Cortical Dysplasia and the mTOR Pathway: How the Study of Human Brain Tissue Has Led to Insights into Epileptogenesis

Lee, Wei Shern; Baldassari, Sara; Stephenson, Sarah E. M.; Lockhart, Paul J.; Baulac, Stéphanie; Leventer, Richard J.

doi:10.3390/ijms23031344

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Cortical Dysplasia and the mTOR Pathway: How the Study of Human Brain Tissue Has Led to Insights into Epileptogenesis

Wei Shern Lee

^1,2,

Sara Baldassari

Sarah E. M. Stephenson

^1,2,

Paul J. Lockhart

^1,2,

Stéphanie Baulac

^3,*,†

and

Richard J. Leventer

^2,4,5,*,†

Bruce Lefroy Centre, Murdoch Children’s Research Institute, Parkville 3052, Australia

Department of Paediatrics, The University of Melbourne, Parkville 3052, Australia

Institut du Cerveau-Paris Brain Institute-ICM, Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, F-75013 Paris, France

⁴

Murdoch Children’s Research Institute, Parkville 3052, Australia

⁵

Department of Neurology, The Royal Children’s Hospital, Parkville 3052, Australia

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Academic Editor: Antonios N. Gargalionis

Int. J. Mol. Sci. 2022, 23(3), 1344; https://doi.org/10.3390/ijms23031344

Received: 21 December 2021 / Revised: 14 January 2022 / Accepted: 16 January 2022 / Published: 25 January 2022

(This article belongs to the Special Issue Frontiers in mTOR Signaling)

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Abstract

Type II focal cortical dysplasia (FCD) is a neuropathological entity characterised by cortical dyslamination with the presence of dysmorphic neurons only (FCDIIA) or the presence of both dysmorphic neurons and balloon cells (FCDIIB). The year 2021 marks the 50th anniversary of the recognition of FCD as a cause of drug resistant epilepsy, and it is now the most common reason for epilepsy surgery. The causes of FCD remained unknown until relatively recently. The study of resected human FCD tissue using novel genomic technologies has led to remarkable advances in understanding the genetic basis of FCD. Mechanistic parallels have emerged between these non-neoplastic lesions and neoplastic disorders of cell growth and differentiation, especially through perturbations of the mammalian target of rapamycin (mTOR) signalling pathway. This narrative review presents the advances through which the aetiology of FCDII has been elucidated in chronological order, from recognition of an association between FCD and the mTOR pathway to the identification of somatic mosaicism within FCD tissue. We discuss the role of a two-hit mechanism, highlight current challenges and future directions in detecting somatic mosaicism in brain and discuss how knowledge of FCD may inform novel precision treatments of these focal epileptogenic malformations of human cortical development. View Full-Text

Keywords: focal cortical dysplasia; hemimegalencephaly; epilepsy; mTOR signalling; genetics

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Lee, W.S.; Baldassari, S.; Stephenson, S.E.M.; Lockhart, P.J.; Baulac, S.; Leventer, R.J. Cortical Dysplasia and the mTOR Pathway: How the Study of Human Brain Tissue Has Led to Insights into Epileptogenesis. Int. J. Mol. Sci. 2022, 23, 1344. https://doi.org/10.3390/ijms23031344

AMA Style

Lee WS, Baldassari S, Stephenson SEM, Lockhart PJ, Baulac S, Leventer RJ. Cortical Dysplasia and the mTOR Pathway: How the Study of Human Brain Tissue Has Led to Insights into Epileptogenesis. International Journal of Molecular Sciences. 2022; 23(3):1344. https://doi.org/10.3390/ijms23031344

Chicago/Turabian Style

Lee, Wei S., Sara Baldassari, Sarah E.M. Stephenson, Paul J. Lockhart, Stéphanie Baulac, and Richard J. Leventer. 2022. "Cortical Dysplasia and the mTOR Pathway: How the Study of Human Brain Tissue Has Led to Insights into Epileptogenesis" International Journal of Molecular Sciences 23, no. 3: 1344. https://doi.org/10.3390/ijms23031344

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