EXPERT REACTION: Vitamin B3 prevents genetic birth defects in mice

The authors identified genetic causes of a rare constellation of malformations at birth called VACTERL. Affected babies have anomalies in at least three of the spine, anus, heart, trachea (windpipe), eosophagus (food tube) and limbs. About 1/20,000 babies are affected and some of these babies die. Note there are about 310,000 babies born in Australia each year.

The paper identifies gene variants in two enzymes in a biochemical pathway that makes Nicotinamide Adenine Dinucleotide or NAD. NAD is a co-enzyme that is important in cellular metabolism, specifically it is essential to the cell’s ability to generate energy from nutrients such as glucose. NAD is synthesized in the body by two pathways from tryptophan, an amino acid, or from niacin also known as Vitamin B3.

The authors undertook whole genome sequencing in 13 affected families. The gene variants were identified in three families with consanguineous marriages [when close relatives marry] with children with VACTERL malformations. This is important because we inherit one copy of each gene from our mother and a second copy from our fathers. Because we are genetically more similar to our blood relations than to non-related individuals babies born to consanguineous marriages are more likely to inherit 2 copies of defective genes that can cause malformations. Inheriting one copy often does not cause problems because the healthy copy can compensate.

The authors also genetically engineered mice to show that absence of the genes caused NAD deficiency and similar malformations in mice. However, when they provided extra niacin to pregnant mice the pups were relatively normal despite the absent gene. This does NOT mean that taking niacin/vitamin B3 in pregnancy prevents birth defects. The Australian population is not considered to be deficient in niacin. Most breakfast cereals have niacin added to them, it is also present in meat and whole grain cereals.

There have been previous publications showing mutations in other genes are also associated with VACTERL and it is likely that different genes contribute to these malformations and that not all babies with VACTERL will have the same mutations. However, it is important that we understand the role of different genes in birth anomalies and this paper has not only identified genetic mutations but also the mechanism by which they cause them.

The key finding is that genetic deficiency of NAD, a coenzyme that is found in all living cells, can lead to birth defects in the developing baby.  From this perspective, the paper is describing a new genetic condition, but one that is likely to be very rare.

What is most interesting is that these birth defects are potentially treatable if the mother is given niacin supplementation during pregnancy. This is because, in addition to being produced in the body, NAD can be also be sourced from dietary niacin.  In fact in mice that had the genetic deficiency of NAD, niacin was shown to be effective in preventing birth defects. Whether this is also the case in humans is yet to be determined.

A broader question is whether dietary niacin deficiency might play a role in birth defects even in the absence of the genetic deficiency of NAD, and whether dietary supplementation of niacin might be of benefit to pregnant women in the general population. This will be an interesting area for future study, but at present there is no reason to believe that dietary niacin deficiency is a major cause of birth defects in the general population.

I should add that the concept of a birth defect that is potentially preventable by diet is very cool, even if it only applies to rare individuals.

This study uses a comprehensive approach to understanding the cause of a relatively rare group of co-occurring congenital malformations (called VACTERL association). Using genetic information from four families in which there was a child with VACTERL association (three families were consanguineous), variants in two genes were identified in affected individuals.  These variants were both involved in a metabolic pathway involving the vitamin niacin in the body.  In mice bred with the same variants, similar congenital malformations and similar metabolic deficiency were found. The metabolic deficiency seen in the mice was  averted with treatment with niacin during pregnancy.

Whilst this is an exciting advance in understanding one mechanism for causing VACTERL, it is not yet clear whether it is the only cause for this group of malformations, whether other malformations may be linked to this cause, and whether dietary supplementation with niacin in humans would prevent this group or other malformations.

The NEJM study:

• The NEJM paper looks at some families where congenital malformations were found in NSW.  They genetically identified the cause and then created a mouse model to replicate the problem.  The authors conclude that disruption in the production of a coenzyme, called NAD, was related to the likelihood of one of these birth defects.
• The study found that niacin (vitamin B3) supplementation prevented birth defects 
• Nicotinamide is part of the vitamin B3 complex.  We commonly also know vitamin B3 as niacin (which is a common generic name that covers nicotinamide and nicotinic acid). 
• Nicotinamide is the "N" in NAD. This co-enzyme is needed for cells throughout the body.
• Hence nicotinamide is required for many of the bodies normal function.

General information:

• The Australian recommended daily intake (RDI) can be found at https://www.nrv.gov.au/nutrients/niacin
• Nicotinamide is the preferred form to give for treatment of vitamin B3 deficiency (pellagra). This is because it does not cause flushing side effects due to vasodilation, unlike nicotinic acid.
• This vitamin is water soluble, which means we do not store it in the body for long periods.
• It can be found often in meat, fish and some nuts etc. Some cereal manufacturers add this vitamin to their products.
• It can be bought over the counter as part of a vitamin supplement 
• It has limited side effects if the dosage is followed, hence it is is relatively safe to take and therefore we do not measure it often in hospital pathology laboratories.

What should people do now?

• Have a balanced healthy diet that includes all vitamins and trace elements. Talk to your doctor (GP) or health professional about your diet.

What may happen in the future ?

• May be fortification of foods with nicotinamide is considered / expanded as more evidence is produced.

The paper of Hongjum Shi et al describes an important discovery about the genetic cause of multiple congenital malformations that occur in combination (MCFs). They identified, in four families with MCFs, defects in genes that code for enzymes (HAAO, KYNU) that convert the amino acid tryptophan to the important cofactor nicotinamide adenine dinucleotide (NAD) which can also be derived from the vitamin niacin (vitamin B3).  

The study was limited by investigation in only four families but strengthened by data from a rodent model with defects in the same genes and increases in metabolites indicative of mutations in the HAAO and KYNU enzymes.

The findings are significant because they show the importance of tryptophan and vitamin B3 deficiencies as a cause of simultaneous multiple congenital defects and the possibility of preventing these abnormalities by adequate maternal supplementation with these nutrients before and during pregnancy. These developmental defects are probably the result of DNA damage and abnormal gene expression because NAD is needed for DNA repair, the control of which genes are switched on or off, as well as for energy production needed to sustain normal metabolism.

The authors hypothesise that  high dose niacin at 140mg/day, which is ten times the USA recommended daily intake of niacin, is required to prevent congenital malformations in families with defects in HAAO and/or KYNU genes but no evidence is provided to support this. Furthermore, this dose may not be safe given that the Tolerable Upper Intake Level for Niacin is only 35mg/day for adults.