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102. Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study

Author

Cavalleri, Gianpiero L, Weale, Michael E, Shianna, Kevin V, Singh, Rinki, Lynch, John M, Grinton, Bronwyn, Szoeke, Cassandra, Murphy, Kevin, Kinirons, Peter, O'Rourke, Deirdre, Ge, Dongliang, Depondt, Chantal, Claeys, Kristl G, Pandolfo, Massimo, Gumbs, Curtis, Walley, Nicole, McNamara, James, Mulley, John C, Linney, Kristen N, Sheffield, Leslie J, Radtke, Rodney A, Tate, Sarah K, Chissoe, Stephanie L, Gibson, Rachel A, Hosford, David, Stanton, Alice, Graves, Tracey D, Hanna, Michael G, Eriksson, Kai, Kantanen, Anne-Mari, Kalviainen, Reetta, O'Brien, Terence J, Sander, Josemir W, Duncan, John S, Scheffer, Ingrid E, Berkovic, Samuel F, Wood, Nicholas W, Doherty, Colin P, Delanty, Norman, Sisodiya, Sanjay M, and Goldstein, David B

Published
2007
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103. Expanding the clinical and genetic spectrum of FDXR deficiency by functional validation of variants of uncertain significance

Author

Stenton, Sarah L., primary, Piekutowska‐Abramczuk, Dorota, additional, Kulterer, Lea, additional, Kopajtich, Robert, additional, Claeys, Kristl G., additional, Ciara, Elżbieta, additional, Eisen, Johannes, additional, Płoski, Rafał, additional, Pronicka, Ewa, additional, Malczyk, Katarzyna, additional, Wagner, Matias, additional, Wortmann, Saskia B., additional, and Prokisch, Holger, additional

Published
2021
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104. Digenic Inheritance Involving a Muscle Specific Protein Kinase and the Giant Titin Protein Causes a Skeletal Muscle Myopathy

Author

Topf, Ana, primary, Zaharieva, Irina, additional, Di Leo, Valeria, additional, Vihola, Anna, additional, Wali, Neha, additional, Savarese, Marco, additional, Laricchia, Kristen, additional, Venturini, Cristina, additional, Vroling, Bas, additional, Cummings, Beryl, additional, Barresi, Rita, additional, Harris, Elizabeth, additional, Marini Bettolo, Chiara, additional, Cox, Dan, additional, Duff, Jennifer, additional, England, Eleina, additional, Patrick, Jane, additional, Biancalana, Valerie, additional, Bommireddipalli, Shobhana, additional, Bonnemann, Carsten, additional, Cairns, Anita, additional, Chiew, Mei, additional, Claeys, Kristl G., additional, Cooper, Sandra, additional, Davis, Mark R., additional, Donkervoort, Sandra, additional, Erasmus, Corrie E., additional, Grosmann, Carla, additional, Jungbluth, Heinz, additional, Kamsteeg, Erik-Jan, additional, Lornage, Xaviere, additional, Löscher, Wolfgang, additional, Malfatti, Edoardo, additional, Manzur, Adnan, additional, Marti, Pilar, additional, Mongini, Tiziana, additional, Muelas, Nuria, additional, Nishikawa, Atsuko, additional, Ogonuki, Narumi, additional, O'Grady, Gina, additional, Paquay, Stephanie, additional, Phadke, Rahul, additional, Pletcher, Beth, additional, Romero, Norma, additional, Schouten, Meyke, additional, Shah, Snehal, additional, Sznajer, Yves, additional, Tasca, Giorgio, additional, Tuite, Allysa, additional, van den Bergh, Peter, additional, Voermans, Nicol, additional, Wanschitz, Julia, additional, Wraige, Elizabeth, additional, Yoshimura, Kimihiko, additional, Oates, Emily, additional, Nakagawa, Osamu, additional, Nishino, Ichizo, additional, Laporte, Jocelyn, additional, Vilchez, Juan, additional, Macarthur, Daniel, additional, Sarkozy, Anna, additional, Udd, Bjarne, additional, Busch-Nentwich, Elisabeth, additional, Muntoni, Francesco, additional, and Straub, Volker, additional

Published
2021
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107. PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot–Marie–Tooth disease

Author

Azzedine, Hamid, Zavadakova, Petra, Planté-Bordeneuve, Violaine, Vaz Pato, Maria, Pinto, Nuno, Bartesaghi, Luca, Zenker, Jennifer, Poirot, Olivier, Bernard-Marissal, Nathalie, Arnaud Gouttenoire, Estelle, Cartoni, Romain, Title, Alexandra, Venturini, Giulia, Médard, Jean-Jacques, Makowski, Edward, Schöls, Ludger, Claeys, Kristl G., Stendel, Claudia, Roos, Andreas, Weis, Joachim, Dubourg, Odile, Leal Loureiro, José, Stevanin, Giovanni, Said, Gérard, Amato, Anthony, Baraban, Jay, LeGuern, Eric, Senderek, Jan, Rivolta, Carlo, and Chrast, Roman

Published
2013
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112. New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy

Author

Alonso-Pérez, Jorge, primary, González-Quereda, Lidia, additional, Bello, Luca, additional, Guglieri, Michela, additional, Straub, Volker, additional, Gallano, Pia, additional, Semplicini, Claudio, additional, Pegoraro, Elena, additional, Zangaro, Vittoria, additional, Nascimento, Andrés, additional, Ortez, Carlos, additional, Comi, Giacomo Pietro, additional, Dam, Leroy ten, additional, De Visser, Marianne, additional, van der Kooi, A J, additional, Garrido, Cristina, additional, Santos, Manuela, additional, Schara, Ulrike, additional, Gangfuß, Andrea, additional, Løkken, Nicoline, additional, Storgaard, Jesper Helbo, additional, Vissing, John, additional, Schoser, Benedikt, additional, Dekomien, Gabriele, additional, Udd, Bjarne, additional, Palmio, Johanna, additional, D'Amico, Adele, additional, Politano, Luisa, additional, Nigro, Vincenzo, additional, Bruno, Claudio, additional, Panicucci, Chiara, additional, Sarkozy, Anna, additional, Abdel-Mannan, Omar, additional, Alonso-Jimenez, Alicia, additional, Claeys, Kristl G, additional, Gomez-Andrés, David, additional, Munell, Francina, additional, Costa-Comellas, Laura, additional, Haberlová, Jana, additional, Rohlenová, Marie, additional, Elke, De Vos, additional, De Bleecker, Jan L, additional, Dominguez-González, Cristina, additional, Tasca, Giorgio, additional, Weiss, Claudia, additional, Deconinck, Nicolas, additional, Fernández-Torrón, Roberto, additional, López de Munain, Adolfo, additional, Camacho-Salas, Ana, additional, Melegh, Béla, additional, Hadzsiev, Kinga, additional, Leonardis, Lea, additional, Koritnik, Blaz, additional, Garibaldi, Matteo, additional, de Leon-Hernández, Juan Carlos, additional, Malfatti, Edoardo, additional, Fraga-Bau, Arturo, additional, Richard, Isabelle, additional, Illa, Isabel, additional, and Díaz-Manera, Jordi, additional

Published
2020
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114. Intracerebroventricular delivery of vascular endothelial growth factor in patients with amyotrophic lateral sclerosis, a phase I study

Author

Van Damme, Philip, primary, Tilkin, Petra, additional, Mercer, Katarina Jansson, additional, Terryn, Joke, additional, D’Hondt, Ann, additional, Herne, Nina, additional, Tousseyn, Thomas, additional, Claeys, Kristl G, additional, Thal, Dietmar R, additional, Zachrisson, Olof, additional, Almqvist, Per, additional, Nuttin, Bart, additional, Jerling, Markus, additional, Bernadotte, Folke, additional, Haegerstrand, Anders, additional, and Robberecht, Wim, additional

Published
2020
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115. Recurrent TTN metatranscript‐only c.39974–11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy

Author

Bryen, Samantha J., primary, Ewans, Lisa J., additional, Pinner, Jason, additional, MacLennan, Suzanna C., additional, Donkervoort, Sandra, additional, Castro, Diana, additional, Töpf, Ana, additional, O'Grady, Gina, additional, Cummings, Beryl, additional, Chao, Katherine R., additional, Weisburd, Ben, additional, Francioli, Laurent, additional, Faiz, Fathimath, additional, Bournazos, Adam M., additional, Hu, Ying, additional, Grosmann, Carla, additional, Malicki, Denise M., additional, Doyle, Helen, additional, Witting, Nanna, additional, Vissing, John, additional, Claeys, Kristl G., additional, Urankar, Kathryn, additional, Beleza‐Meireles, Ana, additional, Baptista, Julia, additional, Ellard, Sian, additional, Savarese, Marco, additional, Johari, Mridul, additional, Vihola, Anna, additional, Udd, Bjarne, additional, Majumdar, Anirban, additional, Straub, Volker, additional, Bönnemann, Carsten G., additional, MacArthur, Daniel G., additional, Davis, Mark R., additional, and Cooper, Sandra T., additional

Published
2019
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117. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy

Author

Claeys, Kristl G., Züchner, Stephan, Kennerson, Marina, Berciano, José, Garcia, Antonio, Verhoeven, Kristien, Storey, Elsdon, Merory, John R., Bienfait, Henriette M. E., Lammens, Martin, Nelis, Eva, Baets, Jonathan, De Vriendt, Els, Berneman, Zwi N., De Veuster, Ilse, Vance, Jefferey M., Nicholson, Garth, Timmerman, Vincent, and De Jonghe, Peter

Published
2009

118. RNF170 mutation causes autosomal dominant sensory ataxia with variable pyramidal involvement.

Author

Van Daele, Sien H., Moisse, Matthieu, Race, Valérie, Van Eesbeeck, Amélie, Keldermans, Liesbeth, Vermeer, Sascha, Van Esch, Hilde, Claeys, Kristl G., and Van Damme, Philip

Subjects
SENSORY ataxia, SPINOCEREBELLAR ataxia, GENETIC variation, FAMILIAL spastic paraplegia, GENETIC mutation, NEUROMUSCULAR diseases
Abstract

Background: Although hereditary ataxias are a group of clinically and genetically heterogeneous disorders, specific clinical clues can sometimes incriminate certain genes. This can trigger genetic testing in sporadic patients or prompt dissecting certain genes more thoroughly when initial genetic testing is negative. Also for the assembly of gene panels and interpretation of the results, genotype−phenotype correlations remain important to establish. Methods: We clinically evaluated a Belgian family with autosomal dominant inherited sensory ataxia and variable pyramidal involvement and performed targeted clinical exome sequencing. Secondly, we retrospectively screened sequencing data of an in‐house cohort of 404 patients with neuromuscular disorders for variants in the identified gene RNF170. Results: All affected family members showed sensory ataxia on examination. Pyramidal involvement, and sometimes slow‐pursuit abnormalities and/or a sensory neuropathy, were more variable findings. We identified the heterozygous variant p.Arg199Cys in RNF170 in all three affected siblings of our family. We did not find additional pathogenic variants in RNF170 in our in‐house neuromuscular cohort. Conclusions: We confirm the heterozygous variant p.Arg199Cys in RNF170 in a Belgian family with autosomal dominant sensory ataxia and variable pyramidal involvement. This constitutes a rare but clinically recognizable phenotype that warrants testing of RNF170. Unlike the distinctive bi‐allelic loss of function variants in RNF170 associated with hereditary spastic paraplegia (HSP), the p.Arg199Cys variant is the only one reported in sensory ataxia. It is important for neurologists to be aware of this characteristic phenotype and to include this gene in gene panels for ataxia and HSP. [ABSTRACT FROM AUTHOR]

Published
2022
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120. Hereditary Spastic Paraplegia 3A Associated With Axonal Neuropathy

Author

Ivanova, Neviana, Claeys, Kristl G., Deconinck, Tine, Litvinenko, Ivan, Jordanova, Albena, Auer-Grumbach, Michaela, Haberlova, Jana, Löfgren, Ann, Smeyers, Gisele, Nelis, Eva, Mercelis, Rudy, Plecko, Barbara, Priller, Josef, Zámečník, Josef, Ceulemans, Berten, Erichsen, Anne Kjersti, Björck, Erik, Nicholson, Garth, Sereda, Michael W., Seeman, Pavel, Kremensky, Ivo, Mitev, Vanio, and De Jonghe, Peter

Published
2007

122. MFN2 mutation distribution and genotype/phenotype correlation in Charcot–Marie–Tooth type 2

Author

Verhoeven, Kristien, Claeys, Kristl G., Züchner, Stephan, Schröder, J. Michael, Weis, Joachim, Ceuterick, Chantal, Jordanova, Albena, Nelis, Eva, De Vriendt, Els, Van Hul, Matthias, Seeman, Pavel, Mazanec, Radim, Saifi, Gulam Mustafa, Szigeti, Kinga, Mancias, Pedro, Butler, Ian J., Kochanski, Andrzej, Ryniewicz, Barbara, De Bleecker, Jan, Van den Bergh, Peter, Verellen, Christine, Van Coster, Rudy, Goemans, Nathalie, Auer-Grumbach, Michaela, Robberecht, Wim, Rasic, Vedrana Milic, Nevo, Yoram, Tournev, Ivajlo, Guergueltcheva, Velina, Roelens, Filip, Vieregge, Peter, Vinci, Paolo, Moreno, Maria Teresa, Christen, H.-J., Shy, Michael E., Lupski, James R., Vance, Jeffery M., De Jonghe, Peter, and Timmerman, Vincent

Published
2006

124. Reply : Adult-onset distal spinal muscular atrophy: a new phenotype associated with KIF5A mutations

Author

Brenner, David, Rosenbohm, Angela, Yilmaz, Ruestem, Mueller, Kathrin, Grehl, Torsten, Petri, Susanne, Meyer, Thomas, Grosskreutz, Julian, Weydt, Patrick, Ruf, Wolfgang, Neuwirth, Christoph, Weber, Markus, Pinto, Susana, Claeys, Kristl G., Schrank, Berthold, Jordan, Berit, Knehr, Antje, Guenther, Kornelia, Huebers, Annemarie, Zeller, Daniel, Kubisch, Christian, Jablonka, Sibylle, Sendtner, Michael, Klopstock, Thomas, de Carvalho, Mamede, Sperfeld, Anne, Borck, Guntram, Volk, Alexander E., Dorst, Johannes, Weis, Joachim, Otto, Markus, Schuster, Joachim, Del Tredici, Kelly, Braak, Heiko, Danzer, Karin M., Freischmidt, Axel, Meitinger, Thomas, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Weyen, Ute, Hermann, Andreas, Winkler, Juergen, Hagenacker, Tim, Koch, Jan Christoph, Lingor, Paul, Goericke, Bettina, Zierz, Stephan, Baum, Petra, Wolf, Joachim, Winkler, Andrea, Young, Peter, Bogdahn, Ulrich, Prudlo, Johannes, Kassubek, Jan, Brenner, David, Rosenbohm, Angela, Yilmaz, Ruestem, Mueller, Kathrin, Grehl, Torsten, Petri, Susanne, Meyer, Thomas, Grosskreutz, Julian, Weydt, Patrick, Ruf, Wolfgang, Neuwirth, Christoph, Weber, Markus, Pinto, Susana, Claeys, Kristl G., Schrank, Berthold, Jordan, Berit, Knehr, Antje, Guenther, Kornelia, Huebers, Annemarie, Zeller, Daniel, Kubisch, Christian, Jablonka, Sibylle, Sendtner, Michael, Klopstock, Thomas, de Carvalho, Mamede, Sperfeld, Anne, Borck, Guntram, Volk, Alexander E., Dorst, Johannes, Weis, Joachim, Otto, Markus, Schuster, Joachim, Del Tredici, Kelly, Braak, Heiko, Danzer, Karin M., Freischmidt, Axel, Meitinger, Thomas, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Weyen, Ute, Hermann, Andreas, Winkler, Juergen, Hagenacker, Tim, Koch, Jan Christoph, Lingor, Paul, Goericke, Bettina, Zierz, Stephan, Baum, Petra, Wolf, Joachim, Winkler, Andrea, Young, Peter, Bogdahn, Ulrich, Prudlo, Johannes, and Kassubek, Jan

Published
2019
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125. An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease

Author

Kulessa, Martin, Weyer‐Menkhoff, Iris, Viergutz, Lara, Kornblum, Cornelia, Claeys, Kristl G., Schneider, Ilka, Plöckinger, Ursula, Young, Peter, Boentert, Matthias, Vielhaber, Stefan, Mawrin, Christian, Bergmann, Markus, Weis, Joachim, Ziagaki, Athanasia, Stenzel, Werner, Deschauer, Marcus, Nolte, Dagmar, Hahn, Andreas, Schoser, Benedikt, Schänzer, Anne, Kulessa, Martin, Weyer‐Menkhoff, Iris, Viergutz, Lara, Kornblum, Cornelia, Claeys, Kristl G., Schneider, Ilka, Plöckinger, Ursula, Young, Peter, Boentert, Matthias, Vielhaber, Stefan, Mawrin, Christian, Bergmann, Markus, Weis, Joachim, Ziagaki, Athanasia, Stenzel, Werner, Deschauer, Marcus, Nolte, Dagmar, Hahn, Andreas, Schoser, Benedikt, and Schänzer, Anne

Abstract

Aims: Pompe disease is caused by pathogenic mutations in the alpha 1,4‐glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype–phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability. Methods: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology‐score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule‐associated protein 1A/1B‐light chain 3, p62 and Bcl2‐associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies. Results: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology‐score. High morphology‐scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology‐score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine‐kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.‐32‐13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type. Conclusions: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.

Published
2019

126. Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions

Author

Instituto de Salud Carlos III, European Commission, Fundación Genzyme, Generalitat de Catalunya, National Health and Medical Research Council (Australia), Cancer Research Trust New Zealand, Australian Research Council, Swedish Research Council, Stockholm County Council, Swedish Brain Foundation, Knut and Alice Wallenberg Foundation, University of Leuven, KOOR, Stiftelsen Frimurare Barnhuset i Stockholm, Royal Society (UK), Promobilia Foundation, National Heart Foundation of Australia, Olivé, Montse, Engvall, Martin, Ravenscroft, Gianina, Cabrera-Serrano, Macarena, Jiao, Hong, Bortolotti, Carlo Augusto, Pignataro, Marcello, Lambrughi, Matteo, Jiang, Haibo, Forrest, Alistair R. R., Benseny-Cases, N., Hofbauer, Stefan, Obinger, Christian, Battistuzzi, Gianantonio, Bellei, Marzia, Borsari, Marco, Di Rocco, Giulia, Viola, Helena M., Hool, Livia C., Cladera, Josep, Lagerstedt-Robinson, Kristina, Xiang, Fengqing, Wredenberg, Anna, Miralles, Frances, Baiges, Juan José, Malfatti, Edoardo, Romero, Norma B., Streichenberger, Nathalie, Vial, Christophe, Claeys, Kristl G., Straathof, Chiara S. M., Goris, An, Freyer, Christoph, Lammens, Martin, Bassez, Guillaume, Kere, Juha, Clemente, Paula, Sejersen, Thomas, Udd, Bjarne, Vidal, Noemí, Ferrer, Isidro, Edström, Lars, Wedell, Anna, Laing, Nigel G., Instituto de Salud Carlos III, European Commission, Fundación Genzyme, Generalitat de Catalunya, National Health and Medical Research Council (Australia), Cancer Research Trust New Zealand, Australian Research Council, Swedish Research Council, Stockholm County Council, Swedish Brain Foundation, Knut and Alice Wallenberg Foundation, University of Leuven, KOOR, Stiftelsen Frimurare Barnhuset i Stockholm, Royal Society (UK), Promobilia Foundation, National Heart Foundation of Australia, Olivé, Montse, Engvall, Martin, Ravenscroft, Gianina, Cabrera-Serrano, Macarena, Jiao, Hong, Bortolotti, Carlo Augusto, Pignataro, Marcello, Lambrughi, Matteo, Jiang, Haibo, Forrest, Alistair R. R., Benseny-Cases, N., Hofbauer, Stefan, Obinger, Christian, Battistuzzi, Gianantonio, Bellei, Marzia, Borsari, Marco, Di Rocco, Giulia, Viola, Helena M., Hool, Livia C., Cladera, Josep, Lagerstedt-Robinson, Kristina, Xiang, Fengqing, Wredenberg, Anna, Miralles, Frances, Baiges, Juan José, Malfatti, Edoardo, Romero, Norma B., Streichenberger, Nathalie, Vial, Christophe, Claeys, Kristl G., Straathof, Chiara S. M., Goris, An, Freyer, Christoph, Lammens, Martin, Bassez, Guillaume, Kere, Juha, Clemente, Paula, Sejersen, Thomas, Udd, Bjarne, Vidal, Noemí, Ferrer, Isidro, Edström, Lars, Wedell, Anna, and Laing, Nigel G.

Abstract

Myoglobin, encoded by MB, is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O2, facilitates its intracellular transport and serves as a controller of nitric oxide and reactive oxygen species. Here, we identify a recurrent c.292C>T (p.His98Tyr) substitution in MB in fourteen members of six European families suffering from an autosomal dominant progressive myopathy with highly characteristic sarcoplasmic inclusions in skeletal and cardiac muscle. Myoglobinopathy manifests in adulthood with proximal and axial weakness that progresses to involve distal muscles and causes respiratory and cardiac failure. Biochemical characterization reveals that the mutant myoglobin has altered O2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. Preliminary studies show that mutant myoglobin may result in elevated superoxide levels at the cellular level. These data define a recognizable muscle disease associated with MB mutation.

Published
2019

129. Comprehensive analysis of the mutation spectrum in 301 German ALS families

Author

Müller, Kathrin, Brenner, David, Kubisch, Christian, Klopstock, Thomas, Zeller, Daniel, Jablonka, Sibylle, Sendtner, Michael, Klebe, Stephan, Knehr, Antje, Günther, Kornelia, Weis, Joachim, Claeys, Kristl G, Weydt, Patrick, Schrank, Berthold, Sperfeld, Anne-Dorte, Hübers, Annemarie, Otto, Markus, Dorst, Johannes, Meitinger, Thomas, Strom, Tim M, Andersen, Peter M, Ludolph, Albert, Weishaupt, Jochen H, Meyer, Thomas, MND-NET, German ALS network, Weyen, Ute, Hermann, Andreas, Regensburger, Martin, Winkler, Jürgen, Linker, Ralf, Winner, Beate, Hagenacker, Tim, Koch, Jan Christoph, Lingor, Paul, Grehl, Torsten, Göricke, Bettina, Zierz, Stephan, Jordan, Berit, Baum, Petra, Wolf, Joachim, Winkler, Andrea, Young, Peter, Bogdahn, Ulrich, Prudlo, Johannes, Kassubek, Jan, Petri, Susanne, Danzer, Karin M, Grosskreutz, Julian, Schuster, Joachim, Volk, Alexander E, and Borck, Guntram

Subjects
0301 basic medicine, DNA Mutational Analysis, Medizin, German, 0302 clinical medicine, Superoxide Dismutase-1, Germany, genetics, Amyotrophic lateral sclerosis, Exome sequencing, Genetics, Amyotrophic Lateral Sclerosis, Whole Exome Sequencing, TDP-43 protein, human, TBK1 protein, human, Protein-Serine-Threonine Kinases, Pedigree, genetics [Superoxide Dismutase-1], DNA-Binding Proteins, Psychiatry and Mental health, Editorial Commentary, genetics [Amyotrophic Lateral Sclerosis], Mutation (genetic algorithm), symbols, language, Genotype, genetics [Protein Serine-Threonine Kinases], genetics [DNA-Binding Proteins], Biology, Protein Serine-Threonine Kinases, genetics [Protein-Serine-Threonine Kinases], 03 medical and health sciences, symbols.namesake, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Gene, genetics [C9orf72 Protein], C9orf72 Protein, medicine.disease, language.human_language, 030104 developmental biology, Mutation, Mendelian inheritance, RNA-Binding Protein FUS, Surgery, Neurology (clinical), Als, genetics [RNA-Binding Protein FUS], 030217 neurology & neurosurgery
Abstract

ObjectivesRecent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.MethodsHere we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.Results49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.ConclusionsWe here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.

Published
2018

130. Regional variation of Guillain-Barré syndrome

Author

Doets, Alex Y., Verboon, Christine, Van Den Berg, Bianca, Harbo, Thomas, Cornblath, David R., Willison, Hugh J., Islam, Zhahirul, Attarian, Shahram, Barroso, Fabio A., Bateman, Kathleen, Benedetti, Luana, Van Den Bergh, Peter, Casasnovas, Carlos, Cavaletti, Guido, Chavada, Govindsinh, Claeys, Kristl G., Dardiotis, Efthimios, Davidson, Amy, Van Doorn, Pieter A., Feasby, Tom E., Galassi, Giuliana, Gorson, Kenneth C., Hartung, Hans-Peter, Hsieh, Sung-Tsang, Hughes, Richard A. C., Illa, Isabel, Islam, Badrul, Kusunoki, Susumu, Kuwabara, Satoshi, Lehmann, Helmar C., Miller, James A. L., Mohammad, Quazi Deen, Monges, Soledad, Nobile Orazio, Eduardo, Pardo, Julio, Pereon, Yann, Rinaldi, Simon, Querol, Luis, Reddel, Stephen W., Reisin, Ricardo C., Shahrizaila, Nortina, Sindrup, Soren H., Waqar, Waheed, Jacobs, Bart C., Jacobs, Bc, Hughes, Rac, Cornblath, Dr, Gorson, Kc, Hartung, Hp, Kusunoki, S, van Doorn PA, Willison, Hj, van Woerkom, M, van den Berg, B, Verboon, C, Doets, Ay, Roodbol, J, Reisin, Rc, Reddel, Sw, Islam, Z, Islam, B, Mohammad, Qd, van den Bergh, P, Feasby, Te, Harbo, T, Péréon, Y, Lehmann, Hc, Dardiotis, E, Nobile-Orazio, E, Shahrizaila, N, Bateman, K, Illa, I, Querol, L, Hsieh, St, Chavada, G, Davidson, A, Addington, Jm, Ajroud-Driss, S, Andersen, H, Antonini, G, Ariatti, A, Attarian, S, Badrising, Ua, Barroso, Fa, Benedetti, L, Beronio, A, Bianco, M, Binda, D, Briani, C, Bunschoten, C, Bürmann, J, Bella, Ir, Bertorini, Te, Bhavaraju-Sanka, R, Brannagan, Th, Busby, M, Butterworth, S, Casasnovas, C, Cavaletti, G, Chao, Cc, Chetty, S, Claeys, Kg, Conti, Me, Cosgrove, Js, Dalakas, Mc, Derejko, Ma, Dimachkie, Mm, Doppler, K, Dornonville de la Cour, C, Echaniz-Laguna, A, Eftimov, F, Faber, Cg, Fazio, R, Fujioka, T, Fulgenzi, Ea, Galassi, G, Garcia-Sobrino, T, Garnero, M, Garssen, Mpj, Gijsbers, Cj, Gilchrist, Jm, Goldstein, Jm, Granit, V, Grapperon, A, Gutiérrez, G, Hadden, Rdm, Holbech, Jv, Holt, Jkl, Homedes Pedret, C, Htut, M, Jericó Pascual, I, Kaida, K, Karafiath, S, Katzberg, Hd, Kiers, L, Kieseier, Bc, Kimpinski, K, Kleyweg, Rp, Kokubun, N, Kolb, Na, Kuitwaard, K, Kuwabara, S, Kwan, Jy, Ladha, Ss, Landschoff Lassen, L, Lawson, V, Ledingham, D, Léon Cejas, L, Lucy, St, Lunn, Mpt, Magot, A, Manji, H, Marchesoni, C, Marfia, Ga, Márquez Infante, C, Martinez Hernandez, E, Mataluni, G, Mcdermott, Cj, Meekins, Gd, Miller, Jal, Monges, Ms, Montero, Mcj, Morís de la Tassa, G, Mozzoni, J, Nascimbene, C, Nowak, Rj, Orizaloa Balaguer, P, Osei-Bonsu, M, Lee Pan EB, Pardo, J, Pasnoor, M, Rajabally, Ya, Rinaldi, S, Ritter, C, Roberts, Rc, Rojas-Marcos, I, Rudnicki, Sa, Ruiz, M, Sachs, Gm, Samijn, Jpa, Santoro, L, Schenone, A, Schwindling, L, Sedano Tous MJ, Sekiguchi, Y, Sheikh, Ka, Silvestri, Nj, Sindrup, Sh, Sommer, Cl, Stein, B, Stino, Am, Spyropoulos, A, Srinivasan, J, Suzuki, H, Tankisi, H, Tigner, D, Twydell, Pt, van Damme, P, van der Kooi AJ, van Dijk GW, van der Ree, T, van Koningsveld, R, Varrato, Jd, Vermeij, Fh, Visser, Lh, Vytopil, Mv, Waheed, W, Wilken, M, Wilkerson, C, Wirtz, Pw, Yamagishi, Y, Zhou, L, Zivkovic, S., Doets, A, Verboon, C, van den Berg, B, Harbo, T, Cornblath, D, Willison, H, Islam, Z, Attarian, S, Barroso, F, Bateman, K, Benedetti, L, van den Bergh, P, Casasnovas, C, Cavaletti, G, Chavada, G, Claeys, K, Dardiotis, E, Davidson, A, van Doorn, P, Feasby, T, Galassi, G, Gorson, K, Hartung, H, Hsieh, S, Hughes, R, Illa, I, Islam, B, Kusunoki, S, Kuwabara, S, Lehmann, H, Miller, J, Mohammad, Q, Monges, S, Nobile Orazio, E, Pardo, J, Pereon, Y, Rinaldi, S, Querol, L, Reddel, S, Reisin, R, Shahrizaila, N, Sindrup, S, Waqar, W, Jacobs, B, Neurology, AII - Infectious diseases, AII - Inflammatory diseases, ANS - Neuroinfection & -inflammation, Immunology, UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (SLuc) Service de neurologie

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, clinical course, Guillain-Barre Syndrome, 03 medical and health sciences, Young Adult, 0302 clinical medicine, axonal degeneration, demyelination, outcome, polyradiculoneuropathy, Internal medicine, Severity of illness, medicine, Humans, 030212 general & internal medicine, Young adult, Child, Geographic difference, Aged, Aged, 80 and over, Guillain-Barre syndrome, Polyradiculoneuropathy, Overlap syndrome, Middle Aged, medicine.disease, Regional variation, Child, Preschool, neurology, Settore MED/26 - Neurologia, Female, Neurology (clinical), 030217 neurology & neurosurgery, Cohort study, polyradiculoneuropathy, demyelination, axonal degeneration, clinical course, outcome
Abstract

Guillain-Barré syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barré syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barré Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barré syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barré syndrome was observed in patients from all countries participating in the International Guillain-Barré Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barré syndrome subtypes: 'Europe/Americas', 'Asia' (without Bangladesh), and 'Bangladesh'. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barré overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (n = 33/573, 6%) and other Asian countries (n = 4/65, 6%) (P < 0.001). In all regions, patients with the axonal subtype were younger, had fewer sensory deficits, and showed a trend towards poorer recovery compared to patients with the demyelinating subtype. The proportion of patients able to walk unaided after 1 year varied between Asia (n = 31/34, 91%), Europe/Americas (n = 334/404, 83%) and Bangladesh (n = 67/97, 69%) (P = 0.003). A similar variation was seen for mortality, being higher in Bangladesh (n = 19/114, 17%) than in Europe/Americas (n = 23/486, 5%) and Asia (n = 1/45, 2%) (P < 0.001). This study showed that factors related to geography have a major influence on clinical phenotype, disease severity, electrophysiological subtype, and outcome of Guillain-Barré syndrome.

Published
2018

132. Serum neurofilament heavy chains as early marker of motor neuron degeneration

Author

De Schaepdryver, Maxim, primary, Goossens, Janne, additional, De Meyer, Steffi, additional, Jeromin, Andreas, additional, Masrori, Pegah, additional, Brix, Britta, additional, Claeys, Kristl G., additional, Schaeverbeke, Jolien, additional, Adamczuk, Katarzyna, additional, Vandenberghe, Rik, additional, Van Damme, Philip, additional, and Poesen, Koen, additional

Published
2019
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134. AB0696 DETECTION OF COEXISTING MYOSITIS-SPECIFIC AUTOANTIBODIES WITH LINE AND DOT IMMUNOASSAYS IN PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHIES

Author

Vulsteke, Jean-Baptiste, primary, Bossuyt, Xavier, additional, Claeys, Kristl G., additional, Dillaerts, Doreen, additional, Vanhorebeek, Nele, additional, Poesen, Koen, additional, Lenaerts, Jan, additional, Westhovens, Rene, additional, Damme, Philip Van, additional, Blockmans, Daniel, additional, Haes, Petra De, additional, and Langhe, Ellen De, additional

Published
2019
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135. Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies

Author

Dohrn, Maike F, Glöckle, Nicola, Mulahasanovic, Lejla, Heller, Corina, Mohr, Julia, Bauer, Christine, Riesch, Erik, Becker, Andrea, Battke, Florian, Hörtnagel, Konstanze, Hornemann, Thorsten, Suriyanarayanan, Saranya, Blankenburg, Markus, Schulz, Jörg B, Claeys, Kristl G, Gess, Burkhard, Katona, Istvan, Ferbert, Andreas, Vittore, Debora, Grimm, Alexander, Wolking, Stefan, Schöls, Ludger, Lerche, Holger, Korenke, G Christoph, Fischer, Dirk, Schrank, Bertold, Kotzaeridou, Urania, Kurlemann, Gerhard, Dräger, Bianca, Schirmacher, Anja, et al, and University of Zurich

Subjects
1303 Biochemistry, 540 Chemistry, 2804 Cellular and Molecular Neuroscience, 610 Medicine & health, 10038 Institute of Clinical Chemistry
Published
2017

136. Comprehensive analysis of the mutation spectrum in 301 German ALS families

Author

Mueller, Kathrin, Brenner, David, Weydt, Patrick, Meyer, Thomas, Grehl, Torsten, Petri, Susanne, Grosskreutz, Julian, Schuster, Joachim, Volk, Alexander E., Borck, Guntram, Kubisch, Christian, Klopstock, Thomas, Zeller, Daniel, Jablonka, Sibylle, Sendtner, Michael, Klebe, Stephan, Knehr, Antje, Guenther, Kornelia, Weis, Joachim, Claeys, Kristl G., Schrank, Berthold, Sperfeld, Anne-Dorte, Huebers, Annemarie, Otto, Markus, Dorst, Johannes, Meitinger, Thomas, Strom, Tim M., Andersen, Peter M., Ludolph, Albert C., Weishaupt, Jochen H., Mueller, Kathrin, Brenner, David, Weydt, Patrick, Meyer, Thomas, Grehl, Torsten, Petri, Susanne, Grosskreutz, Julian, Schuster, Joachim, Volk, Alexander E., Borck, Guntram, Kubisch, Christian, Klopstock, Thomas, Zeller, Daniel, Jablonka, Sibylle, Sendtner, Michael, Klebe, Stephan, Knehr, Antje, Guenther, Kornelia, Weis, Joachim, Claeys, Kristl G., Schrank, Berthold, Sperfeld, Anne-Dorte, Huebers, Annemarie, Otto, Markus, Dorst, Johannes, Meitinger, Thomas, Strom, Tim M., Andersen, Peter M., Ludolph, Albert C., and Weishaupt, Jochen H.

Abstract

Objectives Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions. Methods Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families. Results 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes. Conclusions We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.

Published
2018
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137. Regional variation of Guillain-Barré syndrome.

Author

UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Doets, Alex Y, Verboon, Christine, van den Berg, Bianca, Harbo, Thomas, Cornblath, David R, Willison, Hugh J, Islam, Zhahirul, Attarian, Shahram, Barroso, Fabio A, Bateman, Kathleen, Benedetti, Luana, Van den Bergh, Peter, Casasnovas, Carlos, Cavaletti, Guido, Chavada, Govindsinh, Claeys, Kristl G, Dardiotis, Efthimios, Davidson, Amy, van Doorn, Pieter A, Feasby, Tom E, Galassi, Giuliana, Gorson, Kenneth C, Hartung, Hans-Peter, Hsieh, Sung-Tsang, Hughes, Richard A C, Illa, Isabel, Islam, Badrul, Kusunoki, Susumu, Kuwabara, Satoshi, Lehmann, Helmar C, Miller, James A L, Mohammad, Quazi Deen, Monges, Soledad, Nobile Orazio, Eduardo, Pardo, Julio, Pereon, Yann, Rinaldi, Simon, Querol, Luis, Reddel, Stephen W, Reisin, Ricardo C, Shahrizaila, Nortina, Sindrup, Soren H, Waqar, Waheed, Jacobs, Bart C, IGOS Consortium, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Doets, Alex Y, Verboon, Christine, van den Berg, Bianca, Harbo, Thomas, Cornblath, David R, Willison, Hugh J, Islam, Zhahirul, Attarian, Shahram, Barroso, Fabio A, Bateman, Kathleen, Benedetti, Luana, Van den Bergh, Peter, Casasnovas, Carlos, Cavaletti, Guido, Chavada, Govindsinh, Claeys, Kristl G, Dardiotis, Efthimios, Davidson, Amy, van Doorn, Pieter A, Feasby, Tom E, Galassi, Giuliana, Gorson, Kenneth C, Hartung, Hans-Peter, Hsieh, Sung-Tsang, Hughes, Richard A C, Illa, Isabel, Islam, Badrul, Kusunoki, Susumu, Kuwabara, Satoshi, Lehmann, Helmar C, Miller, James A L, Mohammad, Quazi Deen, Monges, Soledad, Nobile Orazio, Eduardo, Pardo, Julio, Pereon, Yann, Rinaldi, Simon, Querol, Luis, Reddel, Stephen W, Reisin, Ricardo C, Shahrizaila, Nortina, Sindrup, Soren H, Waqar, Waheed, Jacobs, Bart C, and IGOS Consortium

Abstract

Guillain-Barré syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barré syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barré Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barré syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barré syndrome was observed in patients from all countries participating in the International Guillain-Barré Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barré syndrome subtypes: 'Europe/Americas', 'Asia' (without Bangladesh), and 'Bangladesh'. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barré overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (

Published
2018

138. Implementing Motor Unit Number Index (MUNIX) in a large clinical trial: Real world experience from 27 centres

Author

ZL Neuromusculaire Ziekten Medisch, Neuwirth, Christoph, Braun, Nathalie, Claeys, Kristl G., Bucelli, Robert, Fournier, Christina, Bromberg, Mark, Petri, Susanne, Goedee, Stephan, Lenglet, Timothée, Leppanen, Ron, Canosa, Antonio, Goodman, Ira, Al-Lozi, Muhammad, Ohkubo, Takuya, Hübers, Annemarie, Atassi, Nazem, Abrahao, Agessandro, Funke, Andreas, Appelfeller, Martin, Tümmler, Anke, Finegan, Eoin, Glass, Jonathan D., Babu, Suma, Ladha, Shafeeq S., Kwast-Rabben, Olga, Juntas-Morales, Raul, Coffey, Amina, Chaudhry, Vinay, Vu, Tuan, Saephanh, Chow, Newhard, Colleen, Zakrzewski, Marion, Rosier, Esther, Hamel, Nancy, Raheja, Divisha, Raaijman, Jesper, Ferguson, Toby, Weber, Markus, ZL Neuromusculaire Ziekten Medisch, Neuwirth, Christoph, Braun, Nathalie, Claeys, Kristl G., Bucelli, Robert, Fournier, Christina, Bromberg, Mark, Petri, Susanne, Goedee, Stephan, Lenglet, Timothée, Leppanen, Ron, Canosa, Antonio, Goodman, Ira, Al-Lozi, Muhammad, Ohkubo, Takuya, Hübers, Annemarie, Atassi, Nazem, Abrahao, Agessandro, Funke, Andreas, Appelfeller, Martin, Tümmler, Anke, Finegan, Eoin, Glass, Jonathan D., Babu, Suma, Ladha, Shafeeq S., Kwast-Rabben, Olga, Juntas-Morales, Raul, Coffey, Amina, Chaudhry, Vinay, Vu, Tuan, Saephanh, Chow, Newhard, Colleen, Zakrzewski, Marion, Rosier, Esther, Hamel, Nancy, Raheja, Divisha, Raaijman, Jesper, Ferguson, Toby, and Weber, Markus

Published
2018

139. Limb girdle muscular dystrophy due to mutations in POMT2

Author

Østergaard, Sofie Thurø, Johnson, Katherine, Stojkovic, Tanya, Krag, Thomas, De Ridder, Willem, De Jonghe, Peter, Baets, Jonathan, Claeys, Kristl G, Fernández-Torrón, Roberto, Phillips, Lauren, Topf, Ana, Colomer, Jaume, Nafissi, Shahriar, Jamal-Omidi, Shirin, Bouchet-Seraphin, Celine, Leturcq, France, MacArthur, Daniel G, Lek, Monkol, Xu, Liwen, Nelson, Isabelle, Straub, Volker, Vissing, John, Østergaard, Sofie Thurø, Johnson, Katherine, Stojkovic, Tanya, Krag, Thomas, De Ridder, Willem, De Jonghe, Peter, Baets, Jonathan, Claeys, Kristl G, Fernández-Torrón, Roberto, Phillips, Lauren, Topf, Ana, Colomer, Jaume, Nafissi, Shahriar, Jamal-Omidi, Shirin, Bouchet-Seraphin, Celine, Leturcq, France, MacArthur, Daniel G, Lek, Monkol, Xu, Liwen, Nelson, Isabelle, Straub, Volker, and Vissing, John

Abstract

BACKGROUND: Mutations in the gene coding for protein O-mannosyl-transferase 2 (POMT2) are known to cause severe congenital muscular dystrophy, and recently, mutations in POMT2 have also been linked to a milder limb-girdle muscular dystrophy (LGMD) phenotype, named LGMD type 2N (LGMD2N). Only four cases have been reported so far.ClinicalTrials.gov ID: NCT02759302 METHODS: We report 12 new cases of LGMD2N, aged 18-63 years. Muscle involvement was assessed by MRI, muscle strength testing and muscle biopsy analysis. Other clinical features were also recorded.RESULTS: Presenting symptoms were difficulties in walking, pain during exercise, delayed motor milestones and learning disabilities at school. All had some degree of cognitive impairment. Brain MRIs were abnormal in 3 of 10 patients, showing ventricular enlargement in one, periventricular hyperintensities in another and frontal atrophy of the left hemisphere in a third patient. Most affected muscle groups were hip and knee flexors and extensors on strength testing. On MRI, most affected muscles were hamstrings followed by paraspinal and gluteal muscles. The 12 patients in our cohort carried 11 alleles with known mutations, whereas 11 novel mutations accounted for the remaining 13 alleles.CONCLUSION: We describe the first cohort of patients with LGMD2N and show that unlike other LGMD types, all patients had cognitive impairment. Primary muscle involvement was found in hamstring, paraspinal and gluteal muscles on MRI, which correlated well with reduced muscle strength in hip and knee flexors and extensors. The study expands the mutational spectrum for LGMD2N, with the description of 11 novel POMT2 mutations in the association with LGMD2N.CLINICAL TRIAL REGISTRATION: NCT02759302.

Published
2018

140. Clinical and biometrical 12-month follow-up in patients after reconstruction of the sural nerve biopsy defect by the collagen-based nerve guide Neuromaix

Author

Bozkurt, Ahmet, Claeys, Kristl G., Schrading, Simone, Rödler, Jana V., Altinova, Haktan, Schulz, Jörg B., Weis, Joachim, Pallua, Norbert, and van Neerven, Sabien G. A.

Subjects
Adult, Male, Tissue Scaffolds, Guided Tissue Regeneration, Research, lcsh:R, lcsh:Medicine, Middle Aged, Sural Nerve, Peripheral Nerve Injuries, Humans, Female, Collagen, ddc:610, Aged
Abstract

European journal of medical research 22(1), 34 (2017). doi:10.1186/s40001-017-0279-4, Published by BioMed Central, London

Published
2017

141. Congenital myopathies: an update.

Author

Claeys, Kristl G

Subjects
*NEMALINE myopathy, *MUSCLE diseases, *NEUROMUSCULAR diseases, *GENETIC disorders, *NUCLEOTIDE sequencing, *GENE therapy
Abstract

Congenital myopathies comprise a clinical, histopathological, and genetic heterogeneous group of rare hereditary muscle diseases that are defined by architectural abnormalities in the muscle fibres. They are subdivided by the predominant structural pathological change on muscle biopsy, resulting in five subgroups: (1) core myopathies; (2) nemaline myopathies; (3) centronuclear myopathies; (4) congenital fibre type disproportion myopathy; and (5) myosin storage myopathy. Besides the clinical features, muscle biopsy, muscle imaging, and genetic analyses are essential in the diagnosis of congenital myopathies. Using next‐generation sequencing techniques, a large number of new genes are being identified as the cause of congenital myopathies as well as new mutations in known genes, broadening the phenotype–genotype spectrum of congenital myopathies. Management is performed by a multidisciplinary team specialized in neuromuscular disorders, where the (paediatric) neurologist has an essential role. To date, only supportive treatment is available, but novel pathomechanisms are being discovered and gene therapies are being explored. What this paper adds: Many new genes are being identified in congenital myopathies, broadening the phenotype–genotype spectrum.Management is performed by a multidisciplinary team specialized in neuromuscular disorders. What this paper adds: Many new genes are being identified in congenital myopathies, broadening the phenotype–genotype spectrum.Management is performed by a multidisciplinary team specialized in neuromuscular disorders. This article's abstract has been translated into Spanish and Portuguese. Follow the links from the abstract to view the translations. [ABSTRACT FROM AUTHOR]

Published
2020
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142. The Latin American experience with a next generation sequencing genetic panel for recessive limb-girdle muscular weakness and Pompe disease.

Author

Bevilacqua, Jorge A., Guecaimburu Ehuletche, Maria del Rosario, Perna, Abayuba, Dubrovsky, Alberto, Franca, Marcondes C., Vargas, Steven, Hegde, Madhuri, Claeys, Kristl G., Straub, Volker, Daba, Nadia, Faria, Roberta, Periquet, Magali, Sparks, Susan, Thibault, Nathan, Araujo, Roberto, and Franca, Marcondes C Jr

Subjects
GLYCOGEN storage disease type II, MUSCLE weakness, GENETIC disorders, LIMB-girdle muscular dystrophy, SHOULDER girdle, NEUROMUSCULAR diseases
Abstract

Background: Limb-girdle muscular dystrophy (LGMD) is a group of neuromuscular disorders of heterogeneous genetic etiology with more than 30 directly related genes. LGMD is characterized by progressive muscle weakness involving the shoulder and pelvic girdles. An important differential diagnosis among patients presenting with proximal muscle weakness (PMW) is late-onset Pompe disease (LOPD), a rare neuromuscular glycogen storage disorder, which often presents with early respiratory insufficiency in addition to PMW. Patients with PMW, with or without respiratory symptoms, were included in this study of Latin American patients to evaluate the profile of variants for the included genes related to LGMD recessive (R) and LOPD and the frequency of variants in each gene among this patient population.Results: Over 20 institutions across Latin America (Brazil, Argentina, Peru, Ecuador, Mexico, and Chile) enrolled 2103 individuals during 2016 and 2017. Nine autosomal recessive LGMDs and Pompe disease were investigated in a 10-gene panel (ANO5, CAPN3, DYSF, FKRP, GAA, SGCA, SGCB, SGCD, SGCG, TCAP) based on reported disease frequency in Latin America. Sequencing was performed with Illumina's NextSeq500 and variants were classified according to ACMG guidelines; pathogenic and likely pathogenic were treated as one category (P) and variants of unknown significance (VUS) are described. Genetic variants were identified in 55.8% of patients, with 16% receiving a definitive molecular diagnosis; 39.8% had VUS. Nine patients were identified with Pompe disease.Conclusions: The results demonstrate the effectiveness of this targeted genetic panel and the importance of including Pompe disease in the differential diagnosis for patients presenting with PMW. [ABSTRACT FROM AUTHOR]

Published
2020
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143. Implementing Motor Unit Number Index (MUNIX) in a large clinical trial: Real world experience from 27 centres

Author

Neuwirth, Christoph, primary, Braun, Nathalie, additional, Claeys, Kristl G., additional, Bucelli, Robert, additional, Fournier, Christina, additional, Bromberg, Mark, additional, Petri, Susanne, additional, Goedee, Stephan, additional, Lenglet, Timothée, additional, Leppanen, Ron, additional, Canosa, Antonio, additional, Goodman, Ira, additional, Al-Lozi, Muhammad, additional, Ohkubo, Takuya, additional, Hübers, Annemarie, additional, Atassi, Nazem, additional, Abrahao, Agessandro, additional, Funke, Andreas, additional, Appelfeller, Martin, additional, Tümmler, Anke, additional, Finegan, Eoin, additional, Glass, Jonathan D., additional, Babu, Suma, additional, Ladha, Shafeeq S., additional, Kwast-Rabben, Olga, additional, Juntas-Morales, Raul, additional, Coffey, Amina, additional, Chaudhry, Vinay, additional, Vu, Tuan, additional, Saephanh, Chow, additional, Newhard, Colleen, additional, Zakrzewski, Marion, additional, Rosier, Esther, additional, Hamel, Nancy, additional, Raheja, Divisha, additional, Raaijman, Jesper, additional, Ferguson, Toby, additional, and Weber, Markus, additional

Published
2018
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145. Comprehensive analysis of the mutation spectrum in 301 German ALS families

Author

Müller, Kathrin, primary, Brenner, David, additional, Weydt, Patrick, additional, Meyer, Thomas, additional, Grehl, Torsten, additional, Petri, Susanne, additional, Grosskreutz, Julian, additional, Schuster, Joachim, additional, Volk, Alexander E, additional, Borck, Guntram, additional, Kubisch, Christian, additional, Klopstock, Thomas, additional, Zeller, Daniel, additional, Jablonka, Sibylle, additional, Sendtner, Michael, additional, Klebe, Stephan, additional, Knehr, Antje, additional, Günther, Kornelia, additional, Weis, Joachim, additional, Claeys, Kristl G, additional, Schrank, Berthold, additional, Sperfeld, Anne-Dorte, additional, Hübers, Annemarie, additional, Otto, Markus, additional, Dorst, Johannes, additional, Meitinger, Thomas, additional, Strom, Tim M, additional, Andersen, Peter M, additional, Ludolph, Albert C, additional, and Weishaupt, Jochen H, additional

Published
2018
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146. Detection of myositis-specific antibodies

Author

Vulsteke, Jean-Baptiste, primary, De Langhe, Ellen, additional, Claeys, Kristl G, additional, Dillaerts, Doreen, additional, Poesen, Koen, additional, Lenaerts, Jan, additional, Westhovens, René, additional, Van Damme, Philip, additional, Blockmans, Daniel, additional, De Haes, Petra, additional, and Bossuyt, Xavier, additional

Published
2018
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148. PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease

Author

Azzedine, Hamid, Zavadakova, Petra, Planté-Bordeneuve, Violaine, Vaz Pato, Maria, Pinto, Nuno, Bartesaghi, Luca, Zenker, Jennifer, Poirot, Olivier, Bernard-Marissal, Nathalie, Arnaud Gouttenoire, Estelle, Cartoni, Romain, Title, Alexandra, Venturini, Giulia, Médard, Jean-Jacques, Makowski, Edward, Schöls, Ludger, Claeys, Kristl G., Stendel, Claudia, Roos, Andreas, Weis, Joachim, Dubourg, Odile, Leal Loureiro, José, Stevanin, Giovanni, Said, Gérard, Amato, Anthony, Baraban, Jay, LeGuern, Eric, Senderek, Jan, Rivolta, Carlo, Chrast, Roman, Azzedine, Hamid, Zavadakova, Petra, Planté-Bordeneuve, Violaine, Vaz Pato, Maria, Pinto, Nuno, Bartesaghi, Luca, Zenker, Jennifer, Poirot, Olivier, Bernard-Marissal, Nathalie, Arnaud Gouttenoire, Estelle, Cartoni, Romain, Title, Alexandra, Venturini, Giulia, Médard, Jean-Jacques, Makowski, Edward, Schöls, Ludger, Claeys, Kristl G., Stendel, Claudia, Roos, Andreas, Weis, Joachim, Dubourg, Odile, Leal Loureiro, José, Stevanin, Giovanni, Said, Gérard, Amato, Anthony, Baraban, Jay, LeGuern, Eric, Senderek, Jan, Rivolta, Carlo, and Chrast, Roman

Abstract

Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells

Published
2017

149. Metabolic syndrome, neurotoxic 1-deoxysphingolipids and nervous tissue inflammation in Chronic Idiopathic Axonal Polyneuropathy (CIAP)

Author

Hube, Larissa, Dohrn, Maike F, Karsai, Gergely, Hirshman, Sarah, Van Damme, Philip, Schulz, Jörg B, Weis, Joachim, Hornemann, Thorsten, Claeys, Kristl G, Hube, Larissa, Dohrn, Maike F, Karsai, Gergely, Hirshman, Sarah, Van Damme, Philip, Schulz, Jörg B, Weis, Joachim, Hornemann, Thorsten, and Claeys, Kristl G

Abstract

AIM Chronic idiopathic axonal polyneuropathy (CIAP) is a slowly progressive, predominantly sensory, axonal polyneuropathy, with no aetiology being identified despite extensive investigations. We studied the potential role of the metabolic syndrome, neurotoxic 1-deoxysphingolipids (1-deoxySLs), microangiopathy and inflammation in sural nerve biopsies. METHODS We included 30 CIAP-patients, 28 with diabetic distal symmetrical polyneuropathy (DSPN) and 31 healthy controls. We assessed standardised scales, tested for the metabolic syndrome, measured 1-deoxySLs in plasma, performed electroneurography and studied 17 sural nerve biopsies (10 CIAP; 7 DSPN). RESULTS One third of the CIAP-patients had a metabolic syndrome, significantly less frequent than DSPN-patients (89%). Although the metabolic syndrome was not significantly more prevalent in CIAP compared to healthy controls, hypercholesterolemia did occur significantly more frequent. 1-deoxySLs were significantly and equally elevated in both patient groups compared to healthy controls. Mean basal lamina thickness of small endoneurial vessels and the number of CD68- or CD8-positive cells in biopsies of CIAP- and DSPN-patients did not differ significantly. However, the number of leucocyte-common-antigen positive cells was significantly increased in CIAP. CONCLUSIONS A non-significant trend towards a higher occurrence of the metabolic syndrome in CIAP-patients compared to healthy controls was found. 1-deoxySLs were significantly increased in plasma of CIAP-patients. Microangiopathy and an inflammatory component were present in CIAP-biopsies.

Published
2017

150. Sporadic late-onset nemaline myopathy: clinico-pathological characteristics and review of 76 cases

Author

Schnitzler, Lukas J, Schreckenbach, Tobias, Nadaj-Pakleza, Aleksandra, Stenzel, Werner, Rushing, Elisabeth J, Van Damme, Philip, Ferbert, Andreas, Petri, Susanne, Hartmann, Christian, Bornemann, Antje, Meisel, Andreas, Petersen, Jens A, Tousseyn, Thomas, Thal, Dietmar R, Reimann, Jens, De Jonghe, Peter, Martin, Jean-Jacques, Van den Bergh, Peter Y, Schulz, Jörg B, Weis, Joachim, Claeys, Kristl G, Schnitzler, Lukas J, Schreckenbach, Tobias, Nadaj-Pakleza, Aleksandra, Stenzel, Werner, Rushing, Elisabeth J, Van Damme, Philip, Ferbert, Andreas, Petri, Susanne, Hartmann, Christian, Bornemann, Antje, Meisel, Andreas, Petersen, Jens A, Tousseyn, Thomas, Thal, Dietmar R, Reimann, Jens, De Jonghe, Peter, Martin, Jean-Jacques, Van den Bergh, Peter Y, Schulz, Jörg B, Weis, Joachim, and Claeys, Kristl G

Published
2017

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