PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia

Abstract

Malformations of cortical development containing dysplastic neuronal and glial elements, including hemimegalencephaly and focal cortical dysplasia, are common causes of intractable paediatric epilepsy. In this study we performed multiplex targeted sequencing of 10 genes in the PI3K/AKT pathway on brain tissue from 33 children who underwent surgical resection of dysplastic cortex for the treatment of intractable epilepsy. Sequencing results were correlated with clinical, imaging, pathological and immunohistological phenotypes. We identified mosaic activating mutations in PIK3CA and AKT3 in this cohort, including cancer-associated hotspot PIK3CA mutations in dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia type IIa. In addition, a germline PTEN mutation was identified in a male with hemimegalencephaly but no peripheral manifestations of the PTEN hamartoma tumour syndrome. A spectrum of clinical, imaging and pathological abnormalities was found in this cohort. While patients with more severe brain imaging abnormalities and systemic manifestations were more likely to have detected mutations, routine histopathological studies did not predict mutation status. In addition, elevated levels of phosphorylated S6 ribosomal protein were identified in both neurons and astrocytes of all hemimegalencephaly and focal cortical dysplasia type II specimens, regardless of the presence or absence of detected PI3K/AKT pathway mutations. In contrast, expression patterns of the T308 and S473 phosphorylated forms of AKT and in vitro AKT kinase activities discriminated between mutation-positive dysplasia cortex, mutation-negative dysplasia cortex, and non-dysplasia epilepsy cortex. Our findings identify PI3K/AKT pathway mutations as an important cause of epileptogenic brain malformations and establish megalencephaly, hemimegalencephaly, and focal cortical dysplasia as part of a single pathogenic spectrum.

De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia

“…3 Brain-mosaic-activating variants of PI3K-AKT-mTOR were identified in patients with isolated FCD type II, HMEG, MEG and intractable epilepsy without MRI-identifiable lesions. 16,17 The patient brain MRI also revealed a small area with cyst-like appearance, adjacent to the region of dysplastic cortex in the frontal right operculum that could represent either a small dysembryoplastic neuroepithelial tumor or other cyst, a feature not reported in previous cases. Considering the risk of brain cancer, 2 an ongoing surveillance should be considered.…”

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

“…70 HME, which shares neuropathological features such as cytomegalic neurons and cortical dyslamination with FCDII, are also known to be associated with somatic mutations in PIK3CA, PIK3R2, AKT3, and MTOR, as well as germline mutations in PTEN and TSC2. 17,70 These genes encode wellknown regulators of the mTOR pathway, and their dysfunction can lead to aberrant activation of mTOR kinase. Together, these findings and the present results strongly suggest that hyperactivation of mTOR kinase by mutations in mTOR pathway genes underlies the molecular pathogenesis of FCD, which is the most common form of childhood intractable epilepsy and requires surgery as a treatment.…”

Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay

“…HME and FCD. 10,30 As evidence accumulated, the abnormal expression of MTOR and its relative proteins in human pathologic disorder and abnormal positioning in the cortex was described. 11,30,31 However, how the mutations form cortical dysplasia and result in FCD or HME remains to be understood.…”

“…7e9 FCD type IIa was linked to a somatic mutation in PIK3CA. 10 Most of the gene products belong to the major molecules of phosphatidylinositol 3-kinase (PI3K)e AKTsemTOR cell signaling pathway and conclusively upregulate mTOR signaling, resulting in cell overgrowth and abnormal migration through hyperactive phosphorylated proteins. 11 However, Mtor-null mice revealed embryonic lethality at the early stage, whereas heterozygous mice showed normal development.…”