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Complex IV deficiency, also known as cytochrome c oxidase (COX) deficiency, is a very rare inherited metabolic disorder characterized by the absence of this enzyme. Several medical conditions have been associated with the cytochrome c oxidase deficiency (see Table C-2). Clinical features vary according to the type of skeletal muscles affected by the COX deficiency. Two major forms exist and are determined by the organ involvement: encephalopathic or myopathic. Affected infants with the benign infantile mitochondrial myopathy present similar clinical features than infants affected with the more severe infantile form of the disease, without either cardiac (hypertrophic cardiomyopathy) or kidney dysfunction. In Leigh's Disease (Subacute Necrotizing Encephalomyelopathy), a progressive degeneration of the brain is associated with significant dysfunction of the heart, kidneys, skeletal muscles, and the liver. The COX Deficiency French-Canadian Type affects skeletal muscles, connective tissue, and the liver. As observed in Leigh's Disease, the brain can be involved in this form of COX deficiency. Renal Fanconi Syndrome can be the first manisfestation of Complex IV deficiency (intermittent lactic acidosis). Complex IV is the terminal enzyme of the respiratory chain and consists of 13 polypeptide subunits. Three of these proteins are encoded by the mitochondrial DNA and the responsible catalytic subunits that carry out the electron transport function.

Cytochrome C Oxidase Deficiency; COX Deficiency.

Complex IV or cytochrome c oxidase (COX) deficiency is the most common disorder involving complexes of the respiratory chain in the pediatric age. Cytochrome c oxidase deficiency is clinically heterogeneous, ranging from isolated myopathy to severe multisystem disease, with onset from infancy to adulthood. In the French-Canadian population of the Saguenay-Lac St. Jean region of the province of Quebec, the estimated prevalence at birth for cytochrome c oxidase deficiency is believed to be 1 in 2,473, giving a carrier frequency of 1 in 28.

Many cases of COX deficiency are inherited as an autosomal recessive genetic trait. However, it is possible that other cases may be inherited due to abnormal changes in genetic material (mutations in genes needed for the assembly of their subunits) found within mitochondria (mtDNA).

Kuwertz-Broking E, Koch HG, Marquardt T, et al: Renal Fanconi syndrome: First sign of partial respiratory chain complex IV deficiency. Pediatr Nephrol 14:495, 2000.  [PubMed: 10872193]
Thyagarajan D, Byrne E; Mitochondrial disorders of the nervous system: Clinical, biochemical, and molecular genetic features. Int Rev Neurobiol 53:93, 2002.  [PubMed: 12512338]

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