Epilepsy plus blindness in microdeletion of GABRA1 and GABRG2 in mouse and human.

1. Exp Neurol. 2023 Nov;369:114537. doi: 10.1016/j.expneurol.2023.114537. Epub 2023 Sep 11. Epilepsy plus blindness in microdeletion of GABRA1 and GABRG2 in mouse and human. Zhang Q(1), Forster-Gibson C(2), Bercovici E(3), Bernardo A(4), Ding F(5), Shen W(6), Langer K(6), Rex T(4), Kang JQ(7). Author information: (1)Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, United States of America; Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Department of Neurology, Nantong University, 19 Qixiu Road, Nantong, JS 226001, PR China. (2)Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga and Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Canada. (3)Division of Neurology, Faculty of Medicine, University of Toronto, Canada. (4)Department of Ophthalmology & Visual Sciences Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37212, United States of America. (5)Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Department of Neurology, Nantong University, 19 Qixiu Road, Nantong, JS 226001, PR China. (6)Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, United States of America. (7)Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, United States of America; Department of Pharmacology, Vanderbilt University, United States of America; Vanderbilt Brain Institute and Vanderbilt Kennedy Center of Human Development, Vanderbilt University, Nashville, TN 37212, United States of America. Electronic address: jingqiong.kang@vanderbilt.edu. OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Copyright © 2023. Published by Elsevier Inc. DOI: 10.1016/j.expneurol.2023.114537 PMCID: PMC10591898 PMID: 37703949 [Indexed for MEDLINE] Conflict of interest statement: Declaration of Competing Interest None of authors declared any conflict of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.