Everolimus Precision Therapy in Mri-negative nprl2/3-related Epilepsy
Abstract number :
1.111
Submission category :
12. Genetics / 12A. Human Studies
Year :
2024
Submission ID :
1300
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Evelina Carapancea, MD – Institute of Neuroscience (IONS), Catholic University of Louvain, Brussels, Belgium
Helene Verhelst, MD, PhD – Division of Pediatric Neurology, Department of Pediatrics, Ghent University Hospital, University of Ghent, Ghent, Belgium
Maria Roberta Cilio, MD, PhD – Division of Pediatric Neurology, Department of Pediatrics, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
Rationale: mTOR, a key regulator of cell growth and metabolism, is inhibited by the GATOR1 complex. Hyperactivation of mTOR pathway has been observed in patients with loss-of-function variants in DEPDC5 and NPRL2/3 genes encoding for GATOR1 complex. Everolimus, a synthetic mTOR inhibitor, showed efficacy in DEPDC5-epilepsy.1 Seizure worsening was observed in the only patient with NPRL3-epilepsy trialed on everolimus.1 There is one single study reporting on efficacy of everolimus in MRI-negative patients with DEPDC5 and NPRL3, but no report in NPRL2-epilepsy.
Methods: Everolimus was administered as add-on in a 27-year old and a 3-year old patients with frequent episodes of tonic status epilepticus activated by sleep. Both patients had negative MRI, and seizures resistant to multiple ASMs. Genetic testing revealed pathogenic variants in the NPRL2 and NPRL3 genes, respectively. A 60-day baseline seizure frequency and monthly seizure frequency during treatment were assessed. Primary outcome was 50% seizure reduction. Everolimus was provided via Novartis Managed Access. Novartis conducted a scientific accuracy and intellectual property review, and has not influenced the content of the publication.
Results: Patient 1 is a 27-year-old, intellectually normal male, with a de novo NPRL3 variant (p.(C343Sfs*17)) and long-standing, neonatal onset, intractable epilepsy with focal tonic seizures arising from both hemispheres. His baseline seizure frequency was 70 seizures per week, and 13 ASMs have been ineffective. Transient improvement was seen with carbamazepine and vigabatrin. Everolimus was progressively increased up to 7.5 mg/day with trough levels ranging between 6.2 and 8.5 ng/mL.
Patient 2 is a 3-year-old boy with language delay and intractable epilepsy, seizure onset at 5 months, with sleep-activated focal tonic seizures arising from both hemispheres, resistant to 14 ASMs, KD, and VNS, with a baseline of 23 seizures per month. He has a NPRL2 variant (p.(D253GfsTer5)). Everolimus was administered at 3.75 mg/day with a stable trough level of 6.57 ng/mL.
At the 6 month follow-up, patients showed a 80% (Figure 1), and 75% reduction in seizure frequency, respectively. Patient 1 has 13 seizures and up to 4 seizure-free days per week. Patient 2 has 6 seizures per month, and shows continuous improvement in language acquisition. The treatment was well tolerated by both patients.
Conclusions:
Our data suggest that everolimus may be an effective precision therapy for drug-resistant NPRL2/3-epilepsies, particularly in MRI-negative patients who cannot benefit from surgical treatment. Larger studies are necessary to validate and support this treatment.
Reference
1. Moloney PB, Kearney H, Benson KA, et al. Everolimus precision therapy for the GATOR1-related epilepsies: A case series. Eur J Neurol. 2023;30(10):3341-3346.
Funding: E. Carapancea is supported by a PhD bursary from the Marguerite-Marie Delacroix Support Fund. M.R. Cilio received research funding from the Fonds de Recherche Clinique (FRC), Cliniques universitaires Saint-Luc.
Genetics