Pathophysioloy of non-classic epileptic encephalopathies (EE)

• Applicants: Professor Dr. Ingo Helbig; Professorin Dr. Yvonne Weber
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262469906

• Final Report Year: 2019

Final Report Abstract

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.

Publications

• Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures. Am J Hum Genet 2015;96:808-15
  Carvill GL, McMahon JM, Schneider A, Zemel M, Myers CT, Saykally J, Nguyen J, Robbiano A, Zara F, Specchio N, Mecarelli O, Smith RL, Leventer RJ, Møller RS, Nikanorova M, Dimova P, Jordanova A, Petrou S; Helbig I, Striano P, Weckhuysen S, Berkovic SF, Scheffer IE, Mefford HC
  (See online at https://doi.org/10.1016/j.ajhg.2015.02.016)
• 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 K, de Kovel CG, Weckhuysen S, Asselbergh B, Geuens T, Deconinck T, Azmi A, May P, Brilstra E, Becker F, Barisic N, Craiu D, Braun KP, Lal D, Thiele H, Schubert J, Weber YG, van 't Slot R, Nürnberg P, Balling R, Timmerman V, Lerche H, Maudsley S, Helbig I, Suls A, Koeleman BP, De Jonghe P
  (See online at https://doi.org/10.1093/brain/awv263)
• 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 J, Johannesen KM, Ek J, Tang S, Marini C, Blichfeldt S, Kibaek M, von Spiczak S, Weckhuysen S, Frangu M, Neubauer BA, Uldall P, Striano P, Zara F; MAE working group of EuroEPINOMICS RES Consortium, Kleiss R, Simpson M, Muhle H, Nikanorova M, Jepsen B, Tommerup N, Stephani U, Guerrini R, Duno M, Hjalgrim H, Pal D, Helbig I, Møller RS
  (See online at https://doi.org/10.1111/epi.13222)
• Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Ann Neurol 2016;79:428-36
  Gardella E, Becker F, Møller RS, Schubert J, Lemke JR, Larsen LH, Eiberg H, Nothnagel M, Thiele H, Altmüller J, Syrbe S, Merkenschlager A, Bast T, Steinhoff B, Nürnberg P, Mang Y, Bakke Møller L, Gellert P, Heron SE, Dibbens LM, Weckhuysen S, Dahl HA, Biskup S, Tommerup N, Hjalgrim H, Lerche H, Beniczky S, Weber YG
  (See online at https://doi.org/10.1002/ana.24580)
• Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy. Neurology 2016;86:2171-8
  Lemke JR, Geider K, Helbig KL, Heyne HO, Schütz H, Hentschel J, Courage C, Depienne C, Nava C, Heron D, Møller RS, Hjalgrim H, Lal D, Neubauer BA, Nürnberg P, Thiele H, Kurlemann G, Arnold GL, Bhambhani V, Bartholdi D, Pedurupillay CR, Misceo D, Frengen E, Strømme P, Dlugos DJ, Doherty ES, Bijlsma EK, Ruivenkamp CA, Hoffer MJ, Goldstein A, Rajan DS, Narayanan V, Ramsey K, Belnap N, Schrauwen I, Richholt R, Koeleman BP, Sá J, Mendonça C, de Kovel CG, Weckhuysen S, Hardies K, De Jonghe P, De Meirleir L, Milh M, Badens C, Lebrun M, Busa T, Francannet C, Piton A, Riesch E, Biskup S, Vogt H, Dorn T, Helbig I, Michaud JL, Laube B, Syrbe S
  (See online at https://doi.org/10.1212/WNL.0000000000002740)
• Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy. Eur J Hum Genet 2016;24:1761-1770
  Rudolf G, Lesca G, Mehrjouy MM, Labalme A, Salmi M, Bache I, Bruneau N, Pendziwiat M, Fluss J, de Bellescize J, Scholly J, Møller RS, Craiu D, Tommerup N, Valenti-Hirsch MP, Schluth-Bolard C, Sloan-Béna F, Helbig KL, Weckhuysen S, Edery P, Coulbaut S, Abbas M, Scheffer IE, Tang S, Myers CT, Stamberger H, Carvill GL, Shinde DN, Mefford HC, Neagu E, Huether R, Lu HM, Dica A, Cohen JS, Iliescu C, Pomeran C, Rubenstein J, Helbig I, Sanlaville D, Hirsch E, Szepetowski P
  (See online at https://doi.org/10.1038/ejhg.2016.80)
• Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies. Brain 2017;140:2337-2354
  Masnada S, Hedrich UBS, Gardella E, Schubert J, Kaiwar C, Klee EW, Lanpher BC, Gavrilova RH, Synofzik M, Bast T, Gorman K, King MD, Allen NM, Conroy J, Ben Zeev B, Tzadok M, Korff C, Dubois F, Ramsey K, Narayanan V, Serratosa JM, Giraldez BG, Helbig I, Marsh E, O'Brien M, Bergqvist CA, Binelli A, Porter B, Zaeyen E, Horovitz DD, Wolff M, Marjanovic D, Caglayan HS, Arslan M, Pena SDJ, Sisodiya SM, Balestrini S, Syrbe S, Veggiotti P, Lemke JR, Møller RS, Lerche H, Rubboli G
  (See online at https://doi.org/10.1093/brain/awx184)
• Homozygous mutation in TXNRD1 is associated with genetic generalized epilepsy. Free Radic Biol Med 2017;106:270-277
  Kudin AP, Baron G, Zsurka G, Hampel KG, Elger CE, Grote A, Weber YG, Lerche H, Thiele H, Nürnberg P, Schulz H, Ruppert AK, Sander T, Cheng Q, Arnér ES, Schomburg L, Seeher S, Fradejas-Villar N, Schweizer U, Kunz WS
  (See online at https://doi.org/10.1016/j.freeradbiomed.2017.02.040)
• Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes. JAMA Neurol 2017;74:1228-1236
  de Kovel CGF, Syrbe S, Brilstra EH, Verbeek N, Kerr B, Dubbs H, Bayat A, Desai S, Naidu S, Srivastava S, Cagaylan H, Yis U, Saunders C, Rook M, Plugge S, Muhle H, Afawi Z, Klein KM, Jayaraman V, Rajagopalan R, Goldberg E, Marsh E, Kessler S, Bergqvist C, Conlin LK, Krok BL, Thiffault I, Pendziwiat M, Helbig I, Polster T, Borggraefe I, Lemke JR, van den Boogaardt MJ, Møller RS, Koeleman BPC
  (See online at https://doi.org/10.1001/jamaneurol.2017.1714)
• De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet 2018;50:1048-1053
  Heyne HO, Singh T, Stamberger H, Abou Jamra R, Caglayan H, Craiu D, De Jonghe P, Guerrini R, Helbig KL, Koeleman BPC, Kosmicki JA, Linnankivi T, May P, Muhle H, Møller RS, Neubauer BA, Palotie A, Pendziwiat M, Striano P, Tang S, Wu S; Poduri A, Weber YG, Weckhuysen S, Sisodiya SM, Daly MJ, Helbig I, Lal D, Lemke JR
  (See online at https://doi.org/10.1038/s41588-018-0143-7)
• Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun 2018;9:5269
  International League Against Epilepsy Consortium on Complex Epilepsies
  (See online at https://doi.org/10.1038/s41467-018-07524-z)
• 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 FN, Brändl B, Larson A, Pendziwiat M, Friederich MW, White SM, Basinger A, Kücükköse C, Muhle H, Jähn JA, Keminer O, Helbig KL, Delto CF, Myketin L, Mossmann D, Burger N, Miyake N, Burnett A, van Baalen A, Lovell MA, Matsumoto N, Walsh M, Yu HC, Shinde DN, Stephani U, Van Hove JLK, Müller FJ, Helbig I
  (See online at https://doi.org/10.1016/j.ajhg.2018.02.014)