Huntington disease-like 2: insight into neurodegeneration from an African disease

Huntington disease (HD)-like 2 (HDL2) is a rare genetic disease caused by an expanded trinucleotide repeat in the JPH3 gene (encoding junctophilin 3) that shows remarkable clinical similarity to HD. To date, HDL2 has been reported only in patients with definite or probable African ancestry. A single haplotype background is shared by patients with HDL2 from different populations, supporting a common African origin for the expansion mutation. Nevertheless, outside South Africa, reports of patients with HDL2 in Africa are scarce, probably owing to limited clinical services across the continent. Systematic comparisons of HDL2 and HD have revealed closely overlapping motor, cognitive and psychiatric features and similar patterns of cerebral and striatal atrophy. The pathogenesis of HDL2 remains unclear but it is proposed to occur through several mechanisms, including loss of protein function and RNA and/or protein toxicity. This Review summarizes our current knowledge of this African-specific HD phenocopy and highlights key areas of overlap between HDL2 and HD. Given the aforementioned similarities in clinical phenotype and pathology, an improved understanding of HDL2 could provide novel insights into HD and other neurodegenerative and/or trinucleotide repeat expansion disorders. Huntington disease (HD)-like 2 (HDL2) is a rare HD phenocopy that seems to be confined to people with African ancestry. This Review summarizes our current knowledge of HDL2 and highlights the need for further studies of neurodegenerative diseases on the African continent. Huntington disease (HD)-like 2 (HDL2) is a rare autosomal dominant genetic disease caused by a CTG/CAG trinucleotide repeat expansion in a variably spliced exon of the gene (encoding junctophilin 3) located on chromosome 16q24.2.All documented patients with HDL2 have African ancestry and a shared haplotype across the locus, suggesting a common ancient African origin, possibly in West Africa.Fewer than 100 cases of HDL2 have been reported worldwide, emphasizing the need for concerted efforts to systematically ascertain patients for longitudinal studies.HDL2 is the HD phenocopy that has the strongest clinical resemblance to HD across the disease course, with overlapping movement, psychiatric, cognitive and radiological features, progressing to non-verbal and akinetic dementia and premature death.Loss of function of the junctophilin 3 protein, RNA toxicity of the sense strand and expanded CAG, and polyglutamine toxicity from the antisense strand have all been implicated in HDL2 pathogenesis.Studies comparing HDL2 to HD provide unique opportunities to improve our understanding of the role of junctophilin 3 in the brain and of repeat expansion pathogenesis, allowing the development of novel biomarkers and therapeutic options.