Skip to main content
SpringerLink
Log in

Neural tube defects : Prevention by folic acid and other vitamins

  • Symposium: Genetics for Pediatricians-II
  • Published:
The Indian Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Folic acid has been demonstrated in clinical trials to reduce significantly the recurrence (and probably occurrence) of neural tube defects (NTD). In the U.K., there has been no decline in prevalence of NTD since the publication of the findings with folic acid. This article examines a series of questions relating to the action of folic acid, with emphasis on the use of mouse models as a source of experimental information which cannot easily be obtained by direct study of humans. Several mouse genetic NTD models exhibit sensitivity to prevention by folic acid, whereas other mice which develop morphologically similar NTD are resistant. Folic acid normalises neurulation in the sensitive mouse strains, providing evidence for a direct effect on the developing embryo, not on the pregnant female. Mouse studies do not support the proposed action of folic acid in encouraging thein utero demise of affected fetuses (i.e. terathanasia). Polymorphic variants of several folate-related enzymes have been shown to influence risk of NTD in humans and an inherited abnormality of folate metabolism has been demonstrated in one mouse NTD model. However, the biochemical basis of the action of folic acid in preventing NTD remains to be determined in detail. NTD in one folate-resistant mouse strain can be prevented by myoinositol, bothin utero andin vitro, raising the possibility of a therapeutic role also in humans. Gene-gene interactions seem likely to underlie the majority of NTD, suggesting that poly-therapy involving folic acid and other agents, such as myo-inositol, may prove more effective in preventing NTD than folic acid treatment alone.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Copp AJ, Bernfield M. Etiology and pathogenesis of human neural tube defects: Insights from mouse models.Curr Opin Pediatr 1994; 6: 624–631.

    Article  PubMed  CAS  Google Scholar 

  2. Harding BN, Copp AJ. Congenital malformations. In: Graham Dl, Lantos PL, eds.Greenfield’s Neuropathology. 6th ed. London:Arnold; 1997; 397–533.

    Google Scholar 

  3. Copp AJ. Genetic models of mammalian neural tube defects. In: Bock G, Marsh J, eds.Neural Tube Defects (Ciba Foundation Symposium 181). Chichester: John Wiley & Sons; 1994; pp. 118–134.

    Google Scholar 

  4. Brock DJH, Sutcliffe RG. Early prenatal diagnosis of anencephaly.Lancet 1972; 2:1252–1253.

    Article  PubMed  CAS  Google Scholar 

  5. Nicolaides KH, Gabbe SG, Campbell S, Guidetti R. Ultrasound screening for spina bifida: cranial and cerebellar signs.Lancet 1986; 2: 72–74.

    Article  PubMed  CAS  Google Scholar 

  6. Smithells RW, Sheppard S, Schorah CJ, Seller MJ, NevinNC, Harris R, Read AP. Fielding DW. Apparent prevention of neural tube defects by periconceptional vitamin supplementation.Arch Dis Child 1981; 56:911–918.

    PubMed  CAS  Google Scholar 

  7. Wald N, Sneddon J, Densem J, Frost C, Stone R, MRC Vitamin Study Res Group. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study.Lancet 1991; 338:131–137.

    Article  Google Scholar 

  8. Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation.N Engl J Med 1992; 327:1832–1835.

    Article  PubMed  CAS  Google Scholar 

  9. Scott JM, Kirke PN, Weir DG. The role of nutrition in neural tube defects. Annu Rev Nutr 1990;10: 277–295.

    Article  PubMed  CAS  Google Scholar 

  10. Abramsky L, Botting B, Chappie J, Stone D. Has advice on periconceptional folate supplementation reduced neural-tube defects?Lancet 1999; 354:998–999.

    Article  PubMed  CAS  Google Scholar 

  11. Juriloff DM, Harris MJ. Mouse models for neural tube closure defects.Hum Mol Genet 2000; 9: 993–1000.

    Article  PubMed  CAS  Google Scholar 

  12. Hook EB, Czeizel AE. Can terathanasia explain the protective effect of folic-acid supplementation on birth defects?Lancet 1997; 350: 513–515.

    Article  PubMed  CAS  Google Scholar 

  13. Zhao Q, Behringer RR, De Crombrugghe B. Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for theCartl homeobox gene.Nature Genet 1996; 13: 275–283.

    Article  PubMed  CAS  Google Scholar 

  14. Carter M, Ulrich S, Oofuji Y, Williams DA, Ross ME.Crooked tail (Cd) models human folate-responsive neural tube defects.Hum Mol Genet 1999; 8: 2199–2204.

    Article  PubMed  CAS  Google Scholar 

  15. Fleming A, Copp AJ. Embryonic folate metabolism and mouse neural tube defects. Science 1998; 280:2107–2109.

    Article  PubMed  CAS  Google Scholar 

  16. Scott JM, Weir DG, Molloy Aet al. Folk acid metabolism and mechanisms of neural tube defects. In: Bock G, Marsh J, ed.Neural Tube Defects (Ciba Foundation Symposium 181). Chichester:John Wiley & Sons; 1994; 180–187.

    Google Scholar 

  17. Heid MK, Bills ND, Hinrichs SH, Clifford AJ. Folate deficiency alone does not produce neural tube defects in mice.J Nutr 1992; 122: 888–894.

    PubMed  CAS  Google Scholar 

  18. Cockroft DL. Changes with gestational age in the nutritional requirements of postimplantation rat embryos in culture.Teratology 1988; 38: 281–290.

    Article  PubMed  CAS  Google Scholar 

  19. Kirke PN, Molloy AM, Daly LE, Burke H, Weir DG, ScottJM. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects.Q J Med 1993; 86:703–708.

    PubMed  CAS  Google Scholar 

  20. Steegers-Theunissen RPM, Boers GHJ, Trijbels FJM, Eskes TKAB. Neural-tube defects and dearangement of homocysteine metabolism.N Engl J Med 1991; 324:199–200.

    Article  PubMed  CAS  Google Scholar 

  21. Mills JL, McPartlin JM, Kirke PN, Lee YJ, Conley MR, Weir DG, Scott JM. Homocysteine metabolism in pregnancies complicated by neural-tube defects.Lancet 1995; 345:149–151.

    Article  PubMed  CAS  Google Scholar 

  22. Morrison K, Edwards YH, Lynch SA, Burn J, Hoi F, Mariman E. Methionine synthase and neural tube defects.J Med Genet 1997; 34: 958

    Article  PubMed  CAS  Google Scholar 

  23. Van der Put NMJ, Steegers-Theunissen RPM, Frosst P, Trijbels FJM, Eskes TKAB, Van den Heuvel LP, MarimanECM, Den Heyer M, Rozen R, Blom HJ. Mutated methylenetetrahydrofolate reductase as a risk factor for spinabifida.lancet 1995; 346:1070–1071.

    Article  PubMed  Google Scholar 

  24. Whitehead AS, Gallagher P, Mills JL, Kirke PN, Burke H, Molloy AM, Weir DG, Shields DC, Scott JM. A genetic defect in 5,10 methylenetetrahydrofolate reductase in neural tube defects.Q J Med 1995; 88: 763–766.

    CAS  Google Scholar 

  25. Wilson A, Platt R, Wu Q, Lederc D, Christensen B, YangH, Gravel RA, Rozen R. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12 @#@) increases risk for spina bifida.Mol Genet Metab 1999; 67: 317–323.

    Article  PubMed  CAS  Google Scholar 

  26. Seller MJ. Vitamins, folic acid and the cause and prevention of neural tube defects. In: Bock G, Marsh J, eds.Neural Tube Defects (Ciba Foundation Symposium 181). Chichester. John Wiley & Sons; 1994; 161–173.

    Google Scholar 

  27. Greene NDE, Copp AJ. Inositol prevents folate-resistant neural tube defects in the mouse.Nature Med 1997; 3: 60–66.

    Article  PubMed  CAS  Google Scholar 

  28. Cockroft DL, Brook FA, Copp AJ. Inositol deficiency increases the susceptibility to neural tube defects of genetically predisposed (curly tail) mouse embryos in vitro.Teratology 1992; 45: 223–232.

    Article  PubMed  CAS  Google Scholar 

  29. Estibeiro JP, Brook FA, Copp AJ. Interaction betweensplotch (Sp) andcurly tail (ct) mouse mutants in the embryonic development of neural tube defects.Development 1993; 119:113–321.

    PubMed  CAS  Google Scholar 

  30. Essien FB, Wannberg SL. Methionine but not folinic acid or vitamin B-12 alters the frequency of neural tube defects inAxd mutant mice.J Nutr 1993; 123: 27–34.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neural Development Unit, Institute of Child Health, University College, London, 30 Guilford Street, WC1N1EH, London

    Andrew J. Copp

Authors
  1. Andrew J. Copp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas D. E. Greene
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew J. Copp.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Copp, A.J., Greene, N.D.E. Neural tube defects : Prevention by folic acid and other vitamins. Indian J Pediatr 67, 915–921 (2000). https://doi.org/10.1007/BF02723958

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02723958

Keywords

Search

Navigation