An extra dose of vitamin B3 might help prevent certain kinds of complex birth defects, according to a new study. The vitamin can help compensate for defects in the body’s ability to make a molecule, called nicotinamide adenine dinucleotide (NAD), which researchers have linked for the first time to healthy fetal development in humans. The find raises the possibility that boosting levels of B3 in pregnant women’s diets might help lower overall rates of birth defects.
The story started with a search for genes that can cause heart defects. Sally Dunwoodie, a developmental geneticist at the Victor Chang Cardiac Research Institute in Sydney, Australia, and her colleagues study the genes that influence heart development, and for years doctors have connected them with families of children born with heart problems so that the team could try to pinpoint any responsible genes. In 2005, Dunwoodie’s team dealt with a particularly severe case: a baby who had major defects in the heart, backbone, and ribs—the rib problems were so severe that the child’s lungs couldn’t fully inflate. The team found that the family carried a mutation in a gene related to the production of NAD, a molecule crucial for energy storage and DNA synthesis in cells. Both parents carried a mutation in one of their copies of the gene, and the affected baby had inherited two defective copies.
No one had reported any role for NAD in heart or bone development, Dunwoodie says. “We didn’t know what to do with it.”
In 2012, however, the team found a related mutation in a family whose baby had a similar combination of defects. This time the mutant gene was involved in the next step in the reaction that makes NAD. “That was our Eureka moment,” Dunwoodie says. She and her colleagues eventually found that two more families who had children with similar birth defects had mutations in the same two genes. They describe the mutations from the four families today in The New England Journal of Medicine.
To confirm the role of the mutations in organ and bone development, the researchers knocked out the two genes in mice to see whether similar birth defects appeared. At first all the pups were normal. But then the researchers realized that standard mouse chow is rich in niacin and that cells can use either niacin or nicotinamide—both known together as vitamin B3—to make NAD by an alternate pathway.
So the scientists fed pregnant mutant mice a diet without it. Many pups died in utero, and those that survived had defects that closely resembled those seen in the four families’ affected children. Giving the mutant pregnant mice low doses of niacin led to pups with less severe defects, and a niacin-rich diet allowed the mutant mice to give birth to healthy litters. The work suggests that B3 supplements might help families with mutations in NAD-related genes, by preventing birth defects or perhaps even by treating already affected children.
Of course, more human studies are needed before doctors could recommend B3 supplements for pregnant women, says Matthew Vander Heiden, who studies the role of NAD in cancer biology at the Massachusetts Institute of Technology in Cambridge. But the work opens a potentially exciting new area of research for developmental biologists: Trying to understand how cell metabolism affects development. Few people would have guessed that NAD deficiency causes birth defects, he says, “but it fits in with what we’ve been finding” about how NAD can influence cell growth.
The researchers aren’t sure exactly how NAD levels affect development, because the molecule plays a key role in so many different cell functions. It might be that cells without enough NAD don’t have enough energy to keep up with the fast pace of cell growth and division that development requires. The molecule also helps cells respond to certain kinds of stress. But both Dunwoodie and Vander Heiden suspect the role NAD plays in DNA synthesis and repair might be especially important. They note that patients with Fanconi anemia, a disease in which DNA breaks easily, often have birth defects similar to those seen in the families in the study.
Dunwoodie says she has counted at least 95 genes that are involved in NAD levels in the body. It’s possible that mutations in any of those could leave a developing fetus vulnerable to birth defects, even if neither parent has any obvious symptoms. Extra vitamin B3 in a mother’s diet might help compensate for any of the faulty genes, she says.
Physicians already recommend that women consume specific amounts of folic acid, or vitamin B9, to prevent spinal cord defects, but the new work is not enough to offer a similar proposal for B3. Researchers need to learn more about how pregnancy influences NAD levels in general, and what a healthy level is, Vander Heiden says. It’s possible that the extra B3 in standard prenatal vitamins is already helpful. Too much niacin can cause dizziness, nausea, and diarrhea, but low doses don’t have any known side effects. “There’s little downside to adding a bit of niacin” to people’s diets, he says. If it could prevent even a few severe birth defects, “it’s a pretty exciting possibility.”