HUNTINGTON'S DISEASE

HD. Atrophy of the caudate nuclei. HD. Atrophy of the caudate nuclei and dilatation of the lateral ventricles.

GFAP immunostain, showing gliosis. Left: HD; right: normal caudate nucleus. Caudate nucleus from Huntington\'s disease (left) and from normal brain (right)

Huntington's Disease (HD) is a fatal autosomal dominant condition that begins usually in the4th to 5th decade of life and is characterized by behavioral changes, chorea, and dementia. In a small percentage of cases, symptoms begin before age 20. Gross examination of the brain reveals atrophy of the caudate nucleus and putamen and dilatation of the anterior horns of the lateral ventricles, which are obvious on MRI in advanced cases. Milder changes may be detected on neuroimaging years before the onset of symptoms. Cortical atrophy is also present in advanced cases. Microscopically, there is loss of medium size spiny, enkephalin-containing internuncial neurons in the caudate nucleus and putamen, loss of cortical neurons, and gliosis. Proliferation of reactive astrocytes causes the affected nuclei to appear more cellular than normal. There are also neuronal intranuclear inclusions containing huntingtin, the protein encoded by HTT (see below).

The molecular abnormality of HD is CAG trinucleotide expansion of the HTT(HT) gene on chromosome 4p. This adds a polyglutamine segment to huntingtin. This protein is widely expressed throughout the brain. It is thought that the CAG-expanded huntingtin has a toxic function. However, huntingtin is a key cellular protein involved in cellular transport and is important for cell viability. Therefore, loss of huntingtin function may also contribute to the pathogenesis of HD. The CAG triplet expansion is probably due to malfunction of cellular processes that repair strand breaks and remove mispaired bases from DNA. The expanded huntingtin, conjugated with ubiquitin, forms aggregates (inclusions) in the nuclei of affected neurons. These inclusions can be detected by immunohistochemistry using antibodies to huntingtin. These findings suggest that there is an error in the proteolytic degradation of the expanded huntingtin. Normally, this degradation takes place in cellular chambers called proteasomes and involves conjugation of huntingtin with ubiquitin. Impairment of this process apparently causes huntingtin-ubiquitin complexes to be translocated into the nuclei. The expanded CAG repeat is unstable and may increase in size in successive generations. This causes the disease to appear at a younger age and more severe form, a phenomenon known as anticipation. Anticipation occurs more commonly if the mutated allele is inherited from the father.

CAG repeats on other genes are also seen in spinobulbar muscular atrophy (Kennedy's disease), Machado-Joseph disease, an autosomal dominant ataxia seen mainly in Portugese of Azorean descent, and cerebellar degenerations. Paternally inherited HD shows the phenomenon of anticipation, i.e. the number of repeats increases in the offspring, resulting in earlier onset and more severe disease. Biochemical analysis of the striatum in HD shows loss of neurotransmitters, including GABA, acetylcholine and glutamate, which correlates with the loss of small neurons. Decrease of GABA and unbalanced dopamine activity result in chorea.

A rare form of chorea, beginning in adolescence or early adult life, is associated with an erythrocyte abnormality (chorea with acanthocytosis). Pathologically, this entity is similar to Huntington's disease but is caused by a different gene defect. Sydenham Chorea is a transient disorder in rheumatic fever caused by antibodies that react with neuronal antigens in the basal ganglia.