Huntington’s disease

Huntington’s disease

Definition

Genetically inherited progressive chorea and dementia.

Incidence

1 in 20,000

Age

Peak presentation in middle age.

Sex

M = F

Geography

Worldwide

Aetiology

Huntington’s disease is an autosomal dominant condition with full penetrance.

Pathophysiology

There is an expanded trinucleotide repeat sequence (CAG) mutation on the short arm of chromosome 4. Normally, the number of repeats is less than 35, but once this increases to over 36, the gene product called huntingtin causes the disease. The more repeats there are, the earlier and the more severe the disease is, and the expansion tends to increase in subsequent generations (genetic anticipation). It is not clear how the abnormal protein causes the neuropathological effects, but it is thought that the mutant protein may cause biochemical effects, increase apoptosis and also (by interfering with the normal protein) downregulate neuronal growth factors:

·        There is atrophy of the caudate nucleus and putamen in particular (these basal ganglia nuclei are important in control of movement). There is also diffuse cerebral atrophy (which would account for dementia).

·        There are neurochemical effects, such as a depletion of acetylcholine and GABA but an increase in somatostatin and other hormones in the striatum. This results in a loss of inhibition of the dopaminergic pathway, i.e. release of dopamine which leads to chorea.

Clinical features

The disease usually manifests as progressive cognitive impairment and increasing movement disorder. Chorea consists of jerky, quasipurposeful and sometimes explosive movements, following each other but flitting from one part of the body. When seen in middle age Huntington’s disease should be suspected. The family history may be concealed or unknown.

Macroscopy/microscopy

Marked loss of small neurones in the caudate nucleus and putamen.

Investigations

Genetic analysis is becoming available for presymptomatic testing but this raises an ethical dilemma, as there is no treatment. However, it is important, as many young adults wish to know their status before embarking upon having a family.

Management

No treatment arrests the disease but dopamine-blocking drugs such as haloperidol and dopamine-depleting drugs such as tetrabenazine may help to control the chorea. Patients and their families should be offered genetic testing and counselling where appropriate.

Prognosis

There is a relentless progression of dementia and chorea with death usually occurring within 20 years from the onset of symptoms.