Correlation Between Neurophysiologic Phenotype and Genotype of Hemimegalencephaly and Focal Cortical Dysplasia Type 2

Hemimegalencephaly (HME) and focal cortical dysplasia type 2 (FCD2) are most common causes of childhood refractory epilepsy associated with severe developmental brain disorders, characterized by dyslamination, polymicrogyria, white matter heterotopia, immature neurons, calcifications, dysmorphic neurons (DN), and balloon cells (BC). Activating somatic and germline mutations of PI3K/AKT/mTOR signaling pathway have been identified in these phenotypes. Molecular diagnosis only can be reliably made via deep sequencing of affected brain tissue due to mosaicism. For those deemed not eligible for epilepsy surgery, establishing a molecular diagnosis can be challenging. Therefore, efforts have been taken to identify other biomarkers for these diagnoses. Phenotypes, including type of cortical malformation and other associated features, were found to highly correlate with the underlying genetic etiologies (genotype). Certain neurophysiologic features were also unique for these diagnoses. Furthermore, intracranial monitoring for epileptiform discharges could potentially impact the yield of molecular diagnostics. For example, level of mosaicism (variant allele frequency, VAF) was higher in region with more active interictal discharge seen in intraoperative electrocorticogram (ECoG). In this mini review, we will go over the current advance in molecular diagnostics for HME/FCD2, correlation between genotype and phenotype and future direction for expanding the role of neurophysiology in diagnosing these disorders.