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Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle

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Inborn Metabolic Diseases

Zusammenfassung

Owing to the role of pyruvate and the 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 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. Diagnosis depends primarily on biochemical analyses of metabolites in body fluids, followed by definitive enzymatic assays in cells or tissues, and DNA analysis. PC deficiency constitutes a defect both in the Krebs cycle and in gluconeogenesis, but generally presents with severe neurological dysfunction and lactic acidosis rather than with fasting hypoglycaemia. Deficiency of PEPCK is now considered to be a secondary phenomenon. Deficiency of 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) or minimising dietary carbohydrate intake (PDHC) 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, 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. Defects of mitochondrial transport of pyruvate and ketoglutarate have also been identified. Treatment strategies for the TCA cycle defects are limited.

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Authors and Affiliations

  1. Department of Pediatrics, Academisch Ziekenhuis, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium

    Linda de Meirleir

  2. Servicio de Neurologia, Hospital Sant Joan de Deu and CIBERER-ISCIII, Passeig Sant Joan de Deu 2, 8950, Barcelona, Spain

    Angels Garcia-Cazorla

  3. Laboratoire de Biochimie, Hôpital de Bicetre, 78 Rue de General Leclerc, 94275, Le Kremlin Bicetre Cedex, France

    Michèle Brivet

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  1. Linda de Meirleir
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  2. Angels Garcia-Cazorla
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  3. Michèle Brivet
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Correspondence to Linda de Meirleir , Angels Garcia-Cazorla or Michèle Brivet .

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Editors and Affiliations

  1. Department of Neurology, Neurometabolic Unit, Hôpital Pitié Salpêtrière, Paris, France

    Jean-Marie Saudubray

  2. Division of Metabolism, University Children’s Hospital, Zurich, Switzerland

    Matthias R. Baumgartner

  3. Willink Biochemical Genetics Unit Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK

    John Walter

  4. Central Manchester University Hospitals NHS Foundation Trust, St Mary‘s Hospital, Manchester, UK

    John Walter

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de Meirleir, L., Garcia-Cazorla, A., Brivet, M. (2016). Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle. In: Saudubray, JM., Baumgartner, M., Walter, J. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-49771-5_11

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