Nicotinamide adenine dinucleotide (NAD) is synthesised in the body from niacin (vitamin B3). Disruption of its production mechanism due to genetic or other factors can cause NAD deficiency.
Deficiency of this molecule was a critical factor in the cause of birth defects in both humans and mice, reported a research team from the Victor Chang Cardiac Research Institute, Sydney.
Genetic sequencing of families with offspring affected by a rare set of birth defects revealed mutations to the gene responsible for NAD production.
Subsequent trials showed that mice lacking the NAD synthesis genes fed a niacin-free diet gave birth to pups with similar defect to those in human babies with NAD gene mutations. However, when the mice were given niacin rich diets, their offspring were healthy.
“Our findings increase understanding of the genetic and environmental causes of congenital malformation. Our discovery that the genetic disruption of NAD synthesis causes congenital malformations suggests that mutation of many genes might have the same effect,” wrote lead researcher Professor Sally Dunwoodie.
The possibility that the genetically-induced deficiency could be remedied by sufficient intake of a cheap, well-tolerated supplement – vitamin B3 – has enormous implications.
“The ramifications are likely to be huge. This has the potential to significantly reduce the number of miscarriages and birth defects around the world and I do not say those words lightly,” says Dunwoodie.
“Just like we now use folate to prevent spina bifida, Prof. Dunwoodie's research suggests that it is probably best for women to start taking vitamin B-3 very early on, even before they become pregnant. This will change the way pregnant women are cared for around the world,” commented Professor Robert Graham, Executive Director at the Victor Chang Institute.
Multiple genes involved
The researchers’ initial investigations had focused on families with a rare condition known as ‘VACTERL’ (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, or limb abnormalities). People defined as having VACTERL are born with at least three of these congenital malformations.
During their 12-year project, the scientists discovered that NAD deficiency might also explain a wider set of birth defects and miscarriages.
The scientists identified at least 95 genes that influence NAD levels in the body. However, as NAD is involved in so many different functions, the researchers are still unsure of the exact mechanisms of NAD’s effects on foetal development.
Nevertheless, Dunwoodie advocates that additional vitamin B3 in the maternal diet might help overcome the effect of the gene mutations.
The team suggested that further work is needed to identify how pregnancy effects NAD levels, to develop a test for measuring NAD levels and to define what constitutes a healthy NAD status. This will enable identification of mothers-to-be who have a high risk of having a baby with a birth defect and ensure their niacin intake is adequate.
‘High’ dose niacin?
The researchers hypothesised that daily intake of 140 milligrams per day before and during pregnancy might be adequate in preventing recurrence of disease in families where multiple birth defects had been identified. However, formal dosage requirements still have to be established.
One expert advised caution in view of the fact that the hypothesised dose was a multiple of the US recommended daily allowance.
“While exciting, this discovery cannot be translated into recommendations for pregnant women who at most may be deficient in vitamin B3.In particular the doses used in this research were ten times the recommended daily doses for supplementation in women and it is known that high doses of vitamin B3 can cause side effects for the mother and the long term effects on pregnancy and health of children are not known,” said Dr Katie Morris, Senior Clinical Lecturer and Consultant in Maternal Foetal Medicine, University of Birmingham, speaking to Science Media Centre.
Other leading researchers suggested that although the study findings were promising, they stressed the need for replication in human studies, before establishing firm conclusions for vitamin B3 therapy.
Source: The New England Journal of Medicine
Volume 377, issue 6. Pages 544-552, doi: 10.1056/NEJMoa1616361
“NAD Deficiency, Congenital Malformations, and Niacin Supplementation”
Authors: Hongjun Shi, Sally L Dunwoodie et al.