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)

Glutaric aciduria type II, also known as multiple acyl coenzyme A dehydrogenase deficiency, is an autosomal recessive, mitochondrial organic acid disorder that impairs electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase, and causes a defect in flavin metabolism or transport. It has a heterogeneous clinical presentation, with at least three different phenotypic appearances. Magnetic resonance (MR) imaging of the brain in this disorder shows a T2-weighted prolongation in the corpus striatum, putamen, caudate nucleus, middle cerebral peduncles and splenium of the corpus callosum. We report a seven-month-old male Caucasian child who presented at the paediatrics emergency department with a sweetish breath. He was clinically diagnosed with diabetic ketoacidosis. However, on MR imaging, brain evaluation and laboratory analysis, he was found to have glutaric aciduria type II.
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PMID:MR imaging findings of glutaric aciduria type II. 2050 99

In Taiwan, during the period March 2000 to June 2009, 1,495,132 neonates were screened for phenylketonuria (PKU) and homocystinuria (HCU), and 1,321,123 neonates were screened for maple syrup urine disease (MSUD), methylmalonic academia (MMA), medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) deficiency, isovaleric academia (IVA), and glutaric aciduria type 1 (GA-1) using tandem mass spectrometry (MS/MS). In a pilot study, 592,717 neonates were screened for citrullinemia, 3-methylcrotonyl-CoA carboxylase deficiency (3-MCC) and other fatty acid oxidation defects in the MS/MS newborn screening. A total of 170 newborns and four mothers were confirmed to have inborn errors of metabolism. The overall incidence was approximately 1/5,882 (1/6,219 without mothers). The most common inborn errors were defects of phenylalanine metabolism [five classic PKU, 20 mild PKU, 40 mild hyperphenylalaninemia (HPA), and 13 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency]. MSUD was the second most common amino acidopathy and, significantly, most MSUD patients (10/13) belonged to the Austronesian aboriginal tribes of southern Taiwan. The most frequently detected among organic acid disorders was 3-MCC deficiency (14 newborns and four mothers). GA-1 and MMA were the second most common organic acid disorders (13 and 13 newborns, respectively). In fatty acid disorders, five carnitine transport defect (CTD), five short-chain acyl-CoA dehydrogenase deficiency (SCAD), and two medium-chain acyl-CoA dehydrogenase (MCAD) deficiency were confirmed. This is the largest case of MS/MS newborn screening in an East-Asian population to date. We hereby report the incidences and outcomes of metabolic inborn error diseases found in our nationwide MS/MS newborn screening program.
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PMID:Nationwide survey of extended newborn screening by tandem mass spectrometry in Taiwan. 2056 11

Glutaric aciduria type II, or multiple acyl-CoA dehydrogenase deficiency, is a rare metabolic disorder inherited in an autosomal recessive manner. The condition can be caused by mutations in at least 3 genes, including ETFA, ETFB, and ETFDH. When this potentially lethal disorder is known for its clinical and biochemical heterogeneity, mutation analysis will be an invaluable part of diagnosis. We here described a Chinese adolescent boy who enjoyed good health earlier and presented at the age of 14 years with severe vomiting. His condition deteriorated rapidly and he succumbed shortly after. With a travel history before presentation and the late age of onset, diagnosis was particularly difficult. Findings in perimortem biochemical investigations and postmortem autopsy were guiding but not diagnostic. The diagnosis of glutaric aciduria type II was finally confirmed by mutation analysis performed by direct sequencing on genomic DNA from peripheral blood, which identified 2 different unreported missense mutations, c.502G>T (p.V168F) and c.786A>G (p.Q262R), in ETFA. The father and the mother were found to be heterozygous for the 2 mutations in ETFA respectively. Subsequent molecular family screening also ruled out the disease in his elder sister, who had a history of convulsion and a suspicious plasma acylcarnitine profile, and freed her from life-long supplementation. The case showed that molecular autopsies should be part of routine postmortem examination of unexplained sudden death in all age groups and DNA-friendly samples should be routinely collected and archived. In the era of personalized medicine with the power of modern genetics, molecular diagnosis should be obtained for heterogeneous diseases with different genetic defects but sharing similar clinical and/or biochemical phenotypes.
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PMID:Role of postmortem genetic testing demonstrated in a case of glutaric aciduria type II. 2073 50

We describe a 22-year-old male who developed severe hypoglycemia and lethargy during an acute illness at 4 months of age and subsequently grew and developed normally. At age 4 years he developed recurrent vomiting with mild hyperammonemia and dehydration requiring frequent hospitalizations. Glutaric aciduria Type II was suspected based upon biochemical findings and managed with cornstarch, carnitine and riboflavin supplements. He did not experience metabolic crises between ages 4-12 years. He experienced recurrent vomiting, mild hyperammonemia, and generalized weakness associated with acute illnesses and growth spurts. At age 18 years, he developed exercise intolerance and proximal muscle weakness leading to the identification of multiple acyl-CoA dehydrogenase and complex II/III deficiencies in both skeletal muscle and liver. Subsequent molecular characterization of the ETFDH gene revealed novel heterozygous mutations, p.G274X:c.820 G > T (exon 7) and p.P534L: c.1601 C > T (exon 12), the latter within the iron sulfur-cluster and predicted to affect ubiquinone reductase activity of ETFDH and the docking of ETF to ETFDH. Our case supports the concept of a structural interaction between ETFDH and other enzyme partners, and suggests that the conformational change upon ETF binding to ETFDH may play a key role in linking ETFDH to II/III super-complex formation.
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PMID:Novel ETF dehydrogenase mutations in a patient with mild glutaric aciduria type II and complex II-III deficiency in liver and muscle. 2108 98

Fatty acid oxidation in mitochondrial matrix is a major source of energy in muscle, especially when physiological energy demand is increased and exceeds what can be provided through glycolysis. Not surprisingly, a group of muscle disorders due to defects in this system usually leads to the development of acute rhabdomyolysis in conditions such as infection, fasting and prolonged exercise. This group includes beta-oxidation cycle defects and deficiencies of carnitine palmitoyltransferase II (CPTH) and very-long-chain acyl-CoA dehydrogenase (VLCAD). Muscle pathology is usually not very helpful for the diagnosis but immunohistochemistry may be useful for screening VLCAD deficiency. Another group of lipid dysmetablolism is lipid storage myopathy (LSM) that is pathologically characterized by increased lipid droplets both in number and size in muscle fibers. So far, causative genes have been identified in four different LSMs, comprising primary carnitine deficiency, multiple acyl-CoA dehydrogenase deficiency or glutaric aciduria type II, neutral lipid storage disease with ichthyosis, and neutral lipid storage disease with myopathy. Clinically, the LSM patients show slowly progressive muscle weakness unlike the former group. Final diagnosis is usually made by specific biochemical assays with mutation analyses. As some effective drugs have been widely used and some promising therapies are under certified, comprehensive understanding of these diseases from clinical, pathological and molecular aspects would be of much help for the patients.
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PMID:State of the art in muscle lipid diseases. 2131 18

Metabolomics has become an important tool in clinical research and diagnosis of human diseases. In this work we focused on the diagnosis of inherited metabolic disorders (IMDs) in plasma samples using a targeted metabolomic approach. The plasma samples were analyzed with the flow injection analysis method. All the experiments were performed on a QTRAP 5500 tandem mass spectrometer (AB SCIEX, U.S.A.) with electrospray ionization. The compounds were measured in a multiple reaction monitoring mode. We analyzed 50 control samples and 34 samples with defects in amino acid metabolism (phenylketonuria, maple syrup urine disease, tyrosinemia I, argininemia, homocystinuria, carbamoyl phosphate synthetase deficiency, ornithine transcarbamylase deficiency, nonketotic hyperglycinemia), organic acidurias (methylmalonic aciduria, propionic aciduria, glutaric aciduria I, 3-hydroxy-3-methylglutaric aciduria, isovaleric aciduria), and mitochondrial defects (medium-chain acyl-coenzyme A dehydrogenase deficiency, carnitine palmitoyltransferase II deficiency). The controls were distinguished from the patient samples by principal component analysis and hierarchical clustering. Approximately 80% of patients were clearly detected by absolute metabolite concentrations, the sum of variance for first two principle components was in the range of 44-55%. Other patient samples were assigned due to the characteristic ratio of metabolites (the sum of variance for first two principle components 77 and 83%). This study has revealed that targeted metabolomic tools with automated and unsupervised processing can be applied for the diagnosis of various IMDs.
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PMID:Targeted metabolomic analysis of plasma samples for the diagnosis of inherited metabolic disorders. 2201 16

Many newborn screening programmes now use tandem mass spectrometry in order to screen for a variety of diseases. However, countries have embraced this technology with a differing pace of change and for different conditions. This has been facilitated by the ability of this diagnostic method to limit analysis to specific metabolites of interest, enabling targeted screening for particular conditions. MS/MS was introduced in 2009 in England to implement newborn bloodspot screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) raising the possibility of screening for other inherited metabolic disorders. Recently, a pilot screening programme was conducted in order to evaluate the health and economic consequences of screening for five additional inherited metabolic disorders in England. As part of this study we conducted a systematic review and meta-analysis to estimate the birth prevalence of these conditions: maple syrup urine disease, homocystinuria (pyridoxine unresponsive), glutaric aciduria type I, isovaleric acidaemia and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency including trifunctional protein deficiency. We identified a total of 99 studies that were able to provide information on the prevalence of one or more of the disorders. The vast majority of studies were of screening programmes with some reporting on clinically detected cases.
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PMID:Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases. 2502 22

Acylcarnitine profile (ACP) is a useful tool in the biochemical diagnosis and monitoring of many acquired and inherited metabolic disorders. In the present study, acylcarnitines (ACs) were quantified in dried blood spot samples collected from 150 high risk Egyptian newborns and children using LC/MS/MS technique. They were referred to the Biochemical Genetics department in the National Research Center. Their age ranged from 1 to 36 months. Thirty seven patients had abnormal ACP diagnostic of some inherited metabolic disorders and other acquired conditions. The study revealed 5 (13.5%) with medium chain acyl CoA dehydrogenase deficiency (MCADD), 1 (2.7%) with long chain hydroxyacyl CoA dehydrogenase deficiency (LCHADD), 1 (2.7%) with multiple acyl CoA dehydrogenase deficiency (MADD), 28 (75.7%) with secondary carnitine deficiency (SCD), 1 (2.7%) with glutaric aciduria type I (GA I), and 1 (2.7%) with methylmalonic aciduria (MMA) (Tab. 8, Ref. 39).
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PMID:Disorders associated with abnormal acylcarnitine profile among high risk Egyptian children. 2517 60

This study reports on the inborn errors of metabolism (IEM) detected by our national newborn screening between 2011 and 2014. One hundred fourteen patients (55 UAE citizens and 59 residents) were diagnosed during this period. The program was most comprehensive (tested 29 IEM) and universally applied in 2013, giving an incidence of 1 in 1,787 citizens. This relatively high prevalence resulted from the frequent consanguineous marriages (81.5%) among affected families. The following eight disorders accounted for 80% of the entities: biotinidase deficiency (14 of 55), phenylketonuria (11 of 55), 3-methylcrotonyl glycinuria (9 of 55), medium-chain acyl-CoA dehydrogenase deficiency (4 of 55), argininosuccinic aciduria, glutaric aciduria type 1, glutaric aciduria type 2, and methylmalonyl-CoA mutase deficiency (2 of 55 each). Mutation analysis was performed in 48 (87%) of the 55 patients, and 33 distinct mutations were identified. Twenty-nine (88%) mutations were clinically significant and, thus, could be included in our premarital screening. Most mutations were homozygous, except for the biotinidase deficiency. The BTD mutations c.1207T>G (found in citizens) and c.424C>A (found in Somalians) were associated with undetectable biotinidase activity. Thus, the high prevalence of IEM in our region is amenable to newborn and premarital screening, which is expected to halt most of these diseases.
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PMID:Inborn Errors of Metabolism in the United Arab Emirates: Disorders Detected by Newborn Screening (2011-2014). 2658 11

Carnitine transporter defect (CTD; also known as systemic primary carnitine deficiency; MIM 212140) is due to mutations in the SLC22A5 gene and leads to extremely low carnitine levels in blood and tissues. Affected individuals may develop early onset cardiomyopathy, weakness, or encephalopathy, which may be serious or even fatal. The disorder can be suggested by newborn screening. However, markedly low newborn carnitine levels can also be caused by conditions unrelated to CTD, such as the low carnitine levels often associated with normal pregnancies and some metabolic disorders occurring in the mother. In order to clarify the biochemical characteristics most useful for identification of CTD in newborns, we examined California Department of Public Health newborn screening data for CTD from 2005 to 12 and performed detailed chart reviews at six metabolic centers in California. The reviews covered 14 cases of newborn CTD, 14 cases of maternal disorders (CTD, 6 cases; glutaric aciduria, type 1, 5; medium-chain acyl CoA dehydrogenase deficiency, 2; and cobalamin C deficiency, 1), and 154 false-positive cases identified by newborn screening. Our results show that newborns with CTD identified by NBS exhibit different biochemical characteristics, compared to individuals ascertained clinically. Newborns with CTD may have NBS dried blood spot free carnitine near the lower cutoff and confirmatory plasma total and free carnitine levels near the normal lower limit, particularly if obtained within two weeks after birth. These findings raise the concern that true cases of CTD may exist that could have been missed by newborn screening. CTD should be considered as a possible diagnosis in cases with suggestive clinical features, even if CTD was thought to be excluded in the newborn period. Maternal plasma total carnitine and newborn urine total carnitine values are the most important predictors of true CTD in newborns. However, biochemical testing alone does not yield a discriminant rule to distinguish true CTD from low carnitine in newborns due to other causes. Because of this biochemical variability and overlap, molecular genetic testing is imperative to confirm CTD in newborns. Additionally, functional testing of fibroblast carnitine uptake remains necessary for cases in which other confirmatory testing is inconclusive. Even with utilization of all available diagnostic testing methods, confirmation of CTD ascertained by NBS remains lengthy and challenging. Incorporation of molecular analysis as a second tier step in NBS for CTD may be beneficial and should be investigated.
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PMID:Biochemical characteristics of newborns with carnitine transporter defect identified by newborn screening in California. 2871 8


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