Everolimus precision therapy for the GATOR1‐related epilepsies: A case series

Abstract Background Pathogenic variants in the GAP activity towards RAGs 1 (GATOR1) complex genes ( DEPDC5 , NPRL2 , NPRL3 ) cause focal epilepsy through hyperactivation of the mechanistic target of rapamycin pathway. We report our experience using everolimus in patients with refractory GATOR1‐related epilepsy. Methods We performed an open‐label observational study of everolimus for drug‐resistant epilepsy caused by variants in DEPDC5, NPRL2 and NPRL3 . Everolimus was titrated to a target serum concentration (5–15 ng/mL). The primary outcome measure was change in mean monthly seizure frequency compared with baseline. Results Five patients were treated with everolimus. All had highly active (median baseline seizure frequency, 18/month) and refractory focal epilepsy (failed 5–16 prior anti‐seizure medications). Four had DEPDC5 variants (three loss‐of‐function, one missense) and one had a NPRL3 splice‐site variant. All patients with DEPDC5 loss‐of‐function variants had significantly reduced seizures (74.3%–86.1%), although one stopped everolimus after 12 months due to psychiatric symptoms. Everolimus was less effective in the patient with a DEPDC5 missense variant (43.9% seizure frequency reduction). The patient with NPRL3 ‐related epilepsy had seizure worsening. The most common adverse event was stomatitis. Conclusions Our study provides the first human data on the potential benefit of everolimus precision therapy for epilepsy caused by DEPDC5 loss‐of‐function variants . Further studies are needed to support our findings.