Dravet综合征——从癫痫性脑病到离子通道病_Journal of Epilepsy

Authors：

BrunklausA ,  ZuberiSM , 童馨 , 慕洁

Corresponding author：

ZuberiSM, Email: sammeer.zuberi@nbs.net

Keywords：

Dravet综合征; 癫痫性脑病

DOI：

10.7507/2096-0247.20160049

Video：

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编码电压门控钠通道α1亚单位(α1 subunit of the voltage gated sodium channel, SCN1A)的基因突变与多种癫痫综合征相关, 包括相对较轻的家族性全身性癫痫伴热性惊厥附加症(Genetic epilepsy with febrile seizures plus, GEFS+), 到严重的婴儿发病的Dravet综合征。已有证据显示, 大脑中不同神经元网络中SCN1A功能障碍的指向一个离子通道病模型, 使得Dravet综合征的神经科特征超越了单纯的发作相关损伤。基因改变的临床表型会随着其严重程度、个体的基因背景, 以及环境因素的不同而不同, 并且会根据离子通道的分布影响一系列神经元网络。原本就脆弱的系统可能很容易继发恶性事件, 如癫痫持续状态。离子通道模型预示着药物治疗并修复受损的γ-氨基丁酸(γ-aminobutyric acid, GABA)能神经传递也许不仅能预防癫痫发作, 还能治疗合并症。原综述研究关于在Dravet综合征中SCN1A突变的致病性, 及其对更广泛疾病表型的影响的最新证据, 并讨论了对这些特殊基因型的认识是否能影响临床实践。基因技术正在以前所未有的速度发展着, 将增加人们关于新的基因和基因间相互作用网络的知识。临床医生和遗传学家必将密切合作, 以保证基因测试结果能得到很好的解释和咨询服务

Citation： BrunklausA, ZuberiSM, 童馨, 慕洁. Dravet综合征——从癫痫性脑病到离子通道病. Journal of Epilepsy, 2016, 2(3): 264-269. doi: 10.7507/2096-0247.20160049 Copy

1.	Claes L, Del-Favero J, Ceulemans B, et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet, 2001, 68(2):1327-1332.
2.	Escayg A, MacDonal B, Meisler M, et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat Genet, 2000, 24(6):343-345.
3.	Harkin LA, Mc Mahon JM, Iona X, et al. The spectrum of SCN1Arelated infantile epileptic encephalopathies. Brain, 2007, 130(10):843-852.
4.	Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain, 1997, 120(8):479-490.
5.	Zuberi SM, Brunklaus A, Birch R, et al. Genotype-phenotype associations in SCN1A related epilepsies. Neurology, 2011, 76(7):594-600.
6.	Dravet C, Bureau M, Oguni H, et al. Severe myoclonic epilepsy in infancy (Dravet syndrome). In Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P (Eds) Epileptic syndromes in infancy, childhood and adolescence. London:John Libbey, 2005:89-113.
7.	Brunklaus A, Ellis R, Reavey E, et al. Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome. Brain, 2012, 135(12):2329-2336.
8.	Ragona F, Granata T, Bernardina BD, et al. Cognitive development in Dravet syndrome:a retrospective, multicenter study of 26 patients. Epilepsia, 2011, 52(6):386-392.
9.	Nabbout R, Chemaly N, Chipaux M, et al. Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy. Orphanet J Rare Dis, 2013, 8(2):176.
10.	Chieffo D, Battaglia D, Lettori D, et al. Neuropsychological development in children with Dravet syndrome. Epilepsy Res, 2011, 95(8):86-93.
11.	Depienne C, Trouillard O, Saint-Martin C, et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome:analysis of 333 patients. J Med Genet, 2009, 46(5):183-191.
12.	Dravet C. How Dravet syndrome became a model for studying childhood genetic epilepsies. Brain, 2012, 135(10):2309-2311.
13.	Wolff M, Cass-Perrot C, Dravet C. Severe myoclonic epilepsy of infants (Dravet syndrome):natural history and neuropsychological findings. Epilepsia, 2006, 47(8):45-48.
14.	Engel J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy:report of the ILAE Task Force on Classification and Terminology. Epilepsia, 2001, 42(10):796-803.
15.	Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies:report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia, 2010, 51(10):676-685.
16.	Ogiwara I, Miyamoto H, Morita N, et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons:a circuit basis for epileptic seizures in mice carrying anScn1a gene mutation. J Neurosci, 2007, 27(3):5903-5914.
17.	Yu FH, Mantegazza M, Westenbroek RE, et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci, 2006, 9(1):1142-1149.
18.	Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev, 2005, 57(10):397-409.
19.	Skluzacek JV, Watts KP, Parsy O, et al. Dravet syndrome and parent associations:the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia, 2011, 52(8):95-101.
20.	Kalume F, Westenbroek RE, Cheah CS, et al. Sudden unexpected death in a mouse model of Dravet syndrome. J Clin Invest, 2013, 123(9):1798-1808.
21.	Auerbach DS, Jones J, Clawson BC, et al. Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. PLo S ONE, 2013, 8(10):e77843.
22.	Han S, Tai C, Westenbroek RE, et al. Autistic-like behaviour in Scn1a+/mice and rescue by enhanced GABA-mediated neurotransmission. Nature, 2012, 489(20):385-390.
23.	Brunklaus A, Dorris L, Zuberi SM. Comorbidities and predictors of health-related quality of life in Dravet syndrome. Epilepsia, 2011, 52(11):1476-1482.
24.	Bender AC, Natola H, Ndong C, et al. Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiol Dis, 2013, 54(5):297-307.
25.	Liu Y, Lopez-Santiago LF, Yuan Y, et al. Dravet syndrome patientderived neurons suggest a novel epilepsy mechanism. Ann Neurol, 2013, 74(2):128-139.
26.	Cheah CS, Westenbroek RE, Roden WH, et al. Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome. Channels, 2013, 7(3):468-472.
27.	Biella G, Di Febo F, Goffredo D, et al. Differentiating embryonic stem derived neural stem cells show a maturation-dependent pattern of voltage-gated sodium current expression and graded action potentials. Neuroscience, 2007, 149(3):38-52.
28.	Stafstrom CE. Severe epilepsy syndromes of early childhood:the link between genetics and pathophysiology with a focus on SCN1A mutations. J Child Neurol, 2009, 24(Suppl.2):15-23.
29.	Heron SE, Crossland KM, Andermann E, et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet, 2002, 360(12):851-852.
30.	Liao Y, Deprez L, Maljevic S, et al. Molecular correlates of age dependent seizures in an inherited neonatal-infantile epilepsy. Brain, 2010, 133(6):1403-1414.
31.	Nakamura K, Kato M, Osaka H, et al. Clinical spectrum ofSCN2A mutations expanding to Ohtahara syndrome. Neurology, 2013, 81(3):992-998.
32.	Ogiwara I, Ito K, Sawaishi Y, et al. De novo mutations of voltagegated sodium channel alpha 2 geneSCN2A in intractable epilepsies. Neurology, 2009, 73(10):1046-1053.
33.	Hawkins NA, Martin MS, Frankel WN, et al. Neuronal voltage-gated ion channels are genetic modifiers of generalized epilepsy with febrile seizures plus. Neurobiol Dis, 2011, 41(8):655-660.
34.	Martin MS, Tang B, Papale LA, et al. The voltage-gated sodium channelScn8a is a genetic modifier of severe myoclonic epilepsy of infancy. Hum Mol Genet, 2007, 16(6):2892-2899.
35.	Catarino CB, Liu JYW, Liagkouras I, et al. Dravet syndrome as epileptic encephalopathy:evidence from long-term course and neuropathology. Brain, 2011, 134(3):2982-3010.
36.	Kanai K, Yoshida S, Hirose S, et al. Physicochemical property changes of amino acid residues that accompany missense mutations inSCN1A affect epilepsy phenotype severity. J Med Genet, 2009, 46(3):671-679.
37.	Brunklaus A, Dorris L, Ellis R, et al. The clinical utility of anSCN1A genetic diagnosis in infantile-onset epilepsy. Dev Med Child Neurol, 2013, 55(2):154-161.
38.	Hirose S, Scheffer IE, Marini C, et al.SCN1A testing for epilepsy:application in clinical practice. Epilepsia, 2013, 54(6):946-952.
39.	Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy:a randomised placebo-controlled syndrome-dedicated trial. Lancet, 2000, 356(7):1638-1642.
40.	Guerrini R, Dravet C, Genton P, et al. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia, 1998, 39(11):508-512.
41.	Grantham R. Amino acid difference formula to help explain protein evolution. Science, 1974, 185(7):862-864.
42.	Sim NL, Kumar P, Hu J, et al. SIFT web server:predicting effects of amino acid substitutions on proteins. Nucleic Acids Res, 2012, 40(9):452-457.
43.	Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs:server and survey. Nucleic Acids Res, 2002, 3(6):3894-3900.
44.	Catterall WA. From ionic currents to molecular mechanisms:the structure and function of voltage-gated sodium channels. Neuron, 2000, 26(8):13-25.
45.	Ogiwara I, Nakayama T, Yamagata T, et al. A homozygous mutation of voltage-gated sodium channel beta subunit type 1 gene SCN1B in a patient with Dravet syndrome. Epilepsia, 2012, 53(12):200-203.
46.	Patino GA, Claes LR, Lopez-Santiago LF, et al. A functional null mutation of SCN1B in a patient with Dravet syndrome. J Neurosci, 2009, 29(9):10764-10778.
47.	Ottman R, Hirose S, Jain S, et al. Genetic testing in the epilepsies:report of the ILAE Genetics Commission. Epilepsia, 2010, 51(7):655-670.

1. Claes L, Del-Favero J, Ceulemans B, et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet, 2001, 68(2):1327-1332.
2. Escayg A, MacDonal B, Meisler M, et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat Genet, 2000, 24(6):343-345.
3. Harkin LA, Mc Mahon JM, Iona X, et al. The spectrum of SCN1Arelated infantile epileptic encephalopathies. Brain, 2007, 130(10):843-852.
4. Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain, 1997, 120(8):479-490.
5. Zuberi SM, Brunklaus A, Birch R, et al. Genotype-phenotype associations in SCN1A related epilepsies. Neurology, 2011, 76(7):594-600.
6. Dravet C, Bureau M, Oguni H, et al. Severe myoclonic epilepsy in infancy (Dravet syndrome). In Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P (Eds) Epileptic syndromes in infancy, childhood and adolescence. London:John Libbey, 2005:89-113.
7. Brunklaus A, Ellis R, Reavey E, et al. Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome. Brain, 2012, 135(12):2329-2336.
8. Ragona F, Granata T, Bernardina BD, et al. Cognitive development in Dravet syndrome:a retrospective, multicenter study of 26 patients. Epilepsia, 2011, 52(6):386-392.
9. Nabbout R, Chemaly N, Chipaux M, et al. Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy. Orphanet J Rare Dis, 2013, 8(2):176.
10. Chieffo D, Battaglia D, Lettori D, et al. Neuropsychological development in children with Dravet syndrome. Epilepsy Res, 2011, 95(8):86-93.
11. Depienne C, Trouillard O, Saint-Martin C, et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome:analysis of 333 patients. J Med Genet, 2009, 46(5):183-191.
12. Dravet C. How Dravet syndrome became a model for studying childhood genetic epilepsies. Brain, 2012, 135(10):2309-2311.
13. Wolff M, Cass-Perrot C, Dravet C. Severe myoclonic epilepsy of infants (Dravet syndrome):natural history and neuropsychological findings. Epilepsia, 2006, 47(8):45-48.
14. Engel J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy:report of the ILAE Task Force on Classification and Terminology. Epilepsia, 2001, 42(10):796-803.
15. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies:report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia, 2010, 51(10):676-685.
16. Ogiwara I, Miyamoto H, Morita N, et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons:a circuit basis for epileptic seizures in mice carrying anScn1a gene mutation. J Neurosci, 2007, 27(3):5903-5914.
17. Yu FH, Mantegazza M, Westenbroek RE, et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci, 2006, 9(1):1142-1149.
18. Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev, 2005, 57(10):397-409.
19. Skluzacek JV, Watts KP, Parsy O, et al. Dravet syndrome and parent associations:the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia, 2011, 52(8):95-101.
20. Kalume F, Westenbroek RE, Cheah CS, et al. Sudden unexpected death in a mouse model of Dravet syndrome. J Clin Invest, 2013, 123(9):1798-1808.
21. Auerbach DS, Jones J, Clawson BC, et al. Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. PLo S ONE, 2013, 8(10):e77843.
22. Han S, Tai C, Westenbroek RE, et al. Autistic-like behaviour in Scn1a+/mice and rescue by enhanced GABA-mediated neurotransmission. Nature, 2012, 489(20):385-390.
23. Brunklaus A, Dorris L, Zuberi SM. Comorbidities and predictors of health-related quality of life in Dravet syndrome. Epilepsia, 2011, 52(11):1476-1482.
24. Bender AC, Natola H, Ndong C, et al. Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiol Dis, 2013, 54(5):297-307.
25. Liu Y, Lopez-Santiago LF, Yuan Y, et al. Dravet syndrome patientderived neurons suggest a novel epilepsy mechanism. Ann Neurol, 2013, 74(2):128-139.
26. Cheah CS, Westenbroek RE, Roden WH, et al. Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome. Channels, 2013, 7(3):468-472.
27. Biella G, Di Febo F, Goffredo D, et al. Differentiating embryonic stem derived neural stem cells show a maturation-dependent pattern of voltage-gated sodium current expression and graded action potentials. Neuroscience, 2007, 149(3):38-52.
28. Stafstrom CE. Severe epilepsy syndromes of early childhood:the link between genetics and pathophysiology with a focus on SCN1A mutations. J Child Neurol, 2009, 24(Suppl.2):15-23.
29. Heron SE, Crossland KM, Andermann E, et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet, 2002, 360(12):851-852.
30. Liao Y, Deprez L, Maljevic S, et al. Molecular correlates of age dependent seizures in an inherited neonatal-infantile epilepsy. Brain, 2010, 133(6):1403-1414.
31. Nakamura K, Kato M, Osaka H, et al. Clinical spectrum ofSCN2A mutations expanding to Ohtahara syndrome. Neurology, 2013, 81(3):992-998.
32. Ogiwara I, Ito K, Sawaishi Y, et al. De novo mutations of voltagegated sodium channel alpha 2 geneSCN2A in intractable epilepsies. Neurology, 2009, 73(10):1046-1053.
33. Hawkins NA, Martin MS, Frankel WN, et al. Neuronal voltage-gated ion channels are genetic modifiers of generalized epilepsy with febrile seizures plus. Neurobiol Dis, 2011, 41(8):655-660.
34. Martin MS, Tang B, Papale LA, et al. The voltage-gated sodium channelScn8a is a genetic modifier of severe myoclonic epilepsy of infancy. Hum Mol Genet, 2007, 16(6):2892-2899.
35. Catarino CB, Liu JYW, Liagkouras I, et al. Dravet syndrome as epileptic encephalopathy:evidence from long-term course and neuropathology. Brain, 2011, 134(3):2982-3010.
36. Kanai K, Yoshida S, Hirose S, et al. Physicochemical property changes of amino acid residues that accompany missense mutations inSCN1A affect epilepsy phenotype severity. J Med Genet, 2009, 46(3):671-679.
37. Brunklaus A, Dorris L, Ellis R, et al. The clinical utility of anSCN1A genetic diagnosis in infantile-onset epilepsy. Dev Med Child Neurol, 2013, 55(2):154-161.
38. Hirose S, Scheffer IE, Marini C, et al.SCN1A testing for epilepsy:application in clinical practice. Epilepsia, 2013, 54(6):946-952.
39. Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy:a randomised placebo-controlled syndrome-dedicated trial. Lancet, 2000, 356(7):1638-1642.
40. Guerrini R, Dravet C, Genton P, et al. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia, 1998, 39(11):508-512.
41. Grantham R. Amino acid difference formula to help explain protein evolution. Science, 1974, 185(7):862-864.
42. Sim NL, Kumar P, Hu J, et al. SIFT web server:predicting effects of amino acid substitutions on proteins. Nucleic Acids Res, 2012, 40(9):452-457.
43. Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs:server and survey. Nucleic Acids Res, 2002, 3(6):3894-3900.
44. Catterall WA. From ionic currents to molecular mechanisms:the structure and function of voltage-gated sodium channels. Neuron, 2000, 26(8):13-25.
45. Ogiwara I, Nakayama T, Yamagata T, et al. A homozygous mutation of voltage-gated sodium channel beta subunit type 1 gene SCN1B in a patient with Dravet syndrome. Epilepsia, 2012, 53(12):200-203.
46. Patino GA, Claes LR, Lopez-Santiago LF, et al. A functional null mutation of SCN1B in a patient with Dravet syndrome. J Neurosci, 2009, 29(9):10764-10778.
47. Ottman R, Hirose S, Jain S, et al. Genetic testing in the epilepsies:report of the ILAE Genetics Commission. Epilepsia, 2010, 51(7):655-670.

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