Document Detail

2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA dehydrogenase deficiency: application to diagnosis and implications for the R-pathway of isoleucine oxidation.
MedLine Citation:
PMID:  15615815     Owner:  NLM     Status:  MEDLINE    
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.
Stanley H Korman; Brage S Andresen; Avraham Zeharia; Alisa Gutman; Avihu Boneh; James J Pitt
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Publication Detail:
Type:  Journal Article     Date:  2004-12-22
Journal Detail:
Title:  Clinical chemistry     Volume:  51     ISSN:  0009-9147     ISO Abbreviation:  Clin. Chem.     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-03-01     Completed Date:  2005-04-11     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9421549     Medline TA:  Clin Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  610-7     Citation Subset:  IM    
Department of Clinical Biochemistry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
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MeSH Terms
Biological Markers / urine
Butyrates / chemistry,  urine
Butyryl-CoA Dehydrogenase / deficiency*,  genetics
Gas Chromatography-Mass Spectrometry
Glycine / analogs & derivatives*,  urine
Infant, Newborn
Isoleucine / metabolism*
Valerates / urine*
Reg. No./Substance:
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 Dehydrogenase

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