NDUFA2 – Leigh syndrome

Autosomal recessive variants in NDUFA2 have been identified in four unrelated probands presenting with early‐onset Leigh syndrome. Reported variants include a missense change c.170A>C (p.Glu57Ala) and a splice‐site alteration c.208+5G>A, with clinical features of seizures, elevated cerebrospinal fluid lactate, and failure to thrive (PMID:32154054; PMID:24731534). No extended segregation beyond index cases has been documented.

Functional assays demonstrate that c.208+5G>A induces skipping of exon 2, resulting in reduced complex I activity and assembly, mitochondrial membrane depolarization, and partial rescue upon NDUFA2 complementation in patient fibroblasts (PMID:18513682). This supports a loss-of-function mechanism without reported conflicting data. Key take-home: NDUFA2 should be included in diagnostic gene panels for early-onset Leigh syndrome, with available functional assays to confirm pathogenicity.

References

• Orphanet journal of rare diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival. PMID:24731534
• JIMD reports • 2020 • Cavitating and tigroid-like leukoencephalopathy in a case of NDUFA2-related disorder. PMID:32154054
• American journal of human genetics • 2008 • NDUFA2 complex I mutation leads to Leigh disease. PMID:18513682

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