We are proud to be one of the 41 researchers researchers across 34 institutions to be awarded grant money raised from the 2024 Million Dollar Bike Ride fundraiser for rare diseases.
KCNT1-related epilepsy is an autosomal dominant NDD, resulting from de novo pathogenic variants in the KCNT1 (sodium activated potassium channel Type-1) gene. The overwhelmingly majority of variants are gain-of-function (GOF) missense mutations. Differing variants in patients are characterized with differing clinical pathophysiology and neurophysiological properties. Few animal models exist of any of the ~64 known human variants described to date, leading to in vivo experimental models of KCNT1 a severe unmet need. Consequently, we will focus on a novel, unpublished, mouse model of the human variant G288S (corresponding to mouse Kcnt1 G269S), a mutation located within the biochemical domain that codes for the pore of the ion channel. Our overarching hypothesis is that KCNT1/Kcnt1 GOF mutations G288S/G269S cause developmental epileptic encephalopathy. We hypothesize that hyperthermia-induced seizures early in life result in subsequent unpredictable recurring seizures, aberrant neurophysiological and respiratory signatures. Our objectives are to evaluate outcomes of early in life hyperthermia-induced-seizures (HS) on recurrence and severity of seizure phenotypes in young to aged adults measured using neurophysiology, and respiratory physiological phenotypes. Our preliminary data demonstrate increased seizure occurrence and severity following HS induction in early life. Thus, we will begin to explore and inform knowledge gaps by investigating the impact of early life HS on the reoccurrence of seizures across the lifespan and identify the severity of epileptic phenotypes, sleep, and apneas via electroencephalography (EEG) and respiratory physiology using whole body plethysmography (WBP).
Read more at https://orphandiseasecenter.squarespace.com/mdbr-2024-grant-awardees-1