Pathophysiology and treatment of medium-chain acyl-CoA dehydrogenase deficiency

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DESCRIPTION (provided by applicant): The candidate is a junior academic physician, trained in Pediatrics, Genetics and Biochemical Genetics whose long term goal is to conduct patient oriented research that will improve therapies for inborn errors of metabolism (IEM). The training program is designed to enable him to transition to independence as a researcher with expertise in clinical trials related to lEMs through a series of didactic and independent learning opportunities and mentored patient oriented research. This research centers on medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, the most common inborn error of metabolism identified by newborn screening programs in the United States. Scientific evidence is lacking for most of the interventions and management recommendations made for MCAD deficiency, therefore evidence-based management is impossible at this time. Two of the most commonly used interventions for management of MCAD deficiency, supplementation with L-carnitine and dietary fat reduction in particular, have not been subjected to rigorous study. Specifically, the studies described will explore the hypotheses that in MCAD deficiency therapy with oral L-carnitine can protect against metabolic decompensation, that reduction in dietary fat does not provide measurable protection, and that the therapies currently used may have unexpected consequences. Further, a mouse model addresses the hypotheses that there is a predictable physiological and metabolic pattern to the process of metabolic decompensation and that loss of the capacity of carnitine/acylcarnitine flux to buffer and maintain the ratio of mitochondria! free coenzyme A (CoA) to acyl-CoA leads to an acute state of relative insufficiency of free CoA associated with the decompensation process. The research plan describes a prospective clinical trial to test the utility of pharmacological doses of L-carnitine and dietary fat restriction, a collaborative registry for MCAD to monitor for rare complications, and a series of physiological and biochemical studies utilizing a mouse model for questions that cannot be safely answered in human studies. These studies will lead to specific evidenced-based guidelines for the management of the more than 300 children born with MCAD deficiency every year in the US. This career development award presents a key opportunity to foster the candidate's career development as a translational researcher through study of clinical trial design, data analysis and statistics, and ethical issues related to research with human subjects.