Section III: Disorders of Mitochondrial Energy Metabolism. Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle

Michèle Brivet (1) , Pauline Gaignard (2, 3) , Manuel Schiff (4, 5)

1 Service de biochimie métabolique [CHU Necker]
2 Service de Biochimie [CHU Bicêtre]
3 CARPAT (UMRS1180) - Signalisation et physiopathologie cardiovasculaire
4 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
5 Hôpital Necker - Enfants Malades [AP-HP]

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, the range of manifestations extending from overwhelming neonatal lactic acidosis with early death to relatively normal adult life and variable effects on systemic functions. Similar clinical manifestations may be caused by other defects of energy metabolism, especially defects of the mitochondrial respiratory chain. Diagnosis relies primarily on biochemical analyses of accumulated metabolites in body fluids, DNA analysis and, in some instances, confirmation by definitive enzymatic assays in cells or tissues. Prenatal diagnosis is now achieved preferentially by DNA analysis. Pyruvate carboxylase (PC) deficiency constitutes a defect both in the TCA cycle and in gluconeogenesis, but generally presents with severe neurological dysfunction and lactic acidosis rather than with fasting hypoglycaemia. Deficiency of phosphoenolcarboxykinase (PEPCK) is limited to its cytosolic form and affects gluconeogenesis. Deficiency of pyruvate dehydrogenase complex (PDHC) impedes glucose oxidation and aerobic energy production, and ingestion of carbohydrate aggravates lactic acidosis. The defects of mitochondrial pyruvate carrier have the same presentation as PDHC deficiencies.Treatment of disorders of pyruvate metabolism comprises avoidance of fasting (PC deficiency) or minimising dietary carbohydrate intake (PDHC deficiency) and enhancing anaplerosis (restoration of pools of intermediate metabolites). Dihydrolipoamide dehydrogenase (E3) deficiency affects PDHC and also the 2-ketoglutarate dehydrogenase complex (KDHC) and the branched-chain 2-ketoacid dehydrogenase (BCKD) complex, with biochemical manifestations of all three disorders. The deficiencies of the TCA cycle enzymes interrupt the cycle but do not always result in accumulation of the corresponding substrates. Succinyl-CoA ligase deficiency causes a mild methylmalonic accumulation. Succinate dehydrogenase deficiency represents a unique disorder affecting both the TCA cycle and the respiratory chain. The defects of the malate-aspartate shuttle (MAS) impede the import of reduced nicotinamide adenine dinucleotide (NADH) from the cytosol to the mitochondrion and the subsequent pyruvate oxidation. NAXE and NAXD deficiencies disrupt the cellular NAD(P)HX repair system and cause lethal neurometabolic disorders of early childhood.

Mots clés: Lactic Acidosis Pyruvate Dehydrogenase Ketogenic Diet Pyruvate Carboxylase Pyruvate Dehydrogenase Complex; Lactic Acidosis; Pyruvate Dehydrogenase; Ketogenic Diet; Pyruvate Carboxylase; Pyruvate Dehydrogenase Complex

Domaines: Sciences du Vivant [q-bio]

Michèle Brivet, Pauline Gaignard, Manuel Schiff. Section III: Disorders of Mitochondrial Energy Metabolism. Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle. Georg F. Hoffmann, Johannes Zschocke, William L. Nyhan. Inherited Metabolic Diseases, A Clinical Approach., 2017, 978-3-662-49410-3. ⟨10.1007/978-3-662-49410-3⟩. ⟨hal-04440886⟩