Unexplained collapse of cardiac and respiratory rhythmicity is a final common mechanism for SUDEP, a major and preventable cause of death in persons with epilepsy. Recent evidence shows that dysfunctional ion channels and receptors co-expressed in brain, autonomic, heart, and respiratory pathways, along with clinical measures of functional disturbances in these pathways at times surrounding seizures represent detectable and potentially treatable risk factors for SUDEP. This proposal describes an integrated multicenter and multidisciplinary collaborative project that will combine a basic science, human neurogenetics, and clinical physiology approaches to these biological risk factors in a bench to bedside translational research program to identify, validate, and clinically evaluate predictive biomarkers and preventative treatments for SUDEP. The SUDEP Center Research Pipeline will consist of a serially interrelated work flow among 6 investigators in the center. Project 1 (Baylor) will expand the repository of DNA samples from patient at 3 centers (EMU, Dravet Syndrome Clinic, SUDEP DNA Repository) and other national networks which will be analyzed using chip microarrays for >247 prioritized ion channel and receptor genes mediating cardiac arrhythmias, respiratory depression and epilepsy. Projects 2-4 (Baylor U. Michigan, U. Iowa) analyze the biology, physiology, and pharmacology of these and related gene mutations at the cellular and in vivo level in SUDEP mouse models and induced pluripotent stem cells from Dravet Syndrome cases in order to understand and validate the SUDEP phenotypes. Project 5 (U.C. Davis/Childrens Memorial Chicago) will refine clinical respiratory and cardiac biomarkers obtained during epilepsy monitoring of individuals with Dravet Syndrome and others at high risk of sudden death (ictal hypoxemia, cardiac arrhythmia). Once validated, genes from these cases are added to an incremental diagnostic chip in development at Baylor for routine patient risk assessment in clinics in individuals with other clinical biomarkers.

Public Health Relevance

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature mortality in idiopathic epilepsy. Preventing SUDEP depends upon identifying biologically predictive risk factors in individuals with epilepsy and using them to mak appropriate therapeutic interventions. The goal of this program is to validate a combined genetic/clinical SUDEP risk profile to screen and treat individuals with epilepsy. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of th individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory Grants (P20)
Project #
5P20NS076916-02
Application #
8338442
Study Section
Special Emphasis Panel (ZNS1-SRB-B (28))
Program Officer
Whittemore, Vicky R
Project Start
2011-09-26
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$461,048
Indirect Cost
$62,150
Name
Baylor College of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Sedigh-Sarvestani, Madineh; Blumenfeld, Hal; Loddenkemper, Tobias et al. (2015) Seizures and brain regulatory systems: consciousness, sleep, and autonomic systems. J Clin Neurophysiol 32:188-93
Cerpa, V; Gonzalez, A; Richerson, G B (2014) Diphtheria toxin treatment of Pet-1-Cre floxed diphtheria toxin receptor mice disrupts thermoregulation without affecting respiratory chemoreception. Neuroscience 279:65-76
Klassen, Tara L; Bomben, Valerie C; Patel, Ankita et al. (2014) High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile. Epilepsia 55:e6-12
Buchanan, Gordon F; Murray, Nicholas M; Hajek, Michael A et al. (2014) Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality. J Physiol 592:4395-410
Frampton, John P; Shi, Huilin; Kao, Albert et al. (2013) Delivery of proteases in aqueous two-phase systems enables direct purification of stem cell colonies from feeder cell co-cultures for differentiation into functional cardiomyocytes. Adv Healthc Mater 2:1440-4
Auerbach, David S; Jones, Julie; Clawson, Brittany C et al. (2013) Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. PLoS One 8:e77843
Liu, Yu; Lopez-Santiago, Luis F; Yuan, Yukun et al. (2013) Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism. Ann Neurol 74:128-39
Klassen, Tara L; Drabek, Janice; Tomson, Torjborn et al. (2013) Visual automated fluorescence electrophoresis provides simultaneous quality, quantity, and molecular weight spectra for genomic DNA from archived neonatal blood spots. J Mol Diagn 15:283-90