Abstracts

Analysis of MDR1 polymorphisms in children with drug-resistant epilepsy

Abstract number : 1.106;
Submission category : 4. Clinical Epilepsy
Year : 2007
Submission ID : 7232
Source : www.aesnet.org
Presentation date : 11/30/2007 12:00:00 AM
Published date : Nov 29, 2007, 06:00 AM

Authors :
C. von Stuelpnagel1, 5, H. Plischke2, R. Gruber3, P. Zill4, C. Bäumel5, H. Holthausen5, G. Kluger5

Rationale: Investigation of a possible association between pharmacoresistance to antiepileptic drugs and MDR1- polymorphisms C3435T, C1236T and G2677T/A in children with epilepsy?Methods: 231 patients were recruited (130 male (56.3%), mean age 11.5 y.): ● 160 patients (69.3%) with drug-resistant epilepsy (> 3AED, not seizure free and/or after epilepsy-surgery); ● 71 patients (30.7%) in the control group (seizure free > 6 month). Genomic DNA was extracted from 4 ml EDTA-blood and the MDR 1-polymorphisms for C3435T, C1236T and G2677T/A were determined by PCR and snapshot technique Results: 1.In our study the MDR1-polymorphisms C3435T, G2677T/A and C1236T were not associated with a drug-resistant epilepsy in children (s. table 1) (in accordance with the Hardy-Weinberg-Equilibrium 2.With regard to possible haplotype-combinations the following were observed without an association for pharmacoresistance in decreasing frequency: CGC/TTT, CGT/TTT, TTT/TTT, CGC/CGC and CGC/CGT. 3.Only the AED CBZ showed a significant difference regarding the side-effect tiredness. It occurred more often in the TT-group of the C3435T-polymorphism (P= 0.035; Odds Ratio =12.25; CI: 1.27 – 118.43). After applying Bonferroni correction the results were no longer statistically significant. 4.Regarding the development of tolerance for AED in the C3435T-polymorphism there was not a statistically significant difference in the TT-group and the CC-group. Conclusions: In concordance with the results of Kim (1), Tan (4) and Sills (3) we could not confirm Siddiqui’s (2) observed association between the CC-genotype of the MDR1 and the development of a drug-resistant epilepsy. Our study did also fail to confirm an association between the haplotypes CGC, CGT and TTT and the occurrence of therapy-resistant epilepsy as reported by Zimprich et al. (5). We noticed a possible correlation between the occurrence of tiredness as side-effect and the TT-genotype of the C3435T-polymorphism. After applying Bonferroni correction the results were no longer statistically significant. In this respect this polymorphism could be a candidate in further studies investigating the pharmacokinetic interference in combination with other drugtransporterproteins. Literature: (1) Kim YO, Kim MK, Woo YJ et al. Single nucleotide polymorphisms in the multidrug resistance 1 gene in Korean epileptics. Seizure. 2006;15:67-72. (2)Siddiqui A, Kerb R, Weale ME et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med. 2003;348:1442-8. (3)Sills GJ, Mohanraj R, Butler E et al. Lack of association between the C3435T polymorphism in the human multidrug resistance (MDR1) gene and response to antiepileptic drug treatment. Epilepsia. 2005;46:643-7. (4)Tan NC, Heron SE, Scheffer IE et al. Failure to confirm association of a polymorphism in ABCB1 with multidrug-resistant epilepsy. Neurology. 2004;63:1090-2 (5)Zimprich F, Sunder-Plassmann R, Stogmann Eet al. Association of an ABCB1 gene haplotype with pharmacoresistance in temporal lobe epilepsy. Neurology. 2004;63:1087-9
Clinical Epilepsy