MT-CO2 – Cytochrome-c Oxidase Deficiency Disease

MT-CO2 (cytochrome c oxidase subunit II) is encoded by mitochondrial DNA and maternally inherited. Heteroplasmic variants in MT-CO2 have been identified in patients with isolated complex IV deficiency presenting with infantile encephalopathy, cardiomyopathy, and myopathy. A novel m.7587T>C (p.Met1Thr) transition in the initiation codon was found at 67%–91% heteroplasmy in muscle biopsies of an index case and his clinically affected son; mutation load correlated with COX‐negative fibers and a >55% decrease in enzyme activity in single‐fiber assays (PMID:10205264). Independently, a de novo m.8088delT frameshift variant was detected in a 16-year-old girl with exercise intolerance and aberrant acylcarnitine profile; high heteroplasmy in affected muscle fibers segregated with severe COX deficiency on histochemistry and impaired holoenzyme assembly (PMID:30315213).

In a cohort of 41 patients with histochemically defined COX deficiency, 17 exhibited selective loss of mtDNA-encoded subunits I and II on immunostaining, distinguishing mtDNA defects from nuclear causes (PMID:10686181). Functional studies demonstrate that MT-CO2 variants abrogate COX2 synthesis or incorporation, leading to isolated complex IV deficiency. Together, these data provide limited but clinically actionable evidence for MT-CO2 screening in maternally inherited COX deficiency syndromes. Key Take-home: Pathogenic MT-CO2 mutations should be considered in patients with maternal inheritance patterns of isolated cytochrome-c oxidase deficiency presenting with encephalomyopathy and myopathy.

References

• Brain • 2000 • Cytochrome oxidase immunohistochemistry: clues for genetic mechanisms. PMID:10686181
• American journal of human genetics • 1999 • An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy. PMID:10205264
• European Journal of Human Genetics • 2019 • Mitochondrial complex IV deficiency caused by a novel frameshift variant in MT-CO2 associated with myopathy and perturbed acylcarnitine profile. PMID:30315213

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