Anti-Epileptic drug treatment in children: Hyperhomocysteinaemia, B-Vitamins and the 677C→T Mutation of the Methylenetetrahydrofolate Reductase Gene

doi:10.1053/ejpn.2000.0379

European Journal of Paediatric Neurology

Volume 4, Issue 6, November 2000, Pages 269-277

https://doi.org/10.1053/ejpn.2000.0379 Get rights and content

Abstract

The aim of the study was to observe the influence of carbamazepine and valproic acid on plasma total homocysteine and B-vitamin status and the gene–drug interaction with the 677C→T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. Plasma total homocysteine concentrations were determined in 136 epileptic children taking anti-epileptic drugs as monotherapy. Nutritional (folate, B₁₂and B₆vitamins) and genetic (MTHFR 677 C→T) determinants of plasma homocysteine were studied in a random sample of 59 of the 136 epileptic children. Total homocysteine concentrations were significantly increased (p<0.05) and folate and vitamin B₆levels were significantly decreased (p<0.01) in the children taking anti-epileptic drugs compared with our reference ranges. In the carbamazepine-treated group, significantly positive correlation was found between duration of treatment and homocysteine concentration (p<0.01). Homocysteine concentrations showed a significantly negative correlation with vitamin levels (folate: p=0.002, and vitamin B12 : p=0.017) only in the carbamazepine treated group. In children treated with carbamazepine up to 3 years, total homocysteine concentration correlated negatively only with folate (p=0.003), while in patients treated for more than 3 years, total homocysteine correlated negatively only with vitamin B₁₂values (p=0.007). The lowering action of carbamazepine treatment on folate levels seems to be associated with hyperhomocysteinaemia, which seems to be related to the homozygous condition for the MTHFR 677C→T mutation. Valproic acid treatment, although also associated with hyperhomocysteinaemia, only shows a lowering effect on vitamin B₆levels, which seems to be independent of the MTHFR genotype.

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Cited by (65)

Glutamatergic synapse protein composition of wild-type mice is sensitive to in utero MTHFR genotype and the timing of neonatal vigabatrin exposure
2015, European Neuropsychopharmacology
The enzyme methylenetetrahydrofolate-reductase (MTHFR) is part of the homocysteine and folate metabolic pathways. In utero, Mthfr-deficient environment has been reported as a risk factor for neurodevelopmental disorders such as autism and neural tube defects. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between Mthfr deficiency and neonatal exposure to the GABA-potentiating drug vigabatrin (GVG) in mice alters anxiety, memory, and social behavior in a gender-dependent manner. In addition, a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the cerebral cortex was shown. Here we show that in utero MTHFR deficiency is sufficient to alter the levels of glutamate receptor subunits GluR1, GluR2, and NR2B in the cerebral cortex and hippocampus of adult offspring with a WT genotype. In addition, FMRP1, CAMKII α and γ, and NLG1 levels in WT offspring were vulnerable to the in utero genotype. These effects depend on brain region and the cellular compartment tested. The effect of in utero MTHFR deficiency varies with the age of neonatal GVG exposure to modify GluR1, NR2A, reelin, CAMKII α, and NLG1 levels. These changes in molecular composition of the glutamatergic synapse were associated with increased anxiety-like behavior.
Complex, multifactorial disorders of the nervous system show significant association with several genetic and environmental factors. Our data exemplify the contribution of an in utero MTHFR-deficient environment and early exposure to an antiepileptic drug to the basal composition of the glutamatergic synapses. The robust effect is expected to alter synapse function and plasticity and the cortico-hippocampal circuitry.
Atherosclerosis in epilepsy: Its causes and implications
2014, Epilepsy and Behavior
Evidence from epidemiological, longitudinal, prospective, double-blinded clinical trials as well as case reports documents age-accelerated atherosclerosis with increased carotid artery intima media thickness (CA–IMT) in patients with epilepsy. These findings raise concern regarding their implications for age-accelerated cognitive and behavioral changes in midlife and risk of later age-related cognitive disorders including neurodegenerative processes such as Alzheimer's disease (AD). Chronic epilepsy, cerebral atherosclerosis, and age-related cognitive disorders including AD share many clinical manifestations (e.g. characteristic cognitive deficits), risk factors, and structural and pathological brain abnormalities. These shared risk factors include increased CA–IMT, hyperhomocysteinemia (HHcy), lipid abnormalities, weight gain and obesity, insulin resistance (IR), and high levels of inflammatory and oxidative stresses. The resulting brain structural and pathological abnormalities include decreased volume of the hippocampus, increased cortical thinning of the frontal lobe, ventricular expansion and increased white matter ischemic disease, total brain atrophy, and β-amyloid protein deposition in the brain. The knowledge that age-accelerated atherosclerosis may contribute to age-accelerated cognitive and behavioral abnormalities and structural brain pathologies in patients with chronic epilepsy represents an important research path to pursue future clinical and management considerations.
Vascular function and risk factors in children with epilepsy: Associations with sodium valproate and carbamazepine
2014, Epilepsy Research
Citation Excerpt :
Patients with epilepsy have vascular risk factors (Elliott et al., 2007; Hamed et al., 2007) including abnormal lipids, insulin, elevated oxidative stress and elevated total plasma homocyst(e)ine (tHcy). This increase in vascular risk is postulated to result from AED therapy (Apeland et al., 2002; Apeland and Mansoor, 2003; Attilakos et al., 2006; Aydin et al., 2005; Elliott et al., 2007; Hamed et al., 2007; Isojärvi et al., 1994; Karabiber et al., 2003; Pylvänen et al., 2006; Tomoum et al., 2008; Verrotti et al., 1998, 2000; Vilaseca et al., 2000). Elevated tHcy, a risk factor for atherosclerosis, is common in individuals on AED therapy (Apeland et al., 2002; Apeland and Mansoor, 2003; Attilakos et al., 2006; Belcastro et al., 2010; Chuang et al., 2012; Coppola et al., 2012; Hamed et al., 2007; Karabiber et al., 2003; Sener et al., 2006; Verrotti et al., 2000; Vilaseca et al., 2000).
To investigate biochemical cardiovascular risk factors and vascular endothelial function and structure in children with epilepsy on antiepileptic drugs (AEDs), particularly sodium valproate (VPA) and carbamazepine (CBZ).
Individuals with epilepsy have increased risk factors for vascular disease, particularly lipid abnormalities and elevated total plasma homocyst(e)ine (tHcy). AED induced B-vitamin deficiencies have been suggested to contribute to this risk. Vitamin B supplementation has consequently been recommended for children on AEDs. Early vascular endothelial dysfunction and atherosclerosis are detectable by measuring flow-mediated dilation (FMD) and intima-media thickness (IMT).
Thirty children with epilepsy on AEDs (13.3 ± 2.3 years, 14 male) and 30 controls (13.9 ± 2.9 years, 14 male) were recruited. Fasting tHcy, folate, pyridoxal-5-phosphate (PLP), vitamin B12, glucose and lipids were measured. Vascular function and structure were assessed using FMD (brachial artery) and IMT (carotid/aortic arteries).
No differences were found between children with epilepsy and controls for tHcy, folate, PLP, lipids, FMD, carotid or aortic IMT. Vitamin B12 levels were elevated and glucose reduced in children treated with VPA. Elevated total cholesterol, cholesterol/HDL ratio and triglycerides occurred in children treated with CBZ. Aortic IMT correlated with weight (r = 0.75, p < 0.001), BMI (r = 0.54, p = 0.01), and HDL cholesterol (r = −0.58, p = 0.006).
We found no early changes in vascular function or structure in children on valproate or carbamazepine. We were also unable to confirm previous reports of tHcy abnormalities in this group. This may be due to higher B-vitamin intake, which compensates for loss of vitamins induced by this AED therapy. Vitamin supplementation in children with epilepsy on valproate and carbamazepine is not required in populations with adequate dietary intake of B vitamins.
Association between methylenetetrahydrofolate reductase C677T polymorphism and epilepsy susceptibility: A meta-analysis
2014, Seizure
Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been implicated as a potential risk factor for epilepsy. To date, many case–control studies have investigated the association between MTHFR C677T polymorphism and epilepsy susceptibility. However, those findings were inconsistent. The objective of this study is to evaluate the precise association between MTHFR C677T polymorphism and epilepsy.
An electronic search of PubMed, EMBASE for papers on the MTHFR C677T polymorphism and epilepsy susceptibility was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association.
Ten case–control studies containing 1713 cases and 1867 controls regarding MTHFR C677T polymorphism were selected. A significant association between the MTHFR C677T polymorphism and epilepsy susceptibility was revealed in this meta-analysis (for T vs. C: OR = 1.19, 95% CI = 1.08–1.32; for TT + CT vs. CC: OR = 1.20, 95% CI = 1.05–1.38; for TT vs. CC: OR = 1.48, 95% CI = 1.20–1.83; for TT vs. CT + CC: OR = 1.35, 95% CI = 1.12–1.64). In subgroup analysis by ethnicity, the results also indicated the association between the MTHFR C677T polymorphism and epilepsy susceptibility within the Asian populations (for T vs. C: OR = 1.55, 95% CI = 1.15-2.07; for TT + CT vs. CC: OR = 1.67, 95% CI = 1.08-2.59; for TT vs. CC: OR = 2.33, 95% CI = 1.30-4.20; for TT vs. CT + CC: OR = 1.89, 95% CI = 1.12-3.18).
The results indicated that MTHFR C677T polymorphism was associated with an increased risk of epilepsy. However, further studies in various regions are needed to confirm the findings from this meta-analysis.
Assessment of atherosclerosis risk due to the homocysteine-asymmetric dimethylarginine-nitric oxide cascade in children taking antiepileptic drugs
2013, Seizure
Citation Excerpt :
The proposed mechanisms responsible for vitamin depletion in patients under AED treatment can be summarised as interference with vitamin absorption from the intestinal mucosa, increased requirements of vitamins due to dysfunction in Hcy metabolism, and the induction of liver enzymes responsible for increased vitamin metabolism.20,27 There are also contrary reports in the literature revealing unchanged or increased levels of these vitamins in patients taking AEDs.28–31 In our study, no vitamin B12 or folate deficiency was detected in patients receiving AEDs.
The aim of this study was to assess the atherogenicity risk of antiepileptics in children by investigating the cascade, “hyperhomocysteinemia (HHcy) → asymmetric dimethylarginine (ADMA) increase → nitric oxide (NO) decrease”, which is thought to contribute to the developmental process of atherosclerosis.
The participants included 53 epilepsy patients who received either valproic acid (VPA, n = 26) or oxcarbazepine (OXC, n = 27). Twenty-four healthy sex- and age-matched children served as controls. Fasting plasma total homocysteine (tHcy), ADMA and NO levels were measured.
The differences in Hcy, ADMA, NO, vitamin B₁₂ and folate levels between VPA, OXC and control groups were all insignificant (p > 0.05 for all). In the patient group (VPA and OXC groups), 22.6% of the children (12/53) had tHcy levels above the normal cutoff (13.1 μmol/l) for children and 17% of the children (9/53) had tHcy levels of greater than 15 μmol/l which is accepted as the critical value for an increased atherosclerosis risk (p < 0.05 for both). The difference in rate of HHcy between VPA and OXC groups was statistically insignificant (p > 0.05, for both cut off levels of HHCy). There was a positive correlation of tHcy levels and antiepileptic drug treatment duration in the patient group (r = +0.276, p < 0.05).
HHcy may develop in patients using OXC. Contrary to some previous publications, our data do not suggest that OXC is safer than VPA in terms of HHcy risk. Further prospective, large scale and longer term studies investigating all suggested pathways responsible for development of atherosclerosis due to HHcy should be conducted to define the exact mechanism responsible for AEDs related atherosclerosis.
Homocysteine, folic acid and vitamin B12 levels in serum of epileptic children
2012, Egyptian Journal of Medical Human Genetics
The relationship between increased homocysteine (Hcy) level and epileptic seizure remains controversial in human, despite a growing evidence of the pro-convulsive effect of the hyperhomocysteinemia (HHcy) observed in the animal studies. The mechanism of this association with epileptogenesis has not been clearly understood, although there is emerging evidence to support the unfavorable effects of some anti-epileptic drugs (AEDs) on the plasma homocysteine (Hcy) concentrations. The aim of this study was to uncover the relationship between the levels of homocysteine (Hcy), the cofactors involved in its metabolism as folic acid and vitamin B12 and anti-epileptic drugs (AEDs) in epileptic patients. Serum level of homocysteine (Hcy), folic acid and vitamin B12 was measured in 60 patients with idiopathic epilepsy; and its level was compared to 30 healthy children serving as control group. No significant difference was found regarding the plasma homocysteine (Hcy) levels between patients (both receiving anti-epileptics and non anti-epileptic drug users) and controls. Epileptic patients on polytherapy showed higher mean serum levels of homocysteine (Hcy) and lower mean serum levels of folic acid compared to those on monotherapy. However, the mean serum levels of homocysteine (Hcy), vitamin B12 and folic acid showed non significant differences between patients using valproic acid (VPA) or carbamazepine (CBZ). Duration of AED therapy showed a significant positive correlation with mean serum levels of homocysteine (Hcy) and a significant negative correlation with mean serum levels of folic acid. To conclude; AEDs upset the homeostatic balance of homocysteine (Hcy) and its cofactors and cause abnormalities in their serum levels.

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^f1: Correspondence: M^aAntònia Vilaseca, Servei de Bioquı́mica, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2, Barcelona, Spain e-mail:[email protected]

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Ordinary articleAnti-Epileptic drug treatment in children: Hyperhomocysteinaemia, B-Vitamins and the 677C→T Mutation of the Methylenetetrahydrofolate Reductase Gene

Abstract

Ordinary article
Anti-Epileptic drug treatment in children: Hyperhomocysteinaemia, B-Vitamins and the 677C→T Mutation of the Methylenetetrahydrofolate Reductase Gene