VPS13D – Leigh syndrome

Leigh syndrome (LS) is a subacute necrotizing encephalopathy characterized by progressive psychomotor regression and bilateral basal ganglia lesions. VPS13D has been identified in two independent LS cohorts, with biallelic variants detected in three unrelated probands (PMID:36675121; PMID:32020600). A representative truncating allele, c.12499del (p.Ser4167fs), predicts loss of function consistent with autosomal recessive inheritance. No additional segregation data or recurrent founder variants have been reported to date.

Functional work in yeast and Drosophila demonstrates that Vps13D adaptor‐binding domain mutations disrupt mitochondrial–ER contact sites and impair mitophagy, phenocopying mitochondrial dysfunction typical of LS (PMID:31943017; PMID:34019822). These mechanistic data support a pathogenic role for VPS13D loss of function in mitochondrial homeostasis. Further case series with segregation and detailed phenotyping are required to solidify its diagnostic utility. Key Take-home: VPS13D is a candidate autosomal recessive LS gene, but current evidence is limited for definitive clinical inclusion.

References

• Unknown • Unknown • Title unavailable PMID:36675121
• Clinical genetics • 2020 • Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes. PMID:32020600
• Human molecular genetics • 2020 • A VPS13D spastic ataxia mutation disrupts the conserved adaptor-binding site in yeast Vps13. PMID:31943017
• Current biology : CB • 2021 • Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development and disease. PMID:34019822

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