Disclosures. To Cover: To Cover: 3/7/2014. Dan Lowenstein, MD University of California, San Francisco. Research funding:

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1 Disclsures Dan Lwenstein, MD University f Califrnia, San Francisc With special thanks t Samuel F Berkvic, David Gldstein, Erin Heinzen, Heather Medfrd, Ruth Ottman, Ellitt Sherr, Meldie Winawer, EPGP and Epi4K Investigatrs and Persnnel Research funding: NINDS (EPGP, Epi4K, NETT) Epilepsy Study Cnsrtium (unrestricted supprt frm UCB, Lundbeck and the Finding a Cure fr Epilepsy and Seizures Fundatin) T Cver: T Cver: The reality f living with epilepsy Hw imprtant is genetics as a cause f epilepsy? - Genetic epidemilgy A brief verview f epilepsy gene discvery t date The next wave: identifying the genetic causes f mre cmmn, nn-acquired epilepsies The reality f living with epilepsy Hw imprtant is genetics as a cause f epilepsy? - Genetic epidemilgy A brief verview f epilepsy gene discvery t date The next wave: identifying the genetic causes f mre cmmn, nn-acquired epilepsies 1

2 A typical day in clinic 21y man with severe develpmental delay and medically intractable epilepsy since early childhd. Having daily small seizures and mnthly big seizures despite being n 4 AEDs and placement f a vagus nerve stimulatr 16y student s/p left tempral lbectmy 10 years ag, with an apparent fainting spell 6 weeks ag Epilepsy: Impact n the Patient Seizures, typically unpredictable Risk f injury and death C-mrbidities Driving restrictins Underemplyment and unemplyment Lack f independence Stigma, discriminatin and ther scial impacts 2.2M/>65M $9.6B/yr What is the wrst thing abut having epilepsy? T Cver: Fear AED prblems Life limits Stigma The reality f living with epilepsy Hw imprtant is genetics as a cause f epilepsy? - Genetic epidemilgy Lss f cnfidence Family cncerns Medical care prblems Physical prblems Percent f Respndents (n=1023) A brief verview f epilepsy gene discvery t date The next wave: identifying the genetic causes f mre cmmn, nn-acquired epilepsies Fisher. Epilepsy and Behavir 1:S9-S14,

3 Traditinal View f Epilepsy Causatin Genetic Epidemilgy Others Strke Trauma Cngenital Unknwn Idipathic Rchester Study Hauser et al 1975 Res Nerv Ment Dis 26:11, 1947 Vadlamudi et al. Neurlgy 62:1127, 2004 Res Nerv Ment Dis 26:11,

4 Genetic Epidemilgy Twin Studies Case-wise cncrdance Syndrme Mnzygus Dizygus Generalised (n = 99) p = Fcal (n = 103) p = Febrile (n = 180) p = Unclassified (n = 36) p = 0.1 The risks f seizure disrders amng relatives f patients with childhd nset epilepsy J.F. Annegers, Ph.D., W.A. Hauser, M.D., V.E. Andersn, Ph.D., and L.T. Kurland, M.D. NEUROLOGY 1982;32:174-9 Chrt study f descendants f parents f prbands with epilepsy 196 cases f idipathic epilepsy with seizure nset between 0 and 15 years, and 60 cases f islated idipathic seizures frm Rchester, MN frm 1935 and 1974 Berkvic et al Ann Neurl 1998 Vadlamudi and Berkvic 2012 Risks f epilepsy in prbands with epilepsy Relatinship Observed Cases Expected Cases Relative Risk 95% Cnfidence Interval Sibs Children Nieces/nephews Grandchildren Half-sibs Grandnieces/nephews Greatgrandnieces/nephews Annegers et al. Neurlgy 32:174,

5 6 3/7/2014 T Cver: Rare Gene Mutatins The reality f living with epilepsy Hw imprtant is genetics as a cause f epilepsy? - Genetic epidemilgy A brief verview f epilepsy gene discvery t date The next wave: identifying the genetic causes f mre cmmn, nn-acquired epilepsies Nature Genetics 11:201, 1995 VI V IV III II I II III IV V VI Epilepsy Genes: 2014 GENE ARX ATP1A2 CACNA1A CACNAB4 CDKL5 (STK9) CHRNA4 CHRNAB2 CHRNA7 CLCN2 EFHC1 GABRD GABRA1 GABRG2 KCNQ2 KCNQ3 KCNMA1 KCNT1 KCTD7 LGI1 PCDH19 PLCB1 PRRT2 SCN1A SCN1B SCN2A SCN8A SLC2A1 STXBP1 TBC1D24 ASSOCIATED EPILEPSY SYNDROME(S) Infantile spasms Benign familial infantile cnvulsins Familial hemiplegic migraine and epilepsy Absence epilepsy and episdic ataxia Infantile spasms Autsmal dminant ncturnal frntal lbe epilepsy Autsmal dminant ncturnal frntal lbe epilepsy Childhd absence epilepsy Juvenile absence epilepsy Childhd absence epilepsy Benign familial nenatal cnvulsins Ohtahara Syndrme Benign familial nenatal cnvulsins Generalized epilepsy with parxysmal dyskinesia Malignant migrating partial seizures f infancy Severe autsmal dminant ncturnal frntal lbe epilepsy Prgressive myclnic epilepsy Autsmal dminant partial epilepsy with auditry features Epilepsy in females with mental retardatin Migrating partial epilepsy f infancy Benign familial infantile seizures Severe myclnic epilepsy f infancy (Dravet syndrme) Migrating partial epilepsy f infancy Benign familial nenatal/infantile cnvulsins Infantile epileptic encephalpathy + SUDEP Early-nset absence epilepsy Epilepsy with parxysmal exercise-induced dyskinesia Partial nset epilepsy with intellectual disability Familial infantile myclnic epilepsy Fcal epilepsy with develpmental disability Epilepsy Genes: 2014 GENE ARX ATP1A2 CACNA1A CACNAB4 CDKL5 (STK9) CHRNA4 CHRNAB2 CHRNA7 CLCN2 EFHC1 GABRD GABRA1 GABRG2 KCNQ2 KCNQ3 KCNMA1 KCNT1 KCTD7 LGI1 PCDH19 PLCB1 PRRT2 SCN1A SCN1B SCN2A SCN8A SLC2A1 STXBP1 TBC1D24 ASSOCIATED EPILEPSY SYNDROME(S) Infantile spasms Benign familial infantile cnvulsins Familial hemiplegic migraine and epilepsy Absence epilepsy and episdic ataxia Infantile spasms Autsmal dminant ncturnal frntal lbe epilepsy Autsmal dminant ncturnal frntal lbe epilepsy Childhd absence epilepsy Juvenile absence epilepsy Childhd absence epilepsy Benign familial nenatal cnvulsins Ohtahara Syndrme Benign familial nenatal cnvulsins Generalized epilepsy with parxysmal dyskinesia Malignant migrating partial seizures f infancy Severe autsmal dminant ncturnal frntal lbe epilepsy Prgressive myclnic epilepsy Autsmal dminant partial epilepsy with auditry features Epilepsy in females with mental retardatin Migrating partial epilepsy f infancy Benign familial infantile seizures Severe myclnic epilepsy f infancy (Dravet syndrme) Migrating partial epilepsy f infancy Benign familial nenatal/infantile cnvulsins Infantile epileptic encephalpathy + SUDEP Early-nset absence epilepsy Epilepsy with parxysmal exercise-induced dyskinesia Partial nset epilepsy with intellectual disability Familial infantile myclnic epilepsy Fcal epilepsy with develpmental disability 5

6 Epilepsy Genes: 2014 GENE ARX ATP1A2 CACNA1A CACNAB4 CDKL5 (STK9) CHRNA4 CHRNAB2 CHRNA7 CLCN2 EFHC1 GABRD GABRA1 GABRG2 KCNQ2 KCNQ3 KCNMA1 KCNT1 KCTD7 LGI1 PCDH19 PLCB1 PRRT2 SCN1A SCN1B SCN2A SCN8A SLC2A1 STXBP1 TBC1D24 ASSOCIATED EPILEPSY SYNDROME(S) Infantile spasms Benign familial infantile cnvulsins Familial hemiplegic migraine and epilepsy Absence epilepsy and episdic ataxia Infantile spasms Autsmal dminant ncturnal frntal lbe epilepsy Autsmal dminant ncturnal frntal lbe epilepsy Childhd absence epilepsy Juvenile absence epilepsy Childhd absence epilepsy Benign familial nenatal cnvulsins Ohtahara Syndrme Benign familial nenatal cnvulsins Generalized epilepsy with parxysmal dyskinesia Malignant migrating partial seizures f infancy Severe autsmal dminant ncturnal frntal lbe epilepsy Prgressive myclnic epilepsy Autsmal dminant partial epilepsy with auditry features Epilepsy in females with mental retardatin Migrating partial epilepsy f infancy Benign familial infantile seizures Severe myclnic epilepsy f infancy (Dravet syndrme) Migrating partial epilepsy f infancy Benign familial nenatal/infantile cnvulsins Infantile epileptic encephalpathy + SUDEP Early-nset absence epilepsy Epilepsy with parxysmal exercise-induced dyskinesia Partial nset epilepsy with intellectual disability Familial infantile myclnic epilepsy Fcal epilepsy with develpmental disability Helbig and Lwenstein, Current Opin Neurl. 2013; 26: The neurbilgical spectrum f the epilepsies epilepsies with plygenic inheritance Others Strke Trauma Cngenital Unknwn Idipathic Genetic/ Epigenetic The reality f living with epilepsy Hw imprtant is genetics as a cause f epilepsy? - Genetic epidemilgy T Cver: single gene epilepsies Genetic epilepsies with a majr acquired cause trauma, infectins, vascular etc. Structural/Metab lic Mdified frm Helbig et al 2008 A brief verview f epilepsy gene discvery t date The next wave: identifying the genetic causes f mre cmmn, nn-acquired epilepsies 6

7 An internatinal, multi-center, cllabrative research effrt funded by the Natinal Institute f Neurlgical Disrders and Strke designed t advance ur understanding f the genetic basis f epilepsy Ruben Kuzniecki, MD The genesis f the prject: First-hand awareness f the tremendus impact that epilepsy has n individuals and sciety, and the current limitatins f what we ffer ur patients Recgnitin f accelerating advances in mlecular analyses, and the pivtal rle f phenmics Indisputable need fr a natinal effrt t achieve success Lng-term impact f creating a natinal resurce Enthusiasm fr wrking with extremely mtivated, talented, and willing cllabratrs Overview f Study and Prtcl Overall Objective: T create a database cntaining in-depth phentype and gentype data frm a large number f patients with epilepsy frm thrughut the United States, and t investigate the genetic influences n cmmn and rare frms f epilepsy and pharmacresistance. 7

8 IGE Prband (n=750) LRE Prband (n=750) IS Prband (n=250) LGS Prband (n=250) IGE Sibling (n=750) LRE Sibling (n=750) (r parent/child pairs) Parents (n=500) Parents (n=500) Flw f Data fr IGE/LRE Sib Pairs Cnfirm Eligibility fr Prband and Permissin t Cntact Sibling Pre-screen Cnsent Screening Interview Review f Medical Recrd, EEG, MRI Bld Draw and Shipment t Criell: Prband Identify Ptential Prband: Patient with IGE r LRE with a Full-Sibling with Nnacquired Epilepsy Cnfirm Eligibility fr Sibling: Pre-screen Cnsent Screening Interview Review f Medical Recrd, EEG, MRI Bld Draw and Shipment t Criell: Sibling Phentyping f Prband and Sibling: Diagnstic Interview Medical Recrd Abstractin Supplemental Frms AED Data Sheet MCD Prband (n=250) Parents (n=500) EEG Cre Review EEG Review by Site MRI Cre Review Phentyping Cre Review 3,750 1,500 Final Cnsensus f Diagnsis Phentyping Cmplete Study-Wide Enrllment as f 2/22/2014 Ttal Enrllment Target # Cnsented # Eligible Familial Aggregatin f Seizure Semilgy in the Epilepsy Phenme/Genme Prject Meldie Winawer, Rbyn Fahlstrm, Cahtherine Shain, Daniel Rabinwitz and the EPGP Investigatrs Study f 1055 participants, including 412 with nn-acquired fcal epilepsy and 643 with generalized epilepsy. Familial aggregatin was assessed by lgistic regressin analysis f relatives traits (dependent variable) by prbands traits (independent variable), estimating the dds rati fr each symptm in a relative given presence versus absence f the symptm in the prband End f Mnth 33,816 activities 6,960,307 data pints Seizure type Simple fcal Cmplex fcal Secndarily generalized tnic-clnic Fcal Epilepsy Ictal Symptms Mtr Autnmic Psychic Aphasic Generalized Epilepsy generalized tnic-clnic absence myclnic atypical absence atnic reflex generalized 8

9 Phentyping & Clinical Infrmatics Cre Phentype Data Steering Cmmittee Epi4K PIs & NINDS Administrative Cre Data Sharing Publicatins Epi4K Charter Regulatry ELSI Prject 1: Epileptic Encephalpathies Prject 2: Multiplex Families & Pairs Prject 3: Prgnsis Prject 4: CNV Detectin Sequencing Data Sequencing, Bistatistics & Biinfrmatics Cre Epi4K Prject 1- Epileptic Encephalpathies (EE) Infantile Spasms (IS) 1 in 3000 live births and nset between 4-12 mnths f life Characteristic chatic interictal & EEG pattern f hypsarrhythmia, the sine qua nn f the syndrme 50-60% f IS cases have develpmental brain malfrmatins, tuberus sclersis cmplex, chrmsmal syndrmes and metablic cnditins Patients may evlve int LGS Lennx-Gastaut syndrme (LGS) Onset between 1-8 years Characterized by mixed seizure types and intellectual disabilities Cause unknwn in abut 25-35% cases, symptmatic f structural r metablic abnrmalities EPGP: Epileptic Encephalpathies Mst EE d nt shw trans-generatinal transmissin Mst families d nt have sibling recurrence Hypthesis: many IS/LGS patients have de nv causative mutatins Target families t highlight increased chance: Bth bilgical parents available N epilepsy in parents N familial recurrence Target genes that functin at the cre f EE Exclude patients with knwn causes Exclude patients with severe Develpmental Delay prir t seizure nset Nature 501: ,

10 Distributin f de nv mutatins Number f EE prbands Number f de nv mutatins per EE prband Slavé Petrvski Epi4K and EPGP Investigatrs. Nature 501: , 2013 Degree t which genes have mre, r less, cmmn functinal variatin than expected given the amunt f presumably neutral variatin they carry Distributin f de nv mutatins in intlerant genes Sum f all cmmn (>0.1%MAF) functinal variants in gene TOLERANT (extreme 2% f genme) INTOLERANT (extreme 2% f genme) HLA Olfactry receptrs Calcium channels % f de nv mutatins In intlerant genes Sum f all variant sites in gene Epi4K and EPGP Investigatrs. Nature 501: ,

11 Genes with greater than ne de nv SNV in 27 tris, and the prbabilities f getting greater than r equal bserved de nv mutatin tally by chance Gene Chr Average effectively captured length (bp) Weighted mutatin rate De nv mutatin number P-value SCN1A x x10-9 STXBP x x10-11 GABRB x x10-10 CDKL5 X x x10-7 ALG13 X x x10-12 DNM x x10-4 HDAC x x10-4 SCN2A x x10-9 SCN8A x x10-4 Epi4K and EPGP Investigatrs. Nature 501: , likely de nv mutatins in intlerant genes that are already disease-causing: CACNA1A CHD2 FLNA GRIN1 GABRA1 GRIN2B HNRNPU IQSEC2 KCNQ2 KCNT1 MTOR NEDD4L Episdic ataxia, familial hemiplegic migraine, ASD ASD and ID with seizures Periventricular hetertpia ID ASD Variety f neurdevelpmental phentypes ID with seizures ID; ne patient with infantile spasms ID with seizures ADNFLE and epilepsy f infancy with migrating fcal seizures Hemimegalencephaly Phtsensitive epilepsy and indirectly t infantile epilepsy The de nv mutatins are drawn preferentially frm particular gene sets: In channels (p=1.3x10-3 )* Mngenic disrders with epilepsy (p=1.5x10-2 ) ASD (p=9.4x10-2 ) ID (p=7.8x10-3 ) FMRP-regulated genes (p=4.2x10-4 ) *- after excluding genes knwn t cause EE Ingenuity Pathway Analysis EE: p=0.001 ASD/ID: p=0.001 FMRP: p=1.2x10-9 Clinical implicatins Significant genetic hetergeneity underlying IS and LGS These are the first mutatins identified t be likely causative in LGS 3 mutatins fund in genes (MTOR, DCX, FNLA) assciated with brain malfrmatins but nrmal MRIs in all 3 patients 2 genes (SCN8A and GABRB3) each with de nv mutatins in ne pt. with IS and ne pt. with LGS, despite n hx f IS in the LGS pt. 5 pts. with LGS with de nv mutatins in SCN1A; in all 5 cases a re-review suggests these individuals had a clinical curse cnsistent with Dravet syndrme despite an initial diagnsis f LGS 11

12 n=143 MD r DO 73 PhD 24 RN 7 PharmD 3 MPH 11 Masters (ther) persn-years f graduate-level training! Bichemical Genetics Bistatistics Chemistry Clinical Infrmatics Clinical Neurphysilgy Clinical Research Electrical Engineering Epidemilgy Epilepsy Genetic Cunseling Genetics Mental Health Cunseling Micrbilgy Mlecular Bilgy Mlecular Genetics Neurgenetics Neurlgy Neurpathlgy Neurphysilgy Neurscience Neurscience Pediatric Neurlgy Pharmaceutical Sciences Pharmaclgy Psychmetrics Scial Psychlgy Scial Psychlgy Cnclusins Strke Others Trauma Cngen ital Genetic The degree f suffering assciated with epilepsy is hrrible. We appear t again be n the upswing in deciphering the genetic architecture f the epilepsies. Large-scale, cllabrative effrts are essential t future prgress. Thank yu! The results are already having an imprtant impact n clinical care. The latest EPGP/Epi4K results suggest that even thugh patients may carry very rare r private mutatins cnferring risk, many f the genes affected by these mutatins can be rganized int functinally-related grups. This may prvide insight int the develpment f new therapies and individual treatment respnses. 12