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 in pyruvate metabolism and in the TCA cycle almost invariably affect the central nervous system. The severity and the different clinical phenotypes vary widely among patients and are not always 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 respiratory chain (Chap. 15). Diagnosis depends primarily on biochemical analyses of metabolites in body fluids, followed by definitive enzymatic assays in cells or tissues, and DNA analysis. The deficiencies of pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase (PEPCK) constitute defects in gluconeogenesis, and therefore fasting results in hypoglycemia with worsening lactic acidosis. Deficiency of the pyruvate dehydrogenase complex (PDHC) impedes glucose oxidation and aerobic energy production, and ingestion of carbohydrate aggravates lactic acidosis. Treatment of disorders of pyruvate metabolism comprises avoidance of fasting (PC and PEPCK) or minimizing dietary carbohydrate intake (PDHC) and enhancing anaplerosis. In some cases, vitamin or drug therapy may be helpful. Dihydrolipoamide dehydrogenase (E3) deficiency affects PDHC as well as KDHC and the branched-chain 2-ketoacid dehydrogenase (BCKD) complex (Chap. 19), with biochemical manifestations of all three disorders. 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. Succinate dehydrogenase deficiency represents a unique disorder affecting both the TCA cycle and the respiratory chain. Recently, defects of mitochondrial transport of pyruvate and glutamate (▸ Chap. 29) have been identified. Treatment strategies for the TCA cycle defects are limited.