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.

亨廷顿病 (HD) 样 2 (HDL2) 是一种罕见的遗传性疾病，由 JPH3 基因中的三核苷酸重复序列扩展引起（编码 junctophilin 3)，与 HD 具有显着的临床相似性。迄今为止，仅在具有明确或可能非洲血统的患者中发现 HDL2。来自不同人群的 HDL2 患者共享单一单倍型背景，支持扩展突变的共同非洲起源。然而，在南非以外，非洲 HDL2 患者的报告很少，可能是由于整个非洲大陆的临床服务有限。 HDL2 和 HD 的系统比较揭示了密切重叠的运动、认知和精神特征以及相似的大脑和纹状体萎缩模式。 HDL2 的发病机制尚不清楚，但有人认为它是通过多种机制发生的，包括蛋白质功能丧失以及 RNA 和/或蛋白质毒性。这篇综述总结了我们目前对这种非洲特有的 HD 表型的了解，并强调了 HDL2 和 HD 之间重叠的关键领域。鉴于上述临床表型和病理学的相似性，加深对 HDL2 的了解可以为 HD 和其他神经退行性和/或三核苷酸重复扩增疾病提供新的见解。