Zhang Dongming, Guo Jing, Lin Zisheng, Yan Hongjun, Peng Kai, Fei Linxia, Zhai Qiongxiang, Zou Dongfang, Zhong Jiayi, Ding Yan, Ye Hong, Wang Pengyu, Wang Jie, Luo Sheng, Li Bingmei, Li Bin, Liao Weiping
Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China.
Epilepsy Center, Guangdong Sanjiu Brain Hospital, Guangzhou, 510520, China.
Acta Epileptol. 2024 Nov 7;6(1):38. doi: 10.1186/s42494-024-00177-0.
The SLC2A1 gene plays a vital role in brain energy metabolism. SLC2A1 variants have been reported to be associated with early-onset refractory seizures. This study aims to explore the association between the SLC2A1 gene and late-onset epilepsy.
Trios-based whole-exome sequencing was performed on patients with epilepsy without acquired etiologies. The pathogenicity of the variants was assessed according to the American College of Medical Genetics and Genomics (ACMG) guidelines.
A total of 14 heterozygous SLC2A1 variants were identified in 16 unrelated families. The variants were evaluated as "pathogenic" or "likely pathogenic" according to the ACMG guidelines. Ten cases (62.5%) presented with infantile onset seizures and developmental delay/intellectual disability and were diagnosed with developmental and epileptic encephalopathy (DEE). The other six cases (37.5%) exhibited late-onset seizures and normal development. They were diagnosed with idiopathic partial epilepsy (n = 2) or idiopathic generalized epilepsy (n = 4). Further analysis showed that DEE-associated variants tended to cluster in the transmembrane region, whereas the mild epilepsy-associated variants tended to locate in regions outside the transmembrane region, suggesting a potential molecular sub-regional effect. A total of 15 cases had delayed diagnosis, with the longest delay being 22 years. The SLC2A1 expression stage, which is expressed at relatively high level throughout the whole life span, from the embryonic to adult stages with two peaks at approximately four and 14 years, is generally consistent with the seizure onset age. In addition, patients with early-onset age had variants that were potentially associated with severe damage, suggesting a potential correlation between the age of disease onset and the damaging effects of the variants.
SLC2A1 variants are associated with late-onset epilepsy, which is consistent with the genetic-dependent stage feature of SLC2A1. Early genetic diagnosis is important for treatment of patients with SLC2A1 variants.
SLC2A1基因在脑能量代谢中起关键作用。据报道，SLC2A1基因变异与早发性难治性癫痫有关。本研究旨在探讨SLC2A1基因与晚发性癫痫之间的关联。
对无获得性病因的癫痫患者进行基于三联体的全外显子测序。根据美国医学遗传学与基因组学学会（ACMG）指南评估变异的致病性。
在16个无关家庭中总共鉴定出14个杂合SLC2A1基因变异。根据ACMG指南，这些变异被评估为“致病”或“可能致病”。10例（62.5%）表现为婴儿期发作性癫痫和发育迟缓/智力残疾，被诊断为发育性和癫痫性脑病（DEE）。另外6例（37.5%）表现为晚发性癫痫且发育正常。他们被诊断为特发性局灶性癫痫（n = 2）或特发性全面性癫痫（n = 4）。进一步分析表明，与DEE相关的变异倾向于聚集在跨膜区域，而与轻度癫痫相关的变异倾向于位于跨膜区域之外的区域，提示潜在的分子亚区域效应。共有15例诊断延迟，最长延迟时间为22年。SLC2A1在从胚胎期到成年期的整个生命周期中均以相对较高水平表达，在大约4岁和14岁时有两个峰值，其表达阶段与癫痫发作起始年龄总体一致。此外，发病年龄早的患者具有可能与严重损害相关的变异，提示疾病发病年龄与变异的损害作用之间存在潜在关联。
SLC2A1基因变异与晚发性癫痫有关，这与SLC2A1基因的遗传依赖性阶段特征一致。早期基因诊断对SLC2A1基因变异患者的治疗很重要。
