MT-CO1 – Cytochrome-c Oxidase Deficiency Disease

MT-CO1 encodes cytochrome c oxidase subunit I, a core catalytic component of complex IV of the mitochondrial respiratory chain. Cytochrome-c oxidase deficiency disease (MONDO:0009068) manifests with multi-system mitochondrial dysfunction, often presenting in adolescence or early childhood.

A single adult woman presented at 18 years with acute loss of consciousness, non-convulsive status epilepticus, progressive cortical blindness, cognitive decline, exercise intolerance, muscle weakness, hearing impairment and cataract. Muscle biopsy revealed ragged-red and COX-negative fibers with markedly reduced complex IV activity. Next-generation sequencing identified a novel heteroplasmic m.7402delC variant in MT-CO1 causing a frameshift and premature stop; single fiber PCR demonstrated high mutant load exclusively in COX-negative fibers (PMID:24956508).

Immunohistochemical studies in five patients with known mtDNA mutations consistently showed selective loss of mtDNA-encoded COX subunits I and II in COX-deficient fibers, whereas nuclear-encoded subunits were preserved. Among 36 additional patients with histochemical COX deficiency, 12 exhibited this staining pattern, implicating mtDNA defects in their pathology (PMID:10686181).

Inheritance follows a maternal mitochondrial pattern with heteroplasmic transmission. No multi-generation segregation data are available. Clinical functional assays, including single fiber PCR and subunit immunostaining, demonstrate a robust correlation between mutant MT-CO1 load and complex IV dysfunction.

References

• Mitochondrion • 2014 • Mitochondrial encephalomyopathy with cytochrome c oxidase deficiency caused by a novel mutation in the MTCO1 gene. PMID:24956508
• Brain : a journal of neurology • 2000 • Cytochrome oxidase immunohistochemistry: clues for genetic mechanisms. PMID:10686181

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