Elsevier

Metabolism

Volume 48, Issue 8, August 1999, Pages 1047-1051
Metabolism

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

https://doi.org/10.1016/S0026-0495(99)90204-4Get rights and content

Abstract

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 Hinfl digestion in 103 patients with epilepsy and 103 normal controls. The prevalence of hyperhomocysteinemia (≥ 11.4 μmol/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 μmol/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.

References (28)

  • DB Smith et al.

    Interactions between folates and carbamazepine or valporate in the rat

    Neurology

    (1982)
  • RE Billings

    Decreased hepatic 5,10-methylenetetrahydrofolate reductase activity in mice after chronic phenytoin treatment

    Mol Pharmacol

    (1984)
  • CJ Boushey et al.

    A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: Probable benefits of increasing folic acid intakes

    JAMA

    (1995)
  • PM Ueland et al.

    Plasma homocysteine, a risk factor for vascular disease: Plasma levels in health, disease, and drag therapy

    J Lab Clin Med

    (1989)
  • Cited by (86)

    • Association between methylenetetrahydrofolate reductase C677T polymorphism and epilepsy susceptibility: A meta-analysis

      2014, Seizure
      Citation Excerpt :

      Based on the search criteria, a total of 81 potentially relevant publications were identified, and three of them were selected from the reference lists of the identified articles. After careful selection, 10 eligible studies5,18,19,30–36 were finally included in this meta-analysis. All control samples from included studies were in HWE.

    • Homocysteine, folic acid and vitamin B12 levels in serum of epileptic children

      2012, Egyptian Journal of Medical Human Genetics
      Citation Excerpt :

      AEDs may interfere with both absorption and metabolism of folate. It has also been suggested that AED-mediated decrease in plasma folate concentrations may in part represent a drug–gene interaction [30,14]. It is worth noting that in the study done in 2005 by Huemer et al. [11] intervention with folic acid resulted in significantly higher folate and lower tHcy concentrations at weeks 6 and 12 compared with patients receiving placebo [13].

    View all citing articles on Scopus

    Supported by the research fund of Samsung Biomedical Research Institute (C-98-029) and Samsung Medical Center.

    View full text