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356 results on '"Kluger G."'

2. Autoantibody status, neuroradiological and clinical findings in children with acute cerebellitis

Author

Quack, L., Glatter, S., Wegener-Panzer, A., Cleaveland, R., Bertolini, A., Endmayr, V., Seidl, R., Breu, M., Wendel, E., Schimmel, M., Baumann, M., Rauchenzauner, M., Pritsch, M., Boy, N., Muralter, T., Kluger, G., Makoswski, C., Kraus, V., Leiz, S., Loehr-Nilles, C., Kreth, J.H., Braig, S., Schilling, S., Kern, J., Blank, C., Tro Baumann, B., Vieth, S., Wallot, M., Reindl, M., Ringl, H., Wandinger, K.P., Leypoldt, F., Höftberger, R., and Rostásy, K.

Published
2023
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5. Spatio-Temporal Structuring of Brain Activity - Description of Interictal EEG in Paediatric Frontal Lobe Epilepsy

Author

Bunk, W., Aschenbrenner, T., Kluger, G., and Springer, S.

Subjects
Physics - Medical Physics, Physics - Data Analysis, Statistics and Probability
Abstract

A method for the quantitative assessment of spatio-temporal structuring of brain activity is presented. This approach is employed in a longitudinal case study of a child with frontal lobe epilepsy (FLE) and tested against an age-matched control group. Several correlation measures that are sensitive to linear and/or non-linear relations in multichannel scalp EEG are combined with an hierarchical cluster algorithm. Beside a quantitative description of the overall degree of synchronization the spatial relations are investigated by means of the cluster characteristics. The chosen information measures not only demonstrate their suitability in the characterization of the ictal and interictal phases but they also follow the course of delayed recovery of the psychiatric symptomatology during successful medication. The results based on this single case study suggest testing this approach for quantitative control of therapy in an extended clinical trial.

Published
2009

6. GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Author

Stevelink, R, Campbell, C, Chen, S, Abou-Khalil, B, Adesoji, OM, Afawi, Z, Amadori, E, Anderson, A, Anderson, J, Andrade, DM, Annesi, G, Auce, P, Avbersek, A, Bahlo, M, Baker, MD, Balagura, G, Balestrini, S, Barba, C, Barboza, K, Bartolomei, F, Bast, T, Baum, L, Baumgartner, T, Baykan, B, Bebek, N, Becker, AJ, Becker, F, Bennett, CA, Berghuis, B, Berkovic, SF, Beydoun, A, Bianchini, C, Bisulli, F, Blatt, I, Bobbili, DR, Borggraefe, I, Bosselmann, C, Braatz, V, Bradfield, JP, Brockmann, K, Brody, LC, Buono, RJ, Busch, RM, Caglayan, H, Campbell, E, Canafoglia, L, Canavati, C, Cascino, GD, Castellotti, B, Catarino, CB, Cavalleri, GL, Cerrato, F, Chassoux, F, Cherny, SS, Cheung, C-L, Chinthapalli, K, Chou, I-J, Chung, S-K, Churchhouse, C, Clark, PO, Cole, AJ, Compston, A, Coppola, A, Cosico, M, Cossette, P, Craig, JJ, Cusick, C, Daly, MJ, Davis, LK, de Haan, G-J, Delanty, N, Depondt, C, Derambure, P, Devinsky, O, Di Vito, L, Dlugos, DJ, Doccini, V, Doherty, CP, El-Naggar, H, Elger, CE, Ellis, CA, Eriksson, JG, Faucon, A, Feng, Y-CA, Ferguson, L, Ferraro, TN, Ferri, L, Feucht, M, Fitzgerald, M, Fonferko-Shadrach, B, Fortunato, F, Franceschetti, S, Franke, A, French, JA, Freri, E, Gagliardi, M, Gambardella, A, Geller, EB, Giangregorio, T, Gjerstad, L, Glauser, T, Goldberg, E, Goldman, A, Granata, T, Greenberg, DA, Guerrini, R, Gupta, N, Haas, KF, Hakonarson, H, Hallmann, K, Hassanin, E, Hegde, M, Heinzen, EL, Helbig, I, Hengsbach, C, Heyne, HO, Hirose, S, Hirsch, E, Hjalgrim, H, Howrigan, DP, Hucks, D, Hung, P-C, Iacomino, M, Imbach, LL, Inoue, Y, Ishii, A, Jamnadas-Khoda, J, Jehi, L, Johnson, MR, Kalviainen, R, Kamatani, Y, Kanaan, M, Kanai, M, Kantanen, A-M, Kara, B, Kariuki, SM, Kasperaviciute, D, Trenite, DK-N, Kato, M, Kegele, J, Kesim, Y, Khoueiry-Zgheib, N, King, C, Kirsch, HE, Klein, KM, Kluger, G, Knake, S, Knowlton, RC, Koeleman, BPC, Korczyn, AD, Koupparis, A, Kousiappa, I, Krause, R, Krenn, M, Krestel, H, Krey, I, Kunz, WS, Kurki, MI, Kurlemann, G, Kuzniecky, R, Kwan, P, Labate, A, Lacey, A, Lal, D, Landoulsi, Z, Lau, Y-L, Lauxmann, S, Leech, SL, Lehesjoki, A-E, Lemke, JR, Lerche, H, Lesca, G, Leu, C, Lewin, N, Lewis-Smith, D, Li, GH-Y, Li, QS, Licchetta, L, Lin, K-L, Lindhout, D, Linnankivi, T, Lopes-Cendes, I, Lowenstein, DH, Lui, CHT, Madia, F, Magnusson, S, Marson, AG, May, P, McGraw, CM, Mei, D, Mills, JL, Minardi, R, Mirza, N, Moller, RS, Molloy, AM, Montomoli, M, Mostacci, B, Muccioli, L, Muhle, H, Mueller-Schlueter, K, Najm, IM, Nasreddine, W, Neale, BM, Neubauer, B, Newton, CRJC, Noethen, MM, Nothnagel, M, Nuernberg, P, O'Brien, TJ, Okada, Y, Olafsson, E, Oliver, KL, Ozkara, C, Palotie, A, Pangilinan, F, Papacostas, SS, Parrini, E, Pato, CN, Pato, MT, Pendziwiat, M, Petrovski, S, Pickrell, WO, Pinsky, R, Pippucci, T, Poduri, A, Pondrelli, F, Powell, RHW, Privitera, M, Rademacher, A, Radtke, R, Ragona, F, Rau, S, Rees, MI, Regan, BM, Reif, PS, Rhelms, S, Riva, A, Rosenow, F, Ryvlin, P, Saarela, A, Sadleir, LG, Sander, JW, Sander, T, Scala, M, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Schubert-Bast, S, Schulze-Bonhage, A, Scudieri, P, Sham, P, Sheidley, BR, Shih, JJ, Sills, GJ, Sisodiya, SM, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Stefansson, H, Stefansson, K, Steinhoff, BJ, Stephani, U, Stewart, WC, Stipa, C, Striano, P, Stroink, H, Strzelczyk, A, Surges, R, Suzuki, T, Tan, KM, Taneja, RS, Tanteles, GA, Tauboll, E, Thio, LL, Thomas, GN, Thomas, RH, Timonen, O, Tinuper, P, Todaro, M, Topaloglu, P, Tozzi, R, Tsai, M-H, Tumiene, B, Turkdogan, D, Unnsteinsdottir, U, Utkus, A, Vaidiswaran, P, Valton, L, van Baalen, A, Vetro, A, Vining, EPG, Visscher, F, von Brauchitsch, S, von Wrede, R, Wagner, RG, Weber, YG, Weckhuysen, S, Weisenberg, J, Weller, M, Widdess-Walsh, P, Wolff, M, Wolking, S, Wu, D, Yamakawa, K, Yang, W, Yapici, Z, Yucesan, E, Zagaglia, S, Zahnert, F, Zara, F, Zhou, W, Zimprich, F, Zsurka, G, Ali, QZ, Stevelink, R, Campbell, C, Chen, S, Abou-Khalil, B, Adesoji, OM, Afawi, Z, Amadori, E, Anderson, A, Anderson, J, Andrade, DM, Annesi, G, Auce, P, Avbersek, A, Bahlo, M, Baker, MD, Balagura, G, Balestrini, S, Barba, C, Barboza, K, Bartolomei, F, Bast, T, Baum, L, Baumgartner, T, Baykan, B, Bebek, N, Becker, AJ, Becker, F, Bennett, CA, Berghuis, B, Berkovic, SF, Beydoun, A, Bianchini, C, Bisulli, F, Blatt, I, Bobbili, DR, Borggraefe, I, Bosselmann, C, Braatz, V, Bradfield, JP, Brockmann, K, Brody, LC, Buono, RJ, Busch, RM, Caglayan, H, Campbell, E, Canafoglia, L, Canavati, C, Cascino, GD, Castellotti, B, Catarino, CB, Cavalleri, GL, Cerrato, F, Chassoux, F, Cherny, SS, Cheung, C-L, Chinthapalli, K, Chou, I-J, Chung, S-K, Churchhouse, C, Clark, PO, Cole, AJ, Compston, A, Coppola, A, Cosico, M, Cossette, P, Craig, JJ, Cusick, C, Daly, MJ, Davis, LK, de Haan, G-J, Delanty, N, Depondt, C, Derambure, P, Devinsky, O, Di Vito, L, Dlugos, DJ, Doccini, V, Doherty, CP, El-Naggar, H, Elger, CE, Ellis, CA, Eriksson, JG, Faucon, A, Feng, Y-CA, Ferguson, L, Ferraro, TN, Ferri, L, Feucht, M, Fitzgerald, M, Fonferko-Shadrach, B, Fortunato, F, Franceschetti, S, Franke, A, French, JA, Freri, E, Gagliardi, M, Gambardella, A, Geller, EB, Giangregorio, T, Gjerstad, L, Glauser, T, Goldberg, E, Goldman, A, Granata, T, Greenberg, DA, Guerrini, R, Gupta, N, Haas, KF, Hakonarson, H, Hallmann, K, Hassanin, E, Hegde, M, Heinzen, EL, Helbig, I, Hengsbach, C, Heyne, HO, Hirose, S, Hirsch, E, Hjalgrim, H, Howrigan, DP, Hucks, D, Hung, P-C, Iacomino, M, Imbach, LL, Inoue, Y, Ishii, A, Jamnadas-Khoda, J, Jehi, L, Johnson, MR, Kalviainen, R, Kamatani, Y, Kanaan, M, Kanai, M, Kantanen, A-M, Kara, B, Kariuki, SM, Kasperaviciute, D, Trenite, DK-N, Kato, M, Kegele, J, Kesim, Y, Khoueiry-Zgheib, N, King, C, Kirsch, HE, Klein, KM, Kluger, G, Knake, S, Knowlton, RC, Koeleman, BPC, Korczyn, AD, Koupparis, A, Kousiappa, I, Krause, R, Krenn, M, Krestel, H, Krey, I, Kunz, WS, Kurki, MI, Kurlemann, G, Kuzniecky, R, Kwan, P, Labate, A, Lacey, A, Lal, D, Landoulsi, Z, Lau, Y-L, Lauxmann, S, Leech, SL, Lehesjoki, A-E, Lemke, JR, Lerche, H, Lesca, G, Leu, C, Lewin, N, Lewis-Smith, D, Li, GH-Y, Li, QS, Licchetta, L, Lin, K-L, Lindhout, D, Linnankivi, T, Lopes-Cendes, I, Lowenstein, DH, Lui, CHT, Madia, F, Magnusson, S, Marson, AG, May, P, McGraw, CM, Mei, D, Mills, JL, Minardi, R, Mirza, N, Moller, RS, Molloy, AM, Montomoli, M, Mostacci, B, Muccioli, L, Muhle, H, Mueller-Schlueter, K, Najm, IM, Nasreddine, W, Neale, BM, Neubauer, B, Newton, CRJC, Noethen, MM, Nothnagel, M, Nuernberg, P, O'Brien, TJ, Okada, Y, Olafsson, E, Oliver, KL, Ozkara, C, Palotie, A, Pangilinan, F, Papacostas, SS, Parrini, E, Pato, CN, Pato, MT, Pendziwiat, M, Petrovski, S, Pickrell, WO, Pinsky, R, Pippucci, T, Poduri, A, Pondrelli, F, Powell, RHW, Privitera, M, Rademacher, A, Radtke, R, Ragona, F, Rau, S, Rees, MI, Regan, BM, Reif, PS, Rhelms, S, Riva, A, Rosenow, F, Ryvlin, P, Saarela, A, Sadleir, LG, Sander, JW, Sander, T, Scala, M, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Schubert-Bast, S, Schulze-Bonhage, A, Scudieri, P, Sham, P, Sheidley, BR, Shih, JJ, Sills, GJ, Sisodiya, SM, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Stefansson, H, Stefansson, K, Steinhoff, BJ, Stephani, U, Stewart, WC, Stipa, C, Striano, P, Stroink, H, Strzelczyk, A, Surges, R, Suzuki, T, Tan, KM, Taneja, RS, Tanteles, GA, Tauboll, E, Thio, LL, Thomas, GN, Thomas, RH, Timonen, O, Tinuper, P, Todaro, M, Topaloglu, P, Tozzi, R, Tsai, M-H, Tumiene, B, Turkdogan, D, Unnsteinsdottir, U, Utkus, A, Vaidiswaran, P, Valton, L, van Baalen, A, Vetro, A, Vining, EPG, Visscher, F, von Brauchitsch, S, von Wrede, R, Wagner, RG, Weber, YG, Weckhuysen, S, Weisenberg, J, Weller, M, Widdess-Walsh, P, Wolff, M, Wolking, S, Wu, D, Yamakawa, K, Yang, W, Yapici, Z, Yucesan, E, Zagaglia, S, Zahnert, F, Zara, F, Zhou, W, Zimprich, F, Zsurka, G, and Ali, QZ

Abstract

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

Published
2023

7. Sequential Seizures in Neonates: Videos as a Diagnostic Tool for Diagnosis of KCNQ2-Related Self-Limiting Familial Neonatal Epilepsy?

Author

Leppmeier, V., Weckhuysen, S., Pringsheim, M., Berweck, S., and Kluger, G.

Subjects
SINGLE-parent families, EPILEPSY, SEIZURES (Medicine), NEWBORN infants, FAMILY history (Sociology), DIAGNOSIS
Abstract

This article, published in the journal Neuropediatrics, discusses the use of videos taken by parents as a diagnostic tool for the diagnosis of KCNQ2-related self-limiting familial neonatal epilepsy (SLFNE). The study analyzed videos taken by parents of three affected families, which showed neonates experiencing seizures with focal onset and changing manifestation throughout the seizure. The family history of each affected neonate was conclusive, as one parent in each family had also experienced seizures in the same timeframe after birth. Genetic testing confirmed a mutation in the KCNQ2 gene in the affected children and at least one parent in all three families. The authors suggest that analyzing these videos, along with the positive family history, can aid in the diagnosis of SLFNE and promote early genetic testing and treatment initiation. [Extracted from the article]

Published
2023
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8. Providing Quality Care for People with CDKL5 Deficiency Disorder (CDD): An Expert Panel Opinion on the European Patient Journey.

Author

Amin, S., Møller, R., Aledo-Serrano, Á., Arzimanoglou, A., Bager, P., Jóźwiak, S., Kluger, G., López-Cabeza, S., Nabbout, R., Partridge, C.-A., Schubert-Bast, S., Specchio, N., and Kälviäinen, R.

Subjects
CARE of people, PATIENT advocacy, GENETIC disorders, PRESSURE groups, SEIZURES (Medicine)
Abstract

This article, published in the journal Neuropediatrics, discusses the need for evidence-based guidelines for the standardized care of CDKL5 Deficiency Disorder (CDD) in Europe. CDD is a rare genetic disorder characterized by seizures and neurodevelopmental delays. To address this need, clinical experts and patient advocacy group representatives from across Europe collaborated to map the patient journey and provide expert consensus on how to ensure quality care for individuals with CDD. The article highlights the importance of clinical criteria for diagnosis, genetic testing, seizure management, and multidisciplinary care. The authors emphasize the need for European practice recommendations that align on treatment goals, diagnostic criteria, and management approaches. [Extracted from the article]

Published
2023
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9. Acute Disseminated Encephalomyelitis without MOG Antibodies: Clinical Course and Final Diagnosis.

Author

Panagi, M., Wegener-Panzer, A., Cleaveland, R., Blaschek, A., Brantner-Inthaler, S., Baumann, M., Conrad, C., Marina, A. Della, Finsterwalder, J., Fucik, P., Geis, T., Hofstetter, P., Karenfort, M., Kluger, G., Leiz, S., Merkenschlager, A., Munk, I., Nosadini, M., Salandin, M., and Sartori, S.

Subjects
POSTVACCINAL encephalitis, IMMUNOGLOBULINS, DIAGNOSIS, CENTRAL nervous system, MULTIPLE sclerosis
Abstract

This article, published in the journal Neuropediatrics, explores the clinical course and final diagnosis of Acute Disseminated Encephalomyelitis (ADEM) without MOG antibodies. ADEM is a rare inflammatory disorder of the central nervous system (CNS), and MOG antibodies are found in 50% of children with ADEM. The study collected data from 40 children with MOG-negative ADEM and found that in 72.5% of cases, the diagnosis remained ADEM at the last follow-up. However, in 27.5% of cases, the diagnosis was revised to conditions such as multiple sclerosis (MS), glioblastoma, CNS vasculitis, leukoencephalopathy, and autoimmune encephalitis. The study highlights the importance of considering alternative diagnoses in cases of MOG-negative ADEM. [Extracted from the article]

Published
2023
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12. Corrigendum to “Autoantibody status, neuroradiological and clinical findings in children with acute cerebellitis” [Eur. J. Paediatr. Neurol. 47 (2023) 118–130]

Author

Quack, L., Glatter, S., Wegener-Panzer, A., Cleaveland, R., Bertolini, A., Endmayr, V., Seidl, R., Breu, M., Wendel, E., Schimmel, M., Baumann, M., Rauchenzauner, M., Pritsch, M., Boy, N., Muralter, T., Kluger, G., Makoswski, C., Kraus, V., Leiz, S., Loehr-Nilles, C., Kreth, J.H., Braig, S., Schilling, S., Kern, J., Blank, C., Baumann, B. Tro, Vieth, S., Wallot, M., Reindl, M., Ringl, H., Wandinger, K.P., Leypoldt, F., Höftberger, R., and Rostàsy, K.

Published
2024
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13. PIGN encephalopathy: Characterizing the epileptology

Author

Bayat, A, Valles-Ibanez, G, Pendziwiat, M, Knaus, A, Alt, K, Biamino, E, Bley, A, Calvert, S, Carney, P, Caro-Llopis, A, Ceulemans, B, Cousin, J, Davis, S, Portes, V, Edery, P, England, E, Ferreira, C, Freeman, J, Gener, B, Gorce, M, Heron, D, Hildebrand, MS, Jezela-Stanek, A, Jouk, P-S, Keren, B, Kloth, K, Kluger, G, Kuhn, M, Lemke, JR, Li, H, Martinez, F, Maxton, C, Mefford, HC, Merla, G, Mierzewska, H, Muir, A, Monfort, S, Nicolai, J, Norman, J, O'Grady, G, Oleksy, B, Orellana, C, Orec, LE, Peinhardt, C, Pronicka, E, Rosello, M, Santos-Simarro, F, Schwaibold, EMC, Stegmann, APA, Stumpel, CT, Szczepanik, E, Terczynska, I, Thevenon, J, Tzschach, A, Van Bogaert, P, Vittorini, R, Walsh, S, Weckhuysen, S, Weissman, B, Wolfe, L, Reymond, A, De Nittis, P, Poduri, A, Olson, H, Striano, P, Lesca, G, Scheffer, IE, Moller, RS, Sadleir, LG, Bayat, A, Valles-Ibanez, G, Pendziwiat, M, Knaus, A, Alt, K, Biamino, E, Bley, A, Calvert, S, Carney, P, Caro-Llopis, A, Ceulemans, B, Cousin, J, Davis, S, Portes, V, Edery, P, England, E, Ferreira, C, Freeman, J, Gener, B, Gorce, M, Heron, D, Hildebrand, MS, Jezela-Stanek, A, Jouk, P-S, Keren, B, Kloth, K, Kluger, G, Kuhn, M, Lemke, JR, Li, H, Martinez, F, Maxton, C, Mefford, HC, Merla, G, Mierzewska, H, Muir, A, Monfort, S, Nicolai, J, Norman, J, O'Grady, G, Oleksy, B, Orellana, C, Orec, LE, Peinhardt, C, Pronicka, E, Rosello, M, Santos-Simarro, F, Schwaibold, EMC, Stegmann, APA, Stumpel, CT, Szczepanik, E, Terczynska, I, Thevenon, J, Tzschach, A, Van Bogaert, P, Vittorini, R, Walsh, S, Weckhuysen, S, Weissman, B, Wolfe, L, Reymond, A, De Nittis, P, Poduri, A, Olson, H, Striano, P, Lesca, G, Scheffer, IE, Moller, RS, and Sadleir, LG

Abstract

OBJECTIVE: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. METHODS: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. RESULTS: Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. SIGNIFICANCE: PIGN encephalopathy is a complex

Published
2022

14. KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism

Author

Miceli, F., Millevert, C., Soldovieri, M.V., Mosca, I., Ambrosino, P., Carotenuto, L., Schrader, D., Lee, H.K., Riviello, J., Hong, W., Risen, S., Emrick, L., Amin, H., Ville, D. Van De, Edery, P., Bellescize, J. de, Michaud, V., Van-Gils, J., Goizet, C., Willemsen, M.H., Kleefstra, T., Møller, R.S., Bayat, A., Devinsky, O., Sands, T., Korenke, G.C., Kluger, G., Mefford, H.C., Brilstra, E., Lesca, G., Milh, M., Cooper, E.C., Taglialatela, M., Weckhuysen, S., Miceli, F., Millevert, C., Soldovieri, M.V., Mosca, I., Ambrosino, P., Carotenuto, L., Schrader, D., Lee, H.K., Riviello, J., Hong, W., Risen, S., Emrick, L., Amin, H., Ville, D. Van De, Edery, P., Bellescize, J. de, Michaud, V., Van-Gils, J., Goizet, C., Willemsen, M.H., Kleefstra, T., Møller, R.S., Bayat, A., Devinsky, O., Sands, T., Korenke, G.C., Kluger, G., Mefford, H.C., Brilstra, E., Lesca, G., Milh, M., Cooper, E.C., Taglialatela, M., and Weckhuysen, S.

Abstract

Contains fulltext : 284811.pdf (Publisher’s version ) (Open Access), BACKGROUND: Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline. METHODS: Patients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings. FINDINGS: Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits. INTERPRETATION: Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment. FUNDING: Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University

Published
2022

19. Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

Author

Pelletier, F. Perrier, S. Cayami, F.K. Mirchi, A. Saikali, S. Tran, L.T. Ulrick, N. Guerrero, K. Rampakakis, E. Van Spaendonk, R.M.L. Naidu, S. Pohl, D. Gibson, W.T. Demos, M. Goizet, C. Tejera-Martin, I. Potic, A. Fogel, B.L. Brais, B. Sylvain, M. Sébire, G. Lourenço, C.M. Bonkowsky, J.L. Catsman-Berrevoets, C. Pinto, P.S. Tirupathi, S. Strømme, P. De Grauw, T. Gieruszczak-Bialek, D. Krägeloh-Mann, I. Mierzewska, H. Philippi, H. Rankin, J. Atik, T. Banwell, B. Benko, W.S. Blaschek, A. Bley, A. Boltshauser, E. Bratkovic, D. Brozova, K. Cimas, I. Clough, C. Corenblum, B. Dinopoulos, A. Dolan, G. Faletra, F. Fernandez, R. Fletcher, J. Garcia Garcia, M.E. Gasparini, P. Gburek-Augustat, J. Gonzalez Moron, D. Hamati, A. Harting, I. Hertzberg, C. Hill, A. Hobson, G.M. Innes, A.M. Kauffman, M. Kirwin, S.M. Kluger, G. Kolditz, P. Kotzaeridou, U. La Piana, R. Liston, E. McClintock, W. McEntagart, M. McKenzie, F. Melançon, S. Misbahuddin, A. Suri, M. Monton, F.I. Moutton, S. Murphy, R.P.J. Nickel, M. Onay, H. Orcesi, S. Özklnay, F. Patzer, S. Pedro, H. Pekic, S. Pineda Marfa, M. Pizzino, A. Plecko, B. Poll-The, B.T. Popovic, V. Rating, D. Rioux, M.-F. Rodriguez Espinosa, N. Ronan, A. Ostergaard, J.R. Rossignol, E. Sanchez-Carpintero, R. Schossig, A. Senbil, N. Sønderberg Roos, L.K. Stevens, C.A. Synofzik, M. Sztriha, L. Tibussek, D. Timmann, D. Tonduti, D. Van De Warrenburg, B.P. Vázquez-López, M. Venkateswaran, S. Wasling, P. Wassmer, E. Webster, R.I. Wiegand, G. Yoon, G. Rotteveel, J. Schiffmann, R. Van Der Knaap, M.S. Vanderver, A. Martos-Moreno, G.Á. Polychronakos, C. Wolf, N.I. Bernard, G.

Abstract

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting: This was a multicenter retrospective study using information collected from 3 predominant centers. Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder. © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.

Published
2021

20. Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

Author

Pelletier, F., Perrier, S., Cayami, F.K., Mirchi, A., Saikali, S., Tran, L.T., Ulrick, N., Guerrero, K., Rampakakis, E., Spaendonk, R.M.L. van, Naidu, S., Pohl, D., Gibson, W.T., Demos, M., Goizet, C., Tejera-Martin, I., Potic, A., Fogel, B.L., Brais, B., Sylvain, M., Sébire, G., Lourenço, C.M., Bonkowsky, J.L., Catsman-Berrevoets, C., Pinto, P.S., Tirupathi, S., Strømme, P., Grauw, T. de, Gieruszczak-Bialek, D., Krägeloh-Mann, I., Mierzewska, H., Philippi, H., Rankin, J., Atik, T., Banwell, B., Benko, W.S., Blaschek, A., Bley, A., Boltshauser, E., Bratkovic, D., Brozova, K., Cimas, I., Clough, C., Corenblum, B., Dinopoulos, A., Dolan, G., Faletra, F., Fernandez, R., Fletcher, J., Garcia, M.E., Gasparini, P., Gburek-Augustat, J., Moron, D. Gonzalez, Hamati, A., Harting, I., Hertzberg, C., Hill, A., Hobson, G.M., Innes, A. Micheil, Kauffman, M., Kirwin, S.M., Kluger, G., Kolditz, P., Kotzaeridou, U., Piana, R., Liston, E., McClintock, W., McEntagart, M., McKenzie, F., Melançon, S., Misbahuddin, A., Suri, M., Monton, F.I., Moutton, S., Murphy, R.P.J., Nickel, M., Onay, H., Orcesi, S., Özkınay, F., Patzer, S., Pedro, H., Pekic, S., Marfa, M. Pineda, Pizzino, A., Plecko, B., Poll-The, B.T., Popovic, V., Rating, D., Rioux, M.F., Espinosa, N. Rodriguez, Ronan, A., Ostergaard, J.R., Rossignol, E., Sanchez-Carpintero, R., Schossig, A., Senbil, N., Roos, L.K. Sønderberg, Stevens, C.A., Synofzik, M., Sztriha, L., et al., Warrenburg, B.P.C. van de, Wolf, N.I., Bernard, G., Pelletier, F., Perrier, S., Cayami, F.K., Mirchi, A., Saikali, S., Tran, L.T., Ulrick, N., Guerrero, K., Rampakakis, E., Spaendonk, R.M.L. van, Naidu, S., Pohl, D., Gibson, W.T., Demos, M., Goizet, C., Tejera-Martin, I., Potic, A., Fogel, B.L., Brais, B., Sylvain, M., Sébire, G., Lourenço, C.M., Bonkowsky, J.L., Catsman-Berrevoets, C., Pinto, P.S., Tirupathi, S., Strømme, P., Grauw, T. de, Gieruszczak-Bialek, D., Krägeloh-Mann, I., Mierzewska, H., Philippi, H., Rankin, J., Atik, T., Banwell, B., Benko, W.S., Blaschek, A., Bley, A., Boltshauser, E., Bratkovic, D., Brozova, K., Cimas, I., Clough, C., Corenblum, B., Dinopoulos, A., Dolan, G., Faletra, F., Fernandez, R., Fletcher, J., Garcia, M.E., Gasparini, P., Gburek-Augustat, J., Moron, D. Gonzalez, Hamati, A., Harting, I., Hertzberg, C., Hill, A., Hobson, G.M., Innes, A. Micheil, Kauffman, M., Kirwin, S.M., Kluger, G., Kolditz, P., Kotzaeridou, U., Piana, R., Liston, E., McClintock, W., McEntagart, M., McKenzie, F., Melançon, S., Misbahuddin, A., Suri, M., Monton, F.I., Moutton, S., Murphy, R.P.J., Nickel, M., Onay, H., Orcesi, S., Özkınay, F., Patzer, S., Pedro, H., Pekic, S., Marfa, M. Pineda, Pizzino, A., Plecko, B., Poll-The, B.T., Popovic, V., Rating, D., Rioux, M.F., Espinosa, N. Rodriguez, Ronan, A., Ostergaard, J.R., Rossignol, E., Sanchez-Carpintero, R., Schossig, A., Senbil, N., Roos, L.K. Sønderberg, Stevens, C.A., Synofzik, M., Sztriha, L., et al., Warrenburg, B.P.C. van de, Wolf, N.I., and Bernard, G.

Abstract

Contains fulltext : 235629.pdf (Publisher’s version ) (Open Access), CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

Published
2021

21. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, Goldstein, DB, Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, and Goldstein, DB

Abstract

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021

24. Polygenic burden in focal and generalized epilepsies

Author

Leu C., Stevelink R., Smith A. W., Goleva S. B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S. M., Cavalleri G. L., Koeleman B. P. C., Lerche H., Jehi L., Davis L. K., Najm I. M., Palotie A., Daly M. J., Busch R. M., Lal D., Feng Y. -C. A., Howrigan D. P., Abbott L. E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B. M., Berkovic S. F., Goldstein D. B., Lowenstein D. H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E. L., Helbig I., Kwan P., Marson A. G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D. J., Scheffer I. E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B. M., Bellows S. T., Bennett C. A., Johns E. M. C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T. J., Todaro M., Stamberger H., Andrade D. M., Sadoway T. R., Mo K., Krestel H., Gallati S., Papacostas S. S., Kousiappa I., Tanteles G. A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K. M., Rosenow F., Reif P. S., Knake S., Kunz W. S., Zsurka G., Elger C. E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A. D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J. R., Krey I., Weber Y. G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A. F., Steinhoff B. J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C. J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A. -E., Rees M. I., Chung S. -K., Pickrell W. O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M. R., Auce P., Sills G. J., Baum L. W., Sham P. C., Cherny S. S., Lui C. H. T., Barisic N., Delanty N., Doherty C. P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M. S., Mancardi M. M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L. G., King C., Mountier E., Caglayan S. H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B. R., Shain C., Poduri A., Buono R. J., Ferraro T. N., Sperling M. R., Lo W., Privitera M., French J. A., Schachter S., Kuzniecky R. I., Devinsky O., Hegde M., Khankhanian P., Helbig K. L., Ellis C. A., Spalletta G., Piras F., Gili T., Ciullo V., Leu C., Stevelink R., Smith A.W., Goleva S.B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S.M., Cavalleri G.L., Koeleman B.P.C., Lerche H., Jehi L., Davis L.K., Najm I.M., Palotie A., Daly M.J., Busch R.M., Lal D., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B.M., Berkovic S.F., Goldstein D.B., Lowenstein D.H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bellows S.T., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B.R., Shain C., Poduri A., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Commission of the European Communities, Medical Research Council (MRC), Tumienė, Birutė, Mameniškienė, Rūta, Utkus, Algirdas, Praninskienė, Rūta, Grikinienė, Jurgita, Samaitienė-Aleknienė, Rūta, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Helsinki Institute of Life Science HiLIFE, and Department of Medical and Clinical Genetics

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, Epi25 Consortium, Databases, Factual, FEATURES, Genome-wide association study, Epilepsies, 3124 Neurology and psychiatry, Cohort Studies, Epilepsy, 0302 clinical medicine, Cost of Illness, 1ST SEIZURE, HISTORY, genetics, POPULATION, 11 Medical and Health Sciences, education.field_of_study, medicine.diagnostic_test, SCORES, Single Nucleotide, Biobank, 3. Good health, 17 Psychology and Cognitive Sciences, Genetic generalized epilepsy, Epilepsy, Generalized, Female, Partial, Cohort study, Human, medicine.medical_specialty, Population, European Continental Ancestry Group, Clinical Neurology, BIOBANK, Polymorphism, Single Nucleotide, epilepsy, genetic generalized epilepsy, common variant risk, Databases, 03 medical and health sciences, Genetic, Internal medicine, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Generalized epilepsy, education, SEIZURE RECURRENCE, Factual, METAANALYSIS, Genetic testing, Neurology & Neurosurgery, RISK PREDICTION, Generalized, business.industry, 3112 Neurosciences, Common variant risk, Genetic Variation, Original Articles, medicine.disease, Comorbidity, Cost of Illne, Epilepsies, Partial, Genome-Wide Association Study, 030104 developmental biology, Neurology (clinical), Cohort Studie, business, 030217 neurology & neurosurgery
Abstract

See Hansen and Møller (doi:10.1093/brain/awz318) for a scientific commentary on this article. Using polygenic risk scores from a genome-wide association study in generalized and focal epilepsy, Leu et al. reveal a significantly higher genetic burden for epilepsy in multiple cohorts of people with epilepsy compared to population controls. Quantification of common variant burden may be valuable for epilepsy prognosis and treatment., Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10−15; Cleveland: P = 2.85×10−4; Finnish-ancestry Epi25: P = 1.80×10−4) or population controls (Epi25: P = 2.35×10−70; Cleveland: P = 1.43×10−7; Finnish-ancestry Epi25: P = 3.11×10−4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10−4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10−19; Cleveland: P = 1.69×10−6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10−15; Cleveland: P = 1.39×10−2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls—in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

Published
2019
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25. Whole-exome and HLA sequencing in Febrile infection-related epilepsy syndrome

Author

Helbig, I. (Ingo), Barcia, G. (Giulia), Pendziwiat, M. (Manuela), Ganesan, S. (Shiva), Mueller, S.H. (Stefanie H.), Helbig, K.L. (Katherine L.), Vaidiswaran, P. (Priya), Xian, J. (Julie), Galer, P.D. (Peter D.), Afawi, Z. (Zaid), Specchio, N. (Nicola), Kluger, G. (Gerhard), Kuhlenbäumer, G. (Gregor), Appenzeller, S. (Silke), Wittig, M. (Michael), Kramer, U. (Uri), van Baalen, A. (Andreas), Nabbout, R. (Rima), Helbig, I. (Ingo), Barcia, G. (Giulia), Pendziwiat, M. (Manuela), Ganesan, S. (Shiva), Mueller, S.H. (Stefanie H.), Helbig, K.L. (Katherine L.), Vaidiswaran, P. (Priya), Xian, J. (Julie), Galer, P.D. (Peter D.), Afawi, Z. (Zaid), Specchio, N. (Nicola), Kluger, G. (Gerhard), Kuhlenbäumer, G. (Gregor), Appenzeller, S. (Silke), Wittig, M. (Michael), Kramer, U. (Uri), van Baalen, A. (Andreas), and Nabbout, R. (Rima)

Abstract

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epilepsy characterized by new-onset refractory status epilepticus with a prior febrile infection. We performed exome sequencing in 50 individuals with FIRES, including 27 patient–parent trios and 23 single probands, none of whom had pathogenic variants in established genes for epilepsies or neurodevelopmental disorders. We also performed HLA sequencing in 29 individuals with FIRES and 529 controls, which failed to identify prominent HLA alleles. The genetic architecture of FIRES is substantially different from other developmental and epileptic encephalopathies, and the underlying etiology remains elusive, requiring novel approaches to identify the underlying causative factors.

Published
2020
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26. Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17458 subjects

Author

Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, and Becker, F

Abstract

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5-3% of patients carry epilepsy-associated CNVs. The character

Published
2020

27. Whole-exome and HLA sequencing in Febrile infection-related epilepsy syndrome

Author

Helbig, I, Barcia, G, Pendziwiat, M, Ganesan, S, Mueller, S, Helbig, K, Vaidiswaran, P, Xian, J, Galer, PD, Afawi, Zaid, Specchio, N, Kluger, G, Kuhlenbäumer, G, Appenzeller, S, Wittig, M, Kramer, U, van Baalen, A, Nabbout, R, Helbig, I, Barcia, G, Pendziwiat, M, Ganesan, S, Mueller, S, Helbig, K, Vaidiswaran, P, Xian, J, Galer, PD, Afawi, Zaid, Specchio, N, Kluger, G, Kuhlenbäumer, G, Appenzeller, S, Wittig, M, Kramer, U, van Baalen, A, and Nabbout, R

Published
2020

35. PND78 - SOCIO-ECONOMIC IMPACT OF DRAVET SYNDROME IN GERMANY: A REAL-WORLD STUDY

Author

Irwin, J, primary, Strzelczyk, A, additional, Kalski, M, additional, Bast, T, additional, Wiemer-Kruel, A., additional, Bettendorf, U, additional, Kieslich, M, additional, Kluger, G, additional, Kurlemann, G, additional, Mayer, T, additional, Neubauer, B.A., additional, Polster, T, additional, Herting, A, additional, von Spiczak, S., additional, Trollmann, R, additional, Wolff, M, additional, Klein, KM, additional, Rosenow, F, additional, Schubert-Bast, S., additional, Carroll, J, additional, MacDonald, D, additional, and Gibson, E, additional

Published
2018
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36. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders

Author

Wolff, M. (Markus), Johannesen, K.M. (Katrine M.), Hedrich, U.B.S. (Ulrike B. S.), Masnada, S. (Silvia), Rubboli, G. (Guido), Gardella, E. (Elena), Lesca, G. (Gaetan), Ville, D. (Dorothée), Milh, M. (Mathieu), Villard, L. (Laurent), Afenjar, A. (Alexandra), Chantot-Bastaraud, S. (Sandra), Mignot, A., Lardennois, C. (Caroline), Nava, C. (Caroline), Schwarz, N. (Niklas), Gérard, M. (Marion), Perrin, L. (Laurence), Doummar, D. (Diane), Auvin, S. (Stéphane), Miranda, M.J. (Maria J.), Hempel, M. (Maja), Brilstra, E. (Eva), Knoers, N.V.A.M. (Nine), Verbeek, N.E. (Nienke), Kempen, M.J.A. (M. J A) van, Braun, K.P. (Kees P.), Mancini, G.M.S. (Grazia), Biskup, S. (Saskia), Hörtnagel, K. (Konstanze), Döcker, M. (Miriam), Bast, T. (Thomas), Loddenkemper, T. (Tobias), Wong-Kisiel, L. (Lily), Baumeister, F.M. (Friedrich M.), Fazeli, W. (Walid), Striano, P. (Pasquale), Dilena, R. (Robertino), Fontana, E. (Elena), Zara, F. (Federico), Kurlemann, G. (Gerhard), Klepper, J. (Joerg), Thoene, J.G. (Jess G.), Arndt, D.H. (Daniel H.), Deconinck, N. (Nicolas), Schmitt-Mechelke, T. (Thomas), Maier, O. (Oliver), Muhle, H. (Hiltrud), Wical, B. (Beverly), Finetti, C. (Claudio), Brückner, R. (Reinhard), Pietz, J. (Joachim), Golla, G. (Günther), Jillella, D. (Dinesh), Linnet, K.M. (Karen M.), Charles, P. (Perrine), Moog, U. (Ute), Õiglane-Shlik, E. (Eve), Mantovani, J.F. (John F.), Park, K. (Kristen), Deprez, M. (Marie), Lederer, D. (Damien), Mary, S. (Sandrine), Scalais, E. (Emmanuel), Selim, L. (Laila), Coster, R.N.A. (R. N A) van, Lagae, L. (Lieven), Nikanorova, M. (Marina), Hjalgrim, H. (Helle), Korenke, G.C. (Christoph), Trivisano, M. (Marina), Specchio, N. (Nicola), Ceulemans, B. (Berten), Dorn, T. (Thomas), Helbig, K.L. (Katherine L.), Hardies, K. (K.), Stamberger, H. (Hannah), Jonghe, P. (P.) de, Weckhuysen, S. (Sarah), Lemke, J.R. (Johannes R.), Krägeloh-Mann, I. (Ingeborg), Helbig, I. (Ingo), Kluger, G. (Gerhard), Lerche, H. (Holger), Møller, R.S. (Rikke), Wolff, M. (Markus), Johannesen, K.M. (Katrine M.), Hedrich, U.B.S. (Ulrike B. S.), Masnada, S. (Silvia), Rubboli, G. (Guido), Gardella, E. (Elena), Lesca, G. (Gaetan), Ville, D. (Dorothée), Milh, M. (Mathieu), Villard, L. (Laurent), Afenjar, A. (Alexandra), Chantot-Bastaraud, S. (Sandra), Mignot, A., Lardennois, C. (Caroline), Nava, C. (Caroline), Schwarz, N. (Niklas), Gérard, M. (Marion), Perrin, L. (Laurence), Doummar, D. (Diane), Auvin, S. (Stéphane), Miranda, M.J. (Maria J.), Hempel, M. (Maja), Brilstra, E. (Eva), Knoers, N.V.A.M. (Nine), Verbeek, N.E. (Nienke), Kempen, M.J.A. (M. J A) van, Braun, K.P. (Kees P.), Mancini, G.M.S. (Grazia), Biskup, S. (Saskia), Hörtnagel, K. (Konstanze), Döcker, M. (Miriam), Bast, T. (Thomas), Loddenkemper, T. (Tobias), Wong-Kisiel, L. (Lily), Baumeister, F.M. (Friedrich M.), Fazeli, W. (Walid), Striano, P. (Pasquale), Dilena, R. (Robertino), Fontana, E. (Elena), Zara, F. (Federico), Kurlemann, G. (Gerhard), Klepper, J. (Joerg), Thoene, J.G. (Jess G.), Arndt, D.H. (Daniel H.), Deconinck, N. (Nicolas), Schmitt-Mechelke, T. (Thomas), Maier, O. (Oliver), Muhle, H. (Hiltrud), Wical, B. (Beverly), Finetti, C. (Claudio), Brückner, R. (Reinhard), Pietz, J. (Joachim), Golla, G. (Günther), Jillella, D. (Dinesh), Linnet, K.M. (Karen M.), Charles, P. (Perrine), Moog, U. (Ute), Õiglane-Shlik, E. (Eve), Mantovani, J.F. (John F.), Park, K. (Kristen), Deprez, M. (Marie), Lederer, D. (Damien), Mary, S. (Sandrine), Scalais, E. (Emmanuel), Selim, L. (Laila), Coster, R.N.A. (R. N A) van, Lagae, L. (Lieven), Nikanorova, M. (Marina), Hjalgrim, H. (Helle), Korenke, G.C. (Christoph), Trivisano, M. (Marina), Specchio, N. (Nicola), Ceulemans, B. (Berten), Dorn, T. (Thomas), Helbig, K.L. (Katherine L.), Hardies, K. (K.), Stamberger, H. (Hannah), Jonghe, P. (P.) de, Weckhuysen, S. (Sarah), Lemke, J.R. (Johannes R.), Krägeloh-Mann, I. (Ingeborg), Helbig, I. (Ingo), Kluger, G. (Gerhard), Lerche, H. (Holger), and Møller, R.S. (Rikke)

Abstract

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatme

Published
2017
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37. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Author

Depienne, C, Nava, C, Keren, B, Heide, S, Rastetter, A, Passemard, S, Chantot-Bastaraud, S, Moutard, M-L, Agrawal, PB, VanNoy, G, Stoler, JM, Amor, DJ, de Villemeur, TB, Doummar, D, Alby, C, Cormier-Daire, V, Garel, C, Marzin, P, Scheidecker, S, de Saint-Martin, A, Hirsch, E, Korff, C, Bottani, A, Faivre, L, Verloes, A, Orzechowski, C, Burglen, L, Leheup, B, Roume, J, Andrieux, J, Sheth, F, Datar, C, Parker, MJ, Pasquier, L, Odent, S, Naudion, S, Delrue, M-A, Le Caignec, C, Vincent, M, Isidor, B, Renaldo, F, Stewart, F, Toutain, A, Koehler, U, Hackl, B, von Stulpnagel, C, Kluger, G, Moller, RS, Pal, D, Jonson, T, Soller, M, Verbeek, NE, van Haelst, MM, de Kovel, C, Koeleman, B, Monroe, G, van Haaften, G, Study, DDD, Attie-Bitach, T, Boutaud, L, Heron, D, Mignot, C, Depienne, C, Nava, C, Keren, B, Heide, S, Rastetter, A, Passemard, S, Chantot-Bastaraud, S, Moutard, M-L, Agrawal, PB, VanNoy, G, Stoler, JM, Amor, DJ, de Villemeur, TB, Doummar, D, Alby, C, Cormier-Daire, V, Garel, C, Marzin, P, Scheidecker, S, de Saint-Martin, A, Hirsch, E, Korff, C, Bottani, A, Faivre, L, Verloes, A, Orzechowski, C, Burglen, L, Leheup, B, Roume, J, Andrieux, J, Sheth, F, Datar, C, Parker, MJ, Pasquier, L, Odent, S, Naudion, S, Delrue, M-A, Le Caignec, C, Vincent, M, Isidor, B, Renaldo, F, Stewart, F, Toutain, A, Koehler, U, Hackl, B, von Stulpnagel, C, Kluger, G, Moller, RS, Pal, D, Jonson, T, Soller, M, Verbeek, NE, van Haelst, MM, de Kovel, C, Koeleman, B, Monroe, G, van Haaften, G, Study, DDD, Attie-Bitach, T, Boutaud, L, Heron, D, and Mignot, C

Abstract

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

Published
2017

38. Nephrologie 1

Author

Kurz, P., Köhler, H., Hütteroth, T., Knuth, A., Meuer, S., Büschenfelde, K.-H., Scharf, R. E., Frede, M., Finken, C., Grabensee, B., Schneider, W., Meyer-Sabellek, W., Gawlik, D., Gross, U., Heidemann, H., Meusers, P., Mertins, L., Kirch, W., Ohnhaus, E. E., Heine, H., Haunschild, J., Wagner, W., Kluger, G., Gilge, U., Heidbreder, E., Hörl, W. H., Heidland, A., Haag, M., Riegel, W., Miehlke, Klaus, editor, and Bergmann, J. F.

Published
1984
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39. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy

Author

Mignot, C., von Stulpnage, C., Nava, C., Ville, D., Sanlaville, D., Lesca, G., Rastetter, A., Gachet, B., Marie, Y., Korenke, G. C., Borggraefe, I., Hoffmann-Zacharska, D., Szczepanik, E., Rudzka-Dybala, M., Uluc, Yis, Caglayan, H., Isapof, A., Marey, I., Panagiotakaki, E., Korff, C., Rossier, E., Riess, A., Beck-Woedl, S., Rauch, A., Zweier, C., Hoyer, J., Reis, A., Mironov, M., Bobylova, M., Mukhin, K., Hernandez-Hernandez, L., Maher, B., Sisodiya, S., Kuhn, M., Glaeser, D., Wechuysen, S., Myers, C. T., Mefford, H. C., Hortnagel, K., Biskup, S., Lemke, J. R., Heron, D., Kluger, G., Depienne, C., Craiu, D., De Jonghe, P., Helbig, I., Guerrini, R., Lehesjoki, A. -E., Marini, C., Muhle, H., Moller, R. S., Neubauer, B., Pal, D., Selmer, K., Stephani, U., Sterbova, K., Striano, P., Talvik, T., von Spiczak, S., Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Université de Lyon, Klinikum Oldenburg [Oldenburg], Zentrum für Kinder- und Jugendmedizin, Dpt of Pediatric Neurology and Developmental Medicine and Epilepsy Center [Munich], University of Munich, Department of Medical Genetics, Institute of Mother and Child, Division of Child Neurology, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Dpt of Molecular Biology and Genetics Istanbul, Boǧaziçi üniversitesi = Boğaziçi University [Istanbul], Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant, Dpt de l'Enfant et de l'Adolescent, Neuropédiatrie [Genève], Hôpitaux Universitaires de Genève (HUG), Institute of Human Genetics [Tuebingen], University of Tuebingen, Institute of Medical Genetics and Applied Genomics [Tübingen], University of Tübingen, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Svt. Luka's Institute of Child Neurology and Epilepsy, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Genetikum, Neurogenetics Group, Division of Genetic Medicine [Seattle], University of Washington [Seattle], CeGaT GmbH, Institut für Humangenetik, Universität Heidelberg [Heidelberg], Mignot, Cyril, von Stülpnagel, Celina, Korff, Christian, EuroEPINOMICS-RES MAE Working Grp, HAL-UPMC, Gestionnaire, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Boğaziçi University [Istanbul], CHU Trousseau [APHP], and Universität Heidelberg [Heidelberg] = Heidelberg University

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, Encephalopathy, Myoclonic Jerk, SYNGAP1, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, fluids and secretions, Medizinische Fakultät, Intellectual disability, mental disorders, Genetics, medicine, ddc:610, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Exome, Genetics (clinical), reproductive and urinary physiology, ddc:618, business.industry, medicine.disease, Hypotonia, 3. Good health, 030104 developmental biology, Autism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Mae Euroepinomics-Res Mae; International audience; Objective We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype–phenotype correlations.Methods We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.Results We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3′ and 5′ exons. Seizures in patients with mutations in exons 4–5 were more pharmacoresponsive than in patients with mutations in exons 8–15.Conclusions SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.

Published
2016
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40. CLINICAL HETEROGENEITY AND ITS POTENTIAL THERAPEUTIC IMPLICATIONS IN CHILDREN WITH SCN2A-RELATED DISORDERS

Author

Ceulemans, B., Lederer, D., Dorn, T., Helbig, K. L., Hardies, K., Stamberger, H., de Jonghe, P., Weckhuysen, S., Lemke, J. R., Helbig, I, Kluger, G., Moller, R. S., Johannesen, K. M., Wolf, M., Masnada, S., Rubboli, G., Gardella, E., Milh, M., Villard, L., Mignot, C., Lardennois, C., Bourel-Ponchel, Emilie, Nava, C., Lesca, G., Gerard, M., Perrin, L., Doummar, D., Auvin, S., Miranda, M. J., Brilstra, E., Knoers, N., Doecker, M., Bast, T., Loddenkemper, T., Wong-Kisiel, L., Baumeister, F. M., Fazeli, W., Striano, P., Kurlemann, G., Klepper, J., Thoene, J. G., Arndt, D. H., Schmitt-Mechelke, T., Maier, O., Muhle, H., Wical, B., Finetti, C., Brueckner, R., Pietz, J., Golla, G., Jillella, D., Afenjar, A., Linnet, K. M., Charles, P., Oiglane-Slik, E., Mantovani, J. F., Deprez, M., Scalais, E., Lagae, L., Nikanorova, M., Hjalgrim, H., Depienne, C., Scheidecker, S., Kremer, V, Doray, B., Alembik, y., University of British Columbia (UBC), Pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) - Hôpital de la Timone, Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS), Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Insulaire du Vivant et de l'Environnement (LIVE), Université de la Nouvelle-Calédonie (UNC), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Department of Child Neurology, Development and Rehabilitation [Hospital of Eastern Switzerland], Children's Hospital of Eastern Switzerland St.Gallen, Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], IMEC (IMEC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Statens seruminstitut, and Les Hôpitaux Universitaires de Strasbourg (HUS)

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2016

43. Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs

Author

von Stülpnagel, C., primary, Ensslen, M., additional, Møller, R.S., additional, Pal, D.K., additional, Masnada, S., additional, Veggiotti, P., additional, Piazza, E., additional, Dreesmann, M., additional, Hartlieb, T., additional, Herberhold, T., additional, Hughes, E., additional, Koch, M., additional, Kutzer, C., additional, Hoertnagel, K., additional, Nitanda, J., additional, Pohl, M., additional, Rostásy, K., additional, Haack, T.B., additional, Stöhr, K., additional, Kluger, G., additional, and Borggraefe, I., additional

Published
2017
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46. GOAL: Gait Outcome Assessment List

Author

Jelesch, E., additional, König, H., additional, Weir, S., additional, Weinberger, R., additional, Herzig, N., additional, Kluger, G., additional, Michel, J., additional, Bernius, P., additional, von Kries, R., additional, Narayanan, U., additional, Schröder, S., additional, and Berweck, S., additional

Published
2017
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49. Effect of anticonvulsive treatment on neuropsychological performance in children with BECTS

Author

Tacke, Moritz, primary, Gerstl, Lucia, additional, Heinen, Florian, additional, Heukaeufer, Isabel, additional, Bonfert, Michaela, additional, Bast, Thomas, additional, Cornell, Sonia, additional, Neubauer, Bernd Axel, additional, Borggraefe, Ingo, additional, Baumeister, F.A.M., additional, Baethmann, M., additional, Schreiber-Gollwitzer, B., additional, Bentele, K., additional, Blank, C., additional, Held, J., additional, Blank, H.M., additional, Liebrich, K., additional, Bode, H., additional, Braun, J., additional, Bosch, F., additional, Wagner, R., additional, Brandl, U., additional, Wetzel, K., additional, Brockmann, K., additional, Schlockwerder, C., additional, Dahlem, P., additional, Baudler, I., additional, Ernst, J.P., additional, Mayer, H., additional, Feldmann, E., additional, Pattber-Wolff, A., additional, Fiedler, A., additional, Sonnleitner, S., additional, Gerigk, M., additional, Heß, S., additional, Feiereis, T., additional, Hikel, C., additional, Hoffmann, H.G., additional, Rickeshenrich, A., additional, Kieslich, M., additional, Dewitz, R., additional, Baz Bartels, M., additional, Klepper, J., additional, Kleuker, S., additional, Kluger, G., additional, Kirsch, A., additional, Koch, H., additional, Meerpohl, U., additional, Koch, W., additional, Korinthenberg, R., additional, Stehle-Renner, B., additional, Krois, I., additional, Wegener, A., additional, Kühne, H., additional, Weiß, C., additional, Kurlemann, G., additional, Elkemann, U., additional, Mandl, M., additional, Friedl, A., additional, Mause, U., additional, Müller, M., additional, Navratil, P., additional, Iken, U., additional, Opp, J., additional, Walter, J., additional, Penzien, J., additional, Prietsch, V., additional, Siegrist, B., additional, Quattländer, A., additional, Rating, D., additional, Reuner, G., additional, Schara, U., additional, Shamdeen, M.G., additional, Struchholz, H., additional, Sprinz, A., additional, Wendker-Magrabi, H., additional, Stephani, U., additional, Muhle, H., additional, Carlsson, G., additional, Straßburg, H.M., additional, Ottensmeier, H., additional, Töpke, B., additional, Tatsek, K., additional, Trollmann, R., additional, Poida-Herzing, E., additional, Tuschen-Hofstätter, E., additional, Menschig, M., additional, Waltz, S., additional, Pickartz, A., additional, Weber, G., additional, Gehnen, T., additional, Wien, F.U., additional, Antemann, J., additional, Wolff, M., additional, Serra, E., additional, Polster, T., additional, Freitag, H., additional, Sönmez, Ö, additional, Rheinhardt, K., additional, Traus, M., additional, Schröder, A., additional, Hoovey, S., additional, and Navratil, C., additional

Published
2016
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