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)

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

Treatment of 17 children aged 2-9.5 years with a combination of pivmecillinam and pivampicillin (250-500 mumol 24 h-1) for more than 1 year resulted in a reduction of the free carnitine concentration in serum and muscle to less than 10% of the mean reference value. The decline in serum was slow, with an estimated half-life of about 5 months. Spontaneous replenishment occurred at about the same slow rate. Thus, there is no increase in endogenous carnitine synthesis as a response to increased demand of carnitine for detoxification. Supplementation with carnitine during treatment required at least a four-fold molar excess over pivalic acid to achieve and sustain a normal carnitine concentration. The replenishment of carnitine occurred with a half-life of 1.1-3.0 months. From determination of muscle-carnitine concentration in patients treated with pivaloyl-containing antibiotics and in patients with organic aciduris, we conclude that serum carnitine is a good predictor of carnitine stores in the body. Six non-supplemented patients with a serum free-carnitine concentration of 0.7-2.6 mumol l-1 had an inadequate ketone-body increase during a 24-h fast. Vomiting, nausea and tiredness occurred in three cases following the fasting period. After normalization of the serum-carnitine concentration, a normal response to fasting was observed. Thus, in some organic acidurias, for example medium-chain acyl-CoA dehydrogenase deficiency, a low liver concentration of carnitine may be an important contributing factor to hypoglycaemic and Reye-like attacks. We believe that prodrugs which contain pivalic acid should be avoided if acceptable alternatives exist. If used, supplementation with at least four-fold molar excess of carnitine is advisable.
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PMID:Effects of pivalic acid-containing prodrugs on carnitine homeostasis and on response to fasting in children. 151 15

From 65 reported cases of medium chain acyl-CoA dehydrogenase deficiency, we found an average presenting age of 13.5 months and a mean age at death of 18.5 months. One quarter of patients died of a Reye-like syndrome and/or sudden infant death. In half the cases there had been at least one sibling death. Asymptomatic cases were not uncommon (12% of cases). The crises were generally induced by a prolonged fast and after a viral prodromal phase in three quarters of cases. The crises consisted of somnolence progressing to lethargy which could lead to coma. Vomiting was frequent (60% of cases). Seizures, which were found in 29% of cases, represented a bad prognosis. The physical examinations revealed frequently a variable and regressive anicteric hepatomegaly. Blood and urine analysis revealed in most instances hypoglycaemia (96% of cases) with hypoketonuria and sometimes metabolic acidosis. Hepatic and muscular cytolytic enzymes were frequently raised, as were plasma ammonia, urea, and uric acid. Plasma total or free carnitine concentrations, especially non-fasting, were diminished in most cases. Plasma saturated medium chain fatty acids and particularly unsaturated cis-4-decenoate were on the other hand raised during the crises or during fasting. Urinary organic acid analysis revealed a characteristic profile of medium chain aciduria: C6-C10 dicarboxylic acids, hydroxy acids, glycine conjugates, and carnitine conjugates. Oral loading tests with carnitine or phenylpropionate allow a precise diagnosis. The diagnosis is confirmed by specific assays in various tissues. Avoidance of prolonged fasting seems to be the mainstay of treatment.
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PMID:Medium chain acyl-CoA dehydrogenase deficiency. 173 32

Long-chain fatty acids (LCFA) are oxidized by muscle mitochondria after transport in the cytosol by fatty-acid-binding protein(s) and their activation by a thiokinase. Carnitine, two forms of carnitine palmitoyltransferase(s) and carnitine acylcarnitine translocase are involved in LCFA gating. A primary genetic carnitine deficiency occurs in children with dilated cardiomyopathy, hypoglycaemia and low carnitine content in plasma, liver and muscle, owing to a defect in a common high-affinity transport system. This high-affinity transport in muscle differs from a low-affinity transport that has modifications during muscle maturation. The genetic enzyme defects of beta-oxidation (long-chain acyl-CoA dehydrogenase, medium- and short-chain acyl-CoA-dehydrogenase) present with Reye-like attacks that may lead to non-ketotic hypoglycaemia, coma and sudden infant death syndrome. There is elevated urinary excretion of dicarboxylic acids, acylcarnitines and acylglycines. Secondary carnitine deficiency may occur. ETF and ETF dehydrogenase deficiencies may present in a neonatal form with congenital anomalies, or in a later-onset form with ethylmalonic adipic aciduria. A still-unidentified defect leads to LCFA accumulation in fibroblasts, bone marrow, liver and muscle cells in a multisystem triglyceride disorder.
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PMID:Defects of fatty-acid oxidation in muscle. 226 28

The determination of medium chain fatty acids in serum is a useful approach of the diagnosis of medium chain acyl-CoA dehydrogenase deficiency, an increasingly recognized cause of Reye-like syndrome in infants. A reliable and practical method requiring 0.5 ml of serum is presented by which results are obtained within 2.5 h. The preparation of the samples is done by solid phase extraction on reverse phase cartridges, the separation and quantitation by gas chromatography. Reference values for children (n = 24) and adults (n = 40) are given for octanoic, decanoic and dodecanoic acids.
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PMID:Determination of medium chain fatty acids in serum. 337 Aug 37

The clinical and pathologic findings in 12 patients with medium-chain acyl CoA dehydrogenase deficiency and three patients with long-chain acyl CoA dehydrogenase deficiency are summarized. Although these inborn errors of intramitochondrial beta-oxidation of fatty acids present with similar findings to Reye's syndrome, there are clinical, laboratory and hepatic histologic differences. Younger age at presentation, history of unexplained sibling death, a previous episode of lethargy, hypoglycemia or acidosis precipitated by fasting stress and only mildly elevated serum transaminases with normal or only mildly prolonged prothrombin time may all suggest an acyl CoA dehydrogenase deficiency. Long-chain acyl CoA dehydrogenase deficiency is differentiated from medium-chain acyl CoA dehydrogenase deficiency by younger age at presentation, more profound cardiorespiratory depression, evidence of cardiomyopathy, and sequelae of muscle weakness, hypotonia and developmental delay. Definitive diagnosis is made by assay of medium-chain or long-chain enzyme activity in cultured skin fibroblasts or in leukocytes. Hepatic light microscopic alterations are essentially limited to steatosis, which may be either macro- or microvesicular. The cases with microvesicular steatosis can be differentiated morphologically from Reye's syndrome by electron microscopy, showing the absence of the mitochondrial changes characteristic of Reye's. Four of seven cases of acyl CoA dehydrogenase deficiency showed some variations from normal in the appearance of the hepatocyte mitochondria. The relationship of these variations to the basic metabolic defect(s) remains to be determined.
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PMID:Medium-chain and long-chain acyl CoA dehydrogenase deficiency: clinical, pathologic and ultrastructural differentiation from Reye's syndrome. 379 3

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.
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PMID:Genetic deficiency of medium-chain acyl coenzyme A dehydrogenase: studies in cultured skin fibroblasts and peripheral mononuclear leukocytes. 402 73

Capillary gel electrophoresis with laser-induced fluorescence (CGE-LIF) has been developed to detect polymerase chain reaction (PCR) amplified samples. LIF detection was performed using Thiazole Orange as the fluorescent intercalating dye. This method was ca. 100x as sensitive as that with UV detection. The highly sensitive CGE-LIF was applied to the detection of the most prevalent mutation (lysine329-to-glutamic acid substitution) in medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency. The disorder, which shows an autosomal recessive inheritance, is known to be highly prevalent among Caucasian population and often mimics as Reye-like syndrome or sudden infant death. A DNA fragment containing the mutation site was PCR-amplified with two sets of allele specific oligonucleotide primers, followed by CGE-LIF. The mutant allele produced a 175-base pairs DNA fragment, which the normal allele generated a 202-base pairs DNA fragment. CGE-LIF clearly distinguished these PCR products, facilitating rapid diagnosis of MCAD deficiency.
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PMID:Analysis of polymerase chain reaction-product by capillary electrophoresis with laser-induced fluorescence detection and its application to the diagnosis of medium-chain acyl-coenzyme A dehydrogenase deficiency. 798 32

Inherited defects of mitochondrial beta-oxidation of fatty acids lead to hypoketotic hypoglycemia during prolonged fasting. Affected patients may present with episodes of a Reye-like illness or even sudden child death. The number of currently detected patients with medium-chain acyl-CoA dehydrogenase deficiency--the most common disease in this area--is indicative of a high frequency, possibly comparable to that of phenylketonuria. A comprehensive system of biochemical analyses is described, which enables the differential diagnosis of the various defects. An indispensable part of the diagnostic system is the gas chromatographic/mass spectrometric analysis of plasma and urinary organic acids. A correct diagnosis is a prerequisite for the installment of specific treatment.
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PMID:Diagnosis of mitochondrial fatty acid oxidation defects. 844 24

The most frequent metabolic cause of Reye-like syndrome is medium chain acyl-CoA dehydrogenase (MCAD) deficiency. The authors describe a gypsy boy who was repeatedly hospitalised due to symptoms of Reye-like syndrome (serious hypoglycemia, loss of consciousness, seizures, increased values of aminotransferases, decreased values of free carnitine). The diagnosis of MCAD deficiency was established by analysis of plasmatic acylcarnitines by use of tandem mass spectrometry. DNA analysis proved the most common K329E (G985) mutation in gene for MCAD deficiency in homozygous state. The authors have emphasised the advantage of tandem mass spectrometry in the diagnosis of disorders of fatty acid beta-oxidation. This highly sophisticated method can detect most of these disorders from dry blood spots disregarding the symptoms and type of mutation.
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PMID:Metabolic cause of Reye-like syndrome. 1176 81


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