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

Nature Reviews Neurology volume 20, pages 36–49 (2024)Cite this article

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Abstract

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.

Key points

  • 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 JPH3 gene (encoding junctophilin 3) located on chromosome 16q24.2.

  • All documented patients with HDL2 have African ancestry and a shared haplotype across the JPH3 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.

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Fig. 1: Global distribution of HDL2.
Fig. 2: The JPH3 locus.
Fig. 3: Structural MRI findings in HD and HDL2.
Fig. 4: Neuronal aggregates in HD and HDL2.
Fig. 5: Electron micrographs of intranuclear aggregates in HD and HDL2 cortical neurons.
Fig. 6: Proposed mechanisms of HDL2 pathogenesis.

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Authors and Affiliations

  1. Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

    Amanda Krause, David G. Anderson, Jessica Dawson & Fiona Baine-Savanhu

  2. University of Glasgow, Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK

    David G. Anderson

  3. Department of Psychology, School of Human and Community Development, Faculty of Humanities, University of the Witwatersrand, Johannesburg, South Africa

    Aline Ferreira-Correia

  4. Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

    Jessica Dawson

  5. Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Pan P. Li & Russell L. Margolis

  6. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Russell L. Margolis

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Contributions

A.K., D.G.A., A.F.-C. and R.L.M. researched data for the article and made substantial contributions to discussions of the content, and each wrote a section. J.D. and F.B.-S. contributed to the Genetics section. J.D. generated some of the unpublished data mentioned in the article. P.P.L. contributed to the Pathogenesis section and references. All authors edited and reviewed the document before submission.

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Correspondence to Amanda Krause.

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Glossary

Acanthocytes

Red blood cells with spiculated protrusions from the cell membrane of varying size and distribution.

Anticipation

A phenomenon whereby disease onset occurs earlier and more severely with each successive generation.

Synonymous sequence variation

DNA sequence variation that does not change the amino acid sequence of the encoded protein.

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Krause, A., Anderson, D.G., Ferreira-Correia, A. et al. Huntington disease-like 2: insight into neurodegeneration from an African disease. Nat Rev Neurol 20, 36–49 (2024). https://doi.org/10.1038/s41582-023-00906-y

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