遗传性癫痫伴热性惊厥附加症（附1家系报道）

发布时间：2018-07-15 07:55

【摘要】：目的:分析1例仡佬族遗传性癫痫伴热性惊厥附加症(GEFS+)家系的临床特点及基因改变,以期拓展GEEFS+的临床表型谱,探寻少数民族GEFS+家系的致病基因,并提高临床医生对本病的认识。方法:遵义医学院附属医院儿科神经专科门诊于2015年接诊1例仡佬族GEFS+家系,对该家系的临床资料进行总结,并对家系内受累成员进行癫痫相关基因的靶向捕获二代测序。结果:本家系三代共10名成员,表型受累7例(男6例,女1例),表型包括:(1)特发性儿童良性枕叶癫痫1例,为先证者:4岁1月女患,临床表型随年龄演变:10月龄以热性惊厥(FS)起病;2岁时出现强直阵挛和失神发作2种无热发作,表型为热性惊厥附加症(FS+);3岁1月龄出现局灶性发作,即PS。先后接受丙戊酸钠、奥卡西平、左已拉西坦治疗,丙戊酸钠、左已拉西坦短暂有效;但奥卡西平治疗无效,且发作持续时间延长。(2)Dravet综合征1例,为先证者叔叔(10岁已逝,死因不详):出生后反复惊厥,包括肌阵挛、失神等多种发作类型,具有热敏感性,伴精神运动发育迟滞。(3)21三体综合征1例,为先证者哥哥(7岁):有FS病史,智力明显落后,查体见宽眼距、低鼻梁、眼裂小、舌伸出口外等特殊面貌。(4)FS共4例,分别是先证者的祖父、大伯、父亲、堂兄。对家系内所有受累成员及先证者母亲(正常表型)行癫痫相关基因的二代测序,发现受累成员均存在SCN1A杂合错义突变(c.4207CT),突变位于a1亚单位第IV结构域S2-S3跨膜螺旋区的胞内连接环。碱基突变导致编码的1596号氨基酸从精氨酸变为半胱氨酸(p.1596RC),该变异人群突变率极低,不属于多态性变化,蛋白质预测为有害。先证者母亲未携带,符合表型及基因型共分离。结合文献复习,既往未见少数民族GEFS+家系报道,GEFS+具有表型及遗传异质性。PS属特发性局灶性癫痫综合征,在GEFS+家系中罕见报道。大部分GEFS+病因不明,少数与SCN1A突变有关。SCN1A突变导致广泛的癫痫表型谱,表型轻重与突变位置及类型有关。但是基因突变与表型之间关系却并不固定,提示修饰基因及环境因素可能也参与了致病。结论:1.GEFS+具有表型异质性;PS可能是GEFS+表型谱之一;2.GEFS+的发病与SCN1A基因突变有关;钠通道α亚单位p.1596位点氨基酸改变的患者,钠通道阻滞剂可加重发作;3.对治疗效果欠佳、怀疑预后不良的患者进行合理的基因检测及结果解读,有助于指导个体化治疗及预后评估;4.GEFS+基因型与表型之间关系的不确定性有待进一步探索。
[Abstract]:Objective: to analyze the clinical characteristics and gene changes of a family with hereditary epilepsy associated with febrile convulsion additional disorder (GEFS) in Gelao nationality in order to expand the clinical phenotypic spectrum of GEEFS and to explore the pathogenic gene of GEFS family in minority nationalities. And to improve the clinician's understanding of the disease. Methods: a GEFS family of Gelao nationality was diagnosed in 2015. The clinical data of the family were summarized, and the second generation sequence of epileptic-related genes was sequenced for the affected members of the family. Results: there were 10 members in the third generation of this family. There were 7 cases of phenotype involvement (male 6 cases, female 1 case). The phenotypes included: (1) Idiopathic childhood benign occipital epilepsy 1 case, proband 1 year old female. The clinical phenotypes of febrile convulsion (FS) at the age of 10 months after onset of febrile convulsion (FS) appeared tonic-clonus and aphasia at the age of 2 years. The phenotypes were febrile convulsion attach disease (FS) and focal seizure at the age of 3 years and 1 month, I. e., PSs. They were treated successively with sodium valproate, oxcarbazepine, left peracetam, valproate and left lassitam, but oxcarbazepine was ineffective and prolonged. (2) one case of Dravet's syndrome was a proband uncle (10 years old) who had died. Cause of death unknown): recurrent convulsion after birth, including myoclonic, aphasia and other types of seizures, with fever sensitivity, accompanied by mental and motor retardation. (3) trisomy 21 syndrome, 1 case, the elder brother (7 years old) of the proband, has a history of FS, and is obviously retarded in intelligence. There were 4 cases of FS, including grandfather, uncle, father and cousin of the proband. The second generation sequencing of Epilepsy related genes was performed on all the affected members of the family and the mother (normal phenotype) of the proband. It was found that SCN1A heterozygous missense mutation (c. 4207CT) was found in all the involved members, and the mutation was located in the intracellular junctional ring of S2-S3 transmembrane helical region of subunit A1. Base mutation resulted in the transformation of amino acid encoding 1596 from arginine to cysteine (p. 1596RC). The mutation rate of this mutation population was very low, which was not a polymorphic change, and the protein was predicted to be harmful. The mother of the proband was not carried and was cosegregated with phenotype and genotype. According to the review of literature, there was no previous report on the phenotype and genetic heterogeneity of GEFS. PS belongs to idiopathic focal epilepsy syndrome, which is rarely reported in GEFS pedigree. Most of the etiology of GEFS is unknown, and a few are related to SCN1A mutation. SCN1A mutation leads to extensive phenotypic spectrum of epilepsy, and phenotype is related to the location and type of mutation. However, the relationship between gene mutation and phenotype is not fixed, suggesting that the modified gene and environmental factors may also be involved in the pathogenesis. Conclusion: 1. The phenotypic heterogeneity of PS in GEFS may be one of the phenotypic patterns of GEFS. 2. The pathogenesis of GEFS may be related to the mutation of SCN1A gene, and in patients with amino acid changes at p. 1596 of 伪 subunit of sodium channel, sodium channel blocker can aggravate the attack. Reasonable gene detection and result interpretation for patients with poor therapeutic effect and suspected poor prognosis are helpful to guide individualized therapy and prognosis evaluation. 4. The uncertainty of the relationship between genotypes and phenotypes of GEFS needs to be further explored.
【学位授予单位】：遵义医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R742.1

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