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Review
. 2023 Jun 15:182:106144.
doi: 10.1016/j.nbd.2023.106144. Epub 2023 May 4.

mTOR pathway: Insights into an established pathway for brain mosaicism in epilepsy

Anna Gerasimenko  1 , Sara Baldassari  2 , Stéphanie Baulac  3
Affiliations
Free article
Review

mTOR pathway: Insights into an established pathway for brain mosaicism in epilepsy

Anna Gerasimenko et al. Neurobiol Dis. .
Free article

Abstract

The mechanistic target of rapamycin (mTOR) signaling pathway is an essential regulator of numerous cellular activities such as metabolism, growth, proliferation, and survival. The mTOR cascade recently emerged as a critical player in the pathogenesis of focal epilepsies and cortical malformations. The 'mTORopathies' comprise a spectrum of cortical malformations that range from whole brain (megalencephaly) and hemispheric (hemimegalencephaly) abnormalities to focal abnormalities, such as focal cortical dysplasia type II (FCDII), which manifest with drug-resistant epilepsies. The spectrum of cortical dysplasia results from somatic brain mutations in the mTOR pathway activators AKT3, MTOR, PIK3CA, and RHEB and from germline and somatic mutations in mTOR pathway repressors, DEPDC5, NPRL2, NPRL3, TSC1 and TSC2. The mTORopathies are characterized by excessive mTOR pathway activation, leading to a broad range of structural and functional impairments. Here, we provide a comprehensive literature review of somatic mTOR-activating mutations linked to epilepsy and cortical malformations in 292 patients and discuss the perspectives of targeted therapeutics for personalized medicine.

Keywords: Brain mosaicism; Cortical development; Cortical malformation; Epilepsy; FCDII; Hemimegalencephaly; Megalencephaly; Somatic mutations; mTOR signaling.

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Conflict of interest statement

Declaration of Competing Interest None.

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