VPS13D-Related Disorders: Description of New Variant and Phenotypic Spectrum Based on Age of Onset

The VPS13 family plays a crucial role in mitochondrial stabilization. Biallelic pathogenic variants in VPS13D are classically associated with autosomal recessive ataxia 4 (OMIM #607317), but phenotypic expression is increasingly recognized in diverse presentations such as early-onset movement disorders. We report on two siblings with childhood onset chorea and ataxia. Neuroimaging disclosed bilateral striatal hyperintensities. Whole-exome sequencing identified compound heterozygous likely pathogenic, novel variants in VPS13D: c.2504G > A (p.Trp835*) and c.9107T > C (p.Val3036Ala). To date, 45 cases of VPS13D-related movement disorders have been reported in the literature. Here, we summarize the main clinical findings and compare key features observed in pediatric and adult presentations. Our results indicate that pediatric cases display a distinct phenotype, with some manifestations, such as epilepsy, occurring exclusively in childhood. This study highlights the heterogeneity of VPS13D-related clinical phenotypes. Pediatric presentations appear to follow a more disabling course, with distinct characteristics according to age of onset. Recognition of these features supports the inclusion of VPS13D variants in the differential diagnosis of early-onset chorea, particularly when accompanied by neuroimaging abnormalities and/or associated epilepsy.