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)

Effect of L-carnitine (LC) on the metabolism of organic acids and carnitine homeostasis was studied in rats with riboflavin deficiency producing unusual dicarboxylic acidurea and modeling multiple acyl-CoA dehydrogenase deficiency in humans. Riboflavin deficient (RFD) rats exhibited increased excretion of glutaric, ethylmalonic, and methylsuccinic acids, as well as isovaleryl-, butyryl-, isobutyryl-, 2-methyl-butyryl-, and hexanoylglycine, short-chain and medium-chain saturated, and unsaturated dicarboxylic organic acids (C6-C10). RFD rats also showed a decrease in the concentration of free LC in the blood plasma and in tissues, an increase in the level of isobutyryl- and isovalerylcarnitine in muscle tissue, and reduction in the level of acetyl- and propionylcarnitine in the blood plasma, kidney, and liver (all changes detected relative to animals in the control group). The introduction of LC to RFD rats normalized the LC homeostasis by increasing free LC concentration in the blood plasma and tissues, enhanced the acyl-LC excretion with urine and the level in tissues, and reduced the manifestations of organic acidurea.
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PMID:[Effect of L-carnitine on metabolic disorders in rats with experimental acyl-CoA dehydrogenase deficiency]. 1570 16

Skeletal muscle function may be impaired in patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, but the value of L-carnitine in their long-term management is not clear. This study was designed as a pilot to examine the effects of L-carnitine on exercise tolerance in patients with MCAD deficiency. Four clinically asymoptomatic MCAD-deficient patients, aged 8 to 20 years, were studied. Incremental ramp exercise tests were carried out before and after 4 weeks' treatment with oral L-carnitine (100 mg/kg per day). During exercise without L-carnitine supplementation, plasma carnitine concentrations fell, associated with an increased excretion of urinary acylcarnitines, notably acetylcarnitine, hexanoylcarnitine and octanoylcarnitine. L-carnitine treatment prevented this fall in plasma carnitine and resulted in greater increases in excretion of acylcarnitines. All four patients showed biologically significant improvement in peak oxygen uptake (peak VO2, 18-32% improvement), VO2 at a heart rate of 170 beats/min (15-23% improvement), VO2 at anaerobic threshold (27-42% improvement), and/or oxygen pulse (10-32% improvement). Exercise tolerance in MCAD-deficient patients may be improved by short-term L-carnitine supplementation. This may be the direct result of improved intramitochondrial homeostasis induced by L-carnitine in removing accumulating acyl moieties.
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PMID:L-carnitine and exercise tolerance in medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency: a pilot study. 1587 3

Carnitine supplementation does not affect carnitine concentrations in tissues of wild-type and very long-chain acyl-CoA dehydrogenase-deficient mice, but results in an increase in long-chain acylcarnitine production.
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PMID:Carnitine supplementation induces long-chain acylcarnitine production--studies in the VLCAD-deficient mouse. 1676 98

Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD) results in accumulation of C14-C18 acylcarnitines and low free carnitine. Carnitine supplementation is still controversial. VLCAD knockout (VLCAD(+/-)) mice exhibit a similar clinical and biochemical phenotype to those observed in humans. VLCAD(+/-) mice were fed with carnitine dissolved in drinking water. Carnitine, acylcarnitines, and gamma-butyrobetaine were measured in blood and tissues. Measurements were performed under resting conditions, after exercise and after 24 h of regeneration. HepG2 cells were incubated with palmitoyl-CoA and palmitoyl-carnitine, respectively, to examine toxicity. With carnitine supplementation, acylcarnitine production was significantly induced. Nevertheless, carnitine was low in skeletal muscle after exercise. Without carnitine supplementation, liver carnitine significantly increased after exercise, and after 24 h of regeneration, carnitine concentrations in skeletal muscle completely replenished to initial values. Incubation of hepatic cells with palmitoyl-CoA and palmitoyl-carnitine revealed a significantly reduced cell viability after incubation with palmitoyl-carnitine. The present study demonstrates that carnitine supplementation results in significant accumulation of potentially toxic acylcarnitines in tissues. The expected prevention of low tissue carnitine was not confirmed. The principle mechanism regulating carnitine homeostasis seems to be endogenous carnitine biosynthesis, also under conditions with increased demand of carnitine such as in VLCAD-deficiency.
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PMID:Carnitine supplementation induces acylcarnitine production in tissues of very long-chain acyl-CoA dehydrogenase-deficient mice, without replenishing low free carnitine. 1831 32

At present, long-chain fatty acid oxidation (FAO) defects are diagnosed in a number of countries by newborn screening using tandem mass spectrometry. In the majority of cases, affected newborns are asymptomatic at time of diagnosis and acute clinical presentations can be avoided by early preventive measures. Because evidence-based studies on management of long-chain FAO defects are lacking, we carried out a retrospective analysis of 75 patients from 18 metabolic centres in Germany, Switzerland, Austria and the Netherlands with special regard to treatment and disease outcome. Dietary treatment is effective in many patients and can prevent acute metabolic derangements and prevent or reverse severe long-term complications such as cardiomyopathy. However, 38% of patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency had intermittent muscle weakness and pain despite adhering to therapy. Seventy-six per cent of patients with disorders of the mitochondrial trifunctional protein (TFP)-complex including long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, had long-term myopathic symptoms. Of these, 21% had irreversible peripheral neuropathy and 43% had retinopathy. The main principle of treatment was a fat-reduced and fat-modified diet. Fat restriction differed among patients with different enzyme defects and was strictest in disorders of the TFP-complex. Patients with a medium-chain fat-based diet received supplementation of essential long-chain fatty acids. l-Carnitine was supplemented in about half of the patients, but in none of the patients with VLCAD deficiency identified by newborn screening. In summary, in this cohort the treatment regimen was adapted to the severity of the underlying enzyme defect and thus differed among the group of long-chain FAO defects.
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PMID:Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. 1939 38

Body-weight differences in animals may be ascribed to genetic and environmental factors. Here we utilized two divergent porcine genotypes, the highly muscled, leaner PietrianxYorkshire pigs and less muscled, fatter DurocxYorkshire growing pigs (75-110 kg), to examine the role of genetic background on expression of genes associated with anabolic (Fatty acid synthase, FAS; glucose transporter 4, GLUT-4; stearoyl CoA desaturase, SCD; Sterol regulatory binding protein-1, SREBP-1; leptin) and catabolic lipid metabolism (Carnitine palmitoyltransferase-1B, CPT-1B; acyl-CoA dehydrogenase, ACDH) in adipose tissue (AT), liver (L) and skeletal muscle (SKM). Pietrain pigs had lower mRNA abundance for FAS, SREBP-1, SCD and leptin in AT and L, but higher mRNA abundance for L ACDH and SKM ACDH and CPT-1B than Durocs. Duroc pigs exhibited higher expression of FAS, SREBP-1, SCD, leptin in AT and FAS in L and lower expression of ACDH and CPT-1B in L SKM. GLUT-4 expression did not differ in SKM between the two genotypes. Feeding of a beta adrenergic agonist (Paylean) for 52 days lowered expression of lipid anabolic and enhanced lipid catabolic genes expressions similarly in both genotypes. Overall, the lipid metabolism genes differential expression patterns documented here showed that in Pietrain pigs mRNA abundances of synthesis genes were lower and of catabolic genes were higher than in Duroc pigs.
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PMID:Lipid metabolism related gene-expression profiling in liver, skeletal muscle and adipose tissue in crossbred Duroc and Pietrain Pigs. 2048 93

Mouse models have been designed for a number of fatty acid oxidation defects. Studies in these mouse models have demonstrated that different pathogenetic mechanisms play a role in the pathophysiology of defects of fatty acid oxidation. Supplementation with L-carnitine does not prevent low tissue carnitine levels and induces acylcarnitine production having potentially toxic effects, as presented in very-long-chain acyl-CoA dehydrogenase (VLCAD)-deficient mice. Energy deficiency appears to be an important mechanism in the development of cardiomyopathy and skeletal myopathy in fatty acid oxidation defects and is also the underlying mechanism of cold intolerance. Hypoglycemia as one major clinical sign in all fatty acid oxidation defects occurs due to a reduced hepatic glucose output and an enhanced peripheral glucose uptake rather than to transcriptional changes that are also observed simultaneously, as presented in medium-chain acyl-CoA dehydrogenase (MCAD)-deficient mice. There are reports that an impaired fatty acid oxidation also plays a role in intrauterine life. The embryonic loss demonstrated for some enzyme defects in the mouse supports this hypothesis. However, the exact mechanisms are unknown. This observation correlates to maternal hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, as observed in pregnancies carrying a long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)-deficient fetus. Synergistic heterozygosity has been shown in isolated patients and in mouse models to be associated with clinical phenotypes common to fatty acid oxidation disorders. Synergistic mutations may also modulate severity of the clinical phenotype and explain in part clinical heterogeneity of fatty acid oxidation defects. In summary, knowledge about the different pathogenetic mechanisms and the resulting pathophysiology allows the development of specific new therapies.
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PMID:Mitochondrial fatty acid oxidation disorders: pathophysiological studies in mouse models. 2053 23

We report an adult case of late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD) characterized by episodic recurrent rhabdomyolysis and acute renal failure after the age of 46. Muscle biopsy revealed lipid storage myopathy and the finding of serum acylcarnitine and urine organic acid analyses were consistent with MADD. A compound heterozygous mutation was identified in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene, including a novel missense mutation, which confirmed the diagnosis of MADD. After administration of riboflavin and L-carnitine, the muscle weakness and fatigability gradually improved. Acylcarnitine and urine organic acid were also normalized after supplementation. Thus, MADD should be included in one of the differential diagnoses for adult recurrent rhabdomyolysis. Gene analysis is useful to confirm the diagnosis, and early diagnosis is important because riboflavin treatment has been effective in a significant number of patients with MADD.
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PMID:A case of late onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency manifesting as recurrent rhabdomyolysis and acute renal failure. 2204 77

Mitochondrial myopathies commonly present with exercise intolerance typified by breathlessness and fatigue on exercise. In contrast, exercise-induced rhabdomyolysis and myoglobinuria occur rarely. We present a 43-year-old man with a lifelong history of exercise intolerance associated with myalgia and recurrent episodes of exercise-induced myoglobinuria. From early childhood, he had weekly episodes of myoglobinuria, which became infrequent (every 3 months) as an adult. Carnitine transporter defect was suspected, because carnitine levels were low in muscle. During childhood, he was treated with carnitine (4-5 g daily), but without effect. With the advent of acylcarnitines, profiles mimicking but not diagnostic for multiple acyl-CoA dehydrogenase deficiency (MADD) were found. This led to treatment with riboflavin (100 mg/day for 3 years), again without effect. Clinical examination, including echocardiography, revealed no signs of involvement from other organs, and all relatives were asymptomatic.
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PMID:Recurrent myoglobinuria and deranged acylcarnitines due to a mutation in the mtDNA MT-CO2 gene. 2361 64

The 1st International Carnitine Working Group concluded with a round table discussion addressing several areas of relevance. These included the design of future studies that could increase the amount of evidence-based data about the role of carnitine in the treatment of fatty acid oxidation defects, for which substantial controversy still exists. There was general consensus that future trials on the effect of carnitine in disorders of fatty acid oxidation should be randomized, double-blinded, multicentered and minimally include the following diagnoses: medium-chain acyl coenzyme A (CoA) dehydrogenase deficiency, very long-chain acyl-CoA dehydrogenase deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and mitochondrial trifunctional protein deficiency. Another area that generated interest was trials of carnitine in cardiomyopathy and, especially, the use of biomarkers to identify patients at greater risk of cardiotoxicity following treatment with anthracyclines. The possibility that carnitine treatment may lead to improvements in autistic behaviors was also discussed, although the evidence is still not sufficient to make any firm conclusions in this regard. Preliminary data on carnitine levels in children and adolescents with primary hypertension, low birth weight and nephrotic syndrome was also presented. Lastly, the panelists stressed that there remains an objective need to harmonize the terminology used to describe carnitine deficiencies (e.g., primary, secondary and systemic deficiency).
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PMID:Round Table Discussion. 2793 Oct 31


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