Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.3.99.3 (acyl-CoA dehydrogenase)
1,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A case of sudden death associated with fatty liver and encephalopathy is described in a 4-year old white boy with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency. The death was caused by hypoglycemia triggered by fasting and vomiting associated with a minor viral infection. The differential diagnosis of the hepatoencephalopathy is discussed in relation to other conditions, especially Reye's syndrome. The forensic pathologist should be familiar with MCAD and other deficiencies of beta-oxidation of fatty acids as a cause of sudden unexpected death in children in order to advise parents in genetic counseling to prevent disability or death of other affected, but still asymptomatic siblings.
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PMID:Fatty liver, encephalopathy, and sudden unexpected death in early childhood due to medium-chain acyl-coenzyme A dehydrogenase deficiency. 128 65

A four-year-old and a three-year-old boy with somnolence, coma and hypoglycaemia were found to have a defect in the beta-oxidation of medium-chain fatty acids (medium-chain acyl CoA dehydrogenase [MCAD] defect). The brother of one of them had died aged 16 months of an acute disease resembling Reye's syndrome (coma, fatty liver, cerebral oedema). The other two boys have no symptoms now under daily treatment with 100 mg/kg carnitine and frequent carbohydrate-high, fat-poor meals. The MCAD defect is inherited as an autosomal recessive trait and should be considered in the differential diagnosis of unexplained loss of consciousness in children with non-ketotic hypoglycaemia or with Reye's syndrome, as well as in families with sudden infant death.
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PMID:[Medium-chain acyl-CoA dehydrogenase defect. Acute cerebral episodes and nonketotic hypoglycemia in children]. 238 17

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

Rats were maintained on fat-free high carbohydrate diets either with or without orotic acid (1%, w/w), pantethine (1%, w/w), adenine (0.25%, w/w), and/or p-chlorophenoxyisobutyrate (0.25%, w/w). Oxidation of fatty acid by liver mitochondria was inhibited to less than half that of the control after administration of orotic acid. Activities of acyl-CoA dehydrogenases were markedly decreased by orotic acid administration, but the following enzyme activities were not, or only slightly decreased: acyl-CoA synthetase, carnitine acyltransferases, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase. Simultaneous addition of pantethine in the orotic acid-containing diet prevented induction of fatty liver. It also prevented decreases in fatty acid oxidation capacity and acyl-CoA dehydrogenase activity. Introduction of adenine or p-chlorophenoxyisobutyrate, which reverse orotic acid-induced fatty liver, reversed oxidation and acyl-CoA dehydrogenase activities to control levels. The oxidation capacity of the peroxisomal system remained unchanged after administration of orotic acid.
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PMID:Reduction of beta-oxidation capacity of rat liver mitochondria by feeding orotic acid. 710 78

We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor alpha (PPARalpha), plays a pivotal role in the cellular metabolic response to fasting. Short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPARalpha (PPARalpha-/-), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPARalpha+/+ mice, fasting induced the hepatic and cardiac expression of PPARalpha target genes encoding key mitochondrial (medium-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase I) and extramitochondrial (acyl-CoA oxidase, cytochrome P450 4A3) enzymes. In striking contrast, the hepatic and cardiac expression of most PPARalpha target genes was not induced by fasting in PPARalpha-/- mice. These results define a critical role for PPARalpha in a transcriptional regulatory response to fasting and identify the PPARalpha-/- mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.
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PMID:A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. 1037 39

A 5-year-old white female presented with coma and died unexpectedly. She had a history of recurrent episodes of febrile illnesses associated with lethargy and coma. Postmortem investigation revealed a fatty liver, leading to a suspicion of inborn error of fatty acid oxidation. The diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency was suggested by abnormal acylcarnitine profile with increased octanoylcarnitine in the blood, and confirmed by fatty acid oxidation studies and mutation analysis in skin fibroblast cultures. This case emphasizes the need to consider fatty acid oxidation disorders in all children who present with hypoglycemia with absent or mild ketones in the urine and high anion gap metabolic acidosis.
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PMID:Delayed diagnosis of fatal medium-chain acyl-CoA dehydrogenase deficiency in a child. 1060 24

We reported a male infant with multiple acyl CoA dehydrogenase deficiency, probably due to electron transfer flavoprotein dehydrogenase deficiency. He was noted to have severe muscle weakness, a high serum creatine kinase (CK) level up to 6920 IU/L, lipid storage myopathy and fatty liver at 6 months of age. A GC/MS analysis of urinary organic acids showed excess excretion of dicarboxylic acids, including glutaric, 2-hydroxyglutaric, adipic, suberic, sebacic, malonic, ethylmalonic and methylsuccinic acids. On a urinary acylglycine analysis, hexanoylglycine and suberylglycine were increased, but not isovalerylglycine, in amount. No ketosis was noted. The muscle pathology showed increased oil-red O positive lipid droplets of various sizes indicative of lipid storage myopathy. There was diffuse decrease in the activity of cytochrome c oxidase. No ragged-red fibers were noted. His clinical symptoms improved remarkably after the administration of riboflavin (100 mg/day) and L-carnitine (1000 mg/day). He was then diagnosed as having probable riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. The glutaryl CoA dehydrogenase activity in lymphocytes was normal, as were the alpha- and beta-subunits of electron transfer flavoprotein. These findings led us to suspect electron transfer flavoprotein dehydrogenation deficiency. Although he had several episodes of short-term deterioration in clinical and laboratory findings, he developed normally with normal intelligent till 10 years of age.
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PMID:[A case of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (glutaric aciduria type II)]. 1072 93

Hepatic steatosis is a frequent complication in nonobese patients with breast cancer treated with tamoxifen, a potent antagonist of estrogen. In addition, hepatic steatosis became evident spontaneously in the aromatase-deficient (ArKO) mouse, which lacks intrinsic estrogen production. These clinical and laboratory observations suggest that estrogen helps to maintain constitutive lipid metabolism. To clarify this hypothesis, we characterized the expression and activity in ArKO mouse liver of enzymes involved in peroxisomal and mitochondrial fatty acid beta-oxidation. Northern analysis showed reduced expression of mRNAs for very long fatty acyl-CoA synthetase, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase, enzymes required in fatty acid beta-oxidation. In vitro assays of fatty acid beta-oxidation activity using very long (C24:0), long (C16:0), or medium (C12:0) chain fatty acids as the substrates confirmed that the corresponding activities are also diminished. Impaired gene expression and enzyme activities of fatty acid beta-oxidation were restored to the wild-type levels, and hepatic steatosis was substantially diminished in animals treated with 17beta-estradiol. Wild-type and ArKO mice showed no difference in the binding activities of the hepatic nuclear extracts to a peroxisome proliferator response element. These findings demonstrate the pivotal role of estrogen in supporting constitutive hepatic expression of genes involved in lipid beta-oxidation and in maintaining hepatic lipid homeostasis.
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PMID:Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice. 1086 97

An increasing number of women with inborn errors of metabolism are now reaching child-bearing age. For certain disorders there are maternal risks associated with pregnancy. These may be related to an increased likelihood of metabolic decompensation (e.g. disorders of the urea cycle) or to increased stress to systems already compromised by disease (e.g. cardiomyopathy in GSD III). Detrimental effects upon the fetus may also be caused by maternal disease, as occurs with phenylketonuria, or from medication used to treat the mother's condition. Less commonly, fetal inborn errors may adversely effect the mother's health--e.g. fetal long-chain acyl-CoA dehydrogenase deficiency and the maternal HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) and AFLP (acute fatty liver of pregnancy). Because of the rarity of individual disorders, our knowledge of risks associated with pregnancy is limited. Even for more common inborn errors such as phenylketonuria, there remain a number of questions that have not been fully answered.
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PMID:Inborn errors of metabolism and pregnancy. 1086 39


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