Pathogenetic mechanisms of focal cortical dysplasia

Abstract

Focal cortical dysplasias (FCDs) constitute a prevalent cause of intractable epilepsy in children, and is one of the leading conditions requiring epilepsy surgery. Despite recent advances in the cellular and molecular biology of these conditions, the pathogenetic mechanisms of FCDs remain largely unknown. The purpose if this work is to review the molecular underpinnings of FCDs and to highlight potential therapeutic targets. A systematic review of the literature regarding the histologic, molecular, and electrophysiologic aspects of FCDs was conducted. Disruption of the mammalian target of rapamycin (mTOR) signaling comprises a common pathway underlying the structural and electrical disturbances of some FCDs. Other mechanisms such as viral infections, prematurity, head trauma, and brain tumors are also posited. mTOR inhibitors (i.e., rapamycin) have shown positive results on seizure management in animal models and in a small cohort of patients with FCD. Encouraging progress has been achieved on the molecular and electrophysiologic basis of constitutive cells in the dysplastic tissue. Despite the promising results of mTOR inhibitors, large-scale randomized trials are in need to evaluate their efficacy and side effects, along with additional mechanistic studies for the development of novel, molecular-based diagnostic and therapeutic approaches.

Keywords: Focal cortical dysplasia; Giant cell; Mammalian target of rapamycin; PMSE syndrome; mTOR.

FIGURE 1. Neuroimaging and histological features in FCD type Ia and IIb

(Upper panel) Coronal T2-weighted MRI illustrating a dysplastic left medial temporal cortex (arrow) corresponding to FCD type Ia. NeuN staining (neuronal marker) of the resected specimen reveals absence of normal lamination and the characteristic radial distribution of neurons (10×). (Lower panel) Coronal fluid-attenuated inversion recovery (FLAIR) MRI illustrates cortical thickening and hyperintense signal in cortex and subcortical regions of the right parietal lobe in FCD type IIb. Note that the subcortical hyperintensity extends to the margin of the right ventricle (transmantle sign). Hematoxylin and eosin staining of the corresponding resected specimen demonstrates the typical balloon cells (20×).

FIGURE 2. Schematic representation of the mTOR pathway

The mammalian target of rapamycin (mTOR) complex, particularly mTORC1, integrates multiple signals derived from growth factors, hormones and energy status. A first level of integration occurs at TSC1/TSC2 complex where several pathways converge, including RAS-MAKP, PI3K-AKT-mTOR and AMPK. Based on its degree of activation, the TSC1/TSC2 negatively modulates mTOR through the Ras homolog enriched in brain (Rheb). mTOR, in turn, regulates downstream substrates (S6K1/S6, 4E-BP1/eIF4E) that subsequently control protein synthesis, cell growth, and energy metabolism. Other important regulatory proteins of this pathway (PTEN, NF-1 and STRADA) and their sites of action are depicted.^{; ; ; ; ;} Grb2: growth factor receptor-bound protein 2; SOS: Son of sevenless; RAS: Rat sarcoma; RAF: Rapidly Accelerated Fibrosarcoma; MEK: MAPK/ERK kinase; ERK: extracellular signal regulated kinase; PIK3: phosphoinositide 3-kinase; PIP2: phosphatidylinositol-4,5-biphosphate; PIP3: phosphatidylinositol-3,4,5-triphosphate; PDK1: phosphoinositide-3-dependent kinase 1; AKT: protein kinase B; AMPK: AMP activated protein kinase; LKB1: liver kinase B1; STAMBP: STAM-binding protein; NF-1: neurofibromin 1; PTEN: phosphatase and tensin homolog; STRADA: STE20-related kinase adapter protein alpha; TSC1/2: tuberous sclerosis complex 1 and 2; S6K1: ribosomal protein S6 kinase beta-1; S6: ribosomal protein S6; 4E-BP1: 4E binding protein-1; eIF4E: eukaryotic translation initiation factor 4E (abbreviations also apply to Figure 3).

FIGURE 3. Role of mTOR pathway in cortical dysplasias and epileptogenesis

The mTOR pathway can become hyperactive (thick lines) by mutations of genes encoding upstream regulators (TSC1, TSC2, STRADA, PTEN or NF-1), components of the pathways that converge on TCS1/2, such as RAF, AKT, PI3K and also of mTOR (highlighted in red). The recent discovery of HPV16 E6 in FCD type IIa and IIb along with other DNA viruses suggest that an infectious etiology can contribute to the pathogenesis of this condition. Together, activated mTOR pathway results in abnormally increased cell growth and proliferation that could account for the anatomical lesions encountered in cortical dysplasias. In addition, enhanced mTOR signaling can modify the expression of neurotransmitter receptors and ion channels, which can change membrane properties and synaptic organization leading to neuronal hyperexcitability. Both morphological and functional alterations at the cellular and circuit levels may lead to epilepsy, focal deficits and cognitive dysfunction in patients with cortical dysplasias.^{; ; ; ; ; ; ; ;}