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Homocysteine and Neural Tube Defects¹

James L. Mills^*,2, John M. Scott, Peadar N. Kirke, Joseph M. McPartlins, Mary R. Conley^*, Donald G. Weir, Anne M. Molloy and Young Jack Lee^*

^* Division of Epidemiology, Statistics and Prevention Research, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 Department of Biochemistry, Trinity College, Dublin, Ireland Health Research Board of Ireland, Dublin, Ireland Department of Clinical Medicine, Trinity College, Dublin, Ireland

² To whom correspondence should be addressed: Pediatric Epidemiology Section, 6100 Building, Room 7B03, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.

It is now well established that folic acid, when taken periconceptionally, can prevent many neural tube defects. It is also becoming clear that folic acid does not work by correcting a nutritional deficiency in pregnant women. Rather, it appears that a metabolic defect is responsible for these neural tube defects and that this defect or defects can be corrected by a sufficiently large dose of folic acid. Our recent work demonstrates that homocysteine metabolism is likely to be the critical pathway affected by folic acid. We have demonstrated significantly higher homocysteine levels in women carrying affected fetuses than in control women. These findings indicate that one of the enzymes responsible for homocysteine metabolism is likely to be abnormal in affected pregnancies. Animal studies suggest that the conversion of homocysteine to methionine could be the critical step. Rat embryos in culture require methionine for neural tube closure. Methionine synthase, cystathionine synthase, and 5,10 methylene tetrahydrofolate reductase are all important in the metabolism of homocysteine in humans. If methionine synthase is the critical enzyme, it would raise the interesting public health issue that vitamin B-12 might be able to stimulate the abnormal enzyme as folic acid does. Adding vitamin B-12 might make it possible to reduce the dose of folic acid required in fortified food, thus allaying concerns about overexposure to folic acid. J. Nutr. 126: 756S-760S, 1996.