Biochemical study in 28 children with lactic acidosis, in relation to Leigh's encephalomyelopathy

Abstract

An enzymatic study of cultured skin fibroblasts was made in 28 patients with lactic acidosis. In three of these patients a diagnosis of Leigh's encephalomyelopathy was established from autopsy findings. Pyruvate decarboxylase (PDC) deficiency was found in four patients. In two of them, in whom Leigh's encephalomyelopathy was proved by autopsy, PDC activity was lower than 10% of the normal. The other two living patients, who showed 22%-25% of the normal activity, had clinical symptoms and courses different from Leigh's disease. These findings suggest that the patients with severe PDC deficiency develop Leigh's disease but those with mild deficiency may not. A deficiency of cytochrome c oxidase was found in two siblings. One of them, who was diagnosed as having Leigh's encephalomyelopathy by postmortem examination, showed a reduction of cytochrome c oxidase in the liver and brain. In the other sibling, who is living, the reduction of cytochrome c oxidase was demonstrated in the cultured skin fibroblasts and biopsied muscle. In an electron-microscopic study of biopsied muscle, two patients with mitochondrial myopathy were found. Their fundamental enzymatic defects were unclear. In two patients, in whom Leigh's disease was suspected following a brain CT, the production of 14CO2 from [3-14C] pyruvate was found to be low; suggesting a reduced activity of the TCA cycle. In another 18 patients, the fundamental defect was not clear.

Oxidative Phosphorylation Diseases

“…The myopathy usually had nonspecific findings, such as fiber size variation with increased fat. Only two cases had ragged-red fibers and these lacked paracrystalline inclusions (Arts et al, 1987;Miyabayashi et al, 1983Miyabayashi et al, , 1984Miyabayashi et al, , 1985. Liver and heart show the greatest variability in disease expression.…”

“…Liver and heart show the greatest variability in disease expression. Liver may show clinical and biochemical dysfunction (Arts et al, 1987;Miyabayashi et al, 1983Miyabayashi et al, , 1984Miyabayashi et al, , 1985Hoppel et al, 1987;DiMauro et al, 1987) or be unaffected Willens et al, 1977). Hypertrophic cardiomyopathy was seen in two patients Hoppel et al, 1987), but not in others.…”

“…Patients with Leigh's encephalopathy have been reported to have defects in three enzyme complexes associated with mitochondrial respiratory metabolism. Dysfunction in cytochrome c oxidase (Complex IV) is the most commonly reported biochemical abnormality Hoganson et al, 1984;Miyabayashi et a/., 1983Miyabayashi et a/., , 1984Miyabayashi et a/., , 1985Miyabayashi et a/., , 1987Willems eta/., 1977;DiMauro et al, 1987;Berkovic et al, 1987c;Arts et al, 1987;Miranda et al, 1989), followed by NADH dehydrogenase (Complex I) Hoppel et al, 1987;Van Erven et a/., 1987), and then by pyruvate dehydrogenase (Stansbie et al, 1986). Clinically, all three forms of the disease are indistinguishable.…”

Feeding Problems and Lactic Acidosis in a 10-Week-Old Boy

“…One case of Menkes kinkyhair syndrome was shown to be deficient in cytochrome c oxidase [15], explained by the fact that cytochrome c oxidase is a copper-dependent enzyme and these pa tients have a defect in copper absorption. Some cases of Leigh syndrome lack this enzyme [16], although cases of Leigh syndrome have also been shown to lack pyruvate carboxylase [17] and pyruvate dehydrogenase [16]. Alper syndrome is the third disease which can have this deficiency.…”

Congenital Lactic Acidosis

“…the PDH com plex, pyruvate carboxylase (EC 6.4.1.1) and phosphoenolpyruvate carboxykinase (EC 4.1.1.49), and the activities of the compo nents of the respiratory chain including cy tochrome c oxidase (EC 1.9.3.1) in cultured skin fibroblasts from the patients. However, in many patients, no underlying deficiency can be found [3,4]. Three possible reasons may be considered for why no defect is de tectable: (1) the enzyme deficiency might not be clearly expressed in fibroblasts; (2) the deficiency might be expressed in fibroblasts, but the tests might not be sensitive enough for its detection, and (3) the lactic acidosis might be a secondary phenomenon resulting from a primary block elsewhere in metabolism [3].…”