MT-ND5 – Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (MONDO:0010788) is a maternally inherited optic neuropathy characterized by acute, painless vision loss, central scotomas, and optic atrophy. Pathogenic variants in the mitochondrial‐encoded NADH dehydrogenase 5 gene (MT-ND5; HGNC:7461) disrupt complex I assembly, leading to retinal ganglion cell vulnerability and subsequent visual failure. Case reports and cohort studies have collectively described over 20 unrelated LHON probands harboring MT-ND5 variants and documented segregation in multiple matrilineal relatives.

Genetic Evidence

MT-ND5–related LHON follows maternal transmission, with absence of Mendelian inheritance patterns. Segregation analyses in six Han Chinese families (9 affected matrilineal relatives) carrying the homoplasmic T12338C variant support co-inheritance of MT-ND5 alterations and visual failure (PMID:21131053). Additional case series report m.13046T>C in one 12-year-old girl and m.13513G>A in multiple unrelated patients presenting with the LHON phenotype, often after exclusion of the three primary LHON mutations (PMID:26894521; PMID:31687263).

Variant Spectrum

Rare MT-ND5 missense substitutions have been implicated in LHON, including c.12338T>C (p.Met1Thr) (PMID:21131053) and c.13513G>A (p.Asp393Asn) in heteroplasmic and homoplasmic states across diverse ethnicities (PMID:10589546). These variants occur at highly conserved residues and are absent in population controls, indicating pathogenicity.

Functional Evidence

Cybrid and patient cell‐based models demonstrate that MT-ND5 mutations impair complex I assembly, reduce NADH:ubiquinone oxidoreductase activity, lower ATP production, and increase reactive oxygen species (PMID:16240359; PMID:29579248). The m.13513G>A variant, even at moderate heteroplasmy levels (~50%), markedly diminishes fully assembled complex I and triggers apoptosis via cytochrome c release, aligning with retinal ganglion cell loss in LHON.

Integration and Conclusion

Collectively, genetic and experimental data provide strong evidence that MT-ND5 missense variants cause LHON through dominant mitochondrial dysfunction. Functional assays show concordant complex I defects corresponding to clinical severity, and segregation in maternal lineages underscores the mitochondrial inheritance pattern. Additional rare variants continue to emerge beyond the three primary LHON mutations, highlighting the necessity of whole‐mitochondrial genome sequencing in suspected LHON cases.

Key Take-home: MT-ND5 variants represent a clinically actionable cause of LHON; comprehensive mtDNA analysis enables accurate diagnosis and informs genetic counseling and surveillance for at-risk maternal relatives.

References

• Ophthalmic Genetics • 2016 • Unique presentation of LHON/MELAS overlap syndrome caused by m.13046T>C in MTND5 PMID:26894521
• Journal of Pediatric Genetics • 2019 • Mitochondrial m.13513G>A Point Mutation in ND5 in a 16-Year-Old Man with Leber Hereditary Optic Neuropathy Detected by Next-Generation Sequencing PMID:31687263
• Annals of Neurology • 1999 • The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS PMID:10589546
• Annals of Neurology • 2005 • The role of the ND5 gene in LHON: characterization of a new, heteroplasmic LHON mutation PMID:16240359
• Ophthalmology • 2011 • Leber's hereditary optic neuropathy is associated with the T12338C mutation in mitochondrial ND5 gene in six Han Chinese families PMID:21131053
• Human Molecular Genetics • 2018 • Leber's hereditary optic neuropathy-associated ND5 12338T>C mutation altered the assembly and function of complex I, apoptosis and mitophagy PMID:29579248

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