Thompson & Thompson Genetics in Medicine, 8th Edition

Case 24. Huntington Disease (HD Mutation, MIM 143100)

Autosomal Dominant


• Triplet repeat expansion

• Novel property mutation

• Sex-specific anticipation

• Reduced penetrance and variable expressivity

• Presymptomatic counseling

Major Phenotypic Features

• Age at onset: Late childhood to late adulthood

• Movement abnormalities

• Cognitive abnormalities

• Psychiatric abnormalities

History and Physical Findings

M.P., a 45-year-old man, presented initially with declining memory and concentration. As his intellectual function deteriorated during the ensuing year, he developed involuntary movements of his fingers and toes as well as facial grimacing and pouting. He was aware of his condition and became depressed. He had been previously healthy and did not have a history of any similarly affected relatives; his parents had died in their 40s in an automobile accident. M.P. had one healthy daughter. After an extensive evaluation, the neurologist diagnosed M.P.'s condition as Huntington disease. The diagnosis of Huntington disease was confirmed by a DNA analysis showing 43 CAG repeats in one of his HD alleles (normal, <26). Subsequent presymptomatic testing of M.P.'s daughter showed that she had also inherited the mutant HD allele (Fig. C-24). Both received extensive counseling.


FIGURE C-24 Segregation of an HD gene mutation in a family with Huntington disease and a Southern blot analysis of polymerase chain reaction products derived from amplification of the CAG repeats in exon 1 of the HD gene. Each allele generates a full-length fragment as well as two or more shorter fragments because of difficulties with the polymerase chain reaction (PCR) across a triplet repeat. Notice that the affected father and daughter both have an allele with a full mutation (43 CAG repeats) and a normal allele (19 and 16 repeats, respectively). The daughter's unaffected mother and her unaffected paternal uncle have HD alleles with a normal number of CAG repeats. See Sources & Acknowledgments.


Disease Etiology and Incidence

Huntington disease (HD, MIM 143100) is a panethnic, autosomal dominant, progressive neurodegenerative disorder that is caused by mutations in the HD gene (see Chapter 12). The prevalence of HD ranges from 3 to 7 per 100,000 among western Europeans to 0.1 to 0.38 per 100,000 among Japanese. This variation in prevalence reflects the variation in distribution of HD alleles and haplotypes that predispose to mutation.


The HD gene product, huntingtin, is ubiquitously expressed. The function of huntingtin remains unknown.

Disease-causing mutations in HD usually result from an expansion of a polyglutamine-encoding CAG repeat sequence in exon 1; normal HD alleles have 10 to 26 CAG repeats, whereas mutant alleles have more than 36 repeats (see Chapter 12). Approximately 3% of patients develop HD as the result of a new CAG repeat expansion; 97% inherit a mutant HD allele from an affected parent. New mutant HD genes arise from expansion of a premutation (27 to 35 CAG repeats) to a full mutation. When a patient inherits a full mutation from a parent carrying a permutation, that parent is nearly always the father.

Expansion of the huntingtin polyglutamine tract appears to confer a deleterious novel property and to be both necessary and sufficient for the induction of an HD-like phenotype. In addition to the diffuse, severe atrophy of the neostriatum that is the hallmark of HD, expression of mutant huntingtin causes neuronal dysfunction, generalized brain atrophy, changes in neurotransmitter levels, and accumulation of neuronal nuclear and cytoplasmic aggregates. Ultimately, expression of mutant huntingtin leads to neuronal death; however, it is likely that clinical symptoms and neuronal dysfunction precede the development of intracellular aggregates and neuronal death. The mechanism by which expression of this expanded polyglutamine tract causes HD remains unclear.

Phenotype and Natural History

The patient's age at disease onset is inversely proportional to the number of HD CAG repeats. Patients with adult-onset disease usually have 40 to 55 repeats; those with juvenile-onset disease usually have more than 60 repeats (see Fig. 7-20). Patients with 36 to 39 HD CAG repeats exhibit reduced penetrance; that is, they may or may not develop HD in their lifetime. Apart from the relationship to the age at onset, the number of repeats does not correlate with other features of HD.

Instability and expansion of the CAG repeats within mutant HD alleles often results in anticipation, that is, progressively earlier ages at onset with succeeding generations. Once the number of CAG repeats is 36 or more, the CAG repeat length generally expands during paternal transmission; expansions during maternal transmission are less frequent and shorter than are expansions during paternal transmission. Because the age of onset is inversely correlated with CAG repeat length, individuals with a juvenile onset have a massive expansion of the CAG repeat; it turns out that approximately 80% of such juvenile patients inherit the massively expanded HD allele from their father who is already carrying a full mutation.

Approximately one third of patients present with psychiatric abnormalities; two thirds present with a combination of cognitive and motor disturbances. The mean age at presentation is 35 to 44 years; approximately one quarter of patients develop HD after the age of 50 years, however, and one tenth before the age of 20 years. The median survival after diagnosis is 15 to 18 years, and the mean age at death is approximately 55 years.

HD is characterized by progressive motor, cognitive, and psychiatric abnormalities. The motor disturbances involve both voluntary and involuntary movement. Initially these movements interfere little with daily activities but generally become incapacitating as HD progresses. Chorea, which is present in more than 90% of patients, is the most common involuntary movement; it is characterized by nonrepetitive, nonperiodic jerks that cannot be suppressed voluntarily. Cognitive abnormalities begin early in the disease course and affect all aspects of cognition; language is usually affected later than are other cognitive functions. Behavioral disturbances, which usually develop later in the disease course, include social disinhibition, aggression, outbursts, apathy, sexual deviation, and increased appetite. The psychiatric manifestations, which can develop at any time in the disease course, include personality changes, affective psychosis, and schizophrenia.

In the end stages of HD, patients usually develop such severe motor impairments that they are fully dependent on others. They also experience weight loss, sleep disturbances, incontinence, and mutism. Their behavioral disturbances decrease as the disease advances.


Currently no curative treatments are available for HD. Therapy focuses on supportive care as well as pharmacological management of the behavioral and neurological problems.

Inheritance Risk

Each child of a parent with HD has a 50% risk for inheriting a mutant HD allele. Except for those alleles with incomplete penetrance (36 to 39 CAG repeats), all children inheriting a mutant HD allele will develop HD if they have a normal life span.

Children of fathers carrying a premutation have an empirical risk of approximately 3% for inheriting an HD allele in which the premutation has expanded to a full mutation. Not all males carrying a premutation, however, are equally likely to transmit a full mutation.

Presymptomatic testing and prenatal testing are available through analysis of the number of CAG repeats within exon 1 of the HD gene. Presymptomatic testing and prenatal testing are forms of predictive testing (see Chapter 16) and are best interpreted after confirmation of a CAG expansion in an affected family member. Recommendations have been made regarding presymptomatic genetic testing for untreatable conditions such as Huntington disease, including the need for neurological and psychological evaluation before testing and the need for psychological support from family members or friends. Additionally, the patient is required to be 18 years of age or older and competent to make an informed decision regarding his or her desire to have presymptomatic test results. The implications of such results are obviously life altering.

Questions for Small Group Discussion

1. Patients with heterozygous and homozygous mutations of HD have similar clinical expression of HD, whereas individuals with deletion of one HD allele on chromosome 4p have a normal phenotype. How can this be explained?

2. Some studies suggest that a father with a premutation and an affected child has a higher risk of transmitting a full mutation than a father with a premutation and no affected children. Discuss possible mechanisms for this predisposition to transmit HD mutations.

3. Expansion of HD premutations to full mutations occurs through the male germline, whereas expansion of FMR1 (fragile X syndrome) premutations to full mutations occurs through the female germline. Discuss possible mechanisms for sex biases in disease transmission.

4. By international consensus, asymptomatic at-risk children are not tested for HD mutations because testing removes the child's choice to know or not know, testing results open the child to familial and social stigmatization, and testing results could affect educational and career decisions. When would it be appropriate to test asymptomatic at-risk children? What advances in medicine are necessary to make testing of all asymptomatic at-risk children acceptable? (Consider the reasoning underlying newborn screening.)


Bordelon YM. Clinical neurogenetics: Huntington disease. Neurol Clin. 2013;31:1085–1094.

Warby SC, Graham RK, Hayden MR. Huntington disease. [Available from]