Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.99.3 (acyl-CoA dehydrogenase)
 1,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acylcarnitine profiling from blood or plasma samples by electrospray tandem mass spectrometry (ESI-MS/MS) has been recognized recently as a useful tool in the biochemical diagnosis of propionic acidemia, methylmalonic acidemia together with short-chain and medium-chain acyl-CoA dehydrogenase deficiencies. In the current study, we have investigated the diagnostic capabilities of ESI-MS/MS in other types of organic acidemias and amino acid catabolism disorders. Using multiple scanning functions, we examined the potential for the simultaneous profiling of both acylcarnitines and amino acids, in each of the samples. Our method was found to be specific and accurate; allowing quantification of acylcarnitines and amino acids well below, and significantly above, published normal levels. Complete automation of sample introduction has been achieved, allowing the analysis of up to 200 samples in one injection sequence, at a rate of one sample every 3 min, with excellent separation between successive injections. In our hands, this method permits screening for 20 organic acid and amino acid disorders, using a single sample injection. In our laboratory, more than 2000 blood samples have been analyzed, and 52 new cases were diagnosed by this method. We also confirmed the diagnosis of another 75 previously known cases.
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PMID:Diagnosis of inborn errors of metabolism from blood spots by acylcarnitines and amino acids profiling using automated electrospray tandem mass spectrometry. 749 54

The analysis of circulating free carnitine and acyl-carnitines provides a powerful selective screening tool for genetic defects in mitochondrial fatty acid oxidation and defects in the catabolism of branched chain amino acids. Using electrospray tandem mass spectrometry (ESI/MS/MS) we developed a sensitive quantitative analysis of free carnitine and acyl-carnitines in plasma and/or serum. This method was evaluated by analyzing 250 control samples and 103 samples of patients suffering from twelve different defects in either mitochondrial fatty acid oxidation or the catabolism of branched chain amino acids. The reproducibility of the method was acceptable with a day-to-day coefficient of variation ranging from 6-15% for free carnitine and the different acylcarnitines. Except for one patient with a mild form of short chain acyl CoA dehydrogenase (SCAD) deficiency and a single sample from a patient with a mild form of multiple acyl CoA dehydrogenase (MAD) deficiency all patient samples were clearly abnormal under a wide variety of clinical conditions, illustrating the high sensitivity and specificity of the method.
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PMID:Rapid diagnosis of organic acidemias and fatty-acid oxidation defects by quantitative electrospray tandem-MS acyl-carnitine analysis in plasma. 1070 60

Inherited disorders of fatty acid oxidation are a group of acute life-threatening but treatable disorders, clinically complicated by severe hypoketotic hypoglycemia precipitated by prolonged fasting. Among them, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is by far the most frequent disorder. Here we report a modified method for quantitative acylcarnitine profiling by electrospray ionisation-tandem mass spectrometry (ESI-MS-MS) in human skin fibroblasts using unlabelled palmitic acid as substrate. The reliability of this method was tested in cultured skin fibroblasts from previously diagnosed patients with specific carnitine cycle and fatty acid beta-oxidation defects. Furthermore, acylcarnitine profiling was investigated in fibroblasts and dried blood spots from patients with different variants of MCAD deficiency. ESI-MS-MS-based investigation of cultured skin fibroblasts from patients with disorders of fatty acid oxidation revealed a pathognomonic acylcarnitine profiling. In addition, this method delineated different variants of MCAD deficiency, i.e. mild and classical. The octanoylcarnitine (C8)-to-decanoylcarnitine (C10) and C8-to-acetylcarnitine (C2) ratios were the most specific markers to differentiate mild and classical forms of MCAD deficiency in fibroblasts. Similar results were obtained by quantitative acylcarnitine profiling in dried blood spots. In conclusion, this novel technique is a powerful tool for the investigation of fatty acid oxidation disorders under standardized conditions in fibroblasts.
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PMID:A method for quantitative acylcarnitine profiling in human skin fibroblasts using unlabelled palmitic acid: diagnosis of fatty acid oxidation disorders and differentiation between biochemical phenotypes of MCAD deficiency. 1238 91

By January 2007 seven European countries had expanded, and more are considering the expansion of their newborn screening programmes by inclusion of ESI tandem mass spectrometry. We present an overview of the current status of expanded newborn screening programmes in Europe. While the first pilot programmes were initiated in 1998 in Germany, most countries started within the last 3 years. The number of disorders screened for by MS/MS ranges from two disorders (phenylketonuria and medium-chain acyl-CoA dehydrogenase deficiency) in some countries to 20 in others. The number of live births investigated per screening centre varies from 18,000 to 77,000. Few programmes have reported the number of positively identified cases and technical data, although many participate in quality assurance and proficiency test schemes. Given the relatively common genetic background of most European populations and similar health care systems, the reasons for the differences observed appear arbitrary and contrary to the optimal benefit of this important preventive health measure. Harmonization of disease screening panels, spectrum of metabolites analysed, sizes of screening laboratories, analytical procedures, follow-up management and proficiency and quality testing is urgently warranted on the European level. This will hopefully occur before screening by novel applications of tandem mass spectrometry for additional groups of disorders including lysosomal storage disorders and X-linked adrenoleukodystrophy are implemented.
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PMID:Expanded newborn screening in Europe 2007. 1764 97

Over the last years acylcarnitines have emerged as important biomarkers for the diagnosis of mitochondrial fatty acid beta-oxidation (mFAO) and branched-chain amino acid oxidation disorders assuming they reflect the potentially toxic acyl-CoA species, accumulating intramitochondrially upstream of the enzyme block. However, the origin of these intermediates still remains poorly understood. A possibility exists that carnitine palmitoyltransferase 2 (CPT2), member of the carnitine shuttle, is involved in the intramitochondrial synthesis of acylcarnitines from accumulated acyl-CoA metabolites. To address this issue, the substrate specificity profile of CPT2 was herein investigated. Saccharomyces cerevisiae homogenates expressing human CPT2 were incubated with saturated and unsaturated C2-C26 acyl-CoAs and branched-chain amino acid oxidation intermediates. The produced acylcarnitines were quantified by ESI-MS/MS. We show that CPT2 is active with medium (C8-C12) and long-chain (C14-C18) acyl-CoA esters, whereas virtually no activity was found with short- and very long-chain acyl-CoAs or with branched-chain amino acid oxidation intermediates. Trans-2-enoyl-CoA intermediates were also found to be poor substrates for CPT2. Inhibition studies performed revealed that trans-2-C16:1-CoA may act as a competitive inhibitor of CPT2 (K(i) of 18.8 microM). The results obtained clearly demonstrate that CPT2 is able to reverse its physiological mechanism for medium and long-chain acyl-CoAs contributing to the abnormal acylcarnitines profiles characteristic of most mFAO disorders. The finding that trans-2-enoyl-CoAs are poorly handled by CPT2 may explain the absence of trans-2-enoyl-carnitines in the profiles of mitochondrial trifunctional protein deficient patients, the only defect where they accumulate, and the discrepancy between the clinical features of this and other long-chain mFAO disorders such as very long-chain acyl-CoA dehydrogenase deficiency.
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PMID:Carnitine palmitoyltransferase 2: New insights on the substrate specificity and implications for acylcarnitine profiling. 2053 56

In Greece, the National Newborn Screening Program was initiated in 1974 and is performed by the Institute of Child Health (ICH). However, there is a complete absence of conditions that have high rates of mortality and a relatively high prevalence listed in the Catalogue of Disorders screened by the ICH. Our laboratory has expanded the existing NBS program to include newborn screening for inborn errors of metabolism, screening for cystic fibrosis (the most common congenital disorder in the Greek population), congenital adrenal hyperplasia, and for biotinidase deficiency. From July 2007 to December 2009, 45,000 dried blood spots (DBS) were collected from infants born in Athens, Greece, and were analyzed. We present a report of our 30-month experience in the newborn screening area. The samples were tested for amino acidopathies, fatty acid oxidation disorders (FAOD), and organic acid metabolic disorders by applying flow injection analysis-electrospray ionization-tandem mass spectrometry (FIA-ESI-MS/MS); for cystic fibrosis by immunoreactive trypsinogen (IRT) measurement (time-resolved fluoroimmunoassay); for congenital adrenal hyperplasia by fluoroimmunoassay to measure the 17 hydroxy-progesterone level; and for biotinidase deficiency using a colorimetric method and a semiquantitative fluoroimmunoassay to determine biotinidase activity. Sample analysis resulted in establishing cutoff values for the respective disease markers for the first time in the Greek population. Four infants were identified with cystic fibrosis, two with congenital adrenal hyperplasia, two with phenylketonuria (PKU), one with medium-chain acyl CoA dehydrogenase deficiency (MCADD), and one with biotinidase deficiency. To the best of our knowledge, this is the first article reporting the status of expanded newborn screening in Greece.
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PMID:Expanded newborn screening in Greece: 30 months of experience. 2072 92