Advertisement

Effects of Deficiencies of Folic Acid and Vitamin B12 on Central Nervous System Function and Development

  • Victor Herbert
  • Glenn Tisman

Abstract

From studies in lower animals, it is believed that deficiency of folic acid during the intrauterine period may lead to an infant’s being born mentally retarded.(1) The use of antimetabolites to folic acid is known to produce abortion in woman and also to produce a fetus with central nervous system and other deformities.(2,3) Work by Arakawa’s group(4) in Japan suggests that congenital enzyme defects in folate metabolism result in infants born with mental retardation, dilation of the cerebral ventricles, and intracerebral calcification. There is as yet no clear evidence that folate deficiency in adults produces histologically demonstrable damage to the central nervous system. However, folate deficiency in adults is associated with irritability and forgetfulness.(5) Furthermore, it has been suggested, most recently by Reynolds,(6) that anticonvulsants act in part by interfering with folate metabolism and that the supplying of folic acid increases fit frequency in patients whose convulsions would otherwise have been better controlled by anticonvulsant medication. This chapter will review what is known about the mechanisms whereby deficiency of folic acid may produce these alleged effects.

Keywords

Folate Deficiency Serum Folate Central Nervous System Function Methylmalonic Aciduria Methyl Malonic Acidemia 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    V. Herbert, Inborn errors in folate metabolism—a cause of mental retardation? Ann. Int. Med. 68:956–958, 1968.Google Scholar
  2. 2.
    J. B. Thiersch, Therapeutic abortions with folic acid antagonist, 4-aminopteroylglutamic acid (4-amino P.G.A.) administered by oral route, Am. J. Obstet. Gynecol. 63:1298–1304, 1952.Google Scholar
  3. 3.
    J. B. Thiersch, The control of reproduction in rats with the aid of antimetabolites and early experiences with antimetabolites as abortifacient agents in man, Acta Endocrinol. 23:37–45, 1956 (Suppl. 28).Google Scholar
  4. 4.
    T. Arakawa, Congenital defects in folate utilization, Am. J. Med. 48:594–598, 1970.Google Scholar
  5. 5.
    V. Herbert, Experimental nutritional folate deficiency in man, Trans. Ass. Am. Physicians 75:307–320, 1962.Google Scholar
  6. 6.
    E. H. Reynolds, Mental effects of anticonvulsants, and folic acid metabolism, Brain 91:197–214, 1968.Google Scholar
  7. 7.
    M. Victor and A. Lear, Subacute combined degeneration of the spinal cord: Current concepts of the disease process. Value of serum vitamin B12determinations in clarifying some of the common clinical problems, Am. J. Med. 20:896, 1956.Google Scholar
  8. 8.
    V. Herbert, “The Megaloblastic Anemias,” Grune & Stratton, New York, 1959.Google Scholar
  9. 9.
    C. E. Oxnard and W. T. Smith, Neurological degeneration and reduced serum vitamin B12-levels in captive monkeys, Nature 210:507, 1966.Google Scholar
  10. 10.
    S. S. Pant, A. K. Asbury, and E. P. Richardson, Jr., The myelopathy of pernicious anemia: A neurological reappraisal, Acta Neurol. Scand. 44:1–36, 1968 (Suppl. 35).Google Scholar
  11. 11.
    V. Herbert, Studies of folate deficiency in man, Proc. Roy. Soc. Med. (London) 57:377–384, 1964.Google Scholar
  12. 12.
    M. Levitt, P. F. Nixon, J. H. Pincus, and J. R. Bertino, Transport characteristics of folates in cerebrospinal fluid; a study utilizing doubly labeled 5-methyltetrahydrofolate and 5-formyltetrahydrofolate, J. Clin. Invest. 50:1301–1308, 1971.Google Scholar
  13. 13.
    H. Sobotka, H. Baker, and O. Frank, Vitamin levels in normal cerebrospinal fluid, Proc. Soc. Exptl. Biol. Med. 103:801–802, 1960.Google Scholar
  14. 14.
    V. Herbert and R. Zalusky, Selective concentration of folic acid activity in cerebrospinal fluid, Fed. Proc. 20:453, 1961.Google Scholar
  15. 15.
    V. Herbert and L. W. Sullivan, Activity of coenzyme B12in man, Ann. N. Y. Acad. Sci. 112:855–870, 1964.Google Scholar
  16. 16.
    F. M. Huennekens, Folate and B12coenzymes, in“Biological Oxidations” (T. P. Singer, ed.), pp. 439–513, Interscience Publishers, New York, 1968.Google Scholar
  17. 17.
    R. L. Blakley, “The Biochemistry of Folic Acid and Related Pteridines,” John Wiley & Sons, Inc., New York, 1969.Google Scholar
  18. 18.
    H. Weissbach and R. T. Taylor, Roles of vitamin B12 and folic acid in methionine synthesis, Vitamins & Hormones 28:415–440, 1970.Google Scholar
  19. 19.
    V. Herbert, Drugs effective in megaloblastic anaemias: Vitamin B12and folic acid, in“The Pharmacological Basis of Therapeutics” (L. S. Goodman and A. Gilman, ed.), 4th ed., pp. 1414–1444, Macmillan, New York, 1970.Google Scholar
  20. 20.
    V. Herbert (guest ed.), Symposium on vitamin B12and folate, Am. J. Med. 48:539–617, 1970.Google Scholar
  21. 21.
    V. Herbert, Recent developments in cobalamin metabolism, in“The Cobalamins” (H. R. V. Arnstein and R. J. Wrighton, eds.), pp. 2–16, J. & A. Churchill, Ltd., London, 1971.Google Scholar
  22. 22.
    V. Herbert, Folic acid and vitamin B12, in“Modern Nutrition in Health and Disease” (R. S. Goodhart and M. Shils, ed.), 5th ed., Lea & Febiger, Philadelphia, 1972.Google Scholar
  23. 23.
    P. Lanzkowsky, Congenital malabsorption of folate, Am. J. Med. 48:580–583, 1970.Google Scholar
  24. 24.
    A. L. Luhby and J. M. Cooperman, Congenital megaloblastic anemia and progressive central nervous system degeneration. Further clinical and physiological characterization and therapy of syndrome due to inborn error of folate transport, American Pediatric Society, Inc., Annual Meeting, Atlantic City, April 1967.Google Scholar
  25. 25.
    I. Chanarin, J. Laidlaw, L. W. Loughridge, and D. L. Mollin, Megaloblastic anemia due to phenobarbitone, the convulsant action of therapeutic doses of folic acid, Brit. Med. J. 1:1099, 1960.Google Scholar
  26. 26.
    T. F. Walters, Congenital megaloblastic anemia responsive to N 5-formyltetrahydrofolic acid administration, J. Pediat. 70:686, 1967.Google Scholar
  27. 27.
    J. Metz, R. Zalusky, and V. Herbert, Folic acid binding by serum and milk, Am. J. Clin. Nutrition 21:289–297, 1968.Google Scholar
  28. 28.
    FAO/WHO Expert Group, “Requirements of Ascorbic Acid, Vitamin D, Vitamin B12 Folate, and Iron,” WHO Technical Report Series, No. 452, 1970 (available for $1.25 from World Health Organization Distribution and Sales, Geneva, Switzerland).Google Scholar
  29. 29.
    J. C. Woodard and P. M. Newberne, Relation of vitamin B12and one-carbon metabolism to hydrocephalus in the rat, J. Nutrition 88:375, 1966.Google Scholar
  30. 30.
    A. G. Hogan, B. L. O’Dell, and J. R. Whitley, Maternal nutrition and hydrocephalus in newborn rats, Proc. Soc. Exptl. Biol. Med. 74:293, 1950.Google Scholar
  31. 31.
    B. Hoogstraten, J. Cuttner, and B. Natovitz, Sequence of recovery from multiple manifestations of folic acid deficiency, J. Mount Sinai Hosp. N.Y. 31:10–16, 1964.Google Scholar
  32. 32.
    C. E. Butterworth, Jr., Personal communication.Google Scholar
  33. 33.
    R. W. Strachan and J. G. Henderson, Dementia and folate deficiency, Quart. J. Med. 36:189–204, 1967.Google Scholar
  34. 34.
    E. H. Reynolds, J. M. Preece, J. Bailey, and A. Coppen, Folate deficiency in depressive illness, Brit. J. Psychiat. 117:287–292, 1970.Google Scholar
  35. 35.
    M. W. Carney, Serum folate values in 432 psychiatric patients, Brit. Med. J. 4:512–516, 1967.Google Scholar
  36. 36.
    R. Hunter, M. Jones, T. G. Jones, and D. M. Matthews, Serum B12and folate concentrations in mental patients, Brit. J. Psychiat. 113:1291–1295, 1967.Google Scholar
  37. 37.
    H. A. Hansen, P. Nordquist, and P. Sourander, Megaloblastic anemia and neurologic disturbances combined with folic acid deficiency, Acta Med. Scand. 176:243–251, 1964.Google Scholar
  38. 38.
    H. C. Grant, A. V. Hoffbrand, and D. G. Wells, Folate deficiency and neurological disease, Lancet 2:763–767, 1965.Google Scholar
  39. 39.
    R. H. Girdwood, Folic acid, its analogs and antagonists, Advan Clin. Chem. 3:235–297, 1960.Google Scholar
  40. 40.
    V. Herbert and R. Zalusky, Interrelations of vitamin B12and folic acid metabolism: Folic acid clearance studies, J. Clin. Invest. 41:1263–1276, 1962.Google Scholar
  41. 41.
    F. A. Klipstein, Subnormal serum folate and macrocytosis associated with anticonvulsant drug therapy, Blood 23:68–86, 1964.Google Scholar
  42. 42.
    I. Chanarin, “The Megaloblastic Anemias,” Blackwell, Oxford, F. A. Davis Co., Philadelphia, 1969.Google Scholar
  43. 43.
    E. H. Reynolds, Iatrogenic disorders in epilepsy, in“Modern Trends in Neurology” (J. Williams, ed.), pp. 271–286, Butterworths, London, 1970.Google Scholar
  44. 44.
    E. H. Reynolds, G. Milner, D. M. Matthews, and I. Chanarin, Anticonvulsant therapy, megaloblastic haemopoiesis and folic acid metabolism, Quart. J. Med. 35:521–537, 1966.Google Scholar
  45. 45.
    E. H. Reynolds, I. Chanarin, G. Milner, and D. M. Matthews, Anticonvulsant therapy, folic acid and vitamin B12metabolism and mental symptoms, Epilepsia (Amsterdam) 7:261–270, 1966.Google Scholar
  46. 46.
    E. H. Reynolds, Effects of folic acid on the mental state and fit frequency of drug-treated epileptic patients, Lancet 1:1086–1088, 1967.Google Scholar
  47. 47.
    D. G. Wells and H. Casey, Lactobacillus caseiC. S. F. folate activity, Brit. Med. J. 3:834–837, 1967.Google Scholar
  48. 48.
    E. H. Reynolds, J. Preece, and I. Chanarin, Folic acid and anticonvulsants, Lancet 1:1264–1265, 1969.Google Scholar
  49. 49.
    I. H. Rosenberg, H. A. Godwin, R. R. Streiff, and W. B. Castle, Impairment of intestinal deconjugation of dietary folate. A possible explanation of megaloblastic anemia associated with Phenytoin therapy, Lancet 2:530–532, 1968.Google Scholar
  50. 50.
    A. V. Hoffbrand and T. F. Necheles, Mechanism of folate deficiency in patients receiving Phenytoin, Lancet 2:528–530, 1968.Google Scholar
  51. 51.
    C. M. Baugh and C. L. Krumdieck, Effects of Phenytoin on folic acid conjugases in man, Lancet 2:519–521, 1969.Google Scholar
  52. 52.
    L. H. Bernstein, S. Gutstein, S. Weiner, and G. Efron, The absorption and malabsorption of folic acid and its polyglutamates, Am. J. Med. 48:570–579, 1970.Google Scholar
  53. 53.
    C. D. Gerson, N. Cohen, G. W. Hepner, N. Brown, V. Herbert, and H. D. Janowitz, Folic acid absorption in man: Enhancing effect of glucose, Gastroenterology 61:224–227, 1971.Google Scholar
  54. 54.
    G. W. Hepner, L. M. Aledort, D. C. Gerson, N. Cohen, V. Herbert, and H. D. Janowitz, Inhibition of intestinal ATPase by diphenylhydantoin and acetazolamide, Clin. Res. 18:382, 1970.Google Scholar
  55. 54a.
    S. Momtazi and V. Herbert, Studying mechanisms of intestinal absorption using suspensions of vibration-obtained individual small bowel epithelial cells: folate absorption, Am. J. Clin. Nutrii. 25:449–450, 1972.Google Scholar
  56. 55.
    G. Tisman and V. Herbert, Inhibition by human serum, dilantin (diphenylhydantoin), and methotrexate (MTX), and enhancement by 2-deoxyglucose of 3H-pteroylglutamic acid (3HPGA) and 3H-5-methyltetrahydrofolate (M-THF) uptake by human bone marrow cells in vitro, Clin. Res. 19:433, 1971 (Abst.).Google Scholar
  57. 56.
    D. M. Woodbury and J. W. Kemp, Some possible mechanisms of action of anti-epileptic drugs, in“Pharmakopsychiatrie Neuro-Psychopharmakologie. Advances in Theoretical and Clinical Research” (H. Coper, M. Engelmeier, K. Heinrich, A. Herz, H. Hippins, and P. Kielholz, eds.), pp. 201–226, Georg Thieme Verlag, Stuttgart, 1970.Google Scholar
  58. 57.
    B. W. Festoff and S. H. Appel, Effect of diphenylhydantoin on synaptosome sodium-potassium-ATPase, J. Clin. Invest. 47:2752, 1968.Google Scholar
  59. 58.
    S. Waxman, J. Corcino, and V. Herbert, Drugs, toxins and dietary amino acids affecting vitamin B12 or folic acid absorption or utilization, Am. J. Med. 48:599–608, 1970.Google Scholar
  60. 59.
    J. S. Malpas, G. H. Spray, and L. J. Witts, Serum folic acid and vitamin B12 levels in anticonvulsant therapy, Brit. Med. J. 1:955–957, 1966.Google Scholar
  61. 60.
    E. H. Reynolds, I. Chanarin, G. Milner, and D. M. Matthews, Anticonvulsant therapy, folic acid and vitamin B12metabolism and mental symptoms, Epilepsia (Amsterdam) 7:261–270, 1966.Google Scholar
  62. 61.
    R. J. Harrison, Vitamin B12levels in erythrocytes in anaemia due to folate deficiency, Brit. J. Haematol. 20:623–628, 1971.Google Scholar
  63. 61a.
    V. Herbert, G. Tisman, L. T. Go, and L. Brenner, B12-dependence of cell uptake of serum folate: an explanation for high serum folate and cell folate depletion in B12deficiency, Clin. Res. 20:489, 1972.Google Scholar
  64. 62.
    R. P. Snaith, S. Mehta, and A. H. Raby, Serum folate and vitamin B12in epileptics with and without mental illness, Brit. J. Psychiat. 116:179–183, 1970.Google Scholar
  65. 63.
    V. Bonavita, P. Monaco, and E. Tripi, Analisi degli effetti centrali di nucleotidi purinici e pirimidinici e loro derivati, Acta Neurol. 19:215–222, 1964.Google Scholar
  66. 64.
    F. Piccoli, R. Camarda, and V. Bonavita, Purine and pyrimidine nucleotides in the brain of normal and convulsant rats, J. Neurochem. 16:159–169, 1969.Google Scholar
  67. 65.
    V. Bonavita and F. Piccoli, Brain nucleotides and excitatory processes, in“Advances in Experimental Medicine and Biology” (R. Paoletti, ed.), Vol. 13, pp. 355–373, Plenum Press, New York, 1971.Google Scholar
  68. 66.
    E. H. Reynolds, J. M. Preece, J. Bailey, and A. Coppen, Folate deficiency in depressive illness, Brit. J. Psychiat. 117:287–292, 1970.Google Scholar
  69. 67.
    R. Hunter, J. Barnes, H. F. Oakeley, and D. M. Matthews, Toxicity of folic acid given in pharmacologic doses to healthy volunteers, Lancet 1:61–64, 1970.Google Scholar
  70. 68.
    F. B. Gibberd, A. Nicholls, J. F. Dunne, and D. M. Chaput de Saintonge, Toxicity of folic acid, Lancet 1:360–361, 1970.Google Scholar
  71. 69.
    J. H. Pincus, I. Grove, B. B. Marino, and G. E. Glaser, Studies on the mechanism of action of diphenylhydantoin, Arch. Neurol. 22:566–571, 1970.Google Scholar
  72. 70.
    R. R. Streiff, B. J. Wilder, and R. Hammer, Folic acid and diphenylhydantoin toxicity, in“Proceedings of a Symposium on the Pharmacology of Antiepileptic Drugs” (J. Penry, ed.), National Institutes of Health Monograph, to be published June 1972, by Raven Press.Google Scholar
  73. 71.
    H. Kutt, W. Winters, and F. H. McDowell, Depression of parahydroxylation of diphenylhydantoin by antituberculosis chemotherapy, Neurology 16:594–602, 1966.Google Scholar
  74. 72.
    D. M. Shaw, D. A. Macsweeney, A. L. Johnson, R. O’Keefe, D. Naidoo, D. M. Macleod, S. Jog, J. M. Preece, and J. M. Crowley, Folate and amine metabolites in senile dementia: A combined trial and biochemical study, Psychol. Med. 1:166–171, 1971.Google Scholar
  75. 73.
    H. E. M. Kay, P. J. Knapton, J. P. O’Sullivan, D. G. Wells, R. F. Harris, E. M. Innes, J. Stuart, F. C. M. Schwartz, and E. N. Thompson, Severe neurological damage associated with methotrexate therapy, Lancet 2:542, 1971.Google Scholar
  76. 74.
    D. Pinkel, K. Hernandez, L. Borella, C. Holton, R. Aur, G. Samoy, and C. Pratt, Drug dosage and remission duration in childhood lymphocytic leukemia, Cancer 27:247–256, 1971.Google Scholar
  77. 75.
    S. H. Mudd, H. L. Levy, and R. H. Abeles, A derangement in B12metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria, Biochem. Biophys. Res. Commun. 35:121–126, 1969.Google Scholar
  78. 76.
    M. J. Mahoney and L. E. Rosenberg, Inherited defects of B12metabolism, Am. J. Med. 48:584 – 593, 1970.Google Scholar
  79. 77.
    G. Morrow, III, 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. Pediat. 74:680, 1969.Google Scholar
  80. 78.
    G. Morrow, III, L. A. Barness, G. J. Cardinale, R. H. Abeles, and J. G. Flaks, Congenital methylmalonic acidemia: Enzymatic evidence for two forms of the disease, Proc. Natl. Acad. Sci. 63:191, 1969.Google Scholar
  81. 79.
    H. Baker, O. Frank, I. Pasher, H. Ziffer, and H. Sobotka, Pantothenic acid, thiamine and folic acid levels at parturition, Proc. Soc. Exptl. Biol. Med. 103:321–323, 1960.Google Scholar
  82. 80.
    M. Jadhav, J. K. G. Webb, and S. J. Baker, Vitamin B12deficiency in Indian infants, Lancet 1:720, 1963.Google Scholar
  83. 81.
    J. J. Corcino, S. Waxman, and V. Herbert, Absorption and malabsorption of vitamin B12, Am. J. Med. 48:562–569, 1970.Google Scholar
  84. 82.
    E. V. Cox, D. Robertson-Smith, M. Small, and A. M. White, The excretion of propionate and acetate in vitamin B12deficiency, Clin. Sci. 35:123, 1968.Google Scholar
  85. 83.
    E. P. Frenkel, Studies on mechanism of the neural lesion of pernicious anemia, J. Clin. Invest. 50:33a, 1971.Google Scholar
  86. 84.
    A. J. Marcus, H. L. Ullman, L. B. Safier, and H. S. Ballard, Platelet phosphatides. Their fatty acid and aldehyde composition and activity in different clotting systems, J. Clin. Invest. 41:2198–2212, 1962.Google Scholar
  87. 85.
    K. C. Smithburn and L. G. Zerfas, The neural symptoms and signs in pernicious anemia, Arch. Neurol. Psychiat. 25:1110, 1931.Google Scholar
  88. 86.
    H. H. Hyland, G. O. Watts, and R. F. Farquharson, Course of subacute combined degeneration of spinal cord, Can. Med. Ass. J. 65:295, 1951.Google Scholar
  89. 87.
    J. Richmond and S. Davidson, Subacute combined degeneration of the spinal cord in non-addisonian megaloblastic anaemia, Quart. J. Med. 27:517, 1958.Google Scholar
  90. 88.
    S. Davidson, Clinical picture of pernicious anemia prior to introduction of liver therapy in 1926 and in Edinburgh subsequent to 1944, Brit. Med. J. 1:241, 1957.Google Scholar
  91. 89.
    J. G. Greenfield and E. A. Carmichael, The peripheral nerves in cases of subacute combined degeneration of the cord, Brain 58:483, 1935.Google Scholar
  92. 90.
    W. M. Van Der Scheer and H. C. Koek, Peripheral nerve lesions in cases of pernicious anemia, Acta Psychiat Neurol. 13:61, 1938.Google Scholar
  93. 91.
    E. C. C. Jewesbury, Subacute combined degeneration of the cord and achlorhydric peripheral neuropathies without anaemia, Lancet 2:307, 1954.Google Scholar
  94. 92.
    J. M. Holmes, Cerebral manifestation of vitamin B12deficiency, Brit. Med. J. 2:1394, 1956.Google Scholar
  95. 93.
    M. M. Wintrobe, “Clinical Hematology,” Philadelphia, Lea & Febiger, 1956.Google Scholar
  96. 94.
    W. B. Castle, The anemias, in“A Textbook of Medicine” (R. L. Cecil and R. F. Loeb, eds.), 10th ed., W. B. Saunders, Co., Philadelphia, 1959.Google Scholar
  97. 95.
    C. C. Ungley, Treatment with vitamin B12in haematologic disorders, in“Vitamin B12and Intrinsic Factor” (H. C. Heinrich, ed.), Ferdinand Enke Verlag, Stuttgart, 1957.Google Scholar
  98. 96.
    J. M. Heaton, A. J. A. McCormick, and A. G. Freeman, Tobacco amblyopia: A clinical manifestation of vitamin B12deficiency, Lancet 2:286, 1958.Google Scholar
  99. 97.
    H. E. Hamilton, P. P. Ellis, and R. F. Sheets, Visual impairment due to optic neuropathy in pernicious anemia. Report of a case and review of the literature, Blood 14:378, 1959.Google Scholar
  100. 98.
    C. E. C. Harris, Snares and delusions in the recognition of “pernicious anemia,” Connecticut Med. J. 12:543, 1958.Google Scholar
  101. 99.
    Von W. Gassmann and J. Schneeweiss, Diabetes mellitus und perniziose Anamie, Acta Haematol. 16:396, 1956.Google Scholar
  102. 100.
    G. Panzram, Pernicious anemia and diabetes mellitus, Z. Ges. Inn. Med. Leipzig 15:239, 1960.Google Scholar
  103. 101.
    H. Keen and R. Smith, Vitamin B12and the course of diabetic retinopathy, Lancet 1:849, 1956.Google Scholar
  104. 102.
    R. Shulman, A survey of vitamin B12deficiency in an elderly psychiatric population, Brit. J. Psychiat. 113:241–251, 1967.Google Scholar
  105. 103.
    G. J. Henderson, R. W. Strachan, J. Swanson Beck, A. A. Dawson, and M. Daniel, The antigastric-antibody test as a screening procedure for vitamin B12deficiency in psychiatric practice, Lancet 2:809–813, 1966.Google Scholar
  106. 104.
    E. Edwin, K. Holten, K. R. Norum, A. Schrumpf, and O. E. Skaug, Vitamin B12hypovitaminosis in mental disease, Acta Med. Scand. 177:689–699, 1965.Google Scholar
  107. 105.
    R. Shulman, Psychiatric aspects of pernicious anaemia: A prospective controlled investigation, Brit. Med. J. 3:266–270, 1967.Google Scholar

Copyright information

© Plenum Press, New York 1973

Authors and Affiliations

  • Victor Herbert
    • 1
  • Glenn Tisman
    • 1
  1. 1.Veterans Administration HospitalColumbia University College of Physicians and SurgeonsBronxUSA

Personalised recommendations