Disorders of Organic Acid Metabolism

  • Kay Tanaka


Following the widespread amino acid screening programs of the 1950s and early 1960s using paper and ion-exchange column chromatography, numerous amino acidemias were discovered. However, the inborn errors detected by amino acid chromatography were limited to those with defective enzymes in the first two steps of amino acid metabolism. In these cases, the parent amino acid or its keto analogue accumulates.(1) After the two early steps, namely transamination and oxidative decarboxylation, most of the amino acids are metabolized to so-called “organic acids.” The parent amino acids could easily be identified by the ninhydrin reaction, and keto acids could be identified as dinitrophenylhydrozones. The “organic acids,” however, were difficult to detect by the then-existing methods. Because of these technical limitations, enzymatic defects that occur at later stages of amino acid metabolism were not discovered until 1966.


Pyruvate Carboxylase Methylmalonic Acid Isovaleric Acid Pyroglutamic Acid Methylmalonic Aciduria 
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.
    M. L. Efron, Aminoaciduria, New Engl. J. Med. 272:1058–1067 (1965).CrossRefGoogle Scholar
  2. 2.
    K. Tanaka, M. A. Budd, M. L. Efron, and K. J. Isselbacher, Isovaleric acidemia: A new genetic defect of leucine metabolism, Proc. Natl. Acad. Sci. (USA) 56:236–242 (1966).CrossRefGoogle Scholar
  3. 3.
    M. A. Budd, K. Tanaka, L. B. Holmes, M. L. Efron, J. D. Crawford, and K. J. Isselbacher, Isovaleric acidemia: Clinical features of a new genetic defect of leucine metabolism, TV. Engl. J. Med. 277:321–327 (1967).CrossRefGoogle Scholar
  4. 4.
    K. Tanaka and K. J. Isselbacher, The isolation and identification of N-isovalerylglycine from urine of patients with isovaleric acidemia, J. Biol. Chem. 242:2966–2972 (1967).Google Scholar
  5. 5.
    U. G. Oberholzer, B. Levin, E. A. Burgess, and W. F. Young, Methylmalonic aciduria, an inborn error of metabolism leading to chronic metabolic acidosis, Arch. Dis. Child. 42:492–504 (1967).CrossRefGoogle Scholar
  6. 6.
    O. Stokke, L. Eldjarn, K. R. Norum, J. Steen-Johnson, and S. Halvorsen, Methylmalonic acidemia, a new inborn error of metabolism which may cause fatal acidosis in neonatal period, Scan. J. Clin. Lab. Invest. 20:313–328 (1967).CrossRefGoogle Scholar
  7. 7.
    F. A. Hommes, J. R. G. Kuipers, J. D. Elema, J. F. Jansen, and J. H. P. Jonxis, Propionicacidemia, a new inborn error of metabolism, Pediatr. Res. 2:519–524 (1968).CrossRefGoogle Scholar
  8. 8.
    D. Gompertz, Organic acidemias, in “Proceedings of Eighth Symposium on Advanced Medicine” (G. Heale, ed.), pp. 270–284, Pitman, London (1972).Google Scholar
  9. 9.
    J. Dancis and M. Levitz, Abnormalities of branched-chain amino acid metabolism, in “The Metabolic Basis of Inherited Disease” (J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson, eds.) pp. 426–439, McGraw-Hill, New York (1972).Google Scholar
  10. 10.
    D. Steinberg, Refsum’s disease — A recently characterized lipidosis involving the nervous system, Ann. Int. Med. 66:365–395 (1967).Google Scholar
  11. 11.
    E. Jellum, T. Kluge, H. C. Börresen, O. Stokke, and L. Eldjarn, Pyroglutamic aciduria, a new inborn error of metabolism, Scand. J. Clin. Lab. Invest. 26:327–335 (1970).CrossRefGoogle Scholar
  12. 12.
    L. Eldjarn, E. Jellum, O. Stokke, H. Pande, and P. E. Waaler, β-Hydroxyisovaleric aciduria and β-methylcrotonylglycinuria: A new inborn error of metabolism, Lancet 2:521–522 (1970).CrossRefGoogle Scholar
  13. 13.
    O. Stokke, L. Eldjarn, E. Jellum, H. Pande, and P. E. Waaler, β-Methylcrotonyl CoA carboxylase deficiency: A new metabolic error in leucine degradation, Pediatrics 49:726–735 (1972).Google Scholar
  14. 14.
    K. Tanaka, J. C. Orr, and K. J. Isselbacher, Identification of β-hydroxyisovaleric acid in the urine of a patient with isovaleric acidemia, Biochim. Biophys. Acta 15:638–641 (1968).Google Scholar
  15. 15.
    K. Tanaka, Isovaleric acidemia and its induction in experimental animals by hypoglycin A, in “Inborn Errors of Metabolism” (F. A. Hommes and C. J. VandenBerg, eds.) pp. 269–289, Academic Press, New York (1973).Google Scholar
  16. 16.
    K. Rasmussen, T. Ando, W. L. Nyhan, D. Hull, D. Cottom, G. Donnell, W. Wadlington, and A. W. Kilroy, Excretion of propionylglycine in propionic acidemia, Clin. Sci. 42:665–671 (1972).Google Scholar
  17. 17.
    T. Ando, K. Rasmussen, W. L. Nyhan, and D. Hull, 3-Hydroxypropionate: Significance of β-oxidation of Propionate in patients with propionic acidemia and methylmalonic acidemia, Proc. Natl. Acad. Sci. 69:2807–2811 (1972).CrossRefGoogle Scholar
  18. 18.
    T. Ando, K. Rasmussen, J. M. Wright, and W. L. Nyhan, Isolation and identification of methylcytrate, a major metabolic product of Propionate in patients with propionic acidemia, J. Biol. Chem. 247:2200–2204 (1972).Google Scholar
  19. 19.
    L. E. Rosenberg, A. C. Lilljeqvist, and Y. E. Hsia, Methylmalonic aciduria, an inborn error leading to metabolic acidosis, long chain ketonuria and intermittent hyperglycinemia, N. Engl. J. Med. 278:1319–1322 (1968).CrossRefGoogle Scholar
  20. 20.
    G. Morrow, L. A. Barness, V. H. Auerbach, A. M. DiGeorge, T. Ando, and W. L. Nyhan, Observations on the coexistence of methylmalonic acidemia and glycinemia, J. Pediatr. 74:680–690 (1969).CrossRefGoogle Scholar
  21. 21.
    Y. E. Hsia, K. J. Scully, and L. E. Rosenberg, Defective Propionate carboxylation in ketotic hyperglycinemia, Lancet 1:757–758 (1969).CrossRefGoogle Scholar
  22. 22.
    D. Gompertz, C. N. Storrs, D. C. K. Bau, and T. J. Peters, Localization of enzymatic defect in propionic acidemia, Lancet 1:1140–1143 (1970).CrossRefGoogle Scholar
  23. 23.
    T. Ando, K. Rasmussen, W. L. Nyhan, G. N. Downell, and N. D. Barnes, Propionic acidemia in patients with ketotic hyperglycinemia, J. Pediatr. 78:827–832 (1971).CrossRefGoogle Scholar
  24. 24.
    J. P. Keating, R. D. Feigin, S. M. Tenenbaum, and R. E. Hillman, Hyperglycinemia with ketosis due to a defect in isoleucine metabolism: A preliminary report, Pediatrics 50:890–895 (1972).Google Scholar
  25. 25.
    T. Ando, W. G. Klingberg, A. N. Ward, K. Rasmussen, and W. L. Nyhan, Isovaleric acidemia presenting altered metabolism of glycine, Pediatr. Res. 5:478–486 (1971).CrossRefGoogle Scholar
  26. 26.
    N. D. Barnes, D. Hull, L. Balgobin, and D. Gompertz, Biotin responsive propionicacidaemia, Lancet 2:244–245 (1970).CrossRefGoogle Scholar
  27. 27.
    J. Boisse, R. Perelman, J. C. Rudler, C. Charpentier, and J. P. Pausset, L’Acidemie methylmalonique: Une cause nouvelle d’acidocetose grave, Ext. Sem. Hop. 47:53–65 (1971).Google Scholar
  28. 28.
    E. S. Kang, P. J. Snodgrass, and P. S. Gerald, Methylmalonyl CoA racemase defect: Another cause of methylmalonic aciduria, Pediatr. Res. 6:875–879 (1972).CrossRefGoogle Scholar
  29. 29.
    J. H. Menkes, Idiopathic hyperglycinemia: Isolation and identification of three previously undescribed urinary ketones, J. Pediatr. 69:413–421 (1966).CrossRefGoogle Scholar
  30. 30.
    S. Halvorsen, O. Stokke, and L. Eldjarn, Abnormal patterns of urine and serum amino acids in methylmalonic acidemia, Acta Paediatr. Scand. 59:28–32 (1970).CrossRefGoogle Scholar
  31. 31.
    B. Childs, W. L. Nyhan, and M. Borden, Idiopathic hyperglycinemia and hyperglycinuria, a new disorder of amino acid metabolism. I. Pediatrics 27:522–538 (1961).Google Scholar
  32. 32.
    W. L. Nyhan, M. Borden, and B. Childs, Idiopathic hyperglycinemia: A new disorder of amino acid metabolism. II. The concentration of other amino acids in the plasma and their modification by the administration of leucine, Pediatrics 27:539–555 (1961).Google Scholar
  33. 33.
    T. Gerritsen, E. Kaveggia, and H. A. Waisman, A new type of idiopathic hyperglycinemia with hypo-oxaluria, Pediatrics 36:882–891 (1965).Google Scholar
  34. 34.
    R. Baumgartner, T. Ando, and W. L. Nyhan, Nonketotic hyperglycinemia, J. Pediatr. 75:1022–1030 (1969).CrossRefGoogle Scholar
  35. 35.
    T. Ando, W. L. Nyhan, T. Gerritsen, L. Gong, D. C. Heiner, and P. F. Bray, Metabolism of glycine in the nonketotic form of hyperglycinemia, Pediatr. Res. 2:254–263 (1968).CrossRefGoogle Scholar
  36. 36.
    G. J. De Groot, J. A. Troelstra, and F. A. Hommes, Nonketotic hyperglycinemia: An in vitro study of the glycine-serine conversion in liver of three patients and the effect of dietary methionine, Pediatr. Res. 4:238–243 (1970).CrossRefGoogle Scholar
  37. 37.
    M. L. Halperin, C. M. Schiller, and I. B. Fritz, The inhibition by methylmalonic acid of malate transport by the dicarboxylate carrier in rat liver mitochondria, J. Clin. Invest. 50:2276 (1971).CrossRefGoogle Scholar
  38. 38.
    L. E. Rosenberg, A. C. Lilljeqvist, and Y. E. Hsia, Methylmalonic aciduria: Metabolic block localization and vitamin B12 dependency, Science (Wash. D.C.) 162:805–807 (1968).CrossRefGoogle Scholar
  39. 39.
    G. Morrow, L. Barness, G. J. Cardinale, R. H. Abeles, and J. G. Flanks, Congenital methylmalonic acidemia: Enzymatic evidence for two forms of the disease, Proc. Natl. Acad. Sci. 63:191–197(1969).CrossRefGoogle Scholar
  40. 40.
    L. E. Rosenberg, A. C. Lilljeqvist, Y. E. Hsia, and F. M. Rosenbloom, Vitamin B12 dependent methylmalonic aciduria: Defective B12 metabolism in cultured fibroblasts, Biochem. Biophys. Res. Comm. 37:607–614 (1969).CrossRefGoogle Scholar
  41. 41.
    M. J. Mahoney, L. E. Rosenberg, S. H. Mudd, B. W. Uhlendorf, Defective metabolism of vitamin B12 in fibroblasts from children with methylmalonic aciduria, Biochem. Biophys. Res. Comm. 44:375–381 (1971).CrossRefGoogle Scholar
  42. 42.
    L. E. Rosenberg and M. J. Mahoney, Inherited disorders of methylmalonate and vitamin B12metabolism: A progress report, in “Inborn Errors of Metabolism” (F. A. Hommes and C. J. VandenBerg, eds.), pp. 303–320. Academic Press, New York (1973).Google Scholar
  43. 43.
    E. V. Cox and A. M. White, Methylmalonic acid excretion: An index of vitamin B12 deficiency, Lancet 2:853–856 (1962).CrossRefGoogle Scholar
  44. 44.
    K. Tanaka and K. J. Isselbacher, Experimental β-hydroxyisovaleric aciduria induced by biotin deficiency, Lancet 2:930–931 (1970).CrossRefGoogle Scholar
  45. 45.
    K. Tanaka, E. M. Miller, and K. J. Isselbacher, Hypoglycin A: A specific inhibitor of isovaleryl CoA dehydrogenase, Proc. Natl. Acad. Sci. 68:20–24 (1971).CrossRefGoogle Scholar
  46. 46.
    K. Tanaka, K. J. Isselbacher, and V. Shih, Isovaleric and α-methylbutyric acidemias induced by hypoglycin A: Mechanism of Jamaican vomiting sickness, Science (Wash. D.C.) 175:69–71 (1972).CrossRefGoogle Scholar
  47. 47.
    K. Tanaka, R. C. Stephenson, E. M. Miller, J. C. Or, and K. J. Isselbacher, Isolation and identification of Δ4-decene-dioate, Δ4-octene-dioate, Δ4, 7-decadiene-dioate, glutarate, adipate and methylenecyclopropylacetylglycine from urine of hypoglycin A treated rats, Fed. Proc. 30:275 abs. (1971).Google Scholar
  48. 48.
    K. Tanaka, On the mode of action of hypoglycin A III: Isolation and identification of cis-4-decene-1, 10-dioic, cis, cis-4, 7-decadiene-l, 10-dioic, cis-4-octene-l, 8-dioic, glutaric and adipic acids, N-(methylenecyclopropyl)acetylglycine, and N-isovalerylglycine from urine of hypoglycin A treated rats, J. Biol. Chem. 247:7465–7478 (1972).Google Scholar
  49. 49.
    C. G. H. Newman, B. D. R. Wilson, P. Callaghan, and L. Young, Neonatal death associated with isovaleric acidemia, Lancet 2:439–441 (1967).CrossRefGoogle Scholar
  50. 50.
    P. M. Dreyfus and V. E. Dube, The rapid detection of methylmalonic acid in urine — Sensitive index of vitamin B12 deficiency, Clin. Chim. Acta 15:525–528 (1967).CrossRefGoogle Scholar
  51. 51.
    T. Ando and W. L. Nyhan, A simple screening method for detecting isovalerylglycine in urine of patients with isovaleric acidemia, Clin. Chem. 16:420–422 (1970).Google Scholar
  52. 52.
    D. Gompertz and G. H. Draffan, The identification of tiglylglycine in the urine of a child with β-methylcrotonylglycinuria, Clin. Chim. Acta 37:405–410 (1972).CrossRefGoogle Scholar
  53. 53.
    L. Borg, S. Lindstedt, and G. Steen, Aliphatic C6-C14 dicarboxylic acids in urine from an infant with fatal congenital lactic acidosis, Clin. Chim. Acta 41:363–366 (1972).CrossRefGoogle Scholar
  54. 54.
    C. E. Dalgliesch, E. C. Horning, M. G. Horning, K. L. Knox, and K. Yarger, A gas-liquidchromatographic procedure for separating a wide range of metabolites occurring in urine or tissue extracts, Biochem. J. 101:792–810 (1966).Google Scholar
  55. 55.
    J. B. Sidbury, E. K. Smith, and W. Harlan, An inborn error of short chain fatty acid metabolism, J. Pediatr. 70:8–15 (1967).CrossRefGoogle Scholar
  56. 56.
    D. E. Green, S. Mii, H. R. Mahler, and R. M. Bock, Studies on fatty acid oxidizing system of animal tissues. III. Butyryl coenzyme A dehydrogenase, J. Biol. Chem. 206:1–12 (1954).Google Scholar
  57. 57.
    T. Ando, W. L. Nyhan, C. Bachman, K. Rasmussen, R. Scott, and E. K. Smith, Isovaleric acidemia: Identification of isovalerate, isovalerylglycine and 3-hydroxyisovalerate in urine of a patient previously reported as having butyric and hexanoic acidemia, J. Pediatr. 82:243–248 (1973).CrossRefGoogle Scholar
  58. 58.
    E. Jellum, O. Stokke, and L. Eldjarn, Screening for metabolic disorders using gas-liquid chromatography, mass spectrometry and computer technique, Scand. J. Clin. Lab. Invest. 27:273–285 (1971).CrossRefGoogle Scholar
  59. 59.
    O. A. Mamer, J. C. Crawhall, and S. S. Tjoa, The identification of urinary acids by coupled gas chromatography-mass spectrometry, Clin. Chim. Acta 32:171–184 (1971).CrossRefGoogle Scholar
  60. 60.
    D. Gompertz, G. H. Draffan, J. L. Watts, and D. Hull, Biotin-responsive β-methylcrotonylglycinuria, Lancet 2:22–24 (1971).CrossRefGoogle Scholar
  61. 61.
    V. Mahadevan and L. Zieve, Determination of volatile free fatty acids of human blood, J. Lipid Res. 10:338–341 (1969).Google Scholar
  62. 62.
    T. L. Perry, S. Hansen, S. Diamond, B. Bullis, C. Mok, and S. B. Melancon, Volatile fatty acids in normal human physiological fluids, Clin. Chim. Acta 29:369–374 (1970).CrossRefGoogle Scholar
  63. 63.
    D. J. Kurtz, H. L. Levy, W. Plotkin, and Y. Kishimoto, A rapid method for the quantitative analysis of short chain fatty acids in serum or plasma, Clin. Chim. Acta 34:463–466 (1971).CrossRefGoogle Scholar
  64. 64.
    M. J. Mahoney, Y. E. Hsia, and L. E. Rosenberg, Abnormalities of vitamin B12 metabolism, in “Antenatal Diagnosis” (A. Dorfman, ed.), pp. 95–102, University of Chicago Press. Chicago and London. (1972).Google Scholar
  65. 65.
    G. Morrow, R. H. Schwartz, J. A. Hallock, and L. A. Barness, Prenatal detection of methylmalonic acidemia, J. Pediatr. 77:120–123 (1970).CrossRefGoogle Scholar
  66. 66.
    J. Dancis, J. Hutzler, K. Tada, Y. Wade, T. Morikawa, and T. Arakawa, Hypervalinemia: A defect in valine transamination, Pediatrics 39:813–817 (1967).Google Scholar
  67. 67.
    J. H. Menkes, P. L. Hurst, and J. M. Craig, New syndrome: Progressive familial infantile cerebral dysfunction associated with unusual urinary substance, Pediatrics 14:462–466 (1954).Google Scholar
  68. 68.
    B. K. Bachhawat, W. G. Robinson, and M. J. Coon, Enzymatic carboxylation of β-hydroxyisovaleryl coenzyme A, J. Biol. Chem. 219:539–550 (1956).Google Scholar
  69. 69.
    D. Schachter and J. V. Taggart, Glysine N-acylase: Purification and properties, J. Biol. Chem. 208:263–275 (1954).Google Scholar
  70. 70.
    A. DelCampillo-Campbell, E. E. Dekker, and M. J. Coon, Carboxylation of β-methylcrotonyl coenzyme A by a purified enzyme from chicken liver, Biochim. Biophys. Acta 31:290–292 (1959).CrossRefGoogle Scholar
  71. 71.
    K. Baerlocher, H. C. Curtius, U. Redweick, and H. Willi, in discussion on Rasmussen et al., (16) in in “Inborn Errors of Metabolism” (F. A. Hommes and C. J. VandenBerg, eds.), pp. 334–335. Academic Press, New York (1973).Google Scholar
  72. 72.
    H. Den, The biological oxidation of 2,2-dimethyloctanoic acid, Biochim. Biophys. Acta 98:462–469 (1965).Google Scholar
  73. 73.
    B. Preiss and K. Bloch, co-Oxidation of long chain fatty acids in rat liver, J. Biol. Chem. 239:85–88 (1964).Google Scholar
  74. 74.
    F. E. Samson, N. Dahl, and D. S. Dahl, A study on the narcotic action of short chain fatty acids, J. Clin. Invest. 35:1291–1298 (1956).CrossRefGoogle Scholar
  75. 75.
    I. T. Lott, A. M. Erickson, and H. Levy, Dietary treatment of an infant with isovaleric acidemia, Pediatrics 49:617–618 (1972).Google Scholar
  76. 76.
    R. P. White and F. E. Samson, Effects of fatty acid anions on the electroencephalogram of unanesthesized rabbits, Am. J. Physiol. 196:271–274 (1956).Google Scholar
  77. 77.
    B. Holmquist and D. H. Ingvar, Effects of short chain fatty acid anions upon cortical blood flow and EEG in cats, Experientia 13:331–335 (1957).CrossRefGoogle Scholar
  78. 78.
    Y. Muto, Y. Takahashi, and H. Kawamura, Effects of short chain fatty acid anions on the electrical activity of neo-, paleo-and archicortical system, No to Shinkei 16:61–67 (1964).Google Scholar
  79. 79.
    F. J. R. Hird and M. J. Weidemann, Oxidative phosphorylation accompanying oxidation of short chain fatty acids by rat-liver mitochondria, Biochem. J. 98:378–388 (1966).Google Scholar
  80. 80.
    K. Ahmed and P. G. Scholefield, Studies on fatty acid oxidation. 8. The effects of fatty acids on metabolism of rat-brain cortex in vitro, Biochem. J. 81:45–53 (1961).Google Scholar
  81. 81.
    J. Zborowski and L. Wojiczak, Induction of swelling of liver mitochondria by fatty acids of various chain lengths. Biochem. Biophys. Acta 70:596–598 (1963).CrossRefGoogle Scholar
  82. 82.
    D. R. Dahl, Short chain fatty acid inhibition of rat brain Na-K-adenosine triphosphatase, J. Neurochem. 15:815–820(1968).CrossRefGoogle Scholar
  83. 83.
    C. O. Walker, D. W. McCandless, J. D. McGarry, and S. Shenker, Cerebral energy metabolism in short chain fatty acid induced coma, J. Lab. Clin. Med. 76:569–583 (1970).Google Scholar
  84. 84.
    D. Garfinkel and A. Lajthar, A metabolic inhomogeneity of glycine in vivo. I. Experimental determination, J. Biol Chem. 238:2429–2434 (1963).Google Scholar
  85. 85.
    F. Lynen, J. Knappe, E. Lorch, G. Tutting, E. Ringelmann, and J. P. Lachance, Zur biochemische Funktion des Biotins. II. Reinigung und Wirkungsweise der β-Methylcrotonyl carboxylase. Biochem. Z. 335:123–167 (1961).Google Scholar
  86. 86.
    A. Meister, in “Biochemistry of Amino Acids,” Vol. 1, p. 441, Academic Press, New York (1965).Google Scholar
  87. 87.
    U. P. Sydenstricker, S. A. Singel, A. P. Briggs, N. M. DeVaughn, and H. Isbell, Observation on “egg white injury” in man and its cause with biotin concentrate, J. Am. Med. Assoc. 118:1199–1120 (1942).CrossRefGoogle Scholar
  88. 88.
    W. G. Robinson, B. K. Bachhawat, and M. J. Coon, Tiglyl coenzyme A and α-methyla-cetoacetyl coenzyme A, intermediates in the enzymatic degradation of isoleucine, J. Biol. Chem. 218:391–400 (1956).Google Scholar
  89. 89.
    E. Staple, Mechanism of cleavage of the cholesterol side chain in bile acid formation, in “Bile Salt Metabolism”, (L. Schiff, J. B. Carey, Jr., J. M. Dietschy, eds.) pp. 127–139, Charles C Thomas, Springfield, Ill. (1969).Google Scholar
  90. 90.
    A. C. I. Walker, Production of volatile fatty acids in the rumen: Methods of measurement, Nutr. Abstr. Rev. 34:339–352 (1963).Google Scholar
  91. 91.
    M. G. Yang, K. Monoharan, and O. Mickelsen, Nutritional contribution of volatile fatty acids from cecum of rats, J. Nutr. 100:545–550 (1970).Google Scholar
  92. 92.
    M. Flavin and S. Ochoa, Metabolism of propiomic acid in animal tissues. I. Enzymatic conversion of Propionate to succinate, J. Biol. Chem. 229:965–979 (1957).Google Scholar
  93. 93.
    Y. Kaziro, E. Leone, and S. Ochoa, Biotin and propionyl carboxylase, Proc. Natl. Acad. Sci. (USA) 46:1319–1327 (1960).CrossRefGoogle Scholar
  94. 94.
    Y. Kaziro, S. Ochoa, R. C. Warner, and J. Y. Chen, Metabolism of propionic acid in animal tissues. VIII. Crystalline propionyl carboxylase, J. Biol. Chem. 236:1917–1923 (1961).Google Scholar
  95. 95.
    R. Mazumder, J. Sasakawa, Y. Kaziro, and S. Ochoa, Metabolism of propionic acid in animal tissues. IX. Methylmalonyl CoA racemase, J. Biol. Chem. 237:3065–3068 (1962).Google Scholar
  96. 96.
    M. Flavin, P. J. Ortiz, and S. Ochoa, Metabolism of propionic acid in animal tissues, Nature (Lond.) 176:823–824 (1955).CrossRefGoogle Scholar
  97. 97.
    S. Gurnani, S. P. Mirsty, and B. C. Johnson, Function of vitamin B12 in methylmalonate metabolism. I. Effect of a cofactor form of B12 on the activity of methylmalonyl CoA isomerase, Biochim. Biophys. Acta 38:187–189 (1960).CrossRefGoogle Scholar
  98. 98.
    J. R. Stern and D. C. Friedman, Vitamin B12 and methylmalonyl CoA isomerase. I. Vitamin B12 and Propionate metabolism. Biochem. Biophys. Res. Commun. 2:82–87 (1960).CrossRefGoogle Scholar
  99. 99.
    G. Rendina and M. J. Coon, Enzymatic hydrolysis of the coenzyme A thiol esters of β-hydroxypropionic and β-hydroxyisobutyric acids, J. Biol. Chem. 225:523–534 (1957).Google Scholar
  100. 100.
    W. G. Robinson, R. Nagle, B. K. Bachhawat, F. P. Kupiecki, and M. J. Coon, Coenzyme A thiol esters of isobutyric, methacrylic and β-hydroxyisobutyric acids as intermediates in the enzymatic degradation of valine, J. Biol. Chem. 224:1–11 (1957).Google Scholar
  101. 101.
    W. G. Robinson and M. J. Coon, The purification and properties of β-hydroxyisobutyric dehydrogenase, J. Biol. Chem. 225:511–521 (1957).Google Scholar
  102. 102.
    D. S. Kinnory, Y. Takeda, and D. M. Greenberg, Isotope studies on the metabolism of valine, J. Biol. Chem. 212:385–396 (1955).Google Scholar
  103. 103.
    Y. Kaziro and S. Ochoa, The metabolism of propionic acid, Adv. Enzymol. 26:283–387 (1964).Google Scholar
  104. 104.
    A. M. White, The effect of vitamin B12 deficiency on the excretion of propionic acid by the human, Biochem. J. 95:17P (1965).Google Scholar
  105. 105.
    T. Ando, W. L. Nyhan, J. D. Conner, K. Rasmussen, G. Donnell, N. Barnes, D. Cotton, and D. Hull, The oxidation of glycine and proprionic acid in propionic acidemia with ketotic hyperglycinemia, Pediatr. Res. 6:576–583 (1972).CrossRefGoogle Scholar
  106. 106.
    D. E. Hsia, A. C. Lillieqvist, and L. E. Rosenberg, Vitamin B12-dependent methylmalonicaci-duria: Amino acid toxicity, long chain ketonuria and protective effect of vitamin Bi2, Pediatrics 46:497–507 (1970).Google Scholar
  107. 107.
    W. Insull, Jr., P. D. Lang, B. P. Asi, and S. Yoshimura, Studies of arteriosclerosis in Japanese and American men. I. Comparison of fatty acid composition of adipose tissue, J. Clin. Invest. 48:1313–1327 (1969).CrossRefGoogle Scholar
  108. 108.
    M. G. MacFarlane, G. M. Gray, and L. M. Wheeldon, Fatty acids of phospholipids from mitochondria and microsomes, Biochem. J. 74:43p (1960).Google Scholar
  109. 109.
    S. M. Grundy, E. H. Ahrens, and T. A. Miettinen, Quantitative isolation and gas-liquid Chromatographic analysis of total fecal bile acids, J. Lipid Res. 6:397–410 (1965).Google Scholar
  110. 110.
    S. E. Snyderman, C. Sansarico, P. Norton, S. V. Phansalkar, The use of neomycin in the treatment of methylmalonic aciduria. Pediatrics 50:925–927 (1972).Google Scholar
  111. 111.
    S. M. Oace and J. M. Abbott, Methylmalonate formiminoglutamate and aminoimidazole-carboxamide excretion of vitamin B12-deficient germ free and conventional rats, J. Nutr. 102:17–26 (1972).Google Scholar
  112. 112.
    R. S. Daum, P. H. Lamm, O. A. Mamer, and C. R. Scriver, A “new” disorder of isoleucine catabolism, Lancet 2:1289–1290 (1971).CrossRefGoogle Scholar
  113. 113.
    R. S. Daum, C. R. Scriver, O. A. Mamer, E. Devlin, P. Lamm, and H. Goodman, An inherited disorder of isoleucine catabolism causing accumulation of α-methylacetoacetate and α-methyl-β-hydroxybutyrate, and intermittent metabolic acidosis, Pediatr. Res. 7:149–160 (1973).CrossRefGoogle Scholar
  114. 114.
    R. E. Hillman, R. D. Feigin, S. M. Tenenbaum, and J. P. Keating, Defective isoleucine metabolism as a cause of the “ketotic hyperglycinemia” syndrome, Pediatr. Res. 6:393 (1972) (abstract).Google Scholar
  115. 115.
    M. Cornblath, R. L. Gingell, G. A. Fleming, J. T. Tildon, A. T. Leffler, and R. A. Wapnir, A new syndrome of ketoacidosis in infancy, J. Pediatr. 79:413–418 (1971).CrossRefGoogle Scholar
  116. 116.
    J. T. Tildon and M. Cornblath, Succinyl-CoA: 3-ketoacid CoA-transferase deficiency, J. Clin. Invest. 51:493–498 (1972).CrossRefGoogle Scholar
  117. 117.
    Y. E. Hsia, K. J. Scully, and L. E. Rosenberg, Inherited propionyl CoA carboxylase deficiency in “ketotic hyperglycinemia,” J. Clin. Invest. 50:127–130 (1971).CrossRefGoogle Scholar
  118. 118.
    D. Gompertz, The distribution of 17 carbon fatty acids in the liver of a child with propionic acidemia, Lipids 6:576–580 (1971).CrossRefGoogle Scholar
  119. 119.
    M. G. Horning, D. B. Martin, A. Karmen, and P. R. Vagelos, Fatty acid synthesis in adipose tissue. II. Enzymatic synthesis of branched chain and odd-numbered chain fatty acids, J. Biol. Chem. 236:669–672 (1961).Google Scholar
  120. 120.
    F. Lynen, I. Hopper-Kessel, and H. Eggerer, Zur Biosynthese der Fettsäuren. III. Fettsäuresynthetase der Hefe und die Bildung enzymgebundener Acetessigsäure, Biochem. Z. 340:95–124 (1964).Google Scholar
  121. 121.
    W. L. Nyhan, T. Ando, K. Rasmussen, W. Wadlington, A. W. Kilroy, D. Cottom, and D. Hull, Tiglic aciduria in propionic acidemia, Biochem. J. 126:1035–1037 (1927).Google Scholar
  122. 122.
    K. Rasmussen, T. Ando, W. L. Nyhan, D. Hull, D. Cottom, A. W. Kilroy, and W. Wadlington, Excretion of tiglylglycine in propionic acidemia, J. Pediatr. 81:970–972 (1972).CrossRefGoogle Scholar
  123. 123.
    H. W. Moore and K. Folkers, Vitamin B12 — Chemistry, in “The Vitamins II” (W. H. Sebrell, Jr., and R. S. Harris, eds.) pp. 121–139, 181-184, Academic Press, New York, (1968).Google Scholar
  124. 124.
    H. A. Barker, Vitamin B12 — Biochemical systems, in “The Vitamins II” (W. H. Sebrell, Jr., and R. S. Harris, eds.) pp. 184–212, Academic Press, New York (1968).Google Scholar
  125. 125.
    H. Weissbach and R. T. Taylor, Roles of vitamin B12 and folic acid in methionine synthesis, in “Vitamins and Hormones” (R. S. Harris, P. L. Munson, and E. Diczfalusy, eds.) pp. 415–440, Academic Press, New York (1970).Google Scholar
  126. 126.
    R. Silber and C. F. Moldow, The biochemistry of B12 — Mediated reactions in man, Am. J. Med. 48:549–554 (1970).CrossRefGoogle Scholar
  127. 127.
    M. J. Mahoney and L. E. Rosenberg, Inherited defects of B12 metabolism, Am. J. Med. 48:584–593 (1970).CrossRefGoogle Scholar
  128. 128.
    J. L. Toohey and H. A. Barker, Isolation of coenzyme B12 from liver, J. Biol. Chem. 236:560–563 (1961).Google Scholar
  129. 129.
    K. Lindstrand, Isolation of methylcobalamin from natural source material, Nature (Lond.) 204:188–189 (1964).CrossRefGoogle Scholar
  130. 130.
    K. G. Stahlberg, Studies on methyl B12 in man, Scand. J. Haematol. Suppl. 1:7 (1967).Google Scholar
  131. 131.
    K. G. Stahlberg, S. Radner and A. Norden, Liver B12 in subjects with and without vitamin B12 deficiency — A quantitative and qualitative study, Scand. J. Haematol. 4:312–320 (1967).CrossRefGoogle Scholar
  132. 132.
    R. T. Taylor and H. Weissbach, Escherichia coli B N 5-methyltetrahydrofolate-homocysteine methyltransferase: Sequential formation of bound methylcobalamin with S-adenosyl-L-methiomine and N 5-methyltertrahydrofolate, Arch. Biochem. Biophys. 129:728–744 (1969).CrossRefGoogle Scholar
  133. 133.
    R. T. Taylor and H. Weissbach, Escherichia coli B N 5-methyltetrahydrofolate-homocysteine methyltransferase: Activation with S-adenosyl-l-methionine and the mechanism for methyl group transfer, Arch. Biochem. Biophys. 129:745–766 (1969).CrossRefGoogle Scholar
  134. 134.
    G. Morrow, III, and L. A. Barness, Studies in a patient with methylmalonic acidemia, J. Pediatr. 74:691–698 (1969).CrossRefGoogle Scholar
  135. 135.
    B. Lindblad, B. S. Liridblad, P. Olin, B. Svanberg, and R. Zetterström, Methylmalonic acidemia, Acta Paediatr. Scand. 57:417–424 (1968).CrossRefGoogle Scholar
  136. 136.
    B. Lindblad, K. Lindstrand, B. Svanberg, and R. Zetterström, The effect of cobamide coenzyme in methylmalonic acidemia, Acta Paediatr. Scand. 58:178–180 (1969).CrossRefGoogle Scholar
  137. 137.
    R. A. Walker, A. B. Agarwal, and R. Singh, The importance of the falsely positive reaction, J. Pediatr. 74:691 (1969).CrossRefGoogle Scholar
  138. 138.
    L. E. Rosenberg, Disorders of Propionate, methylmalonate, and vitamin B12 metabolism, in “The Metabolic Basis of Inherited Diseases” (J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson, eds.) pp. 440–458, McGraw-Hill, New York (1972).Google Scholar
  139. 139.
    G. Morrow, III, W. J. Mellman, L. A. Barness, and V. D. Dimitrov, Propionate metabolism in cells cultured from a patient with methylmalonic acidemia, Pediatr. Res. 3:217–219 (1969).CrossRefGoogle Scholar
  140. 140.
    S. H. Mudd, H. L. Levy, and R. H. Abeles, A derangement in B12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria, Biochem. Biophys. Res. Comm. 35:121–126 (1969).CrossRefGoogle Scholar
  141. 141.
    H. Levy, S. H. Mudd, J. D. Schulman, P. M. Dreyfus, and R. H. Abeles, A derangement in B12 metabolism associated with homocystinemia, cystathioninemia, hypomethioninemia and methylmalonic aciduria, Am. J. Med. 48:390–397 (1970).CrossRefGoogle Scholar
  142. 142.
    H. Rudiger, and L. Jaenicke, On the role of 5-adenosylmethionine in the vitamin B12 dependent methionine biosynthesis, Europ. J. Biochem. 10:557–560 (1969).CrossRefGoogle Scholar
  143. 143.
    G. T. Burke, J. H. Mangum, and J. D. Brodie, Methylcobalamin as an intermediate in mammalian methionine biosynthesis, Biochemistry 9:4297–4302 (1970).CrossRefGoogle Scholar
  144. 144.
    M. F. Utter, D. B. Keech, and M. C. Scrutton, A possible role for acetyl CoA in the control of gluconeogenesis, in “Advances in Enzyme Regulation” (G. Weber, ed.) Vol. 2, p. 49, Pergamon Press, Oxford, England (1964).Google Scholar
  145. 145.
    J. R. Williamson, R. A. Kreisberg, and P. W. Felts, Mechanism for the stimulation of gluconeogenesis by fatty acids in perfused rat liver, Proc. Natl. Acad. Sci. (USA) 56:247–254 (1965).CrossRefGoogle Scholar
  146. 146.
    H. D. Söling, B. Willms, D. Friedrichs, and J. Kleineke, Regulation of gluconeogenesis by fatty acid oxidation in isolated perfused livers of non-starved rats, Eur. J. Biochem. 4:364–376 (1968).CrossRefGoogle Scholar
  147. 147.
    R. M. Smith, W. S. Osborne-White, and G. R. Russel, Methylmalonic acid and coenzyme A concentrations in the livers of pair-fed vitamin B12-deficient and vitamin B12-treated sheep, Biochem. J. 112:703–707(1969).Google Scholar
  148. 148.
    H.A. Lardy, V. Paetkau, and P. Walter, Paths of carbon in gluconeogenesis and lipogenesis: The role of mitochondria in supplying precursors of phosphoenolpyruvate, Proc. Natl. Acad. Sci. (USA) 53:1410–1415 (1965).CrossRefGoogle Scholar
  149. 149.
    P. Walter, V. Paetkau, and H. A. Lardy, Path of carbon in gluconeogenesis. III. The role and regulation of mitochondrial process involved in supplying precursors of phosphoenolpyruvate, J. Biol. Chem. 241:2523–2532 (1966).Google Scholar
  150. 150.
    J. R. Williamson, J. Anderson, and E. T. Browning, Inhibition of gluconeogenesis by butylmalonate in perfused liver, J. Biol. Chem. 245:1717–1726 (1970).Google Scholar
  151. 151.
    S. Halvorsen, O. Stokke, and L. Eldjarn, Methylmalonic acidemia/hyperglycinemia, Lancet 1:756 (1968).CrossRefGoogle Scholar
  152. 152.
    S. H. Mudd, H. L. Levy, and G. Morrow, Deranged B12 metabolism: Effects on sulfur amino acid metabolism, Biochem. Med. 4:193–214 (1970).CrossRefGoogle Scholar
  153. 153.
    S. H. Mudd, B. W. Uhlendorf, D. H. Hinds, and H. L. Levy, Deranged B12 metabolism: Studies of fibroblasts grown in tissue culture, Biochem. Med. 4:215–239 (1970).CrossRefGoogle Scholar
  154. 154.
    T. Kluge, H. C. Boresen, E. Jellum, O. Stokke, L. Eldjarn, and B. Fretheim, Esophageal hiatus hernia and mental retardation: Life-threatening post-operative metabolic acidosis and potassium deficiency linked with a new inborn error of nitrogen metabolism, Surgery 71:104–109 (1972).Google Scholar
  155. 155.
    L. Eldjarn, E. Jellum, and O. Stokke, Pyroglutamic aciduria: Studies on the enzymic block and on the metabolic origin of pyroglutamic acid, Clin. Chim. Acta. 40:461–476 (1972).CrossRefGoogle Scholar
  156. 156.
    M. Orlowski, and A. Meister, Enzymology of pyrrolidone carboxylic acid, in “The Enzymes” (P. D. Boyer, ed.) Vol. 4, Academic Press. New York (1971).Google Scholar
  157. 157.
    G. M. Edelman, B. A. Cunningham, and W. E. Gall, The covalent structure of an entire γG immunoglobulin molecule, Proc. Natl. Acad. Sci. (USA) 63:78–85 (1969).CrossRefGoogle Scholar
  158. 158.
    A. H. Kang, P. Bornstein, and K. A. Piez, The amino acid sequence of peptides from the cross-linking region of rat skin collagen, Biochemistry 6:788–795 (1967).CrossRefGoogle Scholar
  159. 159.
    R. M. G. Nair, J. F. Barrett, C. Y. Bowers, and A. V. Schally, Structure of porcine thyrotropin releasing hormone, Biochemistry 9:1103–1106 (1970).CrossRefGoogle Scholar
  160. 160.
    R. Tham, L. Nystrom, and B. Holmstedt, Identification by mass spectrometry of pyroglutamic acid as a peak in the gas chromatography of human urine, Biochem. Pharmacol. 17:1735–1738 (1968).CrossRefGoogle Scholar
  161. 161.
    G. E. Connell and C. S. Hanes, Enzymic formation of pyrrolidone carboxylic acid from γ-glutamyl peptides, Nature (Lond.) 177:377–378 (1956).CrossRefGoogle Scholar
  162. 162.
    M. Orlowski and A. Meister, The γ-glutamyl cycle: A possible transport system for amino acid, Proc. Natl. Acad. Sci. 67:1248–1255 (1970).CrossRefGoogle Scholar
  163. 163.
    A. Meister, On the enzymology of amino acid transport, Science (Wash. D.C.) 180:33–39 (1973).CrossRefGoogle Scholar
  164. 164.
    P. VanderWerf, M. Orlowski, and A. Meister, Enzymic conversion of 5-oxo-l-proline (l-pyrolidone carboxylate) to glutamate coupled with cleavage of adenosine triphosphate to ade-nosine diphosphate, a reaction in the γ-glutamyl cycle, Proc. Natl. Acad. Sci. (USA) 68:2982–2985 (1971).CrossRefGoogle Scholar
  165. 165.
    J. H. Strömme and L. Eldjarn, The metabolism of l-pyroglutamic acid in fibroblasts from a patient with pyroglutamic aciduria: The demonstration of an l-pyroglutamate hydrolase system, Scand. J. Clin. Lab. Invest. 29:335–342 (1972).CrossRefGoogle Scholar
  166. 166.
    P. VanderWerf, R. A. Stephanie, M. Orlowski, and A. Meister, Inhibition of 5-oxoprolinase by 2-imidazolidone-4-carboxylic acid, Proc. Natl. Acad. Sci. (USA) 70:759–761 (1973).CrossRefGoogle Scholar
  167. 167.
    J. B. Burke, Partial thoracic stomach in childhood, Br. Med. J. 2:787 (1959).CrossRefGoogle Scholar
  168. 168.
    J. L. Cahill, E. Aberdeen, and D. J. Waterston, Results of surgical treatment of esophageal hiatal hernia in infancy and childhood, Surgery 66:597–000 (1969).Google Scholar
  169. 169.
    P. E. Verkade and J. van der Lee, Research on fat metabolism. II, Biochem. J. 28:31–39 (1934).Google Scholar
  170. 170.
    P. E. Verkade, J. van der Lee, and A. J. S. van Alphen, Untersuchungen über den Fettstoffwechsel. VIII. Fütterungsversuche an Hund mit den Natriumsalzen normaler gesättigter Dicarbonsäuren. Z. Physiol. Chem. 250:47–56 (1937).CrossRefGoogle Scholar
  171. 171.
    P. E. Verkade, The role of dicarboxylic acids in metabolism, Chem. Ind. 704-711 (1938).Google Scholar
  172. 172.
    A. Y. Lu, K. W. Junk, and M. J. Coon, Resolution of the cytochrome P-450-containing ω-hydroxylation system of liver microsomes into three components, J. Biol. Chem. 244:3714–3721 (1969).Google Scholar
  173. 173.
    J. E. Pettersen, E. Jellum, and L. Eldjarn, Short chain dicarboxylic acids in human urine, Scand. J. Clin. Lab. Invest., Suppl. 69 (1971) (abstract).Google Scholar
  174. 174.
    J. E. Pettersen, E. Jellum, and L. Eldjarn, The occurrence of adipic and suberic acid in urine from ketotic patients, Clin. Chim. Acta 38:17–24 (1972).CrossRefGoogle Scholar
  175. 175.
    J. E. Pettersen, Formation of n-hexanedioic acid from hexadecanoic acid by an initial ω-oxidation in ketotic rats, Clin. Chim. Acta 41:231–237 (1972).CrossRefGoogle Scholar
  176. 176.
    B. Axelrod, Glycolysis, in “Metabolic Pathways” (D. M. Greenberg, ed.) pp. 112–145, Academic Press, New York (1967).Google Scholar
  177. 177.
    L. J. Reed, Pyruvate dehydrogenase complex, in “Current Topics in Cellular Regulation” (B. L. Horecker and E. K. Stadtman, eds.) Vol. 1, pp. 233–251, Academic Press, New York (1969).Google Scholar
  178. 178.
    P. Felig, O. E. Owen, J. Warren, and G. F. Cahill, Jr., Amino acid metabolism during prolonged starvation, J. Clin. Invest. 48:584–594 (1969).CrossRefGoogle Scholar
  179. 179.
    D. B. Keech and M. F. Utter, Pyruvate carboxylase. II. Properties, J. Biol. Chem. 238:2609–2614 (1963).Google Scholar
  180. 180.
    H. V. Hemming, I. Seiffert, and W. Seubert, Cortisol induzierter Anstieg der Pyruvatcarboxylaseaktivität in der Rattenleber, Biochim. Biophys. Acta 77:345–348 (1963).CrossRefGoogle Scholar
  181. 181.
    R. C. Nordlie and H. A. Lardy, Mammalian liver phosphoenolpyruvate carboxykinase activities, J. Biol. Chem. 238:2259–2263 (1963).Google Scholar
  182. 182.
    R. Levine and D. E. Haft, Carbohydrate homeostasis, N. Engl. J. Med. 283:175–182 (1970).CrossRefGoogle Scholar
  183. 183.
    J. H. Pincus, Y. Itokawa, and J. R. Cooper, Enzyme-inhibiting factor in subacute necrotizing encephalomyelopathy, Neurology 19:841–845 (1969).CrossRefGoogle Scholar
  184. 184.
    J. B. Chappel, Systems used for the transport of substrates into mitochondria, Br. Med. Bull 24:150–157 (1968).Google Scholar
  185. 185.
    W. E. Hackabee, Abnormal resting blood lactate. II. Lactic acidosis, Am. J. Med. 30:840–848 (1961).CrossRefGoogle Scholar
  186. 186.
    A. F. Hartman, Sr., H. J. Wohltmann, M. L. Puckerson, and M. E. Wesley, Lactic acidosis: Studies of a child with a serious congenital deviation, J. Pediatr. 61:165–180 (1962).CrossRefGoogle Scholar
  187. 187.
    S. Israel, J. C. Haworth, B. Gourley, and J. D. Ford, Chronic acidosis due to an error in lactate and pyruvate metabolism, Pediatrics 34:346–356 (1964).Google Scholar
  188. 188.
    H. E. Worsley, R. W. Brookfield, J. S. Elwood, R. L. Noble, and W. H. Taylor, Lactic acidosis with necrotizing encephalopathy in two sibs, Arch. Dis. Child. 40:492–502 (1965).CrossRefGoogle Scholar
  189. 189.
    B. E. Clayton, R. H. Dobbs, and A. D. Patrick, Leigh’s subacute necrotizing encephalopathy: Clinical and biochemical study, with special reference to therapy with lipoate, Arch. Dis. Child. 42:467–478 (1967).CrossRefGoogle Scholar
  190. 190.
    R. J. Erickson, Familial lactic acidosis, J. Pediatr. 66:1004–1016 (1965).CrossRefGoogle Scholar
  191. 191.
    D. Lonsdale, W. R. Faulkner, J. W. Price, and R. R. Smeby, Intermittent cerebellar ataxia associated with hyperpyruvic acidemia, hyperalaninemia and hyperalaninuria, Pediatrics 43:1025–1034 (1969).Google Scholar
  192. 192.
    S. Skrede, J. H. Strömme, O. Stokke, S. O. Lie, and L. Eldjarn, Fatal congenital lactic acidosis in two siblings. II. Biochemical studies in vivo and in vitro, Acta. Paediatr. Scand. 60:138–145 (1971).CrossRefGoogle Scholar
  193. 193.
    R. R. Howell, D. M. Ashton, and J. B. Wyngaarden, Glucose-6-phosphatase deficiency glycogen storage disease: Studies on the interrelationships of carbohydrate, lipid and purine abnormalities, Pediatrics 29:553–565 (1962)Google Scholar
  194. 194.
    W. C. Hülsmann and J. Fernandes, A child with lactacidemia and fructose diphosphatase deficiency in the liver, Pediatr. Res. 5:633–637 (1971).CrossRefGoogle Scholar
  195. 195.
    A. S. Pagliara, I. E. Karl, J. P. Keating, B. I. Brown, and D. M. Kipnis, Hepatic fructosel,6-diphosphatase deficiency: A cause of lactic acidosis and hypoglycemia in infancy, J. Clin. Invest. 51:2115–2123 (1972).CrossRefGoogle Scholar
  196. 196.
    F. A. Hommes, H. A. Polman, and J. D. Reerink, Leigh’s encephalopathy: An inborn error of gluconeogenesis, Arch. Dis. Child. 43:423–426 (1968).CrossRefGoogle Scholar
  197. 197.
    E. J. Ebels, E. J. Blokzyl, and J. A. Trollstra, A Wernicke-like encephalomyelopathy in children (Leigh), an inborn error of metabolism? Report of 5 cases with emphasis on its familial incidence, Helv. Paediatr. Acta 23:310–324 (1965).Google Scholar
  198. 198.
    K. Tada, T. Yoshida, T. Konno, Y. Wada, Y. Yokoyama, and T. Arakawa, Hyperalaninemia with pyruvicemia, Tohoku J. Exp. Med. 22:99–100 (1969).CrossRefGoogle Scholar
  199. 199.
    T. Yoshida, K. Tada, T. Konno, and T. Arakawa, Hyperalaninemia with pyruvicemia due to pyruvate carboxylase deficiency of the liver, Tohoku J. Exp. Med. 99:121–128 (1969).CrossRefGoogle Scholar
  200. 200.
    J. P. Blass, J. Avigan, and B. W. Uhlendorf, A defect in pyruvate decarboxylase in a child with an intermittent movement disorder, J. Clin. Invest. 49:423–432 (1970).CrossRefGoogle Scholar
  201. 201.
    D. Leigh, Subacute necrotizing encephalomyelopathy in an infant, J. Neurol. Neurosurg. Psychiatry, 14:216–221 (1951).CrossRefGoogle Scholar
  202. 202.
    J. R. Cooper, J. H. Pincus, Y. Itokawa, and K. Piros, Experience with phosphoryl transfease inhibition in subacute necrotizing encephalomyelopathy. N. Engl. J. Med. 283:793–795 (1970).CrossRefGoogle Scholar
  203. 203.
    J. R. Cooper and J. H. Pincus, Role of thiamine triphosphate in subacute necrotizing encephalomyelopathy, Agr. Food. Chem. 20:490–493 (1972).CrossRefGoogle Scholar
  204. 204.
    J. P. Blass, R. A. P. Kark, and W. K. Engel, Clinical studies of a patient with pyruvate decarboxylase deficiency, Arch. Neurol. 25:449–460 (1971).CrossRefGoogle Scholar
  205. 205.
    R. Bressler, C. Corredor, and K. Brendel, Hypoglycin and hypoglycinlike compounds. Pharmacol. Review 21:105–130 (1969).Google Scholar
  206. 206.
    K. R. Hill, The vomiting sickness of Jamaica, West. Ind. Med. J. 1:243–264 (1952).Google Scholar
  207. 207.
    K. R. Hill, G. Bras, and K. P. Clearkin, Acute toxic hypoglycemia occurring in the vomiting sickness of Jamaica, W. Indian Med. J. 4:91–104 (1955).Google Scholar
  208. 208.
    R. D. K. Reye, G. Morgan, and J. Baral, Encephalopathy and fatty degeneration of the viscera: A disease entity in childhood, Lancet 2:749–752 (1963).CrossRefGoogle Scholar
  209. 209.
    P. B. Jelliffe and K. L. Stuart, Acute toxic hypoglycemia in the vomiting sickness of Jamaica, Br. Med. J. 75-77 (1954).Google Scholar
  210. 210.
    C. H. Hassal and K. Reyle, Hypoglycin A and B, two biologically active Polypeptides from Blighia sapida, Biochem. J. 60:334–339 (1955).Google Scholar
  211. 211.
    K. K. Chen, R. C. Anderson, M. C. McCowen, and P. N. Harris, Pharmacologic action of hypoglycin A and B, J. Pharmacol. Exp. Ther. 121:272–285 (1957).Google Scholar
  212. 212.
    P. C. Feng and S. J. Patrick, Studies of the action of hypoglycin A, an hypoglycemic substance, Br. J. Pharmacol 13:125–130 (1958).Google Scholar
  213. 213.
    C. von Holt, Methylenecyclopropylacetic acid, a metabolite of hypoglycin, Biochim. Biophys. Acta 125:1–10 (1966).Google Scholar
  214. 214.
    H. V. Anderson, J. L. Johnson, J. W. Nelson, E. C. Olson, M. E. Speeter, and J. J. Vavra, Hypoglycin A, Chem. Ind. 330-331 (1958).Google Scholar
  215. 215.
    C. Corredor, K. Brendel, and R. Bressler, Studies on the mechanism of the hypoglycemie action of 4-pentanoic acid, Proc. Natl. Acad. Sci. (USA) 58:2299–2306 (1967).CrossRefGoogle Scholar
  216. 216.
    K. Brendel, C. F. Corredor, and R. Bressler, The effect of 4-pentanoic acid on fatty acid oxidation, Biochem. Biophys. Res. Comm. 34:340–347 (1969).CrossRefGoogle Scholar
  217. 217.
    C. Corredor, K. Brendel, and R. Bressler, Effect of 4-pentanoic acid on carbohydrate metabolism in pigeon liver homogenate, J. Biol. Chem. 244:1212–1219 (1969).Google Scholar
  218. 218.
    J. R. Williamson, S. G. Rostand, and M. J. Peterson, Control factors affecting gluconeogenesis in perfused rat liver: Effects of 4-pentanoic acid, J. Biol. Chem. 245:3242–3251 (1970).Google Scholar
  219. 219.
    C. Von Holt and I. Benedict, Biochemie des Hypoglycins A. II. Der Einfluss des Hypoglycins auf die Oxydation von Glucose and Fettsäuren, Biochem. Z. 331:430–435 (1959).Google Scholar
  220. 220.
    C. Von Holt, M. Von Holt, and H. Böhm, Metabolic effects of hypoglycin and methylenecyclopropane-acetic acid, Biochim. Biophys. Acta 125:11–21 (1966).Google Scholar
  221. 221.
    K. W. McKerns, H. H. Bird, E. Kaieita, B. S. Coulomb, and E. D. DeRenzo, Effects of hypoglycin on certain aspects of glucose and fatty acid metabolism in the rat, Biochem. Pharmacol. 3:303–315 (1960).CrossRefGoogle Scholar
  222. 222.
    M. Fukami and J. R. Williamson, On the mechanism of inhibition of fatty acid oxidation by 4-pentanoic acid in rat liver mitochondria, J. Biol. Chem. 246:1206–1212 (1971).Google Scholar
  223. 223.
    N. Ruderman, E. Shafrir, and R. Bressler, Relation of fatty acid oxidation to gluconeogenesis: Effect of pentenoic acid, Life Sci. 7:1083–1089 (1968).CrossRefGoogle Scholar
  224. 224.
    C. J. Towes, C. Lowy, and N. Ruderman, The regulation of gluconeogenesis: The effect of pent-4-enoic acid on gluconeogenesis and on the gluconeogenic metabolite concentrations of isolated perfused rat liver, J. Biol. Chem. 245:818–824 (1970).Google Scholar
  225. 225.
    S. J. Patrick and L. C. Stewart, Effects of hypoglycin A on the metabolism of amino acids by liver slices, Can. J. Biochem. 42:139–142 (1964).CrossRefGoogle Scholar
  226. 226.
    B. I. Posner and M. S. Raben, Inhibition of the oxidation of leucine by hypoglycin, Biochem. Biophys. Acta 136:179–181 (1967).CrossRefGoogle Scholar
  227. 227.
    K. Tanaka and G. Yu, A method for the separate determination of isovalerate and α-methylbutyrate by use of GLC-mass spectrometer, Clin. Chim. Acta 43:151–154 (1973).CrossRefGoogle Scholar
  228. 228.
    K. Tanaka, R. Kerley, and G. Yu, Hypoglycin A — Synergistic hypoglycemie effects with lysine and tryptophan, Fed. Proc. 32:475 abs (1973).Google Scholar
  229. 229.
    K. Tanaka, G. Yu, J. E. McCartney, and H. L. Borison, In preparation.Google Scholar
  230. 230.
    W. Rose, The nephrotoxic action of the dicarboxylic acids and their derivatives. II. Glutaric and malonic acids, J. Pharmacol. and Exp. Ther. 24:147–158 (1924).Google Scholar
  231. 231.
    V. J. Harding and T. F. Nicholson, The nephropathic action of dicarboxylic acids on rabbits, J. Pharmacol. and Exp. Ther. 42:373–381 (1931).Google Scholar
  232. 232.
    H. J. Horn, E. G. Holland, and L. W. Hazelton, Safety of adipic acid as compared with citric and tartaric acid, Agr. Food Chem. 5:759–762 (1957).CrossRefGoogle Scholar
  233. 233.
    K. Tanaka and H. Ramsdell, Application of nuclear magnetic resonance spectrometry to the investigation of metabolic diseases, in “Application of Gas Chromatography-Mass Spectrometry to the Investigation of Human Disease” (O. A. Mamer, W. J. Mitchell, and C. R. Scriver, eds.), pp. 207-223 (1973).Google Scholar
  234. 234.
    M. Jeune, C. Collombel, M. Michel, M. David, P. Guibaud, G. Gurrier, and J. Albert, Hyperleucinisoleucinemie par defaut partiel de transamination associée à une hyperprolinemie de Type 2: Observation familiale d’une double aminoacidopathie, Sem. Hôp. Paris 17:85–99 (1970).Google Scholar
  235. 235.
    P. C. Engel, Possibility of inborn defect in isovalericacidemia involving altered enzyme specific rather than total inactivity, Nature (Lond.) 248:140–142 (1974).CrossRefGoogle Scholar
  236. 236.
    H. S. A. Sherratt, P. C. Holland, H. Osmundsen, and A. E. Senior, On the mechanism of inhibition of fatty acid oxidation by hypoglycin and by pent-4-enoic acid. Presented at “Symposium on Hypoglycin” held at Kingston, Jamaica, 1974.Google Scholar
  237. 237.
    P. Guibaud, P. Divry, Y. Dubois, C. Collombel, and F. Larbre, Une observation d’acidemie isovalerique, Arch. Franç Ped. 30:633–645 (1973).Google Scholar
  238. 238.
    H. L. Levy, A. M. Erickson, I. Lott, and D. J. Kurtz, Isovaleric acidemia: Results of family study and dietary treatment, Pediatrics 52:83–94 (1973).Google Scholar
  239. 239.
    R. A. Ulstrom, Discussed at the Meeting of the Society for Pediatrie Research, Atlantic City, 1966. The case was biochemically confirmed by Tanaka and Isselbacher, 1967.(4) Google Scholar
  240. 240.
    P. M. Allen, T. F. Necheles, R. Rieker, and B. Senior, Reversible neonatal pancytopenia due to isovaleric acidemia, abstract, Soc. Pediatr. Res. (1969).Google Scholar
  241. 241.
    J. M. Saudubray, personal communication.Google Scholar
  242. 242.
    K. Tanaka, R. Mandell, and V. E. Shih, Isovaleric acidemia: A defect of leucine metabolism in cultured fibroblasts, Pediatr. Res. 7:382 abs (1973).Google Scholar
  243. 243.
    V. E. Shih, R. Mandell, and K. Tanaka, Diagnosis of isovaleric acidemia in cultured fibroblasts, Clin. Chim. Acta 48:437–439 (1973).CrossRefGoogle Scholar
  244. 244.
    K. Tanaka, R. Mandell, and V. E. Shih, A defect in leucine metabolism in cultured skin fibroblasts from patients with isovaleric acidemia (in preparation).Google Scholar
  245. 245.
    D. Gompertz, K. Bartlett, D. Blair, and C. M. M. Stern, Child with a defect in leucine metabolism associated with β-hydroxyisovaleric aciduria and β-methylcrotonylglycinuria, Arch. Dis. Child. 48:975–977 (1973).CrossRefGoogle Scholar
  246. 246.
    W. L. Nyhan, Profiles of human disease accessible to analysis by gas chromatography-mass spectrometry, in “Application of Gas Chromatography-Mass Spectrometry to the Investigation of Human Disease” (O. A. Mamer, W. J. Mitchell, and C. R. Scriver, eds.) Montreal (1973).Google Scholar
  247. 247.
    O. Stokke, E. Jellum, L. Eldjarn, and R. Schnittler, The occurrence of β-hydroxy-n-valeric acid in a patient with propionic and methylmalonic acidemia, Clin. Chim. Acta 45:391–401 (1973).CrossRefGoogle Scholar
  248. 248.
    R. A. Chalmers, A. M. Lawson, and R. E. W. Watts, Studies on the urinary acidic metabolites excreted by patient with β-methylcrotonylglycinuria, propionic acidemia and methylmalonic acidemia, using gas-liquid chromatography and mass spectrometry. Clin. Chim. Acta 52:43–51 (1974).CrossRefGoogle Scholar
  249. 249.
    J. R. Sokatch, L. E. Sanders, and V. P. Marshall, Oxidation of methylmalonate semialdehyde to propionyl Coenzyme A in Pseudomonas aeruginosa grown on valine, J. Biol. Chem. 243:2500–2506 (1968).Google Scholar
  250. 250.
    R. E. Hillman, L. H. Sower, and J. L. Cohen, Inhibition of glycine oxidation in cultured fibroblasts by isoleucine, Pediatr. Res. 7:945–947 (1973).CrossRefGoogle Scholar
  251. 251.
    G. Russell, H. Thorn, M. J. Tarlow, and D. Gompertz, Reduction of plasma Propionate by peritoneal dialysis, Pediatrics 52:281–283 (1973).Google Scholar
  252. 252.
    I. K. Brandt, Y. E. Hsia, D. H. Clement, and S. A. Provence, Propionicacidemia (ketotic hyperglycinemia): Dietary treatment resulting in normal growth and development, Pediatrics 53:391–395 (1974).Google Scholar
  253. 253.
    M. J. Mahoney, A. Hart, and L. E. Rosenberg, Defect in 5′-deoxyadenosylcobalamin synthesizing enzyme in methylmalonicacidemia, Pediatr. Res. 8:162 abs (1974).CrossRefGoogle Scholar
  254. 254.
    M. G. Ampola, M. J. Mahoney, E. Nakamura, and K. Tanaka, In utero treatment of methylmalonic acidemia with vitamin B12, Pediatr. Res. 8:387 abs (1974).CrossRefGoogle Scholar
  255. 255.
    L. Hagenfeldt, A. Larsson, and R. Zetterström, Pyroglutamic aciduria: Studies in an infant with chronic metabolic acidosis, Acta Paediatr. Scand. 63:1–8 (1974).CrossRefGoogle Scholar
  256. 256.
    J. Dosoman, J. C. Crawhall, G. A. Klassen, O. A. Mamer, and P. Neumann, Urinary excretion of C6-C10 dicarboxylic acids in glycogen storage disease type I and III, Clin. Chim. Acta 51:93–101 (1974).CrossRefGoogle Scholar
  257. 257.
    M. G. Brunette, E. Devlin, B. Hazel, and C. R. Scriver, Thiamine responsive lactic acidosis in a patient with deficient low K m pyruvate carboxylase activity in liver. Pediatrics 50:702–711 (1972).Google Scholar
  258. 258.
    M. C. Scrutton and M. D. White, Purification and properties of human liver pyruvate carboxylase, Biochem. Med. 9:271–292 (1974).CrossRefGoogle Scholar
  259. 259.
    S. I. Goodman, P. Mae, and S. P. Markey, Glutaric acidemia: A new disorder of amino acid metabolism, Pediatr. Res. 8:115 abs (1974).Google Scholar
  260. 260.
    K. Bartlett and D. Gompertz, The specificity of glycine-N-acylase and acylglycine excretion in the organic acidemia, Biochem. Med. 10:15–23 (1974).CrossRefGoogle Scholar
  261. 261.
    W. L. Nyhan, N. Fawcett, T. Ando, O. M. Rennert, and R. L. Julius, Response to dietary therapy in B12 unresponsive methylmalonic acidemia, Pediatrics 51:539–548 (1973).Google Scholar
  262. 262.
    V. P. Wellner, R. Sekura, A. Meister, and A. Larson, Glutathione synthetase deficiency, an inborn error of metabolism involving the γ-glutamyl cycle in patients with 5-oxoprolinuria (pyroglutamic aciduria). Proc. Natl. Acad. Sci., 71:2505–2509 (1974).CrossRefGoogle Scholar
  263. 263.
    H. D. Söling, J. Kleineke, B. Wilms, G. Jason, and A. Kuhn, Relationship between intracellular distribution of phosphoenol pyruvate carboxykinase, regulation of gluconeogenesis and energy cost of glucose formation. Eur. J. Biochem. 37:243 (1973).CrossRefGoogle Scholar
  264. 264.
    B. H. Robinson, Transport of phosphoenolpyruvate by the tricarboxylate transporting system in mammalian mitochondria. FEBS Letters, 14:309–312 (1970).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1975

Authors and Affiliations

  • Kay Tanaka
    • 1
  1. 1.Department of Human GeneticsYale University School of MedicineNew HavenUSA

Personalised recommendations