Abstract：
BACKGROUND: Children with tuberous sclerosis complex (TSC) are at high risk for drug-resistant epilepsy (DRE). The ability to stratify those at highest risk for DRE is important for counseling and prompt, aggressive management, necessary to optimize neurocognitive outcomes. Using the extensively phenotyped PREVeNT cohort, we aimed to characterize whether the TSC genotype was associated with DRE.
METHODS: The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to first abnormal electroencephalography, and time to epilepsy onset were compared using Fisher exact test and regression models.
RESULTS: Presence of a TSC2 pathogenic variant was significantly associated with DRE, compared with TSC1 and participants with no pathogenic mutation identified. In fact, all participants with DRE had a TSC2 pathogenic variant. Furthermore, TSC2 variants expected to result in no protein product were associated with higher risk for DRE. Finally, TSC1 pathogenic variants were associated with later-onset epilepsy, on average 21.2 months later than those with other genotypes.
CONCLUSIONS: Using a comprehensively phenotyped cohort followed from infancy, this study is the first to delineate genotype-phenotype correlations for epilepsy severity and onset in children with TSC. Patients with TSC2 pathogenic variants, especially TSC2 pathogenic variants predicted to result in lack of TSC2 protein, are at highest risk for DRE, and are likely to have earlier epilepsy onset than those with TSC1. Clinically, these insights can inform counseling, surveillance, and management.
METHODS: The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to first abnormal electroencephalography, and time to epilepsy onset were compared using Fisher exact test and regression models.
RESULTS: Presence of a TSC2 pathogenic variant was significantly associated with DRE, compared with TSC1 and participants with no pathogenic mutation identified. In fact, all participants with DRE had a TSC2 pathogenic variant. Furthermore, TSC2 variants expected to result in no protein product were associated with higher risk for DRE. Finally, TSC1 pathogenic variants were associated with later-onset epilepsy, on average 21.2 months later than those with other genotypes.
CONCLUSIONS: Using a comprehensively phenotyped cohort followed from infancy, this study is the first to delineate genotype-phenotype correlations for epilepsy severity and onset in children with TSC. Patients with TSC2 pathogenic variants, especially TSC2 pathogenic variants predicted to result in lack of TSC2 protein, are at highest risk for DRE, and are likely to have earlier epilepsy onset than those with TSC1. Clinically, these insights can inform counseling, surveillance, and management.
摘要：
背景：结节性硬化症（TSC）儿童发生耐药性癫痫（DRE）的风险很高。对DRE风险最高的人群进行分层的能力对于咨询和提示很重要，积极的管理，优化神经认知结果是必要的。使用广泛表型的PREVENT队列，我们旨在确定TSC基因型是否与DRE相关.
方法：研究组（N=70）包括年龄小于或等于6个月的TSC参与者，他们有详细的癫痫和其他表型和基因型数据，前瞻性收集作为PREVENT试验的一部分。DRE的基因型-表型相关性，第一次异常脑电图的时间，使用Fisher精确检验和回归模型比较癫痫发作时间。
结果：TSC2致病变异体的存在与DRE显著相关，与TSC1和未发现致病突变的参与者进行比较。事实上,所有DRE患者均有TSC2致病变异.此外，预期不会产生蛋白质产物的TSC2变体与较高的DRE风险相关。最后,TSC1致病变异与晚发性癫痫有关，平均比其他基因型晚21.2个月。
结论：使用从婴儿期开始的全面表型队列，这项研究首次描述了TSC患儿癫痫严重程度和发作的基因型-表型相关性.TSC2致病变异的患者，特别是TSC2致病变异预测导致缺乏TSC2蛋白，DRE的风险最高，并且可能比TSC1患者更早发作癫痫。临床上,这些见解可以为咨询提供信息，监视,和管理。
方法：研究组（N=70）包括年龄小于或等于6个月的TSC参与者，他们有详细的癫痫和其他表型和基因型数据，前瞻性收集作为PREVENT试验的一部分。DRE的基因型-表型相关性，第一次异常脑电图的时间，使用Fisher精确检验和回归模型比较癫痫发作时间。
结果：TSC2致病变异体的存在与DRE显著相关，与TSC1和未发现致病突变的参与者进行比较。事实上,所有DRE患者均有TSC2致病变异.此外，预期不会产生蛋白质产物的TSC2变体与较高的DRE风险相关。最后,TSC1致病变异与晚发性癫痫有关，平均比其他基因型晚21.2个月。
结论：使用从婴儿期开始的全面表型队列，这项研究首次描述了TSC患儿癫痫严重程度和发作的基因型-表型相关性.TSC2致病变异的患者，特别是TSC2致病变异预测导致缺乏TSC2蛋白，DRE的风险最高，并且可能比TSC1患者更早发作癫痫。临床上,这些见解可以为咨询提供信息，监视,和管理。
