Introduction
Mitochondrial β-oxidation of fatty acids provides energy, especially during fasting conditions. Fatty acid oxidation occurs in mitochondria and consists of a repeating circuit of four sequential steps. There are four straight-chain acyl-CoA dehydrogenases involved in the initial step. Medium-chain acyl-CoA dehydrogenase (MCAD) (the mouse gene is Acadm, whereas the protein is MCAD), specifically, is responsible for catalyzing the dehydrogenation of medium-chain length (C6–C12) fatty acid thioesters [1]. Acadm is transcribed in the nucleus, translated in the cytosol, and translocated into the mitochondrial matrix [2–4]. Once inside the mitochondrial matrix, the MCAD monomers are assembled into homotetramers to gain enzymatic activity [4].
MCAD activity is essential for complete fatty acid oxidation. Inherited MCAD deficiency exists in humans as an autosomal recessive disorder. MCAD deficiency was first described in 1982—1983 [5–7] and has been described in numerous patients [1,8–11]. The carrier frequency in the Caucasian population has been estimated to be between 1 in 50 to 80 with an incidence of clinical disease expected at around 1 in 15,000 [1,9,12].
MCAD-deficient patients exhibit clinical episodes often associated with fasting. Patients manifest disease usually during the first two years of life. Symptoms include hypoketotic hypoglycemia and Reye-like episodes [1]. It is estimated that approximately 59% of patients presenting clinically between 15 to 26 mo of age die during their first clinical episode [1].
The pathogenesis of the wide range of metabolic disturbances in MCAD deficiency is poorly understood and certain aspects of patient management are controversial. An animal model for MCAD deficiency is essential to better understand the pathogenesis of MCAD deficiency and to develop better management regimens for human patients. To gain further insight into the mechanisms of this disease, we developed a mouse model of MCAD deficiency by gene targeting in embryonic stem (ES) cells (for reviews [13,14]). The mutant mice had many relevant features characteristic of the disease found in human MCAD-deficient patients, along with some unexpected findings.