RESUMEN
We report a new patient with acetoacetyl-CoA thiolase deficiency in whom we found two new missense mutations.
Asunto(s)
Acetil-CoA C-Acetiltransferasa/genética , Errores Innatos del Metabolismo/genética , Mitocondrias/enzimología , Mutación Missense , Acetil-CoA C-Acetiltransferasa/deficiencia , Preescolar , Genotipo , Humanos , Lactante , Masculino , Errores Innatos del Metabolismo/metabolismoRESUMEN
BACKGROUND: Dihydrolipoamide dehydrogenase (DLD) deficiency is a rare cause of primary lactic acidosis in infancy. MATERIAL AND METHODS: This article presents the results of biochemical and molecular analyses and metabolic response to treatment procedures in a 10-week old boy presenting with vomiting, progressive hypotonia, lactic acidosis (pH 7.04; BE - 20; B-lactate 6.6 mmol/l, controls <2.1; CSF-lactate 4.8 mmol/l, controls <2.0), increased levels of branched chain amino acids in blood, and increased urinary excretion of branched chain oxo-acids due to DLD deficiency. RESULTS: DLD activity was less than 5% of control values in lymphocytes, muscle mitochondria and fibroblasts. Western blot analysis in muscle tissue showed a decrease in the quantity of DLD protein to 40% in comparison to control. A high-fat, low-protein diet supplemented with MCT oils and sodium dichloroacetate resulted in normalization of lactate, amino acids and organic acids in body fluids, but there was no improvement in psychomotor development. Novel heterozygous mutations were found in the DLD gene: A1081G and G1123A. Both mutations affect the same region of the binding site for FAD. The G1123A mutation, resulting in the substitution of Glu 375 > Lys, breaks down the possible interaction of glutamic acid with neighboring lysine and causes electrostatic and steric repulsion, which is likely to destabilize structure in this part of the protein. In case of the A1081G mutation, resulting in substitution of Met 361 > Val, no important intermolecular interactions are broken and the reason for destabilization of the protein is not as clear. CONCLUSIONS: The prognosis for children with DLD deficiency is unfavorable, although long-term normalization of most metabolites in body fluids may be achieved with the proper diet and the administration of sodium dichloroacetate.