Isolated isobutyryl-CoA dehydrogenase deficiency: An unrecognized defect in human valine metabolism

A 2-year-old female was well until 12 months of age when she was found to b e anemic and had dilated cardiomyopathy. Total plasma carnitine was 6 mu M and acylcarnitine analysis while receiving carnitine supplement revealed an increase in the four-carbon species. Urine organic acids were normal. In v itro analysis of the mitochondrial pathways for beta oxidation, and leucine , valine, and isoleucine metabolism was performed in fibroblasts using stab le isotope-labeled precursors to these pathways followed by acylcarnitine a nalysis by tandem mass spectrometry. 16-H-2(3)-palmitate was metabolized no rmally down to the level of butyryl-CoA thus excluding SCAD deficiency. C-1 3(6)-leucine and C-13(6)-isoleucine were also metabolized normally. C-13(5) -valine incubation revealed a significant increase in C-13(4)-isobutyrylcar nitine without any incorporation into propionylcarnitine as is observed nor mally. 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 h uman, there is an isobutyryl-CoA dehydrogenase which exists as a separate e nzyme serving only the valine pathway in addition to the 2-methyl branched- chain dehydrogenase which serves both the valine and the isoleucine pathway s in both rat and human. (C) 1998 Academic Press.