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Pyruvate Dehydrogenase Deficiencies

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Mitochondrial Diseases

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Summary

The mammalian pyruvate dehydrogenase complex (PDHC) catalyses the oxidative and irreversible decarboxylation of pyruvate, giving acetyl-CoA, Co2, and NADH + H+. It is located in the mitochondrial inner membrane-matrix space. It plays an essential role in aerobic energy metabolism by controlling the supply of acetyl-CoA arising from carbohydrates and amino acids which are oxidised or converted to fat.

PDHC deficiencies primarily affect the nervous system and are associated with congenital lactic acidosis. The clinical presentation is highly heterogeneous, varying from mild episodic ataxia to severe, rapidly fatal lactic acidosis. The most frequent forms include developmental delay, mental retardation, lactic acidosis and cerebral abnormalities leading to death in early infancy. The most frequent PDHC deficiencies are due to a defect of the Elα subunit. Other defects are very rare and do not differ clinically from the PDH-Elα defects. Fifty-two different mutations have been found in both sexes in the Elα-gene located on the X-chromosome. In girls, due to the variable inactivation of this chromosome in different tissues, the biochemical expression of the deficiency may be difficult to interpret. A lot of mutations are sporadic and most are not found in the mother’s somatic cells. We report here an overview of all mutations described in the literature up until now.

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References

  • Aral B, Benelli C, Ait-Ghezala G, Amessou M, Fouque F, Maunoury C, Créau N, Kamoun P, Marsac C (1997) Mutations in PDX1, the human lipoyl-containing component X of the pyruvate dehydrogenase complex gene on chromosome llpl, in congenital lactic acidosis. Am J Hum Genet 61:1318–1326

    Article  PubMed  CAS  Google Scholar 

  • Awata H, Endo F, Tanoue A, Kitano A, Matsuda I (1994) Characterization of a point mutation in the pyruvate dehydrogenase El alpha gene from two boys with primary lactic acidaemia. J Inherit Metab Dis 17:189–195

    Article  PubMed  CAS  Google Scholar 

  • Blass JP, Avigan J, Uhlendorf BW (1970) A defect of pyruvate decarboxylase in a child with an intermitent movement disorder. J Clin Invest 49:423–432

    Article  PubMed  CAS  Google Scholar 

  • Bonne G, Benelli C, DeMeirleir L, Lissens W, Chaussain M, Diry M, Clot JP, Ponsot G, Geoffroy V, Leroux JP, Marsac C (1993) El pyruvate dehydrogenase deficiency in a child with motor neuropathy. Pediatr Res 33:284–288

    Article  PubMed  CAS  Google Scholar 

  • Brown GK, Otero LJ, LeGris M, Brown RM (1994) Pyruvate dehydrogenase deficiency. J Med Genet 31:875–879

    Article  PubMed  CAS  Google Scholar 

  • Brown RM, Brown GK (1993) X chromosome inactivation and the diagnosis of X-linked disease in females. J Med Genet 30:177–184

    Article  PubMed  CAS  Google Scholar 

  • Chun K, MacKay N, Petrova-Benedict R, Robinson BH (1991) Pyruvate dehydrogenase deficiency due to a 20-bp deletion in exon 11 of the pyruvate dehydrogenase (PDH) Elα gene. Am J Hum Genet 49:414–420

    PubMed  CAS  Google Scholar 

  • Chun K, MacKay N, Petrova-Benedict R, Robinson BH (1993) Mutatins in the X-linked Elα subunit of pyruvate dehydrogenase leading to deficiency of the pyruvate dehydrogenase complex. Hum Mol Genet 4:449–454

    Article  Google Scholar 

  • Chun K, MacKay N, Petrova-Benedict R, Federico A, Fois A, Cole DEC, Robertson E, Robinson BH (1995) Mutations in the X-linked Elα subunit of pyruvate dehydrogenase: exon skipping, insertion of duplicate sequence, and missense mutations leading to the deficiency of the pyruvate dehydrogenase complex. Am J Hum Genet 56:558–569

    PubMed  CAS  Google Scholar 

  • Da Silva LA, De Marcucci OL, Kuhnle ZR (1993) Dietary polyunsaturated fats suppress the highsucrose-induced increase of rat liver pyruvate dehydrogenase levels. Biochem Biophys Physiol 103A: 407–411

    Google Scholar 

  • Dahl HHM (1995) Pyruvate dehydrogenase Elα deficiency: males and females differ yet again. Am J Hum Genet 56:553–557

    PubMed  CAS  Google Scholar 

  • Dahl HHM, Brown GK (1994) Pyruvate dehydrogenase deficiency in a male caused by a point mutation (F205L) in the Elα subunit. Hum Mutat 3:152–155

    Article  PubMed  CAS  Google Scholar 

  • Dahl HHM, Maragos C, Brown RM, Hansen LL, Brown GK (1990) Pyruvate dehydrogenase deficiency caused by deletion of a 7-bp repeat sequence in the Elα gene. Am J Hum Genet 47:286–293

    PubMed  CAS  Google Scholar 

  • Dahl HHM, Brown GK, Brown RM, Hansen LL, Ker DS, Wexler ID, Patel MS, De Meirleir L, Lissens W, Chunk K, MacKay N, Robinson BH (1992a) Mutations and polymorphisms in the pyruvate dehydrogenase Elα gene. Hum Mutat 1:97–102

    Article  PubMed  CAS  Google Scholar 

  • Dahl HHM, Hansen LL, Brown RM, Danks DM, Rogers JG, Brown GK (1992b) X-linked pyruvate dehydrogenase Elα subunit deficiency in heterozygous females: variable manifestation of the same mutation. J Inherit Metab Dis 15:835–847

    Article  PubMed  CAS  Google Scholar 

  • De Marcucci O, Lindsay JG (1985) Component X. An immunologically distinct polypeptide associated with mammalian pyruvate dehydrogenase multi-enzyme complex. Eur J Biochem 149:641–648

    Article  PubMed  Google Scholar 

  • De Meirleir L, Lissens W, Vamos E, Liebaers I (1992) Pyruvate dehydrogenase (PDH) deficiency caused by a 21-base pair insertion mutation in the Elα subunit. Hum Genet 88:649–652

    Article  PubMed  Google Scholar 

  • De Meirleir L, Lissens W, Denis R, Wayenberg JL, Michotte A, Brucher JM, Vamos E, Gerlo E, Liebaers I (1993) Aberrant splicing of exon 6 in the pyruvate dehydrogenase-Ela mRNA linked to a silent mutation in a large family with Leigh’s encephalomyelopathy. Pediatr Res 36:707–712

    Article  Google Scholar 

  • De Vivo DC, Haymond MW, Obert KA, Nelson JS, Pagliara AS (1979) Defective activations of the pyruvate dehydrogenase complex in subacute necrotizing encephalomyelopathy (Leigh disease). Ann Neurol 6:483–494

    Article  Google Scholar 

  • Endo H, Hasegawa K, Narisawa K, Tada K, Kagawa Y, Ohta S (1989) Defective gene in lactic acidosis: abnormal pyruvate dehydrogenase Elα-subunit caused by a frameshift. Am J Hum Genet 44:358–364

    PubMed  CAS  Google Scholar 

  • Endo H, Miyabayashi S, Tada K, Narisawa K (1991) A four-nucleotide insertion at the Elα gene in a patient with pyruvate dehydrogenase deficiency. J Inherit Metab Dis 14:793–799

    Article  PubMed  CAS  Google Scholar 

  • Fujii T, Van Coster RN, Old SE, Medori R, Winter S, Gubits RM, Matthews PM, Brown RM, Brown GK, Dahl HHM, De Vivo DC (1994) Pyruvate dehydrogenase deficiency: molecular basis for intrafamilial heterogeneity. Ann Neurol 36:83–89

    Article  PubMed  CAS  Google Scholar 

  • Fujii T, Alvarez G, Sheu KF, Kranz-Eble P, De Vivo D (1996) Pyruvate dehydrogenase deficiency: The relation of the Elα mutation to the Elβ subunit deficiency. Pediat Neurol 14:328–334

    Article  PubMed  CAS  Google Scholar 

  • Geoffroy V, Fouque F, Benelli C, Poggi F, Lissens W, Marsac C, Sanderson SJ, Lindsay JG (1996) Defect in the X-lipoyl-containing component of the pyruvate dehydrogenase complex in a patient with a neonatal lactic acidemia. Pediatrics 97:267–272

    PubMed  CAS  Google Scholar 

  • Hansen LL, Brown GK, Kirby DM, Dahl HHM (1991) Characterization of the mutations in three patients with pyruvate dehydrogenase Elα deficiency. J Inherit Metab Dis 14:140–151

    Article  PubMed  CAS  Google Scholar 

  • Hansen LL, Brown GK, Brown RM, Dahl HHM (1993) Pyruvate dehydrogenase deficiency caused by a 5 base pair duplication in the Elα subunit. Hum Mol Genet 6:805–807

    Article  Google Scholar 

  • Hansen LL, Horn N, Dahl HHM, Kruse TA (1994) Pyruvate dehydrogenase deficiency caused by a 33 base pair duplication in the PDH Elα subunit. Hum Mol Genet 6:1021–1022

    Article  Google Scholar 

  • Harris RA, Bowker-Kinley MM, Wu P, Jeng J, Popov M (1997) Dihydrolipoamide dehydrogenasebinding protein of the human pyruvate dehydrogenase complex. DNA-derived amino acid sequence, expression, and reconstitution of the pyruvate dehydrogenase complex. J Biol Chem 272:19746–19751

    Article  PubMed  CAS  Google Scholar 

  • Hemalatha SG, Kerr DS, Wexler ID, Lusk MM, Kaung M, Du Y, Kolli M, Schelper L, Patel MS (1995) Pyruvate dehydrogenase complex-deficiency due to a (P188L) within the thiamine pyrophosphate binding loop of the Elα subunit. Hum Mol Genet 4:315–318

    Article  PubMed  CAS  Google Scholar 

  • Ito M, Huq AHMM, Naito E, Saijo T, Takeda E, Kuroda Y (1992a) Mutation of Elα gene in a female patient with pyruvate dehydrogenase deficiency due to rapid degradation of El protein. J Inherit Metab Dis 15:848–856

    Article  PubMed  CAS  Google Scholar 

  • Ito M, Kobashi H, Naito E, Saijo T, Kakeda E, Huq AHMM, Kuroda Y (1992b) Decrease of pyruvate dehydrogenase phosphatase activity in patients with congenital lactic acidemia. Clin Chim Acta 209:1–7

    Article  PubMed  CAS  Google Scholar 

  • Ito M, Naito E, Yokota I, Takeda E, Matsuda J, Hirose M, Sejima H, Aiba H, Hojo H, Kuroda Y (1995) Molecular genetic analysis of a female patient with pyruvate dehydrogenase deficiency: detection of a new mutation and differential expression of mutant gene product in cultured cells. J Inherit Metab Dis 18:547–557

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Ker DS, Wexler ID, Tripatara A, Patel MS (1996) Human defects of the pyruvate dehydrogenase complex. In: Patel MS, Roche TE, Harris RA (eds) Keto acid dehydrogenase complexes. Birkhäuser, Basel, pp 249–269

    Google Scholar 

  • Ling M, McEachern G, Seyda A, MacKay M, Scherer SW, Bratinova S, Beatty B, Giovannucci Uzielli ML, Robinson BH (1998) Detection of a homozygous four base pair deletion in the protein X gene in a case of pyruvate dehydrogenase complex deficiency. Hum Mol Genet 7:501–505

    Article  PubMed  CAS  Google Scholar 

  • Lissens W, Desguerre I, Benelli C, Marsac C, Fouque F, Haenggeli C, Ponsot G, Seneca S, Liebaers I, De Meirleir L (1995) Pyruvate dehydrogenase deficiency in a female due to a 4 base pair deletion in exon 10 of the Elα gene. Hum Mol Genet 4:307–308

    Article  PubMed  CAS  Google Scholar 

  • Lissens W, De Meirleir L, Seneca S, Benelli C, Marsac C, Poll-The BT, Briones P, Ruitenbeek W, Van Diggelen O, Chaigne D, Ramaekers V, Liebaers I (1996) Mutation analysis of the pyruvate dehydrogenase Elα gene in eight patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat 7:46–51

    Article  PubMed  CAS  Google Scholar 

  • Liu TC, Kim H, Arizmendi C, Kitano A, Patel MS (1993) Identification of two missense mutations in a dihydrolipoamide dehydrogenase deficiency patient. Proc Natl Acad Sci USA 90:5186–5190

    Article  PubMed  CAS  Google Scholar 

  • Marsac C, Stansbie D, Bonne G, Cousin J, Jehenson P, Benelli C, Leroux JP, Lindsay G (1993) Defect in the lipoyl-bearing protein X subunit of the pyruvate dehydrogenase complex in two patients with encephalomyelopathy. J Pediatr 123:915–920

    Article  PubMed  CAS  Google Scholar 

  • Marsac C, Benelli C, Desguerre I, Diry M, Fouque F, De Meirleir L, Ponsot G, Seneca S, Poggi F, Saudubray JM, Zabot MT, Fontan D, Lissens W (1997) Biochemical and genetic studies of four patients with pyruvate dehydrogenase Elα deficiency. Hum Genet 99:785–792

    Article  PubMed  CAS  Google Scholar 

  • Matsuda J, Ito M, Naito E, Yokota I, Kuroda Y (1995) DNA diagnosis of pyruvate dehydrogenase deficiency in female patients with congenital lactic acidaemia. J Inherit Metab Dis 18:534–546

    Article  PubMed  CAS  Google Scholar 

  • Matthews PM, Brown RM, Otero LJ, Marchington DR, Leonard JV, Brown GK (1993a) Neurodevelopmental abnormalities and lactic acidosis in a girl with a 20-bp deletion in the X-linked pyruvate dehydrogenase Elα subunit gene. Neurology 43:2025–2030

    PubMed  CAS  Google Scholar 

  • Matthews PM, Marchington DR, Squier M, Land J, Brown RM, Brown GK (1993b) Molecular genetic characterization of an X-linked form of Leigh’s syndrome. Ann Neurol 33:652–655

    Article  PubMed  CAS  Google Scholar 

  • Matthews PM, Brown RM, Otero LJ, Marchington DR, LeGris M, Howes R, Meadows LS, Shevell M, Scriver CR, Brown GK (1994) Pyruvate dehydrogenase deficiency: clinical presentation and molecular genetic characterization of five new patients. Brain 117:435–443

    Article  PubMed  Google Scholar 

  • Murakami N, Iso A, Naoto E, Kuroda Y, Nonaka I (1995) Thiamine responsive congenital lactic acidemia and type I muscle fiber atrophy. Brain Dev 17:78

    Article  PubMed  CAS  Google Scholar 

  • Naito E, Ito M, Takeda E, Yokota I, Yoshijima S, Kuroda Y (1994a) Molecular analysis of abnormal pyruvate dehydrogenase in a patient with thiamine-responsive congenital lactic acidemia. Pediatr Res 36:340–346

    Article  PubMed  CAS  Google Scholar 

  • Naito E, Ito M, Yokota I, Matsuda J, Yara A, Kuroda Y (1994b) Pyruvate dehydrogenase deficiency caused by a four-nucleotide insertion in the Elα subunit gene. Hum Mol Genet 3:1193–1194

    Article  PubMed  CAS  Google Scholar 

  • Pastoris O, Savasta S, Foppa P, Catapano M, Dossena M (1996) Pyruvate dehydrogenase deficiency in a child responsive to thiamine treatment. Acta Paediatr 85:625–628

    Article  PubMed  CAS  Google Scholar 

  • Patel MS, Harris RA (1995) Mammalian α-2-oxo acid dehydrogenase complexes: gene regulation and genetic defects. FASEB J 9:1164–1172

    PubMed  CAS  Google Scholar 

  • Reed LJ (1981) Regulation of mammalian pyruvate dehydrogenase complex by phosphorylation-dephosphorylation cycle. Curr Top Cell Regul 18:95–106

    PubMed  CAS  Google Scholar 

  • Robinson BH (1995) Lactic acidemia (disorders of pyruvate carboxylase, pyruvate dehydrogenase). In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) Metabolic and molecular basis of inherited disease, 7th edn. McGraw-Hill, New York, pp 1479–1499

    Google Scholar 

  • Robinson BH, Taylor J, Sherwood W (1980) The genetic heterogeneity of lactic acidosis occurrence of recognisable inborn errors of metabolism in a paediatric population with lactic acidosis. Pediatr Res 14:956–962

    PubMed  CAS  Google Scholar 

  • Robinson BH, MacKay N, Petrova-Benedict R, Ozalp I, Coskun T, Stacpoole PW (1990) Defects in the E2 lipoyl transacetylase and X-lipoyl containing component of the pyruvate dehydrogenase complex in patients with lactic acidemia. J Clin Invest 85:1821–1824

    Article  PubMed  CAS  Google Scholar 

  • Schölte HR, Busch FM, Luyt-Houwen IEM (1992) Vitamin-responsive pyruvate deficiency in a young girl with external ophthalmoplegia, myopathy and lactic acidosis. J Inherit Metab Dis 15:331–334

    Article  PubMed  Google Scholar 

  • Sorbi S, Blass JP (1982) Abnormal activation of pyruvate dehydrogenase in Leigh disease fibroblasts. Neurology 32:555–558

    PubMed  CAS  Google Scholar 

  • Takakubo F, Thorburn D, Dahl HHM (1993a) A novel mutation and a polymorphism in the X chromosome located pyruvate dehydrogenase Elα gene (PDHA1). Hum Mol Genet 2:1961–1962

    Article  PubMed  CAS  Google Scholar 

  • Takakubo F, Cartwright P, Hoogenraad N, Thorburn DR, Collins F, Lithgow T, Dahl HHM (1995a) An amino acid substitution in the pyruvate dehydrogenase Elα gene, affecting mitochondrial import of the precursor protein. Am J Hum Genet 57:772–780

    PubMed  CAS  Google Scholar 

  • Takakubo F, Thorburn DR, Brown RM, Brown GK, Dahl HHM (1995b) A novel mutation (P316L) in a female with pyruvate dehydrogenase Elα deficiency. Hum Mutat 6:274–275

    Article  PubMed  CAS  Google Scholar 

  • Tripatara A, Ker DS, Lusk MM, Kolli M, Tan J, Patel MS (1996) Three new mutations of the pyruvate dehydrogenase alpha subunit: a point mutation (M181V), 3 bp deletion (-R282), and 16 bp insertion/frameshift (K358VS→TVDQS). Hum Mutat 8:180–182

    Article  PubMed  CAS  Google Scholar 

  • Wexler ID, Hemalatha SG, Liu TC, Berry SA, Kerr DS, Patel MS (1992) A mutation in the Elα subunit of pyruvate dehydrogenase associated with variable expression of pyruvate dehydrogenase complex deficiency. Pediatr Res 32:169–174

    Article  PubMed  CAS  Google Scholar 

  • Wexler ID, Hemalatha SG, McConnell RD, Buist NR, Dahl HHM, Berry SA, Cederbaum SD, Patel MS, Ken TS (1997) Outcome of pyruvate dehydrogenase treated with ketogenic diet. Neurology 49:1655–1661

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Inserm U75 et U30, H00F4pital et Faculté Necker, 149 rue de Sèvres, 75015, Paris, France

    C. Marsac, D. François, F. Fouque & C. Benelli

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  1. C. Marsac
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  2. D. François
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  3. F. Fouque
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  4. C. Benelli
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  1. E 99-29 INSERM, Physiologie Mitochondriale, Université Victor Segalen Bordeaux 2, 146, rue Léo Saignat, 33076, Bordeaux Cedex, France

    Patrick Lestienne (Directeur de Recherche INSERM) (Directeur de Recherche INSERM)

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Marsac, C., François, D., Fouque, F., Benelli, C. (1999). Pyruvate Dehydrogenase Deficiencies. In: Lestienne, P. (eds) Mitochondrial Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59884-5_13

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  • DOI: https://doi.org/10.1007/978-3-642-59884-5_13

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-64166-4

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