Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.3.1.8 (acyl-CoA dehydrogenase)
 785 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are still many problems with the diagnosis and classification of inherited disorders of mitochondrial beta-oxidation. At present only the acyl-CoA dehydrogenase step of the beta-oxidation spiral has been explored in any detail and a large number of patients have disorders that cannot be properly characterized. beta-Oxidation defects may present in a wide variety of ways, the most dramatic being acute encephalopathy with hepatic involvement (atypical Reye's syndrome) or 'sudden' death. Investigations may include urinary and plasma organic acids, metabolic stress tests and assays of overall metabolic pathways or of specific enzymes in cultured fibroblasts, lymphocytes, or other material. Early postnatal diagnosis presents particular difficulties but in medium-chain acyl-CoA dehydrogenase deficiency the diagnosis may be apparent from careful examination of urine. There is as yet little general experience in prenatal diagnosis of this group of disorders except for glutaric aciduria type II. Single prenatal diagnoses of medium-chain acyl-CoA dehydrogenase deficiency and of an incompletely characterized defect of medium-chain fatty acid oxidation have been performed.
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PMID:Disorders of mitochondrial beta-oxidation: prenatal and early postnatal diagnosis and their relevance to Reye's syndrome and sudden infant death. 250 9

Acyl-CoA dehydrogenation deficiencies are defined as disorders of the metabolism of branched chain and straight chain acyl-CoA esters and of glutaryl-CoA. The acyl-CoA dehydrogenation process is comprised of three enzymes, i.e. acyl-CoA dehydrogenase (isovaleryl-CoA, isobutyryl-CoA/2-Me-butyryl-CoA, short-chain acyl-CoA, general (medium-chain) acyl-CoA, long-chain acyl-CoA or glutaryl-CoA), electron transfer flavoprotein (ETF) and electron transfer flavoprotein dehydrogenase (ETF DH). Patients with isovaleryl-CoA dehydrogenase deficiency, glutaryl-CoA dehydrogenase deficiency and general (medium-chain) acyl-CoA dehydrogenase deficiency have been reported. Assays for the enzymatic diagnosis in cells from such patients (especially cultured skin fibroblasts) have been developed and the different methods are reviewed. Patients with apparent defects in all acyl-CoA dehydrogenation processes, designated multiple acyl-CoA dehydrogenation deficiencies, have also been found. I. e. glutaric aciduria type II, ethylmalonicadipic aciduria and riboflavin responsive multiple acyl-CoA dehydrogenation defect. The enzymatic diagnosis has not yet been performed in any of these cases, but the different approaches in this respect are discussed. The excretion pattern of organic acids in urine from patients with acyl-CoA dehydrogenation deficiencies - as measured by means of gas chromatography/mass spectrometry - offers in most cases a tentative diagnosis of the enzyme defect. These excretion patterns are characterized by the presence in urine of different compounds originating from the primary accumulated acyl-CoA ester(s). The most important biochemical processes involved in the formation of these patterns seem to be glycine conjugation, omega-and omega-1-oxidation, carboxylation and dioxygenation. The enzymatic basis for these processes is discussed with respect to the enzyme affinities for acyl-CoA esters relevant to the acyl-CoA dehydrogenation deficiencies. And the knowledge gained from such affinity studies is used to explain the excretion pattern in the different patients, thus increasing the diagnostic power of the gas chromatographic/mass spectrometric analyses. The pathophysiological manifestations in patients with acyl-CoA dehydrogenation deficiencies resemble in many respect those seen in patients with Reye's syndrome, in which the fatty acid oxidation also seems to be compromised. Ethiological factors have not been identified in Reye's syndrome, but in many patients blood accumulation of short- and medium-chain fatty acids has been found.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The acyl-CoA dehydrogenation deficiencies. Recent advances in the enzymic characterization and understanding of the metabolic and pathophysiological disturbances in patients with acyl-CoA dehydrogenation deficiencies. 389 50

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.
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PMID:Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels. 664 97

Rats treated with six to eight doses (80 mg/kg, i.p.) of 4-pentenoic acid, an inhibitor of mitochondrial fatty acid oxidation in vitro, during a 48-hr starvation period developed microvesicular fatty infiltration of the liver similar to that observed in Reye's Syndrome. Hepatic triglycerides were elevated an average of 5-fold, although considerable variability was found between individual rats. Fed rats did not develop fatty liver upon similar treatment with pentenoic acid. Liver mitochondria isolated from rats with pentenoic acid-induced fatty liver showed a persistent inhibition of fatty acid oxidation. Rates of oxidation of palmitoylcarnitine and decanoylcarnitine were decreased about 70%, while that of octanoylcarnitine was decreased 50%. Carnitine-independent oxidation of octanoate was also inhibited. Oxidation rates for substrates other than fatty acids, including glutamate, succinate, pyruvate, and alpha-ketoglutarate, were unaffected. Measurements of flavoprotein reduction in intact mitochondria indicated that neither palmitoylcarnitine nor palmitoyl CoA plus L-carnitine could elicit reduction of acyl-CoA dehydrogenase and electron transferring flavoprotein in mitochondria from rats with pentenoic acid-induced fatty liver. These results support a site of inhibition of mitochondrial beta-oxidation at the level of acyl-CoA dehydrogenase for pentenoic acid treatment in vivo, and they suggest a role for nutritional or hormonal factors in the metabolic disposition of pentenoic acid in vivo and in the development of fatty liver.
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PMID:Inhibition of mitochondrial fatty acid oxidation in pentenoic acid-induced fatty liver. A possible model for Reye's syndrome. 671 30

The authors report on two siblings with a multiple acyl-CoA dehydrogenase deficiency. The first child died from a Reye's syndrome when he was 9 month-old. The diagnosis was made in the neonatal period in his brother. Early treatment with glucose and carnitine should prevent acute attacks.
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PMID:[Multiple acyl-CoA dehydrogenase deficiency. Report of 2 siblings]. 777 88

Medium- and short-chain l-3-hydroxy-acyl-CoA dehydrogenase (M/SCHAD) deficiency is a recessively inherited disorder of fatty acid oxidation. Currently, only four patients from three families have been reported in the literature. All these patients presented with hypoglycemia associated with hyperinsulinism (HI). This association suggests that there is a role for M/SCHAD in regulating the pancreatic secretion of insulin. We present a fifth patient whose presentation was similar to Reye syndrome, a feature in common with most of the previously recognized disorders of fatty acid oxidation but with no clinical evidence of HI. Sequencing of the HAD1 gene on chromosome 4 revealed compound heterozygosity for two novel missense mutations, 170A>G, resulting in D45G, and 676T>C, resulting in Y214H. The mutant enzymes were expressed and subjected to kinetic analysis. Y214H has no detectable activity, whilst D45G, which resides in the cofactor-binding pocket, has an altered K(m) for NADH (96 microM versus 24 microM for the wild-type). This represents the first kinetic M/SCHAD mutant, which explains the high residual activity in skin fibroblasts. The lack of obvious HI in this patient may be related to the high residual activity and indicates that HI associated with M/SCHAD deficiency may only be present with complete deficiency. The spectrum of M/SCHAD phenotype should be broadened to include acute liver disease.
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PMID:Reye-like syndrome resulting from novel missense mutations in mitochondrial medium- and short-chain l-3-hydroxy-acyl-CoA dehydrogenase. 1743 78

Accumulation of organic acids as well as their CoA and carnitine esters in tissues and body fluids is a common finding in organic acidurias, beta-oxidation defects, Reye syndrome, and Jamaican vomiting sickness. Pathomechanistic approaches for these disorders have been often focused on the effect of accumulating organic acids on mitochondrial energy metabolism, whereas little is known about the pathophysiologic role of short- and medium-chain acyl-CoAs and acylcarnitines. Therefore, we investigated the impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on central components of mitochondrial energy metabolism, namely alpha-ketoglutarate dehydrogenase complex, pyruvate dehydrogenase complex, and single enzyme complexes I-V of respiratory chain. Although at varying degree, all acyl-CoAs had an inhibitory effect on pyruvate dehydrogenase complex and alpha-ketoglutarate dehydrogenase complex activity. Effect sizes were critically dependent on chain length and number of functional groups. Unexpectedly, octanoyl-CoA was shown to inhibit complex III. The inhibition was noncompetitive regarding reduced ubiquinone and uncompetitive regarding cytochrome c. In addition, octanoyl-CoA caused a blue shift in the gamma band of the absorption spectrum of reduced complex III. This effect may play a role in the pathogenesis of medium-chain and multiple acyl-CoA dehydrogenase deficiency, Reye syndrome, and Jamaican vomiting sickness which are inherited and acquired conditions of intracellular accumulation of octanoyl-CoA.
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PMID:Impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on mitochondrial energy metabolism. 1858 32

Complex I deficiency causes Leigh syndrome, fatal infant lactic acidosis, and neonatal cardiomyopathy. Mutations in more than 100 nuclear DNA and mitochondrial DNA genes miscode for complex I subunits or assembly factors. ACAD9 is an acyl-CoA dehydrogenase with a novel function in assembly of complex I; biallelic mutations cause progressive encephalomyopathy, recurrent Reye syndrome, and fatal cardiomyopathy. We describe the first autopsy in fatal neonatal lethal lactic acidosis due to mutations in ACAD9 that reduced complex I activity. We identified mitochondrial hyperplasia in cardiac myocytes, diaphragm muscle, and liver and renal tubules in formalin-fixed, paraffin-embedded tissue using immunohistochemistry for mitochondrial antigens. Whole-exome sequencing revealed compound heterozygous variants in the ACAD9 gene: c.187G>T (p.E63*) and c.941T>C (p.L314P). The nonsense mutation causes late infantile lethality; the missense variant is novel. Autopsy-derived fibroblasts had reduced complex I activity (53% of control) with normal activity in complexes II to IV, similar to reported cases of ACAD9 deficiency.
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PMID:Neonatal multiorgan failure due to ACAD9 mutation and complex I deficiency with mitochondrial hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules. 2682 6

A boy aged 6 years and 3 months developed upper respiratory tract infection and pyrexia 2 months ago and was given oral administration of nimesulide by his parents according to directions. Half an hour later, the boy experienced convulsions and cardiopulmonary arrest, and emergency examination found hypoketotic hypoglycemia, metabolic acidosis, significant increases in serum aminotransferases and creatine kinase, and renal damage. Recovery of consciousness and vital signs was achieved after cardiopulmonary resuscitation, but severe mental and movement regression was observed. The boy had a significant reduction in free carnitine in blood and significant increases in medium- and long-chain fatty acyl carnitine, urinary glutaric acid, 3-hydroxy glutaric acid, isovalerylglycine, and ethylmalonic acid, suggesting the possibility of multiple acyl-CoA dehydrogenase deficiency. After the treatment with vitamin B2, L-carnitine, and bezafibrate, the boy gradually improved, and reexamination after 3 months showed normal biochemical parameters. The boy had compound heterozygous mutations in the ETFDH gene, i.e., a known mutation, c.341G>A (p.R114H), from his mother and a novel mutation, c.1484C>G (p.P495R), from his father. Finally, he was diagnosed with multiple acyl-CoA dehydrogenase deficiency. Reye syndrome and sudden death symptoms were caused by nimesulide-induced acute metabolic crisis. It is concluded that inherited metabolic diseases may be main causes of Reye syndrome and sudden death, and biochemical and genetic analyses are the key to identifying underlying diseases.
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PMID:[Reye syndrome and sudden death symptoms after oral administration of nimesulide due to upper respiratory tract infection in a boy]. 3047 28