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Biomedical subjects

C A Stanley

Publications and source records attributed to C A Stanley.

At least 91 records · Page 5Linked to original sources
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

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

New genetic defects in mitochondrial fatty acid oxidation and carnitine deficiency.

There are now nine inherited diseases that have been identified in the pathway of mitochondrial fatty acid oxidation, including LCAD, MCAD, SCAD, and HMG-CoA lyase deficiencies, two forms each of CPT and MAD deficiencies and an incompletely characterized disorder of primary carnitine deficiency. The varied range of clinical manifestations in this new group of diseases should attract the attention not only of general pediatricians (coma, hypoglycemia) but also of pediatric subspecialists in neurology (myopathy), cardiology (cardiomyopathy), and gastroenterology (fatty liver), as well as genetics and metabolism. The presenting features of the genetic defects in fatty acid oxidation fit well with the concept that fatty acid oxidation plays a major role in energy production during prolonged fasting and in working cardiac and skeletal muscle. Life-threatening episodes of coma and hypoglycemia induced by fasting are a common presenting feature in most of the fatty acid oxidation disorders (MCAD, LCAD, and HMG-CoA lyase deficiencies, the infantile form of CPT deficiency, the mild form of MAD deficiency, and in some cases of primary carnitine deficiency). The hypoglycemia in these disorders is most easily explained by the inability of affected patients to use fatty acids as a fuel as a substitute for glucose. It should be stressed, however, that the coma in these disorders may occur from direct toxic effects of fatty acids or fatty acid intermediates before plasma glucose concentrations reach hypoglycemic levels. Severe disturbances of muscle function are a feature in several of the disorders; hypertrophic cardiomyopathy and chronic skeletal muscle weakness occur in both the mild and severe forms of MAD deficiency, in primary carnitine deficiency, and in some patients with LCAD deficiency. In contrast, patients with the adult form of CPT deficiency have normal muscle strength but are prone to episodes of painful rhabdomyolysis induced by prolonged exercise. These manifestations presumably reflect the requirement of working cardiac and skeletal muscle for energy supplied from fatty acid oxidation. In two of the disorders, SCAD deficiency and the severe form of MAD deficiency, chronic CNS toxicity is a dominant feature. The severe effects on the brain in these two disorders may reflect the fact that short-chain fatty acids more readily cross the blood-brain barrier than longer-chain fatty acids.(ABSTRACT TRUNCATED AT 400 WORDS)

Acyl-CoA Dehydrogenase↗
PubMed1986

Impaired chemotaxis and neutrophil (polymorphonuclear leukocyte) function in glycogenosis type IB.

Polymorphonuclear leukocyte (PMN) function was investigated in two patients with glycogen storage disease type IB and neutropenia. Glycogen storage disease type IB was documented by liver biopsy and a normal amount of latent glucose-6-phosphatase activity. Patient A had stomatitis, skin infections, and septicemia; patient B had respiratory infections, periodontitis, and oral candidiasis. Absolute neutrophil counts ranged from 114 to 2580/mm3. Diminished and delayed migration of PMN into a skin "window" occurred in B. Random and directed PMN migration under agarose toward f-Met-Leu-Phe, pepstatin A, and zymosan-activated serum were severely diminished in both patients. At 10(-7) M f-Met-Leu-Phe, mean random and directed migration were 52 and 23% (A, n = 3) and 48 and 13% (B, n = 4) of controls. These results were independent of incubation time and chemoattractant concentration. Patients' PMN had diminished quantitative nitroblue tetrazolium reduction compared to controls. B had a significant defect in PMN bactericidal activity with Escherichia coli with less than 0.2 log killing at 2 h. These results further characterize the defect in PMN migration reported by Beaudet et al. (J Pediatr 97:906, 1980). The finding of other abnormalities of PMN function suggests a metabolic defect in the neutrophil which may be related to the microsomal membrane defect in hepatocytes in glycogen storage disease type IB.

Adolescent↗
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↗
PubMed1985

Genetic deficiency of medium-chain acyl coenzyme A dehydrogenase: studies in cultured skin fibroblasts and peripheral mononuclear leukocytes.

Medium-chain acyl coenzyme A (CoA) dehydrogenase deficiency was demonstrated in fibroblasts and/or mononuclear leukocytes from 14 patients, most of whom initially presented early in childhood with a Reye-like syndrome associated with hypoketotic hypoglycemia, dicarboxylic aciduria, and low levels of plasma carnitine. Parents of these patients had intermediate levels of medium-chain acyl CoA dehydrogenase activity, consistent with their being heterozygous for an autosomal recessive trait. All patients had normal levels of long-chain acyl CoA dehydrogenase activity, but had reduced short-chain acyl CoA dehydrogenase activity. Fatty acid oxidation was examined in cultured fibroblasts from five of the patients, using a series of 14C-labeled fatty acids of different chain length (palmitic, octanoic, and butyric). Oxidation of [1-14C]-octanoic acid was less than 20% of control levels: [1-14C], [6-14C]-, [16(14)C]-, and [14C(U)]-palmitic acid oxidation rates were 88, 51, 13, and 42% of control rates, respectively. [1-14C]-butyric acid was oxidized normally. These data extend our previous findings of medium-chain acyl CoA dehydrogenase deficiency in liver tissue from three of these patients. They demonstrate the value of cultured fibroblasts and leukocytes in the diagnosis and evaluation of inherited disorders of fatty acid oxidation.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1983

The effect of early feeding on plasma glucose levels in SGA infants.

Plasma glucose levels were measured during the first day of life in 24 small-for-gestational-age (SGA) infants who began formula feedings within two hours of birth. In contrast to the high incidence of low blood sugar seen previously in fasted SGA infants, no infant had a plasma glucose below 30 mg/dl; after the first feeding, no values below 40 mg/dl occurred. Mean plasma glucose levels were lower in infants born to mothers with preeclampsia (57.2 +/- 2 vs 69.7 +/- 2.3 mg/dl, p less than .005). The results indicate that hypoglycemia (plasma glucose less than 40 mg/dl) can be easily avoided in SGA infants simply by providing adequate calories without delay after delivery.

Black People↗
PubMed1983

Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels.

Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye's syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate less than 0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 mmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 mumole/liter), liver (200-500 nmole/g), and muscle (500-800 nmole/g); however, treatment with L-carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium-chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA-acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5% normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1982

Fetal and neonatal hazards of maternal hydration with 5% dextrose before caesarean section.

In a prospective randomised study, 47 fasting women undergoing elective caesarean section received one of the following three glucose regimens for prevention of hypotension before administration of epidural bupivacaine to produce anaesthesia from the T4 sensory level: (i) 150 ml of 5% dextrose in water (D5W) and 1000 ml normal saline (7.5 g dextrose); (ii) 150 ml of D5W, 350 ml of 5% dextrose in normal saline (D5NS), and 650 ml of normal saline (25 g dextrose); (iii) 150 ml D5W and 1000 ml D5NS (57.5 g dextrose). The maternal blood sugar at delivery was significantly raised in patients receiving 25 and 57.5 g of dextrose. 57.5 g of dextrose also raised the mean umbilical cord venous levels of glucose to 11.7 mmol/l and of insulin to 70 +/- 7 microU/ml, while decreasing glucagon to 24 +/- 5.3 pg/ml and arterial pH to 7.19 +/- 0.015 compared with the levels with 7.5 g dextrose. The raised insulin level caused neonatal hypoglycaemia (1.8 +/- 0.22 mmol/l) and delayed release of glucagon at 2 hours of age. There was a higher incidence of neonatal jaundice in infants exposed to 57.5 g of dextrose than in those exposed to 7.5 g. The addition of large amounts of dextrose to intravenous fluids was harmful to the fetus and of no benefit to the mother. Until a safe rate of administration is established, it is recommended that dextrose infusions immediately before delivery be limited to no more than 6 g/h.

Anesthesia, Conduction↗
PubMed1981

Dietary-dependent carnitine deficiency as a cause of nonketotic hypoglycemia in an infant.

Recurrent episodes of hypoglycemia, prostration, vomiting, and hepatomegaly were observed in an infant fed a carnitine-free soy formula. The extremely low plasma and urinary carnitine concentrations, elevated plasma free fatty acids, disproportionately low plasma beta hydroxybutyrate, and elevated urinary dicarboxylic acids, in the presence of a fatty liver, suggested that carnitine deficiency was the basis for this child's metabolic disturbance. When the infant was fed an enriched carnitine diet, remarkable clinical, biochemical, and histologic improvement was observed. The possibility that carnitine may be an essential nutrient for some infants is raised by the findings in this patient.

Carnitine↗
PubMed1981

Intragastric feeding in type I glycogen storage disease: factors affecting the control of lactic acidemia.

Continuous nocturnal intragastric feeding, combined with frequent daytime feedings, has been reported to improve both linear growth and the metabolic abnormalities in patients with glucose-6-phosphatase deficiency (Type I Glycogen Storage Disease). However, elevated blood levels of lactate have persisted. The present studies explore the relationship between blood lactate concentrations in six patients with glucose-6-phosphatase deficiency and variations in the rate and composition of the intragastric feeding. Blood lactate and plasma glucose concentrations were determined at rates of dextrose administration ranging from 3-34 mg/kg/min. Dextrose infusion at 100-200% of estimated normal glucose production rates gave the best control of blood lactate concentrations. Lower rates of dextrose infusion resulted in significantly higher blood lactate levels; higher rates produced hyperglycemia, but no significant further reduction of blood lactate. At identical rates of glucose administration, a dextrose-containing infant formula and a high carbohydrate enteric feeding solution gave no significant improvement in control of blood lactate levels compared to dextrose alone. Plasma glucose levels fell more rapidly when intragastric feeding was stopped than after a mixed meal and hypoglycemia appeared to develop before counter-regulatory responses could be mobilized. These observations may account for the increased susceptibility to symptomatic hypoglycemia reported in patients treated with intragastric feeding.

Acidosis↗
PubMed1980

Decreased oxygenation and hyperlipemia during intravenous fat infusions in premature infants.

Eighteen appropriate-for-gestational-age premature infants with birth weights ranging from 0.77 to 1.89 kg received 1 gm/kg of body weight of fat emulsion, intravenously, over a four-hour period. Infants less than 1 week of age developed a significant decrease in PO2 levels (P < 5.0) during the fat infusion period. There were no changes in other pulmonary function parameters. Infants less than 1 week of age also developed significantly higher peak levels of plasma triglycerides than infants 2 to 3 weeks old (P < .05). A correlation between increment in triglyceride levels and postnatal age was demonstrated (r = .75), with the younger infants presenting the higher triglyceride levels. This study demonstrates that: (1) small premature infants receiving intravenous fat are more susceptible to hyperlipemia and hypoxemia during the first week of life; (2) hypoxemia associated with intravenous fat infusion does not result from changes in lung dynamics; (3) the capacity to tolerate intravenous fats is enhanced after the first week of life.

Age Factors↗