The malformations found in fetal anticonvulsant syndromes (FACS) are associated with folic acid deficiency and methylene-tetrahydrofolate reductase (MTHFR) polymorphisms in the general population. To investigate a possible association between FACS and MTHFR genotype, we recruited 200 mothers who had taken anti-epileptic drugs in pregnancy, and delivered at Aberdeen Maternity Hospital over a 26-year period. Clinical findings in the mothers and their 337 children were documented. A clinical algorithm was devised to diagnose FACS objectively. Case-parent triads were genotyped for polymorphisms in MTHFR, serine hydroxymethyl transferase (SHMT1), methionine synthase (MTR), and methionine synthase reductase (MTRR), and analyzed by log-linear regression. No effect of the child's genotype on congenital malformation, neurodevelopmental disorder or FACS was detected using this method. The risk of having a child with congenital malformation or FACS was three to four times higher for mothers who were MTHFR 677TT homozygotes compared with MTHFR 677CC homozygotes. MTR 2756A > G and MTRR 66A > G genotype frequencies in children with FACS and neurodevelopmental disorder were different from those in healthy blood donor controls.
2007 Wiley-Liss, Inc