’s shoulders and pulling backward. Stability decreases over time. The rest of the neurologic examination can be performed in the sitting position on the bench. Having verified that the vision is good, eye movements are tested. These can become abnormal at a very early stage of the disease, often starting with vertical and also horizontal saccadic movements, which can be hidden by blinking. The initiation of eye saccades is delayed, and the velocity of tracking an object becomes slower. Later in the course of the disease, a vertical and horizontal gaze paralysis develops. Finally, the patient can no longer initiate voluntary saccades and cannot resist turning the head instead of the eyes. More specifically, motor tasks become difficult to perform and to maintain with the facial muscles. The nonpersistence of the tongue provides a sensitive and rapid quantifiable task. The patient is asked to open the mouth and protrude the tongue maximally. During the course of the disease, the patient loses the ability to maintain tongue protrusion and eventually is unable to protrude the tongue at all. Articulation starts to become unclear and slurred, and then disappears completely in the later stage. This interferes with speech content and plays an important role in the ability of others to understand the patient. Swallowing becomes difficult and leads to choking, sometimes only between meals, but later on during meals, even after adjusting food consistency to help with this. Performing simple tasks, such as finger tapping and alternating hand clapping, becomes irregular, slower, and with lower amplitude. There is no paresis. Muscle tone can be increased in some patients in the early stage of the disease. With passive movement of the elbow and wrist, an increase in muscle tone can be detected, which, on provocation, can lead to a further increase in rigidity. In the final stage of the disease, spasticity can develop with

increased tendon reflexes and a pathologic foot reflex as described by Babinski. Throughout the consultation, the clinician must be aware of the unwanted choreatic, dystonic movements that occur at rest as well as during action. Chorea certainly disturbs intended movements, and therefore distinguishing these from ataxic movements can become difficult. In the later stages of the disease, a real hypermetria or hypometria occurs in some patients. In the very young, the juvenile cases, and at end-stage disease, pyramidal signs, spasticity, and extensor reflexes (e.g., Babinski’s sign) can be found. It is very likely that these signs are underreported because less is known about late-stage patients. During every visit, in addition to the motor examination, attention must be paid to the psychiatric, psychological, and general aspects of the disease.

Diagnostic Confirmation by DNA Analysis Confirmation of the clinical picture can be obtained by DNA analysis. Huntington’s disease is caused by the elongation of a CAG repeat in the huntingtin gene to 36 or more CAGs. For a detailed description of the correlation between CAG repeat length and HD, see c­ hapter 4 on juvenile HD, c­ hapter 6 on the genetic and molecular basis of HD, and ­chapter  8 and on the genetic counseling and presymptomatic diagnosis of HD. If the disease is suspected on the basis of clinical signs, an elongated CAG repeat provides confirmation.

Onset, Course, and Duration of Illness It is commonly accepted that the age at onset of HD lies between 30 and 50  years for most patients. In a small proportion, it starts before the age of 20 years (see ­chapter 4) and is known as juvenile HD. At the other end of the spectrum, a small proportion of patients do not show any clinical manifestation of HD before the age of 60  years:  the so-called late-onset form. The genetic basis of HD, as well as genotype–phenotype correlations, is discussed in Chapter 6. It is still accepted that the onset of disease should be defined by the appearance of motor signs (see ­chapter  5). Very subtle movements, which can easily be missed and interpreted as nervousness, may only appear under special,

30  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

stressful circumstances. Family members and experienced professionals can probably interpret these as typical HD movements, but here bias may also play a part (de Boo et al., 1998). From clinical practice, we know that Huntington’s disease is a slowly progressive disorder. We know that the motor behavior is strongly influenced by psychological behavior, and vice versa. It is, therefore, likely that cognitive and other nonmotor changes start long before the clear motor signs emerge, and this is the subject of c­ hapter 5. Indeed, long-term follow-up of gene carriers shows that cognitive changes precede motor changes (Witjes-Ané et al., 2007). In the prospective TRACK-HD study, anatomic brain magnetic resonance imaging changes were found many years before expected onset (Tabrizi et al., 2009). In practice, one often sees that gene carriers suffer burnout or become depressed. Although environmental explanations are eagerly sought by the patient, in retrospect one often has to conclude that this period had been the beginning of the clinical manifestation of HD. These findings indicate how difficult it is to determine age at onset. From a clinical point of view, we can place various phases in a logical order (Table  2.1A). First is the at-risk phase when an individual has not been tested but has an affected parent, which confers a 50% chance of developing the disease. The second phase is the gene carrier phase, after disclosure of the DNA test result. In this premanifest phase, all aspects of life—psychological, psychiatric, and locomotoric—superficially appear to be normal. Other terms that apply here are the presymptomatic phase or premotor manifest phase (see ­chapter 5 for more details). After some time, the gene carrier adjusts to this situation, although HD is always at the back of their mind. Very gradually and insidiously, the

Table 2.1A. Phases and Stages of Huntington’s Disease - Phase 1 50% at risk - Phase 2 Gene carrier premanifest phase (formerly: premotor manifest/ presymptomatic) - Phase 3 Prodromal phase - Phase 4 Manifest stage I  TFC 11–13 Manifest stage II TFC 7–10 Manifest stage III TFC 3–6 Manifest stage IV TFC 1–2 Manifest stage V, end of life TFC 0

third phase emerges: the transition from the premanifest to the prodromal and subsequently to the manifest stage. From then on, circumstances determine reaction pattern, behavior, attention, memory, and movements. Many nonspecific changes can appear, often with trivial explanations as mentioned previously, which in essence highlight the emergence of this difficult phase for the gene carrier and the doctor. After recognizing the early signs and symptoms, the clinical diagnosis can usually be made, which often gives the person some peace and helps them move on from this period of uncertainty and also leads to acceptance by society. The phase of obvious disease (phase 4) is split into several functional stages. A functional stage is determined by the following items:  engagement in work, handling financial affairs, managing domestic affairs, performing activities of daily life, and the level of care that is required. This Total Functional Capacity (TFC) scale (Shoulson & Fahn, 1979) is useful for care providers and clinical studies and consists of 13 points (Table  2.1B). In stage I  (TFC 11 to 13), the patients lose 1 to 2 points, usually because work becomes more difficult to maintain and help is needed with complex financial affairs. Motor signs may be present. In stage II (TFC 7 to 10), work often needs to be adapted, help with finances is obligatory, not all domestic tasks can be performed, and sometimes daily life activities require help. In stage III (TFC 3 to 6), regular work becomes impossible, and only a few hours of voluntary work can be managed, all finances are performed with help, and only very simple domestic tasks remain. Help with self-care is required, and some patients will engage in day-care activities. In stage IV (TFC 1 to 2), only a minimal level of self-care remains possible, and day-care facilities are used several days per week. In stage V (TFC 0), complete care is needed, and the patient is usually cared for in a nursing home. The TFC is an assessment scale. Clearly, many patients behave differently. For instance, if extensive family care is available, admission to a nursing home either will not occur or only will occur much later in the progression of the illness. On the other hand, if family care is not available, admission to a nursing home may take place much earlier in the course of the disease, even though self-care and some domestic and financial affairs can still be coped with. The total duration of the illness is between 15 and 20 years. There have been conflicting reports about the influence of the length of the CAG Clinical Neurology  •  31

Table 2.1B. Total Functional Capacity Scale O ccu pat ion

U n abl e

0

Marginal work only Reduced capacity for normal work Normal Finances Unable Major assistance Minor assistance Normal Domestic chores Unable Impaired Normal Activities of daily living Total care Gross tasks only Minimal impairment Normal Care level Full-time skilled nursing home Home with chronic care Home

1 2 3 0 1 2 3 0 1 2 0 1 2 3 0 1 2

From Shoulson & Fahn, 1979

repeat to the course of the disease (see ­chapter 4 for a detailed discussion). (Ravina B, Romer M, Constantinescu R et al., 2008). Finally, all patients will eventually need care, unless they die before reaching that stage of the disease. The main cause of death is pneumonia, either spontaneously or after choking. Cardiac failure and suicide are two other important causes of death. Euthanasia is a realistic choice for many patients, although very few countries allow this procedure.

Assessment Scales Clinical assessment of the symptoms and signs of HD is important for the patient, family, and caregivers. Several scales have been developed that allow patients to be followed systematically, mainly for research purposes. The best known are the Shoulson and Fahn Capability Scale and the UHDRS. The UHDRS consists of motor, behavior, cognitive, and functional assessments, preceded by recording the patient’s history and medication scheme. For the behavior signs, a new scale was developed by Craufurd:  the Problem Behaviour Scale. Other scales, for

instance, regarding the quality of life, are also in use, mainly for research purposes (Huntington Study Group, 1996; Hocaoglu et al., 2012).

Differential Diagnosis The differential diagnosis of HD falls into two groups. The first are the “look-alikes” or so-called phenocopies, and the second are all other choreatic syndromes. Phenocopies are defined by a clinical diagnosis of HD with chorea, psychiatric, or cognitive signs and an autosomal dominant pattern of inheritance or family history. Only approximately 1% of clinical HD cases cannot be confirmed by a DNA diagnosis and therefore fall into the category of phenocopies. An alternative genetic diagnosis can only be determined for a small percentage of these phenocopies, as summarized in Table 2.2 (Wild & Tabrizi, 2007; see also the Online Mendelian Inheritance in Man [OMIM], available at:  www.ncbi.nlm.nih.gov/ omim). More frequent are the choreatic syndromes, whereby patients present with chorea, but do not have any obvious psychiatric and psychological signs. A wide range of differential diagnoses might

32  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

Table 2.2. Phenocopies of Huntington’s Disease

1. HDL1 2. HDL2 3. HDL3 4. SCA17 (HDL4) 5. SCA1/2/3 6. DRPLA 7. Chorea-acanthocytosis 8. McLeod syndrome 9. NBIA2 10. NBIA1/PKAN 11. Friedreich’s ataxia

M u tat ion

Locu s

Octapeptide repeat expansion PRNP-gen CTG/CAG-expansion JPH3-gen Not known CAG/CAA-expansion TBP-gen CAG-expansion ATXN1/2/3-gen CAG-expansion ATN1-gen mutation VPS13A-gen mutation XK-gen mutation PLA2G6-gen mutation PANK2-gen GAA-expansion FXN-gen

20pter.p12 16q24.3 4p15.3 6q27 6p23, 12q24, 14q24-q31 12p13 9q Xp21.2-21.1 22q13.1 20p13-12.3 9q13; 9p23-p11

HDL, Huntington disease like; DRPLA, dentatorubral-pallidoluysian atrophy; NBIA, neurodegeneration with brain iron accumulation 1; PKAN, pantothenate kinase–associated neurodegeneration; SCA, spinocerebellar ataxia. From Online Mendelian Inheritance in Man (OMIM). Available at: www.ncbi.nlm.nih.gov/omim.

explain the patient’s signs, among which is a group of hereditary forms of chorea. Benign hereditary chorea is the most well known of these, but is not progressive and presents without dementia. The rheumatic form and the chorea that can be caused

by systemic disorders are seen more frequently, but these are accompanied by signs of the underlying causative disease. Quite often the choreatic syndrome is the consequence of medication that has been prescribed (Table 2.3).

Table 2.3. Differential Diagnosis for Chorea H e r edi ta ry

Rheumatic disorders Drug induced

Systemic disorders

Hu n t i n gton’s Disease

Benign hereditary chorea Neuroacanthocytosis Dentatorubral-pallidoluysian atrophy Wilson’s disease Sydenham’s chorea Chorea gravidarum - Neuroleptic drugs -  Oral anticonceptive drugs - Phenytoin, carbamazepine - Levodopa -  Cocaine, amphetamine - Digoxin -  Systemic lupus erythematosus - Thyrotoxicosis - Polycythemia vera - Hyperglycaemia - AIDS - Paraneoplastic

According to Wild & Tabrizi, 2007

Clinical Neurology  •  33

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nucleus in Huntington’s disease. J Neuropathol Exp Neurol. 1990;49:371–382. Lanska DJ, Lanska MJ, Lavine L, Schoenberg BS. Conditions associated with Huntington’s disease at death: a case-control study. Arch Neurol. 1988;45:878–880. Lemiere J, Decruyenaere M, Evers-Kiebooms G, Vandenbussche E, Dom R. Cognitive changes in patients with Huntington’s disease (HD) and asymptomatic carriers of the HD mutation—a longitudinal follow-up study. J Neurol. 2004;251:935–942. Myers RH, Sax DS, Koroshetz WJ, et al. Factors associated with slow progression in Huntington’s disease. Arch Neurol. 1991;48:800–804. Online Mendelian Inheritance in Man (OMIM). Available at: www.ncbi.nlm.nih.gov/omim. Paulsen JS, Conybeare RA. Cognitive changes in Huntington’s disease. Adv Neurol. 2005;96:209–225. Pratley RE, Salbe AD, Ravussin E, Caviness JN. Higher sedentary energy expenditure in patients with Huntington’s disease. Ann Neurol. 2000;47:64–70. Quarrell WJ, Brewer HM, Squitieri F, Barker RA. Juvenile Huntington’s disease and other trinucleotide repeat disorders. 2009. Oxford University Press, USA; 1 edition. Ravina B, Romer M, Constantinescu R, et al. The relationship between CAG repeat length and clinical progression in Huntington’s disease. Mov Disord. 2008;23:1223–1227. Reedeker N, Van Der Mast RC, Giltay EJ, Van Duijn E, Roos RA. Hypokinesia in Huntington’s disease co-occurs with cognitive and global dysfunctioning. Mov Disord. 2010;25:1612–1618. Shannon KM. Huntington’s disease: clinical signs, symptoms, presymptomatic diagnosis, and diagnosis. In: Weiner WJ, Tolosa E, eds. Handbook of Clinical Neurology. Vol. 100, 3rd series. Amsterdam: Elsevier; 2011:3–13. Shoulson I, Fahn S. Huntington disease: clinical care and evaluation. Neurology. 1979;29:1–3. Stout JC, Jones R, Labuschagne I, et al. Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington’s disease. J Neurol Neurosurg Psychiatry. 2012;83:687–694. Tabrizi SJ, Langbehn DR, Leavitt BR, et al., for the TRACK-HD Investigators. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol. 2009;8:791–801.

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Trejo A, Boll MC, Alonso ME, Ochoa A, Velasquez L. Use of oral nutritional supplements in patients with Huntington’s disease. Nutrition. 2005;21:889–894. van Duijn E, Kingma EM, Timman R, et al. Cross-sectional study on prevalences of psychiatric disorders in mutation carriers of Huntington’s disease compared with mutation-negative first-degree relatives. J Clin Psychiatry. 2008;69:1804–1810. van Duijn E, Kingma EM, van der Mast RC. Psychopathology in verified Huntington’s disease gene carriers. J Neuropsychiatry Clin Neurosci. 2007;19:441–448. van Vugt JP, Piet KK, Vink LJ, et al. Objective assessment of motor slowness in Huntington’s disease: clinical correlates and 2-year follow-up. Mov Disord. 2004;19:285–297.

van Vugt JP, Siesling S, Piet KK, et al. Quantitative assessment of daytime motor activity provides a responsive measure of functional decline in patients with Huntington’s disease. Mov Disord. 2001;16:481–488. van Vugt JP, van Hilten BJ, Roos RA. Hypokinesia in Huntington’s disease. Mov Disord. 1996;11:384–388. Wild EJ, Tabrizi SJ. Huntington’s disease phenocopy syndromes. Curr Opin Neurol. 2007;20:681–687. Witjes-Ané MN, Mertens B, van Vugt JP, Bachoud-Lévi AC, van Ommen GJ, Roos RA. Longitudinal evaluation of “presymptomatic” carriers of Huntington’s disease. J Neuropsychiatry Clin Neurosci. 2007;19:310–317.

Clinical Neurology  •  35

3 Neuropsychiatry and Neuropsychology Dav i d C r au f u r d a n d J u l i e S . S n owd e n

Huntington’s disease (HD) is characterized by a triad of motor, psychiatric, and cognitive symptoms. Although the motor symptoms are most immediately evident, there is little doubt that the nonmotor symptoms contribute significantly to impaired function (Marder et al., 2000; Hamilton et  al., 2003; Nehl et  al., 2004; Beglinger et  al., 2010; Tabrizi et  al., 2013)  and have the greatest impact on patients’ daily lives. In his original description of the disease, Huntington (1872) wrote that “. . . In all the families, or nearly all in which the choreic taint exists, the nervous temperament greatly predominates, and . . . nervous excitement in a marked degree almost invariably attends upon every disease these people may suffer from . . . . The tendency to insanity, and sometimes that form of insanity which leads to suicide, is marked.” The description illustrates Huntington’s recognition of the central importance of psychiatric aspects of HD. It also shapes some of the preconceptions of HD carried by many people today. Yet, psychiatric symptoms in HD do not always conform to traditional assumptions. Moreover, they are variable and do not follow the same progressive course as motor and cognitive changes. This chapter describes the principal neuropsychiatric features of HD. Cognitive changes in people with HD are distinct and characteristic, reflecting the predominant early degenerative change in the striatum and disruption to striatocortical circuitry. The most salient and well-recognized cognitive changes are in the domains of psychomotor skills, executive functions, and memory. Impairments in the ability to process emotions are also prominent. Primary tools of cognition, such

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as language, which are dependent on neocortical function, are relatively well preserved. This chapter describes the nature of cognitive impairments, considers the evolution and progression of symptoms, and explores the interrelationship between psychiatric and motor aspects of HD. Problem behaviors, which are a prominent feature of HD, are influenced by psychiatric, cognitive, and psychosocial changes. The chapter concludes with a consideration of the biologic and nonbiologic factors that underpin the behavioral problems of HD.

Psychiatric Aspects of Huntington’s Disease Affective Disorders Depression is a common complication of HD and can occasionally become a severe and intractable problem. It can be difficult to diagnose because patients with HD may not spontaneously complain of sadness or low mood, and many of the characteristic symptoms of depression can be masked by other clinical features of HD. For example, the loss of appetite expected in someone with depression may be offset by the increase in appetite that is common in HD. Conversely, HD patients frequently display inactivity and insomnia, whether or not they are depressed. It is important to recognize and treat depression when it occurs in the course of HD because of the potential to exacerbate problems such as apathy and social withdrawal, worsen cognitive performance (Smith et al., 2012), and further impair quality of life (Read et al., 2013).

The high frequency of depression in HD has been recognized from the earliest descriptions of this condition, beginning with Huntington’s own reference to “that form of insanity which leads to suicide” (Huntington, 1872). Much of the early psychiatric literature on HD originated from Germany (reviewed by Morris, 1991)  and emphasized the importance of affective symptoms. Minski and Guttmann (1938) found that 11 of their 43 cases showed affective emotional reactions, depressive in type, in some instances with suicidal tendencies. Heathfield (1967) reported that the most common psychiatric disorder in his study of HD patients ascertained from mental hospitals in northeast London and Essex was an endogenous or reactive depression, occurring in 10 of the 80 cases. Dewhurst et al. (1970) studied 102 affected individuals in Oxfordshire, of whom 15 were admitted to the hospital with a diagnosis of depression. In 7 of these cases, an episode of depression antedated the onset of HD, whereas Oliver (1970) reported that depression was the presenting symptom in 9 of his series of 100 HD patients from Northamptonshire. Bolt (1970) found evidence of depression affecting 20% of the men and 29% of the women in a study of 334 HD patients from the west of Scotland. These early studies can all be criticized for methodologic reasons. Most were carried out using populations ascertained from mental hospitals and lacked systematic methods for eliciting clinical information or defined diagnostic criteria. In many cases, the patients were not even examined in person, the data being gleaned from clinical records. However, more recent studies allow a better estimate of the prevalence of affective symptoms in HD. Folstein et al. (1983, 1987)  attempted to identify all patients with HD in the state of Maryland, who were alive on April 1, 1980, and to examine all of them using a structured psychiatric interview, the Diagnostic Interview Schedule (Robbins et al., 1981). Diagnoses were based on Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-III) criteria (American Psychiatric Association, 1980), and a lifetime history of affective disorder was diagnosed in 61 (33%) of the 186 cases, with a further 9 (5%) meeting the criteria for dysthymic disorder. This study was carried out at the same time as a community survey in the same area using similar diagnostic criteria, which established that the lifetime prevalence of major affective disorder in the general population was 4.3% (Weissman &

Myers, 1978). The figure of 33% in patients with HD was therefore well in excess of the rate that might be expected by chance. Reported estimates of the prevalence of depression or depressive symptoms in patients with manifest HD (based on the presence of unequivocal motor symptoms) vary greatly, from 33% to almost 70% (Caine & Shoulson, 1983; Folstein et  al., 1987; Pflanz et  al., 1991; Craufurd et  al., 2001; Kulisevsky et  al., 2001; Murgod et al., 2001; Leroi et al., 2002; Paulsen et al., 2005a; van Duijn et al., 2007), depending on the methods used, the populations studied, and whether the authors were reporting the presence of depressive symptoms or a diagnosis of depressive disorder. A  number of studies have also discovered increased rates of depressive symptoms in premanifest HD gene carriers compared with controls (Julien et al., 2007; van Duijn et al., 2008; Epping et al., 2013). In a longitudinal study of manifest HD patients followed for an average of 5 years, the cumulative rate of clinically significant depressive symptoms at any assessment during the follow-up period increased from 33% at baseline to about 60%; however, this increase occurred early in the course of the illness, and symptoms of depression did not increase significantly after disease stage two (Thompson et  al., 2012). The latter finding confirmed an earlier observation from cross-sectional data that affective symptoms in HD (depression, anxiety, and suicidal ideation) do not correlate with cognitive and motor markers of disease progression (Thompson et al., 2002). Many authors have suggested that depression in people with HD might well be reactive in nature; as Heathfield (1967) put it, “. . . the depression was due to realisation by a patient that he was suffering from an incurable disease from which a parent had died in a mental hospital.” However, the available evidence suggests that this intuitive explanation may be incorrect. Mindham et al. (1985) compared the frequency of depression in 27 patients with HD and 27 with Alzheimer’s disease, using the Diagnostic Interview Schedule. The prevalence of major affective disorder in the HD patients was twice that of the controls with Alzheimer’s disease, even though the implications for the patient of the two diagnoses are quite similar. Furthermore, many studies have reported that depression can be the initial presenting feature of the illness (Oliver, 1970)  and may precede the onset of motor symptoms by many

Neuropsychiatry and Neuropsychology  •  37

years (Dewhurst et  al., 1970). In the Maryland study, affective symptoms preceded chorea and dementia in 23 of the 34 patients for whom accurate onset data were available, by an average of 5.1  years (Folstein et  al., 1983). To further investigate the causes of depression in HD patients, these authors interviewed first- and second-degree relatives of five consecutively ascertained probands with both HD and affective disorder from the Maryland case series, and five with HD but no associated psychiatric disorder. The average interval between onset of affective disorder and onset of HD was 9.9  years in the 26 relatives with both diagnoses with accurate data about age at onset. Among the affected relatives of probands with HD and affective disorder, 20 of 23 were found to have affective disorder themselves, whereas only 5 of 23 relatives of probands with HD alone had affective disorder, a highly significant difference. Among the spouses, non-HD parents, and “in-laws” of the 10 probands, the lifetime prevalence of major affective disorder was 2%. The authors concluded that the high rate of affective disorder in their case series was unlikely to represent a psychological reaction to the illness, given that affective disorder may precede HD by many years and can occur in persons who are not even aware of their risk for HD. They postulated that the observed association between HD and affective disorder in some families, but not in others, might be due to genetic heterogeneity at the HD locus, or alternatively to a gene predisposing to affective disorder and closely linked to that for HD. The subsequent discoveries that HD is invariably caused by a triplet repeat expansion in the huntingtin gene (Huntington’s Disease Collaborative Research Group, 1993)  and that psychiatric symptoms do not correlate with CAG repeat length (see later) have ruled out the first explanation, and the second now appears less likely in view of the mounting evidence that the genetic basis of affective disorder is multifactorial. However, the findings of Folstein et  al. (1983) strongly suggest a genetic contribution to depression in HD, perhaps caused by an interaction between genes predisposing to affective disorder and the underlying neurodegenerative disease process. Cummings (1995) pointed out that depression is common in disorders associated with caudate nucleus dysfunction, and that the ventral striatum is involved in reward and reinforcement of behaviors. He therefore hypothesized that neuronal loss in this region would diminish the

effectiveness of reward-mediated behaviors and contribute to anhedonia and depression, as well as to loss of motivation and apathy. However, in the absence of a direct relationship between affective symptoms and the severity of motor and cognitive changes (Thompson et al., 2002), it is clear that the relationship is a complex one. There have been very few satisfactory clinical trials of antidepressant treatment for HD (Leroi  & Michalon, 1998; Mestre et  al., 2009). However, clinical experience and a few published case reports (Holl et  al., 2010)  suggest that depressed HD patients respond to the same treatments as do the general population. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment of choice and may also be useful for treatment of other common HD symptoms such as anxiety and irritability. In the authors’ experience, patients with HD may require larger doses than those with depression in the general population and are more likely to relapse when treatment is discontinued. If the response to treatment is inadequate, a second-line antidepressant such as mirtazapine or venlafaxine may be successful. Clomipramine may be useful when there are comorbid obsessive-compulsive behaviors (see later), whereas mirtazapine and clomipramine are probably the antidepressants of choice when the symptoms include significant insomnia.

Suicide Huntington was correct when he drew attention to the increased frequency of suicide among those affected with HD. His reference to the “. . . form of insanity which leads to suicide” suggests that he thought of it as a manifestation of mental illness secondary to the disease, rather than a reaction to adversity. However, it is often assumed that the high rate of suicide is an understandable response to an almost intolerable situation, and it is certainly true that many people with HD talk about the option of suicide if their situation were to become unbearable; in one survey of 35 at-risk individuals, approximately half indicated that they would commit suicide if they became ill (Wexler, 1979). It may be that the possibility of suicide helps the individual to retain a sense of control in the face of an illness that progressively robs them of it. In the authors’ experience, suicidal thoughts of this kind are generally perceived by patients as comforting, and differ from the distressing thoughts that usually lead to suicidal acts. Experience suggests

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that patients who have previously expressed an intention to kill themselves when the condition becomes more advanced seldom actually do so, possibly because the will to live remains strong in spite of appalling circumstances, but perhaps also because cognitive and personality changes such as apathy and affective blunting become more severe as the disease progresses and make suicide less likely. As Minski and Guttmann (1938) put it, “. . . It might be expected that the incidence of suicide among the families of such hereditary diseases, which might be likened to the sword of Damocles, would be extremely high. But if one considers only those cases which must really be attributed to the fear of the disease one finds a comparatively low incidence. Perhaps this may be explained by the progressive deterioration with lack of initiative, loss of insight and emotional facility, that is met with in . . . the condition.” Most of the published studies concerning psychiatric symptoms in HD have commented on the number of suicides in their sample, but the majority cannot be used to estimate the prevalence of suicide among HD patients because the subjects were ascertained mainly from psychiatric hospitals and may be biased toward those with mental health problems. However, Schoenfeld et  al. (1984) attempted to ascertain all known families with HD in New England, and found 20 documented cases of suicide out of 506 deceased individuals with definite or probable HD, a prevalence of 4%. This was significantly greater than the 1% occurrence of suicide reported for the general population of Massachusetts at that time, and the third most common cause of death in the HD patients. Comparison with the Massachusetts population using age-specific rates of suicide revealed that the proportion of deaths due to suicide in HD patients and the general population did not differ in those dying before 50 years of age, but was significantly greater (odds ratio [OR], 8.19) in the 50- to 69-year-old group. The excess of suicides among the HD patients was even more striking when comparison was limited to those for whom a precise cause of death could be established; this was known in only 157 of the 506 cases, and if the remaining 349 individuals are excluded, the proportion who committed suicide rises to 12.7%, significantly more than the general population in both the 10- to 49-year-old group (OR, 2.7) and the 50- to 69-year-old group (OR, 23). However, it is not clear whether the rate of suicide in HD

patients is disproportionately greater than for patients with other medical disorders because there is a well-established association between suicide and serious illness generally. Broadly similar findings emerged from a study of HD patients known to the U.S. National HD Research Roster at Indiana University (Farrer, 1986). There were 25 cases of suicide out of 440 affected individuals for whom the cause of death was stated, a frequency of 5.7%. In keeping with the New England study, this was the third most common cause of death in HD patients after pneumonia and cardiovascular disease. The figure of 5.7% may well be an underestimate because the cause of death was simply listed as “Huntington disease” in 92 cases, without any further details. However, the author noted that a rate of 5.7 suicides per 100 deaths was almost four times greater than the reported rate of 1.5% for the U.S. population as a whole and was consistent with the rate of 3.35% calculated for the HD population in South Africa (Hayden et  al., 1980). A  further 27.6% of affected individuals known to the roster had attempted suicide on at least one occasion. Both studies attempted to address the timing of suicide in relation to the disease onset. Farrer (1986) noted that the suicides in the Indiana study occurred mainly in the middle stages of the disease; on average, those who took their own lives died 7  years earlier and had been affected for 5.8 years fewer than those who died by natural causes. On the other hand, Schoenfeld et al. (1984) pointed out that in their New England sample, the rate of suicide was four times greater in those with suspected HD than among the diagnosed cases, which they interpreted as evidence that patients early in the disease are at greater risk. These observations are supported by a more recent study that examined suicidal ideation in 4,171 patients and at-risk individuals in the Huntington Study Group database (Paulsen et al., 2005b). The frequency of suicidal ideation increased from 9.1% in at-risk individuals to 19.8% in those with soft neurologic signs and to 23.5% in those classified as “possible Huntington’s disease”; in those with diagnosed HD, suicidal ideation was seen in 16.7% at stage one, 21.6% at stage two, and declined thereafter. The authors suggested two critical periods for increased risk for suicide in HD: the first in the period just before diagnosis when the individual is adjusting psychologically to the onset of the illness, and the second in stage two when independence begins to diminish.

Neuropsychiatry and Neuropsychology  •  39

Although the evidence suggests that HD sufferers are more likely to commit suicide than the general population, the causes are complex and poorly understood. In a prospective study of 735 presymptomatic HD gene carriers and 194 gene-negative controls from the PREDICT-HD cohort followed for an average of 3.7  years, Fiedorowicz et al. (2011) identified 1 completed suicide and 12 attempted suicides (1.6%) in the gene carriers, but no suicidal behavior in the controls. A previous history of suicide attempts, a score higher than 13 on the Beck Depression Scale II, and a history of recent incarceration in prison were all significantly associated with suicidal behavior. Hubers et  al. (2012) compared 152 symptomatic and presymptomatic HD gene carriers with gene-negative controls and found evidence of suicidal ideation in 20% of the gene carriers; suicidal individuals were more likely to be depressed or taking antidepressants than those with no suicidal ideation. A larger study of 2,106 symptomatic and presymptomatic participants in the REGISTRY study of the European Huntington’s Disease Network (EHDN) using the behavioral section of the Unified Huntington’s Disease Rating Scale (UHDRS-b) reported that 169 (8%) had suicidal ideation, and found that depressed mood, a previous suicide attempt, aggression, anxiety, and disease duration were all independently correlated with suicidal ideation at baseline (Hubers et  al., 2013). A  further 52 (5.5%) developed suicidal ideation at follow-up. Depressed mood and benzodiazepine use at baseline were independent predictors of incident suicidal ideation. Prevention of suicide in this high-risk group therefore requires careful assessment and vigorous treatment of psychiatric symptoms such as depression and irritability, combined with attention to maintaining and strengthening social support networks, and appropriate efforts to foster an optimistic outlook toward the future. Although it may be unfair to encourage unrealistic expectations of an imminent cure for the disease, it is possible to offer the prospect of good symptomatic treatment and care and a much better quality of life than was available to previous generations of sufferers.

Mania Although symptoms of depression are common in HD, the prevalence of mania or hypomania is less certain. Mania, occurring alone or as part of a bipolar manic-depressive psychosis, is

relatively uncommon in the general population, and some of the early studies of psychiatric disorders in HD appear to suggest an increased frequency. Heathfield (1967) described 4 patients out of 80 with hypomania and delusions of grandeur; whereas Bolt (1970) reported grandiose ideas in 11 of her 334 cases, religiosity in 4, and elation in 3. Two of the 100 patients described by Oliver (1970) had “emotional instability, expressed as excitement.” However, none of the cases reported by Dewhurst et  al. (1970) were described as manic or hypomanic, and there was only 1 out of 199 with a diagnosis of “affective disorder, manic phase” in the study of Saugstad and Ødegård (1986) from Norway. Because most of the patients were ascertained from mental hospital populations, and none used operational diagnostic criteria or systematic methods of data collection, it is not possible to use these reports to estimate the prevalence of mania or hypomania in HD patients. Some of the more recent studies using reliable methods of diagnosis have also reported increased rates of hypomania. Folstein et  al. (1987), using DSM-III diagnostic criteria, found that major affective disorder was the most common psychiatric syndrome among their patients in Maryland, with a lifetime prevalence of 33%. Although frank mania with delusions of grandeur and flight of ideas was uncommon, brief episodes of hypomania were observed in about 10% of the patients; symptoms included increased levels of activity, pressured speech, uncharacteristic cheerfulness, large and inappropriate purchases, and a return of sexual interest after a long period of anhedonia or impotence. Caine and Shoulson (1983) did not find any cases among the 24 patients in their study, but Pflanz et  al. (1991), using the Present State Examination (PSE) (Wing et al., 1984), reported the syndrome of hypomania in 33% of their 86 patients and found that manic or mixed affective psychosis was the most common diagnosis according to the Catego classification system. Interpretation of these findings is difficult. Strictly speaking, the rules employed by diagnostic systems like DSM-III prohibit the diagnosis of bipolar affective disorder (or any other functional psychiatric disorder) in the presence of an organic condition such as HD. Studies using these operational diagnostic criteria to shed light on the psychiatric manifestations of HD therefore have to set aside this rule and apply the criteria as if the patient did not have organic brain disease. Unfortunately,

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mood states such as emotional lability or irritability, which in the absence of organic impairment would certainly indicate the possibility of hypomania, are also seen in many patients with brain injury or disease who do not otherwise have features to suggest bipolar affective disorder. Similarly, behaviors such as inappropriate sexual activity, or making impulsive, ill-judged and unnecessary purchases, would contribute to the suggestion of hypomania in someone who does not have acquired cognitive impairment, but not necessarily in a person with HD. This is especially problematic with systems that use computer algorithms such as Catego to avoid subjective bias when assigning diagnostic categories. When the diagnosis of bipolar affective disorder is restricted to patients who have episodes including uncharacteristically increased activity (severe enough to cause some practical problems for the patient or caregivers) alternating with periods of depression, we have seen only 2 or 3 cases out of more than 350 individuals attending our HD clinic in Manchester. Clinical impressions such as these can never be a substitute for systematic scientific investigations, but the difficulties outlined earlier illustrate the potential problems of reliance on rigid diagnostic algorithms, which may not adequately take account of the complexities involved. A  recent study from the Netherlands using a structured interview and DSM-IV diagnostic criteria found only 3 cases (2.1%) with a manic episode among 140 HD mutation carriers (van Duijn et  al., 2008). On the presently available evidence, the authors are not convinced that a syndrome that genuinely resembles bipolar affective disorder is much more common in HD patients than in the general population. This is in marked contrast to schizophrenia-like symptoms (see later), which do seem to occur with considerably increased frequency in patients with HD.

Irritability Irritability and bad-tempered outbursts are among the most common and troublesome behavioral manifestations of HD. Often, the spouse or another household member will complain that the patient becomes irritable for no very obvious reason, and that during these periods the slightest provocation—such as a minor disagreement or trivial inconvenience—will provoke an outburst of angry or violent behavior; such spells can sometimes go on for hours or even days at a time, during which the family

will describe life as being “like walking on eggshells,” never quite knowing when an innocuous remark will trigger another eruption. Families frequently remark that the irritable behavior is directed mainly toward one particular member of the household, often the spouse or child who is closely involved in the care of the patient. In other cases, the patients themselves will complain that they have become subject to sudden and uncharacteristic upsurges of anger, which often surprise them by their ferocity and lack of warning, but subside equally quickly, leaving the individual feeling shaken and filled with remorse. Patients sometimes report periods of suicidal ideation after such episodes. The prevalence of irritable behavior in HD is difficult to determine in view of the lack of agreed definitions and reliable methods of assessment. Heathfield (1967) noted the high frequency of aggressive traits and irritability, including “attacking people and throwing things,” among patients with HD, in contrast to the other presenile dementias. Bolt (1970) noted that approximately 50% of the patients in her study showed some degree of ill humor, ranging from irritability to actual violence, and that the prevalence of this symptom was very similar in both sexes. She also reported that approximately 10% of both sexes were said to have been difficult, moody, irritable, or “strange” throughout their lives, whereas Oliver (1970) described “emotional instability,” expressed as irritability, quarrelsomeness, childish tantrums, violent outbursts, or abusiveness, as the most common psychiatric presenting symptom of the disorder, occurring in 13 of 94 patients. Using a structured psychiatric interview and DSM-III diagnostic criteria, Folstein et al. (1987) found a prevalence of 31% for intermittent explosive disorder during a large epidemiologic study of HD in Maryland. A further study from this group using a specially constructed scale to measure aggression and irritability found that HD patients were more aggressive and had more severe aggressive outbursts than a comparison group of patients with Alzheimer’s disease (Burns et  al., 1990). Pflanz et al. (1991), using the PSE, found that “irritability” was the second most common PSE syndrome after “organic impairment,” affecting 69% of male and 60% of female HD patients. This is consistent with the findings from our own HD clinic population (Craufurd et  al., 2001), where clinically significant irritability was found in 57% of males and 49% of females, with 40% of patients displaying verbal outbursts of temper, and 22% threatening behavior or actual violence, in the 4 weeks before

Neuropsychiatry and Neuropsychology  •  41

interview. When the same patients were followed annually for an average of 5  years, the percentage with irritability at any assessment had risen to 83%, and the corresponding figure for physical aggression was 49% (Thompson et al., 2012). A number of studies suggest that irritability may be a relatively early manifestation of HD. Berrios et  al. (2002) assessed presymptomatic at-risk individuals before genetic testing and found that the HD gene carriers had significantly higher levels of irritability than noncarriers, although none had a formal psychiatric diagnosis. A  similar study from Julien et  al. (2007) compared HD gene carriers and noncarriers who had been interviewed prospectively before genetic testing, and found that 11% of gene carriers but only 4% of noncarriers reported irritability, although this difference did not quite reach statistical significance. The increased frequency of irritability was seen in patients up to 10 years before the onset of motor abnormalities. Factor analysis of data collected from symptomatic and presymptomatic populations using the Problem Behaviours Assessment for Huntington’s disease (Craufurd et al., 2001; Kingma et al., 2008) or the UHDRS-b (Rickards et al., 2011) has consistently shown that irritability and aggression in HD constitute a separate cluster of behaviors, distinct from the affective, apathy, and psychosis factors. Although apathy scores are highly correlated with both cognitive and motor impairment, irritability is not (Thompson et  al., 2002). Nimmagadda et  al. (2011) reported that irritability scores were correlated with anxiety, but not with dysexecutive syndrome or motor impairment. Irritable behavior and episodes of verbal or physical aggression directed toward close family or friends will inevitably have a damaging effect on personal relationships, and have the potential to contribute to marital breakdown or to rejection of the patient by the relatives and caregivers the patient most relies on. Aggressive behavior directed toward strangers is less common but can place the patient at risk for violence or trouble with the law. Management of this particular symptom is therefore crucial to the overall welfare of the patient and can make the difference between successful care in the community and institutional care. Caregivers are sometimes reluctant to mention irritable or aggressive behavior in front of the patient for fear of recriminations afterward, so it is essential in the clinic to provide the caregiver with an opportunity to talk confidentially to a member

of the clinical team. Fortunately, irritability can usually be treated very successfully. Before resorting to pharmacologic methods of treatment, efforts should be made to identify predisposing and precipitating factors. Educating family members and caregivers about the nature and causes of this behavior (Ranen et al., 1993) can go a long way toward solving the problem. However, pharmacologic treatment of irritability is often required at some stage in the course of the illness, and although there have been no published clinical trials (Leroi & Michalon, 1998; Mestre et al., 2009), case reports (Ranen et al., 1996) and clinical experience suggest a number of approaches that sometimes prove helpful. A recent survey of clinicians regarded as experts in the treatment of HD identified SSRIs as the first-line drug of choice for mild to moderate irritability (Groves et al., 2011), although larger doses may be required than those used for the treatment of depression. A  mood-stabilizing antiepileptic drug such as sodium valproate, or an atypical antipsychotic, were the next most common choices. When the symptom does not respond to treatment with an SSRI, my current practice is to augment this with mirtazapine; switching to sodium valproate may be a successful alternative (van Duijn, 2010). The usefulness of other antiepileptic drugs such as carbamazepine is often limited by side effects such as sedation. Other alternatives include propranolol or buspirone, especially when comorbid anxiety is also present, while one recent pilot study suggested that the synthetic cannabinoid nabilone may also be effective (Curtis et al., 2009). When these measures fail, low doses of neuroleptics such as sulpiride or olanzapine are usually effective, but again the benefits tend to be offset by the occurrence of side effects such as sedation and bradykinesia. Benzodiazepines should probably be avoided; a recent study from the Netherlands found that irritability in HD was highly correlated with benzodiazepine use, and although it was not clear whether benzodiazepine use causes irritability or irritability leads to prescription of benzodiazepines, the possibility that these drugs worsen irritability in patients with organic brain disease by causing disinhibition cannot be excluded (Reedeker et al., 2012).

Apathy Alterations in behavior such as irritability, social withdrawal, and loss of motivation were often referred to collectively as “personality change”

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(Wesensaenderung) by the early German psychopathologists, and were regarded as the hallmark of organic brain disease. Such changes can sometimes occur many years before the onset of definite motor and cognitive symptoms. Dewhurst et  al. (1970) reported that 14 out of 102 patients had “personality disorders” antedating the onset of HD, and in 10 of these cases, personality disorder was the initial diagnosis. Oliver (1970) described personality changes as the earliest sign of HD in 19 of 100 cases, with a further 4 who displayed “apathy, expressed as loss of interest,” which he listed as a symptom of depression. The most frequent and characteristic personality change associated with HD is a loss of motivation, initiative, and spontaneous expression, which has been termed “situational apathy” (Caine et  al., 1978; Caine & Shoulson, 1983). This is particularly common in the middle and later stages of the disease; in the Caine and Shoulson (1983) study, only 4 of the 10 mildly affected individuals, but 13 of 15 moderately impaired and all 5 severely disabled patients, manifested a lack of self-initiated activities. In all but the most severe cases, this was setting dependent, in that apathy would disappear when stimulating input and structure were present. The terms “apathy” and “abulia” are often used interchangeably to describe a state characterized by a diminution of spontaneous thought or activity, lack of perseverance, reduced emotional responsiveness, and an inability to anticipate enjoyment of planned activities. It therefore appears to encompass both emotional and cognitive components and manifests as lack of activity, loss of interest in previously enjoyable pastimes, social withdrawal, and reduced attention to self-care and personal hygiene. Family members complain that the affected person will sit for long periods staring at the wall or looking out of the window, without apparently having any interest in or awareness of what they are looking at, or any obvious discomfort or distress as a result; although no attempt is made to initiate spontaneous activity, an external prompt will often enable the patient to engage in purposeful activity, and derive apparent enjoyment from doing so. A number of studies have attempted to estimate the prevalence of apathy in HD, the results depending on disease stage of the subjects, the definition of apathy, and whether the study was cross-sectional or longitudinal. Apathy was present in 48% of the HD patients studied by Burns et al. (1990), but in approximately 75% of those

reported by Craufurd et  al. (2001). This figure increased to almost 90% when the patients were followed for an average of 5  years (Thompson et  al., 2012). Naarding et  al. (2009) reported severe apathy in 52% of patients. Reedeker et  al. (2011) followed a cohort of patients for 2  years and reported that 14% of those free of apathy at baseline had developed the symptom at follow-up. As Oliver suggested in 1970, loss of motivation may sometimes be secondary to depression. However, a number of studies have found little or no correlation between apathy and depression in populations of patients with HD or other neurodegenerative disorders (Mayberg et  al., 1992; Levy et  al., 1998; Naarding et  al., 2009), suggesting that these are separate disorders, while approaches using factor analysis have consistently extracted separate factors comprising apathy and affective symptoms (Craufurd et al., 2001; Kingma et al., 2008; Rickards et al., 2011). Apathy and depression follow different trajectories in longitudinal studies (Thompson et  al., 2012), while in cross-sectional studies, apathy scores have been shown to correlate with motor, cognitive, and functional markers of disease progression (Thompson et al., 2002; Baudic et  al., 2006; Naarding et  al., 2009), whereas depression does not. Although patients rarely complain of apathy, this symptom has been shown to have a significant effect on disability and quality of life (Banaszkiewicz et al., 2012; Read et al., 2013); the latter may reflect the fact that apathetic patients are likely to experience fewer activities of the kind that enhance quality of life. Treatment is difficult, but it is important that caregivers and relatives understand the nature of the problem and the need to provide external prompts to encourage participation in pleasurable activities. A more structured environment (e.g., attendance at a day-care center) may be helpful in this respect. There are no established pharmacologic treatments (Krishnamoorthy & Craufurd, 2011), but avoidance of unnecessary or excessive use of dopamine antagonists is important given the evidence that these drugs may worsen apathy in HD (van Duijn et al., 2010).

Perseverative and Obsessive-Compulsive Behaviors The typical cognitive profile of HD includes a tendency to impaired set shifting and perseveration of previously learned responses (see later).

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This problem manifests in everyday life as a tendency to mental inflexibility and a wide range of behaviors that are essentially perseverative in nature. For example, family members often complain that if they tell the affected person about a planned trip to the shops or the clinic, they will have to endure being pestered every few minutes by questions such as “Is it time to go yet?” or “Shall I get my coat now?” Other examples of repetitive thinking or behavior include returning to a particular topic of conversation over and over again, or repeatedly lighting and then discarding cigarettes; perseverative sexual behaviors can be a more serious problem. Although many of these examples appear relatively trivial, they can be very difficult to tolerate for family members who have to live with them. A recent study that examined the effect of HD patients’ symptoms on the quality of life of family caregivers found that perseveration was the one symptom that had a significant impact (Read et al., 2013). Family members often attribute such behaviors by the patient to a failure of memory, but the very short time intervals involved make this explanation unlikely. They also complain that the patient is “obsessed” by particular ideas or topics of conversation; however, the repetitive behaviors commonly seen in HD usually lack the essential characteristics of obsessive-compulsive phenomena, which include an awareness that the thought or urge is abnormal, an attempt by the patient to resist doing or thinking it, and an increase in anxiety when they do resist, which is then reduced by giving in to it. Patients with HD who exhibit perseverative behaviors do not recognize them as abnormal, and make no attempt to resist them even if they know that it will elicit an angry response from their caregivers. In our clinical experience, true obsessive-compulsive phenomena are probably no more common in HD than in the general population. Nevertheless, these symptoms are often referred to in the literature as “obsessive-compulsive symptoms” (O/Cs); Anderson et al. (2010) reported significant O/Cs in 27% of a large cohort of HD patients from North America, and noted that patients with O/Cs had a significantly longer duration of illness than those without. The impression that these symptoms occur relatively late in the course of HD was supported by Beglinger et al. (2007), who reported that the probability of having O/Cs was more than three times greater by disease stages 3 and 4 than in an at-risk group with no apparent motor abnormalities. Even so, a report

from the PREDICT-HD study found significantly higher scores in presymptomatic HD gene carriers compared with controls using the Schedule of Compulsions, Obsessions and Pathological Impulses, although mean scores were below those of patients with diagnosed obsessivecompulsive disorder (Beglinger et al., 2008). There is no published evidence base for the treatment of O/Cs or perseverative behaviors in HD, although individual case reports suggest a favorable response to SSRIs (De Marchi et al., 2001). However, a recent survey of 49 clinicians regarded as experts in the treatment of HD found that SSRIs were by far the most favored drug of choice for these symptoms, and clomipramine (another antidepressant with strong serotonergic properties) was the most popular alternative (Anderson et al., 2011).

Disorders of Sexual Behavior It is widely believed that promiscuous behavior and sexual deviations are common in people with HD. In his original description of the disorder, Huntington (1872) wrote of “. . . two married men, whose wives are living, and who are constantly making love to some young lady, not seeming to be aware that there is any impropriety in it. . . . They are men of about 50 years of age, but never let an opportunity to flirt with a girl go past unimproved.” Dewhurst et al. (1970), in their study of the sociopsychiatric consequences of HD, reported that 30 of 102 patients displayed abnormal sexual behavior, of whom 19 showed hypersexuality and 11 were described as hyposexual. They noted that patients’ wives often complained “that their husbands were demanding an inordinate amount of sexual fulfillment at odd times or in inappropriate places, and whenever these desires were rebuffed they became vindictive, abusive and frequently violent.” Although Dewhurst’s paper has been frequently cited in subsequent publications, it should be noted that other contemporary authors reported lower rates of psychosexual disorders. Bolt (1970) found that 20 (6%) of 334 patients had increased libido or sexual deviations, whereas Oliver (1970) also reported 6%, and Heathfield (1967) only 2 (2.5%) of 80 patients, displaying similar behaviors. There is only one published report of a study using modern interviewing methods and defined diagnostic criteria to investigate this issue. Fedoroff et al. (1994) examined 39 HD patients in Baltimore and their 32 partners using a semi-structured interview schedule designed to

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elicit symptoms of sexual dysfunctions and paraphilias according to DSM-III-R diagnostic criteria. Eighty-two percent of the HD patients and 66% of the partners had one or more sexual disorders by DSM-III-R criteria, a statistically significant difference. Hypoactive sexual desire was the most common diagnosis in both male and female patients (63% and 75%, respectively). Inhibited orgasm was the second most common diagnosis in both sexes and was significantly more common in both male and female HD patients than the non-HD partners (56% of HD males vs. 0% of non-HD males; 42% of HD females vs. 9% of non-HD females). Excluding patients taking tricyclic antidepressants, neuroleptics, lithium, or antihypertensive medications did not alter this finding. Thirty percent of the HD males and 25% of the HD females had experienced increased sexual interest, defined as a marked increase of sexual interest over a period of at least a week that could not be attributed to a loss of interest by the person’s partner. There was a numerically greater frequency of paraphilias in the HD cases than in the partners (19% of HD males vs. 10% of non-HD males; 8% of HD females vs. 0% of non-HD females), but this was not a statistically significant difference. Although some participants in the study had been sexually abused as children, the HD patients did not differ from their non-HD partners in this respect (9% vs. 8%), and there were no cases of patients who had molested or abused children. Although the Fedoroff study confirms previous reports that sexual disorders are common in patients with HD, it is apparent that hyposexuality is far more common than hypersexuality in this group of patients. The finding is supported by our own study (Craufurd et al., 2001) of patients attending an HD clinic in which 62% experienced a loss of libido, corroborated by their partners, whereas only 6% reported sexually disinhibited or demanding behavior. Although loss of libido and cessation of sexual activity appears to be the most common pattern in HD patients, there is no doubt that hypersexual behaviors, often rather perseverative in character, can become a very difficult problem in the small proportion of cases in which they do occur. A degree of disinhibition and reduced awareness of emotional responses in others, in combination with a tendency to perseverative behaviors, probably explains the kind of sexually demanding behavior referred to by Dewhurst in his 1970 paper, and is made all the more difficult to cope with if the patient is also irritable and prone to aggressive outbursts after

being refused. This situation requires great care in order to avoid further damage to the patient’s already vulnerable self-esteem, but can usually be greatly improved by effective treatment of perseveration and irritability with SSRIs. It is also important to remember that many patients (and their partners) will be too embarrassed to mention psychosexual problems of this sort in the clinic, unless in response to a tactful inquiry by the doctor.

Psychotic Symptoms There have been many reports of schizophrenialike symptoms in people with HD. Minski and Guttmann (1938) described 1 patient with a frank schizophrenic illness and 3 with paraphrenic reactions in their cohort of 43 HD patients admitted to mental hospitals in London. Heathfield (1967) reported 6 cases of paranoid schizophrenia and 3 of schizophrenia simplex in his sample of 80 patients with HD. Folstein et al. (1979) found 2 patients with auditory hallucinations, neither of whom met  all the Research Diagnostic Criteria for schizophrenia, out of 11 affected individuals referred to outpatient clinics for diagnosis or genetic counseling. The diagnosis of schizophrenia, as with most other psychiatric disorders, presents difficulty in HD patients because there are many symptoms such as social withdrawal, emotional blunting, and loss of volition that are common to both conditions. Furthermore, it has been recognized for many years that psychotic symptoms such as delusions and auditory hallucinations can occur in organic brain disorders, and that sometimes schizophrenic illnesses, which are typical in every respect, can turn out to have an underlying organic basis (Lishman, 1998); for this reason, diagnostic systems such as DSM-III or the Research Diagnostic Criteria of Spitzer et al. (1977) do not allow the diagnosis of schizophrenia to be made in a patient known to suffer from HD or another similar organic brain disease. From a practical point of view, the importance of schizophrenia-like symptoms in HD arises partly from the additional burden for both patient and caregiver imposed by their presence, and partly because the medications usually prescribed to treat such symptoms tend to exacerbate both the cognitive and motor features of the illness. In some cases, the onset of delusions and hallucinations may precede the onset of motor symptoms of HD, with the result that the patient

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is misdiagnosed as suffering from schizophrenia. If dopamine-blocking drugs are used to treat the psychotic symptoms, these will tend to suppress any involuntary movements, whereas clumsiness or bradykinesia will be attributed to side effects of the medication, with the result that the underlying diagnosis of HD gets overlooked until the degree of motor disability can no longer be explained away as drug-induced parkinsonism. Saugstad and Ødegård (1986) carried out a retrospective case record study of 199 HD patients admitted to psychiatric hospitals in Norway between 1916 and 1975, and found that only 60% were correctly diagnosed on first admission, the most common alternative diagnoses (in 39 cases) being schizophrenia and paranoid psychosis. In Oxfordshire, Dewhurst et al. (1970) found that 7 of the 102 HD patients in his study had initially been given a diagnosis of schizophrenia on admission to the hospital, whereas Bolt reported that 8% of her patients in Scotland were at first thought to have schizophrenia or paranoid psychosis. Saugstad and Ødegård noted that the misdiagnosis of schizophrenia was sometimes preserved during three to four admissions, and that the records showed a recent reduction in the amount of information recorded about family history of mental disorders, underlining the importance of paying attention to hereditary factors during history taking. Estimates of the prevalence of schizophrenia or schizophrenia-like symptoms in HD patients vary widely between studies and are difficult to compare because of the differing methodologies employed and the absence of clearly defined diagnostic criteria in the earlier studies. The evidence from more recent studies using unbiased methods of ascertainment and standardized diagnostic criteria suggests that episodes closely resembling schizophrenia in patients with HD are much less common than was previously thought. Caine and Shoulson (1983) evaluated 30 HD patients using the Schedule for Affective Disorders and Schizophrenia (Spitzer & Endicott, 1978)  and found that 3 fulfilled DSM-III criteria for schizophrenic syndrome, whereas 2 more met the criteria for atypical psychotic syndrome; however, many of the subjects had been referred because of “substantial behavioural disturbances” and were not necessarily representative of HD patients in general. In their case series of 88 patients from Maryland, assessed using the Diagnostic Interview Schedule, Folstein et  al. (1983) found only 3 cases meeting the DSM-III criteria for schizophrenia, a prevalence of just

3%. Baxter et al. (1992) administered the lifetime version of the Schedule for Affective Disorders and Schizophrenia to 52 at-risk individuals with an affected first-degree relative and did not find any meeting Research Diagnostic Criteria (Spitzer et al., 1977) for schizophrenia or schizoaffective disorder. However, isolated psychotic symptoms may be much more common; for example, a case-record study of 86 patients from the Grampian region of Scotland using the Present State Examination (Wing et al., 1984) found that 25% of the females and 19% of the males had delusions of persecution (Pflanz et al., 1991). The cause of psychosis seen in some people with HD is not known. The lifetime prevalence of schizophrenia in the general population is approximately 1%, so the research findings cited earlier suggest that schizophrenia-like symptoms occur more often in HD than might be expected by chance. However, psychotic symptoms are certainly not an invariable feature of the disorder, and are seen in only a minority of cases; furthermore, there is no evidence to suggest a relationship between the occurrence of psychotic phenomena and the severity of the underlying neurodegeneration. The question therefore arises as to why some patients are affected in this way, although others are not. Heathfield (1967) described a family in which identical paranoid schizophrenic psychoses were seen in a brother and sister with HD, whereas a further brother suffered from this mental disorder without developing choreiform movements. Lovestone et al. (1996) described a very similar HD family in which all four affected individuals presented with a severe psychiatric disorder, in three cases schizophreniform in nature, and in which one other so far unaffected family member had been treated for schizophrenia. In the three affected family members, schizophrenia had preceded the onset of motor symptoms by up to 9 years. Tsuang et al. (1998) also reported a patient with juvenile-onset HD whose father and paternal grandmother both exhibited schizophrenia-like symptoms in addition to HD, contrasting this case with an otherwise very similarly affected individual with no schizophrenia-like symptoms and no family history of psychosis. The authors could not find any difference in age at onset of HD, number of CAG repeats, or sex of transmitting parent between those with psychotic symptoms and those without. Lovestone et al. (1996) speculated that there may be additional familial factors in the kindred they described that influence the clinical presentation of HD. It may be

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that genes predisposing to schizophrenia are more likely to be expressed in the phenotype of someone who also carries the genetic mutation responsible for HD; this interpretation is supported by a case from our own clinic in Manchester, England, in which two siblings with HD and a history of schizophrenia-like episodes have a half-sibling (the child of their unaffected parent) who suffers from chronic schizophrenia.

Alcoholism It is not uncommon for the symptoms of HD to be mistaken for drunkenness. The slurred speech, clumsiness, and staggering gait all contribute to this impression, especially if the patient is also irritable or aggressive. However, opinion is divided as to whether alcohol abuse and dependence are actually more common in those with HD than in the general population. Hans and Gilmore (1968) commented on the high incidence of alcoholism in a study of hospitalized HD patients in Albany, New York, but did not provide figures to support this assertion, whereas Oliver (1970) implied that alcoholism was frequent among the patients and their unaffected relatives. Dewhurst et al. (1970) found 19 cases of alcoholism among 80 with HD, and suggested that this may be an underestimate because of misleading information from relatives. On the other hand, Bolt (1970) commented that excessive drinking was recorded in the notes of only 11 men and 2 women out of 334 case records examined in the west of Scotland, an area where alcoholism and heavy drinking are common. King (1985) identified a random selection of 42 patients (25 male, 17 female) from the Maryland HD project and interviewed a close relative about each proband using the relevant part of the Diagnostic Interview Schedule. Seven (6 male, 1 female) met the DSM-III criteria for alcoholism; 5 of these could also be classified as alcohol dependent. The overall lifetime prevalence of alcohol abuse in the HD patients was therefore 16.7%, whereas a community survey of an inner-city population in East Baltimore carried out at roughly the same time and using very similar methods identified a lifetime prevalence rate for alcohol abuse of 13.7% (Robbins et al., 1984). The authors therefore concluded that the rate of alcohol abuse in sufferers from HD was little different from prevailing rates in the community, and noted that 5 of the 7 were already abusing alcohol when the first symptoms of HD appeared. The only other published study using a systematic

approach to determine rates of substance abuse in HD patients was that of Pflanz et al. (1991), who identified alcohol or drug abuse in 16% of males and 9% of females using the Present State Examination. The available evidence therefore suggests that rates of alcohol abuse and dependence in HD patients are probably no worse than the (admittedly high) levels in the general population. However, there is no doubt that excessive drinking can give rise to considerable problems when it does occur because the effects of alcohol exacerbate the motor, cognitive, and psychiatric symptoms of this disorder.

Relationship of Psychiatric Changes to CAG Repeat Length Two studies looking at the presenting symptoms of HD (chorea, cognitive impairment, or psychiatric disturbances) found no relationship between this and the number of CAG repeats (Andrew et  al., 1993; MacMillan et  al., 1993). Similarly, Weigell-Weber et  al. (1996), using a classification based on DSM-III criteria, found no relationship between CAG repeat length and psychiatric symptoms; however, personality changes were more often associated with maternal transmission of HD, an observation attributed by the authors to psychosocial factors related to the mother’s illness. Zappacosta et al. (1996) found no correlation between psychiatric symptoms (as measured by the Hamilton Anxiety and Depression Scales and the Brief Psychiatric Rating Scale) and either cognitive impairment, motor deterioration, or CAG repeat length; they concluded that psychiatric disorders in HD patients progress nonlinearly, perhaps because of differential degeneration of striatocortical circuits. A  study examining the psychiatric profile of presymptomatic HD gene carriers using an extensive battery of self-report scales measuring depression, anxiety, irritability, O/Cs, and a variety of personality traits also found no correlation between any psychiatric variable and CAG repeat number (Berrios et al., 2001).

Cognitive Changes in Huntington’s Disease Psychomotor Performance A prominent early feature of HD is psychomotor slowing. It is evident clinically and is readily demonstrated by timed cognitive tests such

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as the Stroop, Digit Symbol Substitution, Trail Making (Bamford et al., 1989; Starkstein et al., 1992; Snowden et  al., 2001), and simple and choice reaction time tasks (Jahanshahi et  al., 1993). Slowed performance is not solely a product of motor abnormalities. Slowing is present on cognitive tasks even when motor speed is controlled (Snowden et al., 2001). Psychomotor slowing is important for three principal reasons. First, it is a feature that distinguishes HD from “cortical” neurodegenerative disorders. The slowing parallels that found in other basal ganglia disorders (Albert et al., 1974; Dubois et al., 1988), suggesting that it is a fundamental, core characteristic of striatal dysfunction. Indeed, psychomotor speed in HD has been shown to correlate with measures of caudate atrophy (Bamford et al., 1989; Starkstein et al., 1992). Second, slowing has an inevitable impact on patients’ performance on tasks for which there are time constraints. It has been reported to contribute, for example, to reduced scores on verbal fluency tasks (Rohrer et al., 1999; Henry et  al., 2005). Processing speed has been linked to performance on tests of spatial attention and simultaneous perception of objects (Finke et al., 2006, 2007). Thus, the potential impact of cognitive and motor slowing needs to be taken into account when interpreting neuropsychological test performance. Third, it provides a sensitive measure of change over time, and of the earliest manifestations of HD (see later sections on progression and evolution of symptoms), suggesting that psychomotor speed represents a useful biomarker in therapeutic studies.

Executive Function Executive function refers to the regulation or control of cognitive performance. Executive skills include the ability to plan, organize, and monitor behavior; abstract and integrate information; and show mental flexibility. In their daily lives, people with HD often exhibit poor planning and judgment. They may appear impulsive and show an absence of forethought, their actions being governed by immediate rather than long-term considerations. Actions are disorganized, a feature that contributes to early occupational and domestic inefficiency. They show impaired ability to self-monitor and often fail to notice errors that are apparent to others, sometimes creating a false impression of a lackadaisical attitude or indolence. People with HD are often reported by relatives to be inflexible

and rigid in their thinking and to have difficulty in seeing another’s point of view. They are poorly adaptable to altered circumstances and prefer routine. A substantial body of empirical neuropsychological evidence has accumulated to support these clinical observations of executive deficits in HD. Several investigators (Lange et al., 1995; Lawrence et al., 1996; Watkins et al., 2000) have demonstrated impaired planning, on the basis of patients’ poor performance on a problem-solving task (Tower of London) that requires the ability to plan a sequence of actions. Impaired sequencing has been demonstrated on a picture-ordering task (Snowden et al., 2001). A number of studies have demonstrated impaired cognitive flexibility and difficulty shifting mental set. Studies have used the Wisconsin Card Sorting test (Josiassen et al., 1983; Weinberger et al., 1988; Pillon et al., 1991; Paulsen et al., 1995), a computer analog of the Card Sort test (Lange et al., 1995; Lawrence et al., 1996), or other related tasks (Hanes et al., 1995). HD patients have been found to show impairment on a spatial working memory task (Lawrence et al., 1996), which requires the subject to plan, to hold information “on line,” and to use feedback from earlier trials to guide subsequent responses. HD patients show poor use of strategy and, as in the Card Sorting test, people do not make effective use of feedback. People with HD typically perform poorly on verbal fluency tasks, involving generation of words belonging to a specified category or beginning with a specified letter, (Monsch et  al., 1994; Rosser & Hodges, 1994; Rich et al., 1999; Rohrer et al., 1999). Impairments have been attributed to defective strategies for retrieval (Rosser & Hodges, 1994)  and impaired ability to switch search strategies (Rich et al., 1999) secondary to patients’ reduced cognitive flexibility. There is compelling evidence of a relationship between executive test performance in HD and changes in the striatum, measured either by structural or functional brain imaging. Folstein et  al. (1992) showed a correlation between attention, sequencing, and sustaining thoughts and atrophy of the caudate. Backman et  al. (1997) used positron emission tomography and magnetic resonance imaging data as predictors of performance on executive as well as spatial, memory, fluency, perceptual speed, and reasoning tasks. Dopamine neurotransmission parameters (D1 and D2 receptor density and dopamine transporter density) and volumetric measurements for caudate and putamen accounted for

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substantial proportions of variance across most tasks. Lawrence et  al. (1998) found that performance on executive tasks, including verbal fluency, spatial span, planning, and sequence generation, correlated with striatal D1 and D2 receptor binding levels on positron emission tomography scanning. Peinemann et  al. (2005) reported strong correlations between performance on standard executive tests (Tower of Hanoi, Stroop, modified Wisconsin Card Sorting) and reduced caudate volume. These findings are important because they challenge the historical assumption that cognitive changes in HD are all cortically driven and independent of the striatal changes underpinning the movement disorder symptoms. The striatum has a central role in cognition as well as motor function.

Attention The ability to sustain, divide, and switch attention is a central aspect of executive function. It is considered here separately because of its importance in HD. People with HD frequently report difficulty concentrating and doing more than one task at a time. Complementing self-reports, formal assessments have demonstrated impaired performance in several aspects of attention: maintenance, divided, switching, suppression of a prepotent response, and disengagement from one visual target to another (Sprengelmeyer et  al., 1995; Georgiou et  al., 1995, 1996; Cope et al., 1996; Couette et al., 2008). Interestingly, impaired dual task performance in HD extends to tasks that normally would be considered relatively undemanding of attention. Motor tapping performance is adversely affected in a bimanual compared with unimanual condition in HD, but not in controls (Thompson et al., 2010). Walking is slowed in the context of a concurrent cognitive task in HD, but not in controls (Delval et al., 2008). This latter finding mirrors the common observation that people with HD have difficulty walking and talking simultaneously, and may stop walking to answer a question. A  plausible interpretation (Thompson et  al., 2010)  is that tasks that are readily automatized in healthy people (supported by striatal function) require more conscious attention in HD and so compete for attentional resources. In keeping with this explanation, functional imaging studies in HD have demonstrated increased cortical recruitment in motor and cognitive tasks (Bartenstein et  al., 1997; Georgiou-Karistianis et  al., 2007), compensating for reduced striatal function. It

would seem that one important factor underlying the attentional disorder in HD is simply that tasks demand more overt attention.

Memory and Learning Ep isodic Me mory

Memory problems are ubiquitous in HD, present early in the course of the illness, and are often noted by patients themselves. Indeed, if HD patients are probed about cognitive symptoms, it is in the realm of memory and concentration that they most commonly report subjective change. Symptoms typically have the quality of absent-mindedness, such as forgetting to turn off the gas after cooking or forgetting to pick the children up from school at the appointed time. Those same patients may demonstrate impressive recall of a news item that caught their interest or of a remark made by the clinician more than a year before. People with HD have inefficient memories, but they are not amnesic in the classic sense of having a fundamental inability to lay down new memories and retain information over time. A variety of empirical studies have confirmed that memory failures in HD arise largely because of strategic or organizational failures at the time that information is acquired and retrieved. Several investigators have shown that recognition memory performance is less impaired than free recall (Butters et al., 1985; 1994; Lundervold et al., 1994; Pillon et al., 1993). HD patients have been shown to demonstrate poor acquisition of information and more use of passive learning strategy than controls, but normal retention over time (Lundervold et al., 1994). A comparative study by Pillon et al. (1993) showed that HD patients performed as poorly as patients with Alzheimer’s disease on free recall of items in a list learning task but performed significantly better with cued recall. A parallel study of our own used a paired-associate learning task, involving unrelated word pairs (e.g., gold–sugar; friend–train). Whereas recall improved over successive trials in controls, neither the HD nor the Alzheimer’s group demonstrated improvement (Snowden et  al., 1987). However, when patients were actively encouraged to form an associative link between words (e.g., imagine a gold bar in a bowl of sugar; imagine a friend getting off a train), recall improved dramatically in HD but showed no change in Alzheimer’s disease. The data

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suggest that HD patients do not spontaneously adopt active strategies for learning, such as mentally linking words, but when such strategies are provided, performance can improve. The quality of memory change in HD, characterized by poor use of active strategies for learning and information retrieval, is similar to that found in patients with frontal lobe disease and suggests disruption to striatal-frontal connections. Complementing these findings, Brandt et  al. (1995) identified impairments in source memory in HD. Patients recalled facts as well as controls, but they had more difficulty attributing the source of those facts, a pattern similar to that found in patients with frontal lobe disease. Correlation with magnetic resonance imaging volumetric measures of caudate nucleus suggested that caudate or its neocortical projections played a role in the encoding of context. Brandt et al. (2005) has also shown disproportionately impaired memory for spatial location compared with object identity and suggested that this may reflect disruption to corticostriatal circuitry linking caudate to parietal cortex. S em a n tic   M e mory

Semantic memory refers to a person’s knowledge about the world. It includes understanding of the meaning of words and objects, as well as encyclopedic knowledge, such as knowing that Paris is the capital of France. Semantic memory loss, predominantly associated with damage to temporal neocortex, is not a notable clinical feature of HD. Indeed, normally taciturn HD patients may surprise their family by their impressive demonstration of factual knowledge when watching television quiz programs. Performance on putative tests of semantic knowledge such as picture naming and word generation may be inefficient (Hodges et  al., 1991; Rich et  al., 1999; Rohrer et al., 1999), but for reasons that are not primarily semantic, such as reduced mental effort and poor use of strategy for accessing information. S k il l L e a r n in g and Prim ing

Conventional memory tests, such as list learning or paired-associate tasks, require explicit recall or recognition of information presented previously (declarative memory). Some aspects of learning, such as the acquisition of a skill, do not depend on conscious recollection of the learning event (procedural or nondeclarative memory). The basal ganglia appear to play a crucial

role in some aspects of nondeclarative memory, and HD patients show impairment on some nondeclarative tasks. Impairments have most commonly been demonstrated on tasks involving motor skill learning, such as rotary pursuit (Heindel et al., 1988; Gabrieli et al., 1997), which involves tracking a rotating target with a stylus, and serial reaction time (Knopman & Nissen, 1991). Normal performance has been demonstrated on a nonmotor skill learning task, involving the learning of an artificial grammar (Knowlton et  al., 1996). HD patients may also perform normally on perceptual priming tasks, in which a subject’s response to a stimulus (e.g., a degraded or fragmented letter, word, or picture) is “primed” by earlier exposure to the same or a related stimulus (e.g., the complete letter, word, or picture). Patients with HD show normal facilitation, in terms of speed and accuracy of identification, in the primed compared with nonprimed condition (Heindel et  al., 1990; Bylsma et  al., 1991). HD patients have, however, shown abnormal priming on a weight judgment task. In normal subjects, weight judgments are biased by earlier handling of heavy or light weights. HD patients do not show that normal bias (Heindel et al., 1991). The foregoing conveys the impression that it is the motor nature of the task that determines whether performance in skill learning and priming is impaired in HD. That is an oversimplification. HD patients have shown normal mirror tracing performance (Gabrieli et al., 1997), suggesting that some motor skills can be learned normally. By contrast, Knowlton et  al. (1996) reported impaired performance on a probabilistic classification learning task, suggesting that some nonmotor skill learning is impaired. Willingham and Koroshetz (1993) and Willingham et  al. (1996) have helped to clarify the core factors that determine success or failure. Some motor skills, such as using a computer mouse, depend on learning to map a perceptual cue with an appropriate motor response (perceptual-motor integration). Other tasks, such as rotary pursuit, involve learning a repeated sequence of movements. It is the latter on which HD patients have difficulty. Willingham et  al. (1996) found that HD patients could learn to track a moving target with a computer joystick provided that the target moved randomly; however, they were impaired when the target moved in a repeated sequence. The inference is that the striatum plays a role in sequence learning, but not perceptual-motor integration. Knowlton et  al. (1996) interpreted

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their patients’ poor performance on a nonmotor skill learning task in parallel terms, suggesting that their task was akin to a habit learning task and thus dependent on the striatum. Studies of sequence learning in HD have not yielded entirely uniform findings, with some demonstrating impairment on both explicit and implicit tasks (Willingham & Koroshetz, 1993)  and others on explicit only (Brown et  al., 2001; Schneider et  al., 2010). Potential differential roles of the putamen and caudate in sequence learning, the contribution of “prefrontal” executive deficits to performance, and the ability to use corrective feedback have been considered as possible explanations of dissociated performance (Schneider et al., 2010). Methodologic factors may also be relevant. “Sequencing” tasks do not make identical demands, some making more frank executive (strategic and attentional) demands than others, and some more closely resembling conventional declarative memory tasks than others. If, as postulated earlier, people with HD are impaired in “automatizing” performance as a result of striatal dysfunction, then one might expect relatively simple cognitive and motor routines that are readily automatized in healthy individuals to be disproportionately compromised in HD.

Language People with HD are not aphasic. They understand words and speak in grammatically correct sentences. In general conversation they do not show frank anomia or make paraphasic errors. These features distinguish HD from cortical degenerative disorders, such as Alzheimer’s disease, in which linguistic deficits are prominent. Nonetheless, language performance is not entirely normal. HD patients are slower than normal to retrieve words on picture naming tests (Bayles & Tomoeda, 1983; Caine et  al., 1986; Hodges et  al., 1991), and they produce fewer words on verbal fluency tests that involve generating exemplars of a category or words beginning with a specified letter (Rich et  al., 1999; Rohrer et al., 1999). With advancing disease they may show increased difficulty following complex instructions (Folstein & McHugh, 1983; Saldert et  al., 2010), and their utterances become simplified in grammatical structure (Podoll et al., 1988). To some extent, such deficits can be regarded as secondary to executive and psychomotor deficits; for example, poor verbal fluency has been linked to impaired switching of search strategies due to reduced

cognitive flexibility (Rich et  al., 1999)  as well as to psychomotor slowing (Rohrer et al., 1999; Henry et al., 2005). Nevertheless, there is growing evidence for the importance of the striatum in sentence processing (Teichmann et al., 2005, 2006, 2008a, 2008b). These authors have argued that the striatum’s role is in the application of language rules, specifically, syntactic movement rules. It is not involved in lexical processing, which is neocortically mediated. Such findings suggest a primary impairment in HD in particular components of language processing. Language needs to be distinguished from motor speech (Gordon & Illes, 1987; Podoll et  al., 1988). Articulatory and prosodic impairments arise early in HD and lead to progressively reduced intelligibility of speech over the course of the disease. The mental effort required for discourse might contribute to the taciturnity commonly associated with HD (Folstein & McHugh, 1983).

Perceptual and Spatial Skills In their daily lives, HD patients recognize objects, do not have difficulty locating objects in their visual field, and are spatially oriented in their external surroundings. They do not exhibit the frank misperceptions, impaired localization skills, and gross spatial disorientation that are common features of disorders such as Alzheimer’s disease that affect posterior neocortex. People with HD do, however, perform poorly on some perceptual, spatial, and visuoconstructional tasks, indicating that at least some aspects of perception and spatial functioning are compromised. Within the perceptual domain, impairments have been demonstrated most commonly on perceptual matching and discrimination tasks (Brouwers et  al., 1984; Lawrence et  al., 1996), on the Hooper test of perceptual integration (Bamford et  al., 1989; Gomez Tortosa et  al., 1996), and on tests of face recognition (Jacobs et  al., 1995). What these tasks have in common is that they are relatively high-level tasks, which require attention to multiple parts of the stimulus or involve complex visual integration and manipulation of information. They make significant executive demands. Performance has also been found to be impaired on visuoconstructional tasks, such as drawing (Rouleau et  al., 1992)  and block design (Bamford et  al., 1989)  tasks, which also require planning and organization.

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In the spatial domain there is evidence that people with HD have deficits in personal or “egocentric” space. Potegal (1971) reported normal localization in external space, except when HD patients’ own position in relation to the target was altered. Impaired performance has been demonstrated on a Road Map test (Brouwers et  al., 1984; Bylsma et  al., 1992; Mohr et  al., 1991; 1997), which requires subjects to track a line through a diagrammatic road map and, at each turn, state whether they would be turning left or right. It is on turns that require the subject to make 90- or 180-degree mental manipulations that performance is notably impaired (Brouwers et al., 1984). Deficits have also been reported on a Mental Rotation test, which requires the subject to mentally rotate complex geometric patterns represented three-dimensionally to compare with a target design (Mohr et  al., 1997). By contrast, performance on tasks involving extrapersonal orientation has been reported to be preserved (Brouwers et al., 1984; Bylsma et al., 1992), in direct contrast to Alzheimer’s disease, in which tasks involving extrapersonal perception and construction are particularly impaired (Brouwers et  al., 1984). These findings indicate that it is in the domain of person-centered space, in which mental manipulation of information is required, that performance in HD is particularly compromised. Deficits have typically been ascribed to striatal pathology or damage to frontostriatal pathways (Potegal, 1971; Bylsma et al., 1992). Potegal (1971) argued that the caudate may play a role in updating the perceived position in space to compensate for self-induced movements, although not all studies have demonstrated a performance dissociation for egocentric and extrapersonal space (Majerova et al., 2012). What is clear, however, is that impaired spatial navigation is not an early feature of HD.

Social Cognition and Theory of Mind The social breakdown that is a common feature of HD raises the question of whether this is cognitively mediated, reflecting an inability to appreciate another person’s perspective or mental state: a failure of theory of mind. There is no doubt that people with HD perform poorly on a range of tasks that involve drawing inferences about the thoughts or feelings of others: recognition of a person’s misunderstanding or false belief (Snowden et  al., 2003), attribution of another’s intentions (Allain et al., 2011),

recognition of socially inappropriate behavior (Eddy et  al., 2012), and judgment of mental states from the eyes (Allain et  al., 2011; Eddy et al., 2012). The precise interpretation of such poor performance is, however, open to debate. Some authors (Eddy et  al., 2012)  have argued for a primary deficit in theory of mind, based on the absence of correlation between performance on theory of mind and several executive tasks. However, other authors (Allain et al., 2011) demonstrated correlations with some executive tests, raising the possibility that theory of mind test performance might be underpinned by specific executive impairments. For example, a correlation between “Reading the Mind’s Eye” performance (interpreting emotional states from the eyes) and Stroop performance raised the suggestion of a common underlying deficit in response inhibition because both tasks involve inhibition of distracters. Snowden et al. (2003) found deficits in cartoon interpretation both when the task required “attribution of a mental state” and when it did not, leading to the conclusion that people with HD have a general problem in inferential thought, which leads them to misconstrue situations, both social and nonsocial. The source of HD patients’ difficulty on tests of cognitive and affective theory of mind requires further clarification. Its importance lies in the potential relevance for understanding breakdown of social behavior in HD.

Emotion Recognition Another domain that is highly pertinent to a person’s social functioning is the processing of emotions. There is abundant evidence that people with HD show impaired recognition of facial expressions of emotion. Early studies (Sprengelmeyer et  al., 1996; 1997; Wang et  al, 2003)  highlighted a disproportionate impairment in the recognition of disgust relative to other emotions (happiness, sadness, surprise, fear, and anger). This is not a universal finding (Milders et  al., 2003; Henley et  al., 2008; Snowden et al., 2008; Aviezer et al., 2009; Hayes et  al., 2009; Calder et  al., 2010), with a number of studies demonstrating greatest impairment for anger (Johnson et  al., 2007; Henley et  al, 2008; Snowden et  al., 2008; Calder et  al, 2010). A systematic review of 16 emotion studies (Henley et al., 2012) identified anger as the emotion most consistently impaired. The basis for disparities across studies is not fully understood. Cultural and linguistic differences in the

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connotation of the Disgust term (visceral or moral) might be relevant (Snowden et al., 2008). Alternatively, there may be individual differences in the relative extent of atrophy of the insula and putamen, structures that have been associated respectively with processing of disgust (Calder et  al., 2007)  and anger (Calder et  al., 2004). In any event, a unifying finding among these studies is the impaired processing of negative emotions. Such impairments are cross-modal, affecting recognition of vocal (Snowden et  al., 2008; Calder et al., 2010) as well as facial emotions. Defective recognition of angry body language has also been demonstrated (De Gelder et  al., 2008). Moreover, impairments in emotional expression have been demonstrated paralleling those in emotion recognition (Trinkler et al., 2013). A limitation of virtually all studies of emotion in HD is that the test materials include more negative than positive emotions. The apparent disproportionate impairment for negative emotions might, therefore, plausibly be an artifact of task difficulty: happy faces are simply more distinct than disgusted and angry faces, which share common features. In line with this argument, a study that incorporated a greater range of positive emotions found that emotion recognition impairment extended to positive as well as negative emotions (Robotham et  al., 2011). On the other hand, negative emotions have been found to be more impaired (Snowden et al., 2008), even when the “happy” emotion is rendered more difficult to recognize (i.e., when judgment is based on eyes only rather than whole face). The precise relationship between recognition of different emotions in HD remains open to debate.

Odor Recognition There is strong evidence that olfactory processing is impaired in HD. Impairments have been demonstrated in early-stage, but not premanifest, disease in both the detection and identification of odors (Nordin et al., 1995; Bylsma et al., 1997; Bacon-Moore et al., 1999; Hamilton et al., 1999; Stout et al., 2012).

Relationship Between Cognition and Motor Function A number of studies have indicated significant correlations between cognitive performance and motor functioning. Correlations are greatest for voluntary aspects of motor functioning

(Brandt et al., 1984; Girotti et al., 1988; Heindel et  al., 1988, 1989; Brandt, 1994; Zappacosta et al., 1996; Snowden et al., 2001; Klempir et al., 2009) and are weak (Brandt et al., 1984; Snowden et al., 2001) or absent (Klempir et al., 2009) for involuntary movements. Motor impairment has been found by some to be a better correlate of cognitive decline than illness duration (Brandt et al., 1984). The presence of strong cognitive-motor correlations provides further support for the view that changes in striatum play a central role in the cognitive as well as motor disorder of HD.

Cognitive Impairment and Functional Disability Patients’ cognitive impairment is a major factor underlying functional disability in HD (Mayeux et  al., 1986; Bamford et  al., 1989; Rothlind et  al., 1993). Indeed, it has been argued that functional disability is due more to cognitive impairment (Mayeux et al., 1986; Bamford et al., 1989) and depression (Mayeux et al., 1986) than to patients’ movement difficulties, particularly chorea. Standard measures of disability such as Total Functional Capacity (Shoulson and Fahn, 1979; Shoulson, 1981), and scales of activities of daily living have been shown to correlate more closely with both cognitive impairment and loss of voluntary movement than with chorea (Brandt & Butters, 1996).

Awareness of Deficit It is commonly observed that people with HD have reduced awareness of their illness (Snowden et  al., 1998; Ho et  al., 2006; Hoth et  al., 2007; Sitek et  al., 2011). They may show poor awareness of changes in behavioral control, emotional control, and activities of daily living (Hoth et al., 2007), and may even deny the presence of involuntary movements that are readily apparent to an observer (Snowden et al., 1998; Sitek et al., 2011). A caveat is that in early-stage HD, self-evaluation of memory deficits has been found to be accurate, although awareness declines with progression of disease (Cleret de Langavant et al., 2013). It has been argued that cognitive impairments contribute to reduced awareness (Hoth et al., 2007). Psychological factors might also reasonably play a part:  people might be unwilling to confront a devastating illness, particularly if they have had a painful experience of HD through other affected family members. However, executive impairment and illness denial do not explain an apparent Neuropsychiatry and Neuropsychology  •  53

anomaly:  HD patients may accurately report consequences of their movement disorder, such as dropping things, bumping into furniture, and falls, despite failing to report the direct experience of choreiform movements (Snowden et al., 1998). People with HD who watch themselves on video film may express surprise that their involuntary movements are so pronounced. Such findings suggest a fundamental impairment in the subjective experience of chorea. The distinction between impaired egocentric and preserved extrapersonal space in HD might arguably be relevant in accounting for the findings. Patients might have impaired awareness of changes in spatial position with respect to their own body, preventing subjective experience of involuntary movements, yet have no difficulty detecting such changes in external space, permitting normal appreciation of involuntary movements depicted on film.

Progression of Cognitive Change Cognitive functioning declines over the disease course. Typically, the degree of annual change in cognition is relatively modest (Bamford et al., 1995; Snowden et al., 2001; Lemiere et al., 2004; Ward et al., 2006; Tabrizi et al., 2009, 2011, 2012, 2013; Stout et al., 2012; Meyer et al., 2012). The most sensitive markers of change are most commonly reported in the psychomotor domain and include performance on tests such as Stroop, Symbol-Digit Substitution, Trail Making, and Circle Tracing. Interestingly, and perhaps counterintuitively, simple psychomotor measures (e.g., word reading of Stroop) have been found to be more sensitive than more demanding tasks (e.g., interference condition of Stroop) (Snowden et al., 2001; Ward et al., 2006; Stout et al., 2012), even when the motor demands are equated (Snowden et al., 2001). Such findings have been interpreted in terms of breakdown in the “automatic” execution of cognitive and motor routines, associated with striatal dysfunction, as a central feature of HD (Snowden et al., 2001). Recognition of negative emotions, visual working memory, and odor identification have also been identified as sensitive to change in early HD (Stout et  al., 2012; Tabrizi et al., 2011, 2012, 2013).

Cognitive Decline and CAG Repeat Length Rate of cognitive decline varies across patients so that duration of illness is a relatively poor

indicator of cognitive performance (Brandt et  al., 1984). Brandt et  al. (1996) found that CAG repeat length was a predictor of rate of decline, demonstrating more rapid deterioration in HD patients with long (≥47) compared with short (37 to 46) CAG repeat length. By contrast, another study (Snowden et al., 2001) found no association with repeat length. It is possible that correlations are influenced by atypical juvenile cases with very large repeat lengths. However, the precise nature of the cognitive change may also be relevant. Ward et  al. (2006) found no overall relationship between CAG repeat length and cognitive decline, but a significant relationship with performance on the Trail Making test (part A), a simple test of psychomotor speed, as well as with neurologic measures. Those authors proposed that CAG repeat length is particularly linked to changes in basal ganglia, hence the predictive relationship to changes associated with automatic response programs. Consistent with this view, Tabrizi et  al. (2013) found an association between repeat length and symbol digit modality test, as well as paced tapping performance, but not performance on other cognitive tasks such as emotion recognition.

Evolution of Cognitive Change: Cognition in Premanifest Disease Symptoms of HD develop insidiously, raising the question whether subtle cognitive changes may be present before the time when people with the HD mutation would conventionally be regarded as clinically affected. An accumulation of evidence suggests that this is so. An important predictor of performance is the proximity to clinical onset of HD (Campodonico et  al., 1996; De Boo et  al., 1997; Hahn-Barma et  al., 1998; Snowden et  al., 2002; Robins Wahlin et al., 2007; Farrow et al., 2007; Brandt et al., 2008; Van Walsem et  al., 2010; Tabrizi et  al., 2011, 2012, 2013). There appears to be a “window” of some years before HD becomes manifest, in which subtle deficits may be detected (Paulsen et  al., 2008). Large-scale studies, which have the power to detect very small changes (e.g., Tabrizi et al., 2013), suggest that this window may extend for as long as 10 years. Early changes have commonly been demonstrated in the psychomotor domain (Foroud et  al., 1995; Siemers et  al., 1996; Kirkwood et al., 1999; Snowden et al., 2002; Jurgens et al., 2008; Maroof et  al., 2011; Stout et  al., 2012; Tabrizi et  al., 2011, 2012, 2013), particularly

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on relatively automatic tasks with low-cognitive demands. Such findings are consistent with structural (Aylward et al., 1994, 1996) and functional (Antonini et  al., 1996; Andrews et  al., 1999)  imaging evidence of striatal changes in premanifest HD and with correlations between striatal change and cognitive performance (Campodonico et  al., 1998; Lawrence et  al., 1998). Changes in premanifest HD have also been demonstrated on emotion recognition tasks (Tabrizi et  al., 2012, 2013; Labuschagne et al., 2013). Understanding the natural history and evolution of cognitive changes is crucial not only for clinical management of people with HD but also for the identification of clinical biomarkers of value in clinical trials. The topic of early and premanifest HD is discussed in detail in c­ hapter 5.

Basis of Behavioral Problems in Huntington’s Disease Behavioral problems in HD are common and varied. Many of these behaviors are mood based. However, it might be anticipated that others relate to altered cognition, as noted previously. People with HD frequently show a loss of drive and a lack of initiative. If left to their own devices, they may spend all day in bed or watching television. They react to events but are no longer proactive. Under normal circumstances, a great behavioral motivator is the capacity for forward thinking:  we see what needs to be done, and this provides the stimulus for action. Because HD patients have an impaired capacity for planning and forethought, this might contribute to their passivity and loss of initiative. Similarly, an inability to think plans through and see the consequences of one’s own actions might be expected to be largely responsible for HD patients’ poor judgment and the increased prevalence of minor offences (Jensen et al., 1998). Impaired self-generated maintenance of attention (Sprengelmeyer et  al., 1995)  would compromise the ability to persist in tasks. Impaired self-monitoring would lead to reduced quality of performance and an increase in errors. Decreased mental flexibility would make it difficult for someone with HD to see alternative points of view, hence the increased self-centeredness, mental rigidity, and loss of sympathy and empathy reported in many HD patients.

The assumption that some problem behaviors in HD relate to patients’ cognitive deficits whereas others are mood based and independent of cognitive change is borne out by our own investigations (Craufurd et al., 2001; Thompson et  al., 2002). A  factor analysis of behavioral symptoms identified three principle factors. The first, the apathy factor, included symptoms of loss of initiative, poor judgment, lack of perseverance, and reduced self-care, and was strongly correlated with measures of cognitive function. The second factor included symptoms related to irritability and temper control, and the third factor to depression. Neither the irritability nor the depression factor correlated with degree of cognitive change. These findings are paralleled by those of Baudic et  al. (2006), who found in early HD a significant association between cognitive impairment (memory, attention, and executive skills) and apathy but not depression. Notably, earlier studies of behavioral symptoms of HD that focused on mood changes of depression and irritability (Folstein et al., 1979; Caine & Shoulson, 1983; Mayberg et  al., 1992; Huntington Study Group, 1996; Zappacosta et al., 1996) found no correlation with cognition. The basis for individual behavioral symptoms is only beginning to be understood, and it is likely that many behaviors are multifactorial. It would be reasonable to suppose, for example, that the commonly reported neglect of self-care is linked to the patients’ loss of initiative and general apathy, and this is supported by the factor analysis. However, studies showing impaired detection and identification of odors in HD (Nordin et  al., 1995; Bacon-Moore et  al., 1999; Hamilton et al., 1999) raise the possibility that impaired sense of smell contributes to reduced concern for personal hygiene. Moreover, reduction in the subjective experience of the emotion of disgust might also contribute to the apparent lack of concern. Similarly, the etiology of irritable behavior in HD may be complex. In some cases, irritability may be secondary to another psychiatric disorder such as depression. Frustration due to clumsiness or difficulties with communication, and physical factors such as hunger and fatigue, may also contribute to the problem. Irritability might, in some instances, occur as a secondary consequence of cognitive difficulties. A difficulty switching attention between two ongoing tasks might lead to irritable outbursts, as a result of the patient feeling cognitively overwhelmed, in much the same way that normal individuals

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become irritable when subjected to excessive stress. Sometimes, irritability occurs in the context of self-centered, demanding behavior, and patients become upset and angry if their requests are not immediately satisfied (Ranen et al., 1993). However, it is also likely that neurodegenerative changes affecting inhibitory frontostriatal circuits play a significant part in the etiology of this common and troublesome symptom. A question that is often asked is whether altered behavior is an integral part of HD, arising as a result of structural brain changes, or occurs as a secondary reaction to a distressing and debilitating illness. The brain basis for much altered behavior has been emphasized throughout this chapter and should not be underestimated, not least because it fosters awareness that difficult behavior is not the “fault” of patients or under their voluntary control. Nevertheless, it would be reasonable to suppose that reactive factors might also play a part. HD imposes profound life changes on a person, with adverse effects on mobility, employment prospects, social life, and functional independence. Moreover, involuntary movements and slurring of speech are commonly misinterpreted by the general public as signs of drunkenness, leading to social ostracism. Feelings of frustration under such circumstances are understandable. In reality, it is likely that behavior reflects a combination of intrinsic and reactive changes. A  patient with HD who, for example, assaults a policeman who falsely accuses him of being drunk is showing an appropriate sense of outrage (reaction to consequence of illness), combined with a failure both to foresee the consequences of his actions and to suppress the surge of anger (action of HD).

Conclusion Cognitive and psychiatric changes are a prominent and integral part of HD and greatly affect patients’ functional capacity. Recognition of those changes is essential for successful management of the disease. People with HD sustain cognitive changes that place limitations on their capabilities, but they also have areas of strength that need to be harnessed. Psychiatric changes are distressing for patients and caregivers alike, but many changes are amenable to symptomatic treatment, so that early detection is vital. Behavioral problems in HD are, however, complex. The multiple factors underlying patients’ altered behavior are beginning to be unraveled,

providing scope for improved patient care and better understanding of HD.

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Neuropsychiatry and Neuropsychology  •  63

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Neuropsychiatry and Neuropsychology  •  65

4 Juvenile Huntington’s Disease O l i v e r W.   J . Q ua r r e l l

Huntington’s disease (HD) may occur at any age. Those with an onset before 20 years of age have been defined as having juvenile Huntington’s disease (JHD); this definition has been accepted for many years, but its origin is obscure. Some confusion exists about whether those with an onset at 20  years are also included:  this review will assume that the definition also includes those with an onset at 20 years; therefore, the definition will be 20 years or younger unless stated otherwise. A definition based on age of onset is arbitrary but convenient; however, it raises two issues: first, onset of HD is insidious, so defining an age of onset is often a best estimate rather than a precise point in time; and second, from a biologic perspective, there is no difference between an individual with an age of onset of, say, 18 years and an individual with an age of onset of, say, 22 years. Nonetheless, it is helpful to describe those with onset in childhood or adolescent years because as a group they are more likely to have larger CAG repeat lengths, to have a phenotype than is more parkinsonian at an earlier stage of illness, and to have pathology that is more widespread. Knowledge of those with a more extreme phenotype is necessary for a complete understanding of the disease process. In addition, we are entering an era when disease-modifying treatments are being considered. Assessment of novel treatments requires an outcome measure, but the standard outcome measures used in current clinical trials may not be wholly applicable to those with very early onset; therefore, these need to be developed. It is interesting to note that in the first three editions of this book, JHD was not separated out as a distinct chapter (Harper, 1991, 1996; Bates

66  • 

et al., 2002). The clinical, pathologic, and genetic features of JHD overlap with classic HD, but it is still useful to gather information on JHD in one place. The term infantile or childhood onset has sometimes been used been used to distinguish those with onset at or before 10 years of age from those with onset from 11 to 20 years; in this chapter, they will be distinguished as childhood and adolescent onset. Like JHD itself, this separation is arbitrary; nonetheless, it is useful because it allows a separate discussion of individuals with very early onset, whose needs are different from those of an older teenager. This chapter aims to summarize the information on JHD, to comment on some perceptions of JHD that are partially correct, and to identify areas of research activity.

Historical Aspects Although George Huntington was not the first to describe the condition that was named after him, his was the first clear succinct description (Huntington, 1872; see c­hapter  1). Similarly, Bruyn reviewed the history of HD (Bruyn, 1968)  and showed that there were reports of early-onset HD before Hofmann’s paper published in 1888, which is often quoted as the first detailed description of JHD (Hoffmann, 1888). In a family with multiply affected members, Hoffmann described a 36-year-old woman who developed seizures between the ages of 2 and 3  years that persisted. The relationship of the onset of epilepsy to HD in this description is unclear. However, he reported abnormal movements beginning before the end of her school years. He described the chorea as

1

2

I 1

II

III

1

2

*2

6

3

4

3

5

*

6

6

Figure 4.1  The pedigree diagram for the family studied by Hoffmann in 1888. Individuals III-2 and III-5 are the individuals with juvenile Huntington’s disease described in that paper. Note that in both cases, the transmitting parent was the mother. More detail was given in the paper for III-5 than for III-2.

being less prominent than in her older brother. Hoffmann reported accounts, given by the family, of a cousin of the above case who had onset of chorea at the age of 10 years and died in her 20s. It is interesting to note that in both cases, the affected parent was a mother (Figure  4.1; Hoffmann, 1888). In his review of the history of JHD, Bruyn reported descriptions of early-onset HD in the later part of the 19th century and early part of the 20th century (Bruyn, 1968). More recently, Roos has reviewed the early history of JHD (Roos, 2009) and commented on Westphal’s case of an 18-year-old patient with hypokinesia and rigidity diagnosed as “pseudosclerosis” from a family in whom other close relatives had “St Vitus’ dance” (chorea) (Westphal, 1883). In the past, there has been reference to a “Westphal variant,” and this eponymous term often related to individuals, of any age, in whom hypokinesia was a prominent feature. In general, hypokinesia is more prominent in JHD but can also occur in those with an onset after the age of 20 years and may be a prominent feature for those with more typical adult onset later in the course of their illness. The term “Westphal variant” is seldom used and is only mentioned as part of the historical note.

Percentage of Cases The percentage of JHD cases is usually expressed as a proportion of the HD cases in a population, and most reports give a figure of between 1% and 10%. Hayden reviewed 11 reports of the prevalence of JHD varying between 1% and 16%, with the highest proportion being in the mixed-race population of South Africa (Hayden, 1981a). A more recent meta-analysis of 62 surveys of HD found an overall figure for the percentage

of JHD cases to be 4.92%, with 95% confidence interval (CI) of 4.07% to 5.84% (Quarrell et al., 2012b). This was refined into 11 studies undertaken since 1980 using multiple methods of ascertainment from high-income countries, as defined by the World Bank, which gave a percentage of 4.81% (95% CI, 3.31% to 6.58%). This was compared with three studies done after 1980 that used multiple methods of ascertainment from middle-income countries (two were from Venezuela, and one was the from the South African mixed-race population), which gave a percentage of 9.95% (95% CI, 6.37% to 14.22%). The separation was an attempt to comment on the fact that if a population has a lower age of death, then the percentage of JHD cases may appear higher as a result of those individuals who would have developed HD in later life dying of other causes. Taken as a whole, a figure of 5% of HD cases having juvenile onset seems reasonable. In addition to the problem of defining JHD by age of onset mentioned previously, another issue is that the term “juvenile” suggests one should think of children, but because the condition has a duration of many years, individuals with HD onset in their late 20s or early 30s could still technically be considered to have JHD. If childhood onset refers to those with an onset at 10 years or younger, then the number of cases becomes much fewer because only approximately 20% of cases of JHD have onset before 10  years of age (Quarrell et  al., 2012b). A study based on diagnoses recorded from family doctors estimated the number of children and adolescents currently aged 20 years or younger in the United Kingdom with a diagnosis of HD to be approximately 100 (Douglas et al., 2013). This is a valuable figure but does not take account of

Juvenile Huntington’s Disease  •  67

any patients with childhood or juvenile onset who are now older than 20 years. The percentage approach relies on an estimate of the prevalence, which can vary (see c­hapter  7), but if we take both an approximate and a convenient prevalence of 10 per 100,000, then the number of HD cases in the United Kingdom with a juvenile onset would be approximately 300 (95% CI, 200 to 400).

Clinical Features As with adult-onset HD, the clinical features can be divided into motor or neurologic signs, behavioral or emotional problems, and cognitive deficit. These will be considered in turn.

Motor or Neurologic Signs Rigidity, bradykinesia, and dystonia are more likely to be prominent signs earlier in the disease process than would be the case for those with adult-onset conditions. This can occur in those with a later age of onset, but it is also the case that chorea may be a prominent sign in those with JHD. There have not been many large series by which to judge this, but they are summarized in Table 4.1. Van Dijk et al. undertook a literature review of JHD cases; they identified 195 cases and divided them on the basis of whether the motor feature was mainly rigid or mainly choreic. Sufficient information was available for 112 of these patients. Although based on a literature review and subject to publication bias, the study does show that rigidity is more common than chorea (Van Dijk et al., 1986). This analysis was repeated using information from the Leiden Roster for Huntington Disease (Siesling et al., 1997), and in both cases, the separation was approximately 60% mainly rigid and 40% mainly choreic. Two studies described the presenting motor signs for their patients:  these varied, but it is clear that chorea was a presenting sign in a significant proportion of patients (Cannella et  al., 2004; Ribbai et al., 2007). Other presenting signs included falls, difficulty writing, cerebellar signs, “Tourettisms,” speech delay, and oropharyngeal problems (Cannella et al., 2004; Gonzalez-Alegre & Afifi, 2006; Yoon et  al., 2006; Ribbai et  al., 2007). There has been one report of a childhood case presenting with excessive blinking approximately 3  years before more typical features of JHD developed (Xing et al., 2008).

Ribbai et  al. also gave details of the motor signs present when the patient was last examined; although 18 had chorea, it was combined with rigidity, dystonia, and bradykinesia in 15 cases (Ribbai et al., 2007). Inspection of Table  4.1 shows that chorea and bradykinesia can coexist, as is the case for classic-onset HD, but the chorea may be relatively mild when compared with rigidity, bradykinesia, and dystonia (Jongen et al., 1980; Hayden, 1981b; Rasmussen et  al., 2000; Cannella et  al., 2004; Ruocco et al., 2006). Epilepsy and myoclonus are more likely to be present in cases of JHD. It is difficult to judge an exact proportion, but it is by no means the case for the majority. Seisling et al. reported epilepsy or myoclonus in 35% of the JHD patients in their register for whom this information was available (Siesling et  al., 1997). Interestingly, a recent review of 90 patients who had been seen in 6 U.S. HD centers found that epilepsy occurred at some stage of the illness in 34 (38%) of the cases (Cloud et  al., 2012). Although the authors commented that they could not be certain that they had full ascertainment, and had to exclude 6 patients with insufficient data, this figure is almost exactly the same as that reported by Seisling et al. described previously. A case was reported of a 27-year-old woman with onset of JHD at 14  years; she developed myoclonus in her teenage years and a generalized seizure at age 20  years (Landau & Cannard, 2003). The authors commented on the paucity of reports of the electroenceophalogram (EEG) findings on HD cases in the literature. In their review, they found descriptions of the EEG in a further 23 cases, with 14 having an age of onset before 20  years; of these, the most common seizure type was generalized tonic-clonic seizures, followed by myoclonic and absence seizures. The Cloud et al. study gave details of the types of seizure that were present in patients with epilepsy. The most common seizure type was generalized tonic-clonic, followed by tonic, myoclonic and staring spells; in 12 cases the seizure type was mixed and in 12 cases no description was available. As might be expected, there were more seizures in those with younger, but not exclusively childhood, onset and higher CAG repeats (Cloud et al., 2012). These authors also commented that seizures were rarely a presenting feature (Cloud et al., 2012). A similar finding was reported in a study of the presenting features of 33 individuals younger than 18 years tested for HD: seizures were mentioned in 6 cases, although in 2 of

68  •  C l i n ica l A s p ec t s of H u n t i n g t o n ’ s D isease

Table 4.1. Summary of Motor Sign in Patients With Juvenile Huntington’s Disease S TU DY

N O. OF S U B JE C T S

N O. W I T H NO. W I T H C HOR E A R IGIDI T Y, BR A DY K INE SI A , A ND DY S TONI A

NO. W I T H R IGIDI T Y, BR A DY K INE SI A , DY S TONI A , A ND C HOR E A

OTHER NO. W I T H M YO C L ONU S A ND EPIL EP SY

Brackenridge, 1980 Jongen et al., 1980

297 7

170 1

127 2

NS  5

83/116 1

51

12

31

17

26

112 53

48 21

64 32

NS NS

NS 17/49

1

4 7

Hayden, 1981b Van Dijk et al., 1986 Siesling et al., 1997 Ho VB et al., 1995 Rasmussen et al., 2000

6 7

4 5 + 1 with a pathologic EEG

Cannella et al., 2004 Ruocco et al., 2006 Yoon et al., 2006

30 4 3

12 0 3

15 1 0

0 3 0

2 0

Ribbai et al., 2007

26

11

8

2

1

Ribbai et al., 2007 29 Barker & Squitieri, 2009 8

3 1

11 6

15 1

11 NS

—

34

Cloud et al., 2012

90

—

—

EEG, electroencephalogram; HD, Huntington’s disease; JHD, juvenile HD; NS, not significant.

NO T E S

Literature review All had All had onset under 10 abnormal EEG 10 Literature review Other = cerebellar signs NS Literature review NS Data from a register of cases in Holland Cerebellar signs NS All had onset