title: Anaplerotic diet therapy in inherited metabolic disease: therapeutic potential.
abstract: Beginning with phenylketonuria, dietary therapy for inborn errors has focused primarily on the restriction of the precursor to an affected catabolic pathway in an attempt to limit the production of potential toxins. Anaplerotic therapy is based on the concept that there may exist an energy deficit in these diseases that might be improved by providing alternative substrate for both the citric acid cycle (CAC) and the electron transport chain for enhanced ATP production. This article focuses on this basic problem, as it may relate to most catabolic disorders, and provides our current experience involving inherited diseases of mitochondrial fat oxidation, glycogen storage, and pyruvate metabolism using the anaplerotic compound triheptanoin. The observations have led to a realization that 'inter-organ' signalling and 'nutrient sensors' such as adenylate monophosphate mediated-protein kinase (AMPK) and mTOR (mammalian target of rapamycin) appear to play a significant role in the intermediary metabolism of these diseases. Activated AMPK turns on catabolic pathways to augment ATP production while turning off synthetic pathways that consume ATP. Information is provided regarding the inter-organ requirements for more normal metabolic function during crisis and how anaplerotic therapy using triheptanoin, as a direct source of substrate to the CAC for energy production, appears to be a more successful approach to an improved quality of life for these patients.
authors.affiliation: Institute of Metabolic Disease, Baylor University Medical Center, 3812 Elm Street, Dallas, TX 75226, USA. charlesr@baylorhealth.edu
authors.forename: Charles R
authors.initials: CR
authors.lastname: Roe
authors.forename: Fanny
authors.initials: F
authors.lastname: Mochel
mesh_terms: D000818:Animals; D002952:Citric Acid Cycle; D005227:Fatty Acids / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000178:diet therapy / Q000378:metabolism; D006537:Heptanoates / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000178:diet therapy / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000178:diet therapy* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D015324:Pyruvate Carboxylase Deficiency Disease / Q000178:diet therapy / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D005227:Fatty Acids; D006537:Heptanoates; D014280:Triglycerides