Huntington disease is an autosomal dominant disorder characterized by chorea, neuropsychiatric symptoms, and progressive cognitive deterioration, usually beginning during middle age. Diagnosis is by genetic testing. First-degree relatives should be offered genetic counseling before genetic tests are done. Treatment is supportive.
(See also Overview of Movement and Cerebellar Disorders.)
Huntington disease affects both sexes equally.
Pathophysiology of Huntington Disease
In Huntington disease, the caudate nucleus atrophies, the inhibitory medium spiny neurons in the corpus striatum degenerate, and levels of the neurotransmitters gamma-aminobutyric acid (GABA) and substance P decrease.
Huntington disease results from a mutation in the huntingtin (HTT) gene (on chromosome 4), causing abnormal repetition of the DNA sequence CAG, which codes for the amino acid glutamine. The resulting gene product, a large protein called huntingtin, has an expanded stretch of polyglutamine residues, which accumulate within neurons and lead to disease via unknown mechanisms. The more CAG repeats, the earlier the onset of disease and the more severe its expression (phenotype). The number of CAG repeats can increase with successive generations when the father transmits the mutation and, over time, can lead to increasingly severe phenotypes within a family (called anticipation).
Symptoms and Signs of Huntington Disease
Symptoms and signs of Huntington disease develop insidiously, starting at about age 35 to 40, depending on phenotype severity.
Dementia or psychiatric disturbances (eg, depression, apathy, irritability, anhedonia, antisocial behavior, full-blown bipolar or schizophreniform disorder) develop before or simultaneously with the movement disorder. These symptoms predispose patients to suicidal ideation and suicide, which are much more common among patients with Huntington disease than among the general population.
Abnormal movements appear; they include chorea, athetosis, myoclonic jerks, and pseudo-tics (one cause of tourettism). Tourettism refers to Tourette-like symptoms that result from another neurologic disorder or use of a drug; tourettism also includes. the repetitive gestural movements and/or phonatory sounds that patients with chorea make. Unlike true tics, the pseudo-tics of Huntington disease cannot be suppressed.
Typical features include a bizarre, puppet-like gait, facial grimacing, inability to intentionally move the eyes quickly without blinking or head thrusting (oculomotor apraxia), and inability to sustain a motor act (motor impersistence), such as tongue protrusion or grasping.
Huntington disease progresses, making walking impossible and swallowing difficult; it results in severe dementia. Most patients eventually require institutionalization. Death usually occurs 13 to 15 years after symptoms begin.
Diagnosis of Huntington Disease
- Clinical evaluation, confirmed by genetic testing
Diagnosis of Huntington disease is based on typical symptoms and signs plus a positive family history. It is confirmed by genetic testing that measures the number of CAG repeats (for interpretation of results, see table Genetic Testing for Huntington Disease).
Neuroimaging helps identify caudate atrophy and often some frontal-predominant cortical atrophy.
Genetic Testing for Huntington Disease
Number of CAG Repeats
Normal but unstable (increased risk that children will have Huntington disease)
Abnormal with variable penetrance; unstable (in some studies, most patients had symptoms and signs)
Abnormal with complete penetrance and anticipation (the greater the number of repeats, the earlier the onset of symptoms)
Treatment of Huntington Disease
- Supportive measures
- Genetic counseling for relatives
Because Huntington disease is progressive, end-of-life care should be discussed early.
Treatment of Huntington disease is supportive and symptomatic. However, researchers continue to look for ways to slow and stop disease progression.
Antipsychotics may partially suppress chorea and agitation. Antipsychotics include
- Chlorpromazine 25 to 300 mg orally 3 times a day
- Haloperidol 5 to 45 mg orally 2 times a day
- Risperidone 0.5 to 3 mg orally 2 times a day
- Olanzapine 5 to 10 mg orally once a day
- Clozapine 12.5 to 100 mg orally 1 or 2 times a day
In patients taking clozapine, white blood cell (WBC) counts must be done frequently because agranulocytosis is a risk. The antipsychotic dose is increased until intolerable adverse effects (eg, lethargy, parkinsonism) develop or symptoms are controlled.
Alternatively, a vesicular monoamine transporter type 2 (VMAT-2) inhibitor (tetrabenazine, deutetrabenazine) may be used. These drugs deplete dopamine and aim to lessen chorea and dyskinesias.
Tetrabenazine is started at 12.5 mg orally once a day and increased to 12.5 mg 2 times a day in the 2nd week, and 12.5 mg 3 times a day in the 3rd week. Dose can be increased by another 12.5 mg in the 4th week. Doses of > 12.5 mg are given orally 3 times a day (resulting in a total dose of 37.5 mg/day); the total dose is increased 12.5 mg/day weekly. The maximum dose is 33.3 mg orally 3 times a day (total dose of 100 mg/day). Doses are increased sequentially as needed to control symptoms or until intolerable adverse effects occur. Adverse effects can include excessive sedation, akathisia, parkinsonism, and depression. Depression is treated with antidepressants.
Deutetrabenazine is now available for treatment of chorea in Huntington disease. The recommended dose is 6 to 48 mg/day, given orally in 2 doses. The starting dose is 6 mg once a day, then increased by 6 mg/day every week (eg, to 6 mg 2 times a day) to a maximum of 24 mg 2 times a day (48 mg/day). (Doses ≥ 12 mg are given in 2 divided doses.) Adverse effects are similar to those of tetrabenazine but are better-tolerated. However, VMAT-2 inhibitors are costly.
Therapies currently under study aim to reduce glutamatergic neurotransmission via the N-methyl-d-aspartate receptor and to bolster mitochondrial energy production. Treatments that aim to increase GABAergic function in the brain have been ineffective.
People who have 1st-degree relatives with Huntington disease, particularly women of childbearing age and men considering having children, should be offered genetic counseling and genetic testing. Genetic counseling should be offered before genetic testing because the ramifications of Huntington disease are so profound.
- Huntington disease, an autosomal dominant disorder that affects either sex, usually causes dementia and chorea during middle age; most patients eventually require institutionalization.
- If symptoms and family history suggest the diagnosis, provide genetic counseling before genetic testing, and consider neuroimaging.
- Treat symptoms and discuss end-of-life care as soon as possible.
- Offer counseling and genetic testing to 1st-degree relatives, particularly potential parents.
Drugs Mentioned In This Article
|Drug Name||Select Trade|
|Chlorpromazine||No US brand name|