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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。
Objective To analyze the genetic characteristics and clinical phenotype of X-linked protocadherin 19 (PCDH19) gene-related epilepsy. Methods From February 2005 to April 2017, 41 patients (39 males and 2 men) diagnosed as PCDH19 gene-related epilepsy and their pedigrees in the Department of Pediatrics, First Hospital of Peking University and Children’s Hospital of Wuhan City, Features to summarize. PCDH19 mutations were screened using Sanger sequencing or Next Generation Sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA). Results Among the 41 probands, 40 cases of PCDH19 gene mutation were found by sequencing, and one case of MLPA was found to have deletion of the entire PCDH19 gene. Two cases of male children with PCDH19 mutation chimera detected by NGS, the proportion of mutant alleles were 85% and 33%; 39 cases of female children, 19 cases of hereditary mutations, 20 cases of newborn mutations. Female patients with mutation penetrance was 90% (53/59). Twelve hemizygous father and one chimerism father had no history of convulsions. Phenotype of the mutation carriers include epilepsy with mental retardation, Dravet syndrome, febrile seizures, a small number of women with normal phenotype. Even in the same family, the female phenotype carrying the same PCDH19 mutation is heterogeneous. 46 cases of PCDH19 mutation positive patients (41 cases of proband and 5 cases of family members involved) the clinical features: the median onset age of 11 months (4 to 42 months), the duration of the full tonic clonic seizures (Generalized tonic clonic seizures (GTCSs) accounted for 87.0% (40/46), focal episodes accounted for 69.6% (32/46), myoclonic seizures (6/46), atypical absences (3/46) and episodes of tension 1/46) rare. Clustered seizures were seen in all patients (46/46), with seizures characterized by heat-sensitivity (37/46) in 80.4% of cases, only three cases of persistent status-induced seizures and 76% of impaired intelligence (35/46 ), A few with autism (7/46, 15.2%). Conclusions The mutation of PCDH19 gene may be a hereditary mutation or a neoplasm mutation. Female patients predominate, and a few male chimeras may be morbid or asymptomatic. PCDH19 gene-related epilepsy with penetrance and phenotypic heterogeneity, clustered seizures and heat-sensitive as its main clinical features.