Phenotypic Spectrum and Prognosis of Epilepsy Patients With GABRG2 Variants

Ying Yang; Xueyang Niu; Miaomiao Cheng; Qi Zeng; Jie Deng; Xiaojuan Tian; Yi Wang; Jing Yu; Wenli Shi; Wenjuan Wu; Jiehui Ma; Yufen Li; Xiaoling Yang; Xiaoli Zhang; Tianming Jia; Zhixian Yang; Jianxiang Liao; Yan Sun; Hong Zheng; Suzhen Sun; Dan Sun; Yuwu Jiang; Yuehua Zhang

doi:10.3389/fnmol.2022.809163

Phenotypic Spectrum and Prognosis of Epilepsy Patients With GABRG2 Variants

Front Mol Neurosci. 2022 Mar 14:15:809163. doi: 10.3389/fnmol.2022.809163. eCollection 2022.

Authors

Ying Yang¹, Xueyang Niu¹, Miaomiao Cheng¹, Qi Zeng², Jie Deng³, Xiaojuan Tian³, Yi Wang⁴, Jing Yu⁵, Wenli Shi⁶, Wenjuan Wu⁷, Jiehui Ma⁸, Yufen Li⁹, Xiaoling Yang¹, Xiaoli Zhang¹⁰, Tianming Jia¹⁰, Zhixian Yang¹, Jianxiang Liao², Yan Sun⁵, Hong Zheng⁶, Suzhen Sun⁷, Dan Sun⁸, Yuwu Jiang¹, Yuehua Zhang¹

Affiliations

¹ Department of Pediatrics, Peking University First Hospital, Beijing, China.
² Department of Neurology, Shenzhen Children's Hospital, Shenzhen, China.
³ Department of Neurology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
⁴ Department of Neurology, National Children's Medical Center, Children's Hospital of Fudan University, Shanghai, China.
⁵ Department of Neurology, Children's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hospital of Beijing Children's Hospital, Ürümqi, China.
⁶ Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China.
⁷ Department of Neurology, Hebei Children's Hospital, Shijiazhuang, China.
⁸ Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁹ Department of Pediatrics, Linyi People's Hospital, Linyi, China.
¹⁰ Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Abstract

Objective: This study aimed to obtain a comprehensive understanding of the genetic and phenotypic aspects of GABRG2-related epilepsy and its prognosis and to explore the potential prospects for personalized medicine.

Methods: Through a multicenter collaboration in China, we analyzed the genotype-phenotype correlation and antiseizure medication (ASM) of patients with GABRG2-related epilepsy. The three-dimensional protein structure of the GABRG2 variant was modeled to predict the effect of GABRG2 missense variants using PyMOL 2.3 software.

Results: In 35 patients with GABRG2 variants, 22 variants were de novo, and 18 variants were novel. The seizure onset age was ranged from 2 days after birth to 34 months (median age: 9 months). The seizure onset age was less than 1 year old in 22 patients (22/35, 62.9%). Seizure types included focal seizures (68.6%), generalized tonic-clonic seizures (60%), myoclonic seizures (14.3%), and absence seizures (11.4%). Other clinical features included fever-sensitive seizures (91.4%), cluster seizures (57.1%), and developmental delay (45.7%). Neuroimaging was abnormal in 2 patients, including dysplasia of the frontotemporal cortex and delayed myelination of white matter. Twelve patients were diagnosed with febrile seizures plus, eleven with epilepsy and developmental delay, two with Dravet syndrome, two with developmental and epileptic encephalopathy, two with focal epilepsy, two with febrile seizures, and four with unclassified epilepsy. The proportions of patients with missense variants in the extracellular region and the transmembrane region exhibiting developmental delay were 40% and 63.2%, respectively. The last follow-up age ranged from 11 months to 17 years. Seizures were controlled in 71.4% of patients, and 92% of their seizures were controlled by valproate and/or levetiracetam.

Conclusion: The clinical features of GABRG2-related epilepsy included seizure onset, usually in infancy, and seizures were fever-sensitive. More than half of the patients had cluster seizures. Phenotypes of GABRG2-related epilepsy were ranged from mild febrile seizures to severe epileptic encephalopathies. Most patients with GABRG2 variants who experienced seizures had a good prognosis. Valproate and levetiracetam were effective treatments for most patients.

Keywords: GABRG2; epilepsy; fever-sensitive; infancy; prognosis.