Challenges and Possibilities in Intellectual Disability Medicine The genetic etiology may help in the treatment of epilepsies

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1 Challenges and Possibilities in Intellectual Disability Medicine The genetic etiology may help in the treatment of epilepsies Thomas Dorn Helsinki, 15th November 2013

2 Overview Principles of epilepsy therapy Remarks on classification and genetic of epilepsies Avoidance of «wrong» antiepileptic drugs (AED) Progressive myoclonic epilepsies (PME) Dravet`s syndrome Special AED for special syndromes Dravet s syndrom Tuberous sclerosis Syndrome specific disease modifying therapies GLUT1-Defekt Tuberous sclersosis Diagnosis of genetic syndromes Summary, Perspectives 2

3 Principles of Epilepsy Therapy Antiepileptic (anticonvulsive) drugs (AED) = suppression of seizures Epilepsy surgery sensu strictu = resection of a localised residual epileptogenic brain pathology: seizure freedom at least with AED Additional treatment of a progressive brain disease (e.g. brain tumor, herpes encephalitis, angioma) Treatment of underlying brain disease only (e.g. limbic encephalitis with LGI1 antibodies) 3

4 Classification and Genetics of Epilepsies Idiopathic (genetic) (genetisch) cryptogenic (= probably symptomatic) symptomatic focal genetic ( oligogenic?) rarely monogenic in part genetic in part genetic generalised genetic ( oligogenic?) rarely monogenic) in part genetic In part genetic Monogenic idiopathic or symptomatic epilepsies incl. mitochiondrial cytopathies (about 1% of all epilepsies) gene proteine pathophysiology? specific therapy? 4

5 PME Differential Diagnosis seizures + myoclonia + ataxia + cognitive decline progressive myoclonic epilepsies Unverricht-Lundborg Lafora Sialidosis Ceroidlipofuscinosis MERRF DPRLA others Clarification of underlying entity by anamnesis, physical examination, EEG, evoked potentials, biopsy and molecular genetics 5

6 PME- Differential Therapy of AED Phenytoine can cause irreversible increase of neurological symptoms (ataxia) in Unverricht Lundborg disease Berkovic SF, Cochius J, Andermann E et al. Epilepsia 1993; 34 Suppl 3: S19 - S30 Valproate can cause severe liver failure in mitochondrial cytopathies (e.g. MERRF, POLG) Krähenbühl S, Brandner S, Kleinle S et al. Liver 2000; 20: (Topiramate may exert positive effects in mitochondrial cytopathies) Kudin AP, Debska-Vielhaber G,Vielhaber S. et al. Epilepsia 2004;45:

7 Dravet s Syndrome (SMEI) Phenotype/Genotype 7

8 Dravet s Syndrome (SMEI) Phenotype/Genotype 8

9 Dravet s Syndrome (SMEI)- Proteine More severe phenotype of GEFS+/SMEI with mutations affecting the pore region? Kanai K et al. Neurology 2004; 63:

10 Dravet s Syndrome (SMEI)- Pathophysiology GEFS+/SMEI with gain of function mutations of SCN1A Rhodes, Thomas H. et al. Proc. Natl. Acad. Sci. USA 2004; 101:

11 Dravet s Syndrome (SMEI)- Pathophysiology GEFS+/SMEI with loss of function mutations of SCNA1 Lossin C et al. J Neurosci 2003;23: GEFS+ with SCNA1 mutations causing impaired channel function Barela AJ et al. J Neurosci 2006; 26: Activation Fast inactivation 11

12 Dravet s Syndrome (SMEI)- Pathophysiology SMEI with non truncating mutations is associated with impaired transport of dysfunctional channel proteins to cell surface, LTG increases pathological sodium current Thomson Ch et al. J Biol Chem. 2012; 287:

13 Dravet s Syndrome (SMEI)- Avoidance of Certain AED Prognostic, clinical and demographic features in SCN1A mutationpositive Dravet syndrome. Brunklaus A, Ellis R, Reavey E, Forbes GH, Zuberi SM. Dravet syndrome is a severe infantile onset epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene SCN1A. To date no large studies have systematically examined the prognostic, clinical and demographic features of the disease. We prospectively collected data on a UK cohort of individuals with Dravet syndrome during a 5-year study period and analysed demographic information based on UK population and birth figures. From structured referral data we examined a range of clinical characteristics including epilepsy phenotype, seizure precipitants, electroencephalography data, imaging studies, mutation class and response to medication. Predictors of developmental outcome were determined by logistic regression. We identified 241 cases with SCN1A mutation-positive Dravet syndrome, 207 of which were UK-based. The incidence of mutation-positive Dravet syndrome is at least 1: UK births. Clinical features predicting a worse developmental outcome included status epilepticus (odds ratio = 3.1; confidence interval = ; P = 0.003), interictal electroencephalography abnormalities in the first year of life (odds ratio = 5.7; confidence interval = ; P = 0.002) and motor disorder (odds ratio = 3.3; confidence interval = ; P < 0.001). No significant effect was seen for seizure precipitants, magnetic resonance imaging abnormalities or mutation class (truncating versus missense). Abnormal magnetic resonance imaging was documented in 11% of cases, principally with findings of nonspecific brain atrophy or hippocampal changes. Sodium valproate, benzodiazepines and topiramate were reported as being the most helpful medications at the time of referral. Aggravation of seizures was reported for carbamazepine and lamotrigine. The identification of factors influencing prognosis both aids counselling and encourages early, syndromespecific therapy. Prevention of status epilepticus with regular medication and emergency protocols is important and may influence developmental outcome. Brain. 2012; 135:

14 Dravet s Syndrome (SMEI)- specific therapy mode of action: lengthening of duration of the open state of GABA A receptor chloride channel complexes via allosteric PB binding site no direct interaction with benzodiazepines Cave: pharmakokinetic interactions Chiron C. Expert Opin. Investig. Drugs 2005; 14:

15 Dravet s Syndrome (SMEI)- specific therapy?? Chiron C. Expert Opin. Investig. Drugs 2005; 14:

16 Dravet s Syndrome (SMEI)- specific therapy Avoid LTG, CBZ, PB (in high dose, iv) Stiripentol as orphan drug with VPA plus CLB TPM, LEV, bromide und ketogenic diet Chiron C. Developmental Medicine & Child Neurology 2011; 53:

17 GLUT1 Defect Phenotype, Pathophysiology and Specific therapy New England Journal of Medicine 1991; 325:

18 GLUT1 Defect - Genotype Mutations of SLC2A1 cause impairment of glucose transport autosomal rezessive and autosomal dominant inheritance Kollros PR, Konkle BA (1992) A candidate mutation in the GLUT-1 gene in a patient with glucose transporter dysfunction at the blood brain barrier (abstract). Ann Neurol 32:445 Kollros PR, Konkle BA (1993) A second candidate mutation in a patient with glucose transporter-1 dysfunction (abstract). Clin Res A Seidner G, Garcia Alvarez M, Yeh J-I, O'Driscoll KR, Klepper J, Stump TS, Wang D, Spinner NB, Birnbaum MJ, De Vivo DC (1998) GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet 18: The Journal of Clinical Investigation 2008; 118:

19 GLUT1 Defect Expanding the Phenotype The Journal of Clinical Investigation 2008; 118:

20 GLUT1 Defect Expanding the Phenotype 20

21 GLUT1 Defect Expanding the Phenotype 21

22 GLUT1 Defect Expanding the Phenotype 22

23 GLUT1 Defect Expanding the Phenotype 23

24 GLUT1 Defect Expanding the Phenotype 24

25 GLUT1 Defect Expanding the Phenotype 25

26 Tuberous Sclerosis Phenotype and Genotype neurocutaneous, genetic syndrome autosomal-dominant inheritance typic tumorous manifestations in CNS, skin and viscera (kidney, heart, lung) often epileptic seizures often intellectual disability Mutations in one of two tumorsuppressor genes TSC1 (Hamartin) (Chromosome 9) TSC2 (Tuberin) (Chromosome 16) 26

27 Tuberous Sclerosis Therapeutic Considerations specific AED VGB for BNS epilepsy disease modifying therapy mtor inhibition with Rapamycine/Everolimus -> reduction of volume of SEGA and angiomyolipoma, positive effects on epilepsy and development? 27

28 Diagnosis: From Phenotype to Genotype Gene Proteine Cell Metabolisma Cell Structure Tissue Organ Organsism Symptoms Syndrome 3rd order unspecific combination of symptoms Syndrome 2nd order (sequence) symptoms with pathogenetic relationship Syndrome 1st order direct relationship to genetic defect Genetic defect 28

29 Diagnosis: From phenotype to genotype Rarely diagnosis at first glance (e.g. Trisomy 21, Tuberous sclerosis) But usually complex relationship between genotype and phenotype due to pleiotropy and heterogeny. Detailed assessment of family history and phenotype (Development, complete medical history, clinical exmanination (neurologic, psychiatric, medical), study of the whole medical dossier)) Search in databases (Online Mendelian Inheritance in Man = OMIM, Human Phenotype ontology = HPO, Phenomizer Advice of a genetist in each case! Genetic Methods (F(luoreszens)-(I)n-(S)itu-(H)ybridization, sequencing of single genes) depend on suspected diagnoses Importance of epileptological phenotype in this process is different in different syndromes 29

30 Diagnosis: Genetic Screening Gene panels (epilepsy, mitochondrial disease): sequencing of up o several hundreds of candidate genes Array techniques (e.g. array comparative genomic hybridization). Detection of copy number variations (CNV) i.e. microdeletions, microduplications, rearranegments Whole exome sequencing Whole genome sequencing 30

31 Diagnosis: (Epilepsy) Gene Panel Lemke et al. Epilepsia. 2012; 53:

32 Diagnosis: Genetic Testing ID with epilepsy Genetic study in residents of swiss epilepsy center Informed consent of patients a/o guardian n= 89 (39 f, 49 m) Epilepsy gene panel, Array-CGH, (whole exome sequencng, whole genome sequencing) 32

33 Diagnosis: Genetic Testing ID with epilepsy Some preliminary results Mutations/variations of ion channel subunits genes (esp. sodium channels) are frequent F, * 1938 with SCN1A p.i1867t, mild ID, seizure free since many years with VPA Combinations of mutations/variants of ion channel subunit genes One male with MECP2 p.r453q (Rett Syndrome) A lot of findings with unknown significance 33

34 Summary/Perspectives Identification of a genetic entities underlying epilepsies and intellectual disability become increasingly important for therapy Modern genetic techniques (Panels, Array-CGH, whole exome/genome sequencing) will become cheap and easily accessible, but interpretation of data is and will remain often difficult Beside efficious anticonvulsive therapies antiepileptogenic and disease modifying therapies are appearing on the horizon New therapeutic options often contain expensive orphan drugs High costs for therapies require discussion society 34

35 Thanks Johannes Lemke, Erik Riesch and co-workers (Berne) Euroepinomics Consortium Patients, caregivers and guardians 35