MT-CO3 – Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder characterized by subacute, painless, bilateral vision loss due to retinal ganglion cell degeneration and optic atrophy. Over 90% of patients present before age 50, with a strong male predominance and progressive visual decline within 6–12 months. LHON is genetically heterogeneous, with primary pathogenic variants affecting Complex I and, less commonly, Complex IV subunits of the mitochondrial respiratory chain.

A series of eight independent LHON probands harbored homoplasmic missense variants in the MT-CO3 gene: c.9438G>A (p.Gly78Ser) in five probands and c.9804G>A (p.Ala200Thr) in three probands, none of which were detected in controls (PMID:8240356). An additional case report described a novel homoplasmic MT-CO3 variant in a patient initially misdiagnosed with a demyelinating disorder (PMID:37808372). These nine unrelated probands demonstrate maternal segregation and absence of MT-CO3 variants in healthy individuals.

Functional studies of patient‐derived cells and biochemical assays revealed a 70–85% reduction in cytochrome c oxidase (Complex IV) activity, decreased synthesis of subunit III, and impaired assembly of the holoenzyme, confirming the deleterious effect of MT-CO3 missense mutations on mitochondrial respiration (PMID:8240356). No studies to date have refuted the pathogenic role of MT-CO3 variants in LHON, although secondary mtDNA variants and nuclear or environmental modifiers can influence penetrance and clinical severity.

Integration of genetic and experimental findings supports a definitive association between MT-CO3 and LHON. Genetic testing for MT-CO3 missense variants, alongside primary Complex I mutations, should be included in molecular diagnostic panels for suspected LHON to inform prognosis and genetic counseling.

Key Take-home: Pathogenic MT-CO3 missense variants cause definitive, maternally inherited LHON via Complex IV deficiency, underscoring the importance of comprehensive mtDNA analysis in optic neuropathy.

References

• Biochemical and biophysical research communications | 1993 | Cytochrome c oxidase mutations in Leber hereditary optic neuropathy PMID:8240356
• Bioinformation | 2023 | Leber hereditary optic neuropathy presenting as bilateral visual loss and white matter disease. PMID:37808372

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