Pathophysiologie von nicht klassischen epileptischen Enzephalopathien (EE)

• Antragstellerinnen / Antragsteller: Professor Dr. Ingo Helbig; Professorin Dr. Yvonne Weber
• Fachliche Zuordnung: Molekulare und zelluläre Neurologie und Neuropathologie
• Förderung: Förderung von 2014 bis 2019
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 262469906

• Erstellungsjahr: 2019

Zusammenfassung der Projektergebnisse

Our study was the first analysis of “non-classical” genetic DEEs combining clinical, genetic and pathophysiological studies. 140 clinically well-defined patient-parent trios were analysed and combined with large European and international cohorts. We were able to identify several novel causative genes for epileptic encephalopathies and some of the functional analysis are still ongoing. The detected genes comprise transporters (SLC6A1, SLC13A5, SLC2A1, SLC6A1, GRIN1), ion channels (SCN8A, KCNA2, KCNC2, KCNB1), metabolic pathways (TXNRD1, PMPCB, AIFM1, AIFM3, OGDHL), the RNA/DNA metabolism (KMT2E, JMJD1C) and brain development (RORB). The results are essential for further pathophysiological analysis with the aim to establish further precision medicine strategies for DEE patients.

Projektbezogene Publikationen (Auswahl)

• Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures. Am J Hum Genet 2015;96:808-15
  Carvill, Gemma L.; McMahon, Jacinta M.; Schneider, Amy; Zemel, Matthew; Myers, Candace T.; Saykally, Julia; Nguyen, John; Robbiano, Angela; Zara, Federico; Specchio, Nicola; Mecarelli, Oriano; Smith, Robert L.; Leventer, Richard J.; Møller, Rikke S.; Nikanorova, Marina; Dimova, Petia; Jordanova, Albena; Petrou, Steven; Helbig, Ingo; ... & Mefford, Heather C.
  
• Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia. Brain 2015;138:3238-50
  Hardies, Katia; de Kovel, Carolien G. F.; Weckhuysen, Sarah; Asselbergh, Bob; Geuens, Thomas; Deconinck, Tine; Azmi, Abdelkrim; May, Patrick; Brilstra, Eva; Becker, Felicitas; Barisic, Nina; Craiu, Dana; Braun, Kees P.J.; Lal, Dennis; Thiele, Holger; Schubert, Julian; Weber, Yvonne; van ‘t Slot, Ruben; Nürnberg, Peter; ... & Koeleman, Bobby P.C.
  
• The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome. Epilepsia 2015;56:e203-8
  Larsen, Jan; Johannesen, Katrine Marie; Ek, Jakob; Tang, Shan; Marini, Carla; Blichfeldt, Susanne; Kibæk, Maria; von Spiczak, Sarah; Weckhuysen, Sarah; Frangu, Mimoza; Neubauer, Bernd Axel; Uldall, Peter; Striano, Pasquale; Zara, Federico; Kleiss, Rebecca; Simpson, Michael; Muhle, Hiltrud; Nikanorova, Marina; Jepsen, Birgit; ... & Møller, Rikke Steensbjerre
  
• Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Ann Neurol 2016;79:428-36
  Gardella, Elena; Becker, Felicitas; Møller, Rikke S.; Schubert, Julian; Lemke, Johannes R.; Larsen, Line H. G.; Eiberg, Hans; Nothnagel, Michael; Thiele, Holger; Altmüller, Janine; Syrbe, Steffen; Merkenschlager, Andreas; Bast, Thomas; Steinhoff, Bernhard; Nürnberg, Peter; Mang, Yuan; Bakke Møller, Louise; Gellert, Pia; Heron, Sarah E.; ... & Weber, Yvonne G.
  
• Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy. Neurology 2016;86:2171-8
  Lemke, Johannes R.; Geider, Kirsten; Helbig, Katherine L.; Heyne, Henrike O.; Schütz, Hannah; Hentschel, Julia; Courage, Carolina; Depienne, Christel; Nava, Caroline; Heron, Delphine; Møller, Rikke S.; Hjalgrim, Helle; Lal, Dennis; Neubauer, Bernd A.; Nürnberg, Peter; Thiele, Holger; Kurlemann, Gerhard; Arnold, Georgianne L.; Bhambhani, Vikas; ... & Syrbe, Steffen
  
• Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy. Eur J Hum Genet 2016;24:1761-1770
  Rudolf, Gabrielle; Lesca, Gaetan; Mehrjouy, Mana M; Labalme, Audrey; Salmi, Manal; Bache, Iben; Bruneau, Nadine; Pendziwiat, Manuela; Fluss, Joel; de Bellescize, Julitta; Scholly, Julia; Møller, Rikke S; Craiu, Dana; Tommerup, Niels; Valenti-Hirsch, Maria Paola; Schluth-Bolard, Caroline; Sloan-Béna, Frédérique; Helbig, Katherine L; Weckhuysen, Sarah; ... & Szepetowski, Pierre
  
• Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies. Brain 2017;140:2337-2354
  Masnada, Silvia; Hedrich, Ulrike B S; Gardella, Elena; Schubert, Julian; Kaiwar, Charu; Klee, Eric W; Lanpher, Brendan C; Gavrilova, Ralitza H; Synofzik, Matthis; Bast, Thomas; Gorman, Kathleen; King, Mary D; Allen, Nicholas M; Conroy, Judith; Ben Zeev, Bruria; Tzadok, Michal; Korff, Christian; Dubois, Fanny; Ramsey, Keri; ... & Rubboli, Guido
  
• Homozygous mutation in TXNRD1 is associated with genetic generalized epilepsy. Free Radic Biol Med 2017;106:270-277
  Kudin, Alexei P.; Baron, Gregor; Zsurka, Gábor; Hampel, Kevin G.; Elger, Christian E.; Grote, Alexander; Weber, Yvonne; Lerche, Holger; Thiele, Holger; Nürnberg, Peter; Schulz, Herbert; Ruppert, Ann-Kathrin; Sander, Thomas; Cheng, Qing; Arnér, Elias SJ; Schomburg, Lutz; Seeher, Sandra; Fradejas-Villar, Noelia; Schweizer, Ulrich; ... & Kunz, Wolfram S.
  
• Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes. JAMA Neurol 2017;74:1228-1236
  de Kovel, Carolien G. F.; Syrbe, Steffen; Brilstra, Eva H.; Verbeek, Nienke; Kerr, Bronwyn; Dubbs, Holly; Bayat, Allan; Desai, Sonal; Naidu, Sakkubai; Srivastava, Siddharth; Cagaylan, Hande; Yis, Uluc; Saunders, Carol; Rook, Martin; Plugge, Susanna; Muhle, Hiltrud; Afawi, Zaid; Klein, Karl-Martin; Jayaraman, Vijayakumar; ... & Koeleman, Bobby P. C.
  
• De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet 2018;50:1048-1053
  Heyne, Henrike O.; Singh, Tarjinder; Stamberger, Hannah; Abou Jamra, Rami; Caglayan, Hande; Craiu, Dana; De Jonghe, Peter; Guerrini, Renzo; Helbig, Katherine L.; Koeleman, Bobby P. C.; Kosmicki, Jack A.; Linnankivi, Tarja; May, Patrick; Muhle, Hiltrud; Møller, Rikke S.; Neubauer, Bernd A.; Palotie, Aarno; Pendziwiat, Manuela; Striano, Pasquale; ... & Lemke, Johannes R.
  
• Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun 2018;9:5269
  Abou-Khalil, Bassel; Auce, Pauls; Avbersek, Andreja; Bahlo, Melanie; Balding, David J.; Bast, Thomas; Baum, Larry; Becker, Albert J.; Becker, Felicitas; Berghuis, Bianca; Berkovic, Samuel F.; Boysen, Katja E.; Bradfield, Jonathan P.; Brody, Lawrence C.; Buono, Russell J.; Campbell, Ellen; Cascino, Gregory D.; Catarino, Claudia B.; Cavalleri, Gianpiero L.; ... & Zimprich, Fritz
  
• Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood. Am J Hum Genet 2018;102:557-573
  Vögtle, F.-Nora; Brändl, Björn; Larson, Austin; Pendziwiat, Manuela; Friederich, Marisa W.; White, Susan M.; Basinger, Alice; Kücükköse, Cansu; Muhle, Hiltrud; Jähn, Johanna A.; Keminer, Oliver; Helbig, Katherine L.; Delto, Carolyn F.; Myketin, Lisa; Mossmann, Dirk; Burger, Nils; Miyake, Noriko; Burnett, Audrey; van Baalen, Andreas; ... & Helbig, Ingo