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At a glance

Complex IV deficiency is caused by Cytochrome-c Oxidase (COX) deficiency, which is associated with several medical conditions (see Table C-1). The 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 type. Affected infants with benign infantile mitochondrial myopathy present similar clinical features as infants affected with the more severe infantile form of the disease, but lack cardiac (hypertrophic cardiomyopathy) or kidney dysfunction. In ☞Leigh’s Disease (Subacute Necrotizing Encephalomyelopathy), the progressive degeneration of the brain is associated with significant dysfunction of heart, kidneys, liver, and skeletal muscles. The French-Canadian Type of COX Deficiency affects skeletal muscles, connective tissue, and liver. Brain involvement can be similar to Leigh’s Disease. Renal Fanconi Syndrome with intermittent lactic acidosis can be the first manifestation of Complex IV deficiency. Complex IV is the terminal enzyme of the respiratory chain and consists of 13 polypeptide subunits.


Cytochrome-c Oxidase Deficiency; COX Deficiency.


Complex IV or Cytochrome-c Oxidase (COX) deficiency is the most common complex disease in the pediatric age range. COX deficiency is a clinically heterogeneous disorder that can be caused by more than 10 different gene defects, clinically 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 in the province of Quebec, the estimated prevalence at birth for COX deficiency is estimated at 1:2,473, resulting in a carrier frequency of 1 in 28.

Genetic inheritance

Many cases of COX deficiency are inherited as an autosomal recessive genetic trait, but mitochondrial transmission has also been described.

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