Huntington's chorea

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Autosomal dominant with late presentation so far lacking a cure

Huntington's chorea (Huntington disease, Huntington's disease, HD) is characterised by:

  • progressive chorea (involuntary movements, choreoathetosis)
  • rigidity (often first manifestation in very young onset)
  • progressive (subcortical) dementia.
  • autosomal dominant transmission with complete penetrance (it can, of course, arise de novo).
  • ataxia
  • ophthalmoplegia

Other manifestations include weight loss (?due to energy expenditure on abnormal movements), Parkinsonism and behavioural change, e.g. becoming more argumentative, impulsive, erratic. Paranoia can occur in about 1:20. Depression is common, in up to 60% during some stage of their illness. Dysphagia, due to impairment of voluntary muscle control is an important development usually late in the disease.

Often the earliest manifestations are nervousness and depression. It may be manifest at any age, this can be correlated with the number of CAG repeats in an individuals genome. The initial manifestations may not be classic, with some delay until another feature develops and the extremely rare de novo presentations can even be confused with the other neurodegenerative conditions of later life, only later generations making the diagnosis clear. The diagnosis will also tend to be challenging if the true biological parents of an affected individual are not known. Incidence is 5-10/100,000 in populations of European stock.

The genetics of over 98% of presentations are well understood and are due to defects in certain molecular pathways, usually due to transcription problems at the DNA level. The classic mutation on chromosome 4 of the huntingtin gene, CAG-trinucleotide repeats, may expand in descendent generations explaining genetic anticipation. The CAG triplet codes for the amino acid glutamic acid, making Huntington's chorea part of the family of polyglutamine diseases. The huntingtin protein accumulates causing the neuropathology. These abnormal aggregates are visible microscopically as intraneuronal intranuclear inclusions.

Several other conditions have overlap phenotypes. These include Huntington's disease-like 2 with an expansion mutation of the JPH3 gene[1] and those causing neuroacanthocytosis[2].

The neuropathology involves the basal ganglia with a preferential loss of medium spiny neurons in the neostriatum. There is marked decrease in levels of the neurotransmitters GABA, substance P and enkephalins. Brain angiotensin converting enzyme levels are also decreased.

Contents

Diagnosis

In the absense of the classic inheritance history, it is likely to be delayed. Genetic testing is accurate but does require appropriate counselling which may take months and involve entire families.

Screening

See screening. Since there is no cure, the ethical debate continues.

Treatment

Is directed at symptom control

As appropriate speech therapy, psychologists, nutritional support (eg PEG) may be needed. Early support and assessment by such services is important and ethical issues such as PEG feeding are best considered when the patient themselves has competence.

Treatments in development

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