Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle

Abstract

Owing to the role of pyruvate and the tricarboxylic acid (TCA) cycle in energy metabolism, as well as in gluconeogenesis, lipogenesis and amino acid synthesis, defects of pyruvate metabolism and of the TCA cycle almost invariably affect the central nervous system. The severity and patterns of clinical phenotypes vary tremendously among affected patients and are not specific, with the range of manifestations extending from overwhelming neonatal lactic acidosis and early death to relatively normal adult life and variable effects on systemic functions. The same clinical manifestations may be caused by other defects of energy metabolism, especially defects of the electron transport (respiratory) chain (Chap. 13). Diagnosis of these disorders depends primarily on biochemical analyses of metabolites in body fluids, followed by definitive enzymatic assays in cells or tissues, and DNA analysis if feasible. Among the three disorders of pyruvate metabolism the deficiencies of pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase (PEPCK) constitute defects in gluconeogenesis, and therefore fasting results in hypoglycemia with worsening lactic acidosis. The deficiency of the pyruvate dehydrogenase complex (PDHC) impedes glucose oxidation and aerobic energy production, and ingestion of carbohydrate aggravates lactic acidosis. Nutritional treatment of these disorders of pyruvate metabolism comprises avoidance of fasting (PC and PEPCK) or minimizing dietary carbohydrate intake (PDHC). In some cases, vitamin or drug therapy may be helpful. The deficiencies of the TCA cycle enzymes, the 2-ketoglutarate dehydrogenase complex (KDHC) and fumarase, interrupt the cycle, resulting in accumulation of the corresponding substrates. Dihydrolipoamide dehydrogenase (E3) deficiency affects PDHC as well as KDHC and the branched-chain 2-ketoacid dehydrogenase (BCKD) complex (Chap. 16), with biochemical manifestations of all three disorders. Succinate dehydrogenase deficiency represents a unique disorder affecting both the TCA cycle and the electron transport chain. A more complex defect of iron-sulfur cluster metabolism involves aconitase, succinate dehydrogenase, and electron transport chain complexes I and III. Treatment strategies for all of these TCA cycle defects are very limited; metabolism of any dietary source of energy is impaired, and these defects are generally not vitamin responsive.