title: Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism.
abstract: A 2-year-old female was well until 12 months of age when she was found to be anemic and had dilated cardiomyopathy. Total plasma carnitine was 6 microM and acylcarnitine analysis while receiving carnitine supplement revealed an increase in the four-carbon species. Urine organic acids were normal. In vitro analysis of the mitochondrial pathways for beta oxidation, and leucine, valine, and isoleucine metabolism was performed in fibroblasts using stable isotope-labeled precursors to these pathways followed by acylcarnitine analysis by tandem mass spectrometry. 16-2H3-palmitate was metabolized normally down to the level of butyryl-CoA thus excluding SCAD deficiency. 13C6-leucine and 13C6-isoleucine were also metabolized normally. 13C5-valine incubation revealed a significant increase in 13C4-isobutyrylcarnitine without any incorporation into propionylcarnitine as is observed normally. These same precursors were also evaluated in fibroblasts with proven ETF-QO deficiency in which acyl-CoA dehydrogenase deficiencies in each of these pathways was clearly identified. These results indicate that in the human, there is an isobutyryl-CoA dehydrogenase which exists as a separate enzyme serving only the valine pathway in addition to the 2-methyl branched-chain dehydrogenase which serves both the valine and the isoleucine pathways in both rat and human.
authors.affiliation: Institute of Metabolic Disease, Baylor University Medical Center, Dallas, Texas. cr.roe@baylordallas.edu
authors.forename: C R
authors.initials: CR
authors.lastname: Roe
authors.forename: S D
authors.initials: SD
authors.lastname: Cederbaum
authors.forename: D S
authors.initials: DS
authors.lastname: Roe
authors.forename: R
authors.initials: R
authors.lastname: Mardach
authors.forename: A
authors.initials: A
authors.lastname: Galindo
authors.forename: L
authors.initials: L
authors.lastname: Sweetman
mesh_terms: D009202:Cardiomyopathies; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D010088:Oxidoreductases / Q000172:deficiency* / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010169:Palmitic Acids / Q000378:metabolism / Q000493:pharmacokinetics; D013379:Substrate Specificity; D014633:Valine / Q000378:metabolism*
chemical_list: D010169:Palmitic Acids; C020381:isobutyryl-1-carnitine; C027333:3-methylbutyrylcarnitine; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C038808:2-methylacyl-CoA dehydrogenase; D014633:Valine; D002331:Carnitine