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 mortality in children and adults living with epilepsy. The incidence of SUDEP is comparable in both children and adults; it is approximately 1.2 per 1000 person years. The pathophysiology of SUDEP is not well understood but may involve mechanisms such as cerebral shutdown, autonomic dysfunction, altered brainstem function, and cardiorespiratory demise. Risk factors for SUDEP include the presence of generalized tonic–clonic seizures, nocturnal seizures, possible genetic predisposition, and non‐adherence to antiseizure medications. Pediatric‐specific risk factors are not fully elucidated. Despite recommendations from consensus guidelines, many clinicians still do not follow the practice of counseling their patients about SUDEP. SUDEP prevention has been an area of important research focus and includes several strategies, such as obtaining seizure control, optimizing treatment regimens, nocturnal supervision, and seizure detection devices. This review discusses what is currently known about SUDEP risk factors and reviews current and future preventive strategies for SUDEP.

Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of developmental regression or stagnation and hypsarrhythmia on EEG. A myriad of aetiologies are associated with the development of IESS; broadly, 60% of cases are thought to be structural, metabolic or infectious in nature, with the remainder genetic or of unknown cause. Epilepsy genetics is a growing field, and over 28 copy number variants and 70 single gene pathogenic variants related to IESS have been discovered to date. While not exhaustive, some of the most commonly reported genetic aetiologies include trisomy 21 and pathogenic variants in genes such as TSC1, TSC2, CDKL5, ARX, KCNQ2, STXBP1 and SCN2A. Understanding the genetic mechanisms of IESS may provide the opportunity to better discern IESS pathophysiology and improve treatments for this condition. This narrative review presents an overview of our current understanding of IESS genetics, with an emphasis on animal models of IESS pathogenesis, the spectrum of genetic aetiologies of IESS (i.e., chromosomal disorders, single-gene disorders, trinucleotide repeat disorders and mitochondrial disorders), as well as available genetic testing methods and their respective diagnostic yields. Future opportunities as they relate to precision medicine and epilepsy genetics in the treatment of IESS are also explored.

Objective: To characterize SUDEP discussion practices of child neurologists approximately 6 and 12 months after publication of the American Academy of Neurology SUDEP Clinical Practice Guideline and explore factors associated with discussion practice.Methods: Child Neurology Society members (~2450) were electronically surveyed in November 2017 and May 2018 regarding their practice of discussing SUDEP with patients with epilepsy or their caregivers. Multivariable proportional odds ordinal logistic regression evaluated factors associated with discussing SUDEP with a greater proportion of epilepsy patients/caregivers. Reasons for changing practice were described.Results: Among the 369 child neurologist respondents, 36% reported discussing SUDEP with at least half of their epilepsy patients/caregivers including 12% who discuss with all or almost all (>90%) of their epilepsy patients/families. Those who discussed SUDEP with an increased proportion of their patients were more likely to agree that they knew enough to talk about SUDEP, agree that healthcare providers have an ethical obligation to discuss SUDEP, and disagree that there is not enough time to talk about SUDEP. Those who agreed SUDEP could provoke excessive anxiety or worry were less likely to discuss SUDEP with an increased proportion of their patients. Reading the SUDEP Clinical Practice Guideline was a frequently cited reason among respondents who reported a recent change in discussion practice.Significance: Most child neurologists do not follow the current SUDEP Clinical Practice Guideline regarding SUDEP discussion. Feeling sufficiently knowledgeable and ethically obligated to discuss SUDEP were associated with increased discussion practice, suggesting an educational intervention may be effective at increasing SUDEP discussion rates.