SLC6A1基因突變致兒童失神發(fā)作1例并文獻(xiàn)復(fù)習(xí)

張赟健 周水珍

SLC6A1基因突變致兒童失神發(fā)作1例并文獻(xiàn)復(fù)習(xí)

張赟健 周水珍

1 病例資料

入院體格檢查：神志清，皮膚未見特殊色素斑，無特殊面容，顱神經(jīng)檢查未見異常，雙側(cè)瞳孔等大等圓，對光反應(yīng)靈敏，伸舌居中，頸軟，四肢肌力、肌張力正常，雙側(cè)膝腱反射可引出，病理征(-)，無震顫，共濟(jì)運(yùn)動(dòng)未見異常。

圖1臨床信息時(shí)間軸

注 VPA：丙戊酸鈉；LEV：左乙拉西坦；LTG：拉莫三嗪

輔助檢查：患兒10歲時(shí)頭顱MRI未見明顯異常(圖2)。8歲7個(gè)月行視頻腦電圖(VEEG)檢查，清醒安靜閉眼時(shí)雙側(cè)枕區(qū)8Hz低至中波幅α節(jié)律，雙側(cè)基本對稱，調(diào)節(jié)調(diào)幅欠佳，閃光刺激未見相關(guān)異常放電，醒睡各期左側(cè)顳區(qū)尖慢波發(fā)放，醒睡廣泛性3～3.5 Hz棘慢波陣發(fā)，并監(jiān)測到清醒期多次典型失神發(fā)作(圖3)。12歲行瑞文智力測試IQ為44。

圖2患兒10歲頭顱MRI

注 頭顱橫斷位T1(左)與T2(右)加權(quán)圖像

圖3患兒8歲時(shí)視頻腦電圖皮膚表現(xiàn)

注 走紙速度30 mm·s-1，靈敏度100 μV·cm-1，高頻濾波70 Hz

圖4患兒及其父母SLC6A1基因測序圖

注 A：患兒SLC6A1基因c.370+1Ggt;T雜合剪切突變(箭頭)；B和C：患兒父和母相同位置堿基未見突變(箭頭)

表1 12例SLC6A1基因突變者臨床資料和基因突變位點(diǎn)

獲得患兒及父母知情同意后，對患兒家系行全外顯子檢測(WES)并行Sanger驗(yàn)證，發(fā)現(xiàn)SLC6A1基因存在雜合剪切突變c.370+1Ggt;T，父母驗(yàn)證未檢測到該變異，為患兒的新發(fā)變異(圖4)。在人類基因突變數(shù)據(jù)庫專業(yè)版(HGMD)、千人基因組數(shù)據(jù)庫和ExAC數(shù)據(jù)集均無該位點(diǎn)突變及單核苷酸多態(tài)性(SNP)報(bào)道。對c.370+1Ggt;T進(jìn)行致病性分析，該位點(diǎn)為罕見變異，位于經(jīng)典的剪切位，應(yīng)用MutationTaster預(yù)測為有害變異。

2 文獻(xiàn)復(fù)習(xí)

3 討論

GABA是哺乳動(dòng)物中樞神經(jīng)系統(tǒng)重要的抑制性神經(jīng)遞質(zhì)，調(diào)節(jié)抑制性突觸傳遞作用，從而防止腦內(nèi)神經(jīng)元過度興奮[12]。神經(jīng)突觸間隙中的GABA主要通過突觸前膜、神經(jīng)膠質(zhì)細(xì)胞膜或囊泡膜上的GABA 轉(zhuǎn)運(yùn)體(GAT)的攝取，使其在突觸間隙中的濃度降低，從而減少或終止GABA的抑制性突觸傳遞。GAT-1是電壓依賴性GABA轉(zhuǎn)運(yùn)體中一種重要的亞型，由SLC6A1基因編碼。

SLC6A1基因定位于染色體3p25.3[13]，該基因在人類和其他動(dòng)物發(fā)育期與成熟大腦中均廣泛表達(dá)，其編碼的GABA轉(zhuǎn)運(yùn)體GAT-1主要位于GABA能中間神經(jīng)元的軸突和神經(jīng)終端，GAT-1可從突觸間隙重?cái)z取GABA。Nelson等[14]最早于1990年對編碼人類大腦神經(jīng)遞質(zhì)GABA轉(zhuǎn)運(yùn)體的cDNA克隆并測序。該cDNA含有1個(gè)編碼599個(gè)氨基酸的疏水蛋白的開放閱讀框，具有12個(gè)跨膜片段。Hirunsatit等[15]報(bào)告，SLC6A1基因包含16個(gè)外顯子，長度約46.5 kb。

動(dòng)物研究發(fā)現(xiàn)，GABA轉(zhuǎn)運(yùn)體Gat1功能缺陷大鼠存在自發(fā)性腦電棘慢波發(fā)放及失神發(fā)作，Gat1敲除大鼠或使用Gat-1抑制劑的大鼠，腦電圖均表現(xiàn)為類似SLC6A1基因突變患者失神發(fā)作的廣泛性棘慢波異常放電[16]。因此，動(dòng)物模型研究證實(shí)了SLC6A1突變者的臨床表型。

[1] Carvill GL, Mcmahon JM, Schneider A, et al. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am J Hum Genet, 2015, 96(5): 808-815

[2] Dikow N, Maas B, Karch S, et al. 3p25. 3 microdeletion of GABA transporters SLC6A1 and SLC6A11 results in intellectual disability, epilepsy and stereotypic behavior. Am J Med Genet A, 2014, 164A(12): 3061-3068

[3] Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature, 2012, 485(7397): 237-241

[4] Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet, 2012, 380(9854): 1674-1682

[5] Palmer S, Towne M C, Pearl P L, et al. SLC6A1 mutation and ketogenic diet in epilepsy with myoclonic-atonic seizures. Pediatr Neurol, 2016, 64: 77-79

[6] Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the international league against epilepsy: position paper of the ILAE commission for classification and terminology. Epilepsia, 2017, 58(4): 522-530

[7] Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia, 2017, 58(4): 512-521

[8] Yalcin O. Genes and molecular mechanisms involved in the epileptogenesis of idiopathic absence epilepsies. Seizure, 2012, 21(2): 79-86

[9] Everett K, Chioza B, Aicardi J, et al. Linkage and mutational analysis of CLCN2 in childhood absence epilepsy. Epilepsy Res, 2007, 75(2-3): 145-153

[10] Guo Y, Yan KP, Qu Q, et al. Common variants of KCNJ10 are associated with susceptibility and anti-epileptic drug resistance in Chinese genetic generalized epilepsies. PLoS One, 2015, 10(4): e124896

[11] Addis L, Rosch RE, Valentin A, et al. Analysis of rare copy number variation in absence epilepsies. Neurol Genet, 2016, 2(2): e56

[12] Scimemi A. Structure, function, and plasticity of GABA transporters. Front Cell Neurosci, 2014, 8: 161

[13] Huang F, Shi LJ, Heng HH, et al. Assignment of the human GABA transporter gene (GABATHG) locus to chromosome 3p24-p25. Genomics, 1995, 29(1): 302-304

[14] Nelson H, Mandiyan S, Nelson N. Cloning of the human brain GABA transporter. FEBS Lett, 1990, 269(1): 181-184

[15] Hirunsatit R, Ilomaki R, Malison R, et al. Sequence variation and linkage disequilibrium in the GABA transporter-1 gene (SLC6A1) in five populations: implications for pharmacogenetic research. BMC Genet, 2007, 8: 71

[16] Cope DW, Di Giovanni G, Fyson SJ, et al. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med, 2009, 15(12): 1392-1398

[17] Whitlow RD, Sacher A, Loo DD, et al. The anticonvulsant valproate increases the turnover rate of gamma-aminobutyric acid transporters. J Biol Chem, 2003, 278(20): 17716-17726

[18] Salat K, Podkowa A, Malikowska N, et al. Novel, highly potent and in vivo active inhibitor of GABA transporter subtype 1 with anticonvulsant, anxiolytic, antidepressant and antinociceptive properties. Neuropharmacology, 2017, 113(Pt A): 331-342

[19] Schousboe A, Madsen KK, Barker-Haliski ML, et al. The GABA synapse as a target for antiepileptic drugs: a historical overview focused on GABA transporters. Neurochem Res, 2014, 39(10): 1980-1987

[20] Yuan FF, Gu X, Huang X, et al. SLC6A1 gene involvement in susceptibility to attention-deficit/hyperactivity disorder: A case-control study and gene- environment interaction. Prog Neuropsychopharmacol Biol Psychiatry, 2017, 77: 202-208

[21] Thoeringer CK, Ripke S, Unschuld PG, et al. The GABA transporter 1 (SLC6A1): a novel candidate gene for anxiety disorders. J Neural Transm (Vienna), 2009, 116(6): 649-657

2017-10-09

2017-10-15)

(本文編輯：張崇凡)

SLC6A1genemutationinachildwithabsenceseizuresandliteraturereview

ZHANGYun-jian,ZHOUShui-zhen

(DepartmentofNeurology,Children'sHospitalofFudanUniversity,Shanghai201102,China)

ZHOU Shui-zhen, E-mail: szzhou@shmu.edu.cn

ObjectiveTo explore the clinical features and genetic characteristics of patients withSLC6A1 gene mutations.MethodsThe clinical data of a patient withSLC6A1 gene mutation from Children's hospital of Fudan university were collected. The related literatures were searched from Wanfang Data Service Platform, China National Knowledge Infrastructure, National Center for Biotechnology Information and Pubmed (up to June 2017) by using search terms "SLC6A1" and "epilepsy". The clinical features, electroencephalogram and treatment of the patients withSLC6A1 gene mutations were studied.ResultsA boy with absence seizures and psychomotor retardation was followed up whose first attack happened at the age of 3 years. The seizures manifested as absence with eyelid flutter, with no limb convulsions and the duration varied from seconds to dozens of seconds. The seizure frequency ranged from once in several weeks to daily cluster seizures. Electroencephalogram was abnormal because of bursts of generalized 3 to 3.5 Hz spike-and-wave activity. Whole exome-sequencing study (trios) identified a de novo splicing mutation of c.370+1Ggt;T inSLC6A1. It was not previously reported in public database and predicted deleterious by Mutation Taster. And this was the first case ofSLC6A1 gene mutation in China. A total of twelve patients including the present case withSLC6A1 gene mutation were studied. Among them, 11 cases had absence seizures, including 5 typical absence and 5 absences with eyelid myoclonias, the other one case was atypical absence. Ten mutations were identified, including 5 missense mutations, 2 truncated mutations, 1 frameshift mutation, 1 splicing mutation and one with chromosome microdeletion.ConclusionSLC6A1 gene mutation is one of the causes of absence seizures with mental retardation or developmental regression.

Epilepsy; Absence; Gene;SLC6A1

上海市衛(wèi)生和計(jì)劃生育委員會(huì)科研課題：201640065；上海市申康新興前沿項(xiàng)目：SHDC12015113

復(fù)旦大學(xué)附屬兒科醫(yī)院神經(jīng)科 上海，201102

周水珍，E-mail：szzhou@shmu.edu.cn

10.3969/j.issn.1673-5501.2017.05.010