Pondering Epilepsy Classification (actually a few thoughts on the impact of genetic analyses of the epilepsies) Genetics of Epilepsies

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1 Pondering Epilepsy Classification (actually a few thoughts on the impact of genetic analyses of the epilepsies) Dan Lowenstein UCSF Department of Neurology and the UCSF Epilepsy Center To Cover: 1. Update on gene mutations that are the basis of certain familial and other rare epilepsy syndromes 2. The role of genetics in more common forms of epilepsy 3. The first example of personalized medicine in the epilepsy space 4. The next horizon: identifying the genetic causes of more common, non-acquired epilepsies, and the role of the Epilepsy Phenome/Genome Project Genetics of Epilepsies Majority of cases: Complex inheritance Polygenic - many genes, currently unknown Modified by environmental factors? < 5% families Nature Genetics 11:201, 1995 (Adapted from Ingrid Scheffer, Melbourne) Rare families: Simple inheritance Multiple single gene disorders? genes relevant to majority of cases 1

2 Monogenic Epilepsies: Genetic defects Voltage-gated ion channel subunits Sodium - GEFS +, Dravet, infantile seizures Potassium - neonatal seizures, absence epilepsy Calcium - absence epilepsy, generalized epilepsies V VI VII Generalized Epilepsy With Febrile Seizures Plus Ligand-gated ion channel subunits Nicotinic receptors - frontal lobe epilepsy GABA receptors - GEFS +, absence epilepsy, juvenile myoclonic epilepsy LGI1 - temporal lobe epilepsy VIII Unaffected male Unaffected female Unwitnessed seizures Deceased Febrile Seizures Febrile Seizures Plus (FS +) FS+ and absences Proband FS+ and myoclonic seizures FS+ and atonic seizures Myoclonic-astatic epilepsy Scheffer & Berkovic Brain 120:479, 1997 Locus Heterogeneity and Variable Expressivity SCN1A * Severe myoclonic epilepsy of infancy (SMEI) Lancet Neurology 5: SCN1B SCN2A GABRG2 (Adapted from Ruth Ottman, Columbia) GEFS+ CAE and FS Benign familial neonatal-infantile seizures Hypothesis: Cases of so-called vaccine encephalopathy could have mutations in the neuronal sodium channel α1 subunit gene (SCN1A) because of a clinical resemblance to severe myoclonic epilepsy of infancy (SMEI) for which such mutations have been identified. 2

3 Genetics of Epilepsies Majority of cases: Complex inheritance Polygenic - many genes, currently unknown Modified by environmental factors? < 5% families (Adapted from Ingrid Scheffer, Melbourne) Rare families: Simple inheritance Multiple single gene disorders? genes relevant to majority of cases Idiopathic Epilepsies: Complex Inheritance Susceptibility Genes: 2009 Juvenile Myoclonic Epilepsy Pro-apoptotic, calcium sensing, ciliary fxn EFHC1 Transcriptional regulator BRD2 (??) Childhood Absence Epilepsy Calcium T channel gene Idiopathic Generalized Epilepsies CACNA1H Chloride channel gene CLCN2 GABA delta subunit gene GABRD Ion channel regulator NEDD4-2 Nicotinic receptor 15q13.1 deletion Genetics of Epilepsies (Adapted from Ingrid Scheffer, Melbourne) Polygenic: Susceptibility alleles Ca 2+ channels, GABA A receptors ion channel regulators, EFHC1 Monogenic: Pathogenic mutations Ion channels - Na +, K +, Cl -, Ca 2+ nicotinic, GABA receptors, LGI1 3

4 Using HLA-B*1502 Genotype to Identify At-Risk Individuals Based on findings, HLA-B*1502 allele should have 100% sensitivity and 97% specificity. Assuming a 0.25% prevalence rate of HLA-B*1502, the presence of this allele has a 7.7% positive predictive value the absence of the allele has 100% negative predictive value. Giving CBZ to an at-risk individual unnecessarily is associated with a high risk of poor outcome (5-15% of SJS cases are fatal; 30% of TEN cases are fatal) Withholding CBZ unnecessarily is associated with low risk of poor outcome; alternative AEDs are available (e.g., lamotrigine) Courtesy of Brian Alldredge, PharmD The genesis of the project: First-hand awareness of the tremendous impact that epilepsy has on individuals and society, and the current limitations of what we offer our patients Recognition of accelerating advances in molecular analyses, and the pivotal role of phenomics Indisputable need for a national effort to achieve success Long-term impact of creating a national resource Enthusiasm for working with extremely motivated, talented, and willing collaborators 4

5 Who We Are More than 100 clinicians, scientists, nurses, study coordinators, site administrators, informatics experts, database engineers, advisory board members, and NINDS personnel Based at 14 academic medical centers and affiliates, and NINDS 1. Boston Children s 2. Children s Hospital Philadelphia 3. Cincinnati Children s 4. Einstein 5. Emory 6. Johns Hopkins 7. Mayo 8. New York University 9. Rush 10. St. Barnabus 11. U of Alabama 12. UCSF 13. U of Michigan 14. UT San Antonio Clinical Centers: Overview of Study and Protocol Overall Objective: To create a database containing in-depth phenotype and genotype data from a large number of patients with epilepsy from throughout the United States, and to investigate the genetic influences on common and rare forms of epilepsy and pharmacoresistance. Participants: Sib Pairs 1. Full-blooded siblings with epilepsy (either Idiopathic Generalized Epilepsy or Localization-Related Epilepsy) 2. Current Age 4 weeks-60 years 3. Clear diagnosis of epilepsy (>2 sz) 4. Age of onset 4 weeks 30 years 5. Good records: history, EEG, MRI, drugs (all or at least 2 years) 6. No recognized genetic syndrome 7. No potential antecedent cause to epilepsy (head injury, stroke, brain tumor, etc.) 5

6 Participants: Triads 1. Infantile Spasms or Lennox-Gastaut Syndrome or certain forms of focal cortical dysplasia 2. Patient current age 4 weeks-60 years 3. Patient has clear diagnosis of epilepsy (>2 sz) 4. Age of onset 4 weeks 30 years 5. No recognized genetic syndrome 6. No potential antecedent cause to epilepsy (head injury, stroke, meningitis/encephalitis, TORCH infection, birth before 32 weeks, etc.) 7. Both biological parents alive 8. Neither parent has history of epilepsy IGE Proband LRE Proband IS Proband (n=250) LGS Proband (n=250) MCD Proband (n=250) IGE Sibling LRE Sibling Normal Control Normal Control Parents (n=500) Parents (n=500) Parents (n=500) 3,750 3,000 epgp.org 6