Nutritional Therapy for Fat Oxidation Disorders
Principal Investigators: Ronald G. Haller, M.D. and Charles R. Roe, M.D.

Nutritional therapy for human inherited fat oxidation disorders (FOD) has been based on three strategies: restriction of dietary fat, the use of dietary medium chain triglycerides (MCT) (with long-chain defects), and supplements (e.g. L-carnitine). These strategies, even in combination, have not been effective. We propose to evaluate and develop new strategies based upon the underlying energy deficit which exists in these disorders due to defective mitochondrial fat oxidation. The long-term goal is to develop effective treatment(s) for these inherited disorders. The specific aims are to determine the efficacy of the triglycerides: Triheptanoin (Tri-C7), Tripentanoin (Tri-C5) and their common metabolite, Beta-Hydroxy-Pentanoate (BHB) as enteral and, potentially, parenteral therapies. These agents are utilized efficiently for energy production, despite a deficiency of enzymes in FOD due to the use of alternate pathways and the anaplerotic nature of propionyl-CoA produced by the thiolytic cleavage of the "odd-carbon" ketone bodies. The efficacy of these agents will be compared to conventional treatment employing metabolic measures and assessment of cardiac and skeletal muscle function employing exercise testing. Collaboration with referring centers around the world will provide, in aggregate, more than 120 patients with carnitine palmitoyltransferases I & II, carnitine-acylcarnitine translocase, very-long chain acyl-CoA dehydrogenase, L-hydroxy-acyl-CoA dehydrogenase, trifunctional protein, medium chain acyl-CoA dehydrogenase, and short chain acyl-CoA dehydrogenase deficiencies. This study will provide unique insights into the clinical, physiological, and biochemical manifestations of these disorders and their responses to therapy.