ALTERED KINETICS OF CYTOCHROME-C-OXIDASE IN A PATIENT WITH SEVERE MITOCHONDRIAL ENCEPHALOMYOPATHY

Deficiency of cytochrome c oxidase activity was established in a girl born to consanguineous parents. She showed symptoms of dysmaturity, ge neralized hypotonia, myoclonic seizures and progressive respiratory fa ilure, leading to death on the seventh day of life. Structural abnorma lities of the central nervous system consisted of severe cerebellar hy poplasia and optic nerve atrophy. Biochemical analysis of a muscle bio psy specimen demonstrated deficiency of cytochrome c oxidase activity. Cultured fibroblasts from this patient also showed a selective decrea se in the activity of cytochrome c oxidase, excluding a muscle-specifi c type of deficiency. Further investigations in cultured fibroblasts r evealed that synthesis, assembly and stability of both the mitochondri al and the nuclear subunits of the enzyme were entirely normal. The st eady-state concentration of cytochrome c oxidase in the fibroblasts of the patient was also normal, suggesting that the kinetic properties o f the enzyme were altered. Analysis of the kinetic parameters of cytoc hrome c oxidase demonstrated an aberrant interaction between cytochrom e c oxidase and its substrate, cytochrome c, most likely because of a mutation in one of the nuclear subunits of the enzyme.