Association between two functional SNPs of SCN1A gene and efficacy of carbamazepine monotherapy for focal seizures in Chinese Han epileptic patients

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1 中南大学学报 ( 医学版 ) J Cent South Univ (Med Sci) 2014, 39(5) ARTICLES 论著 DOI: /j.issn Association between two functional SNPs of SCN1A gene and efficacy of carbamazepine monotherapy for focal seizures in Chinese Han epileptic patients WANG Ping 1,2, ZHOU Qiuhong 3, SHENG Yanghao 1,2, TANG Beisha 4, LIU Zhaoqian 5, ZHOU Boting 1,2,5 (1. Department of Pharmacy, Xiangya Hospital, Central South University, Changsha ; 2. School of Pharmaceutical Sciences, Central South University, Changsha ; 3. Department of Endocrinology, Xiangya Hospital, Central South University, Changsha ; 4. Department of Neurology, Xiangya Hospital, Central South University, Changsha ; 5. Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha , China) ABSTRACT KEY WORDS Objective: To investigate whether single nucleotide polymorphisms (SNPs) of rs and rs of the sodium channel α-subunit type 1 (SCN1A) gene affect the efficacy of carbamazepine (CBZ) treatment for seizures in Chinese Han epileptic patients. Methods: SNP rs and rs of the SCN1A gene from 628 patients were genotyped. CBZ monotherapy was administered to the subjects with new-onset partial seizures. The efficacy was defined as the decrease in the number of seizures. Four semi-quantitative levels were used to assess the efficacy: seizure-free (SF), >75% seizure decrease (SD), 50% 75% SD, and <50% SD in the number of seizures compared with patients initial conditions. Results: After the 12 month treatment with CBZ monotherapy, the rate of SF patients with G allele of the SNP rs was significantly lower than that in patients with the AA genotype (P=0.003). The heterozygote and homozygote of the G allele at SNP rs predicted the low SF rate (OR=2.101, 95% CI ). Marginal significance was observed between the dichotomous efficacy of SF and non-sf in 3 partial seizure types (P=0.028). Conclusion: rs is significantly associated with the efficacy of CBZ monotherapy in Chinese Han epileptic patients. SCN1A; SNP; carbamazepine; efficacy; epilepsy Date of reception: Biography: WANG Ping, postgraduate student, mainly engaged in the research of clinical pharmacy. Corresponding author: ZHOU Boting, botingzhou0918@126.com Foundation item: This work was supported by the National Natural Science Foundation of China ( ) and the Hunan Provincial Natural Science Foundation of China (12JJ6083).

2 434 中南大学学报 ( 医学版 ), 2014, 39(5) 中国汉族部分发作癫痫患者中 SCN1A 基因的两个功能性位点与卡马西平单药治疗疗效的相关性研究 王萍 1,2, 周秋红 3, 盛阳昊 1,2, 唐北沙 4, 刘昭前 5 1,2,5, 周伯庭 ( 中南大学 1. 湘雅医院药学部, 长沙 ;2. 药学院, 长沙 ; 3. 湘雅医院内分泌科, 长沙 ;4. 湘雅医院神经内科, 长沙 ; 5. 临床药理研究所, 遗传药理学湖南省重点实验室, 长沙 ) [ 摘要 ] 目的 : 观察 SCN1A 基因 rs 和 rs 两功能性位点突变对卡马西平抗癫痫疗效的影响 方法 : 研究对象为 628 位癫痫患者, 对 rs 和 rs 两位点进行基因分型, 卡马西平单药治疗新发作的部分发作患者, 与患者起始病情比较, 采用四分类标准对抗癫痫疗效进行半定量 : 发作完全控制, 发作减少 >75%, 发作减少 50%~75%, 发作减少 <50% 结果:351 位患者完成了 12 个月单药治疗 rs 位点 G 等位基因携带者发作完全控制率显著低于 AA 型个体 (P=0.003), 对于发作完全控制和不完全控制二分类疗效, 也表明 G 等位基因为影响疗效的风险因子 结论 :rs 位点与卡马西平抗癫痫的疗效显著相关 [ 关键词 ] SCN1A; 单核苷酸多态性 ; 卡马西平 ; 疗效 ; 癫痫 Epilepsy is the second most common chronic neurological symptom in humans and is characterized by the provoking occurrence of one or more seizure episodes. More than 50 million people worldwide suffer from various types of epilepsy [1]. In China, the morbidity rate is approximately 0.7% and more than nine million people are affected [2-3]. Various environmental factors potentially contribute to the susceptibility to epilepsy [4] while genetic factors [5-8] also play a crucial role. Clinically, therapeutic response may vary from one patient to another, even for patients who display the same syndromes. These differences in therapeutic efficacy are probably influenced by genetic factors. SCN1A is a susceptibility gene for some Mendelian epileptic disorders such as generalized epilepsy with febrile seizure plus [9-14] and encodes the Nav1.1 protein, a molecular target for carbamazepine, phenytoin and other anti-epileptic drugs (AEDs). Mutations in this ion channel gene have been reported to associate with AED effectiveness [15-17]. Previous studies [18-21] reported that many SCN1A gene mutations caused the occurrence of epileptic seizures. Some mutations [18-21] might cause functional deficiency in SCN1A. Recently, Ebrahimi [22] reported that allelic A/G natural distribution frequency of SNP rs , a missense mutation, was significantly correlated with familial epileptic susceptibility in Iranian. Lakhan [16] pointed out that AG genotype frequency of rs was significantly higher in epilepsy patients in the north than other regions in India. Additionally, Abe et al [15] found that the resistance of epileptic patients to CBZ therapy was remarkably correlated with SCN1A rs G/A polymorphism, a splicing mutations, which causes a simultaneous substitution of three amino acids. These results indicate that the structure changes in sodium channel α-subunit type 1 due to amino acid sequence substitution may cause diversity of its function and AED efficacy. CBZ is one of the most important first-line AED used to treat partial-onset seizures in China. CBZ has a broad antiepileptic spectrum and is used to treat partial and complex partial seizures, as well as secondary generalizations. Usually, the decrease of seizure frequency is used to assess the efficacy of CBZ treatment for epilepsy. In clinical practice, CBZ monotherapy is usually administered even though partial-onset patients may not be SF after treatment. Our previous researches reported rs G/ A mutation significantly affect the retention rate and maintenance dose of CBZ monotherapy for epilepsy patients in the Chinese Han population [23]. In the current study, we tried to clarify the relationship between genetic polymorphisms of SNP rs and rs , and the efficacy of CBZ treatment for epilepsy patients. 1 Subjects and methods 1.1 Ethics approval The consent was obtained from every participant before the beginning of the study. The study protocol was approved by the Ethics Committee of Xiangya School of Medicine, Central South University. In the meantime, our

3 SCN1A polymorphism and carbamazepine monotherapy WANG Ping, et al. 435 study was registered in Chinese Clinical Trial Registry and the clinical trial registration number is ChiCTR- TCH ( accessed September 21st 2009). 1.2 Subjects A total of 628 new onset and eligible Chinese Han patients (407 males, 221 females) were recruited between April 2008 and November These participants with consecutive idiopathic focal epilepsy were diagnosed by two neurologists from Xiangya Hospital in the Hunan Province of China. They suffered from either simple partial, complex partial seizures, or secondary generalization according to the International League against Epilepsy Classification (1981; 1989) [2, 24]. Their age ranged from12 to 66 years. The epilepsy patients were included or excluded according to the previously published criteria [23]. No subject had previously received treatment with CBZ prior to entry into the study. Patients demographic and clinical data were collected from questionnaires and medical records in the first month and then every 3 months until the end of the study. The collected information included age, sex, and past seizure history. Subject demographic and clinical characteristics are listed in Table 1. Table 1 Demographic and clinical characteristics of participants before and after 12 months of CBZ monotherapy Characteristics n Before treatment After treatment Male Female Male Female Physical index 628 Age/years 25.8± ± ± ±12.9 Height/cm 165± ± ± ±7.1 Weight/kg 61.3± ± ± ±8.2 BMI/(kg/m 2 ) 24.6± ± ± ±3.7 Seizure types Simple partial (66.7%) 60(33.3%) Complex partial (64.2%) 91(35.8%) Secondary generalization (63.9%) 70(36.1%) EEG test Normal 159(63.6%) 91(36.4%) 149(63.4%) 86(36.6%) Epileptiform 247(65.3%) 131(34.7%) 71(61.2%) 45(38.8%) CBZ dose and serum level 351 CBZ dose /mg 510± ±180 CBZ concentration/ (μg/ml) 5.5± ±2.0 Tolerability Retention (62.7%) 131(37.3%) Non-retention (67.5%) 90(32.5%) Seizure decrease* 351 Seizure-free (61.9%) 74(38.1%) >75% seizure decrease 58 38(65.5%) 20(34.5%) 50%-75% seizure decrease 52 32(61.5%) 20(38.5%) <50% seizure decrease 47 30(63.8%) 17(36.2%) Non-retention 277 Allergies 22 13(59.1%) 9(48.9%) CNS effects 65 43(66.2%) 22(33.8%) Poor seizure decrease (68.9%) 59(31.1%) BMI: Boby mass index; EEG: Electroencephalography; CNS: Central nervous system. * Comparison of seizure decrease rates between the last 3-month and initial 3-month of CBZ treatment

4 436 中南大学学报 ( 医学版 ), 2014, 39(5) Treatment protocol All participants were administered CBZ monotherapy after recruitment and were visited every 3 months for a 12-month period. After the start of CBZ therapy, patients compliance with treatment, the frequency of seizures, and the administered dosages were recorded. The adolescents were given an initial dosage of 200 mg/d with a weekly increase of 100 mg until an appropriate dose was reached. Adults and elders were given an initial dosage of 200 mg/d with a daily increase of 100 mg until a target value. CBZ dosages and serum levels, electroencephalographic (EEG), imaging data [such as computed tomography (CT) and brain magnetic resonance imaging (MRI)], and hematological parameters were also obtained. The dosage of CBZ was increased for those who suffered epileptic recurrence. Adverse side effects and any adjuvant therapy for these side effects, which cause discontinued CBZ medication, were evaluated. The patients were switched to another AED treatment in the case of serious adverse side effects or treatment resistance. 1.4 Definition and evaluation of drug efficacy In this study, we focused on the efficacy, which is the decrease of seizure frequency after CBZ treatment. Efficacy was defined as the proportional decrease in the number of seizures between the first and last 3 months of the 12-month treatment period. The seizure frequency from the start to the end-point was checked by patient set-report, seizure diary, or guardian report. Four semi-quantitative levels were used to assess the efficacy: seizure-free (SF), >75% seizure decrease (SD), 50% 75% SD, and <50% SD in the number of seizures, according to protocols of previous studies [2, 25-27]. 1.5 DNA extraction and genotyping Subjects DNA was extracted from the peripheral blood of the patients using phenol-chloroform. All DNA samples were shipped to GenScript (Nanjing) Co., Ltd., where the SNPs were genotyped by the ABI 3730xl 96-capillary DNA analyzer according to the manufacturer s instructions. 1.6 Clinical laboratory tests All blood samples were collected at 8:30 am after an overnight fasting. CBZ serum level was measured by highperformance liquid chromatography (HPLC, HP 1100, Agilent Technologies, USA). Hematological parameters were measured by the Beckman Coulter LH750 Hematology Analyzer (Beckmann Coulter, Brea, USA). CT (Definition, Siemens, Germany), MRI (Signa HDxt 3.0T, GE, USA), and EEG (EEG-9200K, Nihon Kohden, Japan) were performed on the subjects. Body mass index (BMI) was defined as the individual s body weight divided by the square of his or her height. All clinical tests were performed at the Department of Clinical Biochemistry and the Radiology Department, Xiangya Hospital, Central South University. 1.7 Statistical analysis All analyses were conducted using the Statistical Package for Social Sciences, version 18.0 (SPSS Inc, Chicago, Illinois). The Pearson s χ 2 test was used to assess the differences of the genotypic/allelic frequencies among subjects and the comparisons between the efficacy of different genotypes of SNP rs and rs Analysis of variance (ANOVA) was used to assess the differences between quantitative variables. Population pyramid was used to investigate the frequency distribution of different age intervals. A stepwise multivariate binary logistic regression analysis was used to assess the relation between the rates of SF/non- SF and alleles of A/G of rs after adjustment for the potential confounding factors. Test of significance was twotailed, and alpha was set at Results 2.1 Characteristics of the subjects and tag SNPs Table 1 listed the clinical characteristics of the 628 subjects prior to CBZ treatment and after 12 months of CBZ treatment. Of the 628 participants, 351 patients [male/female (M/F): 220/131] continued CBZ monotherapy over the entire 12-month period. The rest 277 participants (M/F: 187/90) dropped out of the study due to various reasons, including poor efficacy (190 cases, M/F: 131/59), adverse central nervous system effects (65 cases, M/F: 43/22) and allergic reaction (22 cases, M/F: 13/9)(Figure 1). For the 351 patients who were retained in the study, the daily CBZ dose was (511±179) mg [male (510±179) mg, female (510±180) mg], and the CBZ serum level was (5.5±1.7) μg/ml [male (5.5±1.8) mg, female (5.4±2.0) mg]. One hundred ninety four patients (M/F: 120/74, 55.3%) achieved SF; 58 (M/F: 38/20, 16.5%) had an efficacy of >75% SD; 52 (M/F: 32/20, 14.8%) had an efficacy of 50% 75% SD; and 47 (M/F: 30/17, 13.4%) had an efficacy of <50% SD. Two candidate SNPs and their basic characteristics were shown in Table 2. Their genotype distributions were consistent with the Hardy-Weinberg equilibrium test. The minor allele frequency ranged from10.0% to 50.0%. The genotype call rates of the 2 SNPs were between 99.0% and 100.0%.

5 SCN1A polymorphism and carbamazepine monotherapy WANG Ping, et al new on-set patients 3-month follow-ups: 563 retention patients 6-month follow-ups: 488 retention patients 9-month follow-ups: 393 retention patients 65 drop-out: allergies 11 (7 males/4 females), CNS effects 20 (13 males/7 females), poor seizure decrease 34 (24 males/10 females) 75 drop-out: allergies 9 (5 males/4 females), CNS effects 20 (14 males/6 females), poor seizure decrease 46 (31 males/15 females) 95 drop-out: allergies 2 (1 male/1 female), CNS effects 15 (9 males/6 females), poor seizure decrease 78(55 males/23 females) 42 drop-out: CNS effects 10 (7 males/3 females), poor seizure decrease 32 (21 males/11 females) 12-month follow-ups: 351 retention patients Figure 1 Flowchart of participation in the study Table 2 Characteristics of Tag SNPs of SCN1A gene (n=628) SNP Genomic Genetic Allele Call Function MAF/% HWE P position/bp* position (major/minor) rate References rs exon A/G missense Thr>Ala [16] rs intron G/A splice site [12] Allele: Major/minor allele; MAF: Minor allele frequency; HWE P: P value for Hardy-Weinberg equilibrium analysis using Pearson s χ 2 test; *Number of location (bp) from (accessed June 12 th 2011) 2.2 Comparison of rates of partial seizure and retention between males and females Considering the cohort s larger age span, we depicted the population distribution of the different age interval of patients with partial seizures and retention patients after 12-month CBZ monotherapy. Figure 2 indicated that, in the diagnosis cohort, either male or female, the population displayed a Pyramid-type attenuation with progressively increasing age. Meanwhile, male patients had significantly higher rates than female ones for ages (Figure 2A). Likewise, the retention patients had significantly higher rates than female ones for ages (Figure 2B). 2.3 Marginal significance of efficacy associated with patients initial seizure types Except the initial seizure types, we did not collect other data of patients seizure types during the therapeutic periods. Among the patients initial seizure types, the rate of SF was 65.7% for patients with simple partial, 52.9% for patients with complex partial and 48.2% for patients with secondary generalization, respectively. We did not observe significant association between three types of partial seizure and the rates of

6 438 中南大学学报 ( 医学版 ), 2014, 39(5) four semi-quantitative categories using the Pearson s χ 2 test (P=0.261, Table 3). However, we found a marginal significance between three types of partial seizure and the efficacy of dichotomous SF and non-sf using the Pearson s χ 2 test (P=0.028, Table 3). A B Figure 2 Comparison of partial-seizure rates between male and female patients divided into different age intervals in diagnostic cohort (A) and retention cohort (B) Table 3 Association between patients initial seizure types and the various levels of efficacy after 12-month CBZ treatment (n=351) Levels of efficacy n Simple partial (n=105) Complex partial (n=138) Secondary generalization (n=108) Seizure-free (65.7%) 73(52.9%) 52(48.2%) 0.261* Non-seizure-free (34.3%) 65(47.1%) 56(51.8%) >75% SD 58 14(13.3%) 25(18.1%) 19(17.6%) 50% 75% SD 52 11(10.5%) 22(15.9%) 19(17.6%) <50% SD 47 11(10.5%) 18(13.0%) 18(16.7%) SD: Seizure decrease; Non-seizure-free: Sum of >75% seizure decrease, 50% 75% seizure decrease, and <50% seizure decrease; * Association between rates of four semi-quantitative categories of efficacy and three initial seizure types using Pearson s χ 2 test; Association between rates of dichotomous seizure-free/non-seizure-free and three initial seizure types using Pearson s χ 2 test P 2.4 Correlation between rs A/G polymorphism and CBZ efficacy Those patients, who completed at least 12 months of CBZ treatment, were stratified according to CBZ efficacy, genotype, and allele rate for all SNPs. Of the two target SNPs, we only observed a significant association between CBZ efficacy and rs A/G polymorphism (Table 4). Considering the limited sample size, we did not further stratify the cohort according to the subjects gender. Among 351 retention patients, the genotype carriers of AA, AG, and GG of rs were 262, 85, and 4, respectively. We combined the AG and GG genotype carriers together for comparison with AA genotype carriers under dominant model. The SF rate in the carriers of G allele heterozygote or homozygote was 41.6%, significantly lower than that in AA genotype carriers (59.9%, Table 4) using Pearson s χ 2 test (37/52 vs 157/105 for SF/non-SF in carriers of the G allele and AA genotype, respectively; P=0.003; Table 4). The SF rate in A allele was significantly higher than that in G allele with Pearson s χ 2 test (349/260 vs 39/54, P=0.005, Table 4). A marginally significant difference was identified between the SF rate in carriers with AA genotype and that in the combination of AG and GG genotypes after 12-month CBZ medication (P=0.026, Table 4). Similarly, a significance was identified between the SF rate of A allele carriers and that of G allele carriers (P=0.049, Table 4). These results showed that SNP rs affected the efficacy of CBZ treatment for epilepsy and the G allele could be a risk factor for the occurrence of non-sf.

7 SCN1A polymorphism and carbamazepine monotherapy WANG Ping, et al. 439 Table 4 Association between efficacy and SNPs after 12-month CBZ treatment (n=351) Levels of efficacy Seizure-free (n=194) Non-seizurefree (n=157) >75% SD (n=58) 50% 75% SD (n=52) AA AG+GG P A (n=609) (n=262) (n=89) rs G/A rs G/A G AA GA P (n=93) (n=100) (n=164) GG A G P (n=87) (n=364) (n=338) * (59.9%) (41.6%) (57.3%) (41.9%) (50.9%) (54.9%) (55.20%) (55.5%) (55.0%) (40.1%) (58.4%) (42.7%) (58.1%) (49.1%) (45.1%) (44.8%) (44.5%) (45.0%) (14.5%) (22.4%) (15.8%) (21.5%) (15.5%) (15.9%) (17.2%) (16.5%) (16.6%) (13.7%) (18.0%) (14.3%) (18.3%) (12.7%) (15.2%) 14.9%)) (14.6%) (15.1%) P <50% SD (n=47) (11.8%) (18.0%) (12.6%) (18.3%) (11.9%) (14.0%) (12.6%) (13.4%) (13.3%) SD: Seizure decrease; Non-seizure-free: Sum of >75% seizure decrease, 50% 75% seizure decrease, and <50% seizure decrease; * Association between rates of four semi-quantitative categories of efficacy and genotypes grouped into AA and AG+GG using Pearson s χ 2 test; Association between rates of dichotomous seizure-free/non-seizure-free and genotypes grouped into AA and AG+GG using Pearson s χ 2 test; Association between rates of four semi-quantitative categories of efficacy and alleles of A and G using Pearson s χ 2 test; Association between rates of dichotomous seizure-free/non-seizure-free and alleles of A and G using Pearson s χ 2 test; Association between rates of four semi-quantitative categories of efficacy and genotypes grouped into AA, GA and GG using Pearson s χ 2 test; A ssociation between rates of dichotomous seizurefree/non-seizure-free and genotypes grouped into AA, GA and GG using Pearson s χ 2 test 3 Discussion In this study, we investigated how the SCN1A gene polymorphism affected the efficacy of CBZ treatment in partial-seizure patients. The rs A/G polymorphism appears to be significantly correlated with the efficacy of CBZ treatment for epileptic seizures. In spite of its beneficial use in the treatment of seizures, CBZ may produce adverse side effects in patients, such as cytopenias, elevated levels of lipid and transaminases, allergic reactions, and central nervous system effects. Thus, complete blood counts and basic chemistry panels are routinely performed in patients taking CBZ while physical examinations and patient questioning can also detect the presence of adverse side effects. SNP rs A/G is a common polymorphism in the SCN1A exon region. rs A to G variant causes the conversion of threonine to alanine, which may influence the structure and functional properties of ion channels, and further impacts the CBZ s treatments for epilepsy. Ebrahimi et al [22] reported that natural occurrence of allelic A/G frequency in rs was 0.71/0.29 in epilepsy patients from 34 unrelated Iranian families and 0.52/0.48 in healthy control groups. This result indicated A allele might predict a susceptibility for epilepsy although the A allele frequency in the patients is not significantly higher than that in the healthy control in the limited sample size. Lakhan et al [16] reported that AG genotype frequency of rs was significantly higher in epilepsy patients in the north Indian population. Although Kwan et al [28] thought that rs A/G polymorphism was not significantly associated with drug resistance in Han Chinese epileptic patients, our data revealed that there was a significant association between rs A/ G polymorphism and the different levels of efficacy of SD. This discrepancy may be based on the inconsistent criterion of efficacy in the two different cohorts. Due to shortage of electrophysiologic and pharmacological data, it was difficult to elucidate how the changes of ion channel structure affect functional properties. We noticed that, in the diagnosis cohort, the partialseizure rate in male population was significantly higher than that in the female. Additionally, we also found the patients initial seizure types affected the efficacy CBZ monotherapy. So far, the reasons for these correlations are elusive. There are some limitations in this study. First, we did not obtain the data of dosage forms of CBZ (standard tablet or sustained-release tablet). CBZ standard tablet normally causes a serum drug peak level, which likely contributes to adverse effects, whereas sustained-release tablet does not cause serum drug peak level, possibly

8 440 中南大学学报 ( 医学版 ), 2014, 39(5) reducing adverse effects. This may affect the decrease of seizure number. Second, we did not obtain the titration data (to gradually rectify the dosage to the appropriate value) of the CBZ treatment. The determination of optimal CBZ dosage would take a long time through trial and error, which is regarded to be correlated with adverse effect [29-30]. Third, the sample size in this study was not very large. Nevertheless, none of these factors would have affected our ultimate conclusion. In summary, our findings validated that the genetic polymorphism of rs A/G in SCN1A was associated with the efficacy of CBZ treatment to epileptic patients of Chinese Han. Patients with AA genotype of SNP rs A/G enjoyed a significantly higher rate of SF. Results from the study may be beneficial for personalized CBZ treatment to epileptic patients in clinical practice. Acknowledgements WANG Ping performed sample collection and analyzed data; ZHOU Qiuhong performed sample collection; SHENG Yanghao analyzed data; ZHAO Yingchun wrote the paper; TANG Beisha designed the research; XU Xiaojing analyzed the data; QU Jian wrote the paper; LIU Zhaoqian designed the research; ZHOU Boting performed sample collection and designed the research. We also thank the patients and volunteers for their support in the study and the medical staff from Xiangya Hospital of Hunan Province, China for their help and collaboration. References 1. Duncan JS, Sander JW, Sisodiya SM, et al. Adult epilepsy[ J]. Lancet, 2006, 367(9516): Zhou BT, Zhou QH, Yin JY, et al. Effects of SCN1A gene and GABA receptor genetic polymorphisms on carbamazepine tolerability and efficacy in Chinese patients with partial seizures: 2-year longitudinal clinical follow-up[ J]. CNS Neuroscience & Therapeutics, 2012, 18(7): Wang WZ, Wu JZ, Wang DS, et al. The prevalence and treatment gap in epilepsy in China: an ILAE/IBE/WHO study[ J]. Neurology, 2003, 60(9): Stewart I. Environmental risk factors for temporal lobe epilepsy is prenatal exposure to the marine algal neurotoxin domoic acid a potentially preventable cause?[ J]. Med Hypotheses, 2010, 74(3): Soundararajan CC, Adhin A, Tripathi M, et al. Association of CYP2D6 100 C > T and 2850 C > T polymorphisms with generalized tonic clonic seizures among Indians[ J]. J Neural Transm, 2006, 113(12): Michelucci R, Mecarelli O, Bovo G, et al. A de novo LGI1 mutation causing idiopathic partial epilepsy with telephone-induced seizures[ J]. Neurology, 2007, 68(24): Song J, Tanouye M. Role for para sodium channel gene 3' UTR in the modification of Drosophila seizure susceptibility[ J]. Dev Neurobiol, 2007, 67(14): Gloria-Bottini F, Lucarelli P, Saccucci P, et al. Genetic polymorphism and idiopathic generalized epilepsy. Evidence of interaction between haptoglobin and ACP1 systems[ J]. Neuropediatrics, 2008, 39(6): Escayg A, MacDonald BT, Meisler MH, et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2[ J]. Nat Genet, 2000, 24(4): Heron SE, Scheffer IE, Iona X, et al. De novo SCN1A mutations in Dravet syndrome and related epileptic encephalopathies are largely of paternal origin[ J]. J Med Genet, 2011, 47(2): Martin MS, Dutt K, Papale LA, et al. Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acidergic (GABAergic) interneuron abnormalities[ J]. J Biol Chem, 2011, 285(13): Schlachter K, Gruber-Sedlmayr U, Stogmann E, et al. A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures[ J]. Neurology, 2009, 72(11): Pham X, Sun C, Chen X, et al. Association study between GABA receptor genes and anxiety spectrum disorders[ J]. Depress Anxiety, 2009, 26(11): Pun FW, Zhao C, Lo WS, et al. Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor beta(2) subunit[ J]. Mol Psychiatry, 2011, 16(5): Abe T, Seo T, Ishitsu T, et al. Association between SCN1A polymorphism and carbamazepine-resistant epilepsy[ J]. Br J Clin Pharmacol, 2008, 66(2): Lakhan R, Kumari R, Misra UK, et al. Differential role of sodium channels SCN1A and SCN2A gene polymorphisms with epilepsy and multiple drug resistance in the north Indian population[ J]. Br J Clin Pharmacol, 2009, 68(2): Tate SK, Singh R, Hung CC, et al. A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose[ J]. Pharmacogenet Genomics, 2006, 16(10): Cossette P, Loukas A, Lafreniere RG, et al. Functional characterization of the D188V mutation in neuronal voltage-gated sodium channel causing generalized epilepsy with febrile seizures plus (GEFS)[ J]. Epilepsy Res, 2003, 53(1/2):

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