Aetiology
Huntington's disease is caused by an expanded CAG repeat at the N-terminus of the gene that codes for the huntingtin protein.[1] Individuals with ≥40 CAG repeats are certain to develop Huntingon’s disease, though reduced penetrance is observed in those with 36 to 39 repeats.[11] Children with Huntington's disease are more likely to inherit the disorder from an affected father because the pathogenetic trinucleotide repeat is less stable in spermatogenesis than oogenesis, making it more susceptible to expansion.
Pathophysiology
The expanded CAG repeat generates an elongated polyglutamine tail on the huntingtin protein, which leads to cleavage and the generation of toxic fragments of this abnormal protein.[12] The polyglutamine composition of the toxic fragments predisposes them to cross-link, forming aggregates that resist degradation and interfere with a variety of normal cellular functions, particularly mitochondrial energy metabolism.[13][14] However, these aggregates also interfere with the regulation of transcription, axonal and vesicular transport, apoptosis, proteasome function, and cell-cell interactions.[1] Haploinsufficiency, the reduction in levels of wild-type huntingtin, does not cause disease.[1] However, it may contribute to the adverse effects of aggregates. Therapeutic interventions designed to improve mitochondrial function, block huntingtin cleavage at sites that generate toxic fragments, prevent expression of mutant huntingtin, improve cell-cell interactions, enhance autophagic consumption of mutant proteins, and retard apoptosis are under active investigation.[15][16][17]
Huntington's disease primarily affects the striatum, and most clinical features are directly attributable to damage in this area, including cognitive impairment, behavioural changes, and loss of coordination.[18][19] However, pathological changes occur in multiple cortical and sub-cortical structures as well.[20]
Chorea, the most striking feature of Huntington's disease, results from striatal dysfunction.[21]
Classification
Variants of Huntington's disease
Rigid form: children or young adults present with rigidity and may not have chorea. Also called early-onset or rigid Huntington's disease (Westphal variant).[2]
Choreic form: patients have chorea as a significant initial presenting feature. This is the most common phenotype.
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