الفهرس 
Introduction
EpilepsyOnly 14 pages are availabe for public view
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Abstract
Epilepsy is the most common and severe neurological disease affecting large percent of world population most of them in working age groups, with increased risk of mortality, psychological and socioeconomic consequences impairing quality of life.
Pharmacoresistant epilepsy exhibited in more than 40 % of epilepsy patients, despite development of several new antiepileptic drugs (AEDs). In Egypt (at Al-Kharga District, New Valley) the prevalence of PRE was 0.7/1000 which is relatively high and requires proper study of etiological factors that may contribute in this disabling health problem.
The current study aimed at identification of gene mutations (polymorphism) that may be the causative factor for PRE and identify if first degree relatives are at higher risk for future development of epilepsy than healthy non relative control, in addition to quantitative measurement of plasma amino acids that could greatly affect brain health and excitability state.
The present study is a case control study was carried out on 135 subjects divided into three groups: 45 patients with drug resistant epilepsy (group A), 45 first degree healthy relatives (group B), and 45 age and sex matched healthy non relative control (group C).
Amino acid profile was quantitatively estimated in the plasma of epileptic patients, healthy relatives and non-relative control groups in a trial to find a relationship between level of different amino acids and PRE. Firstly, the excitatory amino acid glutamate was found significantly higher in patients than control groups that may indicate a positive association between neuronal hyperexcitability of epilepsy and glutamate and aspartate. Inhibitory amino acids were significantly increased that may be attributed to dysfunction of their receptors at inhibitory synapse. Branched chain amino acids except for leucine were low in patients compared to healthy controls, that may explain the loss of protective role of BCAAs on neurons that increases firing threshold so decrease excitability. Moreover, taurine level found to be lower in patients than controls, the finding that goes parallel to previous concepts proposed that, taurine has a protective role on neurons.
Single nucleotide polymorphism (SNP) genotyping assay was done for Gephyrin (GPHN) T/C (rs928553) and CYP2C9 G/A (rs12782374) in patients and both control groups by real time polymerase chain reaction (PCR) using snp genotyping assay.
The current study concluded that genetic polymorphisms of antiepileptic drug- metabolizing enzyme CYP2C9 play a key role in the variability in pharmacokinetics and pharmacodynamics of AEDs, and affected their efficacy and duration of action; the finding that proved by the highly significant difference in estimated risk in mutated genotype G/A in patients compared to other control groups.
Gephyrin which is a master organizer of inhibitory synapse is essential for regulating neuronal excitability by clustering of GABA and glycine receptors at post synaptic density. So it is not surprising to be proved by the current study that single nucleotide polymorphism disrupting the GPHN protein structure identified at a high significant difference in patients compared to both control groups that indicate that it may be a causative agent or risk factor for development of PRE.
The etiology of epilepsy is a major determinant of clinical course and prognosis, yet the current classifications of epilepsy do not list etiology in any detail. Moreover, the treatment of pharmacoresistant epilepsy will remain incomplete without better understanding of the underlying cellular and molecular mechanisms of the disease.
Based on the fact that knowledge of the intrinsic and extrinsic factors that influence expression and function of the responsible enzymes for drug metabolism is a prerequisite for predicting variable pharmacokinetics and drug response. The current study concluded that many factors as ( difference in clinical types of epilepsy, severity of fits, age at onset based on gender, consanguinity in parents, in addition to other risk factors that increase probability of developing epilepsy) were more evident in relative than non-relative control, the findings that correlated with previous studies.
Finally, interaction between environmental and genetic factor is essential for expression of the mutant protein and the current study tried to link both environmental risk factors and molecular mechanisms that could greatly help in proper treatment.1. Through analysis of risk factors, clinical and therapeutic history of patients with pharmacoresistant epilepsy is an essential need for all cases as it allow for proper diagnosis and exclusion of metabolic causes of seizures.
2. Genotyping should be done for all patients of pharmacoresistant epilepsy for presence of variants of CYP2C9 and Gephyrin gene allow for better understanding of cellular and molecular mechanisms of therapeutic failure and impaired inhibitory synaptic function that contribute in pathogenesis of PRE.
3. The multi-faceted nature of PRE dictates a multidisciplinary approach to future research and therapeutic interventions.
4. Development of novel, targeted therapeutic approaches based on biochemical markers is more recommended than traditional non effective multidrug therapy with sever adverse effects.
5. There is an urgent need to develop novel pharmacological approaches and non-pharmacological interventions such as local drug delivery, cell transplantation, and gene-based therapies