Metabolic changes in mTOR pathway-associated cortical malformation

Malformations of cortical development (MCD) are a common cause of epilepsy, autism spectrum disorder (ASD), and intellectual disability (ID). A unifying mechanistic etiology for epilepsy, ASD, and ID has not been found due, in part, to the heterogeneity of MCD subtypes. However, changes in brain metabolism within MCD have emerged as a possible convergent mechanism across MCD that may have therapeutic potential. While there have been efforts to comprehensively describe known metabolic changes in other neurodevelopmental disorders, no such effort exists for MCD associated with mTOR pathway gene mutations (the most common cause of MCD; mTORopathies'). In this review, we detail finding related to mTORopathies that relate to dysfunctional brain metabolism including abnormal changes in macromolecule processing and mitochondrial metabolism. Further, we discuss cellular and molecular metabolic processes that may serve as key pathways in the development of MCD in utero and that may ultimately produce common mTORopathy phenotypes and sustain abnormal brain activity post-development.