【摘要】：目的:分析1例仡佬族遺傳性癲癇伴熱性驚厥附加癥(GEFS+)家系的臨床特點及基因改變,以期拓展GEEFS+的臨床表型譜,探尋少數(shù)民族GEFS+家系的致病基因,并提高臨床醫(yī)生對本病的認(rèn)識。方法:遵義醫(yī)學(xué)院附屬醫(yī)院兒科神經(jīng)�？崎T診于2015年接診1例仡佬族GEFS+家系,對該家系的臨床資料進(jìn)行總結(jié),并對家系內(nèi)受累成員進(jìn)行癲癇相關(guān)基因的靶向捕獲二代測序。結(jié)果:本家系三代共10名成員,表型受累7例(男6例,女1例),表型包括:(1)特發(fā)性兒童良性枕葉癲癇1例,為先證者:4歲1月女患,臨床表型隨年齡演變:10月齡以熱性驚厥(FS)起病;2歲時出現(xiàn)強直陣攣和失神發(fā)作2種無熱發(fā)作,表型為熱性驚厥附加癥(FS+);3歲1月齡出現(xiàn)局灶性發(fā)作,即PS。先后接受丙戊酸鈉、奧卡西平、左已拉西坦治療,丙戊酸鈉、左已拉西坦短暫有效;但奧卡西平治療無效,且發(fā)作持續(xù)時間延長。(2)Dravet綜合征1例,為先證者叔叔(10歲已逝,死因不詳):出生后反復(fù)驚厥,包括肌陣攣、失神等多種發(fā)作類型,具有熱敏感性,伴精神運動發(fā)育遲滯。(3)21三體綜合征1例,為先證者哥哥(7歲):有FS病史,智力明顯落后,查體見寬眼距、低鼻梁、眼裂小、舌伸出口外等特殊面貌。(4)FS共4例,分別是先證者的祖父、大伯、父親、堂兄。對家系內(nèi)所有受累成員及先證者母親(正常表型)行癲癇相關(guān)基因的二代測序,發(fā)現(xiàn)受累成員均存在SCN1A雜合錯義突變(c.4207CT),突變位于a1亞單位第IV結(jié)構(gòu)域S2-S3跨膜螺旋區(qū)的胞內(nèi)連接環(huán)。堿基突變導(dǎo)致編碼的1596號氨基酸從精氨酸變?yōu)榘腚装彼?p.1596RC),該變異人群突變率極低,不屬于多態(tài)性變化,蛋白質(zhì)預(yù)測為有害。先證者母親未攜帶,符合表型及基因型共分離。結(jié)合文獻(xiàn)復(fù)習(xí),既往未見少數(shù)民族GEFS+家系報道,GEFS+具有表型及遺傳異質(zhì)性。PS屬特發(fā)性局灶性癲癇綜合征,在GEFS+家系中罕見報道。大部分GEFS+病因不明,少數(shù)與SCN1A突變有關(guān)。SCN1A突變導(dǎo)致廣泛的癲癇表型譜,表型輕重與突變位置及類型有關(guān)。但是基因突變與表型之間關(guān)系卻并不固定,提示修飾基因及環(huán)境因素可能也參與了致病。結(jié)論:1.GEFS+具有表型異質(zhì)性;PS可能是GEFS+表型譜之一;2.GEFS+的發(fā)病與SCN1A基因突變有關(guān);鈉通道α亞單位p.1596位點氨基酸改變的患者,鈉通道阻滯劑可加重發(fā)作;3.對治療效果欠佳、懷疑預(yù)后不良的患者進(jìn)行合理的基因檢測及結(jié)果解讀,有助于指導(dǎo)個體化治療及預(yù)后評估;4.GEFS+基因型與表型之間關(guān)系的不確定性有待進(jìn)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 偽 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.
【學(xué)位授予單位】：遵義醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R742.1

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