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
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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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