NDUFS2 – Autosomal recessive Leber hereditary optic neuropathy

Recent evidence defines biallelic NDUFS2 variants as a cause of autosomal recessive Leber hereditary optic neuropathy (arLHON), expanding the classical mtDNA-only paradigm. In a cohort of unresolved LHON cases, homozygous or compound heterozygous NDUFS2 mutations were identified in individuals presenting with acute severe vision loss, telangiectatic peripapillary vessels, retinal nerve fibre layer (RNFL) swelling followed by chronic RNFL thinning, and partial or full visual recovery, with a marked male bias ([PMID:37071596]). These findings break with the dogma of maternal inheritance and warrant inclusion of NDUFS2 in LHON diagnostic panels.

Inheritance is autosomal recessive with limited segregation data; no additional affected relatives were reported. Genetic spectrum includes missense changes such as c.683G>A (p.Arg228Gln) in affected probands. Functional assays from complex I deficiency studies show that NDUFS2 missense mutations impair enzymatic activity and cluster stability, and that wild-type NDUFS2 rescues respiratory chain dysfunction in patient cells, consistent with a loss-of-function mechanism ([PMID:11220739]). Key take-home: NDUFS2 biallelic testing should be considered in LHON phenotypes with negative mtDNA screens to inform accurate diagnosis and management.

References

• Brain • 2023 • Autosomal recessive Leber hereditary optic neuropathy, a new neuro-ophthalmo-genetic paradigm. [PMID:37071596]
• Annals of neurology • 2001 • Mutations in the complex I NDUFS2 gene of patients with cardiomyopathy and encephalomyopathy. [PMID:11220739]

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