目的 评估监测结节性硬化（TSC）伴难治性癫痫患者的mTORC1信号通路活性,以及雷帕霉素血药浓度对治疗效果的影响。方法 收集2019年5月至2020年10月就诊的19例TSC伴难治性癫痫患儿的临床资料,分析血细胞mTORC1信号通路活性,检测雷帕霉素血药浓度以评估治疗效果。结果 19例患儿,男11例、女8例,年龄8个月~13岁(中位年龄6岁),检测TSC基因,4例TSC1变异、12例TSC2变异;其中无义变异6例,移码变异4例,错义变异4例,剪切位点变异2例。19例患儿的mTORC1活性均高于正常对照。使用雷帕霉素治疗后,血药浓度3.0~10.7ng/mL,平均浓度为（6.87±2.01）ng/mL。用药后随访半年以上, 12例患儿惊厥控制,7例患儿惊厥发作次数减少50%以上,血药浓度和惊厥控制无相关性。通过监测外周血中mTORC1活性调整用药剂量,发现惊厥控制患儿6例血药平均浓度在6.87ng/mL以下。结论 雷帕霉素血浓度变化波动大,单纯依靠血浓度变化调整剂量不能满足个体化精准用药方案,结合患儿mTORC1活性变化、用药后惊厥控制情况、药物不良反应调整用药剂量,对有效控制发病并避免不良反应提供一种思路,有望为个体化用药提供更精准的治疗方案。

Objective To detect mTORC1 signaling pathway activity in patients with tuberous sclerosis (TSC) and refractory epilepsy, and to evaluate the patients’ response to different concentrations of rapamycin. Methods The clinical data of 19 children with TSC and refractory epilepsy from May 2019 to October 2020 were collected. The mTORC1 signaling pathway activity of blood cells was analyzed and the blood concentration of rapamycin was measured to evaluate the therapeutic effect. Results The age of 19 children (11 boys and 8 girls) ranged from 8 months to 13 years with a median age of 6 years. TSC gene was detected in 19 children, and TSC1 variation was found in 4 children and TSC2 variation in 12 children. Among them, there were 6 cases of nonsense variation, 4 cases of frameshift variation, 4 cases of missense variation and 2 cases of splicing site variation. The mTORC1 activity of patients was higher than that of normal controls. After maintenance treatment with rapamycin, the blood drug concentration fluctuated from 3.0 to 10.7ng/mL, and the average concentration was (6.87±2.01) ng/mL. After at least 6 months of follow-up, convulsion was controlled in 12 cases, and the frequency of convulsion was reduced by more than 50% in 7 cases. There was no correlation between blood drug concentration and convulsion control. By monitoring the activity of mTORC1 in peripheral blood to adjust the drug dose, it was found that the blood drug concentration of 6 children with convulsion control was lower than the average concentration (6.87ng/mL). Conclusion The blood concentration of rapamycin fluctuates greatly, and the dosage adjustment solely depends on the blood concentration change cannot satisfy the individualized precision drug use program. Combined with mTORC1 activity determination, convulsion control and side effects of the drug make it easier for clinicians to evaluate therapeutic effect in patients in real time, and can be used as a reference basis for the use of rapamycin in the treatment of mTOR spectrum diseases.