Everolimus as a Precision Therapy for Drug-Resistant Seizures in the GATORopathies
Abstract number :
2.32
Submission category :
12. Genetics / 12A. Human Studies
Year :
2021
Submission ID :
1825540
Source :
www.aesnet.org
Presentation date :
12/5/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:44 AM
Authors :
Patrick Moloney, MD - Beaumont Hospital, the FutureNeuro Research Centre and Royal College of Surgeons in Ireland; Michael Doyle, MD - Neurology - Beaumont Hospital, the FutureNeuro Research Centre and Royal College of Surgeons in Ireland; Hugh Kearney, PhD - Neurology - The FutureNeuro Research Centre and St. Vincent's University Hospital; Katherine Benson, PhD - The FutureNeuro Research Centre and Royal College of Surgeons in Ireland; Hany El-Naggar, MD - Beaumont Hospital, the FutureNeuro Research Centre and Royal College of Surgeons in Ireland; Daniel J Costello, MD - The FutureNeuro Research Centre and Cork University Hospital; Gianpiero Cavalleri, PhD - The FutureNeuro Research Centre and Royal College of Surgeons in Ireland; Norman Delanty, FRCPI - Beaumont Hospital, the FutureNeuro Research Centre and Royal College of Surgeons in Ireland
Rationale: GAP activity towards RAGs 1 complex (GATOR1) functions as a negative regulator of mechanistic target of rapamycin (mTOR) signalling. Heterozygous pathogenic variants of genes encoding GATOR1 (DEPDC5; NPRL2; NPRL3) are associated with drug-resistant epilepsy and a disproportionate risk of sudden unexpected death in epilepsy. Similar to tuberous sclerosis complex (TSC), epileptogenesis in the ‘GATORopathies’ appears to be mediated by excessive mTOR activation. Everolimus, an mTOR inhibitor is an approved treatment for drug-resistant seizures in TSC.
Methods: An observational open-label study of everolimus as a treatment for drug-resistant seizures in GATOR1 epilepsies. People with drug-resistant epilepsy caused by mutations in DEPDC5, NPRL2 or NPLR3 genes were identified by research whole genome sequencing and confirmed at an accredited genetics laboratory.
Results: Four individuals with drug-resistant epilepsy and GATOR1 mutations (3 DEPDC5; 1 NPRL3) have started treatment with everolimus. Three have nocturnal frontal lobe epilepsy, and one has multifocal epilepsy with peri-ictal psychiatric symptoms. Two have co-morbid intellectual disability. All have normal MR imaging of brain. Prior to commencing everolimus, two had daily seizures and two had 2-3 seizures per week. The mean duration of treatment is 12.5 months (range 6-19 months). Two have experienced a greater than 50% improvement in seizure frequency since commencing everolimus. Another patient has experienced improved seizure control (difficult to quantify due to co-morbid intellectual difficulties), language fluency and psychiatric symptoms. The patient with NPRL3-related epilepsy has shown no improvement after 6 months of treatment.
Conclusions: Non-TSC mTORopathies are emerging as an important cause of drug-resistant epilepsy. Diagnostic whole exome/genome sequencing should be considered in cases of refractory non-lesional epilepsy or refractory epilepsy due to focal cortical dysplasia. Preliminary data suggests that everolimus may be an effective targeted therapy for drug-resistant epilepsy caused by mutations in GATOR1 genes.
Funding: Please list any funding that was received in support of this abstract.: This publication has emanated from research supported in part by a research grant from Science Foundation Ireland (SFI) under Grant Number 16/RC/3948 and co-funded under the European Regional Development Fund and by FutureNeuro industry partners. P.B.M. receives funding from the RCSI – Blackrock Clinic StAR MD programme, 2020. N.D. has received an unrestricted grant from Novartis Irl. to support the establishment of an epilepsy genetics registry.
Genetics