The enlarging spectrum of focal cortical dysplasias.

Focal malformations of cortical development, including focal cortical dysplasia (FCD), are among the most common causes of intractable epilepsy in children. In this issue of Brain, Jansen and colleagues provide evidence that hemimegalencephaly (HMEG) and FCD type IIa result from mosaic mutations in components of the PI3K/Akt/ mTOR (mammalian target of rapamycin) pathway, i.e. PI3KCA, AKT3, or PTEN, in 4/33 patients using targeted screening of a panel of PI3K, AKT, and PTEN genes (Jansen et al., 2015). These individuals suffered from intractable seizures, and exhibited radiographic and histopathologically defined evidence of either HMEG or FCD. An additional single case of dysplastic megalencephaly (DMEG) was linked to PI3KCA. In the remaining 29 patients with HMEG, or FCD type I, type IIa, or type IIb, no mutations were identified. The phosphorylation profile of components of the PI3K/ Akt/mTOR signalling pathway showed that phosphorylation of Akt at threonine (T)308 and serine (S)473 was enriched in all HMEG and FCD cases, and in conjunction with measured Akt kinase activity, could distinguish mutation-positive dysplasia cortex, mutation-negative dysplasia cortex, and non-dysplasia epilepsy cortex. In conclusion, Jansen et al. suggest that FCD, HMEG and DMEG comprise a spectrum of developmental malformations linked to the PI3K/Akt/ mTOR pathway. Focal malformations of the cerebral cortex have been reported since the 1800s, with the first description of HMEG by Sims in 1835 and tuberous sclerosis complex by Bourneville in 1880. In 1957, Crome published a short pathological report describing abnormally ‘large neurons’ in the brains of three patients with intractable epilepsy within areas of ‘ulegyria’, which set the conceptual stage for the index report of focal dysplasia of the cerebral cortex 14 years later by Taylor et al. (1971). Since neuroimaging had not yet been invented, these early studies relied on histopathological descriptions of large neurons, astrocytosis, and giant or ‘balloon-like’ cells. These cellular features would be critical to understanding the pathogenesis of FCD and would provide clues to some of the cell signalling abnormalities now linked to FCD four decades later. Pathological classification schemes have divided FCDs into types I–III based on distinct histopathological features. In particular, FCD type II (a and b) exhibit the most dramatic alterations in cytoarchitecture with cellular enlargement and dysmorphism. There is no widely accepted classification scheme for HMEG, but there is clearly a spectrum of radiographic and histopathological abnormalities in this disorder. The molecular and developmental pathogenesis of HMEG and FCDs has come under close scrutiny in the past decade. The initial insights came from studies demonstrating enhanced signalling of the mTOR pathway in tuberous sclerosis complex (TSC) and FCDIIb (Baybis et al., 2004; Miyata et al., 2004; Ljungberg et al., 2006). These studies showed enhanced phospho-activation of the mTOR effectors p70S6kinase and ribosomal S6 protein in resected FCD and TSC tuber specimens. The critical link was that loss of function mutations in either TSC1 or TSC2, the genes responsible for TSC and known upstream inhibitors of mTOR, caused constitutive activation of mTOR and thus, these early studies linked FCDIIb with the mTOR cascade. Subsequent studies confirmed aberrant mTOR signalling in HMEG in a pattern that was similar to TSC and FCDIIb (Ljungberg et al., 2006; Aronica et al., 2007). Early speculations based on gene expression profiles suggested that while TSC, FCDIIb, and HMEG shared some histopathological similarities (noted by Taylor et al., 1971), they did not result from identical molecular mechanisms, a notion that has been borne out by molecular analysis. The distribution of cells exhibiting enhanced mTOR activation suggested a cell autonomous profile e.g. enriched in cytomegalic neurons and balloon cells, and in conjunction with a sporadic occurrence, suggested that HMEG and FCD resulted from somatic gene mutations, potentially in PI3K/Akt/mTOR pathway regulatory genes. This has since been confirmed, with the robust mTOR signalling abnormalities in these disorders linked to somatic mutations in genes including PI3KCA, PI3KR and AKT, as well as MTOR in HMEG (Lee et al., 2012; Poduri et al., 2012; D’Gama et al., 2015). Somatic PTEN and AKT mutations have been identified in small FCD cohorts, while recent reports have described new FCD syndromes linked to mutations in DEPDC5 (Baulac et al., 2015), a component of the mTOR regulatory GATOR-1 complex. Jansen and colleagues suggest that socalled ‘hot-spot’ mutations in PI3KCA and AKT are pivotal in HMEG pathogenesis. The evidence for PI3KCA as a common causative gene in FCD is less robust since only a single FCDIIa case in their cohort exhibited a PI3KCA mutation (a missense change). No mutations were identified in FCDI or FCDIIb specimens. However, given that only a targeted gene panel screen was used, many other genes within the PI3K/Akt/mTOR pathway could be responsible for FCDIIb, including MTOR itself. The second portion of the paper examines phospho-activation of 1446 | BRAIN 2015: 138; 1444–1453 Scientific Commentaries