Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life
Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life
复制标题
DOI：
10.1016/j.ajhg.2014.06.006
复制
发表时间：
2014-07-13
影响因子：
9.8
通讯作者：
Riviere, Jean-Baptiste
中科院分区：
文献类型：
--
作者：
Thevenon, Julien;Milh, Mathieu;Riviere, Jean-Baptiste
癫痫性脑病（Epileptic encephalopathy，EE）是指一组临床和遗传异质性的严重疾病，其特征为癫痫发作、发作间期脑电图异常、精神发育迟滞和/或认知功能减退。我们确定了两个多元化的家庭（包括一个血缘家庭）符合一个常染色体隐性遗传模式的EE。所有7个受影响的个人发展亚临床癫痫发作早在生命的第一天，严重的癫痫病，和深刻的发展迟缓，没有面部畸形。鉴于两个家族临床表现的相似性，我们假设观察到的表型是由于同一基因的突变，我们在三个受影响的个体中进行了外显子组测序。对与常染色体隐性遗传模式一致的基因中的罕见变异的分析导致了SLC 13 A5中突变的鉴定，该突变编码细胞质钠依赖性柠檬酸盐载体，特别是在神经元中表达。在其他家庭成员的共分离分析证实了疾病关联。对另外68名不相关的早发性癫痫性脑病患者进行SLC 13 A5突变筛查，发现另外1名受试者具有SLC 13 A5复合杂合突变，其临床表现与索引受试者相似。突变影响了钠结合的关键残基，这对柠檬酸盐转运至关重要。这些发现强调了在高度异质性条件（如EE）中进行遗传研究的仔细临床表征的价值，并进一步强调了柠檬酸盐代谢在癫痫中的作用。
Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.