| 2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA dehydrogenase deficiency: application to diagnosis and implications for the R-pathway of isoleucine oxidation. | |
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MedLine Citation:
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PMID: 15615815 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Isolated excretion of 2-methylbutyrylglycine (2-MBG) is the hallmark of short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD), a recently identified defect in the proximal pathway of L-isoleucine oxidation. SBCADD might be underdiagnosed because detection and recognition of urine acylglycines is problematic. Excretion of 2-ethylhydracrylic acid (2-EHA), an intermediate formed in the normally minor R-pathway of L-isoleucine oxidation, has not previously been described in SBCADD. METHODS: Samples from four patients with 2-MBG excretion were analyzed by gas chromatography-mass spectrometry for urine organic acids, quantification of 2-MBG, and chiral determination of 2-methylbutyric acid. Blood-spot acylcarnitines were measured by electrospray-tandem mass spectrometry. Mutations in the ACADSB gene encoding SBCAD were identified by direct sequencing. RESULTS: SBCADD was confirmed in each patient by demonstration of different ACADSB gene mutations. In multiple urine samples, organic acid analysis revealed a prominent 2-EHA peak usually exceeding the size of the 2-MBG peak. Approximately 40-46% of total 2-methylbutyric acid conjugates were in the form of the R-isomer, indicating significant metabolism via the R-pathway. CONCLUSIONS: If, as generally believed, SBCAD is responsible for R-2-MBG dehydrogenation in the R-pathway, 2-EHA would not be produced in SBCADD. Our observation of 2-ethylhydracrylic aciduria in SBCADD implies that a different or alternative enzyme serves this function. Increased flux through the R-pathway may act as a safety valve for overflow of accumulating S-pathway metabolites and thereby mitigate the severity of SBCADD. Awareness of 2-ethylhydracrylic aciduria as a diagnostic marker could lead to increased detection of SBCADD and improved definition of its clinical phenotype. |
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Authors:
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Stanley H Korman; Brage S Andresen; Avraham Zeharia; Alisa Gutman; Avihu Boneh; James J Pitt |
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Publication Detail:
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Type: Journal Article Date: 2004-12-22 |
Journal Detail:
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Title: Clinical chemistry Volume: 51 ISSN: 0009-9147 ISO Abbreviation: Clin. Chem. Publication Date: 2005 Mar |
Date Detail:
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Created Date: 2005-03-01 Completed Date: 2005-04-11 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9421549 Medline TA: Clin Chem Country: United States |
Other Details:
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Languages: eng Pagination: 610-7 Citation Subset: IM |
Affiliation:
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Department of Clinical Biochemistry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. korman@hadassah.org.il |
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| MeSH Terms | |
Descriptor/Qualifier:
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Biological Markers
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urine Butyrates / chemistry, urine Butyryl-CoA Dehydrogenase / deficiency*, genetics Gas Chromatography-Mass Spectrometry Glycine / analogs & derivatives*, urine Humans Infant, Newborn Isoleucine / metabolism* Mutation Oxidation-Reduction Stereoisomerism Valerates / urine* |
| Chemical | |
Reg. No./Substance:
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0/Biological Markers; 0/Butyrates; 0/Valerates; 116-53-0/2-methylbutyrate; 4374-62-3/2-ethylhydracrylic acid; 52320-67-9/2-methylbutyrylglycine; 56-40-6/Glycine; 73-32-5/Isoleucine; EC 1.3.99.2/Butyryl-CoA Dehydrogenase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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