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Autosomal recessive cerebellar ataxia-saccadic intrusion syndrome is characterized by progressive ataxia, saccadic eye movement intrusions, and variable spasticity. VPS13D, encoding a lipid transporter at organelle contact sites, has been implicated as a novel cause of this movement disorder.
Compound heterozygous mutations in VPS13D were identified by exome sequencing in 12 individuals from 7 unrelated families (PMID:29604224). In a large pedigree, linkage to chromosome 1p36 yielded a LOD score of 3.1, supporting autosomal recessive inheritance and segregation of VPS13D variants with disease status (PMID:29604224).
Variant spectrum included predominantly loss-of-function alleles (nonsense or splice site) on one allele paired with missense changes on the other, consistent with a hypomorphic mechanism. One representative variant is c.3919A>C (p.Met1307Leu). The 12 patients harbored at least 9 unique loss-of-function and 3 missense variants, with disease onset ranging from infancy to 39 years and slowly progressive ataxia often accompanied by spasticity (PMID:29604224).
Functional studies in Drosophila knockout models demonstrated abnormal mitochondrial morphology and impaired axonal distribution of mitochondria in neurons. Patient-derived fibroblasts exhibited fragmented mitochondrial networks and reduced ATP production, confirming a role for VPS13D in mitochondrial homeostasis (PMID:29604224). These concordant in vivo and cellular assays implicate mitochondrial dysfunction as the pathogenic mechanism.
No conflicting reports have been published to date. The combined genetic and experimental evidence supports a strong gene-disease relationship. Additional cohort studies may refine genotype–phenotype correlations and carrier frequencies.
Key Take-home: VPS13D mutations cause a recessive ataxia-saccadic intrusion syndrome via impaired mitochondrial maintenance, enabling molecular diagnosis and guiding genetic counseling.
Gene–Disease AssociationStrong12 probands across 7 families, multi-family segregation (LOD 3.1) and concordant in vivo and cellular functional studies Genetic EvidenceStrongCompound heterozygous variants (9 loss-of-function, 3 missense) in 12 affected individuals with segregation in a large kindred Functional EvidenceModerateDrosophila knockout and patient fibroblast assays show mitochondrial morphology and bioenergetic defects |