ABSTRACT. We report our studies on the metabolic defects which caused a newborn infant to present with a severe lactic acidemia (25 mM) and to die on the 3rd d after birth despite intensive supportive measures. The mitochondrial fractions prepared from skeletal muscle and liver oxidised NAD+-linked substrates and succinate slowly. Spectrophotometric assays for complexes I, 11, and I11 of the respiratory chain demonstrate a specific defect of complex I11 in the skeletal muscle and liver mitochondrial fractions. The concentrations of cytochrome b were 75% lower in the skeletal muscle and heart mitochondria than in control preparations. The amount of non-heme iron sulphur protein of complex I11 was low in skeletal muscle, liver, and heart. This case differs from previous reports of complex I11 deficiency in three respects: the patient presented in the neonatal period, the defect was expressed in several tissues, and it was fatal. (Pediatr Res 25: 553-559, 1989)
424BIOCHEMICAL SOCIETY TRANSACTIONS soma1 oxidase ( H 2 0 , production). Nevertheless, mitochondrial oxidation of sebacyl-carnitine could be recorded. This activity was 10-20% of that measured in the same mitochondrial preparation with palmitoyl-CoA ( + L-carnitine) or decanoyl-carnitine. Further, there was no indication of interference by sebacyl-CoA with carnitine palmitoyltransferase.In conclusion, intravenously infused dodecanedioic acid is readily catabolized in control rats in which less than 30% of the infused dose is recovered in urine as shorter dicarboxylates. Further experiments with radiolabelled dicarboxylates are necessary to determine the fate of the remaining 70%; the possibility exists that they are completely oxidized in mitochondria. Indeed, we showed by experiments in vitro that mitochondria are able to oxidize dicarboxyl-carnitine esters, although the mechanism of formation of these esters was not elucidated. Dicarboxyl-carnitine esters do not appear to be formed by mitochondrial carnitine palmitoyltransferase. Riboflavin deficiency, which induces a profound impairment of the activities of mitochondrial, but not of peroxisomal, flavoproteins and thus induces by itself a dicarboxylic aciduria, considerably increases the proportion of dicarboxylates recovered in urine from the infused dodecanedioic acid. The administration of clofibrate, a drug which, among other effects, stimulates both mitochondrial and peroxisomal p-oxidation in rats, strongly decreases the excretion of dicarboxylates in urine.
A 20-year-old man was shown to have a deficiency of carnitine palmitoyltransferase (CPT) II in skeletal muscle. The evidence was: (i) there was no significant oxidation of [9,10 -3 H]palmitate or of[1-14C]palmitate in mitochondrial fractions from fresh skeletal muscle from the patient; (ii) all the CPT activity in a homogenate of fresh muscle from the patient was overt (CPT I) with no increase in activity after the inner membrane was disrupted; (iii) all the CPT activity in the patient's muscle was inhibited by malonyl-CoA; and (iv) an immunoreactive peptide of 67 kDa corresponding to CPT II, present in mitochondria from controls, was absent in those from the patient.Carnitine palmitoyltransferase deficiency; Carnitine palmitoyltransferase II; Mitochondria; (Skeletal muscle)
Defects of short-chain acylcoenzyme A dehydrogenase (SCAD) may cause a severe metabolic illness in children or a lipid storage myopathy in adults. The childhood form is associated with low enzyme activity, but the synthesis of a normal-size enzyme protein in cultured skin fibroblasts. We report further biochemical studies on the original patient described with myopathic SCAD deficiency. We show an absence of enzyme protein in skeletal muscle, which both confirms the original diagnosis and suggests that the two forms of SCAD deficiency have a different molecular basis.
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