结节性硬化伴难治性癫痫19例mTORC1信号通路活性检测及治疗

doi:10.12372/jcp.2022.21e0800

摘要/Abstract

摘要：

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。

关键词: 结节性硬化, 癫痫, 雷帕霉素, mTORC1活性, 基因

Abstract:

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.

Key words: tuberous sclerosis, epilepsy, rapamycin, mTORC1 activity, gene

贺影忠, 李松, 姚如恩, 王纪文. 结节性硬化伴难治性癫痫19例mTORC1信号通路活性检测及治疗[J]. 临床儿科杂志, 2022, 40(3): 196-201.

HE Yingzhong, LI Song, YAO Ruen, WANG Jiwen. Detection of mTORC1 signaling pathway activity and treatment in 19 children with tuberous sclerosis and refractory epilepsy[J]. Journal of Clinical Pediatrics, 2022, 40(3): 196-201.

图/表 3

表1

19例TSC伴难治性癫痫患者临床、基因变异及抗癫痫药物使用情况"

编号	年龄	性别	癫痫发作类型	抗癫痫药物使用	基因改变	变异类型/ 受累外显子	新生变异
1	8岁	男	全面性强直-阵挛、肌阵挛、局灶性发作	VPA/TPM/OXC /NZP/LEV	TSC2基因, c.5228G>A, p.Arg1743Gln	错义变异 41号外显子	是
2	9岁	男	全面性强直、局灶性发作	OXC/LEV	TSC2基因, c.5228G>A, p.Arg1743Gln	错义变异 41号外显子	是
3	9岁	男	全面性强直-阵挛、惊厥持续状态	LTG/VPA/LCS	TSC1基因, c.560T>C, p.Leu187Pro	错义变异 7号外显子	是
4	11岁	男	全面性强直发作	VPA/OXC/LEV	TSC2基因, c.4952A >G, p.N1651S	错义变异 38号外显子	母亲携带
5	11岁	男	局灶性发作、ESES	OXC/VPA	TSC1基因, c.2503-2delA	剪切位点变异 20号外显子	是
6	3岁	女	肌阵挛、局灶性发作	VPA/TPM/ CZP/ VGB	TSC2基因,c.1361+1G>A	剪切位点变异 13号外显子	父亲携带
7	2岁	女	全面性强直、肌阵挛、局灶性发作	LEV/ OXC	TSC2基因, c.2337C>G, p.Tyr779*	无义变异 21号外显子	是
8	2岁	女	全面性强直-阵挛、肌阵挛发作	VPA/LEV/CZP	TSC2基因, c.4507C>T, p.Q1503*	无义变异 35号外显子	是
9	5岁	男	全面性强直-阵挛发作	OXC/LEV	TSC2基因, c.4027G>T, p.Glu1343*	无义变异 34号外显子	是
10	3岁	女	局灶性发作	LEV/OXC	TSC2基因, c.4375C>T, p.Arg1459*	无义变异 34号外显子	是
11	13岁	男	全面性强直-阵挛、局灶性发作、惊厥持续状态	VPA/OXC/CZP	TSC2基因, c.3412C>T, p.Arg1138*	无义变异 30号外显子	是
12	8月	男	婴儿痉挛症	TPM/VGB/ACTH	TSC2基因, c.4037C>A, p.S1346*	无义变异 34号外显子	父亲携带
13	1岁	男	肌阵挛、局灶性发作、惊厥持续状态	VGB/VPA	TSC2基因, c.5238_ 5255 del.p.His1746 _Arg1751 del	移码变异 41号外显子	是
14	6岁	男	婴儿痉挛症、全面性强直、局灶性发作	ACTH /OXC/TPM	TSC2基因, c.5220_5221 het_insT, p.Ile1741Yfs	移码变异 41号外显子	是
15	7岁	女	肌阵挛、局灶性发作	LEV/VGB	TSC1基因, c.1569_1590 del, p.Ser524*	移码变异 15号外显子	父亲携带
16	2岁	女	全面性强直-阵挛、肌阵挛发作	TPM/VPA/OXC	TSC1基因, c.1739dupT, p.Phe 581Leufs*7	移码变异 15号外显子	是
17	1岁	女	婴儿痉挛症	ACTH/VGB	未见异常	无	无
18	9岁	男	局灶性发作	LEV/OXC	未见异常	无	无
19	6岁	女	全面性强直、局灶性发作	TPM/VPA/LTG	未见异常	无	无

表1

图1

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参考文献 21

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