tiglylglycine and Acidosis

Topics: Acetoacetates; Acetyl-CoA C-Acyltransferase; Acidosis; Amino Acid Metabolism, Inborn Errors; Glycine; Humans; Hydroxybutyrates; Infant; Ketone Bodies; Male; Vomiting

Mitochondrial beta-ketothiolase and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiencies are inherited neurometabolic disorders affecting isoleucine catabolism. Biochemically, beta-ketothiolase deficiency is characterized by intermittent ketoacidosis and urinary excretion of 2-methyl-acetoacetate (MAA), 2-methyl-3-hydroxybutyrate (MHB) and tiglylglycine (TG), whereas in MHBD deficiency only MHB and tiglylglycine accumulate. Lactic acid accumulation and excretion are also observed in these patients, being more pronounced in MHBD-deficient individuals, particularly during acute episodes of decompensation. Patients affected by MHBD deficiency usually manifest severe mental retardation and convulsions, whereas beta-ketothiolase-deficient patients present encephalopathic crises characterized by metabolic acidosis, vomiting and coma. Considering that the pathophysiological mechanisms responsible for the neurological alterations of these disorders are unknown and that lactic acidosis suggests an impairment of energy production, the objective of the present work was to investigate the in vitro effect of MAA and MHB, at concentrations varying from 0.01 to 1.0 mmol/L, on several parameters of energy metabolism in cerebral cortex from young rats. We observed that MAA markedly inhibited CO2 production from glucose, acetate and citrate at concentrations as low as 0.01 mmol/L. In addition, the activities of the respiratory chain complex II and succinate dehydrogenase were mildly inhibited by MAA. MHB, at 0.01 mmol/L and higher concentrations, strongly inhibited CO2 production from all tested substrates, as well as the respiratory chain complex IV activity. The other activities of the respiratory chain were not affected by these metabolites. The data indicate a marked blockage in the Krebs cycle and a mild inhibition of the respiratory chain caused by MAA and MHB. Furthermore, MHB inhibited total and mitochondrial creatine kinase activities, which was prevented by the use of the nitric-oxide synthase inhibitor L-NAME and glutathione (GSH). These data indicate that the effect of MHB on creatine kinase was probably mediated by oxidation or other modification of essential thiol groups of the enzyme by nitric oxide and other by-products derived from this organic acid. In contrast, MAA did not affect creatine kinase activity. Taken together, these observations indicate that aerobic energy metabolism is inhibited by MAA and to a greater extent by MHB, a fact that m

Topics: 3-Hydroxyacyl CoA Dehydrogenases; Acetates; Acetoacetates; Acetyl-CoA C-Acyltransferase; Acidosis; Alcohol Oxidoreductases; Animals; Brain; Carbon Dioxide; Cerebral Cortex; Citrates; Creatine Kinase; Dose-Response Relationship, Drug; Electron Transport; Energy Metabolism; Glucose; Glutathione; Glycine; Hydroxybutyrates; In Vitro Techniques; Intellectual Disability; Lactic Acid; NG-Nitroarginine Methyl Ester; Oxygen; Rats; Rats, Wistar; Time Factors

Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency is an inherited metabolic disorder of isoleucine and ketone body catabolism. We report the cases of two siblings who showed clinically mild forms of this disorder. They did not excrete tiglylglycine in urine. Their EB-transformed lymphocytes contained residual T2 activity, which was confirmed by immunotitration analysis. In immunoblot analysis, the bands corresponding to T2 in the samples of the cell lines from two patients were the most intensely detected among those from 19 T2-deficient cell lines tested.

Topics: Acetyl-CoA C-Acyltransferase; Acidosis; Amino Acid Metabolism, Inborn Errors; Cell Line, Transformed; Child; Coenzyme A-Transferases; Consanguinity; Glycine; Humans; Infant, Newborn; Isoleucine; Japan; Ketone Bodies; Lymphocytes; Male; Nuclear Family

We report two children who presented with hypoglycemia and metabolic acidosis in whom acetoacetyl-CoA thiolase (EC 2.3.1.9) measured in fibroblast homogenates was deficient. Deficiency of this enzyme is normally associated with urinary excretion of 2-methylacetoacetate and in one child the urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine was raised. By contrast, in the other child, the urinary excretion of these metabolites was very low even during ketoacidosis and following an isoleucine load. We suggest that this could be due to deficiency of the extrahepatic isoenzyme, a defect that may be responsible for some of the cases of "ketotic hypoglycemia."

Topics: Acetoacetates; Acetyl-CoA C-Acetyltransferase; Acetyltransferases; Acidosis; Female; Glycine; Humans; Hydroxybutyrates; Hypoglycemia; Infant; Ketosis

Topics: Acetyl-CoA C-Acyltransferase; Acidosis; Acyltransferases; Dietary Proteins; Female; Glycine; Humans; Hydroxybutyrates; Infant

Topics: Acetyl-CoA C-Acyltransferase; Acidosis; Acyltransferases; Adult; Child; Fibroblasts; Glycine; Humans; Hydroxybutyrates; Male; Metabolism, Inborn Errors

A late-onset case of propionic acidaemia with favourable response to restriction of dietary protein is described. During a keto-acidotic crisis, this patient demonstrated unexpectedly low concentrations of propionic acid and glycine in blood and urine but increased urinary output of some secondary metabolites.

Topics: Acidosis; Amino Acid Metabolism, Inborn Errors; Carbon-Carbon Ligases; Female; Glycine; Humans; Hydroxybutyrates; Infant; Ketosis; Ligases; Propionates