Isolated Isobutyryl-CoA Dehydrogenase Deficiency: An Unrecognized Defect in Human Valine Metabolism

Roe, Charles R.; Cederbaum, Stephen D.; Roe, Diane S.; Mardach, Rebecca; Galindo, Alvaro; Sweetman, Lawrence

doi:10.1006/mgme.1998.2758

Cited by 69 publications

(65 citation statements)

References 11 publications

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“…The clinical history of the patient studied has previously been reported [14]. Briefly, she presented at 2-years of age to first cousin parents of Hispanic origins.…”

Section: Resultsmentioning

confidence: 99%

“…The gene for this enzyme was subsequently termed ACADSB (denoting short-branched chain acyl-CoA dehydrogenase) to reflect the broad substrate specificity of the enzyme purified after expression in E. coli [6,7]. More recently, we have suggested that separate enzymes might exist to catalyze each reaction in the isoleucine and valine pathways [6,7,[12][13][14], and preliminary studies of the substrate specificity of human ACAD8 overexpressed in CHANG cells indicated that it had significant enzyme activity with isobutyryl-CoA [13]. The current report confirms the existence of an isobutyryl-CoA dehydrogenase (IBDH) specific to valine metabolism, unequivocally demonstrates identification of an ACD with highest relative activity towards isobutyryl-CoA as substrate, and characterizes a mutation in the gene for this enzyme in a patient with cellular based evidence of a specific defect in valine metabolism [14].…”

Section: Discussionmentioning

confidence: 99%

“…Finally, a patient has been identified in whom metabolic loading studies in fibroblasts revealed decreased oxidation of labeled valine, with an increase in accumulation of isobutyryl carnitine. Metabolism of labeled isoleucine and leucine was normal and a defect in a valine specific ACD was proposed [14].…”

Section: Introductionmentioning

confidence: 99%

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Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans

Nguyen

Andresen

Corydon

et al. 2002

Molecular Genetics and Metabolism

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The acyl-CoA dehydrogenases (ACDs) are a family of related enzymes that catalyze the a,b-dehydrogenation of acyl-CoA esters. Two homologues active in branched chain amino acid metabolism have previously been identified. We have used expression in Escherichia coli to produce a previously uncharacterized ACD-like sequence (ACAD8) and define its substrate specificity. Purified recombinant enzyme had a k cat =K m of 0.8, 0.23, and 0.04 (lM À1 s À1 ) with isobutyryl-CoA, (S) 2-methylbutyryl-CoA, and n-propionylCoA, respectively, as substrates. Thus, this enzyme is an isobutyryl-CoA dehydrogenase. A single patient has previously been described whose fibroblasts exhibit a specific deficit in the oxidation of valine. Amplified ACAD8 cDNA made from patient fibroblast mRNA was homozygous for a single nucleotide change (905G > A) in the ACAD8 coding region compared to the sequence from control cells. This encodes an Arg302Gln substitution in the full-length protein (position 280 in the mature protein), a position predicted by molecular modeling to be important in subunit interactions. The mutant enzyme was stable but inactive when expressed in E. coli. It was also stable and appropriately targeted to mitochondria, but inactive when expressed in mammalian cells. These data confirm further the presence of a separated ACD in humans specific to valine catabolism (isobutyryl-CoA dehydrogenase, IBDH), along with the first enzymatic and molecular confirmation of a deficiency of this enzyme in a patient. Ó

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“…The clinical history of the patient studied has previously been reported [14]. Briefly, she presented at 2-years of age to first cousin parents of Hispanic origins.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans

Nguyen

Andresen

Corydon

et al. 2002

Molecular Genetics and Metabolism

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“…Several reports have described how these unique markers reflect the status of mitochondrial ␤-oxidation (91)(92)(93)(94). Fig.…”

Section: Fatty Acid Acylcarnitinesmentioning

confidence: 99%

Use of Tandem Mass Spectrometry for Multianalyte Screening of Dried Blood Specimens from Newborns

Chace¹,

Kalas²,

Naylor³

2003

Clinical Chemistry

566

366

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Background: Over the past decade laboratories that test for metabolic disorders have introduced tandem mass spectrometry (MS/MS), which is more sensitive, specific, reliable, and comprehensive than traditional assays, into their newborn-screening programs. MS/MS is rapidly replacing these one-analysis, one-metabolite, one-disease classic screening techniques with a oneanalysis, many-metabolites, many-diseases approach that also facilitates the ability to add new disorders to existing newborn-screening panels. Methods: During the past few years experts have authored many valuable articles describing various approaches to newborn metabolic screening by MS/MS. We attempted to document key developments in the introduction and validation of MS/MS screening for metabolic disorders. Our approach used the perspective of the metabolite and which diseases may be present from its detection rather than a more traditional approach of describing a disease and noting which metabolites are increased when it is present. Content: This review cites important historical developments in the introduction and validation of MS/MS screening for metabolic disorders. It also offers a basic technical understanding of MS/MS as it is applied to multianalyte metabolic screening and explains why MS/MS is well suited for analysis of amino acids and acylcarnitines in dried filter-paper blood specimens. It also describes amino acids and acylcarnitines as they are detected and measured by MS/MS and their significance to the identification of specific amino acid, fatty acid, and organic acid disorders. Conclusions: Multianalyte technologies such as MS/MS are suitable for newborn screening and other mass

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“…[2][3][4][5] The first patient presented with dilated cardiomyopathy, anemia, and carnitine deficiency. 2 An elevated C 4 -acylcarnitine was noted in a plasma acylcarnitine profile, but a subsequent urine organic acid analysis was normal. Treatment with oral L-carnitine supplementation led to catch-up growth and normalization of the cardiac status.…”

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confidence: 99%

Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

Oglesbee¹,

Majumder

et al. 2007

Genetics in Medicine

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Purpose: Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. We identified 13 isobutyryl-CoA dehydrogenasedeficient patients through newborn screening due to an elevation of C 4 -acylcarnitine in dried blood spots. Because C 4 -acylcarnitine represents both isobutyryl-and butyrylcarnitine, elevations are not specific for isobutyryl-CoA dehydrogenase deficiency but are also observed in short-chain acyl-CoA dehydrogenase deficiency. To delineate the correct diagnosis, we have developed a follow-up algorithm for abnormal C 4 -acylcarnitine newborn screening results based on the comparison of biomarkers for both conditions. Methods: Fibroblast cultures were established from infants with C 4 -acylcarnitine elevations, and the analysis of in vitro acylcarnitine profiles provided confirmation of either isobutyryl-CoA dehydrogenase or short-chain acyl-CoA dehydrogenase deficiency. Isobutyryl-CoA dehydrogenase deficiency was further confirmed by molecular genetic analysis of the gene encoding isobutyryl-CoA dehydrogenase (ACAD8). Plasma acylcarnitines, urine acylglycines, organic acids, and urine acylcarnitine results were compared between isobutyryl-CoA dehydrogenase-and short-chain acyl-CoA dehydrogenase-deficient patients. Results: Quantification of C 4 -acylcarnitine in plasma and urine as well as ethylmalonic acid in urine allows the differentiation of isobutyryl-CoA dehydrogenase-deficient from short-chain acyl-CoA dehydrogenase-deficient cases. In nine unrelated patients with isobutyryl-CoA dehydrogenase deficiency, 10 missense mutations were identified in ACAD8. To date, 10 of the 13 isobutyryl-CoA dehydrogenase-deficient patients remain asymptomatic, two were lost to follow-up, and one patient required frequent hospitalizations due to emesis and dehydration but is developing normally at 5 years of age. Conclusion: Although the natural history of isobutyryl-CoA dehydrogenase deficiency must be further defined, we have developed an algorithm for rapid laboratory evaluation of neonates with an isolated elevation of C 4 -acylcarnitine identified through newborn screening. Genet Med 2007:9(2):108-116.

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Isolated Isobutyryl-CoA Dehydrogenase Deficiency: An Unrecognized Defect in Human Valine Metabolism

Cited by 69 publications

References 11 publications

Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans

Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans

Use of Tandem Mass Spectrometry for Multianalyte Screening of Dried Blood Specimens from Newborns

Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

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