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Observational Study
. 2023 Oct;30(10):3341-3346.
doi: 10.1111/ene.15975. Epub 2023 Aug 7.

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

Patrick B Moloney  1   2   3   4 , Hugh Kearney  2   4 , Katherine A Benson  1   2 , Daniel J Costello  2   5 , Gianpiero L Cavalleri  1   2 , Kathleen M Gorman  6   7 , Bryan J Lynch  6 , Norman Delanty  1   2   4
Affiliations
Observational Study

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

Patrick B Moloney et al. Eur J Neurol. 2023 Oct.

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.

Keywords: DEPDC5; NPRL3; GATOR1-related epilepsy; everolimus; precision therapy.

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References

REFERENCES

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