The enlarging spectrum of focal cortical dysplasias

Abstract

This scientific commentary refers to ‘PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia’, by Jansen et al. (doi: 10.1093/brain/awv045).

Figure 1

Mutations in PI3K, PTEN and AKT have dual effects on neuronal development leading to the formation of HMEG and FCD. First, PI3K and AKT mutations have effects on cell signalling that do not involve the downstream mTOR pathway but likely alter distinct cellular processes including growth, survival, metabolism, and motility (downstream targets). Second, mutations causing activation of PI3K and Akt, or inhibition of PTEN, inescapably lead to enhanced downstream mTOR signalling. The mTOR pathway has well-established links to cell growth, maintenance of cell size, motility and polarity via substrate phosphorylation and effects of protein translation. Combined effects of changes in upstream and downstream signalling likely cause altered expression of numerous neuronal genes and proteins, leading to enhanced excitability, loss of network regulation, and epileptogenesis.