Fatal infantile mitochondrial cardiomyopathy and myopathy with heterogeneous tissue expression of combined respiratory chain deficiencies

Abstract

A 5-month-old boy died of progressive heart failure that started at the age of 3 months. Autopsy revealed a mitochondrial cardiomyopathy and a mitochondrial myopathy of the limb muscle and diaphragm. Cytochemically random defects of cytochrome c oxidase were visualized by light and electron microscopy in the diaphragm and especially the heart muscle, the limb muscle showing a diffuse attenuation whereas the liver and kidneys reacted normally. The activities of NADH-dehydrogenase (complex I) and cytochrome c oxidase (complex IV) were severely diminished (20% residual activity of controls) in the skeletal and heart muscle. In the heart, succinate cytochrome c reductase (complex II/III) was additionally decreased to the same degree. Loss of cytochrome c oxidase activity was based on a reduction of both mitochondrial and nuclear derived subunits in the heart and diaphragm as revealed by immunohistochemical analysis, whereas the limb muscle showed a normal immunoreactive protein content. The results illustrate heterogeneous tissue expression of respiratory chain enzyme defects and demonstrate that a cardiomyopathy may be the leading presentation of a mitochondrial disorder in early infancy.

Multiple respiratory chain abnormalities associated with hypertrophic cardiomyopathy and 3-methylglutaconic aciduria

“…Isolated cardiomyocytes deficient in cytochrome c oxidase were also observed in our patient, suggesting the possibility of a mitochondrially encoded defect [26]. In limb muscle, however, cytochrome c oxidase activity was diffusely attenuated [26]. This is consistent with the much more severe reduction in respiratory chain activities in skeletal muscle mitochondria than in heart mitochondria reported here (Table 3).…”

“…There have also been reports of mitochondrial cardiomyopathy in Kearns-Sayre syndrome, with focal deficiency of cytochrome c oxidase in cardiac and skeletal muscle [25]; this presumably reflects the non-uniform distribution of normal and deleted mitochondrial DNA (mtDNA) in that disease [35]. Isolated cardiomyocytes deficient in cytochrome c oxidase were also observed in our patient, suggesting the possibility of a mitochondrially encoded defect [26]. In limb muscle, however, cytochrome c oxidase activity was diffusely attenuated [26].…”

“…Both in heart and skeletal muscle as well as in the liver and kidney, fatty metamorphosis was demonstrated being most pronounced in the liver. A detailed histochemical description of this patient has been reported [26].…”

Mitochondrial disease in superoxide dismutase 2 mutant mice

“…A transgenic mouse model of ATP deficiency in the heart has been shown to cause hypertrophic cardiomyopathy (53). In humans, both dilated and hypertrophic cardiomyopathies have been associated with defects of the respiratory chain, aconitase inactivation, and 3-MGC aciduria (21,22,(54)(55)(56)(57)(58). The respiratory chain defects in the Sod2Ϫ͞Ϫ mice, in conjunction with the dilated cardiomyopathy, aconitase deficiency, and organic aciduria argue that mitochondrial ROS may give rise to a number of human diseases of diverse presentation.…”

Mitochondrial Myopathy inSenna occidentalis-Seed-Fed Chicken

“…Deficiencies of cytochrome c oxidase or of NADH-dehydrogenase of the respiration chain are the most commonly observed defects, having either a benign or a fatal course (Di Mauro et al, 1987;Morgan-Hughes et al, 1988). However, cases of combined deficiencies of the respiratory chain were described (Desnuelle et al, 1989;Müller-Höcker et al, 1991). Since a large proportion of these cases of mitochondrial myopathy occurs in early infancy, it is important to investigate if S. occidentalis intoxication causes the same myopathy in young animals as that in older ones.…”