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