耐藥性癲癇及其分子遺傳學機制研究_Journal of Epilepsy

Authors：

吳華敏 ¹ ,  續蕾 ²

1. ;
2. ;

Corresponding?author：

續蕾, Email: xiaoxu19821982@163.com

Keywords：

耐藥性癲癇; 分子遺傳學; 藥物轉運蛋白; 離子通道; 藥物代謝酶

DOI：

10.7507/2096-0247.20190074

Video：

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盡管近年來，大量新型抗癲癇藥物涌現，但仍有超過 1/3 的癲癇患者癥狀沒有得到有效控制，發展成為耐藥性癲癇。未經控制的癲癇可導致多種行為和精神障礙，造成患者的死亡率升高和生活質量降低。針對耐藥性癲癇的特定生物學機制進行精準醫療，能夠有效提高抗癲癇藥物的有效性和耐受度。文章主要從分子遺傳學的角度，對耐藥性癲癇的研究進展作一綜述。

Citation： 吳華敏, 續蕾. 耐藥性癲癇及其分子遺傳學機制研究. Journal of Epilepsy, 2019, 5(6): 458-462. doi: 10.7507/2096-0247.20190074 Copy

1.	Thurman DJ, Beghi E, Begley CE, et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia, 2011, 52(Suppl 7): 2-26.
2.	Hirtz D, Thurman DJ, Gwinn-Hardy K, et al. How common are the "common" neurologic disorders? Neurology, 2007, 68(5): 326-337.
3.	Chen Z, Brodie MJ, Liew D, et al. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol, 2018, 75(3): 279-286.
4.	Nickels KC, Zaccariello MJ, Hamiwka LD, et al. Cognitive and neurodevelopmental comorbidities in paediatric epilepsy. Nat Rev Neurol, 2016, 12(8): 465-476.
5.	Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on therapeutic strategies. Epilepsia, 2010, 51(6): 1069-1077.
6.	Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology, 2012, 78(20): 1548-1554.
7.	Kalilani L, Sun X, Pelgrims B, et al. The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia, 2018, 59(12): 2179-2193.
8.	Wang GX, Wang DW, Liu Y, et al. Intractable epilepsy and the P-glycoprotein hypothesis. Int J Neurosci, 2016, 126(5): 385-392.
9.	Volk HA, Loscher W. Multidrug resistance in epilepsy: rats with drug-resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures. Brain, 2005, 128(Pt 6): 1358-1368.
10.	Cox DS, Scott KR, Gao H, et al. Effect of P-glycoprotein on the pharmacokinetics and tissue distribution of enaminone anticonvulsants: analysis by population and physiological approaches. J Pharmacol Exp Ther, 2002, 302(3): 1096-1104.
11.	Aronica E, Gorter JA, Ramkema M, et al. Expression and cellular distribution of multidrug resistance-related proteins in the hippocampus of patients with mesial temporal lobe epilepsy. Epilepsia, 2004, 45(5): 441-451.
12.	Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA, 2004, 101(26): 9861-9866.
13.	Coulter DA. Mossy fiber zinc and temporal lobe epilepsy: pathological association with altered "epileptic" gamma-aminobutyric acid a receptors in dentate granule cells. Epilepsia, 2000, 41(Suppl 6): 96-99.
14.	Loscher W, Brandt C. Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research. Pharmacol Rev, 2010, 62(4): 668-700.
15.	Grewal GK, Kukal S, Kanojia N, et al. Effect of oxidative stress on ABC transporters: contribution to epilepsy pharmacoresistance. Molecules, 2017, 22(3): E365.
16.	Garbelli R, Frassoni C, Condorelli DF, et al. Expression of connexin 43 in the human epileptic and drug-resistant cerebral cortex. Neurology, 2011, 76(10): 895-902.
17.	Kim WJ, Lee JH, Yi J, et al. A nonsynonymous variation in MRP2/ABCC2 is associated with neurological adverse drug reactions of carbamazepine in patients with epilepsy. Pharmacogenet Genomics, 2010, 20(4): 249-256.
18.	Puranik YG, Birnbaum AK, Marino SE, et al. Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy. Pharmacogenomics, 2013, 14(1): 35-45.
19.	Qu J, Zhou BT, Yin JY, et al. ABCC2 polymorphisms and haplotype are associated with drug resistance in Chinese epileptic patients. CNS Neurosci Ther, 2012, 18(8): 647-651.
20.	Seo T, Ishitsu T, Ueda N, et al. ABCB1 polymorphisms influence the response to antiepileptic drugs in Japanese epilepsy patients. Pharmacogenomics, 2006, 7(4): 551-561.
21.	Kwan P, Wong V, Ng PW, et al. Gene-wide tagging study of association between ABCB1 polymorphisms and multidrug resistance in epilepsy in Han Chinese. Pharmacogenomics, 2009, 10(5): 723-732.
22.	Hung CC, Ho JL, Chang WL, et al. Association of genetic variants in six candidate genes with valproic acid therapy optimization. Pharmacogenomics, 2011, 12(8): 1107-1117.
23.	Shahwan A, Murphy K, Doherty C, et al. The controversial association of ABCB1 polymorphisms in refractory epilepsy: an analysis of multiple SNPs in an Irish population. Epilepsy Res, 2007, 73(2): 192-198.
24.	Tate SK, Depondt C, Sisodiya SM, et al. Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci USA, 2005, 102(15): 5507-5512.
25.	Daci A, Beretta G, Vllasaliu D, et al. Polymorphic variants of SCN1A and EPHX1 influence plasma carbamazepine concentration, metabolism and pharmacoresistance in a population of kosovar albanian epileptic patients. PLoS One, 2015, 10(11): e0142408.
26.	Bertok S, Dolzan V, Goricar K, et al. The association of SCN1A p. Thr1067Ala polymorphism with epilepsy risk and the response to antiepileptic drugs in slovenian children and adolescents with epilepsy. Seizure, 2017, 51: 9-13.
27.	Tate SK, Singh R, Hung CC, et al. A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose. Pharmacogenet Genomics, 2006, 16(10): 721-726.
28.	Zhou BT, Zhou QH, Yin JY, et al. Effects of SCN1A and GABA receptor genetic polymorphisms on carbamazepine tolerability and efficacy in Chinese patients with partial seizures: 2-year longitudinal clinical follow-up. CNS Neurosci Ther, 2012, 18(7): 566-572.
29.	Ma CL, Wu XY, Zheng J, et al. Association of SCN1A, SCN2A and ABCC2 gene polymorphisms with the response to antiepileptic drugs in Chinese han patients with epilepsy. Pharmacogenomics, 2014, 15(10): 1323-1336.
30.	Haerian BS, Baum L, Kwan P, et al. SCN1A, SCN2A and SCN3A gene polymorphisms and responsiveness to antiepileptic drugs: a multicenter cohort study and meta-analysis. Pharmacogenomics, 2013, 14(10): 1153-1166.
31.	Kumari R, Lakhan R, Garg RK, et al. Pharmacogenomic association study on the role of drug metabolizing, drug transporters and drug target gene polymorphisms in drug-resistant epilepsy in a north Indian population. Indian J Hum Genet, 2011, 17(Suppl 1): 32-40.
32.	Thorn CF, Whirl-Carrillo M, Leeder JS, et al. PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics, 2012, 22(6): 466-470.
33.	Chung WH, Chang WC, Lee YS, et al. Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA, 2014, 312(5): 525-534.
34.	Dorado P, Lopez-Torres E, Penas-Lledo EM, et al. Neurological toxicity after phenytoin infusion in a pediatric patient with epilepsy: influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms. Pharmacogenomics J, 2013, 13(4): 359-361.
35.	Argikar UA, Cloyd JC, Birnbaum AK, et al. Paradoxical urinary phenytoin metabolite (S)/(R) ratios in CYP2C19^1/^2 patients. Epilepsy Res, 2006, 71(1): 54-63.
36.	Ortega-Vazquez A, Dorado P, Fricke-Galindo I, et al. CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy. Pharmacogenomics J, 2016, 16(3): 286-292.
37.	Smith RL, Haslemo T, Refsum H, et al. Impact of age, gender and CYP2C9/2C19 genotypes on dose-adjusted steady-state serum concentrations of valproic acid-a large-scale study based on naturalistic therapeutic drug monitoring data. Eur J Clin Pharmacol, 2016, 72(9): 1099-1104.
38.	Kosaki K, Tamura K, Sato R, et al. A major influence of CYP2C19 genotype on the steady-state concentration of n-desmethyl clobazam. Brain Dev, 2004, 26(8): 530-534.
39.	Wang P, Yin T, Ma HY, et al. Effects of CYP3A4/5 and ABCB1 genetic polymorphisms on carbamazepine metabolism and transport in Chinese patients with epilepsy treated with carbamazepine in monotherapy and bitherapy. Epilepsy Res, 2015, 117: 52-57.
40.	Talwar P, Kanojia N, Mahendru S, et al. Genetic contribution of CYP1A1 variant on treatment outcome in epilepsy patients: a functional and interethnic perspective. Pharmacogenomics J, 2017, 17(3): 242-251.
41.	Chang Y, Yang LY, Zhang MC, et al. Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of northern nhina. Eur J Clin Pharmaco, 2014, 70(8): 941-946.
42.	Milosheska D, Lorber B, Vovk T, et al. Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: influence of polymorphism of UDP-glucuronosyl transferases and drug transporters. Br J Clin Pharmacol, 2016, 82(2): 399-411.
43.	Wen ZP, Fan SS, Du C, et al. Influence of acylpeptide hydrolase polymorphisms on valproic acid level in Chinese epilepsy patients. Pharmacogenomics, 2016, 17(11): 1219-1225.
44.	Guo Y, Hu C, He X, et al. Effects of UGT1A6, UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy. Drug Metab Pharmacokine, 2012, 27(5): 536-542.
45.	Krishnaswamy S, Hao Q, Al-Rohaimi A, et al. UDP glucuronosyl transferase (UGT) 1A6 pharmacogenetics: II. functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S). J Pharmacol Exp Ther, 2005, 313(3): 1340-1346.
46.	Mei S, Feng W, Zhu L, et al. Genetic polymorphisms and valproic acid plasma concentration in children with epilepsy on valproic acid monotherapy. Seizure, 2017, 51: 22-26.

1. Thurman DJ, Beghi E, Begley CE, et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia, 2011, 52(Suppl 7): 2-26.
2. Hirtz D, Thurman DJ, Gwinn-Hardy K, et al. How common are the "common" neurologic disorders? Neurology, 2007, 68(5): 326-337.
3. Chen Z, Brodie MJ, Liew D, et al. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol, 2018, 75(3): 279-286.
4. Nickels KC, Zaccariello MJ, Hamiwka LD, et al. Cognitive and neurodevelopmental comorbidities in paediatric epilepsy. Nat Rev Neurol, 2016, 12(8): 465-476.
5. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on therapeutic strategies. Epilepsia, 2010, 51(6): 1069-1077.
6. Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology, 2012, 78(20): 1548-1554.
7. Kalilani L, Sun X, Pelgrims B, et al. The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia, 2018, 59(12): 2179-2193.
8. Wang GX, Wang DW, Liu Y, et al. Intractable epilepsy and the P-glycoprotein hypothesis. Int J Neurosci, 2016, 126(5): 385-392.
9. Volk HA, Loscher W. Multidrug resistance in epilepsy: rats with drug-resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures. Brain, 2005, 128(Pt 6): 1358-1368.
10. Cox DS, Scott KR, Gao H, et al. Effect of P-glycoprotein on the pharmacokinetics and tissue distribution of enaminone anticonvulsants: analysis by population and physiological approaches. J Pharmacol Exp Ther, 2002, 302(3): 1096-1104.
11. Aronica E, Gorter JA, Ramkema M, et al. Expression and cellular distribution of multidrug resistance-related proteins in the hippocampus of patients with mesial temporal lobe epilepsy. Epilepsia, 2004, 45(5): 441-451.
12. Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA, 2004, 101(26): 9861-9866.
13. Coulter DA. Mossy fiber zinc and temporal lobe epilepsy: pathological association with altered "epileptic" gamma-aminobutyric acid a receptors in dentate granule cells. Epilepsia, 2000, 41(Suppl 6): 96-99.
14. Loscher W, Brandt C. Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research. Pharmacol Rev, 2010, 62(4): 668-700.
15. Grewal GK, Kukal S, Kanojia N, et al. Effect of oxidative stress on ABC transporters: contribution to epilepsy pharmacoresistance. Molecules, 2017, 22(3): E365.
16. Garbelli R, Frassoni C, Condorelli DF, et al. Expression of connexin 43 in the human epileptic and drug-resistant cerebral cortex. Neurology, 2011, 76(10): 895-902.
17. Kim WJ, Lee JH, Yi J, et al. A nonsynonymous variation in MRP2/ABCC2 is associated with neurological adverse drug reactions of carbamazepine in patients with epilepsy. Pharmacogenet Genomics, 2010, 20(4): 249-256.
18. Puranik YG, Birnbaum AK, Marino SE, et al. Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy. Pharmacogenomics, 2013, 14(1): 35-45.
19. Qu J, Zhou BT, Yin JY, et al. ABCC2 polymorphisms and haplotype are associated with drug resistance in Chinese epileptic patients. CNS Neurosci Ther, 2012, 18(8): 647-651.
20. Seo T, Ishitsu T, Ueda N, et al. ABCB1 polymorphisms influence the response to antiepileptic drugs in Japanese epilepsy patients. Pharmacogenomics, 2006, 7(4): 551-561.
21. Kwan P, Wong V, Ng PW, et al. Gene-wide tagging study of association between ABCB1 polymorphisms and multidrug resistance in epilepsy in Han Chinese. Pharmacogenomics, 2009, 10(5): 723-732.
22. Hung CC, Ho JL, Chang WL, et al. Association of genetic variants in six candidate genes with valproic acid therapy optimization. Pharmacogenomics, 2011, 12(8): 1107-1117.
23. Shahwan A, Murphy K, Doherty C, et al. The controversial association of ABCB1 polymorphisms in refractory epilepsy: an analysis of multiple SNPs in an Irish population. Epilepsy Res, 2007, 73(2): 192-198.
24. Tate SK, Depondt C, Sisodiya SM, et al. Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci USA, 2005, 102(15): 5507-5512.
25. Daci A, Beretta G, Vllasaliu D, et al. Polymorphic variants of SCN1A and EPHX1 influence plasma carbamazepine concentration, metabolism and pharmacoresistance in a population of kosovar albanian epileptic patients. PLoS One, 2015, 10(11): e0142408.
26. Bertok S, Dolzan V, Goricar K, et al. The association of SCN1A p. Thr1067Ala polymorphism with epilepsy risk and the response to antiepileptic drugs in slovenian children and adolescents with epilepsy. Seizure, 2017, 51: 9-13.
27. Tate SK, Singh R, Hung CC, et al. A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose. Pharmacogenet Genomics, 2006, 16(10): 721-726.
28. Zhou BT, Zhou QH, Yin JY, et al. Effects of SCN1A and GABA receptor genetic polymorphisms on carbamazepine tolerability and efficacy in Chinese patients with partial seizures: 2-year longitudinal clinical follow-up. CNS Neurosci Ther, 2012, 18(7): 566-572.
29. Ma CL, Wu XY, Zheng J, et al. Association of SCN1A, SCN2A and ABCC2 gene polymorphisms with the response to antiepileptic drugs in Chinese han patients with epilepsy. Pharmacogenomics, 2014, 15(10): 1323-1336.
30. Haerian BS, Baum L, Kwan P, et al. SCN1A, SCN2A and SCN3A gene polymorphisms and responsiveness to antiepileptic drugs: a multicenter cohort study and meta-analysis. Pharmacogenomics, 2013, 14(10): 1153-1166.
31. Kumari R, Lakhan R, Garg RK, et al. Pharmacogenomic association study on the role of drug metabolizing, drug transporters and drug target gene polymorphisms in drug-resistant epilepsy in a north Indian population. Indian J Hum Genet, 2011, 17(Suppl 1): 32-40.
32. Thorn CF, Whirl-Carrillo M, Leeder JS, et al. PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics, 2012, 22(6): 466-470.
33. Chung WH, Chang WC, Lee YS, et al. Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA, 2014, 312(5): 525-534.
34. Dorado P, Lopez-Torres E, Penas-Lledo EM, et al. Neurological toxicity after phenytoin infusion in a pediatric patient with epilepsy: influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms. Pharmacogenomics J, 2013, 13(4): 359-361.
35. Argikar UA, Cloyd JC, Birnbaum AK, et al. Paradoxical urinary phenytoin metabolite (S)/(R) ratios in CYP2C19^*1/^*2 patients. Epilepsy Res, 2006, 71(1): 54-63.
36. Ortega-Vazquez A, Dorado P, Fricke-Galindo I, et al. CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy. Pharmacogenomics J, 2016, 16(3): 286-292.
37. Smith RL, Haslemo T, Refsum H, et al. Impact of age, gender and CYP2C9/2C19 genotypes on dose-adjusted steady-state serum concentrations of valproic acid-a large-scale study based on naturalistic therapeutic drug monitoring data. Eur J Clin Pharmacol, 2016, 72(9): 1099-1104.
38. Kosaki K, Tamura K, Sato R, et al. A major influence of CYP2C19 genotype on the steady-state concentration of n-desmethyl clobazam. Brain Dev, 2004, 26(8): 530-534.
39. Wang P, Yin T, Ma HY, et al. Effects of CYP3A4/5 and ABCB1 genetic polymorphisms on carbamazepine metabolism and transport in Chinese patients with epilepsy treated with carbamazepine in monotherapy and bitherapy. Epilepsy Res, 2015, 117: 52-57.
40. Talwar P, Kanojia N, Mahendru S, et al. Genetic contribution of CYP1A1 variant on treatment outcome in epilepsy patients: a functional and interethnic perspective. Pharmacogenomics J, 2017, 17(3): 242-251.
41. Chang Y, Yang LY, Zhang MC, et al. Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of northern nhina. Eur J Clin Pharmaco, 2014, 70(8): 941-946.
42. Milosheska D, Lorber B, Vovk T, et al. Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: influence of polymorphism of UDP-glucuronosyl transferases and drug transporters. Br J Clin Pharmacol, 2016, 82(2): 399-411.
43. Wen ZP, Fan SS, Du C, et al. Influence of acylpeptide hydrolase polymorphisms on valproic acid level in Chinese epilepsy patients. Pharmacogenomics, 2016, 17(11): 1219-1225.
44. Guo Y, Hu C, He X, et al. Effects of UGT1A6, UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy. Drug Metab Pharmacokine, 2012, 27(5): 536-542.
45. Krishnaswamy S, Hao Q, Al-Rohaimi A, et al. UDP glucuronosyl transferase (UGT) 1A6 pharmacogenetics: II. functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S). J Pharmacol Exp Ther, 2005, 313(3): 1340-1346.
46. Mei S, Feng W, Zhu L, et al. Genetic polymorphisms and valproic acid plasma concentration in children with epilepsy on valproic acid monotherapy. Seizure, 2017, 51: 22-26.

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耐藥性癲癇及其分子遺傳學機制研究

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