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Background <p><i>VPS13A</i> disease, historically known as chorea-acanthocytosis, is a rare autosomal recessive neurodegenerative disorder characterized by variable combinations of chorea, dystonia, orolingual involvement, cognitive or psychiatric changes, acanthocytosis, and peripheral neuromuscular abnormalities. Although phenotypic heterogeneity is well recognized, neuropathy-predominant onset may delay diagnostic recognition, particularly before typical hyperkinetic or orolingual features become apparent.</p> Case presentation <p>We describe two affected siblings from a consanguineous family who carried the same homozygous <i>VPS13A</i> missense variant and were followed for more than 10 years. The younger sister developed symptoms at 27 years of age with severe choreiform movements and prominent lingual/orofacial dystonia, which was partially relieved by placing a towel in the mouth and was considered consistent with a possible sensory trick. The older brother developed symptoms at 32 years of age with mild peripheral neuropathic symptoms and later developed facial/orofacial involuntary movements that progressed to more prominent choreiform and orofacial features in the later disease stage. Cognitive decline, acanthocytosis, and mild axonal peripheral neuropathy were documented in both siblings. Brain MRI in the younger sister showed findings suggestive of mild caudate atrophy. Genetic testing identified a homozygous <i>VPS13A</i> c.2964G &gt; C [p.(Lys988Asn)] variant in both affected siblings, whereas family validation showed heterozygous carrier status in the parents. The variant was absent from the gnomAD East Asian population database and remained classified as a variant of uncertain significance by the reporting laboratories.</p> Conclusions <p>This family illustrates that a VPS13A disease-like phenotype associated with a plausible candidate VPS13A variant may follow markedly different clinical trajectories even within the same sibship, including neuropathy-predominant onset and a hyperkinetic-dystonic presentation. The findings emphasize the need to reconsider <i>VPS13A</i> disease when peripheral neuropathy is accompanied or followed by progressive choreiform movements, orolingual dystonia, cognitive decline, acanthocytosis, or caudate atrophy. Although functional validation was unavailable, the characteristic phenotype, rarity of the variant, and segregation pattern support its clinical relevance as a plausible candidate variant associated with the phenotype, rather than as definitive proof of pathogenicity.</p>

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Neuropathy-predominant and hyperkinetic-dystonic presentations in two siblings with a homozygous VPS13A variant: long-term follow-up and family-based clinical analysis

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  • 发表日期：

    2026年7月9日

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  • Yong Luo,
  • Jian Chen,
  • Tao Ling,
  • Xiaowei Ni,
  • Yandong Xue,
  • Yong Luo

摘要

Background

VPS13A disease, historically known as chorea-acanthocytosis, is a rare autosomal recessive neurodegenerative disorder characterized by variable combinations of chorea, dystonia, orolingual involvement, cognitive or psychiatric changes, acanthocytosis, and peripheral neuromuscular abnormalities. Although phenotypic heterogeneity is well recognized, neuropathy-predominant onset may delay diagnostic recognition, particularly before typical hyperkinetic or orolingual features become apparent.

Case presentation

We describe two affected siblings from a consanguineous family who carried the same homozygous VPS13A missense variant and were followed for more than 10 years. The younger sister developed symptoms at 27 years of age with severe choreiform movements and prominent lingual/orofacial dystonia, which was partially relieved by placing a towel in the mouth and was considered consistent with a possible sensory trick. The older brother developed symptoms at 32 years of age with mild peripheral neuropathic symptoms and later developed facial/orofacial involuntary movements that progressed to more prominent choreiform and orofacial features in the later disease stage. Cognitive decline, acanthocytosis, and mild axonal peripheral neuropathy were documented in both siblings. Brain MRI in the younger sister showed findings suggestive of mild caudate atrophy. Genetic testing identified a homozygous VPS13A c.2964G > C [p.(Lys988Asn)] variant in both affected siblings, whereas family validation showed heterozygous carrier status in the parents. The variant was absent from the gnomAD East Asian population database and remained classified as a variant of uncertain significance by the reporting laboratories.

Conclusions

This family illustrates that a VPS13A disease-like phenotype associated with a plausible candidate VPS13A variant may follow markedly different clinical trajectories even within the same sibship, including neuropathy-predominant onset and a hyperkinetic-dystonic presentation. The findings emphasize the need to reconsider VPS13A disease when peripheral neuropathy is accompanied or followed by progressive choreiform movements, orolingual dystonia, cognitive decline, acanthocytosis, or caudate atrophy. Although functional validation was unavailable, the characteristic phenotype, rarity of the variant, and segregation pattern support its clinical relevance as a plausible candidate variant associated with the phenotype, rather than as definitive proof of pathogenicity.