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Review
. 2022 Jan 25;23(3):1344.
doi: 10.3390/ijms23031344.

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  3 , Sarah E M Stephenson  1   2 , Paul J Lockhart  1   2 , Stéphanie Baulac  3 , Richard J Leventer  2   4   5
Affiliations
Review

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

Wei Shern Lee et al. Int J Mol Sci. .

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.

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

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The mechanistic target of rapamycin (mTOR) signalling pathway. Pathogenic germline or somatic variants are identified in the coloured components. Specifically, PTEN and S6 are associated with hemimegalencephaly (HME) only, while the rest are associated with both focal cortical dysplasia (FCD) and HME.
Figure 2
Figure 2
Illustration of two-hit mechanism in cortical dysplasia. In the unaffected cortex, a heterozygous germline DEPDC5 variant is present in all cells but does not cause “visible” lesion at MRI. In the lesional cortex, it is hypothesised that a postzygotic somatic DEPDC5 variant (or variant in another mTOR pathway genes) occurred in a subset of cells, leading to localised brain lesion.
Figure 3
Figure 3
Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) as a continuum of cortical dysplasias caused by commonly shared genetic variants with different mutation load. In small FCD, a small subset of cells is affected, which contribute to the small mutation load and restricted lesion. In HME, a larger number of cells carry the somatic variant, resulting in higher mutation load and a more diffuse lesion. It is important to acknowledge that there are even smaller lesions including presumed MRI-negative lesions within this spectrum, associated with ultra-low mutation load.
Figure 4
Figure 4
Cortical development and hypothetical occurrence of somatic variant in a subset of brain cells during neurogenesis. During cortical development, neuroepithelial cells undergo symmetric division to generate more progenitors. Neuroepithelial cells then convert into radial glia, which are able to divide asymmetrically to generate intermediate progenitor cells, migrating neurons, and more radial glia. Intermediate progenitor cells can divide symmetrically to generate clones of neurons. Neurons migrate radially along radial glia to the designated cortical layer to become mature neurons. Radial glia also give rise to outer radial glia, which also have the potential to undergo asymmetric division. In a hypothetical scenario, a somatic variant may occur in intermediate progenitor cells during the process of proliferation (red). These variant-carrying intermediate progenitor cells give rise to neurons that similarly harbour the variant. Neurons of a different clonal origin can continue to be produced normally without somatic variant (blue). This process results in a mixture of brain cells in which only a proportion of cells may carry the somatic variant. Furthermore, interneurons migrate tangentially from the ganglionic eminence (not shown), astrocytes, oligodendrocytes and microglial cells further complicate the clonal diversity in any given cortical region.
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