Mitochondrial myopathy with loosely coupled oxidative phosphorylation in a case of Zellweger syndrome. A cytochemical-ultrastructural study.

A newborn female, the second child of consanguineous parents, exhibited general muscle hypotonia, apathy, hepatomegaly and failure to thrive from birth and signs of craniofacial dysmorphia were present. Pipecolic and trihydroxicoprostanoic acid were excreted in the urine and serum transferrin, ferritin and iron were markedly elevated. At the age of 7 weeks the baby died of respiratory insufficiency. Besides malformations of the brain, renal cysts, liver damage with hypoplastic intrahepatic bile ducts and cholestasis, increased storage of iron and cytochemically proven deficiency of peroxisomes in liver and kidney, morphological studied provided evidence of a mitochondrial myopathy in striated muscle with the accumulation of enlarged bizarre mitochondria, showing only minor structural abnormalities. No defects of NADH-reductase, succinate-dehydrogenase or cytochrome-c-oxidase were demonstrated histochemically. Cytochemical-ultrastructural investigation of mitochondrial ATPase revealed activation of the ATP-synthesising enzyme even before the addition of an uncoupler, this indicating loosely coupled oxidative phosphorylation. In addition a high rate of subcellular autophagy with segregation of mitochondria and focal loss of fibrils was present. Muscle damage in Zellweger syndrome appears to be the consequence of complex, interacting metabolic processes. The mitochondrial myopathy thereby induced allows a better understanding of general muscle hypotonia, one of the leading symptoms of this disorder.