Huntingtons disease Huntingtons chorea

Huntington's disease is a rare form of inherited presenile dementia. Its molecular genetics and the clinical implications thereof have been extensively studied.

Epidemiology

Five per 100 000 of the population are affected, with marked regional variation. Men and women are equally at risk.

Cause

The cause is an abnormality in the IT-15 gene, located on the short arm of chromosome 4, which encodes the protein huntingtin. This results in an autosomal dominant inheritance pattern with about 90 per cent penetrance. The number of repeat sequences of the abnormal DNA triplicate (CAG) - leading to excessive glutamine in the protein - has some relationship to the age of onset and severity of the clinical disorder. However, the role of the protein in brain function is still unclear in spite of enormous research effort.

Half the children of an affected parent develop the condition, and because the age of onset is usually in midlife, many patients have already had children themselves by the time symptoms begin. 'Anticipation' is also seen; that is, age of onset decreases in succeeding generations. Occasionally, patients have no family history, and such cases may be explained by spontaneous mutation or doubtful parentage.

Neuropathology and neurophysiology

Generalized atrophy of the brain is most severe in the frontal lobes, caudate nuclei, and putamen. Low-energy metabolism in the caudate nucleus, identified by PET scan, is characteristic and could be used as a presymptomatic test. Deficiency of GABA and excess dopamine have been demonstrated at post-mortem.

Clinical features

Onset may be at any age, but is most often in midlife (mean age 49). The juvenile form, starting in adolescence, accounts for 10 per cent of cases. Choreiform movements and dementia are the most characteristic symptoms, but there may be any type of psychiatric abnormality - for example, neurotic, depressive, or schizophrenic symptoms or psychopathic personality features - and great variation in the clinical course.

Treatment

Choreiform movements can be modified with phenothiazines or tetrabenazine. Any psychiatric symptoms present should be treated with appropriate drugs.

Diagnosis

Presymptomatic testing by genetic probes is now available through departments of medical genetics. The test may be carried out on an adult individual or an unborn child. Testing raises ethical issues, since there is no means of preventing or treating the disorder in those carrying the gene, and tests should be carried out only in the context of thorough family counselling. In practice, only a minority of at-risk individuals choose to be tested.

Prognosis

The average survival time is about 15 years.

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