The C677T mutation in the methylenetetrahydrofolate reductase gene contributes to hyperhomocysteinemia in patients taking anticonvulsants

Ono, Hiroaki; Sakamoto, Akiko; Mizoguchi, Nobuyuki; Sakura, Nobuo

doi:10.1016/s0387-7604(02)00004-9

Cited by 43 publications

(41 citation statements)

References 9 publications

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“…MTHFR is a key enzyme in the homocysteine remethylation pathway, which plays an important role in the transmethylation of homocysteine to methionine. Ono et al 19 indicated that there was a relationship between hyperhomocysteinaemia and the homozygote MTHFR gene variant in patients with epilepsy receiving multidrug therapy, but not in those receiving monotherapy. However, Vurucu et al 7 found that the variations in the MTHFR gene had no significant contribution on hyperhomocysteinaemia in patients with epilepsy receiving AEDs therapy.…”

Section: Discussionmentioning

confidence: 99%

Increased homocysteine levels in valproate-treated patients with epilepsy: a meta-analysis

Qin

Fang

et al. 2014

BMJ Open

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ObjectiveTo determine whether valproate (VPA) monotherapy influences homocysteine metabolism in patients with epilepsy.DesignSystematic review and meta-analysis.Data sourcesWe searched all articles in English through PubMed, Web of Science and EMBASE published up to August 2013 concerning the homocysteine levels in VPA monotherapeutic patients with epilepsy.ParticipantsVPA-treated patients with epilepsy (n=266) and matched healthy controls (n=489).Outcome measuresHeterogeneity between studies was assessed using I2 statistics. Pooled standardised mean difference (SMD) and 95% CIs were calculated using a random effect model.ResultsA total of eight eligible studies were enrolled in our meta-analysis. We compared the plasma levels of homocysteine in VPA-treated patients with epilepsy and healthy controls. There was significant heterogeneity in the estimates according to the I2 test (I2=65.6%, p=0.005). Plasma homocysteine levels in VPA-treated patients with epilepsy were significantly higher than in healthy controls under a random effect model. (SMD, 0.62; 95% CI 0.32 to 0.92). Further subgroup analyses suggested that no signiﬁcant differences were present when grouped by ethnicity and age, but the risk of heterogeneity in the West Asian group (I2=47.4%, p=0.107) was diminished when compared with that of the overall group (I2=65.6%, p=0.005).ConclusionsOur meta-analysis indicates that VPA monotherapy is associated with the increase in plasma homocysteine levels in patients with epilepsy. Whether this association is influenced by ethnicity needs further research.

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Section: Discussionmentioning

confidence: 99%

Increased homocysteine levels in valproate-treated patients with epilepsy: a meta-analysis

Qin

Fang

et al. 2014

BMJ Open

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“…The results of adult patients with epilepsy were contradictory (Dinç & Schulte, ). Some prior studies have also found that the MTHFR C677T mutation determined HHcy in patients with epilepsy receiving valproic acid (Ono, Sakamoto, Mizoguchi, & Sakura, ; Yoo & Hong, ), and the MTHFR 677T allele was found to be associated with increased Hcy levels only in males (Nilsson et al, ), suggesting that sex differences in a gene–drug interaction may lead to the changes of homologous system, which may provide reasonable explanations for conflicting results, and thus, further studies are needed to verify our findings.…”

Section: Discussionmentioning

confidence: 99%

“…The results of adult patients with epilepsy were contradictory (Dinç & Schulte, 2018). Some prior studies have also found that the MTHFR C677T mutation determined HHcy in patients with epilepsy receiving valproic acid (Ono, Sakamoto, Mizoguchi, & Sakura, 2002;Yoo & Hong, 1999), and the MTHFR 677T allele was found to be associated with increased Hcy levels only in males (Nilsson et al, 2014), suggesting that sex differences in a gene-drug interaction may lead to the changes of homologous system, which may provide rea- were given to patients based on their severity and type of mood episode (manic, depression, or mixed). However, we did not collect information on the corresponding drugs in different mood phase, as well as information on different dosage, duration of treatment, or in combination with other drugs.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the prevalence and clinical correlates of hyperhomocysteinemia in patients with bipolar disorder

Lin

Huang

et al. 2020

Human Psychopharmacology

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Objective Sex differences in bipolar disorder are well recognized but little attention has been paid to sex differences in homocysteine or hyperhomocysteinemia in bipolar patients. This study compared gender differences in homocysteine levels and rates of hyperhomocysteinemia in Chinese inpatients with bipolar disorder. Methods A total of 198 BD patients and 84 healthy controls were enrolled. The Young Mania Rating Scale, Hamilton Depression Rating Scale, and the Clinical Global Impressions–Severity scale were used to assess the affective symptomatology. Fasting plasma Hcy levels were measured by high‐performance liquid chromatography. Results Men had higher homocysteine levels than women and the prevalence of hyperhomocysteinemia in male patients was approximately twice that in female patients. Logistic regression analyses showed that HHcy was associated with less frequent use of valproate in males and being overweight in females. Further correlation analysis and multivariate regression analysis demonstrated that Hcy levels were inversely correlated with valproate treatment in men and positively associated with overweight in women. Conclusions In bipolar patients, there are significant differences between sexes in the levels of homocysteine and prevalence of hyperhomocysteinemia. This appears to be associated with lower prevalence of valproate prescribing in men and with being overweight in women.

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“…Experimental studies have shown that Hcy does play a role in epileptogenesis by decreasing the seizure threshold via inhibitory effects on adenosine. Some evidence from animal studies to clinical trials have suggested that when tHcy levels were increased, seizures could not be controlled optimally [16,18]. According to the results from Sener et al [22], increased Hcy levels have been observed in patients receiving antiepileptics, but the levels were normal in epileptic children not receiving treatment, as well as in healthy controls.…”

Section: Discussionmentioning

confidence: 99%

Serum asymmetric dimethylarginine (ADMA), homocysteine, vitamin B12, folate levels, and lipid profiles in epileptic children treated with valproic acid

et al. 2010

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Recent reports have demonstrated elevated serum homocysteine (Hcy) levels in children receiving valproic acid (VPA) therapy. Elevated Hcy levels might play a potential role in the resistance to antiepileptic drugs, and might lead to an increased risk for a vascular disease. It has been reported that elevated total homocysteine (tHcy) levels are associated with elevated asymmetric dimethylarginine (ADMA) levels, which are factors that may be better indicators of endothelial dysfunction compared to serum homocysteine levels, because they are less sensitive to changes, such as fasting status, physical activity, and other factors. In this study, we aim to evaluate serum ADMA, Hcy, lipid, folate, and vitamin B₁₂ levels in epileptic children, receiving VPA monotherapy. Forty-four epileptic children, receiving VPA monotherapy for at least 6 months and 28 healthy children aged between 4 and 16 years, were recruited. Serum lipids, lipoproteins, folate, vitamin B₁₂, Hcy, and ADMA levels were analyzed in both study groups. Serum Hcy, ADMA, and vitamin B₁₂ levels were higher in patients than in controls (p < 0.001 for tHcy and ADMA levels; p < 0.05 for vitamin B₁₂ levels); however, serum lipid, lipoprotein, and folate levels were similar. According to the duration of epilepsy, serum tHcy, ADMA, and triglyceride (TG) levels were higher in patients with epilepsy for ≥ 2 years than in patients with epilepsy for < 2 years (p < 0.001 for serum ADMA levels, p < 0.01 for tHcy levels, and p < 0.05 for serum TG levels). Similarly, with respect to the duration of VPA therapy, serum tHcy, ADMA, and TG levels were higher in patients who had received VPA therapy for more than 2 years (p < 0.001 for serum ADMA levels, p < 0.05 for serum tHcy levels, p < 0.01 for TG levels). Serum ADMA levels were significantly higher in patients receiving VPA at the dose of 25-30 mg/kg/day than in those receiving 20 mg/kg/day (p < 0.01). In conclusion, our study found increased serum ADMA levels and increased tHcy levels in epileptic children receiving VPA monotherapy. Increased serum ADMA levels were demonstrated in epileptic children who have had a seizure history greater than 2 years, and have used VPA therapy for more than 2 years, and have received higher doses of VPA. Routine monitoring of serum ADMA and tHcy levels might have beneficial effects for patients receiving long-term VPA therapy, especially in children who have other potential risk factors for vascular diseases. Further studies are needed to investigate serum ADMA and Hcy levels, and the presence of vascular disease, as well as the potential interactions between serum ADMA levels and seizure control.

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The C677T mutation in the methylenetetrahydrofolate reductase gene contributes to hyperhomocysteinemia in patients taking anticonvulsants

Cited by 43 publications

References 9 publications

Increased homocysteine levels in valproate-treated patients with epilepsy: a meta-analysis

Increased homocysteine levels in valproate-treated patients with epilepsy: a meta-analysis

Sex differences in the prevalence and clinical correlates of hyperhomocysteinemia in patients with bipolar disorder

Serum asymmetric dimethylarginine (ADMA), homocysteine, vitamin B12, folate levels, and lipid profiles in epileptic children treated with valproic acid

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