IRF2BPL最近被描述为具有多系统回归的神经发育障碍的新原因,癫痫,小脑症状,吞咽困难,肌张力障碍,和锥体的迹象。我们在三名新受试者中描述了与进行性肌阵挛性癫痫(PME)一致的新IRF2BPL表型,并回顾了先前报道的31名患有IRF2BPL相关疾病的受试者的特征。我们的三个先证者,年龄28-40岁,IRF2BPL[c.370C>T,p.(Gln124*)和c.364C>T;p.(Gln122*)]。从童年后期/青春期开始,他们出现了严重的肌阵挛性癫痫,刺激敏感性肌阵鸣,和渐进的认知,演讲,和小脑损伤,与典型的PME综合征一致。皮肤活检显示一个先证者有大量细胞内糖原内含物,提示与其他贮积症相似的致病途径。虽然两名较年长的先证者受到严重影响,年轻人的PME表型较轻,与一些先前报道的IRF2BPL病例部分重叠,这表明其中一些可能是无法识别的PME。有趣的是,所有三名患者都携带蛋白质截断变异,聚集在近端,“卷曲螺旋”结构域周围高度保守的基因区域。我们的数据表明,PME可能是IRF2BPL相关疾病谱中的另一种表型,并表明IRF2BPL是PME的新致病基因。
IRF2BPL has recently been described as a novel cause of neurodevelopmental disorders with multisystemic regression, epilepsy, cerebellar symptoms, dysphagia, dystonia, and pyramidal signs. We describe a novel
IRF2BPL phenotype consistent with progressive myoclonus epilepsy (PME) in three novel subjects and review the features of the 31 subjects with
IRF2BPL-related disorders previously reported. Our three probands, aged 28-40 years, harbored de novo nonsense variants in
IRF2BPL (c.370C > T, p.[Gln124*] and c.364C > T; p.[Gln122*], respectively). From late childhood/adolescence, they presented with severe myoclonus epilepsy, stimulus-sensitive myoclonus, and progressive cognitive, speech, and cerebellar impairment, consistent with a typical PME syndrome. The skin biopsy revealed massive intracellular glycogen inclusions in one proband, suggesting a similar pathogenic pathway to other storage disorders. Whereas the two older probands were severely affected, the younger proband had a milder PME phenotype, partially overlapping with some of the previously reported IRF2BPL cases, suggesting that some of them might be unrecognized PME. Interestingly, all three patients harbored protein-truncating variants clustered in a proximal, highly conserved gene region around the \"coiled-coil\" domain. Our data show that PME can be an additional phenotype within the spectrum of IRF2BPL-related disorders and suggest
IRF2BPL as a novel causative gene for PME.