Dravet syndrome (DS) is a severe, pediatric epileptic encephalopathy (EE) that typically presents in the first year of life. In addition to seizures, patients suffer from behavioral and developmental delay, ataxia, intellectual disability, and an increased risk (~18%) of Sudden Unexpected Death in EPilepsy (SUDEP). The mechanism of SUDEP is not clear and there are no biomarkers currently known to identify at risk patients. We study DS because of its high incidence of SUDEP to better understand SUDEP mechanisms. In most cases (>80%) DS is linked to mutations in genes which encode voltage-gated sodium channel (VGSC) subunits, SCN1A and SCN1B, which encode the Nav1.1 ? subunit and the VGSC ?1 subunit, respectively. SCN1A and SCN1B are expressed in both brain and heart. ?1 regulates gating and kinetics of the ion channel pore, functions as a cell adhesion molecule (CAM), and initiates cell signaling. In ventricular myocytes, phosphorylated ?1 localizes to intercalated disks and associates with the tetrodotoxin (TTX)- insensitive VGSC ? subunit Nav1.5, while non-phosphorylated ?1 localizes to t-tubules where it associates with the TTX-sensitive VGSC ? subunits, Nav1.1, Nav1.3 and Nav1.6. We propose the high incidence of SUDEP in DS patients results from neuronal hyperexcitability and cardiac arrhythmia due to expression of mutant VGSC subunits in brain and heart. Scn1b null mice model DS. Scn1b null mice display prolonged QT intervals by electrocardiogram, abnormal calcium handling that is sensitive to TTX, and increased transient and persistent sodium currents in acutely isolated ventricular myocytes. Scn1b null mice show increased expression of Scn3a and Scn5a, encoding Nav1.3 and Nav1.5, respectively. ? subunits are substrates for sequential cleavage by ?-site APP cleaving enzyme 1 (BACE1) and ?-secretase. Sequential cleavage generates a soluble intracellular domain (ICD). We hypothesize that ?1 cleavage in heart, followed by ?1-ICD translocation to the nucleus, is critical for the transcriptional regulation of VGSC ? subunits and potentially other genes important in regulating cardiac excitability. When ?1 is not functional, as in DS, ?1-mediated transcriptional regulation and ?1-mediated current modulation are disrupted, resulting in changes in excitability and arrhythmias. Understanding the mechanism of ?1-mediated signal transduction in heart may lead to new methods for the identification and treatment of patients at risk of SUDEP.
Patients with Dravet syndrome (DS), a severe pediatric epileptic encephalopathy, have a high risk of Sudden Unexpected Death in EPilepsy (SUDEP), which has been proposed to involve altered excitability in both brain and heart. No biomarkers currently exist to identify patients at risk for SUDEP or treatments to prevent SUDEP. The study aims to identify the underlying cardiac mechanism(s) of SUDEP to identify biomarkers for at risk patients and determine novel therapeutic targets to prevent SUDEP from occurring for those at risk.
