INFLUENCE OF THE SCN1A IVS5N + 5 G>A POLYMORPHISM ON THERAPY WITH CARBAMAZEPINE FOR EPILEPSY
Sterjev Z1,*, Kiteva G2, Cvetkovska E2, Petrov I2, Kuzmanovski I2, Ribarska TJ3, Nestorovska KA1, Matevska N1,Trajkovik-Jolevska S3, Dimovski AJ1, Suturkova, Lj1
*Corresponding Author: Zoran Sterjev, M. Sei. Pharm Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University “St. Cyril and Methodius,” str. Vodnjanska 17, 1000 Skopje, Republic of Macedonia; Tel./Fax:+38-923-120-229; E-mail: zost@ff.ukim.edu.mk
page: 19

INTRODUCTION

Voltage-gated sodium channels that are responsible for enabling neurons to fi re action potentials at a high frequency are important targets for the commonly used anti epileptic drugs such as Carbamazepine (CBZ), Oxcarbazepine, Phenytoin, Lamotrigin and Zonisamide. The -subunit of the fi rst neuronal sodium channel (SCN1A) gene regulates the activity of one of the ion channels in the brain, the sodium channel, which may exhibit different electrophysiological properties in patients with pharmacoresistant epilepsy as compared to responsive patients [1]. Carbamazepine is a commonly used anti convulsive drug for the treatment of partial, generalized tonic-clonic and mixed seizures. It blocks neuronal sodium channels in a voltage- and frequency-dependent manner, delaying their recovery from the inactivated state, reducing the number of action potentials within a burst, and decreasing burst duration. Sodium channels are heteromultimeric complexes that comprise the large (approximately 260 kDa) pore-forming -subunit and smaller accessory -subunits [2,3]. Eleven genes, designated SCN1A through SCN11A, encode the  subunit, and at least three, designated SCN1B through SCN3B, encode the -subunit [4]. A common synonymous polymorphism (SCN1A IVS5N + 5 G>A or rs3812718) exists in exon 5 of the SCN1A gene, which is associated with a requirement for maximum doses of CBZ and phenytoin [5]. Other studies have failed to establish an association between this polymorphism and dosages of CBZ and other sodium channel blockers [6-8] (Table 1). Two alternatively spliced versions of exon 5 in the SCN1A gene are present in the genomic DNA, a “neonatal” and an “adult” version, which differ in three amino acids in the fi nal product [5]. Normally, both exons are coexpressed in the adult brain. The neonatal exon can be drastically up-regulated under various circumstances including seizures, according to some studies [1]. The SCN1A IVS5N + 5 G>A polymorphism determines whether the neonatal or the adult version of exon 5 is incorporated into the fi nal gene product. The wild-type G allele allows both exons to be expressed, whereas the mutant A allele almost abolishes expression of the neonatal exon by disrupting the consensus sequence. Thus, in individuals with the GG genotype, up to 50% of the gene transcripts include the neonatal version of exon 5, compared with an often undetectable level of the neonatal version in some subjects with the AA genotype [9]. We here report on the association of the SCN1A IVS5N + 5 G>A single nucleotide polymorphism (SNP) and epilepsy, and on the effi cacy and dose-dependence of the CBZ therapy in Macedonian epileptic patients.



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