31/50. Defective glycine cleavage system in nonketotic hyperglycinemia. Occurrence of a less active glycine decarboxylase and an abnormal aminomethyl carrier protein.The activities of then glycine cleavage system in the liver and brain of patient with nonketotic hyperglycinemia was extremely low as compared with those of control human liver and brain. The activities of glycine decarboxylase (P-protein) and the aminomethyl carrier protein (H-protein), two of the four protein components of the glycine cleavage system, were considerably reduced in both the liver and brain; the extent of reduction was greater in the H-protein. The activity of the T-protein was normal. Purified H-protein from the patient did not react with lipoamide dehydrogenase, and titration of thiol groups with [2,3-14C]N-ethylmaleimide suggested that this H-protein is devoid of lipoic acid. This structural abnormality in the H-protein is considered to constitute the primary molecular lesion in this patient with non-ketotic hyperglycinemia. Immunochemical studies using an antibody specific for P-protein showed that the patient was due to reduction of the catalytic activity of the protein rather than a decrease in the actual amount of the P-protein. Partial inactivation of P-protein could result secondarily from impaired metabolism of glycine resulting from deficiency in the activity of H-protein. However, the H-protein from the patient could stimulate the P-protein catalyzed exchange of the carboxyl carbon of glycine with 14CO2, although the specific activity of the purified H-protein from the patient was only 4% of that of control human H-protein. The content of H-protein in the liver of the patient was approximately 35% of that of control human liver.- - - - - - - - - - ranking = 1keywords = carboxylase (Clic here for more details about this article) |
32/50. Late onset type of propionic acidaemia: case report and biochemical studies.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.- - - - - - - - - - ranking = 0.00069302346189778keywords = late-onset (Clic here for more details about this article) |
33/50. Propionic acidaemia presenting with pancytopaenia in infancy.A 2-month-old infant presented with vomiting, lethargy and pancytopaenia. She was found to have propionic acidaemia, and the activity of propionyl-CoA carboxylase in cultured fibroblasts was defective (McKusick 23200). Abnormal amounts of glycine, 3-hydroxypropionate, methylcitrate, tiglyglycine, propionylglycine, 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, 3-oxovalerate and 3-hydroxyvalerate were found in body fluids. It appears that the organic acidaemia leads to an inhibition in the maturation of cells in the bone marrow.- - - - - - - - - - ranking = 0.2keywords = carboxylase (Clic here for more details about this article) |
34/50. Mutant holocarboxylase synthetase: evidence for the enzyme defect in early infantile biotin-responsive multiple carboxylase deficiency.biotin-responsive multiple carboxylase deficiency is an inherited disorder of organic acid metabolism in man in which there are deficiencies of propionyl-coenzyme a (CoA), 3-methylcrotonyl-CoA, and pyruvate carboxylases that can be corrected with large doses of biotin. It has been proposed that the basic defect in patients with the early infantile form of the disease is in holocarboxylase synthetase, the enzyme that covalently attaches biotin to the inactive apocarboxylases to form active holocarboxylases. We have developed an assay for holocarboxylase synthetase in extracts of human fibroblasts using as substrate apopropionyl-CoA carboxylase partially purified from livers of biotin-deficient rats. fibroblasts from the initial patient with the infantile form of biotin-responsive multiple carboxylase deficiency were shown to have abnormal holocarboxylase synthetase activity with a maximum velocity about 30-40% of normal, a Km for ATP of 0.3 mM similar to the normal Km of 0.2 mM, and a highly elevated Km for biotin of 126 ng/ml, about 60 times the normal Km of 2 ng/ml. These results show that the primary defect in this patient is a mutation affecting holocarboxylase synthetase activity, and thus a genetic defect of the metabolism of biotin.- - - - - - - - - - ranking = 7.6156712217652keywords = carboxylase deficiency, carboxylase (Clic here for more details about this article) |
35/50. Increased excretion of four acetyl-CoA precursors during clinical episode of propionic acidaemia.Propionic acidaemia (McKusick 23200) is caused by reduced activity of propionyl-CoA carboxylase (EC 6.4.1.3). A number of metabolites characteristic of this disease are excreted in patients' urine. We have developed a method of chemical diagnosis using gas chromatography-mass spectrometry (GC-MS). Since our first chemical diagnosis (Matsumoto et al., 1978), we have diagnosed seven patients. Profiles of urinary acids, however, varied from patient to patient. Factors affecting these profiles may be genetic make-up, age, or the patient's clinical and nutritional conditions. We have compared two metabolic profiles of a girl under different clinical conditions and found increased excretion of acetyl-CoA precursors during clinical episodes.- - - - - - - - - - ranking = 0.2keywords = carboxylase (Clic here for more details about this article) |
36/50. The measurement of propionyl-CoA carboxylase and pyruvate carboxylase activity in hair roots: its use in the diagnosis of inherited biotin-dependent enzyme deficiencies.Two mitochondrial biotin-dependent enzymes, propionyl-CoA carboxylase and pyruvate carboxylase, are measurable in hair roots. A third biotin-dependent enzyme, beta-methylcrotonyl-CoA carboxylase, was barely detectable in hair roots. The diagnosis of isolated propionyl-CoA carboxylase deficiency was confirmed in hair roots of a known affected patient. This method should be a rapid and accurate method for the diagnoses of the various carboxylase deficiencies, particularly isolated pyruvate carboxylase deficiency in individuals with lactic acidosis, as well as for the assessment of biotin responsiveness in these patients.- - - - - - - - - - ranking = 4.1385570739217keywords = carboxylase deficiency, carboxylase (Clic here for more details about this article) |
37/50. Increased excretion of lactate, glutarate, 3-hydroxyisovalerate and 3-methylglutaconate during clinical episodes of propionic acidemia.Metabolic changes dependent upon clinical conditions were studied in an eight-month-old girl with propionyl CoA carboxylase deficiency. Only methylcitric acid and 2-methyl-3-oxovaleric acid were detected in the urine of the patient under clinically favorable conditions. During episodes of clinical decompensation, she excreted increased amounts of all the metabolites associated with this disorder. Four acetyl CoA precursors increased during clinical episodes: glutaric acid, a catabolic intermediate of lysine; 3-hydroxyisovaleric acid and 3-methylglutaconic acid, catabolic intermediates of leucine; and lactic acid. This suggests that under clinically favorable conditions the patient has an altered propionate metabolism which proceeds via normal acetyl CoA metabolism with sufficient capacity for acetyl CoA plus propionyl CoA metabolism. When the production of propionyl CoA exceeds the metabolic capacity, however, the catabolism of potent ketogenic amino acids is effectively suppressed in order to reduce acetyl CoA production.- - - - - - - - - - ranking = 0.86927853696087keywords = carboxylase deficiency, carboxylase (Clic here for more details about this article) |
38/50. argininosuccinic aciduria in a Finnish woman presenting with psychosis and mental retardation.argininosuccinic aciduria (ASA-uria) is a rare inborn error of the urea cycle, in which there is massive excretion of argininosuccinic acid (ASA) in the urine together with elevated concentrations of ASA in the plasma and the CSF. The characteristic symptoms are either those of overwhelming metabolic disease in the newborn period, or variable psychomotor retardation. The present patient, the first Finnish one to be reported, was a 49-year-old woman. She was hospitalized at the age of 26 with a diagnosis schizophrenia and mental retardation. Her clinical symptoms consisted of ataxia, disturbance of coordination, clumsiness, intention tremor and a positive Romberg's sign. The laboratory findings were consistent with the mild, late-onset type of ASA-uria.- - - - - - - - - - ranking = 0.00069302346189778keywords = late-onset (Clic here for more details about this article) |
39/50. Propionyl-CoA carboxylase deficiency: case report, effect of low-protein diet and identification of 3-oxo-2-methylvaleric acid 3-hydroxy-2-methylvaleric acid, and maleic acid in urine.vomiting, lethargy and metabolic acidosis were the main initial symptoms of metabolic disease in a 1 month old girl. Her older sister had died from a similar disease, considered to be Reye's syndrome, at an age of 15 months. The urine of the present case contained 2-methylcitric acid, 3-hydroxypropionic acid, N-propionylglycine, 2-hydroxy-3-methylbutyric acid, N-tiglylglycine, 3-hydroxyvaleric acid and glutaric acid. These metabolites are all known to be associated with propionyl-CoA accumulation. Free propionic acid was not detected in the urine. In addition, the urine contained 3-oxo-2-methylvaleric acid and 3-hydroxy-2-methylvaleric acid, probably formed by condensation of two molecules of propionyl-CoA. The identity of these metabolites was confirmed by synthesis. An elevated urinary concentration of maleic acid and fumaric acid was another constant abnormality. The activity of propionyl-CoA carboxylase in leucocytes was about 20% of the normal activity. The girl was teated with a low-protein diet since the diagnosis was made at an age of 1 month, and her psychomotor development was satisfactory at an age of 2 1/2 years. She had a few episodes of acidosis during infections.- - - - - - - - - - ranking = 3.6771141478435keywords = carboxylase deficiency, carboxylase (Clic here for more details about this article) |
40/50. Dysautonomia in an infant with secondary hyperammonemia due to propionyl coenzyme a carboxylase deficiency.A male infant who had vomiting and coma in the absence of ketoacidosis was initially thought to have dysautonomia because of abnormal responses to methacholine and histamine, as well as abnormal urinary catecholamine excretion. Following an episode of hyperammonemia, a liver biopsy was performed which revealed a partial deficiency of carbamyl phosphate synthetase activity. The patient was treated with a protein-restricted diet supplemented with a mixture of ketoacid analogues of the essential amino acids, which precipitated ketosis and acidosis. A primary deficiency of propionyl coenzyme a (CoA) carboxylase was subsequently demonstrated. Because disorders of propionate metabolism may not initially present with ketoacidosis, we recommend examination of both plasma and urine for metabolites of this pathway, as well as direct measurement of propionyl CoA carboxylase activity in peripheral blood leukocytes, before performing a liver biopsy to evaluate urea cycle enzyme activities, and particularly before adding keto acid/amino acid mixtures to a protein-restricted diet.- - - - - - - - - - ranking = 3.8771141478435keywords = carboxylase deficiency, carboxylase (Clic here for more details about this article) |
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