MT-ND2 – Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder characterized by subacute, bilateral central vision loss with central scotoma (HP:0000603). A multi-pedigree analysis identified a rare ND2 variant c.5244G>A in one LHON proband and absent in 2103 controls, suggesting a possible contributory role of MT-ND2 in LHON pathogenesis, but no extended segregation data are available (PMID:1732158). No additional unrelated probands with MT-ND2 primary variants have been reported, and the absence of multiple pedigrees limits genetic evidence.

Functional studies specific to these ND2 LHON variants are lacking, and experimental assays directly linking ND2 dysfunction to retinal ganglion cell degeneration have not been performed. While broader complex I dysfunction is a recognized mechanism in LHON, the direct contribution of MT-ND2 variants remains uncharacterized. Additional case series, segregation studies, and targeted functional assays (e.g., cybrid models, optic nerve histology) are needed to clarify the pathogenicity of ND2 variants in LHON. Key take-home: current evidence for MT-ND2 in LHON is limited, and routine diagnostic testing should prioritize established primary mtDNA mutations pending further validation.

References

• Genetics • 1992 • Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy PMID:1732158
• Human mutation • 1995 • Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations. PMID:8680405

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