Chorea–Acanthocytosis and the Huntington Disease Allele in an Irish Family

Genetic analysis of the VPS13A (ChAc) gene (NM_033305.2) demonstrated that the three affected siblings are compound heterozygotes, with one copy of the Arg3143fs*5 (c.9427_9428delAG in exon 72) mutation that was previously reported in a homozygous state in another (unrelated) Irish family from the same region,2 and one copy of the novel Pro322Alafs*19 (c.962dupT in exon 12) mutation. The function of this protein is not well understood, but it is thought to be involved in architecture of the cytoskeleton and cell survival.3 Cytoskeletal abnormalities may explain the unusual erythrocyte morphology seen in this condition, but the degree of acanthocytosis is variable and does not seem to correlate with clinical severity.4,5 Furthermore, while routine laboratory techniques actually demonstrate limited sensitivity in detecting acanthocytosis, the use of isotonically diluted blood and unfixed wet blood preparation improves sensitivity and specificity.6 In addition, muscle creatine kinase is another useful blood marker that is almost ubiquitously elevated in affected individuals.7 Symptoms of ChAc typically begin in the third decade (or less frequently in the fourth decade) with dysphagia, dysarthria, chorea, and unsteady or “rubber man” gait.7 Involuntary movements of the orofacial region, with feeding dystonia and self-mutilation from teeth grinding and lip biting are characteristic of the disorder. [...]post-mortem neuropathological findings in the eldest sibling were consistent with the clinical diagnosis of ChAc, demonstrating marked gliosis and extensive neuronal loss in the striatum (less gliosis would be expected in HD, and neuronal loss should only be extensive in advanced HD).8 Further support for the hypothesis that the abnormal HD allele is an incidental finding includes evidence that the incidence of the HD allele in the general population is almost certainly higher than previously suspected. A recent large study reported 18 of 7,315 individuals from Western populations had ≥36 CAG repeats (15 of these were in the reduced penetrance range of 36–39 CAG repeats), suggesting an incidence of HD gene abnormalities of approximately one in 400 in the general population.9 While penetrance rates of up to 65% have been reported with 36–39 CAG repeats in a cohort attending for diagnostic/predictive testing for HD (i.e., in those with a known family history),10 the penetrance rate with 36–39 CAG repeats among the general population is closer to 0.2% (although und