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)

The authors publish for the first time the Hungarian frequency of the medium chain acyl-CoA dehydrogenase (MCAD) deficiency. The determination was carried out with molecular biological methods in 1121 newborns. The disease is inherited as an autosomal recessive trait, caused by mutation in the enzyme gene. The deficiency is extremely frequent in the Anglo-Saxon populations. Here it is as common as phenylketonuria. The first episode presents usually in the first 2 years of life, and the mortality may approach 60 percent. Early and prompt diagnosis can lead to an effective management of the disorder. The severity of the disease and its frequency in foreign countries made the screening necessary.
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PMID:[Screening of newborn infants for medium-chain acyl-CoA dehydrogenase deficiency in Hungary]. 763 77

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

OBJECTIVES. To establish a database of literature and other evidence on neonatal screening programmes and technologies for inborn errors of metabolism. To undertake a systematic review of the data as a basis for evaluation of newborn screening for inborn errors of metabolism. To prepare an objective summary of the evidence on the appropriateness and need for various existing and possible neonatal screening programmes for inborn errors of metabolism in relation to the natural history of these diseases. To identify gaps in existing knowledge and make recommendations for required primary research. To make recommendations for the future development and organisation of neonatal screening for inborn errors of metabolism in the UK. HOW THE RESEARCH WAS CONDUCTED. There were three parts to the research. A systematic review of the literature on inborn errors of metabolism, neonatal screening programmes, new technologies for screening and economic factors. Inclusion and exclusion criteria were applied, and a working database of relevant papers was established. All selected papers were read by two or three experts and were critically appraised using a standard format. Seven criteria for a screening programme, based on the principles formulated by Wilson and Jungner (WHO, 1968), were used to summarise the evidence. These were as follows. Clinically and biochemically well-defined disorder. Known incidence in populations relevant to the UK. Disorder associated with significant morbidity or mortality. Effective treatment available. Period before onset during which intervention improves outcome. Ethical, safe, simple and robust screening test. Cost-effectiveness of screening. A questionnaire which was sent to all newborn screening laboratories in the UK. Site visits to assess new methodologies for newborn screening. The classical definition of an inborn error of metabolism was used (i.e., a monogenic disease resulting in deficient activity in a single enzyme in a pathway of intermediary metabolism). RESEARCH FINDINGS. INBORN ERRORS OF METABOLISM. Phenylketonuria (PKU) (incidence 1:12,000) fulfilled all the screening criteria and could be used as the 'gold standard' against which to review other disorders despite significant variation in methodologies, sample collection and timing of screening and inadequacies in the infrastructure for notification and continued care of identified patients. Of the many disorders of organic acid and fatty acid metabolism, a case can only be made for the introduction of newborn screening for glutaric aciduria type 1 (GA1; estimated incidence 1:40,000) and medium-chain acyl CoA dehydrogenase (MCAD) deficiency (estimated incidence 1:8000-1:15,000). Therapeutic advances for GA1 offer prevention of neurological damage but further investigation is required into the costs and benefits of screening for this disorder. MCAD deficiency is simply and cheaply treatable, preventing possible early death and neurological handicap. Neonatal screening for these diseases is dependent upon the introduction of tandem mass spectrometry (tandem MS). This screening could however also simultaneously detect some other commonly-encountered disorders of organic acid metabolism with a collective incidence of 1:15,000.(ABSTRACT TRUNCATED)
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PMID:Newborn screening for inborn errors of metabolism: a systematic review. 948 56

A UK national programme to screen all newborn infants for phenylketonuria was introduced in 1969, followed in 1981 by a similar programme for congenital hypothyroidism. Decisions to start these national programmes were informed by evidence from observational studies rather than randomised controlled trials. Subsequently, outcome for affected children has been assessed through national disease registers, from which inferences about the effectiveness of screening have been made. Both programmes are based on a single blood specimen, collected from each infant at the end of the first week of life, and stored as dried spots on a filter paper or 'Guthrie' card. This infrastructure has made it relatively easy for routine screening for other conditions to be introduced at a district or regional level, resulting in inconsistent policies and inequitable access to effective screening services. This variation in screening practices reflects uncertainty and the lack of a national framework to guide the introduction and evaluation of new screening initiatives, rather than geographical variations in disease prevalence or severity. More recently, developments in tandem mass spectrometry have made it technically possible to screen for several inborn errors of metabolism in a single analytical step. However, for each of these conditions, evidence is required that the benefits of screening outweigh the harms. How should that evidence be obtained? Ideally policy decisions about new screening initiatives should be informed by evidence from randomised controlled trials but for most of the conditions for which newborn screening is proposed, large trials would be needed. Prioritising which conditions should be formally evaluated, and developing a framework to support their evaluation, poses an important challenge to the public health, clinical and scientific community. In this chapter, issues underlying the evaluation of newborn screening programmes will be discussed in relation to medium chain acyl CoA dehydrogenase deficiency, a recessively inherited disorder of fatty acid oxidation.
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PMID:Evaluating newborn screening programmes based on dried blood spots: future challenges. 1036 20

Investigations of genetic diseases such as cystic fibrosis, alpha-1-antitrypsin deficiency, phenylketonuria, mitochondrial acyl-CoA dehydrogenase deficiencies, and many others have shown that enhanced proteolytic degradation of mutant proteins is a common molecular pathological mechanism. Detailed studies of the fate of mutant proteins in some of these diseases have revealed that impaired or aberrant folding of mutant polypeptides typically results in prolonged interaction with molecular chaperones and degradation by intracellular proteases before the functional conformation is acquired. This appears to be the case for many missense mutations and short in-frame deletions or insertions that represent a major fraction of the mutations detected in genetic diseases. In some diseases, or under some circumstances, the degradation system is not efficient. Instead, aberrant folding leads to accumulation of protein aggregates that damage the cell. Mechanisms by which misfolded proteins are selected for degradation have first been delineated for the endoplasmatic reticulum; this process has been termed "protein quality control." Similar mechanisms appear to be operative in all cellular compartments in which proteins fold. Within the context of genetic diseases, we review knowledge on the molecular processes underlying protein quality control in the various subcellular compartments. The important impact of such systems for variability of the expression of genetic deficiencies is emphasised.
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PMID:Protein misfolding and degradation in genetic diseases. 1047 27

Development of acylcarnitine and amino acid profiling using tandem mass spectrometry, and its application for use with dried blood specimens collected on filter-paper cards, has introduced an innovative new technology for detecting inborn errors of fatty acid, organic acid, and amino acid metabolism. From November 1, 1992 through June 30, 1999 we screened more than 700,000 newborns in Pennsylvania, Ohio, North Carolina, and Louisiana. We have prospectively detected 163 inborn errors of metabolism. Eighty-six patients have amino acid metabolism errors. Among them are phenylketonuria, hyperphenylalaninemia, maple syrup urine disease, and several urea cycle disorders. Thirty-two have organic acid metabolism errors, including glutaric aciduria type 1; 3-methylcrotonyl coenzyme A (CoA) carboxylase deficiency, propionic acidemia, methylmalonic acidemia, and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency; and 45 have fatty acid oxidation errors, including 36 with medium-chain acyl-CoA dehydrogenase deficiency. Details of the methodology are presented and the potential of this screening technology is discussed.
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PMID:Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism. 1059 60

Since 1998, the NSW Newborn Screening Program has used electrospray tandem mass spectrometry (MS/MS) to analyse samples from all babies born in NSW and the ACT (approximately 95000 per year) for selected amino acids and acylcarnitines. The software rules editor initially interprets all results where ratio of analyte to internal standard is modified by input from the external standard curves per analyte. The numerical results are then downloaded to the NSW Newborn Screening database, which provides automatic, analyte specific follow-up test cascade. We have analysed samples from 137 120 consecutive newborns received by the program, requested repeat samples from 122 babies, and found abnormal levels in 17 babies with phenylketonuria, 1 tetrahydrobiopterin deficiency, 3 hyperphenylalaninaemia, 1 maple syrup urine disease, 1 tyrosinaemia type II, 1 congenital lactic acidosis, 2 medium-chain acyl CoA dehydrogenase deficiency, 1 short-chain acyl CoA dehydrogenase deficiency, 1 beta-ketothiolase deficiency, 2 vitamin B12 deficient babies of vegan mothers and 1 glutaric aciduria type I. Using population data plus that obtained from retrospective samples with proven disorders we have established cut-off levels for each analyte tested. This coupled with the ability of the database to provide ratios of various analytes gives excellent screening specificity and sensitivity for the detection of at least 40 rare inborn errors of metabolism.
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PMID:Newborn screening with tandem mass spectrometry: 12 months' experience in NSW Australia. 1062 78

An increasing number of women with inborn errors of metabolism are now reaching child-bearing age. For certain disorders there are maternal risks associated with pregnancy. These may be related to an increased likelihood of metabolic decompensation (e.g. disorders of the urea cycle) or to increased stress to systems already compromised by disease (e.g. cardiomyopathy in GSD III). Detrimental effects upon the fetus may also be caused by maternal disease, as occurs with phenylketonuria, or from medication used to treat the mother's condition. Less commonly, fetal inborn errors may adversely effect the mother's health--e.g. fetal long-chain acyl-CoA dehydrogenase deficiency and the maternal HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) and AFLP (acute fatty liver of pregnancy). Because of the rarity of individual disorders, our knowledge of risks associated with pregnancy is limited. Even for more common inborn errors such as phenylketonuria, there remain a number of questions that have not been fully answered.
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PMID:Inborn errors of metabolism and pregnancy. 1086 39

Advances in technology provide new challenges to public health to implement screening programs that are effective, cost-efficient, and available to all infants regardless of ability to pay. The Newborn Metabolic Disorder Screening Program (NMDSP) of the Oklahoma State Department of Health is evaluating the expansion of newborn screening for the disorders of cystic fibrosis, congenital adrenal hyperplasia, and medium-chain acyl coenzyme A dehydrogenase deficiency (MCAD) to the current screening battery of disorders (phenylketonuria, congenital hypothyroidism, galactosemia, and sickle cell disease). The challenge is to offer these new screening tests in a cost-efficient manner that ensures all newborns have access to screening and that an infrastructure exists to diagnose and provide the specialized comprehensive care affected infants will require to reduce the morbidity, mortality, and disability associated with these disorders. Essential components of an effective newborn screening system include the smooth integration of sample collection, laboratory testing, follow-up, diagnosis, timely treatment, and tracking components. The NMDSP has recommended that screening should be expanded, but issues of cost and the establishment of a sustainable infrastructure of comprehensive medical services must be addressed.
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PMID:Public health explores expanding newborn screening for cystic fibrosis, congenital adrenal hyperplasia, and medium-chain acyl coenzyme A dehydrogenase deficiency (MCAD). 1139 80

Electrospray tandem mass spectrometry was applied to detect a series of inherited metabolic disorders during a newborn-screening pilot study and a selective screening in Japan. In our mass screening of 102,200 newborns, five patients with propionic acidemia, two with methylmalonic acidemia, two with medium-chain acyl-CoA dehydrogenase deficiency, three with citrullinemia type II, and one with phenylketonuria were identified. In a selective screening of 164 patients with symptoms mainly related to hypoglycemia and/or hyperammonemia, 12 with fatty acid oxidation disorders and six with other disorders were found. The results indicated the importance of newborn screening using this technology in Japan.
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PMID:Newborn mass screening and selective screening using electrospray tandem mass spectrometry in Japan. 1212 23


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