癫痫杂志

癫痫杂志

原钙黏蛋白19基因相关癫痫的遗传特点及临床表型谱研究

查看全文

目的分析原钙黏蛋白19(X-linked protocadherin 19, PCDH19) 基因相关癫痫的遗传学特点及临床表型谱。方法对2005年2月-2017年4月在北京大学第一医院儿科及武汉市儿童医院神经内科确诊的41例(女39例,男2例)PCDH19基因相关癫痫患儿及家系受累成员的临床特点进行总结。采用Sanger测序或靶向捕获二代测序(Next generation sequencing, NGS)和多重连接依赖的探针扩增技术(Multiple ligation-dependent probe amplification, MLPA)筛查PCDH19突变。结果41例先证者中,测序发现40例携带PCDH19基因突变,MLPA发现1例为整个PCDH19基因缺失。2例男性患儿经NGS检测为PCDH19突变嵌合体,突变等位基因占比分别为85%和33%;39例女性患儿中,19例为遗传性突变,20例为新生突变。女性携带突变者外显率为90%(53/59)。12例半合子父亲和1例嵌合体父亲均无抽搐病史。突变携带者表型包括癫痫伴智力低下、Dravet综合征、热性惊厥,少数女性携带者表型正常。即使在同一家系内,携带相同PCDH19突变的女性表型具有异质性。46例PCDH19突变阳性患者(41例先证者及5例家系受累成员)的临床特点:起病中位年龄为11个月(4~42个月),病程中全面强直阵挛发作(Generalized tonic clonic seizures, GTCSs)占87.0%(40/46),局灶性发作占69.6%(32/46),肌阵挛发作(6/46),不典型失神(3/46) 和失张力发作(1/46) 少见。丛集性发作见于所有患者(46/46),80.4%发作具有热敏感的特点(37/46),仅3例曾有发热诱发的癫痫持续状态,76%有不同程度的智力损害(35/46),少数有孤独症样表现(7/46,15.2%)。结论PCDH19基因突变可为遗传性突变或新生突变,受累者以女性为主,少数男性嵌合体可发病或无症状。PCDH19基因相关癫痫具有外显率不全和表型异质性,丛集性发作和热敏感为其主要临床特点。

ObjectiveTo explore the genotype and phenotype of PCDH19 gene related epilepsy.Methods41 probands, including 39 girls and 2 boys collected from pediatric department of the Peking University and Neurology Department of Wuhan Children's Hospital from February 2005 to April 2017, were diagnosed as PCDH19 gene related epilepsy. The clinical features of the probands and affected relatives were retrospectively analyzed. PCDH19 mutations were detected by Sanger sequencing or targeted next generation sequencing (NGS) and multiple ligation-dependent probe amplification (MLPA).Results40 in 41 probands with PCDH19 mutations were detected by sequencing and one was detected by MLPA.Two male epilepsy patients with mosaic PCDH19 mutations were detected by NGS with the mutant allele fraction of 85% and 33%. Among 39 female probands, 19 were with inherited mutations and 20 were de novo mutations. The penetrance of females with PCDH19 mutation was estimated as 90% (53/59). Twelve hemizygous fathers and one mosaic father were asymptomatic.The clinical phenotypes of female mutation carriers included epilepsy with mental retardation, Dravet syndrome, febrile seizures, or even asymptomatic. The phenotypic heterogeneity was noticed in females with identical mutations even in members from the same family. The median seizure onset age of 46 patients (including 41 probands and 5 affected relatives) were 11 months (range 4~42months).During the course, 87% (40/46) patients experienced generalized tonic clonic seizures (GTCSs) and 69.6% (32/46) experienced focal seizures. Other rare seizures types included myoclonic seizures (6/46), absence seizures (3/46) and atonic seizures (1/46). Seizures in clusters were observed in all patients, fever sensitivity in 80.4% (37/46), and status epilepticusin only three, cognitive impairment in 76% (35/46) and 7 with autistic features.ConclusionMutations in PCDH19 can be inherited or de novo. Most patients are females, rare mosaic males can be affected or asymptomatic. PCDH19 gene related epilepsy shows incomplete penetrance and variable expressivity.Seizures occurring in clusters and sensitive to fever are the major features.

关键词: 癫痫; PCDH19基因; 突变; 嵌合体

Key words: Epilepsy; PCDH19; Mutation; Mosaicism

引用本文: 刘爱杰, 许小菁, 孙丹, 曾琦, 杨小玲, 杨志仙, 吴晔, 刘晓燕, 姜玉武, 吴希如, 张月华. 原钙黏蛋白19基因相关癫痫的遗传特点及临床表型谱研究. 癫痫杂志, 2017, 3(4): 283-291. doi: 10.7507/2096-0247.20170042 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. Dibbens LM, Tarpey PS, Hynes K, et al. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet, 2008, 40(6): 776-781.
2. Depienne C, Bouteiller D, Keren B, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet, 2009, 5(2): e1000381.
3. Terracciano A, Trivisano M, Cusmai R, et al. PCDH19-related epilepsy in two mosaic male patients. Epilepsia, 2016, 57(3): 51-55.
4. Thiffault I, Farrow E, Smith L, et al. PCDH19-related epileptic encephalopathy in a male mosaic for a truncating variant. Am J Med Genet A, 2016, 170(6): 1585-1589.
5. Fabisiak K, Erickson RP. A familial form of convulsive disorder with or without mental retardation limited to females: extension of a pedigree limits possible genetic mechanisms. Clin Genet, 1990, 38(5): 353-358.
6. Scheffer IE, Turner SJ, Dibbens LM, et al. Epilepsy and mental retardation limited to females: an under-recognized disorder. Brain, 2008, 131(Pt 4): 918-927.
7. Marini C, Mei D, Parmeggiani L, et al. Protocadherin 19 mutations in girls with infantile-onset epilepsy. Neurology, 2010, 75(7): 646-653.
8. Ikeda H, Imai K, Ikeda H, et al. Characteristic phasic evolution of convulsive seizure in PCDH19-related epilepsy. Epileptic Disord, 2016, 18(1): 26-33.
9. 胡春辉, 王龙飞, 王华.不明原因早发性癫痫脑病62例临床特点及相关基因突变分析.中华实用儿科临床杂志, 2016, 31(5): 371-375.
10. 庄嘉鑫, 林彩梅, 吴小慧, 等.原钙黏蛋白19(PCDH19) 基因突变相关的癫痫性脑病一例.中国小儿急救医学, 2016, 23(3): 211-213.
11. 刘爱杰, 张月华, 许小菁, 等. PCDH19基因突变导致的女性Dravet综合征的基因型和表型特点.中华儿科杂志, 2016, 54(5): 327-331.
12. Liu A, Xu X, Yang X, et al. The clinical spectrum of female epilepsy patients with PCDH19 mutations in a Chinese population. Clin Genet, 2017, 91(1): 54-62.
13. Zhang Y, Kong W, Gao Y, et al. Gene mutation analysis in 253 chinese children with unexplained epilepsy and intellectual/developmental disabilities. PLoS One, 2015, 10(11): e141782.
14. Wu J, Matthaei H, Maitra A, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med, 2011, 3(92): 66-92.
15. Depienne C, Leguern E. PCDH19-related infantile epileptic encephalopathy: an unusual X-linked inheritance disorder. Hum Mutat, 2012, 33(4): 627-634.
16. Duszyc K, Terczynska I, Hoffman-Zacharska D. Epilepsy and mental retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance. J Appl Genet, 2015, 56(1): 49-56.
17. Hynes K, Tarpey P, Dibbens LM, et al. Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families. J Med Genet, 2010, 47(3): 211-216.
18. van Harssel JJ, Weckhuysen S, van Kempen MJ, et al. Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders. Neurogenetics, 2013, 14(1): 23-34.
19. Specchio N, Marini C, Terracciano A, et al. Spectrum of phenotypes in female patients with epilepsy due to protocadherin 19 mutation. Epilepsia, 2011, 52(7): 1251-1257.
20. Depienne C, Trouillard O, Bouteiller D, et al. Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females. Hum Mutat, 2011, 32(1): E1959-E1975.
21. Dimova PS, Kirov A, Todorova A, et al. A novel PCDH19 mutation inherited from an unaffected mother. Pediatr Neurol, 2012, 46(6): 397-400.