Genetics of SUDEP CLAE 2016 Danielle M. Andrade, MD, MSc, FRCPC. Medical Director, Epilepsy Program Director, Epilepsy Genetics Research Program Director, Epilepsy Transition Program, Associate Professor, Neurology University of Toronto

Progress in sudden cardiac death and sudden infant death syndrome helped understanding SUDEP.

Disclosures NARSAD grant OBI grant McLaughlin grant UCB consultant Eisai consultant

SINGLE GENES ASSOCIATED WITH SUDEP Epileptic encephalopathies Epilepsy Cardiac arrhythmia Vagus nerve dysfunction Respiratory dysfunction SCN1A SCN8A (gof) DEPDC5 KCNH2 KCNA1 EFHC1 KCNQ1 GABRB3 SCN1B RYR2 SCN2A PAFAH1B1G SENP2 HCN SUDEP ASSOCIATED WITH INCREASED POLYGENIC BURDEN

Epileptic Encephalopathies Intractable seizures Intellectual disability With or without behavioral problems

Dravet syndrome Effects of SCN1A +/- Mouse Model +/- +/- +/+ Seizures + SUDEP Seizures +/- +/+ Seizures + SUDEP QT prolongation ventricular ectopic foci idioventricular rhythms ventricular fibrillation, and ictal bradycardia Cheah, Proc Natl Acad Sci USA 2012; Auerback, PLoS ONE 2013.; Kalume, J Clin Invest 2013;

Cardiac arrhythmias, epilepsy and the vagus nerve hyperexcitation. Scn1a model VAGUS NERVE Atropine reduces SUDEP in Scn1a mice

Single gene associated with epilepsy without evidence of cardiac or respiratory dysfunction PHENOTYPE SCN1A GEFS+ SCN1B DEPDC5 Familial focal epilepsy EFHC1 Juvenile myoclonic epilepsy LGI1 Temporal neocortical epilepsy

DEPDC5 GENE AND SUDEP

CARDIOCEREBRAL CHANNELOPATHY Ion channel dysfunction underlies many cases of epilepsy as well as AD cardiac arrhythmias. K+, Na+ CA2+: genetic cause or risk factor?

Long QT Syndrome Genes Abnormal cardiac ventricular repolarization (long QT and abnormal T waves). Patients susceptible to polymorphic ventricular tachycardia and torsades de pointes. Syncopal events and sudden death in otherwise healthy individuals. 15 genes associated with LQTS, but 90% of mutations in 3 genes: KCNQ1, KCNH2, SCN5A. 30% of patients with LONG QT SYNDROME have a “seizure phenotype”. 10% of SUDEP cases have mutations in LQTS (KCNQ1; KCNH2; SCN5A)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) RYR2 gene (Ca2+ channel) CPVT & Seizures in 50% of Dutch families with RYR2 mutations CPVT & Seizures in 100% of animal models of RYR2 mutations. GTC seizures 3x/week. Exercise-induced syncope with 30-50% mortality before the age of 30 years One confirmed SUDEP case in a 8 year old boy with normal resting ECG and RYR2 gene mutation.

Audiogenic Seizure Mouse Model Seizures Audiogenic mouse Respiratory Arrest + noise SSRIs SUDEP Faingold, Epilepsy Behav 2011; Faingold, Epilepsy Beahav 2013

SSRI and SUDEP Partial seizures leading to desaturation <85% was significantly less frequent in patients taking SSRIs. No difference for secondarily generalized convulsions. Non-significant increase in seizure duration in patients taking SSRIs (Bateman 2010, Trinka 2010).

What more on respiratory causes of SUDEP? Congenital central hypoventilation syndrome: often caused by PHOX2B gene mutations. PHOXB2 not a significant cause of SUDEP. Five other genes associated with respiratory control: negative in SUDEP cases. Coll, Int J Legal Med 2016; Bagnall, Neurology 2014.

Polygenic Burden Several genetic/genomic alterations in the same individual 18 SUDEP 87 Epilepsy 1479 Non-epilepsy control Patients with SUDEP had higher number of deleterious variants per individual and over-representation of variants likely to be deleterious in the SUDEP cohort. Five genes appeared overburdened in the SUDEP group: SCN1A, LGI1, SMC4, COL6A3, TIE1. Patients also had more copy number variations (deletions, duplications).

Conclusion Genes associated with epileptic encephalopathies Genes associated with cardiac arrhythmias and vagal nerve hyperexcitation. Very likely respiratory genes, but no one single gene involved in respiratory dysfunction has clearly stood out yet. Genes that are associated with common epilepsies without large number of seizures.

Kcna1 mouse model Seizures Cardiac arrhythmias Vagal hyperexcitability Premature sudden death At least 1 SUDEP in a patient with epileptic encephalopathy. Glasscock, J Neurosc 2010 Klassen, Epilepsia 2014

HyperSUMOylation of K7 channels SENP2 knockout mouse: seizures and cardiac arrythymias. Hippocampal neurons: decreased M currents of K+ channels. Retigabine rescues phenotype. Qi, Neuron 2014