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

Abstract

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid β-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. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inherited disorders of metabolism. This defect in fatty acid oxidation can lead to severe and sometimes fatal disease, especially in young children because they are unable to tolerate a fasting episode. Metabolic complications include very low blood glucose concentrations and generation of toxic by-products. This disorder can result in sudden infant death. Using a process known as gene targeting in mouse embryonic stem cells, the authors have developed a mouse model with the same enzyme deficiency. This mouse model of MCAD deficiency develops many of the same disease characteristics found in affected children. The MCAD-deficient mouse model shows a high rate of newborn loss, intolerance to cold, and the characteristic biochemical changes in the blood, tissues, and urine that are very similar to those found in the human disease counterpart. The MCAD-deficient mouse model will allow researchers to better understand disease mechanisms so that new preventive measures or therapies can be developed.