Variants in two genes responsible for nicotinamide adenine dinucleotide (NAD) synthesis caused NAD deficiency and were tied to multiple congenital malformations in humans and mice, research shows. The study also shows that supplementation with niacin during gestation prevents the congenital defects in mice, even in the presence of the mutations.
Hongjun Shi, PhD, from the Division of Developmental and Stem Cell Biology, Victor Chang Cardiac Research Institute, Darlinghurst, and the Faculties of Medicine and Science, University of New South Wales, both in New South Wales, Australia, and colleagues report their findings online August 9 in the New England Journal of Medicine.
Relatively little is known about the causes of cooccurring congenital malformations. Although genetic testing has helped identify causes of many isolated congenital malformations, determining the origins of multiple cooccurring congenital malformations has been more elusive. For example, “the genetic causes of isolated cardiac or vertebral defects appear to have little relevance when these defects occur in combination,” the authors write.
One such nonrandom combination of malformations with no previously known cause is the vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (VACTERL) association.
“We identified mutations blocking de novo NAD synthesis that cause multiple congenital malformations, including those found in the VACTERL association. The NAD de novo synthesis pathway catabolizes tryptophan, leading to the production of NAD,” the researchers explain. “Although metabolite levels upstream of the block are elevated and the metabolites have postnatal functions, we found that it is the deficiency in embryonic NAD, downstream of the block, that is disrupting embryogenesis. We found that in mice, supplementing dietary niacin during gestation prevents embryo defects caused by NAD deficiency.”
To identify variants that were potentially pathogenic, the researchers performed genomic sequencing in families in which a patient (n = 4 patients) had multiple congenital malformations. Three families were consanguineous, and one family had no history of consanguinity. All patients had vertebral defects and cardiac defects, as well as other malformations.
Postnatal growth and cognitive defects occurred as well. “Patients A, B, and C had microcephaly. Patients A and D have extreme short stature. Patient A has moderate intellectual disability and behavioral issues at 12 years of age, and Patient D has speech delay at 3 years of age,” the researchers note. Patient C died at 4 months of age, and patient B died at 11 months.
Testing revealed loss-of-function mutations in both copies of the gene that encodes 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) or of the gene that encodes kynureninase (KYNU). Three patients carried homozygous variants (patient A, HAAO p.D162*; patient B, HAAO p.W186*; patient C, KYNU p.V57Efs*21). Patient D carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4).
The truncated enzymes were much less active in vitro.
“Engineering the same enzyme deficiencies in mice resulted in birth defects similar to those found in humans, but only if they were combined with dietary interventions to reduce NAD levels,” Matthew G. Vander Heiden, MD, PhD, from the Koch Institute for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, and the Dana-Farber Cancer Institute, Boston, Massachusetts, writes in a related perspective. “Deletion of Haao or Kynu in mice was sufficient to increase levels of upstream pathway intermediates but had no effect on development provided that sufficient NAD levels were maintained through diet. Therefore, the authors could conclude that NAD depletion, rather than the buildup of the upstream intermediates, was responsible for the congenital malformations,” Dr Vander Heiden explains.
“We theorize that supplementation with high-dose niacin (140 mg per day, which is 10 times the U.S. recommended daily allowance for women) before and during pregnancy might prevent recurrence of disease in these four families. It is also possible that niacin supplementation may benefit the speech and developmental delays in the surviving patients,” the researchers suggest.
“In conclusion, many genetic and environmental factors have the potential to cause NAD deficiency during gestation. We propose that cases of congenital malformation that occur because of a deficit in NAD be collectively referred to as congenital NAD deficiency disorders.”
The authors have disclosed no relevant financial relationships. Dr Vander Heiden reports receiving personal fees from Agios Pharmaceuticals and personal fees from Aeglea Biotherapeutics outside the submitted work.
N Engl J Med. 2017;377:509-511, 544-552. Article abstract, Perspective extract
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