SLC6A1基因变异相关儿童癫痫5例病例系列报告

背景：SLC6A1基因编码γ 氨基丁酸（GABA）转运蛋白GAT 1，该基因变异可降低GAT 1活性，影响突触间隙GABA的重摄取，在癫、智力障碍和孤独症谱系障碍等神经系统疾病的发病中起重要作用。 目的：总结SLC6A1基因变异相关儿童癫的临床表型及基因变异情况。 设计：病例系列报告。 方法：回顾性收集2007年12月至2021年10月复旦大学附属儿科医院神经科诊治的SLC6A1基因变异相关癫患儿的临床资料，总结其临床表现、治疗效果及基因检测结果，并检索文献，总结已报道SLC6A1基因变异与临床表型的关系。 主要结局指标：临床表型和SLC6A1基因突变位点。 结果：5例患儿纳入分析，男4例，女1例，起病年龄1~3岁，癫发作类型包括：肌阵挛发作4例，失神发作3例，肌阵挛 失张力发作2例，全面性强直阵挛发作1例。5例均存在精神运动发育落后，其中语言发育落后突出。随访5例患儿中4例无发作，丙戊酸单药治疗、丙戊酸联合左乙拉西坦治疗各2例。5例均携带SLC6A1基因杂合变异，且均为新发突变，其中错义变异3个，剪接变异和无义变异各1个。c.1379T>G (p.L460R)、c.1485G>A (p.W495X)尚未见报道。CAT 1蛋白胞外结构域EC3 4和跨膜区TM7是致病性或可能致病性错义变异致氨基酸改变的集中区域。 结论：SLC6A1基因变异所致癫多在幼儿期起病，癫发作类型多样，丙戊酸对其癫发作疗效好，但大多数患儿伴精神运动发育落后。新变异的发现丰富了SLC6A1基因变异谱。

Clinical features and genetic variants among patients with SLC6A1 mutations: A case series report of 5 cases

Background：SLC6A1 encodes the gamma aminobutyric acid (GABA) transporter protein 1 (GAT 1), which is responsible for the reuptake of GABA from the synapse. It plays an important role in the pathogenesis of neurological disorders such as epilepsy, intellectual disability and autism. Objective：To summarize the clinical phenotypes and results of genetic testing in children with SLC6A1 mutations. Design：Case series report. Methods：Patients with SLC6A1 mutations treated in the Department of Neurology, Children's Hospital of Fudan University from December 2007 to October 2021 were enrolled. The clinical data of patients were collected to summarize the clinical manifestations, therapeutic effects and genetic results. The relationship between reported gene variants and clinical phenotypes was summarized through searching databases. Main outcome measures：Mutation sites of SLC6A1 gene and clinical phenotypes. Results：Five children were included in the study, including 4 males and 1 female. They experienced seizure onset from 1 to 3 years old. Among them, 4 had myoclonic seizures，3 cases had absence seizures, 2 cases had myoclonic atonic seizures, and 1 had generalized tonic clonic seizures. Developmental delay was present in all patients. Delayed language development was prominent. Four of the 5 patients became seizure free. Two patients received valproic acid monotherapy, and the other two received valproic acid in combination with levetiracetam. De novo heterozygous SLC6A1 gene mutations were identified in these patients, including 3 missense mutations, 1 splicing mutation and 1 nonsense mutation. Two mutations including c.1379T>G (p.L460R), and c.1485G>A (p.W495X) have not been previously reported in public. Alteration of amino acids of GAT 1 caused by pathogenic or likely pathogenic missense variants are largely clustered around the extracellular domain of EC3 4 and the seventh transmembrane domain. Conclusion：Most of the patients associated with SLC6A1 gene mutations experienced seizure onset in early childhood. The patients presented with various types of seizures. Valproic acid was effective to control seizures. Most of the patients had developmental delays. The discovery of new variants has enriched the spectrum of SLC6A1 gene variants.