SPEC – Handbook of Clinical Neurology, Volume 144, Huntington Disease, 12-Month Access, eBook

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• Publisher: Elsevier
• Year: 2017
• Print ISBN: 9780128018934
• eBook ISBN: 9780128019030
• Topic: Psychology
• Subtopic: Neurology
• Index: Psychology

Huntington Disease summarizes the most recent findings related to the disease, providing both cutting edge coverage for clinical/research specialists looking to expand their knowledge base of Huntington disease information, as well as solid groundwork for advanced students from various backgrounds (neurology, psychiatry, neuropsychology, genetics). The volume includes all major areas of Huntington disease clinical care and research, whereas many other HD texts focus solely on neurological symptoms. This book also addresses behavioral and cognitive symptoms, brain imaging, and family dynamics and therapeutic alliances in working with individuals affected by HD. Clinical trials are covered extensively, including design considerations for therapeutic studies. The devastating nature of Huntington's disease is well appreciated throughout the neuroscience, neurology, and psychiatric communities, and a great amount of basic and clinical research is currently taking place. However, much of that occurs in isolated research silos, and it is critical that an interdisciplinary resource be developed to provide in depth information to enhance communication and collaboration. This volume in the Handbook of Clinical Neurology series is that resource. - Includes coverage of both basic science and clinical aspects of the disease, as well as treatment, experimental therapeutics, and biomarkers - Provides an essential resource for the non-neurologist, including necessary background for understanding the disease before making a more detailed study proposal - Provides an interdisciplinary approach that can be applied in everyday clinic and research efforts - Features chapters edited by leaders in the field around the globe—the broadest expert coverage available

Section II

Clinical aspects

Chapter 3

Epidemiology of Huntington disease

Chris Kay; Michael R. Hayden; Blair R. Leavitt* Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada
^* Correspondence to: Blair R. Leavitt, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, 950 W 28th Ave, Vancouver BC V5Z 4H4, Canada. Tel: [phone] email address: [email protected]

Abstract

Huntington disease (HD) is an autosomal-dominant neurologic disorder caused by an expanded CAG trinucleotide repeat mutation in patients with characteristic motor signs and specific brain pathology. A repeat of 36 CAG or more can lead to the disease, with increased penetrance and decreased age of onset at longer CAG repeats. The epidemiology of HD thus depends on ascertainment of individuals with the expanded CAG mutation, and on examination of clinical signs to accurately assess disease onset. A larger number of individuals have an expanded CAG repeat than actively manifest the disease due to adult onset in the majority of cases. Because of incomplete penetrance at the lower end of the pathogenic CAG repeat range, the frequency of the expanded CAG repeat in the general population may be higher than previously thought. Genetic differences and changing demographics may account for geographic and ethnic variation in the prevalence of HD between populations and over time. There are gross differences in the prevalence of HD by ancestry, with a much higher rate of the disease in populations of European descent. Molecular studies have elucidated genetic causes for these population-specific differences, possibly resulting from differences in the HD new mutation rate.

Keywords

Huntington disease; epidemiology; genetics; neurodegeneration; trinucleotide repeat; prevalence; haplotypes; genetic testing; de novo mutation; penetrance

Epidemiology before the genetic test

Huntington disease (HD) was first widely recognized as a distinct and hereditary form of movement disorder following the publication of “On chorea” in 1872 by George Huntington, a physician working on Long Island, New York. The disease presents with a spectrum of choreiform movements, rigidity, cognitive impairments, and behavioral disturbances, most often in midlife, with chorea as the first presenting symptom (Ross et al., 2014). An autosomal-dominant pattern of inheritance was shown in the early 20th century on account of the 50% chance of transmission of the disease to offspring, following an unbroken line of affected relatives. Only those who inherit the mutation can pass it to the next generation.

Despite early descriptions of its striking presentation and autosomal-dominant inheritance, several puzzling clinical aspects of HD eluded explanation before identification of the causative CAG repeat expansion. HD can manifest at any age, from early childhood to old age, but tends to develop in middle age. Among juvenile HD patients, inheritance is predominantly paternal. Age of onset tends to decrease over successive generations, particularly among individuals who inherit the mutation from their father, in a phenomenon known as anticipation. It was understood that more presymptomatic individuals bear the mutation than actively manifest the disease, and that risk of disease onset increases with age, but individuals with the mutation could only be ascertained through development of overt signs. Rigorous definitions of disease onset were also substantially lacking, given the progressive development of symptoms and the inability to identify and track premanifest individuals who had inherited the mutation. New mutations for HD were considered rare or nonexistent, as sporadic cases often presented late in life and therefore after the death of one or both parents. No molecular confirmation could exclude nonpaternity in these sporadic cases, and HD in one parent was suspected even in the absence of characteristic neurologic symptoms in the family history.

Epidemiologic ascertainment of HD before identification of the mutation therefore depended on diagnosis by a neurologist, most commonly in the context of an established family history, with ultimate confirmation only by autopsy. Variation in familiarity with the disease between physicians and service areas resulted in widely differing estimates of its prevalence. In regions where established specialists attempted methodical ascertainment and revision of all known pedigrees, such as Walker and Quarrell in South Wales or Shokeir in Canada (Shokeir, 1975; Walker et al., 1981; Quarrell et al., 1988), pre-molecular prevalence rates of 7.6–8.9 per 100,000 were reported. Broad regional studies that utilized existing clinical and institutional records, by contrast, reported proportionally lower rates. It is clear that many individuals with HD were never ascertained in these pre-molecular studies, particularly individuals lacking a family history and believed to suffer from a distinct disorder.

Genetic testing and ascertainment

The mutation causative of HD was discovered in 1993 by a consortium of investigators, following a decade of painstaking positional cloning from the linked G8 marker (Gusella et al., 1983; The Huntington's Disease Collaborative Research Group, 1993). All HD patients have an expanded CAG trinucleotide repeat within exon 1 of the Huntingtin gene, abbreviated HTT (Kremer et al., 1994). The expanded CAG repeat is translated into repetitive glutamine residues in the corresponding huntingtin (HTT) protein, and translation of the expanded repeat is believed to be necessary to elicit its toxic effects (Trottier et al., 1995; Goldberg et al., 1996). Presence of an expanded CAG repeat became the accepted molecular standard for confirmation of HD in those presenting with suggestive signs of the disease.

The development of a rapid, inexpensive, and precise test for the HD mutation, based on polymerase chain reaction (PCR) amplification of the CAG repeat region and analysis of its size, enabled unambiguous genetic diagnosis of patients (Warner et al., 1993; Andrew et al., 1994b). In addition, the genetic test allowed for definitive presymptomatic testing of individuals, previously possible only with linked chromosomal markers, revealing the exact HD genotype years or even decades before clinical diagnosis. The effect of the genetic test on the epidemiologic study of HD has been profound. Many sporadic cases, often with onset of mild symptoms in old age, have been genotyped with a CAG repeat expansion in the pathogenic range (James et al., 1994). Elderly individuals who carry the CAG expansion without signs of HD have also been reported (Rubinsztein et al., 1996). This has led many to conclude that senile chorea may not exist as a separate clinical category and instead represents HD of milder and later onset.

A small proportion of individuals have been shown to present with signs of HD and characteristic pathology on postmortem examination, but without an expanded CAG repeat in HTT (Andrew et al., 1994a; Persichetti et al., 1994; Rosenblatt et al., 1998). Many of these HD-like cases without an expanded CAG repeat, termed “HD phenocopies,” demonstrate autosomal-dominant inheritance and have been shown to be caused by heritable repeat expansions in other transcripts such as JHP3 (Holmes et al., 2001; Wild et al., 2008). However, approximately 99% of cases clinically suspected as HD are positively genotyped with the HTT CAG expansion in Western clinical series. HD therefore demonstrates little genetic heterogeneity, and the genetic test remains the definitive diagnostic tool.

With the widespread availability of genetic testing for HD and clinical centers to facilitate ascertainment, it has become possible to track phenotypic measures in gene-positive individuals prior to overt onset of the disease. Revision of HD diagnostic categories has been proposed in light of the arbitrary nature of clinical diagnosis, which has continued to rely on confidence scores from a consulting neurologist (Reilmann et al., 2014). Consequently, epidemiologic measures of HD may change in future surveys with revisions in diagnostic standards and ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Handbook of Clinical Neurology 3rd Series
• Foreword
• Preface
• Contributors
• Section I: Basic science
• Section II: Clinical aspects
• Section III: Treatment of Huntington disease
• Section IV: Experimental therapeutics
• Section V: Biomarkers
• Index