Focal malformations of cortical development: New vistas for molecular pathogenesis

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…Several immunohistochemical studies provide evidence of enhanced mTOR signaling in FCD II with strong expression of the mTOR marker pS6 in dysmorphic neurons and in balloon cell ( [115][116][117], reviewed in [30,118]; Fig. 1j; Fig.…”

“…Inactivating TSC1 or TSC2 mutations in neuroglial progenitor cells has been shown to result in constitutive activation of the TORC1 signaling cascade, which plays a critical role in the regulation of cell growth and proliferation (Fig. 2) [117,118,207,208]. Cell-associated activation of the targetof-rapamycin complex 1 pathway has been detected in dysmorphic neurons and giant cells [115-117, 137, 193].…”

“…The identification of mTOR signaling overactivation in HME (as in TSC and FCD IIb) suggests a pathogenic link between these malformations, possibly representing a spectrum of disorders of mTOR signaling (so-called "TORopathies") [118,252,253]. Accordingly, Barkovich et al [5] include HME in the non-neoplastic malformations secondary to cortical dysgenesis with abnormal cell proliferation (together with TSC and co FCD IIb; Table 2; Fig.…”

Rheb in neuronal degeneration, regeneration, and connectivity

“…The neurological symptoms of TSC include mental retardation, intractable epilepsy, and autism (Crino et al, 2006;Curatolo et al, 2008;Lim and Crino, 2013). Mouse models carrying mutations in the TSC1 or TSC2 genes have been extensively investigated to clarify the mechanisms of the TSC pathogenesis (Lim and Crino, 2013).…”

“…Mouse models carrying mutations in the TSC1 or TSC2 genes have been extensively investigated to clarify the mechanisms of the TSC pathogenesis (Lim and Crino, 2013). Such studies emphasize that these TSC model mice exhibit impairments in neuronal morphology, dendritic spine formation, synaptic long-term depression and cognitive behaviors (Brown et al, 2012;Sugiura et al, 2015).…”