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(Huntington's Disease; Huntington Chorea; Chronic Progressive Chorea; Hereditary Chorea)
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.
Huntington disease affects both sexes equally.
The caudate nucleus atrophies, the inhibitory medium spiny neurons in the corpus striatum degenerate, and levels of the neurotransmitters γ-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 repeats can increase with successive generations and, over time, lead to increasingly severe phenotypes within a family (called anticipation).
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.
Abnormal movements appear; they include chorea, myoclonic jerks, and pseudo-tics (one cause of tourettism). Tourettism refers to Tourette-like symptoms that result from a neurologic disorder or use of a drug.
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.
The disorder progresses, making walking impossible and swallowing difficult; it results in severe dementia. Most patients eventually require institutionalization. Death usually occurs 13 to 15 yr after symptoms begin.
Diagnosis of Huntington disease is based on typical symptoms and signs plus a positive family history and 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
Because Huntington disease is progressive, end-of-life care should be discussed early (see The Dying Patient).
Treatment of Huntington disease is supportive.
Antipsychoticsmay partially suppress chorea and agitation. Antipsychotics include
In patients taking clozapine, 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, tetrabenazine may be used. The dose is started at 12.5 mg po once/day and increased to 12.5 mg bid in the 2nd wk, 12.5 mg tid in the 3rd wk, and 12.5 mg po qid in the 4th wk. Doses of > 12.5 mg po qid (total dose of 50 mg po/day) are given in tid doses; the total dose is increased 12.5 mg/day weekly. The maximum dose is 33.3 mg po tid (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.
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 (see also Prenatal Genetic Counseling and Evaluation). 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.
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 counselling and genetic testing to 1st-degree relatives, particularly potential parents.
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