1. Evan J. Fertig, MD

2. Introduction  A common question is epilepsy inherited? How and when?  Genetics is “the study of heredity”  This talk will therefore be about the genetics of epilepsy

3. Overview  A Brief History of Epilepsy Genetics  Basic concepts of genetics  What are my child’s chances of getting epilepsy?  Genetic Testing. Worth it?  The future: Pharmacogenetics

5. History of Epilepsy Genetics Hippocrates (400 B.C.E.) On the Sacred Disease Recognized epilepsy could be inherited Through history this has been another burden for person w epilepsy

6. Photograph and EEG of Constance and Kathryn, identical twins both w/ childhood absence epilepsy, both with seizure onset at age 6 years! Vadlamudi, L. et al. Neurology 2004;62:1127-1133

7. Concordance rate for epilepsy in IDENTICAL vs. FRATERNAL Twins Epilepsy or not SameDifferent Concordance Rate Identical Twins 291090.35 Fraternal Twins 112140.09 Henriksen, Corey et al. Epilepsia 1999 -Data combined from US and Norwegian Twin Registries essexcc.gov.ukpublications.nigms.nih.gov

8. StudyYear Number of probands Number of offspring Affecte d N% Conrad19375191,568704.5 Alstrom1950897339103.0 Harvald1951162252114.4 Lennox19514,2311,237342.7 Tsuboi and Endo1977263506122.4 Annegers et al.1978336687253.6 Janz and Scheffner1980384672243.6 Beck-Mannagetta et al. 1989427840394.6 *Probands (parents) had any kind of epilepsy; single seizures were excluded. Source: Beck-Mannagetta and Janz 1991 (12). Risk for epilepsy in children of parents with epilepsy (any type)

10. Peas, Genes, and DNA 1856 1953

11. The Structure of the Genome http:// davidmaybury.ie Genome Chromosome

12. Genes, Protein, and Disease Gene Protein Neuron Nih.gov Mutation Cell

13. What We Know Today  Epilepsy frequently does have a genetic basis  Hundreds of inherited conditions have seizures as feature  Only a few of these conditions have seizures as their ONLY feature

14. How do Genetic Factors cause Epilepsy?  Chromosomal abnormalities  Genes involved in BRAIN FORMATION (migration)  Genes involved in BRAIN METABOLISM  Genes involved in BRAIN COMMUNICATION (ion channel function)

15. Chromosomal Abnormalities

16. Chromosome Abnormality http://ghr.nlm.nih.gov/handbook/ illustrations/ringchromosome.jpg

17. Brain Formation: Genes are GPS for the Developing Brain eurekalert.org

18. Brain Communication http://www.niaaa.nih.gov/NR/rdonlyres/9E5D5B9F-C28E-49F2-A925-33886A82E4D5/0/synapsebetween_neurons.gif

19. Brain Metabolism Gene (DNA) Enzyme Mutation Toxic Metabolite Substrat e, eg. Fat

20. So, how is Epilepsy Inherited? SIMPLE INHERITANCE With “STRONG” GENES COMPLEX INHERITANCE With “WEAK” GENES

21. “Strong” Genes  Are biologically very important. Therefore “bad” strong genes have obviously “bad” effects  Strong Genes are rare  However when they occur in a family, the can occur very commonly in the family tree

22. Simple Inheritance (Mendel) shinerama.naitsa.ca

23. Epilepsy Genes and Simple Inheritance  There are very few “strong” epilepsy genes out there (sharks)  Over 10 have been identified to date  “Strong” genes account for very few cases of epilepsy

24. Known Major Epilepsy Genes GeneSyndromeYr Discovered CHRNA4ADNFLE1995 KCNQ2BFNS/(myokymia)1998 KCNQ3BFNS1998 SCN1BGEFS+1998 SCN1AGEFS+/(SMEI)2000 CHRNB2ADNFLE2000 GABRG2CAE/FS/GEFS+2001 SCN2AGEFS+/(BFNIS)2001 GABRA1ADJME2002 LGI1ADPEAF2002 CLCN2JME2003 EFHC1JME2004

25. Weak Genes and Complex Inheritance  Weak genes may not be powerful enough to cause epilepsy alone, but may be an influencing factor, with other genes or environment stimuli  “Runs in the Family”  Most medical diseases, e.g. high blood pressure

26. Reasons for Complex Inheritance  No single gene causes the disease in the family  Many bad “weak” genes cause the disease  School of piranha  Ion channel polymorphisms and idiopathic generalized epilepsy  Environmental factors contribute Smoking with alpha-1-antitrypsin mutation increases risk of early emphysema

28. What does this all mean for the patient with epilepsy? Question: Can predict if a child will have epilepsy? Answer: Most times we can only give very rough odds

29. Case study: Counseling risk  33 year old woman with epilepsy is planning to get pregnant, but she first wants to know…  “What’s the chance my child will have seizures?” Winawer, Epilepsia, 2005

30. Assessing Risk: Patient Factors Exclude Non-Genetic Causes of Epilepsy  Central nervous system infection  Stroke  Brain Trauma  Alcohol  Brain tumors  Degenerative Disease (Parkinson’s Disease)  Static Conditions from birth Hauser WA, Epilepsia, 1993;34:453-68.

31. Classification of Seizures GeneralizedFocal Focus

32. Patient Factors: Determine Seizure Type and Epilepsy Syndrome  She first noted bilateral muscle jerks riding on a school bus at age 15  First GTC at age 16 preceded by jerks  Normal exam  Generalized polyspike wave on EEG superimposed on normal background  Epilepsy well-controlled on LTG DIAGNOSIS?

33. Assessing Risk: Family Factors Questions to ask about family members with epilepsy 1) Seizure type or types 2) Triggering factors (fever, alcohol) 3) Other nongenetic risk factors 4) Age of onset Winawer, Epilepsia, 2005

34. Case study: Family History Winawer, Epilepsia, 2004 GTC upon awakening Juvenile Myoclonic Epilepsy

35. Genetic risk to offspring Risk Factors based on Parent  Parent Gender:  Maternal effect (2.8-8.7%)  Father (1.0-3.6%)  Age of onset  < 20 (2-6%)  20+ (1.0-2.8%)  Increases with # of affected  Generalized spike wave on EEG (4-6%) Winawer, Epilepsia, 2004

36. Effect of Parent Seizure Type Winawer, Shinnar 2005

37. So what do we tell her?  Generalized epilepsy, Juvenile Myoclonic Epilepsy  A remote relative has IGE, no first degree relatives: Likely Complex  Gene testing not possible at this point for syndromes with complex inheritance Winawer, 2004

38. The bottom line….  Population risk to offspring: 1%  Patient factors  Mom has epilepsy: 6%  Early onset: 6%  GSW EEG: 6%  Myoclonic Seizures: 4-8%  > 90% chance child will be seizure free

39. Mom has another question…  “If my child gets epilepsy, will it be worse than mine? Will she be developmentally delay from the epilepsy?  Does epilepsy syndrome “breed true”?

40. Identical vs. Fraternal twins Identical Twins  29 twins had epilepsy  25/29 had same type of epilepsy  Fraternal Twins  11 concordant for epilepsy  1/11 concordant for seizure type and syndrome Henriksen, Corey et al. Epilepsia 1999 -from Shlomo Shinnar, AES, 2004

41. Epilepsy Syndromes in Concordant and Discordant Identical Twins SyndromeConcordantDiscordant Idiopathic Generalized 129 Idiopathic Localization- Related 23 Symptomatic Generalized 02 Symptomatic Localization- Related 353 Undetermined 843 Henriksen, Corey et al. Epilepsia 1999 -from Shlomo Shinnar, AES, 2004

42. Epilepsy Syndrome, Same or Different in a Child?  Syndromes do not always “breed true” but most often do!  The most heritable epilepsies tend also to be benign (childhood absence epilepsy)

43. Exceptions to be aware of…..  Tuberous Sclerosis  Rare genetic cause of epilepsy w/ other features Child can be more severely affected than the parent

45. Role of Genetic Testing  There are no official guidelines for when and who should be tested  Most often there is complex inheritance and there is no definite genetic test to send  Many genetic tests are very expensive and may not be covered by insurance

46. Role of Genetic Testing (Continued)  Patients with epilepsy associated with developmental delays or other features may benefit from other types of genetic test:  Microscopic examination of the chromosomes  Metabolic tests- Blood tests to see how some genes are functioning  MRI and other clinical features might suggest other genetic tests

47. Role of Genetic Tests  For some patients, genetic testing is very important  To help guide medical therapy (eg, decide what drugs to avoid)  Determine the long term prognosis  Family planning

49. Pharmacogenetics: The Future  Initiating seizure medications  What drug?  What dose?  New onset epilepsy: 40-50% won’t respond to seizure medication  Pharmacogenetics- Use individual genetic variation to predict response

50. How Pharmacogenetics works in theory  Genes influence how well each seizure medication “bind” to their targets (where they work) in the brain  Genes (eg. in the liver) influence how much seizure medication reaches the brain  Too little: Seizures  Too much: Side effects

52. Conclusion  Advances in epilepsy genetics will alter how we treat epilepsy from diagnosis to treatment  More research remains to be done!  Have multiple family members with epilepsy? Consider joining a research study