A South African mixed ancestry family with Huntington disease‐like 2: Clinical and genetic features

Abstract

Huntington disease-like 2 (HDL2) is a neurodegenerative disorder caused by an expansion of a CTG repeat in the junctophilin-3 gene (JPH3). A limited number of HDL2 families have been reported, all of apparently Black African ancestry. We report on a South African family that presented with progressive dementia and a movement disorder affecting numerous family members. Genotyping of the JPH3 CTG repeat revealed pathogenic expansions in three affected individuals. Whereas HDL2 is thought to be clinically indistinguishable from Huntington disease (HD), 2 of the patients in this study presented with clinical symptoms that differed substantially from HD; one had myoclonus and the other had Parkinsonism. Moreover, brain magnetic resonance imaging scans of these patients showed imaging features atypical for HD. Mitochondrial DNA and Y-chromosome DNA analysis on a family member showed that his maternal and paternal ancestries are typical of that found among the South African mixed ancestry or colored population. A difference in the distribution of CTG repeats between Caucasian and Black individuals was detected. We conclude that the phenotype of HDL2 is broad and can differ from that of typical HD. The diagnosis therefore should be considered in a wide spectrum of neuropsychiatric and abnormal movement presentations.