Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies
Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies
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GABRA1基因的表型谱：从全身性癫痫到严重癫痫性脑病
DOI：
10.1212/wnl.0000000000003087
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发表时间：
2016-09-13
期刊：
影响因子：
9.9
通讯作者：
Maljevic, Snezana
中科院分区：
文献类型：
--
作者：
Johannesen, Katrine;Marini, Carla;Maljevic, Snezana
目的：为了描绘表型异质性，我们描述了一组 GABRA1 基因突变患者的临床特征。方法：通过国际合作确定 GABRA1 突变患者。收集临床、脑电图和遗传数据。使用非洲爪蟾卵母细胞表达系统对 4 个选定的突变进行功能分析。结果：该研究包括 16 名新先证者和 3 名在 GABRA1 基因中存在致病突变的其他家庭成员。表型谱各不相同，从未特指的癫痫 (1)、青少年肌阵挛性癫痫 (2)、光敏性特发性全身性癫痫 (1)、全身性癫痫伴热性惊厥加 (1) 到严重癫痫性脑病 (11)。在癫痫性脑病组中，患者从出生第一天到 15 个月期间开始癫痫发作，平均 7 个月。所有患者的主要癫痫发作类型为强直阵挛（9 名参与者（56%））和肌阵挛性癫痫发作（5 名（31%））。脑电图显示 6 名患者 (37%) 出现全身光阵发性反应。四个选定的功能性突变研究显示功能丧失，但没有明确的基因型-表型相关性。结论：GABRA1 突变对良性和严重癫痫综合征的遗传病因学做出了重大贡献。对光刺激有病理反应的肌阵挛和强直阵挛发作是轻度和重度表型的常见和共有特征。
Objective:To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations.Methods:Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected. Functional analysis of 4 selected mutations was performed using the Xenopus laevis oocyte expression system.Results:The study included 16 novel probands and 3 additional family members with a disease-causing mutation in the GABRA1 gene. The phenotypic spectrum varied from unspecified epilepsy (1), juvenile myoclonic epilepsy (2), photosensitive idiopathic generalized epilepsy (1), and generalized epilepsy with febrile seizures plus (1) to severe epileptic encephalopathies (11). In the epileptic encephalopathy group, the patients had seizures beginning between the first day of life and 15 months, with a mean of 7 months. Predominant seizure types in all patients were tonic-clonic in 9 participants (56%) and myoclonic seizures in 5 (31%). EEG showed a generalized photoparoxysmal response in 6 patients (37%). Four selected mutations studied functionally revealed a loss of function, without a clear genotype-phenotype correlation.Conclusions:GABRA1 mutations make a significant contribution to the genetic etiology of both benign and severe epilepsy syndromes. Myoclonic and tonic-clonic seizures with pathologic response to photic stimulation are common and shared features in both mild and severe phenotypes.