癫痫杂志

癫痫杂志

1 岁前起病的良性家族性癫痫基因突变谱研究

查看全文

目的1 岁前起病的良性家族性癫痫包括良性家族性新生儿癫痫(Benign familial neonatal epilepsy,BFNE)、良性家族性新生儿-婴儿癫痫(Benign familial neonatal-infantile epilepsy,BFNIE)和良性家族性婴儿癫痫(Benign familial infantile epilepsy,BFIE)。研究对我国 1 岁前起病的良性家族性癫痫家系进行基因突变分析,探索其基因突变谱。方法收集 2006 年 9 月—2018 年 1 月在北京大学第一医院儿科就诊的 1 岁前起病的良性家族性癫痫家系的临床资料和外周血 DNA。对 BFIE 家系首先采用 Sanger 测序方法筛查PRRT2 基因突变;对于 BFNE 和 BFNIE 家系以及 Sanger 测序方法未发现 PRRT2 基因突变的 BFIE 家系,采用靶向捕获二代测序癫痫基因检测包进行基因突变筛查。结果共收集 89 个 1 岁前起病的良性家族性癫痫家系,其中包括 4 个 BFNE 家系、7 个 BFNIE 家系和 78 个 BFIE 家系。基因检测发现 68 个家系有相关基因突变(76.4%),其中 50 个家系为 PRRT2 基因突变(热点突变 c.649dupC 和 c.649delC 分别见于 32 个家系和 6 个家系),9 个家系为 KCNQ2 基因突变,8 个家系为 SCN2A 基因突变,1 个家系为 GABRA6 基因突变。在 4 个 BFNE 家系中,发现 3 个家系为 KCNQ2 突变,1 个家系未发现致病基因;在 7 个 BFNIE 家系中,发现 3 个家系为 KCNQ2 突变,3 个家系为 SCN2A 突变,1 个家系为 PRRT2 突变;在 78 个 BFIE 家系中,有 58 个家系发现基因突变(74.4%), 其中 49 个家系为 PRRT2 突变(62.8%),5 个家系为 SCN2A 突变, 3 个家系为 KCNQ2 突变,1 个家系携带未报道的 GABRA6 突变;其余 20 个 BFIE 家系未发现致病基因。在 78 个 BFIE 家系中,有 18 个家系进一步诊断为婴儿惊厥伴阵发性舞蹈手足徐动症家系,其中 17 个发现 PRRT2 突变(17/18, 94.4%),其余 1 个家系未发现致病基因。结论KCNQ2SCN2APRRT2 基因是我国 1 岁前起病的良性家族性癫痫的重要致病基因,基因突变检出率高。KCNQ2 是 BFNE 的主要致病基因,PRRT2 是 BFIE 的主要致病基因,KCNQ2SCN2A 基因突变在 BFNIE 中常见。GABRA6 可能是 BFIE 新发现的致病基因。发现家系致病基因对指导家庭遗传咨询及治疗具有重要作用。

ObjectiveBenign familial epilepsies that present themselves in the first year of life include benign familial neonatal epilepsy (BFNE), benign familial neonatal-infantile epilepsy (BFNIE) and benign familial infantile epilepsy (BFIE). We aim to investigate gene mutations and the relationship between genotypes and clinical phenotypes in benign familial epilepsies in the first year of life.MethodsWe recruited families with benign familial epilepsies in the first year of life at Peking University First Hospital from September 2006 to January 2018. Clinical information and blood samples were obtained from probands and their family members. For BFIE families, mutation screening of PRRT2 was performed by using the polymerase chain reaction (PCR) and Sanger sequencing at first. The PRRT2 mutation negative probands of BFIE families were further screened for pathogenic mutations by targeted next-generation sequencing. The probands of BFNE and BFNIE families were screened for pathogenic mutations by targeted next-generation sequencing.ResultsA total of 89 families with benign familial epilepsies in the first year of life were collected. Of the 89 families, 4 were classified as BFNE, 7 as BFNIE, and 78 as BFIE. Genetic testing led to the identification of gene mutations in 68 families (76.4%), including 50 families had PRRT2 mutations (hotspot mutation c.649dupC was detected in 32 families; c.649delC was detected in 6 families), 9 families had KCNQ2 mutations, 8 families had SCN2A mutations, and one family had GABRA6 mutation. In the 4 BFNE families, causative mutations were only found in KCNQ2, which was identified as the causative gene in 3 families. The remaining one BFNE family was not detected with any pathogenic mutation. All 7 BFNIE families had identifiable gene mutations, KCNQ2 was found in 3 families, SCN2A in 3 families, and PRRT2 in one family. In the 78 BFIE families, gene mutations were identified in 58 families (74.4%), with PRRT2 mutations found in 49 families (62.8%), SCN2A mutations found in 5 families, KCNQ2 mutations found in 3 families, and a novol GABRA6 mutation found in one family. Twenty BFIE families were not identified with any gene mutations. In 78 BFIE families, 18 were subclassified as infantile convulsions with paroxysmal choreoathetosis syndrome(ICCA). 17 of 18 ICCA families were detected with PRRT2 mutations (17/18, 94.4%). The remaining ICCA family was not detected with any pathogenic mutation.ConclusionsOur results confirmed that mutations in KCNQ2, SCN2A, and PRRT2 are major genetic causes of benign familial epilepsy in the first year of life in the Chinese population. KCNQ2 is the major gene related to BFNE. PRRT2 is the main gene responsible for BFIE. KCNQ2 and SCN2A mutations are common in BFNIE families. GABRA6 mutation might be a new cause of BFIE. Identification of underlying gene mutation can be helpful for clinical diagnosis and judgement of the prognosis.

关键词: 癫痫; KCNQ2基因; SCN2A基因; PRRT2基因; GABRA6基因

Key words: Epilepsy; KCNQ2 gene; PRRT2 gene; SCN2A gene; GABRA6 gene

引用本文: 曾琦, 张月华, 杨小玲, 张静, 陈娇阳, 蒲利华, 于晓莉, 张秀菊, 刘爱杰, 杨志仙, 王爽, 吴晔, 刘晓燕, 吴希如. 1 岁前起病的良性家族性癫痫基因突变谱研究. 癫痫杂志, 2018, 4(4): 290-305. doi: 10.7507/2096-0247.20180049 复制

登录后 ,请手动点击刷新查看全文内容。 没有账号,
登录后 ,请手动点击刷新查看图表内容。 没有账号,
1. Vigevano F, Fusco L, Di Capua M, et al. Benign infantile familial convulsions. Eur J Pediatr, 1992, 151(8): 608-612.
2. Okumura A, Hayakawa F, Kato T, et al. Early recognition of benign partial epilepsy in infancy. Epilepsia, 2000, 41(6): 714-717.
3. Tomlinson SE, Bostock H, Grinton B, et al. In vivo loss of slow potassium channel activity in individuals with benign familial neonatal epilepsy in remission. Brain, 2012, 135(Pt 10): 3144-3152.
4. Kaplan RE, Lacey DJ. Benign familial neonatal-infantile seizures. Am J Med Genet, 1983, 16(4): 595-599.
5. Vigevano F. Benign familial infantile seizures. Brain Dev, 2005, 27(3): 172-177.
6. Szepetowski P, Rochette J, Berquin P, et al. Familial infantile convulsions and paroxysmal choreoathetosis: a new neurological syndrome linked to the pericentromeric region of human chromosome 16. Am J Hum Genet, 1997, 61(4): 889-898.
7. Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet, 1998, 18(1): 25-29.
8. Charlier C, Singh NA, Ryan SG, et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet, 1998, 18(1): 53-55.
9. Zara F, Specchio N, Striano P, et al. Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. Epilepsia, 2013, 54(3): 425-436.
10. Heron SE, Crossland KM, Andermann E, et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet, 2002, 360(9336): 851-852.
11. Berkovic SF, Heron SE, Giordano L, et al. Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy. Ann Neurol, 2004, 55(4): 550-557.
12. Chen WJ, Lin Y, Xiong ZQ, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet, 2011, 43(12): 1252-1255.
13. Heron SE, Grinton BE, Kivity S, et al. PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet, 2012, 90(1): 152-160.
14. Yang X, Zhang Y, Xu X, et al. Phenotypes and PRRT2 mutations in Chinese families with benign familial infantile epilepsy and infantile convulsions with paroxysmal choreoathetosis. BMC Neurol, 2013, 13: 209.
15. Grinton BE, Heron SE, Pelekanos JT, et al. Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome. Epilepsia, 2015, 56(7): 1071-1080.
16. Zhou X, Ma A, Liu X, et al. Infantile seizures and other epileptic phenotypes in a Chinese family with a missense mutation of KCNQ2. Eur J Pediatr, 2006, 165(10): 691-695.
17. Chen Z, Wang L, Wang C, et al. Mutational analysis of CHRNB2, CHRNA2 and CHRNA4 genes in Chinese population with autosomal dominant nocturnal frontal lobe epilepsy. Int J Clin Exp Med, 2015, 8(6): 9063-9070.
18. Kurahashi H, Wang JW, Ishii A, et al. Deletions involving both KCNQ2 and CHRNA4 present with benign familial neonatal seizures. Neurology, 2009, 73(15): 1214-1217.
19. Pascual FT, Wierenga KJ, Ng YT. Contiguous deletion of KCNQ2 and CHRNA4 may cause a different disorder from benign familial neonatal seizures. Epilepsy Behav Case Rep, 2013, 1: 35-38.
20. Becker F, Schubert J, Striano P, et al. PRRT2-related disorders: further PKD and ICCA cases and review of the literature. J Neurol, 2013, 260(5): 1234-1244.
21. Guerrero-Lopez R, Ortega-Moreno L, Giraldez BG, et al. Atypical course in individuals from Spanish families with benign familial infantile seizures and mutations in the PRRT2 gene. Epilepsy Res, 2014, 108(8): 1274-1278.
22. Schubert J, Paravidino R, Becker F, et al. PRRT2 mutations are the major cause of benign familial infantile seizures. Hum Mutat, 2012, 33(10): 1439-1443.
23. Ishii A, Yasumoto S, Ihara Y, et al. Genetic analysis of PRRT2 for benign infantile epilepsy, infantile convulsions with choreoathetosis syndrome, and benign convulsions with mild gastroenteritis. Brain Dev, 2013, 35(6): 524-530.
24. Scheffer IE, Grinton BE, Heron SE, et al. PRRT2 phenotypic spectrum includes sporadic and fever-related infantile seizures. Neurology, 2012, 79(21): 2104-2108.
25. Cloarec R, Bruneau N, Rudolf G, et al. PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine. Neurology, 2012, 79(21): 2097-2103.
26. Lee HY, Huang Y, Bruneau N, et al. Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep, 2012, 1(1): 2-12.
27. Hortiguela M, Fernandez-Marmiesse A, Cantarin V, et al. Clinical and genetic features of 13 Spanish patients with KCNQ2 mutations. J Hum Genet, 2017, 62(2): 185-189.
28. Millichap JJ, Park KL, Tsuchida T, et al. KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet, 2016, 2(5): e96.
29. Al Yazidi G, Shevell MI, Srour M. Two Novel KCNQ2 Mutations in 2 Families With Benign Familial Neonatal Convulsions. Child Neurol Open, 2017, 4: 2329048X17691396.
30. Hewson S, Puka K, Mercimek-Mahmutoglu S. Variable expressivity of a likely pathogenic variant in KCNQ2 in a three-generation pedigree presenting with intellectual disability with childhood onset seizures. Am J Med Genet A, 2017, 173(8): 2226-2230.
31. Singh NA, Westenskow P, Charlier C, et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain, 2003, 126(Pt 12): 2726-2737.
32. Labate A, Tarantino P, Viri M, et al. Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation, episodic ataxia, and absences. Epilepsia, 2012, 53(12): e196-199.
33. Hernandez CC, Gurba KN, Hu N, et al. The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 6beta22 and 6beta2 GABA(A) receptor channel gating and expression. J Physiol, 2011, 589(Pt 23): 5857-5878.
34. Prasad DK, Shaheen U, Satyanarayana U, et al. Association of GABRA6 1519 T>C (rs3219151) and Synapsin II (rs37733634) gene polymorphisms with the development of idiopathic generalized epilepsy. Epilepsy Res, 2014, 108(8): 1267-1273.
35. Sands TT, Balestri M, Bellini G, et al. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia, 2016, 57(12): 2019-2030.