PDF(Pubmed)
Abstract：
GABAA receptor subunit gene (GABR) mutations are significant causes of epilepsy, including syndromic epilepsy. This report for the first time, describes intractable epilepsy and blindness due to optic atrophy in our patient, who has a microdeletion of the GABRA1 and GABRG2 genes. We then characterized the molecular phenotypes and determined patho-mechanisms underlying the genotype-phenotype correlations in a mouse model who is haploinsufficient for both genes (Gabra1+/-/Gabrg2+/- mouse).
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.
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.
摘要：
目的：GABAA受体亚单位基因（GABR）突变是癫痫的重要原因，包括综合征性癫痫。这份报告第一次，描述了我们患者由于视神经萎缩引起的难治性癫痫和失明，具有GABRA1和GABRG2基因的微缺失。然后，我们对分子表型进行了表征，并确定了两种基因（Gabra1/-/Gabrg2/-小鼠）单倍不足的小鼠模型中基因型-表型相关性的病理机制。
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。
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。
