Huntington disease

What it is

Huntington disease is a neurodegenerative movement disorder marked by involuntary and irregular movements of the limbs, neck, head and face, that is, chorea. It is inherited in an autosomal dominant way and is caused by an increased number of CAG trinucleotide repeats in the huntingtin gene, which eventually leads to dysfunction of the subcortical motor circuits. On average it leads to death within 15 to 20 years after symptom onset. It is also described as a progressive brain disorder with a late onset presentation, with full penetrance and variable expression among affected individuals, giving uncontrolled movements and impaired cognitive abilities.

Causes and risk

The cause is an autosomal dominant trinucleotide CAG repeat expansion in the huntingtin gene, HTT, on chromosome 4, and the mnemonic ties the two together: hunt, inside huntingtin, is 4 letters. Symptoms manifest between the ages of 20 and 50 and are sometimes initially mistaken for substance abuse. Anticipation results from further expansion of the CAG repeats, so every later generation can be hit more severely. In the brain the caudate loses ACh and GABA, and the same row gives dopamine raised with GABA and ACh reduced in brain, and neuronal death via NMDA-R binding and glutamate excitotoxicity. It belongs to two lists worth holding together. The first is the autosomal dominant pattern, whose clue is vertical transmission with male equal to female, and whose other examples are Marfan, achondroplasia, NF1 and tuberous sclerosis. The second is the trinucleotide repeat disorders: Friedreich ataxia with a GAA repeat, giving ataxia and cardiomyopathy; Huntington disease with a CAG repeat, giving chorea and dementia; Fragile X syndrome with a CGG repeat, giving a big jaw, ears and testicles; and myotonic dystrophy with a CTG repeat, giving muscle wasting, cataracts, balding and testicular atrophy. The age of onset is given differently in two places: one page has symptoms manifesting between the ages of 20 and 50, another puts onset at 35-45y.