Pyruvate dehydrogenase deficiencies

  • J. P. Blass


The extraordinary complexity of the pyruvate dehydrogenase complex (PDHC) is clearly documented in Chapter 12. PDHC contains three catalytic and two regulatory enzymes. It is subject to an intricate array of controls, including phosphorylation and dephosphorylation of the α-subunit of its thiamin-dependent component, end-product inhibition by NADH and acetyl-coenzyme A, and the action of a number of effectors. Furthermore, there is relatively little excess of this enzyme compared to the normal flux of its substrate, both in brain1 and in other tissues2. The control of PDHC in health and disease is a subject of intense research in a number of laboratories at the present time, particularly in relation to diabetes and the mechanism of action of insulin. Even subtle changes in the structure of one of the proteins in PDHC could lead to metabolically significant impairment of its activity. Conversely, one can conceive of a wide variety of metabolic alterations which could lead to secondary impairment of the activity of PDHC and present clinically as deficiencies of PDHC. In view of this complexity, it is not surprising that the deficiencies of PDHC which have been described have not yet been fully characterized in biochemical detail.


Lactic Acidosis Pyruvate Dehydrogenase Ketogenic Diet Pyruvate Dehydrogenase Complex High Carbohydrate Diet 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    S. F. Reynolds and J. P. Blass, (1976). A possible mechanism for selective cerebellar damage in partial PDH deficiency. Neurology, 26, 625PubMedGoogle Scholar
  2. 2.
    O. H. Wieland, E. A. Siess, L. Weiss, G. Loffler, C. Patzelt, R. Portenhauser, U. Hartmann and A. Shirmann, (1973). Regulation of the mammalian pyruvate dehydrogenase complex by covalent modification. Symp. Soc. Exp. Biol, 27, 371PubMedGoogle Scholar
  3. 3.
    T. L. Sourkes, (1962). Biochemistry of Mental Disease, pp. 151–155. (Hober-Harper New York)Google Scholar
  4. 4.
    B. K. Siesjo H. Johnannsson B. Ljunggren and K. Norberg (1974). Brain dysfunction in cerebral hypoxia and ischemia. In F. Plum (ed.). Brain Dysfunction in Metabolic Disorders pp. 75–112. Raven Press New YorkGoogle Scholar
  5. 5.
    R. A. Peters 1969. Biochemical lesion and its historical development. Br. Med. Bull 25 22Google Scholar
  6. 6.
    J. H. Quastel, (1974). Fifty years of biochemistry. A personal account. Can. J. Biochem., 52, 71Google Scholar
  7. 7.
    D. H. Henneman, M. D. Altschule and R. M. Goncz, (1954). Carbohydrate metabolism in brain disease. II. Glucose metabolism in schizophrenic manic depressive and involutional psychoses. Arch. Intern. Med., 54, 402Google Scholar
  8. 8.
    R. E. Kendell (1975). The Role of Diagnosis in Psychiatry p. 176. (Blackwell Scientific Publications LondoGoogle Scholar
  9. 9.
    R. J. Erickson, (1965). Familial infantile lactic acidosis. J. Pediatr., 66, 1005Google Scholar
  10. 10.
    S. Israels, J. C. Haworth, B. Courley and J. D. Ford, (1964). Chronic acidosis due to an error in lactate and pyruvate metabolism. Pediatrics, 34, 346PubMedGoogle Scholar
  11. 11.
    B. E. Clayton, R. H. Dobbs and A. D. Patrick, (1967). Leigh’s subacute necrotizing encephalopathy: clinical and biochemical study; therapy with lipoate. Arch. Dis. Child., 42, 467PubMedCrossRefGoogle Scholar
  12. 12.
    A. F. Hartman, H. J. Wohltmann, M. C. Puckerson and M. E. Wesley, (1962). Lactate metabolism-studies of a child with a serious congenital deviation. J. Pediatr., 61, 165CrossRefGoogle Scholar
  13. 13.
    J. C. Haworth, J. D. Ford and M. K. Younoszai, (1967). Familial chronic acidosis due to an error in lactate and pyruvate metabolism. Can. Med. Assoc. J., 97, 773PubMedGoogle Scholar
  14. 14.
    H. L. Greene, W. K. Schubert and G. Hug, (1970). Chronic lactic acidosis of infancy. J. Pediatr., 76, 853PubMedCrossRefGoogle Scholar
  15. 15.
    R. D. Eastham and J. Jancar, (1968). Clinical Pathology in Mental Retardation, pp. 159–161. (John Wright & Sons Bristol)Google Scholar
  16. 16.
    D. Lonsdale, W. R. Faulkner, J. W. Price and R. R. Smeby, (1969). Intermittent cerebellar ataxia associated with hyperpyruvic acidemia and hyperalaninuria. Pediatrics, 43, 1025PubMedGoogle Scholar
  17. 17.
    J. P. Blass, J. Avigan and B. W. Uhlendorf, (1970). A defect in pyruvate decarboxylase in a child with an intermittent movement disorder. J. Clin. Invest., 49, 423PubMedCrossRefGoogle Scholar
  18. 18.
    J. P. Blass, D. Lonsdale, B. W. Uhlendorf and E. Horn, (1971). Intermittent ataxia with pyruvate decarboxylase deficiency. Lancet, 1, 1302PubMedCrossRefGoogle Scholar
  19. 19.
    J. P. Blass, J. D. Schulman, D. S. Young and E. Horn, (1972). An inherited defect affecting the tricarboxylic acid cycle in a patient with congenital lactic acidosis. J. Clin. Invest., 51, 1845PubMedCrossRefGoogle Scholar
  20. 20.
    S. D. Cederbaum, J. P. Blass and N. Minkoff, et al. (1976). Sensitivity to carbohydrate in a patient with familial intermittent lactic acidosis and pyruvate dehydrogenase deficiency. Pediat. Res., 10,713PubMedGoogle Scholar
  21. 21.
    R. E. Falk, S. D. Cederbaum, J. P. Blass, R. J. Pruss and R. E. Carrell, (1976). Ketonic diet in the management of pyruvate dehydrogenase deficiency. Pediatrics, 58, 713PubMedGoogle Scholar
  22. 22.
    J. C. Haworth, T. L. Perry, J. P. Blass, S. Hansen and N. Urquhart, (1976). Lactic acidosis in three sibs due to defects in both pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes. Pediatrics, 58, 564PubMedGoogle Scholar
  23. 23.
    H. Wick, K. Schweizer and R. Baumgartner, (1977). Thiamine dependency in a patient with congenital lacticacidemia due to pyruvate dehydrogenase deficiency. Agents Actions, 7, 405PubMedCrossRefGoogle Scholar
  24. 24.
    J. H. Strome O. Borud and P. J. Moe 1976. Fatal lactic acidosis in a newborn attributable to a congenital defect of pyruvate dehydrogenase. Pediatr. Res. 10 6Google Scholar
  25. 25.
    D. F. Farrell, A. F. Clark, C. R. Scott and R. P. Wennberg, (1975). Absence of pyruvate decarboxylase activity in man: a cause of congenital lactic acidosis. Science, 187, 1082PubMedCrossRefGoogle Scholar
  26. 26.
    D. F. Farrell, (1977). Pyruvate dehydrogenase (E1) deficiency associated with congenital lactic acidosis. In P. Mittler (ed.). Research to Practice in Mental Retardation: Biomedical Aspects, Vol. 3, pp. 147–155. (IASSMD New York)Google Scholar
  27. 27.
    B. H. Robinson, J. Taylor and W. G. Sherwood, (1977). Deficiency of dihydrolipoyl dehydrogenase (a component of the pyruvate and α-ketoglutarate dehydrogenase complexes): a cause of congenital chronic lactic acidosis in infancy. Pediatr. Res., 11, 1198PubMedGoogle Scholar
  28. 28.
    T. W. Farmer, L. Veath, A. L. Miller, J. S. O’Brien and R. M. Rosenberg, (1973). Pyruvate decarboxylase deficiency in a patient with subacute necrotizing encephalomyelopathy. Neurology, 23, 429Google Scholar
  29. 29.
    J. Fernandes and W. Blom 1976. Urinary lactate excretion in rmal children and in children with enzyme defects of carbohydrate metabolism. Clin. Chim. Acta. 66 34Google Scholar
  30. 30.
    R. A. P. Kark and M. Rodriguez-Budelli, (1977). The spectrum of ataxia syndromes due to lipoamide dehydrogenase deficiency. Neurology, 27, 359Google Scholar
  31. 31.
    Y. Kuroda, L. Sweetman, W. L. Nyhan, J. J. Kling and T. D. Groshong, (1978). Abnormal pyruvate and a-ketoglutarate dehydrogenases in a patient with lactic acidemia. Clin. Res., 26, 176Google Scholar
  32. 32.
    Y. Oka, I. Matsuda, S. Arashima, M. Anakura, T. Mitsuyama and I. Nagamatsu, (1976). Citrate treatment in a patient with pyruvate decarboxylase deficiency. Tohoku J. Exp. Med., 118, 131PubMedCrossRefGoogle Scholar
  33. 33.
    Y. Oka, I. Matsuda, S. Arashima, M. Anakura, T. Mitsuyama and H. Nambu, (1975). Transient hyperalaninuria and hyperpyruvic acidemia. Neuropaediatrie, 6, 202CrossRefGoogle Scholar
  34. 34.
    B. H. Robinson and W. G. Sherwood, (1975). Pyruvate dehydrogenase phosphatase deficiency. Cause of congenital chronic lactic acidosis in infancy. Pediatr. Res., 9, 935PubMedGoogle Scholar
  35. 35.
    M. Rodriguez-Budelli and R. A. P. Kark, (1977). Analysis of a defect in lipoamide dehydrogenase in Friedreich’s Ataxia. Trans. Am. Soc. Neurochem., 8, 116Google Scholar
  36. 36.
    J. L. Willems, L. A. H. Monnens, J. M. F. Trijbels, R. A. C. Sengers and J. H. Veerkamp, (1974). Pyruvate decarboxylase deficiency in liver. N. Engl. J. Med., 290, 406PubMedGoogle Scholar
  37. 37.
    J. P. Blass, R. A. P. Kark, N. Menon and S. H. Harris, (1976). Decreased activities of the pyruvate and ketoglutarate dehydrogenase complexes in fibroblasts from five patients with Friedreich’s ataxia. N. Engl. J. Med., 295, 62PubMedCrossRefGoogle Scholar
  38. 38.
    J. P. Blass, S. D. Cederbaum and H. G. Dunn, (1976). Biochemical defect in Leigh’s disease. Lancet, 1, 1237PubMedCrossRefGoogle Scholar
  39. 39.
    R. A. P. Kark and M. Rodriguez-Budelli, (1979). Pyruvate dehydrogenase deficiencies in six of fourteen unselected patients with spinocerebellar degenerations. Neurology, 29,126PubMedGoogle Scholar
  40. 40.
    J. P. Blass, S. D. Cederbaum and R. A. P. Kark, (1976). Pyruvate dehydrogenase deficiency: summary of results with 25 patients. Trans. Am. Soc. Neurochem., 7, 167Google Scholar
  41. 41.
    J. P. Blass, S. D. Cederbaum and R. A. P. Kark, (1978). Pyruvate dehydrogenase deficiency. In O. Sperling, A. de Vries (eds.) Monographs in Human Genetics. Vol. 9, 12–15. (S. Karger Basel)Google Scholar
  42. 42.
    D. Stansbie and R. M. Denton, (Personal communication)Google Scholar
  43. 43.
    F. A. Hommes, (Personal communication)Google Scholar
  44. 44.
    A. Yoshida, (1973). Hemolytic anemia and G6PD deficiency. Science, 179, 532PubMedCrossRefGoogle Scholar
  45. 45.
    A. Filla, R. F. Butterworth, G. Geoffrey, B. Lemieux and A. Barbeau, (1978). Serum and platelet lipoamide dehydrogenase in Friedreich’s ataxia. Can. J. Neurol. Sci., 5,111PubMedGoogle Scholar
  46. 46.
    J. P. Blass, S. D. Cederbaum and G. E. Gibson, (1976). Clinical and metabolic abnormalities accompanying deficient oxidation of pyruvate. In F. A. Hommes and C. J. Van Den Berg (eds.). Normal and Pathological Development of Energy Metabolism, p. 193. (Academic Press New York)Google Scholar
  47. 47.
    A. A. Moncrieff, O. P. Koumides, B. E. Clayton, A. D. Patrick, A. G. G. Renwick and G. E. Roberts, (1964). Lead poisoning in children. Arch. Dis. Child., 39, 1PubMedCrossRefGoogle Scholar
  48. 48.
    B. H. Robinson, D. G. Gall and E. Cutz, (1977). Deficient activity of hepatic pyruvate dehydrogenase and pyruvate carboxylase in Reye’s syndrome. Pediatr. Res., 11, 279PubMedGoogle Scholar
  49. 49.
    R. A. P. Kark, J. P. Blass and W. K. Engel, (1974). Pyruvate oxidation in neuromuscular disease: evidence of a genetic defect in two families with the clinical syndrome of Friedreich’s ataxia. Neurology, 24, 964PubMedGoogle Scholar
  50. 50.
    A. P. Halestrap, (1975). Mitochondrial pyruvate carrier. Kinetics and specificity for substrates and inhibitors. Biochem. J., 148, 85PubMedGoogle Scholar
  51. 51.
    J. M. Land, J. Mowbray and J. B. Clark, (1976). Control of pyruvate and f$-hydroxybutyrate utilisation in rat brain mitochondria and its relevance to phenylketonuria and maple-syrup-urine disease. J. Neurochem., 26, 823PubMedCrossRefGoogle Scholar
  52. 52.
    J. P. Blass, R. A. P. Kark and W. K. Engel, (1971). Clinical studies of a patient with pyruvate-decarboxylase deficiency. Arch. Neurol., 25, 449PubMedGoogle Scholar
  53. 53.
    L. Sokoloff, (1973). Metabolism of ketone bodies by the brain. Annu. Rev. Med., 24, 271PubMedCrossRefGoogle Scholar
  54. 54.
    N. Friedreich, (1863). Ueber degenerative atrophie der spinalen hinterstrange. Virchows Arch. (Pathol. Anat.), 26, 391CrossRefGoogle Scholar
  55. 55.
    F. Anderman, (1976). Nicolaus Friedreich and degenerative atrophy of the posterior columns of the spinal cord. Can. J. Neurol. Sci., 3,275Google Scholar
  56. 56.
    J. G. Greenfield, (1954). The Spinocerebellar Degenerations. (Charles C. Thomas Springfield Illinois)Google Scholar
  57. 57.
    T. Sjogren, (1943). Klinische und erbbiologische untersuchungen uber die heredoataxien. Acta. Psychiatr. Neurol., 27, 1Google Scholar
  58. 58.
    R. D. Adams and M. Victor, (1977). Principles of Neurology, p. 836. (McGraw-Hill New York)Google Scholar
  59. 59.
    W. R. Brain and J. N. Walton, (1969). Diseases of the Nervous System, p. 589. (Oxford University Press Oxford)Google Scholar
  60. 60.
    R. A. P. Kark, R. Rosenberg and L. Schut, (1978). The Ataxias. Advances in Neurology, p. 21. (Raven Press New York)Google Scholar
  61. 61.
    C. R. Scott and D. F. Farrell, (Personal communication)Google Scholar
  62. 62.
    D. A. Stumpf and J. D. Parks, (1978). Friedreich’s ataxia. I. Normal pyruvate dehydrogenase complex activity in platelets. Ann. Neurol., 4,366PubMedCrossRefGoogle Scholar
  63. 63.
    A. Barbeau, R. F. Butterworth, T. Ngo, G. Breton, S. Melancon, D. Shapcott, G. Geoffroy and B. Lemieux, (1976). Pyruvate metabolism in Friedreich’s ataxia. Can. J. Neurol. Sci.,,379Google Scholar
  64. 64.
    A. Barbeau, (1978). Friedreich’s ataxia 1978 — an overview. Can. J. Neurol. Sci., 5, 161PubMedGoogle Scholar
  65. 65.
    H. G. Dunn and C. L. Dolman, (1969). Necrotizing encephalomyelopathy: report of a case with relapsing polyneuropathy and hyperalaninemia and withmanifestations resembling Friedreich’s ataxia. Neurology, 19, 536PubMedGoogle Scholar
  66. 66.
    R. Exss, F. Gulotta, H. C. Kallfelz and M. Volpel, (1974). Wernicke’s encephalopathy and Friedreich’s ataxia. Neuropaediatrie, 5, 162CrossRefGoogle Scholar
  67. 67.
    M. A. Guggenheim and D. A. Stumpf, (1977). Familial metabolic disease with clinicopathological findings of both Leigh’s Disease and adult-type spinocerebellar degeneration. Ann. Neurol., 2, 264Google Scholar
  68. 68.
    DeVivo, D. (Personal communication)Google Scholar
  69. 69.
    R. A. P. Kark, J. P. Blass and A. Spence, (1975). Physostigmine in patients with familial ataxias. Neurology, 27, 70Google Scholar
  70. 70.
    M. M. Rodriguez-Budelli, R. A. P. Kark, J. P. Blass, M. A. Spence, (1978). Action of physostigmine on inherited ataxias. Adv. Neurol., 21, 195PubMedGoogle Scholar
  71. 71.
    A. Barbeau, (1978). Emerging treatments: replacement therapy with choline or lecithin in neurological diseases. Can. J. Neurol. Sci., 5, 157PubMedGoogle Scholar
  72. 72.
    A. Barbeau, (1978). Phosphatidylcholine (Lecithin) in neurologic disorders. Proc. Am. Acad. Neurol., 30, 81Google Scholar
  73. 73.
    S. Whitehouse, R. H. Cooper and P. J. Randle, (1974). Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids. Biochem. J., 141, 761PubMedGoogle Scholar
  74. 74.
    P. W. Stacpoole, G. W. Moore and C. M. Kornhauser, (1978). Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. N. Engl. J. Med., 298, 526PubMedCrossRefGoogle Scholar
  75. 75.
    Saudubray, J. M. (Personal communication)Google Scholar
  76. 76.
    McKhan, G. (Personal communication)Google Scholar
  77. 77.
    O. B. Evans, A. W. Kilroy and G. M. Fenichel, (1978). Acetazolamide in the treatment of pyruvate dysmetabolism syndromes. Arch. Neurol, 35, 302PubMedGoogle Scholar
  78. 78.
    J. R. DiPalma and D. M. Ritchie, (1977). Vitamin toxicity. Annu. Rev. Phar macol. Toxicol, 17, 133CrossRefGoogle Scholar
  79. 79.
    G. G. Nahas, (1959). Use of an organic carbon dioxide buffer in vivo. Science, 26, 782CrossRefGoogle Scholar
  80. 80.
    J. P. Blass and C. A. Lewis, (1973). Kinetic properties of the partially purified pyruvate dehydrogenase complex of ox brain. Biochem. J., 130, 31Google Scholar
  81. 81.
    J. R. Butler, F. H. Pettit, P. F. Davis and L. J. Reed, (1977). Binding of thiamin thiazolone pyrophosphate to mammalian pyruvate dehydrogenase and its effect on kinase and phosphatase activities. Biochem. Biophys. Res. Commun., 74, 1667PubMedCrossRefGoogle Scholar
  82. 82.
    J. H. Pincus, G. B. Solitare and J. R. Cooper, (1976). Thiamine triphosphate levels and histopathology. Correlation in Leigh’s disease. Arch. Neurol, 33, 759PubMedGoogle Scholar
  83. 83.
    L. E. Rosenberg, (1974). Vitamin-responsive inherited diseases affecting the nervous system. In F. Plum (ed.). Brain Dysfunction in Metabolic Disorders, p. 271. (Raven Press New York)Google Scholar
  84. 84.
    W. M. Taylor and M. L. Halperin, (1973). Regulation of pyruvate dehydrogenase in muscle. Inhibition by citrate. J. Biol. Chem., 248, 6080PubMedGoogle Scholar
  85. 85.
    Holtzman, D. (Personal communication)Google Scholar
  86. 86.
    Y. Shapira, S. D. Cederbaum, P. A. Cancilla, D. Nielsen and B. M. Lippe, Familial poliodystrophy, mitochondrial myopathy, and lactate acidemia. Neurology, 25, 614Google Scholar
  87. 87.
    G. E. Gibson R. Jope and J. P. Blass 1975. Reduced synthesis of acetylcholine accompanying impaired oxidation of pyruvic acid in rat brainminces. Biochem. J. 148 1PubMedGoogle Scholar
  88. 88.
    J. P. Blass and G. E. Gibson, (1977). Cholinergic systems and disorders of carbohydrate catabolism. In D. Jenden (ed.). Cholinergic Mechanisms and Psychopharmacology, pp. 791–803. (Plenum Press New York)Google Scholar
  89. 89.
    R. J. Wurtman, M. J. Hirsch and J. H. Growdon, (1977). Lecithin consumption raises serum-free-choline levels. Lancet, 2, 68PubMedCrossRefGoogle Scholar
  90. 90.
    Evans, O. B. (Personal communication)Google Scholar
  91. 91.
    F. Manfredi, H. O. Sicker, A. P. Spoto and H. A. Saltzman, (1960). Severe carbon dioxide intoxication. Treatment with organic buffer (Trishydroxy-methylaminomethane). J. Am. Med. Assoc., 173, 999Google Scholar
  92. 92.
    G. E. Gibson, M. Shimada, and J. P. Blass, (1979). Protection by THAM against behavioral and neurochemical effects of hypoxia. Biochem. Pharm., 28, 747PubMedCrossRefGoogle Scholar
  93. 93.
    J. P. Blass S. D. Cederbaum and R. A. P. Kark 1976. Rapid diagsis of pyruvate and ketoglutarate dehydrogenase deficiencies in platelet enriched preparations from blood. Clin. Chim. Acta. 75 2CrossRefGoogle Scholar
  94. 94.
    E. Silverstein and P. D. Boyer, (1964). Instability of pyruvate-C14 in aqueous solutions as detected by enzymic assay. Anal. Biochem., 8, 470PubMedCrossRefGoogle Scholar
  95. 95.
    A. F. Clark, D. F. Farrell, W. Burke and C. R. Scott, (1976). The effect of mycoplasma contamination on the in vitro assay of pyruvate dehydrogenase activity in cultured fibroblasts. Clin. Res., 24, 147Google Scholar
  96. 96.
    T. R. Chen, (1977). In situ detection of mycoplasma contamination in cell culture by fluorescent Hoechst 33258 stain. Exp. Cell. Res., 104, 255PubMedCrossRefGoogle Scholar
  97. 97.
    E. L. Schneider, E. J. Stanbridge and C. J. Epstein, (1974). Incorporation of 3H-Uridine and 14C-Uracil into RNA. A simple technique for the detection of mycoplasma contamination of cultured cells. Exp. Cell. Res., 84, 311PubMedCrossRefGoogle Scholar
  98. 98.
    P. A. Mardh, (1975). Elimination of mycoplasmas from cell cultures with sodium polyanethol sulphonate. Nature, 254, 515PubMedCrossRefGoogle Scholar
  99. 99.
    Gibson, G. E. and Vasil, A. (Personal communication)Google Scholar
  100. 100.
    D. Stansbie, (1976). Regulation of the human pyruvate dehydrogenase complex. Clin. Sci. Mol.Med., 51, 445PubMedGoogle Scholar
  101. 101.
    W. G. Johnson and A. M. Chutorian, (1977). Inheritance of a new form of hexosaminidase deficiency. Ann. Neurol, 2, 266CrossRefGoogle Scholar

Copyright information

© The Society for the Study of Inborn Errors of Metabolism 1980

Authors and Affiliations

  • J. P. Blass

There are no affiliations available

Personalised recommendations