Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China.
Institute of Biological Information Processing (IBI-1), Molecular and Cell Physiology, Jülich Research Center, Jülich, Germany.
Epilepsia. 2021 Jun;62(6):1401-1415. doi: 10.1111/epi.16906. Epub 2021 May 5.
This study was undertaken to expand the phenotypic and genetic spectrum of CLCN4-related epilepsy and to investigate genotype-phenotype correlations.
We systematically reviewed the phenotypic and genetic spectrum of newly diagnosed and previously reported patients with CLCN4-related epilepsy. Three novel variants identified in four patients reported in this study were evaluated through in silico prediction and functional analysis by Western blot, immunofluorescence, and electrophysiological measurements.
Epilepsy was diagnosed in 54.55% (24/44) of individuals with CLCN4-related disorders and was drug-resistant in most cases. Of 24 patients, 15 had epileptic encephalopathy and four died at an early age; 69.57% of patients had seizure onset within the first year of life. Myoclonic seizures are the most common seizure type, and 56.25% of patients presented multiple seizure types. Notably, seizure outcome was favorable in individuals with only one seizure type. All patients showed intellectual disability, which was severe in 65.22% of patients. Additional common features included language delay, behavioral disorders, and dysmorphic features. Five patients benefitted from treatment with lamotrigine. Most variants, which were mainly missense (79.17%), were inherited (70.83%). Whereas frameshift, intragenic deletion, or inherited variants were associated with milder phenotypes, missense or de novo variants led to more severe phenotypes. All evaluated CLCN4 variants resulted in loss of function with reduced ClC-4 currents. Nonetheless, genotype-phenotype relationships for CLCN4-related epilepsy are not straightforward, as phenotypic variability was observed in recurrent variants and within single families.
Pathogenic CLCN4 variants contribute significantly to the genetic etiology of epilepsy. The phenotypic spectrum of CLCN4-related epilepsy includes drug-resistant seizures, cognitive and language impairment, behavioral disorders, and congenital anomalies. Notably, the mutation type and the number of seizure types correlate with the severity of the phenotype, suggesting its use for clinical prognosis. Lamotrigine can be considered a therapeutic option.
本研究旨在扩展 CLCN4 相关癫痫的表型和遗传谱，并探讨基因型-表型相关性。
我们系统地回顾了新诊断和以前报道的 CLCN4 相关癫痫患者的表型和遗传谱。在本研究中报告的 4 名患者中发现的 3 种新变体通过计算机预测和 Western blot、免疫荧光和电生理测量的功能分析进行了评估。
CLCN4 相关疾病患者中 54.55%（24/44）被诊断为癫痫，且大多数病例为耐药性癫痫。24 名患者中，15 名患有癫痫性脑病，4 名在早期死亡；69.57%的患者在生命的第一年就出现了癫痫发作。肌阵挛性发作是最常见的发作类型，56.25%的患者出现多种发作类型。值得注意的是，只有一种发作类型的患者预后良好。所有患者均存在智力障碍，其中 65.22%的患者为重度智力障碍。其他常见特征包括语言发育迟缓、行为障碍和发育畸形。5 名患者受益于拉莫三嗪治疗。大多数变异主要为错义（79.17%），为遗传变异（70.83%）。虽然移码、内含子缺失或遗传变异与较轻的表型相关，但错义或新生变异导致更严重的表型。所有评估的 CLCN4 变体均导致 ClC-4 电流减少的功能丧失。然而，CLCN4 相关癫痫的基因型-表型关系并不简单，因为在反复出现的变异和单个家族中都观察到了表型的可变性。
致病性 CLCN4 变体是癫痫遗传病因的重要因素。CLCN4 相关癫痫的表型谱包括耐药性发作、认知和语言障碍、行为障碍和先天异常。值得注意的是，突变类型和发作类型的数量与表型的严重程度相关，提示其可用于临床预后。拉莫三嗪可被视为一种治疗选择。
