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Biomedical subjects

K M Gibson

Publications and source records attributed to K M Gibson.

157 records · Page 9Linked to original sources
PubMed1984

A child with acute pancreatitis and recurrent hypoglycemia due to 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

A five-year-old-girl with a history of recurrent hypoglycemia presented with acidosis, intractable vomiting, and abdominal tenderness; the diagnosis of acute pancreatitis was made by abdominal ultrasonography and supportive biochemical studies. Urinary organic acid analysis revealed metabolites suggestive of HMG-CoA lyase deficiency, and subsequent enzyme assays of lymphocytes and fibroblasts confirmed this diagnosis. Acute pancreatitis, an uncommon condition in childhood, is seen with increased frequency in patients with Reye syndrome, a metabolic disorder with which HMG-CoA lyase deficiency may be confused. The pathogenesis of pancreatitis in Reye syndrome or in HMG-CoA lyase deficiency has not been determined.

Acute Disease↗
PubMed1984

3-Hydroxy-3-methylglutaric aciduria.

3-Hydroxy-3-methylglutaric aciduria was found in a newborn infant whose parents are first cousins. The patient presented at 5 days of life with hyperammonemia, hypoglycemia, and metabolic acidosis. There was no ketonuria. Diagnosis was made by analysis of the pattern of organic acids excreted in the urine. A profound deficiency in activity of 3-hydroxy-3-methylglutaryl-coenzyme A lyase was found in cultured skin fibroblasts. The parents had intermediate levels of enzyme activity.

Cells, Cultured↗
PubMed1984

Succinic semialdehyde dehydrogenase deficiency.

A coupled assay using [14C]4-aminobutyric acid and a direct assay using [14C]succinic semialdehyde have been designed to assay te activity of succinic semialdehyde dehydrogenase in a patient with 4-hydroxybutyric aciduria and family members. In the coupled assay less than 3% of control succinic semialdehyde dehydrogenase activity was found in lysates of lymphocytes isolated from whole blood of the patient. In the direct assay there was no detectable activity of the enzyme in lysates of isolated lymphocytes or cultured lymphoblasts. Results indicated the parents to be heterozygous carriers carriers of the abnormal gene, consistent with an autosomal recessive inheritance.

Adult↗
PubMed1984

Genetic complementation analysis of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency in cultured fibroblasts.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency is an inherited metabolic disorder of leucine catabolism showing variability in clinical expression. We have examined the possibility of a biochemical and genetic basis for this heterogeneity by measuring the residual enzyme activities in fibroblast cultured from seven patients. The mean activity of HMG-CoA lyase was 1.1% +/- 0.3% of normal with no significant differences between the patients. Genetic complementation was studied in heterokaryons obtained by fusion with polyethylene glycol using the incorporation of 1-[14C]isovaleric acid into trichloroacetic acid precipitable material to determine the activity of the leucine catabolic pathway. Unfused cells from the patients with a deficiency of HMG-CoA lyase had incorporations of less than 5% of normal. Unfused cells from patients with isovaleric acidemia or a deficiency of 3-methylcrotonyl-CoA carboxylase also had incorporations of less than 5% of normal, and when fused with cells of patients with a deficiency of HMG-CoA lyase, gave positive complementation with an incorporation of 30% of normal. None of the fusions between the seven different lines deficient in HMG-CoA lyase resulted in increased incorporation. Thus, no evidence was obtained for biochemical or genetic heterogeneity in fibroblasts of these seven patients with a deficiency of HMG-CoA lyase that would account for their different clinical presentations.

Cell Fusion↗
PubMed1983

Succinic semialdehyde dehydrogenase deficiency: an inborn error of gamma-aminobutyric acid metabolism.

Gamma-hydroxybutyric aciduria is a disorder of gamma-aminobutyric acid metabolism in which a compound of known neuropharmacologic activity accumulates. We have studied two patients in whom high levels of gamma-hydroxybutyric acid were found in blood, urine and cerebrospinal fluid. A coupled assay has been developed which estimates succinic semialdehyde dehydrogenase activity in isolated human lymphocytes. The mean activity of succinic semialdehyde dehydrogenase in a control and the four parents and two healthy siblings of these patients was 8.8 +/- 1.9 pmol . min-1 . mg-1 protein. In the patients the activities were 0.8 and 1.1 pmol . min-1 . mg-1 protein, approximately 9-13% of control. In the presence of saturating amounts of NAD+, lymphocyte sonicates, derived from the patients accumulated a significant amount of 14C-succinic semialdehyde from 14C-gamma aminobutyric acid, whereas none could be detected in controls. The data suggest a deficiency of succinic semialdehyde dehydrogenase in these patients, the first documented defect of the metabolism of gamma-aminobutyric acid in man.

4-Aminobutyrate Transaminase↗
PubMed1983

Enzymatic preparation of radiolabeled succinic semialdehyde.

[U-14C]Succinic semialdehyde was prepared with yields of 30-40% by oxidation of purified [U-14C]4-aminobutyric acid with commercially available bovine plasma monoamine oxidase. [U-14C]Succinic semialdehyde was purified by cation-exchange chromatography and quantified as the oxime and methoxime derivatives using liquid partition chromatography on silicic acid. The availability of [U-14C]succinic semialdehyde permits the reliable assay of succinic semialdehyde dehydrogenase in crude cell extracts of lymphocytes isolated from human blood, cultured human lymphoblasts, and other tissues where 4-aminobutyric acid metabolism is known to occur.

Animals↗
PubMed1982

3-hydroxy-3-methylglutaric aciduria: a new assay of 3-hydroxy-3-methylglutaryl-coa lyase using high performance liquid chromatography.

A new assay has been developed for 3-hydroxy-3-methylglutaryl-CoA lyase, the final enzyme in the leucine degradative pathway. The assay was performed by incubating lysates of fibroblasts with [glutaryl-3-14C](D,L)-3-hydroxy-3-methyl-glutaryl coenzyme A. The products were analysed by high performance liquid chromatography with continuous liquid scintillation counting. This provided simultaneous identification and quantification of one of the enzymatic products, [3-14C]acetoacetic acid. The mean 3-hydroxy-3-methylglutaryl-CoA lyase activity in fibroblasts from five controls was 732 +/- 81 (SD) pmol/min X mg protein. Using this assay, we have studied skin fibroblasts cultured from a patient with 3-hydroxy-3-methylglutaric aciduria and found 3% of normal 3-hydroxy-3-methylglutaryl-CoA lyase activity. The activities in skin fibroblasts cultured from the parents were 46 and 53% of control activity which is consistent with heterozygocity. Kinetic studies of 3-hydroxy-3-methylglutaryl-CoA lyase in skin fibroblasts cultured from two normal subjects yielded Km values of 14.4 and 18.8 mumol/l for 3-hydroxy-3-methylglutaryl-CoA.

Acetoacetates↗
PubMed1982

Oxidation of fatty acids in cultured fibroblasts: a model system for the detection and study of defects in oxidation.

A number of recently described inherited disorders interfere with the oxidation of fatty acids. In these disorders at least three different metabolic steps may be affected: (1) transport of long chain fatty acids into the mitochondria as in carnitine deficiency and carnitine palmitoyl transferase deficiency (CPT); (2) multiple acyl CoA dehydrogenase deficiency or glutaric aciduria type II (GAII) due presumably to a defective common electron transfering flavoprotein or iron sulfur flavoprotein; (3) specific long or medium chain fatty acyl CoA dehydrogenase deficiency as in inherited dicarboxylic aciduria. In order to develop a system for the detection and the study of the consequences of defects such as these on the oxidation of fatty acids, we investigated the metabolism of oleate (18 carbons), octanoate (eight carbons) and butyrate (four carbons) in intact cultured fibroblasts from patients with CPT deficiency, GAII, and dicarboxylic aciduria. In CPT deficient cells there was a markedly deficient ability to oxidize [1-14C] and [U-14C] oleate (19 and 5% of normal, respectively), whereas oxidations of [1-14C] octanoate and [1,4-14C] succinate were significantly increased (150 and 222%, respectively), and [1-14C] butyrate oxidation was normal. GAII cells displayed a nearly complete defect in the oxidation of [1-14C] and [U-14C] oleate (8 and 1%, respectively), as well as of [1-14C] octanoate and [1-14C] butyrate (8 and 5% of normal, respectively). The oxidation of [1,4-14C] succinate by GAII cells was normal. Cells from a patient with dicarboxylic aciduria showed a significant reduction in [14CO2] production from [U-14C] oleate (57%) and [1-14C] octanoate (31%) and a normal oxidation of [1-14C] oleate, [1-14C] butyrate, and [1,4-14C] succinate. These observations are consistent with available information on the normal metabolism of fatty acids in liver and muscle and also with the hypothesis about the molecular localization of the defects in GAII and inherited dicarboxylic aciduria. They demonstrate that intact cultured skin fibroblasts represent a reliable and convenient model for the investigation of fatty acid oxidation in man. Many aspects of the human acyl CoA dehydrogenases and their physiologic functions remain unknown, among them the problem of their acyl chain length specificity. Studies in cultured fibroblasts from patients with presumed mutations affecting the metabolism of fatty acids provide a means for the elucidation of these defects and at the same time give information on normal metabolic functions. It appears likely that a number of previously unrecognized defects in this area of metabolism remain to be found. The availability of a model system for their study in cultured fibroblasts should facilitate their discovery.

Carnitine O-Palmitoyltransferase↗
PubMedDate not supplied

Activity of biotin-dependent and GABA metabolizing enzymes in chorionic villus samples: potential for 1st trimester prenatal diagnosis.

We have documented the presence of five mitochondrial enzymes in samples of chorionic villus tissue and measured the levels of activity. Three of the enzymes catalyse biotin-dependent reactions. These are propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase and pyruvate carboxylase. The other enzymes, 4-aminobutyric acid aminotransferase and succinic semialdehyde dehydrogenase, are involved in the degradation of the central inhibitory neurotransmitter GABA. Distinct diseases in which there is deficiency of each of these enzymes have been documented in man. Significant levels of activity were observed for all five enzymes in chorionic villus tissue. This methodology should permit early prenatal diagnosis of deficiencies of these enzymes by chorionic villus biopsy in the first trimester.

4-Aminobutyrate Transaminase↗
PubMedDate not supplied

Metabolism of [U-14C]-4-hydroxybutyric acid to intermediates of the tricarboxylic acid cycle in extracts of rat liver and kidney mitochondria.

The metabolism of [U-14C]-4-hydroxybutyric acid (GHB) was investigated in sonicates of mitochondria of rat heart, kidney and liver. The conversion of this precursor to 14C-organic acids was monitored and quantified by sequential liquid-partition chromatography on hydrated columns of silicic acid using a concave-upward gradient of 2-methylbutan-2-ol in chloroform. Sonicates of liver and kidney mitochondria, but not heart, readily converted [U-14C]-GHB to 14C organic acids via a pathway of conversion to 14C-succinic acid, followed by further metabolism through the tricarboxylic acid cycle. This conversion was facilitated by exogenous NAD+ and NADP+. No evidence for the beta-oxidation of GHB was obtained in any of the mitochondrial sonicates. Studies with exogenous non-labelled succinic semialdehyde indicated that this compound was an intermediate in the conversion of GHB to succinic acid.

Animals↗
PubMedDate not supplied

Multiple syndromes of 3-methylglutaconic aciduria.

The most common clinical syndromes associated with 3-methylglutaconic aciduria are presented. In some patients these syndromes are multisystemic, progressive disorders of unknown etiology. Tissues deriving significant energy through oxidative metabolism (notably brain and cardiac muscle) are most often affected and in some the primary defect may reside within the mitochondrial respiratory chain. Although increasing biochemical evidence suggests that 3-methylglutaconic aciduria may correlate with deranged mitochondrial energy metabolism, the biochemical origin of 3-methylglutaconic acid and the significance of its increased excretion remain unknown. This review describes these syndromes and illustrates the necessity of urinary organic acid analysis to assist in the differential diagnosis.

Brain Diseases, Metabolic↗
PubMedDate not supplied

[3-hydroxy-3-methylglutaraturia. Clinical aspects, follow-up and therapy in a young child].

This is a report of an infant with 3-hydroxy-3-methylglutaryl-CoA-lyase deficiency. During infancy vomiting and feeding difficulties had been found repeatedly. Nutrition consisted in a mixture of one third of milk diluted with two thirds of water. Shortly before admission a change to whole milk had taken place. The one year old girl was admitted to the hospital because of vomiting and diarrhoea. Liver was enlarged and consciousness reduced. There was acidosis, hypoglycemia and an elevation of the transaminases. The typical pattern of organic acids in urine and dicarboxylic aciduria was pathognomonic. The diagnosis was proved by a deficiency of 3-hydroxy-3-methylglutaryl-CoA-lyase in fibroblasts. A protein and fat restricted diet, but also carnitine supplement was introduced. With the exception of severe hypoglycemia seizures on one morning the more than 2 1/2 year old girl is developed normally. It is of importance for future to avoid hypoglycemia after fasting, infections diseases or stress. The possible impairment of pancreatic function even in a normal clinical condition with normal values of transaminases is especially pointed out.

Amino Acid Metabolism, Inborn Errors↗