A GENETIC-DEFECT IN 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE IN NEURAL-TUBE DEFECTS

It is now well-established that folic acid, taken periconceptionally, can reduce the risk of neural tube defects (NTDs). Recent work has dem onstrated that an abnormality of homocysteine metabolism is a critical factor. The gene for 5, 10 methylenetetrahydrofolate reductase, an en zyme important in homocysteine metabolism, was studied in relation to NTDs. To determine the frequency of the allele for the thermolabile fo rm of the reductase, DNA samples were collected from people with NTDs, parents of people with NTDs, and normal controls. Of 82 people with N TDs, 15 (18.3%) were homozygous for the abnormal, thermolabile allele. This was significantly higher (p = 0.01) than the rate of 6.1% in the control population (odds ratio 3.47, 95% Cl 1.28-9.41). This is the f irst specific genetic abnormality to be identified in NTDs. It explain s the association between some NTDs and elevated homocysteine, given t hat the reductase is important in homocysteine metabolism. It also exp lains how folic acid supplementation prevents some NTDs, by overcoming a partial block in the conversion of 5,10 methylenetetrahydrofolate t o 5 methyltetrahydrofolate. Genetic screening could identify women who will require folic acid supplements to reduce their risk of having a child with an NTD.