HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: clinchem.2004.043265v1 51/3/610    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Korman, S. H. Articles by Pitt, J. J. Search for Related Content PubMed PubMed Citation Articles by Korman, S. H. Articles by Pitt, J. J. Related Collections Molecular Diagnostics and Genetics Pediatric Clinical Chemistry Endocrinology and Metabolism Automation and Analytical Techniques

2-Ethylhydracrylic Aciduria in Short/Branched-Chain Acyl-CoA Dehydrogenase Deficiency: Application to Diagnosis and Implications for the R-Pathway of Isoleucine Oxidation

¹ Department of Clinical Biochemistry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
² Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Science, Skejby Sygehus, and Institute of Human Genetics, Aarhus University, Aarhus, Denmark.
³ Day Hospitalization Unit, Schneider Children’s Medical Center of Israel, Sackler School of Medicine, Tel Aviv University, Petach Tikvah, Israel.
⁴ Genetic Health Services Victoria, Murdoch Childrens Research Institute, Melbourne, Australia.

^aAddress correspondence to this author at: Department of Clinical Biochemistry, Hadassah University Hospital, PO Box 12000, Jerusalem 91120, Israel. Fax 972-2-6435778; e-mail korman{at}hadassah.org.il.

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.