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

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

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

949 pages
10 hours
Sep 22, 2017


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
Sep 22, 2017

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

Huntington Disease

First Edition

Series Editors

Michael J. Aminoff

François Boller

Dick F. Swaab

Volume Editors

Andrew S. Feigin

Karen E. Anderson

Volume 144

3rd Series

Table of Contents

Cover image

Title page


Handbook of Clinical Neurology 3rd Series




Section I: Basic science

Chapter 1: Genetics of Huntington disease



Historic aspects

The HD gene

Definition of normal and abnormal CAG repeat lengths

Clinical genetics and epidemiology of HD

Animal models of HD

Gene-based therapies

Summary and conclusions

Chapter 2: Mechanisms underlying neurodegeneration in Huntington disease: applications to novel disease-modifying therapies



Genetic insights into huntington disease pathogenesis

Huntington disease and selective neuronal vulnerability

The normal function of Htt and loss-of-function toxicity

Transcription and knockdown of mutant Htt

Translation and clearance of mutant Htt

Conformation and aggregation of Htt

Cell–cell interaction mechanisms and Htt propagation

Posttranslational modifications of Htt

Proteolytic cleavage of Htt

Htt and gene transcription

Vesicular trafficking, cytoskeleton, and other cell signaling


Excitotoxicity and inflammation

Alternative mechanisms of pathogenesis

Conclusion and questions for future study


Section II: Clinical aspects

Chapter 3: Epidemiology of Huntington disease


Epidemiology before the genetic test

Genetic testing and ascertainment

The expanded CAG repeat

Factors influencing prevalence

Ethnic differences in prevalence


The Americas and Oceania



Genetic epidemiology

Complete genetic ascertainment


Chapter 4: Statistical modeling of Huntington disease onset



Regression Models for Age-At-Onset

Survival Models for Age-At-Onset



Chapter 5: The diagnosis and natural history of Huntington disease


Chapter 6: Cognitive and behavioral changes in Huntington disease before diagnosis


Introduction: the prodrome and diagnosis of huntington disease

The prodromal stages of HD

Cognitive changes in huntington disease individuals before diagnosis

Clinical trials for cognitive outcomes in huntington disease prodrome

Behavioral and personality changes in huntington disease individuals before diagnosis


Chapter 7: Preclinical motor manifestations of Huntington disease



Efforts to identify preclinical motor changes in HD

Large prospective studies



Chapter 8: The highly anxious individual presenting for Huntington disease-predictive genetic testing: the psychiatrist's role in assessment and counseling



Chapter 9: Preimplantation genetics and other reproductive options in Huntington disease




Chapter 10: Genetic testing for Huntington disease


Mapping the gene

DNA bank

Preparing for predictive testing: first do no harm

Preliminary results with linkage

The development of testing guidelines

Testing Of Minors

Anonymous testing

Testing Persons At 25% Risk

Revisiting protocols

Prenatal testing

The discovery of the HD gene

Intermediate alleles (IAs)

Direct testing

Preimplantation genetic diagnosis

Attitudes towards genetic testing

Test outcomes

Effect on partners

Adverse events after testing

Psychologic impact

Documenting trends through long-term follow-up



Section III: Treatment of Huntington disease

Chapter 11: Medical treatment of behavioral manifestations of Huntington disease




Obsessive-compulsive behaviors




Suicidal ideation and suicidal behavior


Chapter 12: Medical management of motor manifestations of Huntington disease


General principles

Assessing the motor disorder in huntington disease

Management of specific motor features

The future


Chapter 13: The role of rehabilitation therapy in Huntington disease



Effects of cognitive, behavioral, and motor impairments on physical functioning in HD

Functional limitations in HD

Outcome measures to evaluate rehabilitation interventions

Rehabilitation interventions in HD

Directions for future research


Chapter 14: Contemporary health care for Huntington disease



Stage of disease and care complexity

Barriers to care

The financial and human cost of care in HD

Improving care delivery in HD


Chapter 15: The impact of Huntington disease on young people


Chapter 16: Making a measurable difference in advanced Huntington disease care







Common issues experienced by people with advanced HD

Advanced HD family concerns

Proposed pre-admission process to facilitate interagency communication

Current collaborating models of care

Outside the united states

Review of the literature

Proposed approaches to care in advanced HD

Letters requesting exceptions to the rule

Nonpharmacologic approach

Advance directives

End of life


Section IV: Experimental therapeutics

Chapter 17: New symptomatic therapies for Huntington disease



Motor symptom treatment

Surgical treatment

Nonpharmacologic intervention

Cognitive symptom treatment

Neuropsychiatric symptom treatment

Neuroprotective treatment

Quality of life

Areas of need


Chapter 18: Motor outcome measures in Huntington disease clinical trials




Q-Motor: quantitative-motor assessments

Chapter 19: Cognitive assessment in Huntington disease clinical drug trials


Possible roles of cognitive assessment tools in clinical trials

Cognitive measures in preclinical drug development

Cognitive assessment in HD clinical trials: a review

Cognitive assessment in schizophrenia and alzheimer disease trials

Guidance for the selection of cognitive outcome measures

Development of a purpose-built cognitive assessment battery for HD clinical trials: the HD-CAB




Section V: Biomarkers

Chapter 20: Structural imaging in premanifest and manifest Huntington disease




Structural changes in premanifest huntington disease

Structural changes in manifest huntington disease

Predicting disease onset

Influences on rates of disease progression

Correlations with clinical measures

Comparison with nonimaging biomarkers

Structural imaging for clinical trials


Chapter 21: Functional imaging in Huntington disease



Radiotracer imaging

Functional magnetic resonance imaging




Handbook of Clinical Neurology 3rd Series


Michael J. Aminoff; François Boller; Dick F. Swaab

Huntington disease (HD), long known as Huntington's chorea, has an ancient history as a disease entity, dating back to the first half of the 19th century, if not earlier. As is often the case, knowledge of the condition progressed slowly for many years. Considered at first an American tragedy because of the location of the first well-documented cases, it soon became apparent that the disease is nearly ubiquitous, even though its worldwide prevalence varies widely. Its dominant inheritance was clearly established in 1872 by Dr. George Huntington, who therefore fully deserves the eponym. In his masterful review of the topic in volume 6 of the Handbook of Clinical Neurology (HCN), published in 1968, Dr. George Bruyn, one of the two founding editors of the HCN series, was forced to admit that the cause of the disease is as yet unknown. Later in that chapter, when discussing apparently sporadic cases, he stated that one can never know who the real father is and he quoted the old adage, "pater semper incertus," a statement rendered obsolete by modern DNA technology. A quantum leap in our understanding of the disease occurred in the 1980s when James Gusella, Nancy Wexler, and their coworkers obtained the genetic material that contributed to the localization and later the identification of the HD gene. This has led to a flurry of research that has made HD one of the most rapidly developing areas of investigation in neurology. It is therefore a pleasure to present this volume of the Handbook, which is dedicated to Huntington disease.

The volume opens with chapters describing in detail the pathogenesis and particularly the genetics of the disease, as well as its epidemiology. It then focuses on the diagnosis and clinical manifestations of the disease, with emphasis on the cognitive, behavioral, and psychiatric changes that occur when the disease is clinically apparent and also when it is still in a preclinical stage. Emphasis is also given to HD biomarkers, again both in the manifest and premanifest phases of the disease. An important chapter discusses the practical and deontologic problems associated with genetic testing of individuals at risk. Nine of the 21 chapters in the volume are dedicated directly or indirectly to treatment, including a chapter on preimplantation and other reproductive options. This goes along the lines of a recent article that referred to the disease as the most curable incurable brain disorder.

We have been fortunate to have as volume editors two distinguished scholars and clinicians, Andrew Feigin and Karen E. Anderson. Both have been at the forefront of research on HD for many years. They have assembled a truly international group of authors with acknowledged expertise and produced this authoritative, comprehensive, and up-to-date volume. Its availability electronically on Elsevier's Science Direct site as well as in print format should ensure its ready accessibility and facilitate searches for specific information.

We are grateful to Dr. Feigin, Dr. Anderson, and all the contributors for their efforts in creating such an invaluable resource. As series editors we read and commented on each of the chapters with great interest and we were impressed by the high quality of their work. We are therefore confident that both clinicians and researchers in many different disciplines will find much in this volume to appeal to them.

And last, but not least, we thank Elsevier, our publisher – and, in particular, Michael Parkinson in Scotland, and Mara Conner, Nikki Levy, and Kristi Anderson in San Diego – for their unfailing and expert assistance in the development and production of this volume.


Andrew S. Feigin, M.D.; Karen E. Anderson, M.D.

Huntington disease (HD) is a complex inherited, neurodegenerative condition. Its triad of neurologic, cognitive, and psychiatric symptoms results in intense suffering in families afflicted by the condition. The genetic mutation that causes HD was identified a quarter of a century ago, leading to optimism that this would quickly lead to meaningful therapies and perhaps even a cure. But progress toward effective treatments has been slow, and the search for disease-modifying therapies continues.

Today we are at a point where this progress is accelerating. Our understanding of the principles of good clinical care means that there is much to help improve the daily lives of HD patients. In addition, great strides have been made toward understanding the pathophysiologic mechanisms underlying the neurodegenerative process in HD. Based upon these advances, multiple ongoing clinical trials for both symptomatic and disease-modifying therapies offer renewed hope for patients and their families.

Because it is a rare disease, much of the clinical care of HD is based on expert knowledge, learned in training and specialty settings, but not grounded in clinical trials or rigorous studies. Some parts of this book are purposely redundant, so that information can be found with ease in different locations, depending on the reader's interests. In developing this volume for the Handbook of Clinical Neurology series, we sought expertise from many disciplines, including neurologists, neuropsychiatrists, neuropsychologists, geneticists, physical therapists, basic scientists, and other clinicians and researchers. We also included a chapter that reflects the voice of the patient, describing the experiences of someone growing up in a family where HD influenced every aspect of daily life.

A main goal of this book is to promote our current understanding of HD for all, from experts to those who see only a few patients with HD, such as a general neurologist, psychiatrist, or internist who encounters an HD family for the first time. It includes information on diagnosis, natural history, genetic testing, and clinical care. As such, the book may also serve as a useful resource for students, fellows, and other trainees, as well as for those who are well versed in the disorder but encounter a new clinical situation or one outside their area of expertise.

Because basic research in HD has proceeded at such a rapid pace in the last several years, another goal of this book is to help clinicians to understand developments in research into the disease. The volume therefore includes sections on biomarkers, clinical trials, and the basic science research that underlies much of the clinical trial work. Bridging the clinical and basic science realms, this volume also highlights new work on prodromal and early-manifest HD, an area where drug development is particularly active.

It is our hope that readers will find this volume of the Handbook of Clinical Neurology to be a helpful addition to their libraries, regardless of their own level of expertise. In particular, we believe it will be a valuable resource to guide them through the advances yet to come in HD care and research.

We sincerely thank all the contributors for their efforts to make this the best possible scholarly volume. Without their dedication and knowledge, we would not have the breadth and depth found in this work, which is beyond the scope of any single expert's ability.


Section I

Basic science

Chapter 1

Genetics of Huntington disease

Martha A. Nance*    Struthers Parkinson's Center, Golden Valley

Department of Neurology, Hennepin County Medical Center and Department of Neurology, University of Minnesota, Minneapolis, MN, United States

* Correspondence to: Martha A. Nance, MD, Medical Director, Struthers Parkinson's Center, 6701 Country Club Drive, Golden Valley MN 55427, United States. Tel: +1-952-993-6592, Fax: +1-952-993-2250 email address:


In this chapter, we review the evolution of our understanding of the genetic aspects of HD, and the applications of our understanding in the management of Huntington's disease patients and families over the last 150 years. Important aspects of the clinical genetics and epidemiology of Huntington's disease are discussed, such as the definition of normal and abnormal numbers of CAG (cytosine-adenine-guanine) repeats in the critical spot within the huntingtin gene, meiotic instability of CAG repeat numbers, common Huntington's disease genetic haplotypes, compound heterozygosity for an abnormal gene, and somatic mosaicism for CAG repeat expansions. We touch only briefly on the creation of multiple animal models for Huntington's disease that have profoundly impacted our understanding of the disease and permitted the development of potential disease-modifying treatments, and end with what is, at the time of writing, the dawn of a new era: the advent of gene-based therapies (gene silencing, gene editing) for Huntington's disease.


Huntington’s disease; genetics; CAG repeat; meiotic instability; genetic modifiers; gene silencing; gene editing


We summarize below almost 150 years of work to define and refine our understanding of the genetic aspects of Huntington disease (HD). It is these genetic aspects that led Dr. George Huntington and others in the 19th century to distinguish HD from other neurologic conditions, spurred a century of scientific work in the 20th century that culminated in the discovery of the HD gene in 1993, and provided the premise for human gene therapy trials in HD, which began in 2015.

Historic aspects

There is space here to touch on only a few of the many works by numerous researchers that have contributed to our knowledge of HD, and also to remind the reader of the interesting and not always favorable social implications and applications of this research. Readers interested in the first century of HD research are referred to the comprehensive review by Dr. George Bruyn in the 1968 edition of the Handbook of Clinical Neurology, and to his painstakingly compiled, pre-PubMed era, A centennial bibliography of Huntington's chorea, published in 1974 (Bruyn et al., 1974).

The dominant inheritance of HD was described eloquently by Dr. George Huntington in 1872:

When either or both the 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 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.

Anticipation, the earlier onset of symptoms in succeeding generations, was recognized in an address by Charles Davenport to the National Academy of Sciences in April 1915, although he emphasized the selection bias in cross-sectional or retrospective family studies and felt that this accounted for most of the observed apparent anticipation.

Davenport's detailed and influential genealogic studies of four New England-based kindreds provided the foundation for a generation of eugenic HD activities, as researchers recognized the potential for an adult-onset autosomal-dominant disorder such as HD to be prevented by voluntary or involuntary prevention of reproduction in persons belonging to choreic lines.

In Minnesota, as an example, research on the genetic aspects of HD in the first half of the 20th century was performed at the Dight Institute at the University of Minnesota, founded in 1923 by Dr. Charles F. Dight, a supporter of Adolf Hitler's efforts regarding racial hygiene. John Pearson, a psychologist in Rochester, Minnesota, ascertained individuals with a diagnosis of HD who were residents of state (psychiatric) hospitals in Minnesota, and used family informants to assist in drawing up their genealogies. The families were then provided with educational materials regarding their genetic risk, with the hope that they would restrict their reproduction. The results of this work, An educational approach to the social problem of Huntington's chorea (Pearson et al., 1955), was one of the early attempts to facilitate the provision of genetic information to families at risk for genetic diseases, through a process soon defined as genetic counseling (Reed, 1955). Subsequent work with these families showed that premorbid psychometric indicators of HD could be identified in at-risk individuals who subsequently developed the disease (Lyle and Gottesman, 1977), and increased reproductive fitness among those who developed HD (Marx, 1971; also reported by Shokeir, 1975, in Canada, and others).

By the mid-1950s, an astute physician in Venezuela, Dr. Americo Negrette, recognized a high incidence of what he suspected was HD in a rural community on Lake Maracaibo in the state of Zulia, Venezuela (Okun and Thommi, 2004). This observation ultimately led to a decades-long collaborative genealogic, clinical, and molecular genetic study that ultimately included information on some 18,000 members of the kindred, and DNA analysis of over 4,000 individuals. In addition to providing the genetic material that contributed to the localization and later the identification of the HD gene (Gusella et al., 1983; Huntington's Disease Collaborative Research Group, 1993), annual field trips to Venezuela created an important medical and social relationship that continues today (Wexler, 2013).

The HD gene

HD (OMIM143100) is caused by expansion of a polymorphic trinucleotide repeat (CAG)n, encoding glutamine, located in exon 1, at the N-terminal coding region of the huntingtin (HTT) gene, which is located on chromosome 4p16.3. The HTT gene spans 180 kb, and contains 67 exons (Ambrose et al., 1994). The only disease-causing mutation identified in the HTT gene is the CAG repeat expansion.

HD is one of a group of nine polyglutamine disorders, in which CAG repeat expansions in the coding portion of the gene lead to expressed proteins containing polyglutamine sequences. The other known polyglutamine disorders include the dominantly inherited disorders spinocerebellar ataxias (SCA) types 1, 2, 3, 6, 7, and 17, and dentatorubropallidoluysian atrophy; and the X-linked disorder spinobulbar muscular atrophy (Kennedy disease). Of note, these are all neurodegenerative disorders, with little or no effects on internal organs such as the heart, kidneys, lungs, liver, pancreas, skin, bones, immune, hematologic, or endocrine function (even in spinobulbar muscular atrophy, which is caused by CAG repeat expansions within the androgen receptor gene, evidence of androgen insensitivity begins somewhat later and is relatively mild in comparison to the testicular feminization that arises from point mutations or deletions in the same gene). The location of the CAG repeat within the gene varies among the different genes, but its presence within the coding portion of the gene puts constraints on both the normal, and the pathogenic, number of CAG repeats. There are also differences in the degree of repeat number variability within the normal population; CAG repeat lengths in HTT vary significantly in the general population, from 6 to 35, with about 2% of the general population carrying HTT CAG repeat lengths in the upper 20s to low 30s. For SCA type 2, in contrast, the vast majority of normal alleles carry 22 or 23 CAG repeats (Nance, 1997). Pathogenic CAG repeat lengths for these disorders generally begin in the high 30s or low 40s, with the vast majority of patients having 90 or fewer repeats, and only rare cases of repeat numbers >100. (It should be noted that SCA6, the CACNA1A gene, is slightly different, with normal CAG repeat lengths being up to about 18, with reported abnormal lengths of 20–30.)

The polyglutamine disorders form a subset of the repeat expansion disorders, which also include fragile X syndrome and fragile X tremor-ataxia syndrome, Friedreich's ataxia, SCA types 8, 10 (pentanucleotide repeat), and 12, HD-like 2, and myotonic dystrophy type 1 and type 2 (CCTG repeat). In these conditions, the repeat sequences are not within a coding portion of the gene, and for some of them, pathogenic repeat lengths have been seen to extend to >1,000 repeats. In the case of fragile X syndrome, very large repeat lengths lead to transcriptional silencing of the gene and a multisystem phenotype. For several of these conditions, pathogenesis has been shown to be related to aberrant processing, splicing, or other toxic effects of the RNA transcript, rather than effects of a mutant protein on cellular function (reviewed in Todd and Paulson, 2010). It is possible but not proven that pathogenesis of very large CAG repeat expansions in conditions such as HD and SCA2 is also, at least in part, mediated by RNA toxicity.

The normal functions of huntingtin, and which of these functions are relevant to pathogenesis in the setting of a protein that contains an elongated polyglutamine stretch, continue to be studied intensely even now, over 20 years since the gene and its protein were identified. The biochemistry of huntingtin is discussed in Chapter 2.

Definition of normal and abnormal CAG repeat lengths

As soon as the HD gene was identified in 1993, researchers at many laboratories rapidly ran through their banked HD research samples, and patients began coming for clinical testing. A slight revision to clinical genetic testing protocols soon ensued, as it was found that the original PCR primers used to flank the CAG repeat sequence in the HD gene also flanked a nearby CCG sequence, which was also polymorphic (commonly having either 7 or 10 repeats). By 1998, a working group of the American College of Medical Genetics/American Society of Human Genetics, based on a review of the United States and published world experience with HD genetic testing, defined the clinical diagnostic boundaries shown in Table 1.1, which have largely held up since that time.

Table 1.1

Clinical interpretation of CAG repeat lengths (American College of Medical Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group, 1998)

Normal (10–26 CAG repeats)

No confirmed cases of HD have been reported in individuals with CAG repeat lengths of 26 or less, nor have repeat numbers of this length been reported in the parent of a new mutation or sporadic case of HD. It should be noted that this definition of normal is incorrect on the low end, as CAG repeat lengths as small as 6 have been reported in normal individuals.

Normal, mutable (27–35 CAG repeats)

This was defined as the CAG repeat range that had not been associated with the diagnosis of HD, but was either suspected or proven to have undergone further expansion in meiosis, to lead to HD in one or more offspring. Normal refers to the idea that the individual carrying a CAG repeat length in this range would not be expected to develop HD. Mutable refers to the idea that CAG repeat lengths in this range could undergo expansion during meiosis, leading to HD in the next generation. Some have used the term intermediate, gray zone, or premutation to refer to this range, paralleling the use of similar terms in other CAG and trinucleotide repeat disorders. The term normal, mutable is preferred for its more specific meaning.

It is important to note that the mutable range was defined through studies of the parents of probands with HD, and does not imply that an individual from the general population who has a repeat number in that range does (or doesn’t) have a risk of having a child with HD. About 2–3% of normal huntingtin alleles in subjects participating in a United States-based observational trial of people affected with and at-risk for HD have CAG repeat numbers in this range (Huntington Study Group COHORT Investigators and Dorsey, 2012). Other genetic or environmental factors that contribute to meiotic instability are not well known (see the section below, Meiotic instability of the CAG repeat), and in the clinical situation it is best to admit a lack of knowledge rather than to imply a specific risk that may be incorrect or misleading.

For CAG repeat lengths in the mutable range, there is a graded risk of meiotic expansion into the pathogenic range, with a greater risk for repeat numbers close to the 35/36 boundary (Semaka et al., 2006, 2010; Hendricks et al., 2009). Pathogenic expansions are probably more likely to occur during male meiosis (as is true for further expansions of abnormal CAG repeat lengths).

Over the last few years, there have been several reports of individuals who appear to have HD, who have high normal CAG repeat lengths (Kenney et al., 2007; Herishanu et al., 2009; Groen et al., 2010; Ha and Jankovic, 2011), and the Venezuelan HD Research Consortium considers 35 to be an abnormal CAG repeat length (Wexler et al., 2004; Paradisi et al., 2008). These authors feel that it is time to revise the boundary between normal and abnormal to include CAG repeat lengths in this range, but to this date, no consensus group or panel has moved in this direction.

Abnormal, incomplete penetrance (36–39 CAG repeats)

Repeat numbers in this range are clearly associated with the presence of HD, but because of the age-related penetrance of the gene, there are individuals living up to or beyond a normal life expectancy who do not develop symptoms of HD. This concept has been well accepted by patients and their physicians.

Abnormal, complete penetrance (40 and above)

This is generally agreed as representing the CAG repeat range that will always lead to HD within a normal lifespan.

There remain some unexplained features of CAG repeat analysis in the patient population. CAG repeat numbers of 27–35 are quite uncommon, as are repeat numbers in the 36–39 range. The most common abnormal CAG repeat number in convenience samples of people with HD is 43, and the most common normal repeat number is 17. It is not clear why there should be more people with 43 CAG repeats than with 40–42 repeats.

It is also worth noting that, whereas most mouse models of HD have used DNA fragments containing over 100 CAG repeats, the number of people reported with repeat numbers in this range are very few, probably less than 50 worldwide, and all are children with very young onset disease and with clinical features (rigidity, seizures, lack of chorea, and cerebellar atrophy) that often differ from those seen in the usual adult form of the disease. This disparity is worth recalling as researchers attempt to translate research performed in animal models to human adult-onset HD.

Clinical genetics and epidemiology of HD

The epidemiology of HD was summarized brilliantly by Professor Peter Harper in the third edition of his textbook, Huntington's Disease, published in 2002, and the reader is referred to his chapter for both its succinct summary and its awareness of the historical and social context surrounding research in this area. The discussion below will focus on work that has occurred since that time, and particularly on the molecular genetic epidemiology of the disease.

Studies of the prevalence of HD in a region or population in the last ten years are shown in Table 1.2. Investigators have emphasized the low prevalence of the disease in Iceland (where all but one case were descended from a single founder couple) and Finland. In contrast, several authors have recently emphasized the significantly greater prevalence of the disease (10.6–13.7/100,000) in these post-DNA era studies from Europe and Canada than was found in the earlier studies summarized by Harper (generally in the 3–8/100,000 range).

Table 1.2

Prevalence of Huntington disease in a region or population over the last 10 years

A meta-analysis of eleven large epidemiological studies showed that the prevalence of HD in countries in Europe/North America/Australia was 5.70 per 100,000 (95% CI: 4.42–7.35) compared to a prevalence in two Asian studies of 0.40 per 100,000 (95% CI: 0.26–0.61) (Pringsheim et al., 2012).

Populations with a local founder effect resulting in common ancestry of many or most cases in the community have been described in Iceland (Sveinsson et al., 2012), Spain (García-Planells et al., 2005), and South Africa (Scholefield and Greenberg, 2007).

Juvenile-onset HD

A recent meta-analysis identified 62 studies in which the proportion of juvenile HD (JHD) cases to all HD cases was estimated. The authors found that while individual studies reported a proportion of anything from 1 to 15% (pooled proportion of 4.92%), and analysis of 25 studies that used multiple methods of ascertainment and 11 studies from high-income countries yielded similar results (5.32% and 4.81%, respectively), three studies from upper middle income countries (South Africa and Venezuela) yielded a somewhat higher pooled proportion of JHD cases of 9.95% (Quarrell et al., 2012).

The relationship between CAG repeat number and onset age has been clear since the HD gene was first identified. It is easy to understand, then, that most children with HD will have CAG repeat numbers of >50, or at least >45. However, because children are not the usual focus of genotype–phenotype correlation studies coming from individual centers, children with apparent onset in the first 20 years whose CAG repeat numbers are in the 36–45 range have been understudied, although they could represent an important group of outliers with particularly severe/early phenotypic expression.

It should also be noted the routine polymerase chain reaction analysis used in clinical HD molecular genetic analysis may miss the very large CAG repeat expansions that may accompany very-young-onset HD (Nance et al., 1999); additional techniques are required to identify large expansions. It is also worth noting that several of the youngest children with the largest CAG repeat expansions have inherited their HD gene from an affected mother, thus serving as exceptions to the usual rule that large meiotic expansions of CAG repeat number occur during paternal meiosis (Nance et al., 1999; Nahhas et al., 2005; Papapetropoulos et al., 2005). For these reasons, the clinician seeing a very young child suspected of having HD should not be put off by apparent maternal inheritance, and should communicate with the testing laboratory to ensure that both HD alleles are clearly identified.

New mutations

Older studies found an incidence of de novo or new mutation cases of 3–10% in the HD clinic population (Goldberg et al., 1994; Nance et al., 1996). However, this rate may increase dramatically if late-onset HD (onset at age 60 or above) forms the base population. One recent study, for example, found that a family history of HD was absent in 29.3% of late-onset cases (Koutsis et al., 2014). Given that the majority of HD new mutations arise from a parental (usually paternal) intermediate-sized expansion (27–35 CAG repeats, called intermediate alleles), Semaka et al. studied the frequency of intermediate alleles in the general population in British Columbia, and were surprised to find that they were seen in 5.8% of the general population, and 60% of those were on the regional haplotype associated with HD. This same group has also attempted to define CAG repeat-specific risk estimates for expansion of intermediate alleles into the pathogenic range, and discussed the genetic counseling implications of their work (Semaka et al., 2013b; Semaka and Hayden, 2014).

Compound heterozygosity for HD gene mutation

Multiple cases have been reported of individuals carrying mutations in both HD genes (Rubinsztein et al., 1997; Alonso et al., 2002; Squitieri et al., 2003). Although this has been referred to as homozygosity, Uhlmann et al. (2015) have pointed out that this should more properly be referred to as compound heterozygosity or biallelic mutations. The effects of compound heterozygosity on disease onset or progression, if any, are not striking.

A Huntington disease chromosomal haplotype

Importantly, the majority of European CAG repeat expansions occur against the background of a particular regional chromosomal haplotype (referred to as haplogroup A by Warby et al., 2011). This haplogroup is absent in the East Asian population, which may account for the lower prevalence of HD in that region than in Europe or areas with a greater European heritage (Warby et al., 2011). In the East Asian population, the average CAG repeat length is lower than it is European populations, and when CAG repeat expansion does occur, it is generally on a haplogroup C background. In contrast, a study from Bangalore, India, showed that most huntingtin mutations in that population are on the European haplogroup A background (Moily et al., 2014).

The presence of a common haplotype leaves open the possibility of targeting the single-nucleotide polymorphisms that create haplogroup A, rather than the CAG repeat sequence itself, in gene-silencing approaches to HD (Kay et al., 2015).

Meiotic instability of the CAG repeat

Meiotic instability of the CAG repeat sequence has been known since the discovery of the gene, based on CAG repeat lengths in parent–child dyads (Duyao et al., 1993). Identical twins have the same CAG repeat numbers, indicating that the CAG repeat length is determined during gametogenesis (MacDonald et al., 1993) (but note that there is a single case report of monozygotic twins who were both mosaic for two different upper repeat numbers, 37 and 47; one twin displayed mosaicism in hair and fibroblasts, while the affected twin showed mosaicism only in blood and buccal tissues; Nørremølle et al., 2004). There is also a recombination hot spot adjacent to the D4S10 marker that originally localized the HD gene (Hubert et al., 1994). The tendency for a CAG repeat sequence that has expanded into the pathogenic range to undergo further expansion during meiosis has been shown to be more likely in paternal meiosis than in maternal meiosis. This correlates with the observation made many years ago that most children with juvenile-onset HD have affected fathers.

Single sperm analysis has confirmed that there is little instability for repeat numbers in the normal range (0.6%) (Leeflang et al., 1995), but significant instability for CAG repeat numbers in the pathogenic range. Meiotic variability in CAG repeat length reaches 98% for individuals with somatic repeat lengths of >50 in the Venezuelan HD population (Leeflang et al., 1999). However, there is also striking variability in the degree of CAG repeat instability among individuals, so that some individuals with >50 CAG repeats produce a collection of sperm with CAG repeat lengths of –1 to +3 of the somatic CAG length, while others produce a smear of widely varying repeat lengths (Wheeler et al., 2007). This does not appear to depend on paternal age.

The underlying molecular genetic basis of CAG repeat instability remains uncertain. Repeat expansions appear to occur before, during, and even after meiosis in male gametes (Yoon et al., 2003). Postulated mechanisms include cis-acting modifiers, such as the GC content of nearby regions in the genome (Brock et al., 1999), sex of the embryo (Kovtun et al., 2000 (in mice); Wheeler et al., 2007 (in humans)), and DNA methylation (Flanagan et al., 2006). Both somatic and gametic instability of the huntingtin CAG repeat number were reported in a transgenic rhesus monkey model of HD (Putkhao et al., 2013). The potential to impact disease expression in the offspring by modification of epigenetic factors in the affected parent was demonstrated in a recent study that showed benefits on the expression of HD in the offspring of transgenic HD mice treated with histone deacetylase inhibitors (Jia et al., 2015).

In the clinic, the possibility of meiotic instability for CAG repeat length is particularly important for individuals who have a CAG repeat length in the intermediate range (27–35 CAG repeats). Risks of expansion into the pathogenic range in the offspring have been empirically determined for each CAG repeat number in this range (Semaka et al., 2013a).

Somatic mosaicism for CAG repeat length

Somatic mosaicism for CAG repeat length is present to a varying degree in different tissues, and in different regions of the brain. Brain regions most affected in HD, such as the striatum and cortex, show the most variability, while less affected regions show less (Telenius et al., 1994). Somatic mosaicism appears not always to be evident (MacDonald et al., 1993; Zühlke et al., 1993; Kahlem and Djian, 2000), but a growing body of literature in both human brains and animal models suggests that it is the rule rather than the exception, and that it is important in disease pathogenesis (Aronin et al., 1995; De Rooij et al., 1995; Wheeler et al., 1999; Kennedy and Shelbourne, 2000; Fortune et al., 2000; Kaplan et al., 2007; Shelbourne et al., 2007; Veitch et al., 2007; Gonitel et al., 2008; Cannella et al., 2009; Dragileva et al., 2009). Swami et al. (2009) found that somatic mosaicism in the brains of humans with unusually early or late onset was based on constitutive CAG repeat length (outliers), and found that further expansion of CAG repeat length was associated with earlier disease onset.

Treatment of mammalian cells in culture with caffeine increases CAG repeat variability/expansion, while treatment with genotoxic drugs such as ethidium bromide, cytosine arabinoside, and 5-azacytidine reduced CAG repeat expansion (Gomes-Pereira and Monckton, 2004).

The mechanisms underlying somatic mosaicism for CAG repeat length are unknown, but it is known that CAG repeat expansion can occur in the absence of cell division, and that cell cycle arrest does not prevent further expansions (Gomes-Pereira et al., 2014). Genes involved in transcription-coupled repair (CSB) and base excision repair (OGG), as well as other DNA repair genes (the MSH group of genes), are known to be important in maintaining CAG repeat length. CSB, in particular, appears to stabilize or reduce CAG repeat numbers in the germline, while OGG tends to promote further expansion of CAG repeats (Berger et al., 2013; Tomé et al., 2013; Mason et al., 2014).

Genetic modifiers of age of onset of HD

The last 15 years have seen an explosion of research to uncover genetic (and environmental) modifiers of the age of onset of HD once it was confirmed repeatedly that variation in CAG repeat length only accounts for about 70% of the variability in HD onset age, and for the common repeat sizes of 40–50 CAG repeats, only up to about 50%. Initial work to define the heritability of the residual variance in onset age was performed by the HD-MAPS consortium (Djousse et al., 2003) and the Venezuelan HD consortium (Wexler et al., 2004). Gusella and Macdonald (2009) reviewed the state of the work up until that time, emphasizing the challenges of the candidate gene approach, as well as the limitations of genomewide association studies. Table 1.3 summarizes some of the larger and more recent published work on genetic modifiers.

Table 1.3

Summary of larger and more recent published work on genetic modifiers

SNP, single-nucleotide polymorphism.

Genomewide association studies, next-generation sequencing, and other array and gene chip studies in HD have been summarized recently (Valor, 2015). Loci that accelerate the onset of disease on chromosomes 2, 5, and 6 were reported from the Venezuelan samples (Gayán et al., 2008), and on chromosome 8 and chromosome 15 from a multicenter consortium of subjects primarily of Caucasian European descent (Genetic Modifiers of Huntington's Disease (GeM-HD) Consortium, 2015).

Animal models of HD

The discovery of the HD gene facilitated the creation of genetic models of HD in organisms ranging from roundworms (Li and Le, 2013) and Drosophila (reviewed by Green and Giorgini, 2012) to mouse, pig, sheep, and monkey (Yang et al., 2008, 2010; Jacobsen et al., 2010; Baxa et al., 2013).

Therapeutic trials in mouse models are reviewed in Figiel et al. (2012) and Switonski et al. (2012). Mouse models include both knockin and transgenic models, with transgenic models created using full-length huntingtin or the N-terminal fragment, under a variety of genetic environments. A conditional HD mouse model has also been used. The most widely used rodent HD model is the R6/2 mouse, which carries exon 1 of human Htt with 144 CAG repeats under the control of the human Htt promoter. Other commonly used transgenic mouse models of HD include the N171-82Q mouse, the YAC128 and BACHD (with 97 CAG/CAA repeats). Htt knockin mice with a range of CAG repeat lengths from 111 to 175 are also available. It is notable that all of these mouse models bear CAG repeat numbers that are far greater than the repeat numbers commonly seen in adults with HD, and that they may more closely model juvenile-onset HD than the more common adult form of the disease. The use of transgenic animal models for the study of HD has recently been reviewed (Chang et al., 2015).

Gene-based therapies

Antisense oligonucleotide (ASO) and small interfering RNA (siRNA) studies have been ongoing since 2005, with multiple groups reporting success in animal models (some of the earliest reports included those of Harper et al., 2005; Rodriguez-Lebron et al., 2005; Wang et al., 2005; Machida et al., 2006; DiFiglia et al., 2007). Reduction in expression of the abnormal huntingtin gene has been reported, using both ASOs directed at the trinucleotide repeat, and against the haplotype on which the huntingtin gene is most commonly seen.

More recently, Stanek et al. (2013, 2014) have reported improvement in striatal transcriptional output, reduction in striatal huntingtin aggregates, and improvement of behavioral phenotypes in YAC128 mice treated with an adeno-associated virus-mediated siRNA targeting the Htt transcript. Finally, Kordasiewicz et al. (2012) reported sustained biochemical, pathologic, and neurologic benefits in a BACHD mouse model, after a transient (2-week) intraventricular infusion of a huntingtin-specific ASO. Based on this decade of laboratory and animal work, human safety trials of gene-silencing therapy began in 2015.

Genetic correction of the expanded Htt gene in induced pluripotent stem cells (iPSCs) derived from HD patient fibroblasts by homologous recombination has been reported (An et al., 2012). More recently, the same group reported the use of the CRISPR/Cas9 system in a genome-editing capacity, inserting a human Htt exon 1 containing 97 CAG, into normal human iPSCs (An et al., 2014). This approach could be used to generate a panel of cell lines carrying different CAG repeat lengths.

Summary and conclusions

The genetic nature of HD has been simultaneously a remarkable and terrible thing. After the recognition of the condition as a specific entity because of its genetic nature by Dr. George Huntington, HD was specifically targeted in the Nazi racial hygiene laws of the early 1930s as a condition for which affected persons could be involuntarily euthanized. Recognition of a large isolated HD kindred in Venezuela led to a much more favorable collaboration between researchers and the community that has lasted for over 30 years, and was integral to the discovery of the HD gene. Discovery of the gene led to a simple diagnostic test for HD, which has also been used for predictive, prenatal, and preimplantation genetic diagnosis, and also permitted the development of animal models for HD and essentially allowed the era of hypothesis-driven research to begin. To the chagrin of the HD community, however, the discovery of the HD gene did not lead to an immediate cure, or even a disease-modifying treatment. As we move towards the 25th anniversary of the discovery of the gene (in 2018) and the sesquicentennial of George Huntington's seminal paper (in 2022), it is extraordinarily exciting to see gene-based therapies for HD begin human trials, and to even consider the possibility of gene repair. If there is success to be reported by the time of those anniversaries, it will be because of the coordinated work of the worldwide HD family and research community.


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