Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Gene-Targeted Mice

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid - oxidation in humans. To better understand the pathogenesis of this disease, we developed a mouse model for MCAD deficiency (MCAD/) by gene targeting in embryonic stem (ES) cells. The MCAD/ mice developed an organic aciduria and fatty liver, and showed profound cold intolerance at 4 C with prior fasting. The sporadic cardiac lesions seen in MCAD/ mice have not been reported in human MCAD patients. There was significant neonatal mortality of MCAD/ pups demonstrating similarities to patterns of clinical episodes and mortality in MCAD-deficient patients. The MCAD-deficient mouse reproduced important aspects of human MCAD deficiency and is a valuable model for further analysis of the roles of fatty acid oxidation and pathogenesis of human diseases involving fatty acid oxidation.