肌阵挛性失张力癫痫的表型与遗传谱_Journal of Epilepsy

Authors：

 ShanTang , LauraAddis , AnnaSmith , 郭崇伦 , 慕洁　审

Corresponding author：

ShanTang, Email: shan-shan.tang@gstt.nhs.uk

Keywords：

Doose综合征; 癫痫/癫痫发作; 遗传学; 肌阵挛性失张力癫痫

DOI：

10.7507/2096-0247.20220018

Video：

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文章旨在描述一个大样本量的癫痫伴肌阵挛性失张力发作（MAE）患者神经发育损害程度，并确定其遗传学病因。采用标准化的神经心理学仪器对MAE患者的癫痫特征、智力残疾、自闭症谱系障碍和注意缺陷/多动障碍进行深入的表型分析。我们对癫痫和神经精神疾病的基因集进行外显子分析（全外显子测序），以确定遗传学病因。研究共分析了101例MAE患者（70%为男性）。发作年龄中位数为34月龄（范围6～72月龄）。主要发作类型为肌阵挛性失张力发作或失张力发作100%、全身强直阵挛性发作72%、肌阵挛性发作69%、失神性发作60%、强直性发作19%。研究观察到62%的患者有智力障碍，69%的患者适应行为评分极低。此外，24%表现出自闭症症状，37%表现出注意力缺陷/多动症状。85例患者中的12例（14%）发现了致病性变异，包括5例先前发表的患者。这些基因是SYNGAP1（n=3）、KIAA2022（n=2）、SLC6A1（n=2）以及KCNNA2、SCN2A、STX1B、KCNB1和MECP2（各n=1）。此外，研究还分别在3例患者中分别鉴定了1个新的候选基因—ASH1L、CHD4和SMARCA2。研究发现，MAE与明显的神经发育障碍有关。MAE具有遗传异质性，通过外显子分析在14%的队列中确定了致病的遗传病因。这些发现表明MAE是几种病因的表现，而不是一个离散的综合征实体。

Citation： ShanTang, LauraAddis, AnnaSmith, 郭崇伦, 慕洁　审. 肌阵挛性失张力癫痫的表型与遗传谱. Journal of Epilepsy, 2022, 8(1): 74-81. doi: 10.7507/2096-0247.20220018 Copy

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2.	Doose H, Gerken H, Leonhardt R, Völzke E, Völz C. Centrencephalic myoclonic-astatic petit mal. clinical and genetic investigation. Neuropadiatrie. 1970, 2(10: 59-78.
3.	Kaminska A, Ickowicz A, Plouin P, et al. Delineation of cryptogenic Lennox-Gastaut syndrome and myoclonic astatic epilepsy using multiple correspondence analysis. Epilepsy Res, 1999, 36(1): 15-29.
4.	Oguni H, Tanaka T, Hayashi K, et al. Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood. Neuropediatrics, 2002, 33(1): 122-132.
5.	Kilaru S, Bergqvist AG. Current treatment of myoclonic astatic epilepsy: clinical experience at the Children's Hospital of Philadelphia. Epilepsia, 2007, 48(9): 1703-1707.
6.	Trivisano M, Specchio N, Cappelletti S, et al. Myoclonic astatic epilepsy: an age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution. Epilepsy Res, 2011, 97: 133-141.
7.	Nolte R, Wolff M. Behavioural and developmental aspects of primary generalized myoclonic-astatic epilepsy. Epilepsy Res, 1992, 6(Suppl): 175-183.
8.	Nabbout R. Absence of mutations in major GEFS+ genes in myoclonic astatic epilepsy. Epilepsy Res, 2003, 56: 127-133.
9.	Wallace RH, Wang DW, Singh R, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet, 1998, 19(2): 366-370.
10.	Escayg A, Heils A, MacDonald BT, et al. A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus-and prevalence of variants in patients with epilepsy. Am J Hum Genet, 2001, 68(3): 866-873.
11.	Mullen SA. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Ann Neurol, 2011, 68(9): 1152-1155.
12.	Carvill GL, Heavin SB, Yendle SC, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet, 2013, 45(4): 825-830.
13.	Mignot C, von Stulpnagel C, Nava C, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet, 2016, 53(2): 511-522.
14.	Syrbe S, Hedrich UBS, Riesch E, et al. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet, 2015, 47(2): 393-399.
15.	Schubert J, Siekierska A, Langlois M, et al. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat Genet, 2014, 46(6): 1327-1332.
16.	Carvill G, McMahon J, Schneider A, et al. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am J Hum Genet, 2015, 96(3): 808-815.
17.	Balestrini S, Milh M, Castiglioni C, et al. TBC1D24 genotype-phenotype correlation: epilepsies and other neurologic features. Neurology, 2016, 87(1): 77-85.
18.	de Lange IM, Helbig KL, Weckhuysen S, et al. De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy. J Med Genet, 2016, 53(3): 850-858.
19.	Wolff M, Johannesen KM, Hedrich UBS, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain, 2017, 140(5): 1316-1336.
20.	Moller RS, Wuttke TV, Helbig I, et al. Mutations in GABRB3: from febrile seizures to epileptic encephalopathies. Neurology, 2017, 88(2): 483-492.
21.	Routier L, Verny F, Barcia G, et al. Exome sequencing findings in 27 patients with myoclonic-atonic epilepsy: is there a major genetic factor? Clin Genet, 2019, 96(2): 254-260.
22.	Helbig I, Lopez-Hernandez T, Shor O, et al. A recurrent missense variant in AP2M1 impairs clathrin-mediated endocytosis and causes developmental and epileptic encephalopathy. Am J Hum Genet, 2019, 104(6): 1060-1072.
23.	Tang S, Hughes E, Lascelles K, EuroEPINOMICS RES Myoclonic Astatic Epilepsy Working Group, Simpson MA, Pal DK. New SMARCA2 mutation in a patient with Nicolaides-Baraitser syndrome and myoclonic astatic epilepsy. Am J Med Genet A, 2017, 173(2): 195-199.
24.	Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia, 1989, 30(2): 389-399.
25.	Oguni H, Fukuyama Y, Tanaka T, et al. Myoclonic-astatic epilepsy of early childhood-clinical and EEG analysis of myoclonic-astatic seizures, and discussions of the nosology of the syndrome. Brain Dev, 2001, 23(3): 757-764.
26.	Eom S, Fisher B, Dezort C, Berg AT. Routine developmental, autism, behavioral, and psychological screening in epilepsy care settings. Dev Med Child Neurol, 2014, 56(5): 1100-1105.
27.	Meltzer HG, Goodman R, Ford F. Mental health of children and adolescents in Great Britain. London, UK: The Stationery Office, 2000.
28.	Suls A, Jaehn J, Kecskés A, et al. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet, 2013, 93(4): 967-675.
29.	de Ligt J, Willemsen MH, van Bon BWM, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med, 2012, 367(6): 1921-1929.
30.	Hamdan FF, Srour M, Capo-Chichi J-M, et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet, 2014, 10: e1004772.
31.	Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet, 2012, 380(5): 1674-1682.
32.	Large-scale discovery of novel genetic causes of developmental disorders. Nature, 2015, 519: 223-8.
33.	Allen AS, Berkovic SF, Cossette P, et al. De novo mutations in epileptic encephalopathies. Nature, 2013, 501(2): 217-221.
34.	O’Roak BJ, Vives L, Girirajan S, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature, 2012, 485(1): 246-250.
35.	Neale BM, Kou Y, Liu LI, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature, 2012, 485(1): 242-245.
36.	Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature, 2012, 485(1): 237-241.
37.	de Kovel CGF, Syrbe S, Brilstra EH, et al. Neurodevelopmental disorders caused by de novo variants in KCNB1 genotypes and phenotypes. JAMA Neurol, 2017, 74(4): 1228-1236.
38.	Saitsu H, Akita T, Tohyama J, et al. De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing. Sci Rep, 2015, 5(1): 15199.
39.	Zhu T, Liang C, Li D, et al. Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1alpha. Sci Rep, 2016, 6: 26597.
40.	Eschbach K, Moss A, Joshi C, et al. Diagnosis switching and outcomes in a cohort of patients with potential epilepsy with myoclonic-atonic seizures. Epilepsy Res, 2018, 147: 95-101.
41.	Caraballo RH, Chamorro N, Darra F, et al. Epilepsy with myoclonic atonic seizures: an electroclinical study of 69 patients. Pediatr Neurol, 2013, 48(2): 355-362.
42.	Inoue T, Ihara Y, Tomonoh Y, et al. Early onset and focal spike discharges as indicators of poor prognosis for myoclonic-astatic epilepsy. Brain Dev, 2014, 36(3): 613-619.
43.	Heyne HO, Singh T, Stamberger H, et al. De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet, 2018, 50(4): 1048-1053.
44.	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. Hum Mutat, 2017, 38(2): 216-225.
45.	De Rubeis S, He X, Goldberg AP, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 2014, 515(2): 209-215.
46.	Stessman HAF, Xiong BO, Coe BP, et al. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet, 2017, 49(2): 515-526.
47.	Weiss K, Terhal PA, Cohen L, et al. De novo mutations in CHD4, an ATP-dependent chromatin remodeler gene, cause an intellectual disability syndrome with distinctive dysmorphisms. Am J Hum Genet, 2016, 99(4): 934-941.
48.	Mefford HC, Muhle H, Ostertag P, et al. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalised and focal epilepsies. PLoS Genet, 2010, 6: e1000962.
49.	Mefford HC, Yendle SC, Hsu C, et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol, 2011, 70(4): 974-985.
50.	Møller RS, Liebmann N, Larsen LHG, et al. Parental mosaicism in epilepsies due to alleged de novo variants. Epilepsia, 2019, 60(1): 63-66.

1. 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(3): 676-685.
2. Doose H, Gerken H, Leonhardt R, Völzke E, Völz C. Centrencephalic myoclonic-astatic petit mal. clinical and genetic investigation. Neuropadiatrie. 1970, 2(10: 59-78.
3. Kaminska A, Ickowicz A, Plouin P, et al. Delineation of cryptogenic Lennox-Gastaut syndrome and myoclonic astatic epilepsy using multiple correspondence analysis. Epilepsy Res, 1999, 36(1): 15-29.
4. Oguni H, Tanaka T, Hayashi K, et al. Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood. Neuropediatrics, 2002, 33(1): 122-132.
5. Kilaru S, Bergqvist AG. Current treatment of myoclonic astatic epilepsy: clinical experience at the Children's Hospital of Philadelphia. Epilepsia, 2007, 48(9): 1703-1707.
6. Trivisano M, Specchio N, Cappelletti S, et al. Myoclonic astatic epilepsy: an age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution. Epilepsy Res, 2011, 97: 133-141.
7. Nolte R, Wolff M. Behavioural and developmental aspects of primary generalized myoclonic-astatic epilepsy. Epilepsy Res, 1992, 6(Suppl): 175-183.
8. Nabbout R. Absence of mutations in major GEFS+ genes in myoclonic astatic epilepsy. Epilepsy Res, 2003, 56: 127-133.
9. Wallace RH, Wang DW, Singh R, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet, 1998, 19(2): 366-370.
10. Escayg A, Heils A, MacDonald BT, et al. A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus-and prevalence of variants in patients with epilepsy. Am J Hum Genet, 2001, 68(3): 866-873.
11. Mullen SA. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Ann Neurol, 2011, 68(9): 1152-1155.
12. Carvill GL, Heavin SB, Yendle SC, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet, 2013, 45(4): 825-830.
13. Mignot C, von Stulpnagel C, Nava C, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet, 2016, 53(2): 511-522.
14. Syrbe S, Hedrich UBS, Riesch E, et al. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet, 2015, 47(2): 393-399.
15. Schubert J, Siekierska A, Langlois M, et al. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat Genet, 2014, 46(6): 1327-1332.
16. Carvill G, McMahon J, Schneider A, et al. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am J Hum Genet, 2015, 96(3): 808-815.
17. Balestrini S, Milh M, Castiglioni C, et al. TBC1D24 genotype-phenotype correlation: epilepsies and other neurologic features. Neurology, 2016, 87(1): 77-85.
18. de Lange IM, Helbig KL, Weckhuysen S, et al. De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy. J Med Genet, 2016, 53(3): 850-858.
19. Wolff M, Johannesen KM, Hedrich UBS, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain, 2017, 140(5): 1316-1336.
20. Moller RS, Wuttke TV, Helbig I, et al. Mutations in GABRB3: from febrile seizures to epileptic encephalopathies. Neurology, 2017, 88(2): 483-492.
21. Routier L, Verny F, Barcia G, et al. Exome sequencing findings in 27 patients with myoclonic-atonic epilepsy: is there a major genetic factor? Clin Genet, 2019, 96(2): 254-260.
22. Helbig I, Lopez-Hernandez T, Shor O, et al. A recurrent missense variant in AP2M1 impairs clathrin-mediated endocytosis and causes developmental and epileptic encephalopathy. Am J Hum Genet, 2019, 104(6): 1060-1072.
23. Tang S, Hughes E, Lascelles K, EuroEPINOMICS RES Myoclonic Astatic Epilepsy Working Group, Simpson MA, Pal DK. New SMARCA2 mutation in a patient with Nicolaides-Baraitser syndrome and myoclonic astatic epilepsy. Am J Med Genet A, 2017, 173(2): 195-199.
24. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia, 1989, 30(2): 389-399.
25. Oguni H, Fukuyama Y, Tanaka T, et al. Myoclonic-astatic epilepsy of early childhood-clinical and EEG analysis of myoclonic-astatic seizures, and discussions of the nosology of the syndrome. Brain Dev, 2001, 23(3): 757-764.
26. Eom S, Fisher B, Dezort C, Berg AT. Routine developmental, autism, behavioral, and psychological screening in epilepsy care settings. Dev Med Child Neurol, 2014, 56(5): 1100-1105.
27. Meltzer HG, Goodman R, Ford F. Mental health of children and adolescents in Great Britain. London, UK: The Stationery Office, 2000.
28. Suls A, Jaehn J, Kecskés A, et al. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet, 2013, 93(4): 967-675.
29. de Ligt J, Willemsen MH, van Bon BWM, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med, 2012, 367(6): 1921-1929.
30. Hamdan FF, Srour M, Capo-Chichi J-M, et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet, 2014, 10: e1004772.
31. Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet, 2012, 380(5): 1674-1682.
32. Large-scale discovery of novel genetic causes of developmental disorders. Nature, 2015, 519: 223-8.
33. Allen AS, Berkovic SF, Cossette P, et al. De novo mutations in epileptic encephalopathies. Nature, 2013, 501(2): 217-221.
34. O’Roak BJ, Vives L, Girirajan S, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature, 2012, 485(1): 246-250.
35. Neale BM, Kou Y, Liu LI, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature, 2012, 485(1): 242-245.
36. Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature, 2012, 485(1): 237-241.
37. de Kovel CGF, Syrbe S, Brilstra EH, et al. Neurodevelopmental disorders caused by de novo variants in KCNB1 genotypes and phenotypes. JAMA Neurol, 2017, 74(4): 1228-1236.
38. Saitsu H, Akita T, Tohyama J, et al. De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing. Sci Rep, 2015, 5(1): 15199.
39. Zhu T, Liang C, Li D, et al. Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1alpha. Sci Rep, 2016, 6: 26597.
40. Eschbach K, Moss A, Joshi C, et al. Diagnosis switching and outcomes in a cohort of patients with potential epilepsy with myoclonic-atonic seizures. Epilepsy Res, 2018, 147: 95-101.
41. Caraballo RH, Chamorro N, Darra F, et al. Epilepsy with myoclonic atonic seizures: an electroclinical study of 69 patients. Pediatr Neurol, 2013, 48(2): 355-362.
42. Inoue T, Ihara Y, Tomonoh Y, et al. Early onset and focal spike discharges as indicators of poor prognosis for myoclonic-astatic epilepsy. Brain Dev, 2014, 36(3): 613-619.
43. Heyne HO, Singh T, Stamberger H, et al. De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet, 2018, 50(4): 1048-1053.
44. 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. Hum Mutat, 2017, 38(2): 216-225.
45. De Rubeis S, He X, Goldberg AP, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 2014, 515(2): 209-215.
46. Stessman HAF, Xiong BO, Coe BP, et al. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet, 2017, 49(2): 515-526.
47. Weiss K, Terhal PA, Cohen L, et al. De novo mutations in CHD4, an ATP-dependent chromatin remodeler gene, cause an intellectual disability syndrome with distinctive dysmorphisms. Am J Hum Genet, 2016, 99(4): 934-941.
48. Mefford HC, Muhle H, Ostertag P, et al. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalised and focal epilepsies. PLoS Genet, 2010, 6: e1000962.
49. Mefford HC, Yendle SC, Hsu C, et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol, 2011, 70(4): 974-985.
50. Møller RS, Liebmann N, Larsen LHG, et al. Parental mosaicism in epilepsies due to alleged de novo variants. Epilepsia, 2019, 60(1): 63-66.

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