SLC25A4 – Leigh syndrome

A multicenter cohort of 130 Leigh syndrome patients (130 patients (PMID:24731534)) identified pathogenic mitochondrial gene variants across diverse loci including SLC25A4. Among these, a single proband harbored a homozygous c.653A>C (p.Gln218Pro) variant in SLC25A4 (PMID:29654543) consistent with autosomal recessive inheritance. No additional familial segregation data were reported.

Functional studies reveal that analogous SLC25A4 variants, such as c.97A>T (p.Lys33Gln), severely impair ADP/ATP transport in Lactococcus lactis and reduce complex I, III, and IV protein levels in patient muscle (PMID:30046662). These in vitro data support a loss-of-function mechanism concordant with the neurologic and metabolic features of Leigh syndrome. Key take-home: SLC25A4 sequencing should be considered in autosomal recessive Leigh syndrome genetic testing panels.

References

• Orphanet journal of rare diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival PMID:24731534
• JIMD reports • 2019 • Muscle Weakness, Cardiomyopathy, and L-2-Hydroxyglutaric Aciduria Associated with a Novel Recessive SLC25A4 Mutation PMID:29654543
• Neurology. Genetics • 2018 • Expanding the phenotype of de novo SLC25A4-linked mitochondrial disease to include mild myopathy PMID:30046662

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