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Pathophysiologische Mechanismen genetischer Epilepsien

Pathophysiological mechanisms of genetic epilepsies

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Zusammenfassung

Epileptische Anfälle sind auf eine erhöhte Erregbarkeit neuronaler Zellen im Gehirn zurückzuführen, die bei bis zu einem Drittel der Epilepsien überwiegend genetisch bedingt ist. Bei monogen vererbten idiopathischen Epilepsien konnten bereits sehr viele relevante Mutationen identifiziert werden, die hauptsächlich Ionenkanalgene betreffen und eine wichtige Ursache für fokale und generalisierte erbliche Epilepsieformen sind. Im gesunden Gehirn sorgen Ionenkanäle in den Membranen von erregenden und hemmenden Neuronen für eine neuronale Balance. Eine Störung dieser Balance kann durch Veränderung der Ionenkanalfunktion zu einem epileptischen Anfall führen. In dieser Übersicht werden bekannte epilepsieassoziierte Mutationen in Ionenkanalgenen und deren funktionelle Auswirkungen beschrieben sowie die resultierenden Krankheitsmechanismen diskutiert.

Abstract

Epileptic seizures occur because of the increased excitability of neuronal cells in the brain that is of a mainly genetic origin in at least one third of all epilepsies. The so far identified mutations in inherited monogenic idiopathic epilepsies mainly affect ion channel genes and could be linked to both focal and generalized forms of inherited epilepsy. In a healthy brain, ion channels in the membranes of excitatory and inhibitory neurons are responsible for a neuronal balance. Disruption of this balance by changing the ion channel function can therefore lead to epileptic seizures. In this overview, we describe and discuss known epilepsy-associated mutations in ion channel genes, their functional consequences, and the resulting disease mechanisms.

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Literatur

  1. Barcia G, Fleming MR, Deligniere A et al (2012) De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet 44:1255–1259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Becker F, Schubert J, Striano P et al (2013) PRRT2-related disorders: further PKD and ICCA cases and review of the literature. J Neurol 260:1234–1244

    Article  CAS  PubMed  Google Scholar 

  3. Claes L, Del-Favero J, Ceulemans B et al (2001) De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 68:1327–1332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Escayg A, Macdonald BT, Meisler MH et al (2000) Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat Genet 24:343–345

    Article  CAS  PubMed  Google Scholar 

  5. Glauser TA, Cnaan A, Shinnar S et al (2010) Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 362:790–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hedrich UB, Liautard C, Kirschenbaum D et al (2014) Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human NaV1.1 mutation. J Neurosci 34:14874–14889

    Article  PubMed  PubMed Central  Google Scholar 

  7. Heron SE, Smith KR, Bahlo M et al (2012) Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 44:1188–1190

    Article  CAS  PubMed  Google Scholar 

  8. Hirose S (2014) Mutant GABAA receptor subunits in genetic (idiopathic) epilepsy. Prog Brain Res 213:55–85

    Article  PubMed  Google Scholar 

  9. Imbrici P, Jaffe SL, Eunson LH et al (2004) Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain 127:2682–2692

    Article  PubMed  Google Scholar 

  10. Kegele J, Weber Y (2015) Relevante genetische Befunde für die Praxis. Z Epileptol. doi:10.1007/s10309-015-0035-0

  11. Klassen T, Davis C, Goldman A et al (2011) Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell 145:1036–1048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lemke JR, Lal D, Reinthaler EM et al (2013) Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet 45:1067–1072

    Article  CAS  PubMed  Google Scholar 

  13. Lerche H, Shah M, Beck H et al (2013) Ion channels in genetic and acquired forms of epilepsy. J Physiol 591:753–764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liao Y, Deprez L, Maljevic S et al (2010) Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy. Brain 133:1403–1414

    Article  PubMed  Google Scholar 

  15. Maljevic S, Krampfl K, Cobilanschi J et al (2006) A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy. Ann Neurol 59:983–987

    Article  CAS  PubMed  Google Scholar 

  16. Maljevic S, Lerche H (2013) Potassium channels: a review of broadening therapeutic possibilities for neurological diseases. J Neurol 260:2201–2211

    Article  CAS  PubMed  Google Scholar 

  17. Maljevic S, Wuttke TV, Lerche H (2008) Nervous system KV7 disorders: breakdown of a subthreshold brake. J Physiol 586:1791–1801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Miceli F, Striano P, Soldovieri MV et al (2015) A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability. Epilepsia 56:e15–e20

    Article  CAS  PubMed  Google Scholar 

  19. Neubauer BA, Hahn A (2015) Fokale genetisch bedingte Epilepsiesyndrome Z Epileptol. doi:10.1007/s10309-015-0032-3

  20. Orhan G, Bock M, Schepers D et al (2014) Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol 75:382–394

    Article  CAS  PubMed  Google Scholar 

  21. Saitsu H, Kato M, Mizuguchi T et al (2008) De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet 40:782–788

    Article  CAS  PubMed  Google Scholar 

  22. Schubert J, Siekierska A, Langlois M et al (2014) Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat Genet 46:1327–1332

    Article  CAS  PubMed  Google Scholar 

  23. Steinlein OK, Kaneko S, Hirose S (2012) Nicotinic acetylcholine receptor mutations. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (Hrsg) Jasper’s Basic Mechanisms of the Epilepsies, 4. Aufl. National Center for Biotechnology Information (US), Bethesda (MD)

    Google Scholar 

  24. Syrbe S, Hedrich UB, Riesch E et al (2015) De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet 47:393–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tan HO, Reid CA, Single FN et al (2007) Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy. Proc Natl Acad Sci USA 104:17536–17541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Veeramah KR, O’brien JE, Meisler MH et al (2012) De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet 90:502–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wagnon JL, Korn MJ, Parent R et al (2015) Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy. Hum Mol Genet 24:506–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Weckhuysen S, Korff CM (2014) Epilepsy: old syndromes, new genes. Curr Neurol Neurosci Rep 14:447

    Article  PubMed  Google Scholar 

  29. Wimmer VC, Li MY, Berkovic SF et al (2015) Cortical microarchitecture changes in genetic epilepsy. Neurology 84:1308–1316

    Article  CAS  PubMed  Google Scholar 

  30. Wimmer VC, Reid CA, Mitchell S et al (2010) Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus. J Clin Investig 120:2661–2671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zamponi GW, Lory P, Perez-Reyes E (2010) Role of voltage-gated calcium channels in epilepsy. Pflugers Arch 460:395–403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zuberi SM, Brunklaus A, Birch R et al (2011) Genotype-phenotype associations in SCN1A-related epilepsies. Neurology 76:594–600

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Abt. Neurologie mit Schwerpunkt Epileptologie, Hertie Institut für Klinische Hirnforschung, Hoppe-Seyler-Str. 3, 72076, Tübingen, Deutschland

    Ulrike B. S. Hedrich &  Snezana Maljevic

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  1. Ulrike B. S. Hedrich
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  2. Snezana Maljevic
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Correspondence to Ulrike B. S. Hedrich.

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U. B. S. Hedrich und S. Maljevic geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

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Hedrich, U.B.S., Maljevic, S. Pathophysiologische Mechanismen genetischer Epilepsien. Z. Epileptol. 29, 77–83 (2016). https://doi.org/10.1007/s10309-015-0037-y

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  • DOI: https://doi.org/10.1007/s10309-015-0037-y

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