目的:WWOX是早期婴儿发育性和癫痫性脑病(WWOX-DEE)的常染色体隐性遗传原因,也称为WOREE(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,尤其是在生存方面。
方法:我们研究了来自12个WWOX-DEE家庭的13名患者。关于癫痫发作符号学的信息,合并症,收集面部畸形和疾病转归。分析EEG和脑MRI数据。来自我们队列和文献的致病性WWOX变体被编码为null或错义,允许将个体分为三个基因型类别之一:1)null/null2)null/missense,3)错觉/错觉。使用Kaplan-Meier方法估计生存结果的差异。
结果:所有患者都经历了多种发作类型(中位发病5周,范围:1天-10个月);最常见的是病灶(85%),癫痫性痉挛(77%)和强直性癫痫(69%)。6/13例患者的IctalEEG记录显示补品(n=5),肌阵挛性(n=2),癫痫性痉挛(n=2),局灶性(n=1)和转移性局灶性(n=1)癫痫发作。发作间脑电图显示背景活动缓慢,多灶性放电,主要在额叶或颞枕区。11/13患者有运动障碍,最常见的肌张力障碍。脑部核磁共振显示严重额颞叶,海马,和视神经萎缩,薄的call体,和白质信号异常。致病性变体位于整个WWOX中,并且包括错义和无效变化,包括5个拷贝数变体(4个缺失;1个重复)。生存分析显示具有两个无效变体的患者处于较高的死亡风险(p值=0.0085,对数秩检验)。
结论:双等位基因WWOX致病变异体可引起早期婴儿发育性和癫痫性脑病综合征。最常见的癫痫发作类型是局灶性癫痫发作和癫痫痉挛。死亡率风险与突变类型相关;与携带至少一个假定的低形错义致病变异的患者相比,具有双等位基因无效WWOX致病变异的患者的生存概率显着降低。
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.