Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Epilepsia. 2023 May;64(5):1351-1367. doi: 10.1111/epi.17542. Epub 2023 Mar 11.
WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (WWOX-DEE), also known as WOREE (WWOX-related epileptic encephalopathy). We analyzed the epileptology and imaging features of WWOX-DEE, and investigated genotype-phenotype correlations, particularly with regard to survival.
We studied 13 patients from 12 families with WWOX-DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense, allowing individuals to be classified into one of three genotype classes: (1) null/null, (2) null/missense, (3) missense/missense. Differences in survival outcome were estimated using the Kaplan-Meier method.
All patients experienced multiple seizure types (median onset = 5 weeks, range = 1 day-10 months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic (n = 5), myoclonic (n = 2), epileptic spasms (n = 2), focal (n = 1), and migrating focal (n = 1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo-occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p-value = .0085, log-rank test).
Biallelic WWOX pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.
WWOX 是一种常染色体隐性遗传的早发性婴儿发育性癫痫性脑病（WWOX-DEE）的病因，也称为 WOREE（与 WWOX 相关的癫痫性脑病）。我们分析了 WWOX-DEE 的癫痫学和影像学特征，并研究了基因型-表型相关性，特别是与生存相关的相关性。
我们研究了 12 个家系中的 13 名 WWOX-DEE 患者。收集了关于发作症候学、合并症、面型异常和疾病结局的信息。分析了脑电图（EEG）和脑磁共振成像（MRI）数据。对来自我们队列和文献中的致病性 WWOX 变异进行了分类，要么是无义要么是错义，使个体可以分为以下三种基因型类别之一：（1）无义/无义，（2）无义/错义，（3）错义/错义。使用 Kaplan-Meier 方法估计生存结果的差异。
所有患者均经历多种发作类型（中位数发病年龄为 5 周，范围为 1 天至 10 个月），最常见的是局灶性（85%）、癫痫性痉挛（77%）和强直发作（69%）。13 名患者中的 6 名在癫痫发作期间进行了脑电图记录，显示强直（n=5）、肌阵挛（n=2）、癫痫性痉挛（n=2）、局灶性（n=1）和移行性局灶性（n=1）发作。发作间期脑电图显示背景活动缓慢，伴有多灶性放电，主要分布在前额或颞枕区。13 名患者中有 11 名患有运动障碍，最常见的是肌张力障碍。脑 MRI 显示严重的额颞叶、海马和视神经萎缩、薄胼胝体和白质信号异常。致病性变异位于 WWOX 的整个区域，包括错义和无义改变，包括 5 种拷贝数变异（4 种缺失，1 种重复）。生存分析表明，携带两个无义变异的患者死亡率更高（p 值=0.0085，对数秩检验）。
双等位基因 WWOX 致病性变异导致早发性婴儿发育性癫痫性脑病综合征。最常见的发作类型是局灶性发作和癫痫性痉挛。死亡率与突变类型相关；与携带至少一个假定低功能错义致病性变异的患者相比，携带双等位基因无义 WWOX 致病性变异的患者的生存概率显著降低。
