Fetal anticonvulsant syndrome and mutation in the maternal MTHFR gene

Around 6% of infants born to mothers taking anticonvulsants have malformati ons, including neural tube defects, and a further proportion show developme ntal delay in later childhood. Three commonly used anticonvulsants, carbama zepine, phenytoin and sodium valproate, interfere with folic acid metabolis m. We investigated the common 677 C > T mutation in the methylenetetrahydro folate reductase (MTHFR) gene in samples from 57 patients and their parents and 152 controls to determine its contribution to the risk of fetal antico nvulsant syndrome. The 677 C > T mutation frequency was significantly highe r in the mothers than in the controls, but there was no significant differe nce in 677 C > T frequency in the patients or in the fathers. Genotype freq uencies in the mothers were significantly different from controls, there be ing an excess of 677 C > T homozygotes. Amongst the patients, there was an apparent excess of heterozygotes (not statistically significant), and the f athers were not significantly different from controls. Mutation in the MTHF R gene in a mother taking sodium valproate, phenytoin or carbamazepine duri ng pregnancy is associated with fetal anticonvulsant syndrome in her offspr ing. The skewed distribution of genotypes in the affected children probably reflects the association of fetal anticonvulsant syndrome with the materna l genotype.