Mitochondrial ATP-synthase deficiency in a child with 3-methylglutaconic aciduria

Abstract

We report the finding of mitochondrial ATP-synthase deficiency in a child with persistent 3-methylglu-taconic aciduria. The child presented in the neonatal period with severe lactic acidosis, which was controlled by Na-HCO3 and glucose infusions. During the 1st y of life, there were several episodes of lactic acidosis precipitated by infections or prolonged intervals between meals. The ex­cretion of lactate in urine was variable, but there was a persistent high excretion of 3-methylglutaconic acid. The activity of 3-methylglutaconyl-CoA hydratase in fibro­blasts was normal. The child had a hypertrophic cardio­myopathy and magnetic resonance images revealed hypo­plasia of corpus callosum. The gross motor and mental development was retarded, but there were no other neuro­logic signs. Investigation of muscle mitochondrial function at 1 y of age revealed a severe mitochondrial ATP-synthase deficiency (oligomycin-sensitive, dinitrophenol-stimulated Mg2+ ATPase activity: 27 nmol × min-1 × (mg protein)-1, control range 223-673 nmol × min-1 × (mg protein)-1. The mitochondrial respiratory rate was low and tightly coupled. The respiratory rate was normalized by the addi­tion of an uncoupler. Low Mg2+ ATPase activity was also demonstrated by histochemical methods. Morphologic ex­amination revealed ultrastructural abnormalities of mito­chondria. There was no deletion of mitochondrial DNA. The sequences of the ATP synthase subunit genes of mitochondrial DNA were in accordance with published normal sequences. © 1992 International Pediatric Research Foundation, Inc.