Robyn Whitney

The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been shown to cause malformations of cortical development, medically refractory epilepsies, and neurodevelopmental disorders, collectively described as mTORopathies. Tuberous sclerosis complex (TSC) serves as the prototypical mTORopathy. Characterized by the development of benign tumors in multiple organs, pathogenic variants in TSC1 or TSC2 disrupt the TSC protein complex, a negative regulator of the mTOR pathway. Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity. Variants in less crucial exons and non-coding regions, as well as those undetectable with conventional testing, may lead to milder phenotypes. Despite the assumption of complete penetrance, expressivity varies within families, and certain variants delay disease onset with milder neurological effects. Understanding these genotype–phenotype correlations is crucial for effective clinical management. Notably, 15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic TSC1/TSC2 variants which present complex diagnostic challenges. Advancements in genetic testing, prenatal screening, and precision medicine hold promise for changing the diagnostic and treatment paradigm for TSC and related mTORopathies. Herein, we explore the genetic and molecular mechanisms of TSC and other mTORopathies, emphasizing contemporary genetic methods in understanding and diagnosing the condition.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy‐related death in children and adults living with epilepsy. Several recent clinical practice guidelines have recommended that all individuals living with epilepsy and their caregivers be informed about SUDEP as a part of routine epilepsy counseling. Furthermore, several studies over the last two decades have explored the state of SUDEP counseling. Patients with epilepsy and their families want to be informed about the risk of SUDEP at or near the time of diagnosis, and preferably in person. Despite guideline recommendations, many pediatric and adult neurologists do not routinely inform individuals with epilepsy and their families about SUDEP. Some neurologists discuss SUDEP with only a subset of patients with epilepsy, such as those with risk factors like frequent generalized or focal to bilateral tonic–clonic seizures, nocturnal seizures, noncompliance, or medically refractory epilepsy. Proponents of routine SUDEP counseling argue that patients with epilepsy and their families have a “right to know” and that counseling may positively impact epilepsy self‐management (i.e., behavioral modification and risk reduction). Some neurologists still believe that SUDEP counseling may cause unnecessary stress and anxiety for patients and their families (although this is erroneous) and that they also have a “right not to know.” This narrative review explores the current gaps in SUDEP counseling, patients' and caregivers' perspectives of SUDEP counseling, and SUDEP prevention.