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Biomedical subjects

P M Coates

Publications and source records attributed to P M Coates.

At least 55 records · Page 3Linked to original sources
PubMed1989

Medium-chain acyl-CoA dehydrogenase deficiency.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most frequently diagnosed defect in fatty acid metabolism and is one of the most common inborn errors of metabolism. Diagnosis may be difficult, since the disorder may present as hypoglycemia, sudden infant death syndrome or a Reye's syndrome-like illness. Because of the abrupt clinical deterioration seen with MCAD deficiency, as well as its treatable nature and its genetic implications, this disorder presents a significant challenge for family physicians.

Acyl-CoA Dehydrogenase↗
PubMed1988

Medium-chain acyl-CoA dehydrogenase deficiency. Diagnosis by stable-isotope dilution measurement of urinary n-hexanoylglycine and 3-phenylpropionylglycine.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, one of the most common inherited metabolic disorders, is often mistaken for the sudden infant death syndrome or Reye's syndrome. Diagnosing it has been difficult because of a lack of fast and reliable diagnostic methods. We developed a stable-isotope dilution method to measure urinary n-hexanoylglycine, 3-phenylpropionylglycine, and suberylglycine, and we retrospectively tested its accuracy in diagnosing MCAD deficiency. We measured the concentrations of these three acylglycines in 54 urine samples from 21 patients with confirmed MCAD deficiency during the acute and asymptomatic phases of the illness and compared the results with the concentrations in 98 samples from healthy controls and patient controls with various diseases. The levels of urinary hexanoylglycine and phenylpropionylglycine were significantly increased in all samples from the patients with MCAD deficiency, clearly distinguishing them from both groups of controls. Although urinary suberylglycine was increased in the patients, the range of values in the normal controls who were receiving formula containing medium-chain triglycerides was very wide, overlapping somewhat with the values in the patients with asymptomatic MCAD deficiency. These results indicate that the measurement of urinary hexanoylglycine and phenylpropionylglycine by our method is highly specific for the diagnosis of MCAD deficiency. The method is fast and can be applied to random urine specimens, without any pretreatment of patients.

Acyl-CoA Dehydrogenase↗
PubMed1988

Genetic deficiency of short-chain acyl-coenzyme A dehydrogenase in cultured fibroblasts from a patient with muscle carnitine deficiency and severe skeletal muscle weakness.

Genetic deficiency of short-chain acyl-coenzyme A (CoA) dehydrogenase activity was demonstrated in cultured fibroblasts from a 2-yr-old female whose early postnatal life was complicated by poor feeding, emesis, and failure to thrive. She demonstrated progressive skeletal muscle weakness and developmental delay. Her plasma total carnitine level (35 nmol/ml) was low-normal, but was esterified to an abnormal degree (55% vs. control of less than 10%). Her skeletal muscle total carnitine level was low (7.6 nmol/mg protein vs. control of 14 +/- 2 nmol/mg protein) and was 75% esterified. Mild lipid deposition was noted in type I muscle fibers. Fibroblasts from this patient had 50% of control levels of acyl-CoA dehydrogenase activity towards butyryl-CoA as substrate at a concentration of 50 muM in a fluorometric assay based on the reduction of electron transfer flavoprotein. All of this residual activity was inhibited by an antibody against medium-chain acyl-CoA dehydrogenase. These data demonstrated that medium-chain acyl-CoA dehydrogenase accounted for 50% of the activity towards the short-chain substrate, butyryl-CoA, under these conditions, but that antibody against that enzyme could be used to unmask the specific and virtually complete deficiency of short-chain acyl-CoA dehydrogenase in this patient. Fibroblasts from her parents had intermediate levels of activity towards butyryl-CoA, consistent with the autosomal recessive inheritance of this metabolic defect.

Acyl-CoA Dehydrogenase↗
PubMed1988

Relationship between unusual hepatic acyl coenzyme A profiles and the pathogenesis of Reye syndrome.

This study examines the relationship between impaired fatty acid oxidation and the pathogenesis of Reye syndrome. We present a hypothesis proposing that many clinical signs of this childhood disease are caused by accumulation of unusual acyl CoA esters, precursors to deacylated metabolites found in the patients' blood and urine. A new method was developed to measure acyl CoA compounds in small human liver biopsy samples, offering several advantages over previous techniques. A major finding was an accumulation in Reye syndrome patients of short- and medium-chain acyl CoA intermediates of fatty acid and branched-chain amino acid oxidation. These metabolites included octanoyl, isovaleryl, butyryl, isobutyryl, propionyl, and methylmalonyl CoA esters. The findings were explained in a model of hepatic fatty acid oxidation involving three interrelated pathways: mitochondrial beta-oxidation, peroxisomal beta-oxidation, and omega-oxidation in the endoplasmic reticulum. The results suggest that pathogenesis in Reye syndrome stems from generalized mitochondrial damage resulting in accumulation of acyl CoA esters. High levels of these compounds lead to inhibition of mitochondrial pathways for ureogenesis, gluconeogenesis, and fatty acid oxidation. The inhibited pathways, in turn, could cause the hyperammonemia, hypoglycemia, and hypoketonemia observed in patients. The model also explains underlying biochemical differences between patients with Reye syndrome and medium-chain acyl CoA dehydrogenase deficiency, another disorder of fatty acid metabolism. Acetyl CoA levels, in the latter disease, were dramatically decreased, compared with both human controls and Reye syndrome patients.

Acyl Coenzyme A↗
PubMed1987

Cholesteryl ester storage disease: pathologic changes in an affected fetus.

The prenatal diagnosis of cholesteryl ester storage disease, a rare autosomal recessive disorder, was made by demonstration of deficient lysosomal acid lipase activity in cultured amniocytes from an at-risk fetus. The histochemical and ultrastructural changes in the affected fetus (at 17 gestational weeks) are described and compared to findings in liver and duodenal biopsy specimens from a 9-year-old homozygous female. Massive lysosomal cholesterol and lipid accumulation was demonstrated in fetal hepatocytes, adrenal cells and syncytiotrophoblasts. Of particular note was the observation of extensive necrosis in the fetal adrenal glands. Necrosis of the adrenals may precede the calcification observed in some patients with cholesteryl ester storage disease and in most patients with Wolman disease, an allelic variant due to lysosomal acid lipase deficiency. Fibrosis of the liver and lipid accumulation in macrophages in liver and duodenum, which were present in the 9-year-old homozygote, were not observed in the affected fetus, and therefore, may represent later manifestations of the disease.

Child↗
PubMed1987

Kinetics of chylomicron remnant clearance in normal and in hyperlipoproteinemic subjects.

The kinetics of chylomicron metabolism have been studied by measuring retinyl palmitate in chylomicrons and their remnants for 10-12 hr following oral administration of vitamin A and Lipomul in three groups of adult male subjects: A) normal plasma triglyceride levels (n = 7); B) endogenous hypertriglyceridemia (n = 12); C) apolipoprotein E (apoE) phenotype E2/2, with Type 3 hyperlipoproteinemia (n = 4) or normal plasma lipids (n = 1). A multicompartmental model was developed using SAAM 27 to characterize the appearance, intravascular metabolism, and clearance from the plasma of retinyl palmitate-labeled dietary lipoproteins. The half-times for retinyl palmitate clearance from the chylomicron remnant fraction (T1/2 REMNANT) were 14.1 +/- 9.7 min in Group A; they were prolonged in Group B (50.7 +/- 20.8 min) and were extremely prolonged for Type 3 subjects in Group C (611.9 +/- 419.9 min). One subject with the apoE 2/2 phenotype and normal plasma triglycerides had a T1/2 REMNANT of 66.8 min. T1/2 REMNANT was highly correlated with fasting plasma triglycerides in Group A and B (r = 0.77, slope = 0.15), and in Group C (r = 0.97, slope = 0.85). These results support the interpretation that delayed chylomicron remnant clearance in subjects with endogenous hypertriglyceridemia may be largely secondary to overproduction of VLDL particles, whose remnants compete with chylomicron remnants for removal by the liver via apoE receptor-mediated endocytosis. The subjects with apoE 2/2 have an additional defect in the removal of chylomicron remnants presumably due to the structural abnormality in their apoE.

Adult↗
PubMed1986

Genetic variation of human mononuclear leukocyte lysosomal acid lipase activity. Relationship to atherosclerosis.

Lysosomal acid lipase activity was measured in mononuclear leukocytes of patients selected on the basis of premature cardiovascular disease, with or without hyperlipidemia. Enzyme activity was significantly lower in the patient population (4.8 +/- 1.3 nmol/min/mg protein, n = 190 males) than in an age-matched control population (5.4 +/- 1.3 nmol/min/mg protein, n = 124 males). There was no effect of hypercholesterolemia or hypertriglyceridemia on the enzyme activity. In the group of patients with normal plasma lipids (n = 77), 18% had mononuclear leukocyte acid lipase activity which fell below the control population 5th percentile, and in the range of enzyme activity observed in cells from obligate heterozygotes for inherited acid lipase deficiency (Wolman disease and cholesteryl ester storage disease). Studies of acid lipase activity in families of our patients provided evidence that an autosomal mutation is associated with (or responsible for) this reduced enzymatic activity and may represent an independent risk factor for the premature development of atherosclerosis.

Adult↗
PubMed1986

Genetic polymorphism of esterase B3 in human leukocytes.

Human tissues contain an esterase activity called ESB3, detectable by starch gel electrophoresis followed by staining with alpha-naphthyl butyrate. Using mononuclear leukocytes, we demonstrated an electrophoretic variant of ESB3. Family studies suggest that the variant is inherited as a simple Mendelian trait; individuals with the ESB3 2-1 phenotype are heterozygotes, designated ESB3(1)ESB3(2), to distinguish them from the more common homozygotes, ESB3(1)ESB3(1). The frequency of the ESB3(2) allele is estimated to be 0.035 in U.S. Whites. No homozygotes for this allele have yet been found. Our studies suggest that the enzyme from ESB3 1 individuals exists primarily as a trimer of three identical subunits with a molecular weight of approximately 58,000 daltons. The genetic variant (ESB3(2) allele) appears to be the result of a mutation that does not affect the charge of the subunit, but rather reduces its ability to form and maintain the trimeric structure.

Chromatography, Gel↗
PubMed1986

Biosynthesis of variant medium chain acyl-CoA dehydrogenase in cultured fibroblasts from patients with medium chain acyl-CoA dehydrogenase deficiency.

We prepared monospecific antiserum in rabbits against medium chain acyl-CoA dehydrogenase (MCAD) purified from rat liver and studied the biosynthesis of MCAD in cultured skin fibroblasts from patients with MCAD deficiency using the antibody. Cells were incubated with [35S]methionine. The labeled MCAD was immunoprecipitated using the anti-rat MCAD antiserum and Staphylococcus aureus cells and then analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. We first demonstrated that antirat MCAD antibody crossreacted specifically with human MCAD. In 13 MCAD-deficient cell lines tested, the residual MCAD activity ranged from 5-12% of the mean of normal controls, but the variant MCAD in all of these cells was indistinguishable from the normal human MCAD on the basis of molecular size, indicating that MCAD deficiency in all of these patients is most likely due to point mutation(s) in the MCAD gene.

Acyl-CoA Dehydrogenase↗
PubMed1986

Direct measurement of apolipoprotein B synthesis in human very low density lipoprotein using stable isotopes and mass spectrometry.

Stable isotope methodology has been adapted to the study of lipoprotein turnover in human subjects. Using endogenous [15N]glycine labeling and gas-liquid chromatographic-mass spectrometric analysis, synthesis of apolipoprotein B in very low density lipoprotein (VLDL) was measured directly in five normal and two hyperlipidemic subjects. An isotopic precursor steady state was achieved during the studies by utilizing a priming dose and constant infusion containing [15N]glycine. Measurement of the plateau in 15N enrichment in the urinary hippurate produced during each study was used to estimate the 15N enrichment of the hepatic glycine precursor pool. The range of values for the fractional synthetic rate of VLDL apoB in the normal subjects obtained by this method was 5.9 to 11.5 day-1, with a mean of 9.2 +/- 2.4 (SD). This value agrees with the results of previous investigations which have utilized other methods. The method was also tested in two hypertriglyceridemic subjects and gave fractional synthetic rates of VLDL apoB that were significantly lower than in normals (1.5 and 2.8 day-1). This stable isotope method allows calculation of the fractional synthetic rate of VLDL apoB by maintaining an isotopic steady state throughout the study. It makes possible repeated studies in the same individual since no risk of exposure to radioisotopes is involved.

Apolipoproteins B↗
PubMed1985

Long-chain acyl coenzyme A dehydrogenase deficiency: an inherited cause of nonketotic hypoglycemia.

Three children from unrelated families presented in early childhood with hypoglycemia and cardiorespiratory arrests associated with fasting. Significant hepatomegaly, cardiomegaly, and hypotonia were present at the time of initial presentation. Ketones were not present in the urine at the time of hypoglycemia in any patient; however, dicarboxylic aciduria was documented in one patient at the time of the acute episode and in two patients during fasting studies. Total plasma carnitine concentration was low with an increased esterified carnitine fraction. These findings suggested a defect in mitochondrial fatty acid oxidation, and specific assays were performed for the acyl coenzyme A (CoA) dehydrogenases. These analyses showed that the activity of the long-chain acyl CoA dehydrogenase was less than 10% of control values in fibroblasts, leukocytes, and liver tissue. Activities of the medium-chain, short-chain, and isovaleryl CoA dehydrogenases were not different from control values. With cultured fibroblasts, CO2 evolution from long-chain fatty acids was significantly reduced, while CO2 evolution from medium-chain and short-chain fatty acids was comparable to control values--findings consistent with a defect early in the beta-oxidation sequence. Studies of acyl CoA dehydrogenase activities in fibroblasts and leukocytes from parents of the patients showed levels of long-chain acyl CoA dehydrogenase activity intermediate between affected and control values and indicated an autosomal recessive form of inheritance of this enzymatic defect.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyl-CoA Dehydrogenase, Long-Chain↗