1. 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

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

3. Disclosures NARSAD grant OBI grant McLaughlin grant UCB consultant
Eisai consultant

4. 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

5. Epileptic Encephalopathies
Intractable seizures
Intellectual disability
With or without behavioral problems

6. 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;

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

8. 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

9. DEPDC5 GENE AND SUDEP

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

11. 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)

12. 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.

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

14. 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).

15. 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.

16. 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).

17. 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.

18. 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

19. 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