Megalencephaly (ME) is a malformation of cortical development defined by an enlarged brain. Individuals with ME often suffer from drug resistant epilepsy, intellectual disability, and autism spectrum disorder. Several clinical ME subtypes result from pathogenic variants in mTOR pathway genes (MPG) which cause diffuse brain overgrowth likely as a consequence of hyperactive mechanistic target of rapamycin (mTOR) signaling during brain development. Unfortunately, resected surgical or post-mortem ME brain tissue specimens are not widely available, and thus, there is only limited understanding of the histopathology of MPG associated ME. Thus, research strategies including new mouse models and human cerebral organoids have been developed to study the developmental pathogenesis of ME linked to MPG variants. These model systems provide a platform to study the mechanisms leading to brain overgrowth in ME as well as the establishment of the epileptic network. Perhaps most compelling, pre-clinical research approaches in ME models may pave the way for therapeutic development that could be deployed in utero to prevent ME formation.
Pan et al. (Thu,) studied this question.