U.S., Irish Researchers Identify Important Clue to Genetic Basis for Neural Tube Defects

A team of U.S. and Irish researchers has come one step closer to understanding why a high proportion of the population is genetically at risk for neural tube defects, according to a genetic study by researchers in Ireland and at two of the National Institutes of Health, the National Institute of Child Health and Human Development, and the National Human Genome Research Institute.

Specifically, the researchers learned that having only one copy of a variant gene is enough to increase the chances of being born with a neural tube defect. Previously, researchers believed that two copies of the gene were needed to increase someone's risk of being born with a neural tube defect.

The finding underscores the need for all women of childbearing age to follow the current recommendation to take 400 micrograms of the vitamin folic acid each day.

The study appears on the Web site of the British Medical Journal, at British Medical Journal, at http://bmj.com External Web Site Policy and will appear in the print edition of the journal at a later date.

Neural tube defects are a class of birth defects affecting the brain and spinal cord. In one type, spina bifida, a piece of the spinal cord protrudes from the spinal column, causing paralysis below the protrusion. In anencephaly, a fatal neural tube defect, the brain and skull are grossly underdeveloped.

The study was funded by the NICHD and the Health Research Board of Ireland.

Although the gene increases the chances for a neural tube defect, not all people who have the gene will develop a neural tube defect. Neural tube defects occur in about 7 of every 10,000 pregnancies. Women can reduce their chances of giving birth to a child with a neural tube defect if they take a tablet containing 400 micrograms of folic acid each day in the weeks before they become pregnant and throughout their early pregnancies. All women of childbearing age are advised to take 400 micrograms of folic acid each day, regardless of whether or not they are planning to become pregnant, as the majority of pregnancies in the United States are unplanned.

"Although we've made great progress in reducing the number of neural tube defects in the United States, not all women are receiving the recommended amount of folic acid," said Duane Alexander, M.D., Director of the NICHD. "This study underscores the need for all women of childbearing age to make sure they're taking 400 micrograms of folic acid a day."

In the current study, the researchers tested the DNA of 395 individuals with a neural tube defect and 848 individuals who did not have a neural tube defect. The researchers tested these people to see if they had a variant of a gene known as 5,10-methylenetetrahydro-folate reductase, involved in processing folate. The researchers conducted the study in Ireland because that country has a high proportion of individuals born with neural tube defects.

Human beings typically have two copies of a given gene, one inherited from the father, and one from the mother. Previously, researchers thought that an individual had to have two copies of the C677T variant to be at increased risk of neural tube defects. However, the study authors found that individuals having just one copy of C677T were one and a half times more likely to have a neural tube defect than were people who didn't have a copy of the variant gene. People with two copies of C677T were two and a half times as likely to have a neural tube defect than were people with two normal copies of the gene.

The researchers estimated that about 59 percent of the European population and 53 percent of the North American population has either one or two copies of the C677T variant.

In 1992, the U.S. Public Health Service recommended that all women of childbearing age capable of becoming pregnant consume 400 micrograms of folic acid, the synthetic form of the vitamin folate, from pills or tablets. To reduce the number of neural tube defects, the U.S. Food and Drug Administration required that folic acid be added to the U.S. grain supply in 1998.

The addition of folic acid to grains has cut the amount of neural tube defects in North America by about 50 percent, said the NICHD author of the study, James Mills, M.D., chief of the NICHD's Pediatric Epidemiology Section. Still, he added, on average, U.S. women of childbearing age receive only about 200 micrograms a day of folic acid from fortified grain. Women who don't eat grain products and who don't take a vitamin preparation that contains folic acid may be getting far less. In Ireland, where the study was conducted, grains are not routinely fortified with folic acid.

"?[O]ur study provides new data underscoring the importance of public health intervention programmes of folic acid supplementation and food fortification targeted at all women of childbearing age to prevent neural tube defects," the study authors wrote.

Dr. Mills explained that this gene could not be used as the basis of a prenatal genetic test to diagnose neural tube defects. Although having the gene increases the risk for neural tube defects, not all individuals who have the gene are born with a neural tube defect.


The NICHD is part of the National Institutes of Health (NIH), the biomedical research arm of the federal government. NIH is an agency of the U.S. Department of Health and Human Services. The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. NICHD publications, as well as information about the Institute, are available from the NICHD Web site, http://www.nichd.nih.gov, or from the NICHD Information Resource Center, 1-800-370-2943; e-mail NICHDInformationResourceCenter@mail.nih.gov.

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