Epilepsy in the mTORopathies....pdf (791.57 kB)
Epilepsy in the mTORopathies: opportunities for precision medicine
journal contribution
posted on 2023-11-13, 15:23 authored by Patrick MoloneyPatrick Moloney, Gianpiero CavalleriGianpiero Cavalleri, Norman DelantyNorman DelantyThe mechanistic target of rapamycin signalling pathway serves as a ubiquitous regulator of cell metabolism, growth, proliferation and survival. The main cellular activity of the mechanistic target of rapamycin cascade funnels through mechanistic target of rapamycin complex 1, which is inhibited by rapamycin, a macrolide compound produced by the bacterium Streptomyces hygroscopicus. Pathogenic variants in genes encoding upstream regulators of mechanistic target of rapamycin complex 1 cause epilepsies and neurodevelopmental disorders. Tuberous sclerosis complex is a multisystem disorder caused by mutations in mechanistic target of rapamycin regulators TSC1 or TSC2, with prominent neurological manifestations including epilepsy, focal cortical dysplasia and neuropsychiatric disorders. Focal cortical dysplasia type II results from somatic brain mutations in mechanistic target of rapamycin pathway activators MTOR, AKT3, PIK3CA and RHEB and is a major cause of drug-resistant epilepsy. DEPDC5, NPRL2 and NPRL3 code for subunits of the GTPase-activating protein (GAP) activity towards Rags 1 complex (GATOR1), the principal amino acid-sensing regulator of mechanistic target of rapamycin complex 1. Germline pathogenic variants in GATOR1 genes cause non-lesional focal epilepsies and epilepsies associated with malformations of cortical development. Collectively, the mTORopathies are characterized by excessive mechanistic target of rapamycin pathway activation and drug-resistant epilepsy. In the first largescale precision medicine trial in a genetically mediated epilepsy, everolimus (a synthetic analogue of rapamycin) was effective at reducing seizure frequency in people with tuberous sclerosis complex. Rapamycin reduced seizures in rodent models of DEPDC5- related epilepsy and focal cortical dysplasia type II. This review outlines a personalized medicine approach to the management of epilepsies in the mTORopathies. We advocate for early diagnostic sequencing of mechanistic target of rapamycin pathway genes in drug-resistant epilepsy, as identification of a pathogenic variant may point to an occult dysplasia in apparently non-lesional epilepsy or may uncover important prognostic information including, an increased risk of sudden unexpected death in epilepsy in the GATORopathies or favourable epilepsy surgery outcomes in focal cortical dysplasia type II due to somatic brain mutations. Lastly, we discuss the potential therapeutic application of mechanistic target of rapamycin inhibitors for drug-resistant seizures in GATOR1-related epilepsies and focal cortical dysplasia type II.
Funding
Science Foundation Ireland under Grant Number 16/RC/3948
European Regional Development Fund
FutureNeuro industry partners
Royal College of Surgeons in Ireland — Blackrock Clinic StAR MD programme, 2020
Novartis Ireland
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The original article is available at https://academic.oup.com/Published Citation
Moloney PB, Cavalleri GL, Delanty N. Epilepsy in the mTORopathies: opportunities for precision medicine. Brain Commun. 2021;3(4):fcab222Publication Date
25 September 2021External DOI
PubMed ID
34632383Department/Unit
- Beaumont Hospital
- FutureNeuro Centre
- School of Pharmacy and Biomolecular Sciences
Research Area
- Neurological and Psychiatric Disorders
Publisher
Oxford University Press (OUP)Version
- Published Version (Version of Record)
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Keywords
GATOR1-related epilepsieseverolimusfocal cortical dysplasia type IIthe mTORopathiestuberous sclerosis complexEpilepsyRare DiseasesNeurodegenerativeBrain DisordersDEPDC5- related epilepsyGTPase-activating protein (GAP)rapamycin signalling pathwaycell metabolismrapamycin complex 1Streptomyces hygroscopicusPrecision medicinePersonalized medicine