Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse

Although many patients have been found to have very long-chain acyl-CoA deh ydrogenase (VLCAD) deficiency, none have been documented with long-chain ac yl-CoA dehydrogenase (LCAD) deficiency. In order to understand the metaboli c pathogenesis of long-chain fatty acid oxidation disorders, we generated m ice with VLCAD deficiency (VLCAD(-/-)) and compared their pathologic and bi ochemical phenotypes of mice with LCAD deficiency (LCAD(-/-)) and wild-type mice. VLCAD(-/-) mice had milder fatty change in liver and heart. Dehydrog enation of various acyl-CoA substrates by liver, heart and skeletal muscle mitochondria differed among the three genotypes. The results for liver were most informative as VLCAD(-/-) mice had a reduction in activity toward pal mitoyl-CoA and oleoyl-CoA (58 and 64% of wild-type, respectively), whereas LCAD(-/-) mice showed a more profoundly reduced activity toward these subst rates (35 and 32% of wild-type, respectively), with a significant reduction of activity toward the branched chain substrate 2,6-dimethylheptanoyl-CoA. Cis and C-18 acylcarnitines were elevated in bile, blood and serum of fast ed VLCAD(-/-) mice, whereas abnormally elevated C-12 and C-14 acylcarnitine s were prominent in LCAD(-/-) mice. Progeny with the combined LCAD(+/+)//VL CAD(+/-) genotype were over-represented in offspring from sires and dams he terozygous for both LCAD and VLCAD mutations. In contrast, no live mice wit h a compound LCAD(-/-)//VLCAD(-/-) genotype were detected.