huntington’s disease

Huntington’s disease is an autosomal dominant disorder characterized by chorea and progressive cognitive deterioration, usually beginning in middle age. Diagnosis is by genetic testing. Treatment is supportive. First-degree relatives are encouraged to have genetic testing.

Huntington’s 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’s disease results from a gene mutation causing abnormal repetition of the DNA sequence CAG that codes for the amino acid glutamine. The resulting gene product, a large protein called huntingtin, has an expanded stretch of polyglutamine residues, which leads to disease via unknown mechanisms. The more CAG repetitions, the earlier the disease begins and the more severe the effects. The number of repeats can increase with successive generations and, over time, lead to a more severe phenotype within a family tree.

Symptoms and Signs

Symptoms and signs develop insidiously, starting at about age 35 to 50 but can develop before adulthood. 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 myoclonic jerks or irregular movements of the extremities, a lilting gait (like a puppet’s), facial grimacing, ataxia, and inability to sustain a motor act (motor impersistence) such as tongue protrusion.

The disorder progresses, making walking impossible, swallowing difficult, and dementia severe. Most patients eventually require institutionalization. Death usually occurs 13 to 15 yr after symptoms begin. The cause is usually pneumonia or coronary artery disease

Diagnosis
Clinical evaluation, confirmed by genetic testing
MRI to rule out other causes

Diagnosis is based on typical symptoms and signs plus a positive family history and is confirmed by genetic testing. Neuroimaging is done to exclude other disorders; in advanced Huntington’s disease, MRI and CT coronal views show boxcar ventricles (ie, squared-off edges due to atrophy of the caudate head).

Treatment

Supportive measures

Genetic counseling

Because the disease is progressive, end-of-life care should be discussed early (see The Dying Patient).

Treatment is supportive. Chorea and agitation may be partially suppressed by antipsychotics (eg, chlorpromazine

25 to 300 mg po tid, haloperidol

5 to 45 mg po bid); dose is
increased until intolerable or undesirable adverse effects (eg, lethargy, parkinsonism) occur. Alternatively, tetrabenazine may be used. The dose is started at 12.5 mg po once/day; dosage is increased (to 12.5 mg bid in the 2nd wk, 12.5 mg tid in the 3rd wk, up to a total of 100 mg/day divided into 3 doses) until intolerable adverse effects (eg, sedation, akathisias, parkinsonism, depression) occur or chorea resolves.

Experimental therapies aim to reduce glutamatergic neurotransmission via the N-methyl-d-aspartate receptor and bolster mitochondrial energy production. Treatment to supplement GABA in the brain has been ineffective.

People who have 1st-degree relatives with the disease should have genetic testing and counseling (see also Prenatal Genetic Counseling and Evaluation) because people are likely to have children before symptoms appear. If such people are interested in testing, they are referred to centers that have expertise in dealing with the complex ethical and psychologic issues involved.

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