COX8A – Cytochrome-c Oxidase Deficiency Disease

In the first case report, isolated complex IV deficiency with prenatal biventricular hypertrophy, hypertrophic cardiomyopathy and severe pulmonary hypertension led to fetal demise at day 6, defining a lethal variant of cytochrome-c oxidase deficiency disease associated with COX8A (PMID:15505378). More recently, a patient presenting with leukodystrophy and severe epilepsy was found to harbor a homozygous splice‐site mutation c.115-1G>C in COX8A, resulting in aberrant splicing, a frameshift in exon 2 and marked transcript depletion (PMID:26685157).

Functional assays demonstrate that loss of COX8A destabilizes the entire cytochrome c oxidase complex, causing isolated complex IV deficiency in muscle and fibroblasts; lentiviral expression of wild-type COX8A fully rescues complex stability and enzymatic activity, confirming haploinsufficiency as the pathogenic mechanism (PMID:26685157). Key take-home: biallelic COX8A variants cause autosomal recessive cytochrome-c oxidase deficiency with prenatal cardiopulmonary manifestations, and targeted sequencing of COX8A is warranted in similar presentations.

References

• Journal of inherited metabolic disease • 2004 • Congenital cardiomyopathy and pulmonary hypertension: another fatal variant of cytochrome‐c oxidase deficiency. PMID:15505378
• Brain : a journal of neurology • 2016 • Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy. PMID:26685157

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