Fetal anticonvulsant syndromes and polymorphisms in MTHFR, MTR, and MTRR.
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.
Dean
John
J
Department of Medical Genetics, Clinical Genetics Centre, University of Aberdeen, Aberdeen, Scotland, United Kingdom. j.dean@abdn.ac.uk
Robertson
Zoe
Z
Reid
V
V
Wang
Q Diana
QD
Hailey
Hazel
H
Moore
Sue
S
Rasalam
A Dee
AD
Turnpenny
Peter
P
Lloyd
David
D
Cardy
Amanda
A
Shaw
Duncan
D
Little
Julian
J
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D000927:Anticonvulsants; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005787:Gene Frequency; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D013577:Syndrome
D000927:Anticonvulsants; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase