Electroencephalography was conducted in both human and mice with the same gene loss. GABAA receptor expression was evaluated by biochemical and imaging approaches. Optic nerve atrophy was evaluated with fundus photography in human while electronic microscopy, visual evoked potential and electroretinography recordings were conducted in mice.
The patient has bilateral optical nerve atrophy. Mice displayed spontaneous seizures, reduced electroretinography oscillatory potential and reduced GABAA receptor α1, β2 and γ2 subunit expression in various brain regions. Electronic microscopy showed that mice also had optic nerve degeneration, as indicated by increased G-ratio, the ratio of the inner axonal diameter to the total outer diameter, suggesting impaired myelination of axons. More importantly, we identified that phenobarbital was the most effective anticonvulsant in mice and the patient\'s seizures were also controlled with phenobarbital after failing multiple anti-seizure drugs.
This study is the first report of haploinsufficiency of two GABR epilepsy genes and visual impairment due to altered axonal myelination and resultant optic nerve atrophy. The study suggests the far-reaching impact of GABR mutations and the translational significance of animal models with the same etiology.
方法:在具有相同基因缺失的人和小鼠中进行脑电图。通过生化和成像方法评估GABAA受体表达。在电子显微镜下,通过眼底照相对人类进行视神经萎缩评估,在小鼠中进行视觉诱发电位和视网膜电图记录。
结果:患者双侧视神经萎缩。小鼠表现出自发性癫痫发作,视网膜电图振荡电位降低,各个脑区GABAA受体α1,β2和γ2亚基表达降低。电子显微镜显示小鼠也有视神经变性,如增加的G比所示,内轴突直径与总外径之比,提示轴突髓鞘形成受损.更重要的是,我们发现苯巴比妥是小鼠中最有效的抗惊厥药,在多种抗惊厥药失效后,患者的癫痫发作也被苯巴比妥控制.
结论:本研究首次报道了两个GABR癫痫基因的单倍体功能不全和由于轴突髓鞘形成改变和视神经萎缩导致的视力损害。该研究表明GABR突变的深远影响以及具有相同病因的动物模型的翻译意义。