Neurology -- Correspondence for Yerby, 61 (90062) 23-26

Correspondence published:

Management issues for women with epilepsy: Neural tube defects and folic acid supplementation: Sebastiano Bianca, Marco Bianca (17 December 2003)

Management issues for women with epilepsy: Neural tube defects and folic acid supplementation 17 December 2003

Sebastiano Bianca,
Sicilian Registry of Congenital Malformations
Dipartimento di pediatria, Via S. Sofia, 78-95123 Catania-Italy,
Marco Bianca
Send Correspondence to journal:
Re: Management issues for women with epilepsy: Neural tube defects and folic acid supplementation

sebastiano.bianca{at}tiscali.it Sebastiano Bianca, et al.

Yerby [1] discussed the association between prenatal exposures to antiepileptic drugs (AED), neural tube defects (NTDs) and folic acid supplementation. The association of AED prenatal exposure and NTDs has been well established. NTDs can occur as a result of defects in many genes and beside a genetic basis, environmental factors affect the occurence of NTD modulating gene expression. It is also well known that folate deficiencies have been implicated in the development of birth defects and low levels of folate are associated with hyperhomocysteinemia. AED intake interfere with folic acid metabolism and may be associated with hyperhomocysteinemia. A high homocysteine level in women who bear a NTD child, and protective folic acid effect, suggest that the genes encoding proteins connected with folic acid and methionine metabolism, can be involved in NTDs. An association between the 5, 10-methylenetetrahydrofolate reductase (MTHFR) mutations and homocysteine have been demonstrated. Dean [2], suggest that mutation in the MTHFR gene in a mother taking AED during pregnancy is associated with fetal anticonvulsant syndrome in her offspring. Ono [3], found that among patients receiving multi AED therapy, hyperhomocysteinemia in homozygotes for MTHFR C677T mutation, occurred significantly more often than in heterozygotes or patients with no mutantions and concluded that the C677T mutation is closely related to hyperhomocysteinemia and folate deficiency in epileptic patients taking multiple anticonvulsants. The finding that C677T homozygosity in the mother but not in the father is associated with an increased risk for spina bifida in the infant, suggests that the mother�s genotype might independently contribute to her child�s risk of disease4. Yoo et al5, showed that MTHFR TT genotype was an independent predictor of hyperhomocysteinemia in epileptic patients receiving anticonvulsants (phenytoin and carbamazepine but not valproic acid), suggesting that gene- drug interactions induce hyperhomocysteinemia and concluding that epileptic patients receiving anticonvulsants may have a higher folate requirement to maintain homocysteine level, especially homozygotes for MTHFR C677T mutation. In his paper, Yerby1 do not consider a possible gene-environment interaction, i.e. with MTHFR mutations, and NTDs in women prenatal exposed to AED and asserted that unfortunately, periconceptional folic acid supplementation may not be protective for women with epilepsy. We think that a MTHFR mutations study like blood homocysteine measuring may be useful in women taking AED and planning pregnancy to give periconceptional folic acid supplementation that, particularly in cases with DNA mutations, may be higher than the 400 �g/day dosage recommended for the general population.
REFERENCES 1. Yerby MS. Management issues for women with epilepsy. Neural tube defects and folic acid supplementation Neurology. 2003; 61: S23-S26 2. Dean JC, Moore SJ, Osborne A, Howe J, Turnpenny PD. Fetal anticonvulsant syndrome and mutation in the maternal MTHFR gene. Clin Genet. 1999; 56: 216-220.
3. Ono H, Sakamoto A, Mizoguchi N, Sakura N. The C677T mutation in the methylenetetrahydrofolate reductase gene contributes to hyperhomocysteinemia in patients taking anticonvulsants. Brain Dev. 2002; 24: 223-226.
4. Botto LD, Yang O. 5,10-Methylenetetrahydrofolate Reductase Gene Variants and Congenital Anomalies: A HuGE Review. Am J Epidemiol. 2000; 151: 862-877
5. Yoo JH, Hong SB A common mutation in the methylenetetrahydrofolate reductase gene is a determinant of hyperhomocysteinemia in epileptic patients receiving anticonvulsants. Metabolism. 1999; 48: 1047-51.