SCN8A基因相關癲癇研究進展_Journal of Epilepsy

Authors：

張俊嬌 ,  蔣莉

重慶醫科大學附屬兒童醫院神經內科，國家兒童健康與疾病臨床醫學研究中心，兒童發育疾病研究教育部重點實驗室，兒科學重慶市重點實驗室（重慶 400014）;

Corresponding?author：

蔣莉, Email: dr_jiangli@126.com

Keywords：

電壓門控鈉離子通道; SCN8A; 癲癇; 基因

DOI：

10.7507/2096-0247.202111004

Video：

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SCN8A基因編碼電壓門控鈉離子通道亞基Nav1.6，該通道廣泛分布于中樞神經系統，是動作電位產生及傳導的重要分子基礎。SCN8A基因突變與一系列由輕到重的疾病表型譜相關，其中包括良性家族性嬰兒驚厥、中間型癲癇、癲癇性腦病、智力障礙、孤獨癥譜系疾病、孤立性肌陣攣等。文章旨在在提高醫務人員對SCN8A基因相關疾病認識，將圍繞發病機制、臨床特征、遺傳學特點、治療等方面進行闡述。

Citation： 張俊嬌, 蔣莉. SCN8A基因相關癲癇研究進展. Journal of Epilepsy, 2022, 8(2): 151-154. doi: 10.7507/2096-0247.202111004 Copy

1.	Gasser A, Ho T, Cheng X, et al. An ankyrinG-binding motif is necessary and sufficient for targeting Nav1. 6 sodium channels to axon initial segments and nodes of Ranvier. The Journal of neuroscience:the official journal of the Society for Neuroscience, 2012, 32(21): 7232-7243.
2.	Veeramah K, O'brien J, Meisler M, et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. American journal of human genetics, 2012, 90(3): 502-510.
3.	Gardella E, Becker F, M?ller R, et al. Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Annals of neurology, 2016, 79(3): 428-436.
4.	Johannesen K, Gardella E, Encinas A, et al. The spectrum of intermediate SCN8A-related epilepsy. Epilepsia, 2019, 60(5): 830-844.
5.	Larsen J, Carvill G, Gardella E, et al. The phenotypic spectrum of SCN8A encephalopathy. Neurology, 2015, 84(5): 480-489.
6.	Wagnon J, Barker B, Ottolini M, et al. SCN8ALoss-of-function variants of in intellectual disability without seizures. Neurology. Genetics, 2017, 3(4): e170.
7.	Butler K, Da Silva C, Shafir Y, et al. De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis. Epilepsy research, 2017, 129: 17-25.
8.	Wagnon J, Mencacci N, Barker B, et al. Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus. Human mutation, 2018, 39(7): 965-969.
9.	Johannesen K, Gardella E, Scheffer I, et al. Early mortality in SCN8A-related epilepsies. Epilepsy research, 2018, 143: 79-81.
10.	Gardella E, Marini C, Trivisano M, et al. SCN8AThe phenotype of developmental and epileptic encephalopathy. Neurology, 2018, 91(12): e1112-e1124.
11.	Kruger L, Isom L. Voltage-gated Na+ channels: not just for conduction. Cold Spring Harbor perspectives in biology, 2016, 8(6): a029264.
12.	Brunklaus A, Lal D. Sodium channel epilepsies and neurodevelopmental disorders: from disease mechanisms to clinical application. Developmental medicine and child neurology, 2020, 62(7): 784-792.
13.	Meisler M, Helman G, Hammer M, et al. SCN8A encephalopathy: Research progress and prospects. Epilepsia, 2016, 57(7): 1027-1035.
14.	Ademuwagun I, Rotimi S, Syrbe S, et al. Voltage gated sodium channel genes in epilepsy: mutations, functional studies, and treatment dimensions. Frontiers in neurology, 2021, 12: 600050.
15.	Blanchard M, Willemsen M, Walker J, et al. De novo gain- of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. Journal of medical genetics, 2015, 52(5): 330-337.
16.	Gardella E, M?ller R. Phenotypic and genetic spectrum of SCN8A-related disorders, treatment options, and outcomes. Epilepsia, 2019: S77-S85.
17.	Liu Y, Schubert J, Sonnenberg L, et al. Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability. Brain:a journal of neurology, 2019, 142(2): 376-390.
18.	Johannesen K, Liu Y, Koko M, et al. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. Brain : a journal of neurology, 2021.
19.	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 an Scn1a gene mutation. The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007, 27(22): 5903-5914.
20.	Wagnon J, Meisler M. Recurrent and Non-Recurrent Mutations of SCN8A in Epileptic Encephalopathy. Frontiers in neurology, 2015, 6: 104.
21.	Tidball A, Lopez-Santiago L, Yuan Y, et al. Variant-specific changes in persistent or resurgent sodium current in SCN8A-related epilepsy patient-derived neurons. Brain:a journal of neurology, 2020, 143(10): 3025-3040.
22.	Luo H, Xie L, Hong S, et al. The genotype and phenotype of proline-rich transmembrane protein 2 associated disorders in Chinese children. Frontiers in pediatrics, 2021, 9: 676616.
23.	Anand G, Collett-White F, Orsini A, et al. Autosomal dominant SCN8A mutation with an unusually mild phenotype. European journal of paediatric neurology:EJPN:official journal of the European Paediatric Neurology Society, 2016, 20(5): 761-765.
24.	Wang J, Gao H, Bao X, et al. SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures. BMC medical genetics, 2017, 18(1): 104.
25.	Parrini E, Marini C, Mei D, et al. Diagnostic targeted resequencing in 349 patients with drug-resistant pediatric epilepsies identifies causative mutations in 30 different genes. Human mutation, 2017, 38(2): 216-225.
26.	Bagnasco I, Dassi P, Blé R, et al. A relatively mild phenotype associated with mutation of SCN8A. Seizure, 2018, 56: 47-49.
27.	Wagnon J, Barker B, Hounshell J, et al. Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy. Annals of clinical and translational neurology, 2016, 3(2): 114-123.
28.	Denis J, Villeneuve N, Cacciagli P, et al. Clinical study of 19 patients with SCN8A-related epilepsy: Two modes of onset regarding EEG and seizures. Epilepsia, 2019, 60(5): 845-856.
29.	Mcnally M, Johnson J, Huisman T, et al. SCN8A epileptic encephalopathy: detection of fetal seizures guides multidisciplinary approach to diagnosis and treatment. Pediatric neurology, 2016, 64: 87-91.
30.	Trivisano M, Pavia G, Ferretti A, et al. Generalized tonic seizures with autonomic signs are the hallmark of SCN8A developmental and epileptic encephalopathy. Epilepsy & behavior:E& B, 2019, 96: 219-223.
31.	De Kovel C, Meisler M, Brilstra E, et al. Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy. Epilepsy research, 2014, 108(9): 1511-1518.
32.	Ohba C, Kato M, Takahashi S, et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia, 2014, 55(7): 994-1000.
33.	姚春美, 趙榮江, 鄧亞仙, 等. SCN8A基因突變相關癲癇性腦病2例報告并文獻復習. 臨床兒科雜志, 2019, 37(6): 462-465.
34.	Schreiber J, Tochen L, Brown M, et al. A multi-disciplinary clinic for SCN8A-related epilepsy. Epilepsy research, 2020, 159: 106261.
35.	Nickels K, Grossardt B, Wirrell E. Epilepsy-related mortality is low in children: a 30-year population-based study in Olmsted County, MN. Epilepsia, 2012, 53(12): 2164-2171.
36.	Keller A, Whitney R, Li S, et al. Incidence of sudden unexpected death in epilepsy in children is similar to adults. Neurology, 2018, 91(2): e107-e111.
37.	Abdel-Mannan O, Taylor H, Donner E, et al. A systematic review of sudden unexpected death in epilepsy (SUDEP) in childhood. Epilepsy & behavior:E& B, 2019, 90: 99-106.
38.	Frasier C, Wagnon J, Bao Y, et al. SCN8ACardiac arrhythmia in a mouse model of sodium channel epileptic encephalopathy. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(45): 12838-12843.
39.	Trudeau M, Dalton J, Day J, et al. Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. Journal of medical genetics, 2006, 43(6): 527-530.
40.	Canafoglia L, Franceschetti S, Granata T, et al. SCN8A splicing mutation causing skipping of the exon 15 associated with intellectual disability and cortical myoclonus. Seizure, 2020, 82: 56-58.
41.	Boerma R, Braun K, Van Den Broek M, et al. Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsy: a molecular neuropharmacological approach. Neurotherapeutics, 2016, 13(1): 192-197.
42.	M?ller R, Johannesen K. Precision medicine: SCN8A encephalopathy treated with sodium channel blockers. Neurotherapeutics, 2016, 13(1): 190-191.
43.	Atkin T, Maher C, Gerlach A, et al. A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy. Epilepsia, 2018, 59(4): 802-813.
44.	Lenk G, Jafar-Nejad P, Hill S, et al. Scn8a antisense oligonucleotide is protective in mouse models of SCN8A encephalopathy and dravet syndrome. Annals of neurology, 2020, 87(3): 339-346.

1. Gasser A, Ho T, Cheng X, et al. An ankyrinG-binding motif is necessary and sufficient for targeting Nav1. 6 sodium channels to axon initial segments and nodes of Ranvier. The Journal of neuroscience:the official journal of the Society for Neuroscience, 2012, 32(21): 7232-7243.
2. Veeramah K, O'brien J, Meisler M, et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. American journal of human genetics, 2012, 90(3): 502-510.
3. Gardella E, Becker F, M?ller R, et al. Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Annals of neurology, 2016, 79(3): 428-436.
4. Johannesen K, Gardella E, Encinas A, et al. The spectrum of intermediate SCN8A-related epilepsy. Epilepsia, 2019, 60(5): 830-844.
5. Larsen J, Carvill G, Gardella E, et al. The phenotypic spectrum of SCN8A encephalopathy. Neurology, 2015, 84(5): 480-489.
6. Wagnon J, Barker B, Ottolini M, et al. SCN8ALoss-of-function variants of in intellectual disability without seizures. Neurology. Genetics, 2017, 3(4): e170.
7. Butler K, Da Silva C, Shafir Y, et al. De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis. Epilepsy research, 2017, 129: 17-25.
8. Wagnon J, Mencacci N, Barker B, et al. Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus. Human mutation, 2018, 39(7): 965-969.
9. Johannesen K, Gardella E, Scheffer I, et al. Early mortality in SCN8A-related epilepsies. Epilepsy research, 2018, 143: 79-81.
10. Gardella E, Marini C, Trivisano M, et al. SCN8AThe phenotype of developmental and epileptic encephalopathy. Neurology, 2018, 91(12): e1112-e1124.
11. Kruger L, Isom L. Voltage-gated Na+ channels: not just for conduction. Cold Spring Harbor perspectives in biology, 2016, 8(6): a029264.
12. Brunklaus A, Lal D. Sodium channel epilepsies and neurodevelopmental disorders: from disease mechanisms to clinical application. Developmental medicine and child neurology, 2020, 62(7): 784-792.
13. Meisler M, Helman G, Hammer M, et al. SCN8A encephalopathy: Research progress and prospects. Epilepsia, 2016, 57(7): 1027-1035.
14. Ademuwagun I, Rotimi S, Syrbe S, et al. Voltage gated sodium channel genes in epilepsy: mutations, functional studies, and treatment dimensions. Frontiers in neurology, 2021, 12: 600050.
15. Blanchard M, Willemsen M, Walker J, et al. De novo gain- of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. Journal of medical genetics, 2015, 52(5): 330-337.
16. Gardella E, M?ller R. Phenotypic and genetic spectrum of SCN8A-related disorders, treatment options, and outcomes. Epilepsia, 2019: S77-S85.
17. Liu Y, Schubert J, Sonnenberg L, et al. Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability. Brain:a journal of neurology, 2019, 142(2): 376-390.
18. Johannesen K, Liu Y, Koko M, et al. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. Brain : a journal of neurology, 2021.
19. 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 an Scn1a gene mutation. The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007, 27(22): 5903-5914.
20. Wagnon J, Meisler M. Recurrent and Non-Recurrent Mutations of SCN8A in Epileptic Encephalopathy. Frontiers in neurology, 2015, 6: 104.
21. Tidball A, Lopez-Santiago L, Yuan Y, et al. Variant-specific changes in persistent or resurgent sodium current in SCN8A-related epilepsy patient-derived neurons. Brain:a journal of neurology, 2020, 143(10): 3025-3040.
22. Luo H, Xie L, Hong S, et al. The genotype and phenotype of proline-rich transmembrane protein 2 associated disorders in Chinese children. Frontiers in pediatrics, 2021, 9: 676616.
23. Anand G, Collett-White F, Orsini A, et al. Autosomal dominant SCN8A mutation with an unusually mild phenotype. European journal of paediatric neurology:EJPN:official journal of the European Paediatric Neurology Society, 2016, 20(5): 761-765.
24. Wang J, Gao H, Bao X, et al. SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures. BMC medical genetics, 2017, 18(1): 104.
25. Parrini E, Marini C, Mei D, et al. Diagnostic targeted resequencing in 349 patients with drug-resistant pediatric epilepsies identifies causative mutations in 30 different genes. Human mutation, 2017, 38(2): 216-225.
26. Bagnasco I, Dassi P, Blé R, et al. A relatively mild phenotype associated with mutation of SCN8A. Seizure, 2018, 56: 47-49.
27. Wagnon J, Barker B, Hounshell J, et al. Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy. Annals of clinical and translational neurology, 2016, 3(2): 114-123.
28. Denis J, Villeneuve N, Cacciagli P, et al. Clinical study of 19 patients with SCN8A-related epilepsy: Two modes of onset regarding EEG and seizures. Epilepsia, 2019, 60(5): 845-856.
29. Mcnally M, Johnson J, Huisman T, et al. SCN8A epileptic encephalopathy: detection of fetal seizures guides multidisciplinary approach to diagnosis and treatment. Pediatric neurology, 2016, 64: 87-91.
30. Trivisano M, Pavia G, Ferretti A, et al. Generalized tonic seizures with autonomic signs are the hallmark of SCN8A developmental and epileptic encephalopathy. Epilepsy & behavior:E& B, 2019, 96: 219-223.
31. De Kovel C, Meisler M, Brilstra E, et al. Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy. Epilepsy research, 2014, 108(9): 1511-1518.
32. Ohba C, Kato M, Takahashi S, et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia, 2014, 55(7): 994-1000.
33. 姚春美, 趙榮江, 鄧亞仙, 等. SCN8A基因突變相關癲癇性腦病2例報告并文獻復習. 臨床兒科雜志, 2019, 37(6): 462-465.
34. Schreiber J, Tochen L, Brown M, et al. A multi-disciplinary clinic for SCN8A-related epilepsy. Epilepsy research, 2020, 159: 106261.
35. Nickels K, Grossardt B, Wirrell E. Epilepsy-related mortality is low in children: a 30-year population-based study in Olmsted County, MN. Epilepsia, 2012, 53(12): 2164-2171.
36. Keller A, Whitney R, Li S, et al. Incidence of sudden unexpected death in epilepsy in children is similar to adults. Neurology, 2018, 91(2): e107-e111.
37. Abdel-Mannan O, Taylor H, Donner E, et al. A systematic review of sudden unexpected death in epilepsy (SUDEP) in childhood. Epilepsy & behavior:E& B, 2019, 90: 99-106.
38. Frasier C, Wagnon J, Bao Y, et al. SCN8ACardiac arrhythmia in a mouse model of sodium channel epileptic encephalopathy. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(45): 12838-12843.
39. Trudeau M, Dalton J, Day J, et al. Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. Journal of medical genetics, 2006, 43(6): 527-530.
40. Canafoglia L, Franceschetti S, Granata T, et al. SCN8A splicing mutation causing skipping of the exon 15 associated with intellectual disability and cortical myoclonus. Seizure, 2020, 82: 56-58.
41. Boerma R, Braun K, Van Den Broek M, et al. Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsy: a molecular neuropharmacological approach. Neurotherapeutics, 2016, 13(1): 192-197.
42. M?ller R, Johannesen K. Precision medicine: SCN8A encephalopathy treated with sodium channel blockers. Neurotherapeutics, 2016, 13(1): 190-191.
43. Atkin T, Maher C, Gerlach A, et al. A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy. Epilepsia, 2018, 59(4): 802-813.
44. Lenk G, Jafar-Nejad P, Hill S, et al. Scn8a antisense oligonucleotide is protective in mouse models of SCN8A encephalopathy and dravet syndrome. Annals of neurology, 2020, 87(3): 339-346.

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