Journal Article

Neural tube defects and folate: case far from closed

Finnell, Richard H., den Heijer, Martin, Shaw, Gary M., Blom, Henk J.

2006

Overview

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. Failure of neural tube closure leads to neural tube defects, such as spina bifida and anencephaly, and has been linked to insufficiency of folate. The genetic and molecular mechanisms that link folate metabolism to neural tube defects are now being unravelled. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Acids / Animal Genetics and Genomics / Animals / Behavioral Sciences / Biological and medical sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Births / Central Nervous System - abnormalities / Central Nervous System - metabolism / Central Nervous System - physiopathology / Epidemiology / Folic Acid - metabolism / Folic Acid - therapeutic use / Folic Acid Deficiency - complications / Folic Acid Deficiency - physiopathology / Folic Acid Deficiency - prevention & control / Fundamental and applied biological sciences. Psychology / General aspects. Models. Methods / Genes / Genetic Predisposition to Disease - genetics / Homocysteine - metabolism / Human viral diseases / Humans / Infectious diseases / Life sciences / Medical sciences / Metabolism / Methionine - biosynthesis / Methylation - drug effects / Methylenetetrahydrofolate Reductase (NADPH2) - genetics / Methylenetetrahydrofolate Reductase (NADPH2) - metabolism / Neural Tube Defects - etiology / Neural Tube Defects - physiopathology / Neural Tube Defects - prevention & control / Neurobiology / Neurosciences / Post offices / Pregnancy / review-article / Spina bifida / Vertebrates: nervous system and sense organs / Viral diseases / Viral diseases of the nervous system / Vitamin B