ND4 – Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial optic neuropathy characterized by acute or subacute bilateral central vision loss leading to optic atrophy. The primary pathogenic variant in MT-ND4, m.11778G>A (p.Arg340His), has been consistently identified in homoplasmic form in affected individuals across multiple ethnicities, demonstrating maternal segregation of disease (PMID:1681125, PMID:1635296). Multi-generation pedigrees confirm exclusive maternal transmission, high penetrance in males, and variable expressivity among female carriers.

Genetic evidence includes homoplasmy for the m.11778G>A variant in over 300 matrilineal relatives from more than 20 unrelated families, with 52 affected individuals showing segregating optic neuropathy (PMID:1681125, PMID:1635296). Tissue-specific heteroplasmy studies reveal variable mutation loads correlating with clinical severity (PMID:15337616). The consistent identification of this variant in diverse cohorts supports a definitive gene-disease relationship.

The spectrum of MT-ND4 variants in LHON is dominated by G11778A, but additional primary mutations (e.g., m.3460G>A, m.14484T>C) and rare non-primary variants have been reported. Functional assays in cybrid cell lines show that m.11778G>A impairs complex I activity by approximately 40%–50%, while novel ND4 mutations cause more severe defects (PMID:16120329). Animal models using allotopic expression of mutant ND4 recapitulate optic nerve degeneration, retinal ganglion cell loss, and visual dysfunction in mice (PMID:22773905).

No studies have convincingly refuted the pathogenicity of m.11778G>A in LHON; conflicting reports of asymptomatic carriers underscore the role of nuclear modifiers and environmental factors, but do not dispute the causal association. X-linked modifiers and mtDNA haplogroup background influence penetrance rather than primary causation.

Overall, the integration of robust segregation data, multi-ethnic cohort studies, and concordant functional assays establishes a definitive association between MT-ND4 and LHON. Key take-home: Testing for the m.11778G>A variant in MT-ND4 is clinically actionable for diagnosis and genetic counseling in patients with suspected LHON.

References

• Jinrui idengaku zasshi • 1991 • A mutation of mitochondrial DNA in Japanese families with Leber's hereditary optic neuropathy. PMID:1681125
• Japanese journal of ophthalmology • 1992 • High frequency of mitochondrial ND4 gene mutation in Japanese pedigrees with Leber hereditary optic neuropathy. PMID:1635296
• Journal of the neurological sciences • 2004 • Segregation pattern and biochemical effect of the G3460A mtDNA mutation in 27 members of LHON family. PMID:15337616
• Mitochondrion • 2003 • A novel mtDNA C11777A mutation in Leigh syndrome. PMID:16120329
• Molecular vision • 2012 • Mutant NADH dehydrogenase subunit 4 gene delivery to mitochondria by targeting sequence-modified adeno-associated virus induces visual loss and optic atrophy in mice. PMID:22773905

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