全面性癫痫伴热性惊厥附加症39个家系的临床表型和SCNlA基因突变分析

Phenotype and SCN1A gene mutation screening in 39 families with generalized epilepsy with febrileseizures plus

目的分析全面性癫痫伴热性惊厥附加症（generalized epilepsy with febrile seizuresplus，GEFS^＋）家系的临床表型，并筛查家系钠离子通道α1亚单位基因SCNIA突变，分析GEFS^＋基因型与表型的相关性。方法收集先证者及其家系成员临床资料及外周血DNA，对家系受累者临床表型进行分析，并采用PCR和DNA直接测序的方法进行SCNlA基因突变筛查。结果在39个GEFS^＋家系中，共有196例受累者，每个家系中有2-22例受累者不等。196例受累者的临床表型包括热性惊厥（febrile seizures，FS）92例（46．9％），热性惊厥附加症（febrile seizuresplus，FS^＋）62例（31．6％），FS或FS^＋伴部分性发作12例（6．1％），无热全面强直阵挛发作（afebrile generalized tonic-clonic seizures，AGTCS）11例（5．6％），肌阵挛失张力癫痫8例（4．1％），Dravet综合征2例（1．0％），儿童失神癫痫1例（0．5％），FS^＋伴肌阵挛发作1例（0．5％），AGTCS和肌阵挛发作1例（0．5％），部分性发作1例（0．5％），发作分类不能明确5例（2．6％）。39个GEFS^＋家系中发现4个家系（10．3％）有SCNlA基因突变，其中3例错义突变（N935H、R101Q、G1382R），1例碱基缺失（C373fsx378）。3例有错义突变的家系表型包括FS、FS^＋、FS^＋伴部分性发作和AGTCS。截断突变位点C373fsx378的家系表型包括FS、FS^＋和Dravet综合征。有错义突变R101Q的家系其先证者的母亲和有截断突变C373fsx378的家系先证者的父亲均为体细胞突变嵌合体，表型均为FS^＋。结论GEFS^＋家系最常见的表型为FS和FS^＋，最严重的表型为Dravet综合征。GEFS^＋家系SCNlA基因突变率约为10％，突变类型以错义突变为主，可有截断突变。GEFS^＋家系中少数受累成员SCNIA突变可为体细胞嵌合体，表型相对较轻。

Objective To summarize the phenotypes and identify SCN1A mutations in families with generalized epilepsy with febrile seizures plus （GEFS ^＋ ）, and analyze the genotype- phenotype correlations in GEFS ^＋ families. Method Genomie DNA was extracted from peripheral blood lymphoeytes of the proband and other available members in the GEFS ^＋ families. The phenotypes of the affected members were analyzed. The coding regions and flanking intronie regions of the SCNIA gene were screened for mutations using PCR and direct DNA sequencing. Result In 39 GEFS^＋ families, there were 196 affected members, ranging from 2 to 22 affected members in each family. Their phenotypes included febrile seizures （FS） in 92 （46. 9% ） , febrile seizures plus （FS^＋ ） in 62（31.6% ） , FS or FS^＋ with partial seizures in 12（6. 1% ） , afebrile generalized tonic-elonic seizures （AGTCS） in 11 （5.6%） , myoclonic atonic epilepsy in 8 （4. 1% ）, Dravet syndrome in 2（ 1.0% ）, childhood absence epilepsy in 1 （0. 5% ）, FS^＋ with myoelonie seizures in 1 （0. 5% ） , AGTCS and myoelonie seizures in 1 （0. 5% ） , partial seizures in 1 （0. 5% ） , unclassified seizures in 5 （2. 6% ）. Four families were found with SCNIA mutations, including three families with missense mutation （N935H, R101Q, G1382R） and one family with truncation mutation （C373fsx378）. In three families with missense mutations, the phenotypes include FS, FS ^＋ , FS^＋ with partial seizures, andAGTCS. In one family with truncation mutation, the phenotypes included FS, FS ^＋ , and Dravet syndrome. The mother of proband in the family with missense mutation （ R101 Q） and the father of proband in the family with truncation mutation （C373fsx378） were both somatic mosaicism. Both of their phenotypes were FS^＋ . Conclusion The most common phenotypes of GEFS^ ＋ were FS and FS ^＋ , followed by the FS/FS ^＋ with partial seizures and AGTCS. The most severe phenotype was Dravet syndrome. SCN1A mutation rate in GEFS^＋ was about 10%. Missense mutation was common in GEFS^＋ families, few with truncation mutation. Few members of GEFS^＋ families had somatic mosaicism of SCN1A mutations and their phenotypes were relatively mild.