The many clinical faces of cytochrome c oxidase deficiency.

Cytochrome c oxidase (COX) catalyzes the last step in respiration, transferring electrons from cytochrome c to molecular oxygen and coupling electron transfer with proton translocation from the mitochondrial matrix to the intermembrane space. COX is composed of 13 subunits, three larger catalytic subunits encoded by mitochondrial DNA (mtDNA) and ten subunits encoded by nuclear DNA. Clinically heterogeneous human diseases were attributed to COX deficiency since the 1970s, mostly based on histochemical or biochemical data in muscle biopsies. Here, we revisit the COX deficiencies described before the molecular era, assess the value of COX histochemistry in conjunction with succinate dehydrogenase (SDH) stain, and review the clinical presentations of primary COX deficiencies defined at the molecular level. In general, mutations in mtDNA COX genes are associated with milder and later onset clinical syndromes, probably due to heteroplasmy. Mutations affecting nuclear-encoded COX subunits ("direct hits") are extremely rare whereas mutations affecting assembly proteins ("indirect hits") account for most COX deficiencies and the list keeps growing. Onset is generally in infancy and survival into adolescence or adult life is infrequent. The most common neurological disorder is Leigh syndrome, either alone or associated with cardiopathy, hepatopathy, or nephropathy.