Genetic factors associated with drug-resistance of epilepsy: Relevance of stratification by patient age and aetiology of epilepsy

Abstract

Epilepsy drug-resistance may depend on the metabolism of antiepileptic drugs (AEDs), transport to the epileptic focus and/or target sensitivity. Furthermore, drug response depends on multiple characteristics of the patient, the epilepsy, and the antiepileptic drugs used. We have investigated the association between polymorphisms related to antiepileptic drug metabolism (CYP2C9, CYP2C19, and UGT), transport (ABCB1), and targets (SCN1A) both in a crude analysis and after adjusting by clinical factors associated with drug-resistance, and stratifying by patient age or aetiology of epilepsy. Caucasian outpatients (N=289), children (N=80) and adolescent-adults (N=209), with idiopathic (N=69), cryptogenic (N=97) or symptomatic epilepsies (N=123) were selected when they had either drug-resistance (with at least four seizures over the previous year after treatment with more than three appropriate AEDs at appropriate doses) or drug responsiveness (without seizures for at least a year). Samples were genotyped by allelic discrimination using TaqMan probes. No significant association between polymorphisms and drug-resistance was found either in the crude analysis or in the adjusted analysis. However, adults with the ABCB1_3435TT or 2677TT genotypes had a lower risk of drug-resistance than those with the CC or the GG genotypes. Furthermore, patients with symptomatic epilepsies with the ABCB1_3435CT or TT genotypes had a lower risk of drug-resistance than those with the CC genotype. An opposite but insignificant tendency was found in children and in idiopathic epilepsies. Although replication studies will be needed to confirm our results, they suggest that stratification by patient age and by the aetiology of epilepsy could contribute to unmask the association between ABCB1 polymorphisms and drug-resistance of epilepsy.

ABCB1 gene polymorphisms is not associated with drug-resistant epilepsy in Romanian children

“…These results are in contradiction with data published by Sanchez et al where this association was present but in symptomatic, not in idiopathic epilepsies. [4] A highly significant linkage disequilibrium was shown among exons 12, 21, 26 in MDR1 gene (C1236T, G2677T, C3435T). [17] Naumovska et al [32] concluded in their study that CG haplotype was over-represented in the study population, followed by TT haplotype.…”

“…Also, the genetic factors is possible to generate in structural lesions of the CNS, epileptogenic potential wich underliyng symptomatic epilepsies. [4] In 1995, Thisel et al suggested the absence of response to antiepileptic treatment to be secondary to a reduction in drug penetration into the CNS. [5] In this study the authors noticed an increased expression of MDR1 in the brain tissue of patients undergoing surgery.…”

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

“…A replication of their study in 2004 [177], however, failed to confirm the results. Subsequently, the majority of the studies on this subject have shown no significant results [178][179][180][181][182][183][184]. In a Japanese cohort, even the opposite effect was observed [185].…”

An overview on antiepileptic drugs

“…They hypothesized that polymorphisms in the drug transporter gene (CC genotype at the ABCB1 C3435T) is associated with increased expression of the ABCB1 protein which inturn influences the response to AED treatment. Although no genetic stratification is underpinned, a recent study found a significant association between ABCB1 polymorphisms and drug resistance when patients were stratified by the same type of epilepsy and/or in those treated with the same AEDs (137). Researchers' efforts might target development of AEDs that are not recognized by MDR proteins or that can evade ABCB1.…”