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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Robinson BH (1989) Lacticacidemia. Biochemical, clinical, and genetic considerations. Adv Hum Genet 18:151–179, 371–372
Robinson BH (1995) Lactic acidemia (Disorders of pyruvate carboxylase, pyruvate dehydrogenase). In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) Metabolic and molecular bases of inherited disease, 7th edn. McGraw-Hill, New York, pp 1479–1499
Higgins JJ, Glasgow AM, Lusk MM, Kerr DS (1994) MRI, clinical, and biochemical features of partial pyruvate carboxylase deficiency. J Child Neurol 9: 436–439
Stern HJ, Nayar R, Depalma L, Rifai N (1995) Prolonged survival in pyruvate carboxylase deficiency: lack of correlation with enzyme activity in cultured fibroblasts. Clin Biochem 28: 85–89
Wexler ID, Du Y, Lisgaris MV et al. (1994) Primary amino acid sequence and structure of human pyruvate carboxylase. Biochim Biophys Acta 1227: 46–52
Carbone MA, MacKay N, Ling M et al. (1998) Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations. Am J Hum Genet 62: 1312–1319
Wexler ID, Kerr DS, Du Y et al. (1998) Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families. Pediatr Res 43: 579–584
Van Coster RN, Janssens S, Misson JP, Verloes A, Leroy JG (1998) Prenatal diagnosis of pyruvate carboxylase deficiency by direct measurement of catalytic activity on chorionic villi samples. Prenat Diagn 18:1041–1o44
Van den Berghe G (1996) Disorders of gluconeogenesis. J Inherit Metab Dis 19: 470–477
Hanson RW, Patel YM (1994) Phosphoenolpyruvate carboxykinase (GTP): the gene and the enzyme. Adv Enzymol Relat Areas Mol Biol 69: 203–281
Stoffel M, Xiang KS, Espinosa R et al. (1993) cDNA sequence and localization of polymorphic human cytosolic phosphoenolpyruvate carboxykinase gene (PCK1) to chromosome 20, band g13.31: PCK1 is not tightly linked to maturity-onset diabetes of the young. Hum Mol Genet 2: 1–4
Kerr DS, Wexler ID, Tripatara A, Patel MS (1996) Defects of the human pyruvate dehydrogenase complex. In: Patel MS, Roche T, Harris RA (eds) Alpha keto acid dehydrogenase complexes. Birkhauser, Basel, pp 249–270
Otero LJ, Brown RM, Brown GK (1998) Arginine 302 mutations in the pyruvate dehydrogenase Eialpha subunit gene: identification of further patients and in vitro demonstration of pathogenicity. Hum Mutat 12: 114–121
Medina L, Chi TL, DeVivo DC, Hilal SK (199o) MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect. AJNR 11379–384
De Vivo DC (1998) Leigh syndrome: historical perspective and clinical variations. Biofactors 7: 269–271
Robinson BH, MacMillan H, Petrova-Benedict R, Sherwood WG (1987) Variable clinical presentation in patients with defective E, component of pyruvate dehydrogenase complex. J Pediatr 111: 525–533
Shevell MI, Matthews PM, Scriver et al. (1994) Cerebral dysgenesis and lactic acidemia: an MRI/MRS phenotype associated with pyruvate dehydrogenase deficiency. Pediatr Neurol 11: 224–229
Sheu KFR, Hu CWC, Utter MF (1981) Pyruvate dehydrogenase complex activity in normal and deficient fibroblasts. J Clin Invest 67: 1463–1471
Ito M, Kobashi H, Naito E et al. (1992) Decrease of pyruvate dehydrogenase phosphatase activity in patients with congenital lactic acidemia. Clin Chim Acta 209: 1–7
Robinson BH, MacKay N, Petrova-Benedict R et al. (1990) Defects in the E lipoyl transacetylase and the X-lipoyl containing component of the pyruvate dehydrogenase complex in patients with lactic acidemia. J Clin Invest 85: 182–139. 1824
Kerr DS, Berry SA, Lusk MM, Ho L, Patel MS (1988) A deficiency of both subunits of pyruvate dehydrogenase which is not expressed in fibroblasts. Pediatr Res 24: 95–100.
Kerr DS, Ho L, Berlin CM et al. (1987) Systemic deficiency of the first component of the pyruvate dehydrogenase complex. Pediatr Res 22: 312–318
Huq AHMM, Ito M, Naito E et al. (1991) Demonstration of an 41. unstable variant of pyruvate dehydrogenase protein (E,) in cultured fibroblasts from a patient with congenital lactic acidemia. Pediatr Res 30: 11–14 42.
Falk RE, Cederbaum SD, Blass JP et al. (1976) Ketogenic diet in the management of pyruvate dehydrogenase deficiency. Pediatrics 58: 713–721
Wexler ID, Hemalatha SG, McConnell J et al. (1997) Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology 49: 1655–1661
Naito E, Ito M, Takeda E et al. (1994) Molecular analysis of 44. abnormal pyruvate dehydrogenase in a patient with thiamine-responsive congenital lactic acidemia. Pediatr Res 36: 340–346 45.
Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL, Kerr DS (1997) Treatment of congenital lactic acidosis with dichloroacetate: a review. Arch Pediatr Adolesc Med 77: 535–541
Brown RM, Dahl HHM, Brown GK (1989) X-chromosome 46 localization of the functional gene for the E,a subunit of the human pyruvate dehydrogenase complex. Genomics 4: 174–181.
Young JC, Gould JA, Kola I, Iannello RC (1998) Review: Pdha2, past and present. J Exp Zool 282: 231–238
Dahl HHM (1995) Pyruvate dehydrogenase E,a deficiency: males and females differ yet again. Am J Hum Genet 56: 553–557
Dahl HHM, Brown GK, Brown RM et al. (1992) Mutations and polymorphisms in the pyruvate dehydrogenase E,a gene. Hum Mutat 1: 97–102.
Aral B, Benelli C, Ait-Ghezala G et al. (1997) Mutations in PDX1, the human lipoyl-containing component X of the pyruvate dehydrogenase-complex gene on chromosome 11p1, 5o. in congenital lactic acidosis. Am J Hum Genet 61: 1318–1326
Kerr DS, Lusk MM (1992) Infrequent expression of heterozygosity or deficiency of pyruvate dehydrogenase (E,) among 51. parents and sibs of affected patients. Pediatr Res 31: 133.
Brown RM, Brown GK (1994) Prenatal diagnosis of pyruvate 52. dehydrogenase E, alpha subunit deficiency. Prnat Diagn 14: 435–441
Bonnefont JP, Chretien D, Rustin P et al. (1992) Alphaketoglutarate dehydrogenase deficiency presenting as con- 53. genital lactic acidosis. J Pediatr 121: 255–258
Bustin P, Bourgeron T, Parfait B et al. (1997) Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim Biophys Acta 1361: 185–197.
Chuang DT, Hu CW, Patel MS (1983) Induction of the branched-chain 2-oxo acid dehydrogenase complex in 3T3- L1 adipocytes during differentiation. Biochem J 214: 177–181
Koike K (1998) Cloning, structure, chromosomal localization and promoter analysis of human 2-oxoglutarate dehydrogenase gene. Biochim Biophys Acta 1385: 373–384
Matalon R, Stumpf DA, Michals K et al. (1984) Lipoamide dehydrogenase deficiency with primary lactic acidosis: favorable response to treatment with oral lipoic acid. J Pediatr 104: 65–69
Sakaguchi Y, Yoshino M, Aramaki S et al. (1986) Dihydrolipoyl dehydrogenase deficiency: a therapeutic trial with branched-chain amino acid restriction. Eur J Pediatr 145: 271–274
Elpeleg ON, Ruitenbeek W, Jakobs C et al. (1995) Congenital lacticacidemia caused by lipoamide dehydrogenase deficiency with favorable outcome. J Pediatr 126: 72–74
Elpeleg ON, Shaag A, Glustein JZ et al. (1997) Lipoamide dehydrogenase deficiency in Ashkenazi Jews: an insertion mutation in the mitochondrial leader sequence. Hum Mutat 10: 256–257
Hong YS, Kerr DS, Liu TC et al. (1997) Deficiency of dihydrolipoamide dehydrogenase due to two mutant alleles (E34o K and Gioidel). Analysis of a family and prenatal testing. Biochim Biophys Acta 1362: 160–168
Scherer SW, Otulakowski G, Robinson BH, Tsui LC (1991) Localization of the human dihydrolipoamide dehydrogenase gene (DLD) to 7Q31 Q32. Cytogenet Cell Genet 56: 176–177
Hong YS, Kerr DS, Craigen WJ et al. (1996) Identification of two mutations in a compound heterozygous child with dihydrolipoamide dehydrogenase deficiency. Hum Mol Genet 5: 1925–1930
Zinn AB, Kerr DS, Hoppel CL (1986) Fumarase deficiency: a new cause of mitochondrial encephalomyopathy. N Engl J Med 315: 469–475
Coughlin EM, Chalmers RA, Slaugenhaupt SA et al. (1993) Identification of a molecular defect in a fumarase deficient patient and mapping of the fumarase gene. Am J Hum Genet 53: 869
Bourgeron T, Chretien D, Poggi-Bach J et al. (1994) Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. J Clin Invest 93: 2514–2518
Coughlin EM, Christensen E, Kunz PL et al. (1998) Molecular analysis and prenatal diagnosis of human fumarase deficiency. Mol Genet Metab 63: 254–262
Rivner MH, Shamsnia M, Swift TR et al. (1989) Kearns-Sayre syndrome and complex II deficiency. Neurology 39: 693–696
Bourgeron T, Bustin P, Chretien D et al. (1995) Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 11: 144–149
Taylor RW, Birch-Machin MA, Schaefer J et al. (1996) Deficiency of complex II of the mitochondrial respiratory chain in late-onset optic atrophy and ataxia. Ann Neurol 39: 224–232
Haller RG, Henriksson KG, Jorfeldt L et al. (1991) Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect. J Clin Invest 88: 1197–1206
Hall RE, Henriksson KG, Lewis SF, Haller RG, Kennaway NG (1993) Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins. J Clin Invest 92: 2660–2666
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2000 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Kerr, D.S., Wexler, I.D., Zinn, A.B. (2000). Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle. In: Fernandes, J., Saudubray, JM., Van den Berghe, G. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-04285-4_10
Download citation
DOI: https://doi.org/10.1007/978-3-662-04285-4_10
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-04287-8
Online ISBN: 978-3-662-04285-4
eBook Packages: Springer Book Archive