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Neural tube defects and folate: case far from closed

Nature Reviews Neuroscience volume 7, pages 724–731 (2006)Cite this article

Key Points

  • Neural tube closure is a highly complex process that occurs during embryogenesis. Failure of the neural tube to close can lead to neural tube defects (NTDs) such as anencephaly and spina bifida.

  • Periconceptional use of folic acid supplements prevents about a half to three-quarters of cases of NTDs. The main function of the metabolism of the vitamin folate is to transport one-carbon units, which are used in the synthesis of DNA building blocks (purines and thymidine) and for methylation of numerous compounds, including DNA, RNA, proteins and lipids.

  • A variant of the gene methylenetetrahydrofolate reductase (MTHFR) is the first genetic risk factor to be identified for NTDs. This role goes some way to explaining the prevention of NTDs by folic acid, a precursor of the natural substrate of MTHFR.

  • Knowledge of folate metabolism and the biochemical role of MTHFR has led to the development of the methylation hypothesis for NTDs, which suggests that reduced cellular methylation hampers neural tube closure.

  • If folic acid prevents NTDs through improved methylation, new therapeutic strategies, such as the administration of agents involved in donating a methyl group, for example, riboflavin, vitamin B12, methionine and choline, must be explored.

Abstract

Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents ∼50–75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.

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Figure 1: Neural tube closure in the developing mouse.
Figure 2: Structures of folates.
Figure 3: Simplified folate metabolism.
Figure 4: The three MTHFR genotypes affect methylation and DNA synthesis to different extents.
Figure 5: Folate metabolism is influenced by environmental and genetic factors.

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Acknowledgements

We gratefully acknowledge I. van der Linden for her critical comments and valuable support. Our work is supported by grants from the Princess Beatrix Fund and the National Institutes of Health (National Institute of Neurological Disorders and Stroke).

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Authors and Affiliations

  1. Laboratory of Pediatrics and Neurology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Post Office Box 9101, Nijmegen, 6500 HB, The Netherlands

    Henk J. Blom

  2. California Birth Defects Monitoring Program, 1830 Embarcadero, Suite 100, Oakland, 94606, California, USA

    Gary M. Shaw

  3. Departments of Endocrinology and Epidemiology and Biostatistics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Post Office Box 9101, Nijmegen, 6500 HB, The Netherlands

    Martin den Heijer

  4. Institute of Biosciences and Technology, Texas A&M University System Health Science Center, 2121 West Holcombe Boulevard, Houston, 77030, Texas, USA

    Richard H. Finnell

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Supplementary information

Supplementary information S1 (box)

Meta-analysis of MTHFR 677 C>T as risk factor for neural tube defects in mothers and their offspring (PDF 433 kb)

Supplementary information S2 (movie)

Normal neurulation of chicken embryos. (WMV 2591 kb)

Embryos were cultured in a Petri dish at 39°C starting with somite stage of about four and developing until about somite stage nine. Digital images were recorded using a video camera.

Supplementary information S3 (movie)

Inhibition of neurulation by homocysteine. (WMV 2552 kb)

Shows how homocysteine administration hampers normal neurulation, as shown by the widening of the anterior neuropore. Also the closure of the rhombencephalic neuropore is reduced. Control experiments with the same concentrations of leucine and cysteine did not significantly affect neurulation (data not shown).

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DATABASES

OMIM

Anencephaly

Spina bifida

Glossary

Anencephaly

A neural tube defect that occurs when there is a failure of neurulation, in which the neural folds do not fuse at the cranial end of the developing embryo. In these infants, most or all of the brain tissue is missing.

Spina bifida

A posterior neural tube defect that is caused by the failure of the neural tube to fuse at the caudal end. Infants with spina bifida can have an open lesion on their spine, where significant damage to the nerves and spinal cord has occurred, or the lesion can be closed.

Neural plate

Neural epithelial cells that form in the early embryo after neuronal induction and give rise to the nervous system.

Neural crest

Groups of cells that migrate from the neural tube to the periphery, where they give rise to a wide variety of cell types.

Biomarker

A characteristic that is objectively measured and evaluated as an indicator of normal biological or pathogenic processes, or pharmacological responses to a therapeutic intervention.

Single nucleotide polymorphism

(SNP). A specific location in a DNA sequence at which different people can have a different DNA base. Differences in a single base could change the protein sequence, leading to disease (for example, sickle-cell disease), or have no known consequences.

Somites

Paired blocks of mesoderm cells along the vertebrate body axis that form during early vertebrate development and differentiate into dermal skin, bone and muscle.

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Blom, H., Shaw, G., den Heijer, M. et al. Neural tube defects and folate: case far from closed. Nat Rev Neurosci 7, 724–731 (2006). https://doi.org/10.1038/nrn1986

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