A common mutation in the methylenetetrahydrofolate reductase gene is a determinant of hyperhomocysteinemia in epileptic patients receiving anticonvulsants

Metabolism. 1999 Aug;48(8):1047-51. doi: 10.1016/s0026-0495(99)90204-4.


Hyperhomocysteinemia is a condition caused by both genetic and nongenetic factors. To determine whether a common methylenetetrahydrofolate reductase (MTHFR) variant is related to elevated homocysteine concentrations in epileptic patients receiving anticonvulsants, we investigated the plasma total homocysteine (tHcy) level, folate level, and MTHFR 677 C --> T mutation using a polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis with HinfI digestion in 103 patients with epilepsy and 103 normal controls. The prevalence of hyperhomocysteinemia (> or = 11.4 micromol/L, 90th percentile of control group) was higher in patients than in controls (25% v 10.0%, P = .007). The homozygosity for the 677 C --> T mutation of MTHFR was associated with elevated tHcy and low folate levels. The magnitude of hyperhomocysteinemia in MTHFR TT homozygotes was more pronounced in epileptic patients than in controls (18.2 +/- 1.6 v 9.1 +/- 1.2 micromol/L, P = .04). In epileptic patients, hyperhomocysteinemia was more frequent in MTHFR TT genotypes versus CT or CC genotypes (58% v 17% and 16%, P < .001). Multiple logistic regression analysis 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. These findings indicate that epileptic patients receiving anticonvulsants may have a higher folate requirement to maintain a normal tHcy level, especially homozygotes for MTHFR 677 C --> T mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anticonvulsants / therapeutic use
  • Epilepsy / drug therapy
  • Epilepsy / genetics*
  • Epilepsy / metabolism
  • Female
  • Folic Acid / blood
  • Homozygote
  • Humans
  • Hyperhomocysteinemia / genetics*
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Point Mutation


  • Anticonvulsants
  • Folic Acid
  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)