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From Daly LE, Kirke PN, Molloy A, Weir DG and Scott JM (1995) Folate levels and neural tube defects—Implications for prevention. Journal of the American Medical Association 274: 1968-1702. Copyright © 1995, American Medical Association.

From Daly LE, Kirke PN, Molloy A, Weir DG and Scott JM (1995) Folate levels and neural tube defects—Implications for prevention. Journal of the American Medical Association 274: 1968-1702. Copyright © 1995, American Medical Association.

NTD point to a metabolic explanation for the aetiology of these conditions. Since it is estimated that folic acid can prevent up to 71% of NTDs, defects in folate-related enzymes or processes have been candidates for study. There are 16 folate-dependent enzymes in the internal metabolism of mammalian cells. The finding in the Dublin study of significantly higher plasma homocysteine levels in case mothers than in controls suggested that one or more enzymes involved in homocysteine metabolism may be abnormal. The main folate-related enzymes involved in homocysteine metabolism are illustrated in Figure 1. Homocysteine levels in the amniotic fluid of women carrying a fetus with an NTD have been reported as being higher compared with those of normal pregnancies. Evidence of deranged homo-cysteine metabolism also comes from metabolic studies conducted in Holland. In a study in which women who had given birth to an NTD baby were given a methionine-loading test, methionine intolerance and very high peak levels of homocysteine were found in a subgroup of the NTD women. Cystathio-nine synthase levels in skin fibroblasts taken from the methionine-intolerant women were normal. Plasma folate and vitamin B12 were found to be independent risk factors for NTDs in the Dublin study. Although the results of this study pointed to an abnormality in the methionine synthase enzyme, there is no strong evidence linking genetic variants of the enzyme to NTDs. However, it is possible that vitamin B12 status may influence NTD risk in ways other than directly affecting the activity of this enzyme.

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