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

The urinary excretion of metabolites of orally administered phenylpropionic acid (PPA) in 72 children, aged 2 days to 16 years, thought to be at-risk of medium acyl CoA dehydrogenase deficiency has been studied. Forty had presented as Reye Syndrome, 9 as a Reye-like syndrome and 24 were sibs of decreased RS, sibs of RLS cases or sibs of infants who had died suddenly and without explanation where an autopsy revealed the presence of very heavy fatty infiltration of the liver. These studies demonstrated that PPA metabolites are maximally excreted during the 3 hours following the oral load and that this urine collection should be diagnostic. PPA loading is a relatively simple, safe test which is part of the investigation of a patient suspected of having an inborn error of metabolism.
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PMID:The phenylpropionic acid load test: experience with 72 children at-risk for beta-oxidation disorders. 147 38

In summary, the vitamin pantothenic acid is an integral part of the acylation carriers, CoA and acyl carrier protein (ACP). The vitamin is readily available from diverse dietary sources, a fact which is underscored by the difficulty encountered in attempting to induce pantothenate deficiency. Although pantothenic acid deficiency has not been linked with any particular disease, deficiency of the vitamin results in generalized malaise clinically. In view of the fact that pantothenate is required for the synthesis of CoA, it is surprising that tissue CoA levels are not altered in pantothenate deficiency. This suggests that the cell is equipped to conserve its pantothenate content, possibly by a recycling mechanism for utilizing pantothenate obtained from degradation of pantothenate-containing molecules. Although the steps involved in the conversion of pantothenate to CoA have been characterized, much remains to be done to understand the regulation of CoA synthesis. In particular, in view of what is known about the in vitro regulation of pantothenate kinase, it is surprising that the enzyme is active in vivo, since factors that are known to inhibit the enzyme are present in excess of the concentrations known to inhibit the enzyme. Thus, other physiological regulatory factors (which are largely unknown) must counteract the effects of these inhibitors, since the pantothenate-to-CoA conversion is operative in vivo. Another step in the biosynthetic pathway that may be rate limiting is the conversion of 4'-phosphopantetheine (4'-PP) to dephospho-CoA, a step catalyzed by 4'-phosphopantetheine adenylyl-transferase. In mammalian systems, this step may occur in the mitochondria or in the cytosol. The teleological significance of these two pathways remains to be established, particularly since mitochondria are capable of transporting CoA from the cytosol. Altered homeostasis of CoA has been observed in diverse disease states including starvation, diabetes, alcoholism, Reye syndrome (RS), medium-chain acyl CoA dehydrogenase deficiency, vitamin B12 deficiency, and certain tumors. Hormones, such as glucocorticoids, insulin, and glucagon, as well as drugs, such as clofibrate, also affect tissue CoA levels. It is not known whether the abnormal metabolism observed in these conditions is the result of altered CoA metabolism or whether CoA levels change in response to hormonal or nonhormonal perturbations brought about in these conditions. In other words, a cause-effect relation remains to be elucidated. It is also not known whether the altered CoA metabolism (be it cause or result of abnormal metabolism) can be implicated in the manifestations of a disease. Besides CoA, pantothenic acid is also an integral part of the ACP molecule.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pantothenic acid in health and disease. 174 61

The medium-chain acyl-CoA dehydrogenase (MCAD) deficiency of mitochondrial beta oxidation has been identified in a nine-year old boy with a very bland course and easy fatigue as the main symptom. Repeated low frequency stimulation test and EMG for excluding a myasthenia gravis, and screening for urinary organic acid excretion were helpful for the diagnosis. The EMG test at the m. trapezius by stimulation of the n. accessorius showed an extreme decrease of muscle power down to 49%. After i.v. injection of Edrophonium the loss of power of 20% was still significant, so that we could exclude a myasthenia gravis, but we had found signs of a generalised defect in cell chemistry. The diagnosis could be confirmed by a positive 3-phenylpropionic acid-test and moleculargenetic proof of the Adenine to Guanine mutation at position 985 in the MCAD cDNA (G985) with the polymerase chain reaction. The incidence of this organic aciduria is probably 1:60,000 in Germany, but with more attention to this disease and diagnosis of cases with bland courses the incidence will be higher. The MCAD-defect should be considered in the differential diagnosis of patients with Reye syndrome-like encephalopathies, non-ketotic hypoglycaemia or sudden unexpected deaths in infancy.
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PMID:[Acyl coenzyme A dehydrogenase deficiency of medium-chain fatty acids in a 9-year-old boy with adymia. A rare mitochondrial cytopathy which may be more common than previously assumed]. 177 46

The clinical, laboratory, and pathologic findings in a patient with a previously undescribed deficiency in fatty acid oxidation are summarized. The patient had a fatal defect in fatty acid metabolism profoundly affecting heart, skeletal muscle, liver, and kidney. Oxidation of palmitate was 38-51% of controls. Complementation assays demonstrated that the patient's fibroblasts complemented fibroblast lines from all known defects in fatty acid oxidation except long-chain acyl-CoA dehydrogenase deficiency. Urine and serum carnitine profiles also were indicative of a defect in the oxidation of long-chain substrate; however, the palmitoyl-CoA dehydrogenase activity was actually increased. This finding indicates that the patient had a defect that was distinct from, but possibly related to, long-chain acyl-CoA dehydrogenase deficiency. This patient demonstrates the laboratory and pathologic findings in defects in fatty acid oxidation and how they differ from those in Reye syndrome.
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PMID:Defect in fatty acid oxidation: laboratory and pathologic findings in a patient. 205 53

Inborn errors involving the oxidative metabolism of fatty acids may present clinically with a Reye syndrome-like picture. This case report of a patient with medium-chain acyl CoA dehydrogenase (MCAD) deficiency illustrates that electron microscopy may help to differentiate this disorder from Reye syndrome even if a liver biopsy is performed in a patient who recovered from an acute metabolic decompensation. Together with this case, a review of the few reports in the literature of pathological findings in MCAD deficiency is given. Changes uncharacteristic for Reye syndrome are a large-droplet steatosis and the presence of distinctive mitochondrial abnormalities on electron microscopy. The detection of an electron dense mitochondrial matrix and a widened space of inner mitochondrial membranes rules out Reye syndrome and is suggestive of a disorder of mitochondrial fatty acid oxidation.
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PMID:Medium-chain acyl CoA dehydrogenase deficiency: electron microscopic differentiation from Reye syndrome. 227 5

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

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

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.
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PMID:Relationship between unusual hepatic acyl coenzyme A profiles and the pathogenesis of Reye syndrome. 341 71

A family is described in which the father and three (and probably all four) of his children had a decreased capacity for the oxidation of medium-chain fatty acids. One of the children suddenly died at the age of 16 months following an episode of a rapidly deteriorating Reye syndrome-like illness with hypoketotic hypoglycemia and dicarboxylic aciduria, but without any previous alarming symptoms. The eldest sibling had died at the age of 19 months under similar conditions. The other family members had always been healthy. On fasting, all affected family members accumulated in their plasma the medium-chain fatty acids octanoic, decanoic, and cis-4-decenoic acids. Their urinary organic acid excretion profile could be characterized as "dicarboxylic aciduria." A deficiency of medium-chain acyl-coenzyme A dehydrogenase was demonstrated in a postmortem liver sample of the index patient. Cultured fibroblasts from the father and the two healthy children had a decreased rate of [14C]octanoate oxidation. It is suggested that a deficiency of medium-chain acyl-coenzyme A dehydrogenase may lead to a life-threatening illness when other complicating factors such as diarrhea and vomiting result in an abnormal depletion of the body's glycogen stores. Careful monitoring of at-risk patients during a minor illness is necessary.
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PMID:Sudden child death and 'healthy' affected family members with medium-chain acyl-coenzyme A dehydrogenase deficiency. 378 30


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