Hyperhomocysteinemia in Children Treated with Antiepileptic Drugs Is Normalized by Folic Acid Supplementation

Abstract

Summary:Purpose: To assess the prevalence of hyperhomocysteinemia in pediatric patients treated with antiepileptic drugs (AEDs) and to evaluate the effect of folic acid supplementation on plasma total homocysteine (tHcy) concentrations in hyperhomocysteinemic patients.Methods: 123 patients from three regional hospitals participated in the study. Patients with hyperhomocysteinemia were included in a 3-month double-blind randomized trial testing oral folic acid supplementation (1 mg/day) versus placebo.Results: Hyperhomocysteinemia (tHcy >10.4 µmol/L) was present in 19 of 123 patients. Patients with hyperhomocysteinemia were older (13.7 ± 4 vs. 11.0 ± 3.9 years) and had significantly lower folate and cobalamin concentrations. Multidrug (two or more) AED treatment and duration of therapy correlated significantly with elevated total homocysteine (tHcy) and low folate. In contrast, polymorphisms in the methylene tetrahydrofolate reductase gene (MTHFR 677 C→T, 1298 A→C, 1793 G→A) had no significant impact on tHcy. Nine of 19 patients with hyperhomocysteinemia were randomized to placebo, whereas the remaining 10 patients received folic acid supplementation. Folic acid supplementation resulted in a significant increase of folate and decrease of tHcy, whereas both parameters remained unchanged in the placebo group.Conclusions: Hyperhomocysteinemia is present in 15.5% of children receiving long-term AED treatment. Multidrug treatment and long duration of therapy enhance the risk for hyperhomocysteinemia. Folic acid supplementation significantly reduces tHcy. We recommend assessment of serum folate and plasma tHcy in children receiving AEDs.

Total Homocysteine, Folate, and Cobalamin, and Their Relation to Genetic Polymorphisms, Lifestyle and Body Mass Index in Healthy Children and Adolescents

“…Moreover, the impact of genetic polymorphisms, vitamin concentrations and exogenous factors on tHcy in children has not yet been studied in detail. Since safe and cost effective strategies for prevention and treatment of hyperhomocysteinemia are well established (7,15), the present study is aimed at investigating tHcy, defining hyperhomocysteinemia and identifying factors influencing tHcy concentrations in a pediatric population. Therefore genetic polymorphisms, folate, Cbl, body mass index (BMI), blood pressure (BP), cholesterol, triglycerides, creatinine and lifestyle factors were investigated in a population of 264 young individuals.…”

Hyperhomocysteinämie und B-Vitaminmangel bei neurologischen und psychiatrischen Erkrankungen

“…Die Einnahme der meisten klassischen Antiepileptika (Phenobarbital, Carbamazepin, Primidon, Valproat und Phenytoin) kann eine Hcy-Erhçhung auslçsen [135 -137], während dies nicht bei neueren Präparaten wie Lamotrigin oder Pergabalin beobachtet wurde [138]. Multimedikamentçse Behandlung und Langzeittherapie erhçhen das Risiko für HHcy [134]. Es gibt verschiedene Erklärungen für die Assoziation von HHcy mit antiepileptischen Pharmaka.…”

“…Der gestçrte Folat-Metabolismus erklärt wahrscheinlich die hç-here Rate an kongenitalen Mißbildungen bei Kindern von Müt-tern mit Antikonvulsivaeinnahme im ersten Trimester [144]. Eine orale Folsäure-Supplementation (1 mg/Tag) bei Kindern reduzierte erhçhte Hcy-Spiegel (> 10,4 ìmol/l) nach 6 bis 12 Wochen Behandlung signifikant [134]. Die Behandlung von Epileptikern mit Folatmangel mit 5 mg/Tag Folsäure über 1 -3 Jahre verbesserte deutlich die kognitiven Parameter, die Konzentrationsfähigkeit, die Stimmung und das Sozialverhalten [145].…”

Phenobarbital-Associated Bone Marrow Aplasia: A Case Report and Review of the Literature

“…AEDs are synergic with the C677T mutation in the methylenetetrahydrofolate reductase gene [48], but folate deficiency is promptly reversed by folate supplementation [49]. Other authors have reported myelodysplastic features in association with VPA [50].…”