50 results on '"Smets, Katrien"'
Search Results
2. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial
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Schöls, Ludger, Rattay, Tim W, Martus, Peter, Meisner, Christoph, Baets, Jonathan, Fischer, Imma, Jägle, Christine, Fraidakis, Matthew J, Martinuzzi, Andrea, Saute, Jonas Alex, Scarlato, Marina, Antenora, Antonella, Stendel, Claudia, Höflinger, Philip, Lourenco, Charles Marques, Abreu, Lisa, Smets, Katrien, Paucar, Martin, Deconinck, Tine, Bis, Dana M, Wiethoff, Sarah, Bauer, Peter, Arnoldi, Alessia, Marques, Wilson, Jardim, Laura Bannach, Hauser, Stefan, Criscuolo, Chiara, Filla, Alessandro, Züchner, Stephan, Bassi, Maria Teresa, Klopstock, Thomas, De Jonghe, Peter, Björkhem, Ingemar, and Schüle, Rebecca
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- 2017
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3. The spectrum of epilepsy caused by POLG mutations
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Janssen, Wouter, Quaegebeur, Annelies, Van Goethem, Gert, Ann, Löfgren, Smets, Katrien, Vandenberghe, Rik, and Van Paesschen, Wim
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- 2016
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4. TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
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van der Zee, Julie, Gijselinck, Ilse, Van Mossevelde, Sara, Perrone, Federica, Dillen, Lubina, Heeman, Bavo, Bäumer, Veerle, Engelborghs, Sebastiaan, De Bleecker, Jan, Baets, Jonathan, Gelpi, Ellen, RojasGarcía, Ricardo, Clarimón, Jordi, Lleó, Alberto, DiehlSchmid, Janine, Alexopoulos, Panagiotis, Perneczky, Robert, Synofzik, Matthis, Just, Jennifer, Schöls, Ludger, Graff, Caroline, Thonberg, Håkan, Borroni, Barbara, Padovani, Alessandro, Jordanova, Albena, Sarafov, Stayko, Tournev, Ivailo, de Mendonça, Alexandre, MiltenbergerMiltényi, Gabriel, Simões do Couto, Frederico, Ramirez, Alfredo, Jessen, Frank, Heneka, Michael T., GómezTortosa, Estrella, Danek, Adrian, Cras, Patrick, Vandenberghe, Rik, De Jonghe, Peter, De Deyn, Peter P., Sleegers, Kristel, Cruts, Marc, Van Broeckhoven, Christine, Goeman, Johan, Nuytten, Dirk, Smets, Katrien, Robberecht, Wim, Damme, Philip Van, Bleecker, Jan De, Santens, Patrick, Dermaut, Bart, Versijpt, Jan, Michotte, Alex, Ivanoiu, Adrian, Deryck, Olivier, Bergmans, Bruno, Delbeck, Jean, Bruyland, Marc, Willems, Christiana, Salmon, Eric, Pastor, Pau, OrtegaCubero, Sara, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Hernández, Isabel, Boada, Mercè, Ruiz, Agustín, Sorbi, Sandro, Nacmias, Benedetta, Bagnoli, Silvia, Sorbi, Sandro, SanchezValle, Raquel, Llado, Albert, Santana, Isabel, Rosário Almeida, Maria, Frisoni, Giovanni B, Maetzler, Walter, Matej, Radoslav, Fraidakis, Matthew J., Kovacs, Gabor G., Fabrizi, Gian Maria, and Testi, Silvia
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- 2017
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5. Investigating the role of ALS genes CHCHD10 and TUBA4A in Belgian FTD-ALS spectrum patients
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Nuytten, Dirk, Smets, Katrien, Versijpt, Jan, Michotte, Alex, Ivanoiu, Adrian, Deryck, Olivier, Bergmans, Bruno, Delbeck, Jean, Bruyland, Marc, Willems, Christiana, Salmon, Eric, Perrone, Federica, Nguyen, Hung Phuoc, Van Mossevelde, Sara, Moisse, Matthieu, Sieben, Anne, Santens, Patrick, De Bleecker, Jan, Vandenbulcke, Mathieu, Engelborghs, Sebastiaan, Baets, Jonathan, Cras, Patrick, Vandenberghe, Rik, De Jonghe, Peter, De Deyn, Peter P., Martin, Jean-Jacques, Van Damme, Philip, Van Broeckhoven, Christine, and van der Zee, Julie
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- 2017
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6. Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration
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van der Zee, Julie, Van Langenhove, Tim, Kovacs, Gabor G., Dillen, Lubina, Deschamps, William, Engelborghs, Sebastiaan, Matěj, Radoslav, Vandenbulcke, Mathieu, Sieben, Anne, Dermaut, Bart, Smets, Katrien, Van Damme, Philip, Merlin, Céline, Laureys, Annelies, Van Den Broeck, Marleen, Mattheijssens, Maria, Peeters, Karin, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Borroni, Barbara, Padovani, Alessandro, Archetti, Silvana, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Hernández, Isabel, Boada, Mercè, Ruiz, Agustín, de Mendonça, Alexandre, Miltenberger-Miltényi, Gabriel, do Couto, Frederico Simões, Sorbi, Sandro, Nacmias, Benedetta, Bagnoli, Silvia, Graff, Caroline, Chiang, Huei-Hsin, Thonberg, Håkan, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Frisoni, Giovanni B., Bonvicini, Christian, Synofzik, Matthis, Maetzler, Walter, vom Hagen, Jennifer Müller, Schöls, Ludger, Haack, Tobias B., Strom, Tim M., Prokisch, Holger, Dols-Icardo, Oriol, Clarimón, Jordi, Lleó, Alberto, Santana, Isabel, Almeida, Maria Rosário, Santiago, Beatriz, Heneka, Michael T., Jessen, Frank, Ramirez, Alfredo, Sanchez-Valle, Raquel, Llado, Albert, Gelpi, Ellen, Sarafov, Stayko, Tournev, Ivailo, Jordanova, Albena, Parobkova, Eva, Fabrizi, Gian Maria, Testi, Silvia, Salmon, Eric, Ströbel, Thomas, Santens, Patrick, Robberecht, Wim, De Jonghe, Peter, Martin, Jean-Jacques, Cras, Patrick, Vandenberghe, Rik, De Deyn, Peter Paul, Cruts, Marc, Sleegers, Kristel, and Van Broeckhoven, Christine
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- 2014
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7. Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions
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Denora, Paola S., Smets, Katrien, Zolfanelli, Federica, Ceuterick-de Groote, Chantal, Casali, Carlo, Deconinck, Tine, Sieben, Anne, Gonzales, Michael, Zuchner, Stephan, Darios, Frédéric, Peeters, Dirk, Brice, Alexis, Malandrini, Alessandro, De Jonghe, Peter, Santorelli, Filippo M., Stevanin, Giovanni, Martin, Jean-Jacques, and El Hachimi, Khalid H.
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- 2016
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8. SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study
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Synofzik, Matthis, Smets, Katrien, Mallaret, Martial, Di Bella, Daniela, Gallenmüller, Constanze, Baets, Jonathan, Schulze, Martin, Magri, Stefania, Sarto, Elisa, Mustafa, Mona, Deconinck, Tine, Haack, Tobias, Züchner, Stephan, Gonzalez, Michael, Timmann, Dagmar, Stendel, Claudia, Klopstock, Thomas, Durr, Alexandra, Tranchant, Christine, Sturm, Marc, Hamza, Wahiba, Nanetti, Lorenzo, Mariotti, Caterina, Koenig, Michel, Schöls, Ludger, Schüle, Rebecca, de Jonghe, Peter, Anheim, Mathieu, Taroni, Franco, and Bauer, Peter
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- 2016
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9. First line management of prolonged convulsive seizures in children and adults: good practice points
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De Waele, Liesbeth, Boon, Paul, Ceulemans, Berten, Dan, Bernard, Jansen, Anna, Legros, Benjamin, Leroy, Patricia, Delmelle, Francoise, Ossemann, Michel, De Raedt, Sylvie, Smets, Katrien, Van De Voorde, Patrick, Verhelst, Helene, and Lagae, Lieven
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- 2013
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10. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy
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Reinthaler, Eva M., Lal, Dennis, Lebon, Sebastien, Hildebrand, Michael S., Dahl, Hans-Henrik M., Regan, Brigid M., Feucht, Martha, Steinböck, Hannelore, Neophytou, Birgit, Ronen, Gabriel M., Roche, Laurian, Gruber-Sedlmayr, Ursula, Geldner, Julia, Haberlandt, Edda, Hoffmann, Per, Herms, Stefan, Gieger, Christian, Waldenberger, Melanie, Franke, Andre, Wittig, Michael, Schoch, Susanne, Becker, Albert J., Hahn, Andreas, Männik, Katrin, Toliat, Mohammad R., Winterer, Georg, Lerche, Holger, Nürnberg, Peter, Mefford, Heather, Scheffer, Ingrid E., Berkovic, Samuel F., Beckmann, Jacques S., Sander, Thomas, Jacquemont, Sebastien, Reymond, Alexandre, Zimprich, Fritz, Neubauer, Bernd A., Reinthaler, Eva M., Zimprich, Fritz, Feucht, Martha, Steinböck, Hannelore, Neophytou, Birgit, Geldner, Julia, Gruber-Sedlmayr, Ursula, Haberlandt, Edda, Ronen, Gabriel M., Roche, Laurian, Lal, Dennis, Nürnberg, Peter, Sander, Thomas, Lerche, Holger, Neubauer, Bernd, Zimprich, Fritz, Mörzinger, Martina, Feucht, Martha, Suls, Arvid, Weckhuysen, Sarah, Claes, Lieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Møller, Rikke S, Klitten, Laura L., Hjalgrim, Helle, Møller, Rikke S, Campus, Kiel, Helbig, Ingo, Muhle, Hiltrud, Ostertag, Philipp, von Spiczak, Sarah, Stephani, Ulrich, Nürnberg, Peter, Sander, Thomas, Trucks, Holger, Elger, Christian E., Kleefu-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Gaus, Verena, Janz, Dieter, Sander, Thomas, Schmitz, Bettina, Rosenow, Felix, Klein, Karl Martin, Reif, Philipp S., Oertel, Wolfgang H., Hamer, Hajo M., Becker, Felicitas, Weber, Yvonne, Lerche, Holger, Koeleman, Bobby P.C., de Kovel, Carolien, Lindhout, Dick, Lindhout, Dick, Ameil, Agnès, Andrieux, Joris, Bouquillon, Sonia, Boute, Odile, de Flandre, Jeanne, Cuisset, Jean Marie, Cuvellier, Jean-Christophe, Salengro, Roger, David, Albert, de Vries, Bert, Delrue, Marie-Ange, Doco-Fenzy, Martine, Fernandez, Bridget A., Heron, Delphine, Keren, Boris, Lebel, Robert, Leheup, Bruno, Lewis, Suzanne, Mencarelli, Maria Antonietta, Mignot, Cyril, Minet, Jean-Claude, Moerman, Alexandre, Morice-Picard, Fanny, Mucciolo, Mafalda, Ounap, Katrin, Pasquier, Laurent, Petit, Florence, Ragona, Francesca, Rajcan-Separovic, Evica, Renieri, Alessandra, Rieubland, Claudine, Sanlaville, Damien, Sarrazin, Elisabeth, Shen, Yiping, van Haelst, Mieke, and Silfhout, Anneke Vulto-van
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- 2014
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11. Recommendations for the treatment of epilepsy in adult patients in general practice in Belgium: an update
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Boon, Paul, Engelborghs, Sebastiaan, Hauman, Henri, Jansen, An, Lagae, Lieven, Legros, Benjamin, Ossemann, Michel, Sadzot, Bernard, Smets, Katrien, Urbain, Etienne, and van Rijckevorsel, Kenou
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- 2012
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12. PRRT2 mutations: exploring the phenotypical boundaries
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Djémié, Tania, Weckhuysen, Sarah, Holmgren, Philip, Hardies, Katia, Van Dyck, Tine, Hendrickx, Rik, Schoonjans, An-Sofie, Van Paesschen, Wim, Jansen, Anna C, De Meirleir, Linda, Selim, Laila Abdel Moteleb, Girgis, Marian Y, Buyse, Gunnar, Lagae, Lieven, Smets, Katrien, Smouts, Iris, Claeys, Kristl G, Van den Bergh, Vic, Grisar, Thierry, Blatt, Ilan, Shorer, Zamir, Roelens, Filip, Afawi, Zaid, Helbig, Ingo, Ceulemans, Berten, De Jonghe, Peter, and Suls, Arvid
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- 2014
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13. Meningoencephalitis caused by Streptococcus pneumoniae: a diagnostic and therapeutic challenge: Diagnosis with diffusion-weighted MRI leading to treatment with corticosteroids
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Jorens, Philippe G., Parizel, Paul M., Demey, Hendrik E., Smets, Katrien, Jadoul, Kris, Verbeek, M. M., Wevers, R. A., and Cras, Patrick
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- 2005
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14. KCNQ2 encephalopathy: Emerging phenotype of a neonatal epileptic encephalopathy
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Weckhuysen, Sarah, Mandelstam, Simone, Suls, Arvid, Audenaert, Dominique, Deconinck, Tine, Claes, Lieve R.F., Deprez, Liesbet, Smets, Katrien, Hristova, Dimitrina, Yordanova, Iglika, Jordanova, Albena, Ceulemans, Berten, Jansen, An, Hasaerts, Danièle, Roelens, Filip, Lagae, Lieven, Yendle, Simone, Stanley, Thorsten, Heron, Sarah E., Mulley, John C., Berkovic, Samuel F., Scheffer, Ingrid E., and Peter de Jonghe
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- 2012
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15. The SCN1A Variant Database: a Novel Research and Diagnostic Tool
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Claes, Lieve RF, Deprez, Liesbet, Suls, Arvid, Baets, Jonathan, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, Jordanova, Albena, and De Jonghe, Peter
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- 2009
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16. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31
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Beetz, Christian, Schüle, Rebecca, Deconinck, Tine, Tran-Viet, Khanh-Nhat, Zhu, Hui, Kremer, Berry P. H., Frints, Suzanna G. M., van Zelst-Stams, Wendy A. G., Byrne, Paula, Otto, Susanne, Nygren, Anders O. H., Baets, Jonathan, Smets, Katrien, Ceulemans, Berten, Dan, Bernard, Nagan, Narasimhan, Kassubek, Jan, Klimpe, Sven, Klopstock, Thomas, Stolze, Henning, Smeets, Hubert J. M., Schrander-Stumpel, Constance T. R. M., Hutchinson, Michael, van de Warrenburg, Bart P., Braastad, Corey, Deufel, Thomas, Pericak-Vance, Margaret, Schöls, Ludger, de Jonghe, Peter, and Züchner, Stephan
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- 2008
17. FAHN/SPG35: a narrow phenotypic spectrum across disease classifications
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Rattay, Tim W, primary, Lindig, Tobias, additional, Baets, Jonathan, additional, Smets, Katrien, additional, Deconinck, Tine, additional, Söhn, Anne S, additional, Hörtnagel, Konstanze, additional, Eckstein, Kathrin N, additional, Wiethoff, Sarah, additional, Reichbauer, Jennifer, additional, Döbler-Neumann, Marion, additional, Krägeloh-Mann, Ingeborg, additional, Auer-Grumbach, Michaela, additional, Plecko, Barbara, additional, Münchau, Alexander, additional, Wilken, Bernd, additional, Janauschek, Marc, additional, Giese, Anne-Katrin, additional, De Bleecker, Jan L, additional, Ortibus, Els, additional, Debyser, Martine, additional, Lopez de Munain, Adolfo, additional, Pujol, Aurora, additional, Bassi, Maria Teresa, additional, D’Angelo, Maria Grazia, additional, De Jonghe, Peter, additional, Züchner, Stephan, additional, Bauer, Peter, additional, Schöls, Ludger, additional, and Schüle, Rebecca, additional
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- 2019
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18. Occupational airborne allergic contact dermatitis caused by N -(4-hydroxyphenyl)benzenesulfonamide
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Aerts, Olivier, primary, Mangodt, Evelyne, additional, Smets, Katrien, additional, Mertens, Michelle, additional, Constandt, Lieve, additional, and Goossens, An, additional
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- 2018
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19. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy
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Reinthaler, Eva M., Lal, Dennis, Lebon, Sebastien, Hildebrand, Michael S., Dahl, Hans-Henrik M., Regan, Brigid M., Feucht, Martha, Steinböck, Hannelore, Neophytou, Birgit, Ronen, Gabriel M., Roche, Laurian, Gruber-Sedlmayr, Ursula, Geldner, Julia, Haberlandt, Edda, Hoffmann, Per, Herms, Stefan, Gieger, Christian, Waldenberger, Melanie, Franke, Andre, Wittig, Michael, Schoch, Susanne, Becker, Albert J., Hahn, Andreas, Männik, Katrin, Toliat, Mohammad R., Winterer, Georg, Lerche, Holger, Nürnberg, Peter, Mefford, Heather, Scheffer, Ingrid E., Berkovic, Samuel F., Beckmann, Jacques S., Sander, Thomas, Jacquemont, Sebastien, Reymond, Alexandre, Zimprich, Fritz, Neubauer, Bernd A., Neubauer, Bernd, Mörzinger, Martina, Suls, Arvid, Weckhuysen, Sarah, Claes, Lieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Møller, Rikke S., Klitten, Laura L., Hjalgrim, Helle, Campus, Kiel, Helbig, Ingo, Muhle, Hiltrud, Ostertag, Philipp, von Spiczak, Sarah, Stephani, Ulrich, Trucks, Holger, Elger, Christian E., Kleefuß-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Gaus, Verena, Janz, Dieter, Schmitz, Bettina, Rosenow, Felix, Klein, Karl Martin, Reif, Philipp S., Oertel, Wolfgang H., Hamer, Hajo M., Becker, Felicitas, Weber, Yvonne, Koeleman, Bobby P.C., de Kovel, Carolien, Lindhout, Dick, Ameil, Agnès, Andrieux, Joris, Bouquillon, Sonia, Boute, Odile, de Flandre, Jeanne, Cuisset, Jean Marie, Cuvellier, Jean-Christophe, Salengro, Roger, David, Albert, de Vries, Bert, Delrue, Marie-Ange, Doco-Fenzy, Martine, Fernandez, Bridget A., Heron, Delphine, Keren, Boris, Lebel, Robert, Leheup, Bruno, Lewis, Suzanne, Mencarelli, Maria Antonietta, Mignot, Cyril, Minet, Jean-Claude, Moerman, Alexandre, Morice-Picard, Fanny, Mucciolo, Mafalda, Ounap, Katrin, Pasquier, Laurent, Petit, Florence, Ragona, Francesca, Rajcan-Separovic, Evica, Renieri, Alessandra, Rieubland, Claudine, Sanlaville, Damien, Sarrazin, Elisabeth, Shen, Yiping, van Haelst, Mieke, and Silfhout, Anneke Vulto-van
- Abstract
Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65 046 European population controls (5/393 cases versus 32/65 046 controls; Fisher's exact test P = 2.83 × 10−6, odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10−4). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE
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- 2017
20. Additional file 1: of STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations
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Hayer, Stefanie, Deconinck, Tine, Bender, Benjamin, Smets, Katrien, ZĂźchner, Stephan, Reich, Selina, SchĂśls, Ludger, SchĂźle, Rebecca, Jonghe, Peter De, Baets, Jonathan, and Synofzik, Matthis
- Abstract
Protein network analysis. (DOCX 1176Â kb)
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- 2017
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21. Additional file 2: of STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations
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Hayer, Stefanie, Deconinck, Tine, Bender, Benjamin, Smets, Katrien, Züchner, Stephan, Reich, Selina, Schöls, Ludger, Schüle, Rebecca, Jonghe, Peter De, Baets, Jonathan, and Synofzik, Matthis
- Abstract
Western blots of CHIP in mutation carriers. (DOCX 241 kb)
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- 2017
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22. STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations
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Hayer, Stefanie Nicole, Deconinck, Tine, Bender, Benjamin, Smets, Katrien, Züchner, Stephan, Reich, Selina, Schöls, Ludger, Schüle, Rebecca, De Jonghe, Peter, Baets, Jonathan, and Synofzik, Matthis
- Subjects
Adult ,Male ,Cerebellar Ataxia ,Ubiquitin-Protein Ligases ,diagnostic imaging [Neurodegenerative Diseases] ,genetics [Hypogonadism] ,Neurodegenerative disease ,Gonadotropin-Releasing Hormone ,Magnetic resonance imaging ,metabolism [Ubiquitin-Protein Ligases] ,Protein Domains ,genetics [Gonadotropin-Releasing Hormone] ,Recessive ataxia ,Humans ,Genetics(clinical) ,Pharmacology (medical) ,ddc:610 ,Amino Acid Sequence ,Neurodegeneration ,STUB1 protein, human ,Medicine(all) ,genetics [Ubiquitin-Protein Ligases] ,genetics [Cerebellar Ataxia] ,CHIP ,Hypogonadism ,Research ,pathology [Neurodegenerative Diseases] ,Spastic ataxia ,Neurodegenerative Diseases ,deficiency [Gonadotropin-Releasing Hormone] ,Middle Aged ,Pedigree ,Early onset ataxia ,Gordon Holmes syndrome ,genetics [Neurodegenerative Diseases] ,Mutation ,Early-onset dementia ,Ataxia ,Dementia ,Female ,Human medicine - Abstract
Background CHIP, the protein encoded by STUB1, is a central component of cellular protein homeostasis and interacts with several key proteins involved in the pathogenesis of manifold neurodegenerative diseases. This gives rise to the hypothesis that mutations in STUB1 might cause a far more multisystemic neurodegenerative phenotype than the previously reported cerebellar ataxia syndrome. Methods Whole exome sequencing data-sets from n = 87 index subjects of two ataxia cohorts were screened for individuals with STUB1 mutations. In-depth phenotyping by clinical evaluation and neuroimaging was performed in mutation carriers. Results We identified four novel STUB1 mutations in three affected subjects from two index families (frequency 2/87 = 2.3%). All three subjects presented with a severe multisystemic phenotype including severe dementia, spastic tetraparesis, epilepsy, and autonomic dysfunction in addition to cerebellar ataxia, plus hypogonadism in one index patient. Diffusion tensor imaging revealed degeneration of manifold supra- and infratentorial tracts. Conclusions Our findings provide clinical and imaging support for the notion that CHIP is a crucial converging point of manifold neurodegenerative processes, corresponding with its universal biological function in neurodegeneration. Further, our data reveal the second STUB1 family with ataxia plus hypogonadism reported so far, demonstrating that Gordon Holmes syndrome is indeed a recurrent manifestation of STUB1. However, it does not present in isolation, but as part of a broad multisystemic neurodegenerative process. This supports the notion that STUB1 disease should be conceptualized not by historical or clinical syndromic names, but as a variable multisystemic disease defined by disturbed function of the underlying STUB1 gene, which translates into a multidimensional gradual spectrum of variably associated clinical signs and symptoms. Electronic supplementary material The online version of this article (doi:10.1186/s13023-017-0580-x) contains supplementary material, which is available to authorized users.
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- 2017
23. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial
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Schoels, Ludger Rattay, Tim W. Martus, Peter Meisner, Christoph Baets, Jonathan Fischer, Imma Jaegle, Christine and Fraidakis, Matthew J. Martinuzzi, Andrea Saute, Jonas Alex and Scarlato, Marina Antenora, Antonella Stendel, Claudia and Hoeflinger, Philip Lourenco, Charles Marques Abreu, Lisa and Smets, Katrien Paucar, Martin Deconinck, Tine Bis, Dana M. and Wiethoff, Sarah Bauer, Peter Arnoldi, Alessia Marques, Wilson Jardim, Laura Bannach Hauser, Stefan Criscuolo, Chiara Filla, Alessandro Zuchner, Stephan Bassi, Maria Teresa Klopstock, Thomas De Jonghe, Peter Bjorkhem, Ingemar and Schuele, Rebecca
- Subjects
polycyclic compounds ,lipids (amino acids, peptides, and proteins) - Abstract
SPG5 is a rare subtype of Hereditary Spastic Paraplegia caused by mutations in the oxysterol-7 alpha-hydroxylase gene CYP7B1. Schols et al. study properties of lipid biomarkers in SPG5 and evaluate a treatment strategy targeting oxysterol accumulation in a randomized controlled trial (STOP-SPG5).Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7 alpha-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683-1113] to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.
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- 2017
24. Investigation of GRIN2A in common epilepsy phenotypes
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Lal, Dennis, Steinbrücker, Sandra, Schubert, Julian, Sander, Thomas, Becker, Felicitas, Weber, Yvonne, Lerche, Holger, Thiele, Holger, Krause, Roland, Lehesjoki, Anna Elina, Nürnberg, Peter, Palotie, Aarno, Neubauer, Bernd A., Muhle, Hiltrud, Stephani, Ulrich, Helbig, Ingo, Becker, Albert J., Schoch, Susanne, Hansen, Jörg, Dorn, Thomas, Hohl, Christin, Lüscher, Nicole, von Spiczak, Sarah, Lemke, Johannes R., Zimprich, Fritz, Feucht, Martha, Suls, Arvid, Weckhuysen, Sarah, Claes, Lieve, Deprez, Liesbet, Smets, Katrien, Dyck, Tine Van, Deconinck, Tine, De Jonghe, Peter, Møller, Rikke S., Klitten, Laura L., Hjalgrim, Helle, Campus, Kiel, Ostertag, Philipp, Trucks, Hol ger, Elger, Christian E., Kleefuß-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Gaus, Verena, Janz, Dieter, Schmitz, Bettina, Klein, Karl Martin, Reif, Philipp S., Oertel, Wolfgang H., Hamer, Hajo M., Rosenow, Felix, Kapser, Claudia, Schankin, Christoph J., Koeleman, Bobby P C, de Kovel, Carolien, Lindhout, Dick, Reinthaler, Eva M., Steinboeck, Hannelore, Neo-phytou, Birgit, Geldner, Julia, Gruber-Sedlmayr, Ursula, Haberlandt, Edda, Ronen, Gabriel M., Altmueller, Janine, Nuernberg, Peter, Neubauer, Bernd, Sirén, Auli, Neuroscience Center, Research Programs Unit, Department of Medical and Clinical Genetics, Anna-Elina Lehesjoki / Principal Investigator, Research Programme for Molecular Neurology, Medicum, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Suls, Arvid, Weckhuysen, Sarah, Claes, Godelieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Epicure Consortium, and EuroEPINOMICS-CoGIE Consortium
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Pathology ,Idiopathic generalized epilepsy ,DEPDC5 ,Genotyping Techniques ,CHILDHOOD ,Bioinformatics ,GRIN2A ,3124 Neurology and psychiatry ,Cohort Studies ,Epilepsy ,0302 clinical medicine ,Databases, Genetic ,Medicine ,Copy-number variation ,TERMINOLOGY ,Non-U.S. Gov't ,Temporal lobe epilepsy ,FOCAL EPILEPSIES ,Exome sequencing ,Sanger sequencing ,0303 health sciences ,Research Support, Non-U.S. Gov't ,Phenotype ,Neurology ,symbols ,Epilepsy, Generalized ,medicine.medical_specialty ,DNA Copy Number Variations ,DISORDERS ,Clinical Neurology ,Research Support ,Receptors, N-Methyl-D-Aspartate ,CLASSIFICATION ,Juvenile Absence Epilepsy ,03 medical and health sciences ,symbols.namesake ,Journal Article ,Humans ,Biology ,030304 developmental biology ,business.industry ,MUTATIONS ,Copy number variation ,3112 Neurosciences ,INCLUDING GRIN2A ,medicine.disease ,DELETIONS ,Epilepsy, Absence ,Epilepsy, Temporal Lobe ,Epilepsy syndromes ,Mutation ,SEIZURES ,Neurology (clinical) ,Human medicine ,business ,030217 neurology & neurosurgery - Abstract
Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the more severe phenotypes. This study aimed to explore the phenotypic boundaries of GRIN2A mutations by investigating patients with the two most common epilepsy syndromes: (i) idiopathic generalized epilepsy (IGE) and (ii) temporal lobe epilepsy (TLE). Whole exome sequencing data of 238 patients with IGE as well as Sanger sequencing of 84 patients with TLE were evaluated for GRIN2A sequence alterations. Two additional independent cohorts comprising 1469 IGE and 330 TLE patients were screened for structural deletions (>40 kb) involving GRIN2A. Apart from a presumably benign, non-segregating variant in a patient with juvenile absence epilepsy, neither mutations nor deletions were detected in either cohort. These findings suggest that mutations in GRIN2A preferentially are involved in genetic variance of pediatric IFE and do not contribute significantly to either adult focal epilepsies as TLE or generalized epilepsies. (C) 2015 Elsevier B.V. All rights reserved.
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- 2015
25. A detailed clinical analysis of 13 patients with AUTS2 syndrome further delineates the phenotypic spectrum and underscores the behavioural phenotype
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Beunders, Gea, van de Kamp, Jiddeke, Vasudevan, Pradeep, Morton, Jenny, Smets, Katrien, Kleefstra, Tjitske, de Munnik, Sonja A., Schuurs-Hoeijmakers, Janneke, Ceulemans, Berten, Zollino, Marcella, Hoffjan, Sabine, Wieczorek, Stefan, So, Joyce, Mercer, Leanne, Walker, Tanya, Velsher, Lea, Parker, Michael J., Magee, Alex C., Elffers, Bart, Frank Kooy, R., Yntema, Helger G., Meijers-Heijboer, Elizabeth J., Sistermans, Erik A., The DDD study, DDD study, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and DDD Study
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0301 basic medicine ,Male ,Pediatrics ,Microcephaly ,Haploinsufficiency ,Settore MED/03 - GENETICA MEDICA ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Intellectual disability ,Developmental ,Copy-number variation ,Child ,Genetics (clinical) ,Sequence Deletion ,Genetics ,Psychiatry ,Mental Disorders ,Exons ,Syndrome ,Middle Aged ,Phenotype ,Child, Preschool ,Medical genetics ,Female ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Adult ,medicine.medical_specialty ,Copy-number ,Biology ,Clinical genetics ,03 medical and health sciences ,Young Adult ,Molecular genetics ,Intellectual Disability ,medicine ,Humans ,Genetic Association Studies ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Infant ,Proteins ,medicine.disease ,Cytoskeletal Proteins ,030104 developmental biology ,Mutation ,Autism ,Human medicine ,Transcription Factors - Abstract
Item does not contain fulltext BACKGROUND: AUTS2 syndrome is an 'intellectual disability (ID) syndrome' caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children. METHODS: We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist. RESULTS: All patients have borderline to severe ID/developmental delay, 83-100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5' deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo. CONCLUSIONS: The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.
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- 2016
26. Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48)
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Hirst, Jennifer, Madeo, Marianna, Smets, Katrien, Deconinck, Tine, Baets, Jonathan, and De Jonghe, Peter
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Human medicine - Abstract
Objective: Biallelic mutations in the AP5Z1 gene encoding the AP-5 ζ subunit have been described in a small number of patients with hereditary spastic paraplegia (HSP) (SPG48); we sought to define genotypephenotype correlations in patients with homozygous or compound heterozygous sequence variants predicted to be deleterious. Methods: We performed clinical, radiologic, and pathologic studies in 6 patients with biallelic mutations in AP5Z1. Results: In 4 of the 6 patients, there was complete loss of AP-5 ζ protein. Clinical features encompassed not only prominent spastic paraparesis but also sensory and motor neuropathy, ataxia, dystonia, myoclonus, and parkinsonism. Skin fibroblasts from affected patients tested positive for periodic acid Schiff and autofluorescent storage material, while electron microscopic analysis demonstrated lamellar storage material consistent with abnormal storage of lysosomal material. Conclusions: Our findings expand the spectrum of AP5Z1-associated neurodegenerative disorders and point to clinical and pathophysiologic overlap between autosomal recessive forms of HSP and lysosomal storage disorders.
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- 2016
27. Exploring hereditary ataxia and spasticity in the era of whole exome sequencing
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Smets, Katrien
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Human medicine - Published
- 2016
28. Investigating the role of ALS genes CHCHD10 and TUBA4A in Belgian FTD-ALS spectrum patients
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Perrone, Federica, primary, Nguyen, Hung Phuoc, additional, Van Mossevelde, Sara, additional, Moisse, Matthieu, additional, Sieben, Anne, additional, Santens, Patrick, additional, De Bleecker, Jan, additional, Vandenbulcke, Mathieu, additional, Engelborghs, Sebastiaan, additional, Baets, Jonathan, additional, Cras, Patrick, additional, Vandenberghe, Rik, additional, De Jonghe, Peter, additional, De Deyn, Peter P., additional, Martin, Jean-Jacques, additional, Van Damme, Philip, additional, Van Broeckhoven, Christine, additional, van der Zee, Julie, additional, Nuytten, Dirk, additional, Smets, Katrien, additional, Versijpt, Jan, additional, Michotte, Alex, additional, Ivanoiu, Adrian, additional, Deryck, Olivier, additional, Bergmans, Bruno, additional, Delbeck, Jean, additional, Bruyland, Marc, additional, Willems, Christiana, additional, and Salmon, Eric, additional
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- 2017
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29. Automated non-EEG based seizure detection: Do users have a say?
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Van de Vel, Anouk, primary, Smets, Katrien, additional, Wouters, Kristien, additional, and Ceulemans, Berten, additional
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- 2016
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30. Complicated spastic paraplegia in patients withAP5Z1mutations (SPG48)
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Hirst, Jennifer, primary, Madeo, Marianna, additional, Smets, Katrien, additional, Edgar, James R., additional, Schols, Ludger, additional, Li, Jun, additional, Yarrow, Anna, additional, Deconinck, Tine, additional, Baets, Jonathan, additional, Van Aken, Elisabeth, additional, De Bleecker, Jan, additional, Datiles, Manuel B., additional, Roda, Ricardo H., additional, Liepert, Joachim, additional, Züchner, Stephan, additional, Mariotti, Caterina, additional, De Jonghe, Peter, additional, Blackstone, Craig, additional, and Kruer, Michael C., additional
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- 2016
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31. Interacties tussen valproaat en antidepressiva
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Hermans, B., Van Den Eede, Filip, Smets, Katrien, and Sabbe, Bernard
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Human medicine - Abstract
Aan de hand van een literatuuronderzoek werd nagegaan wat er bekend is over de interacties tussen valproaat en fluoxetine, alsook tussen valproaat en antidepressiva in het algemeen. Er bestaan enkele aanwijzingen voor interacties tussen enerzijds valproaat en anderzijds fluoxetine, amitriptyline, nortriptyline en clomipramine, maar de wetenschappelijke evidentie hiervoor is globaal genomen beperkt en omvat voornamelijk enkele farmacokinetische studies en gevalsbeschrijvingen. Het lijkt desalniettemin raadzaam om bij de combinatie van valproaat en antidepressiva de bloedspiegels te controleren.
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- 2012
32. First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy
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Smets, Katrien, primary, Duarri, Anna, additional, Deconinck, Tine, additional, Ceulemans, Berten, additional, van de Warrenburg, Bart P., additional, Züchner, Stephan, additional, Gonzalez, Michael Anthony, additional, Schüle, Rebecca, additional, Synofzik, Matthis, additional, Van der Aa, Nathalie, additional, De Jonghe, Peter, additional, Verbeek, Dineke S., additional, and Baets, Jonathan, additional
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- 2015
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33. The spectrum of epilepsy caused by POLG mutations
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Janssen, Wouter, primary, Quaegebeur, Annelies, additional, Van Goethem, Gert, additional, Ann, Löfgren, additional, Smets, Katrien, additional, Vandenberghe, Rik, additional, and Van Paesschen, Wim, additional
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- 2015
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34. Opsoclonus-myoclonus syndrome: a clinicopathological confrontation
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Baets, Jonathan, Pals, Philippe, Bergmans, B., Foncke, E., Smets, Katrien, Hauman, H., Vanderwegen, L., and Cras, Patrick
- Published
- 2006
35. Occupational airborne allergic contact dermatitis caused by N‐(4‐hydroxyphenyl)benzenesulfonamide.
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Aerts, Olivier, Mangodt, Evelyne, Smets, Katrien, Mertens, Michelle, Constandt, Lieve, and Goossens, An
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OCCUPATIONAL dermatitis ,ECZEMA ,POLYETHYLENE terephthalate manufacturing ,BENZENESULFONAMIDES ,ALLERGY diagnosis ,CONTACT dermatitis - Abstract
A case study is presented of two male patients, aged 53 years and 58 years, suffering severe dermatitis of the eyelids, lips, and nose along with eczema on the neck. It states both patients worked as laborers in a factory producing polyethylene terephthalate (PET) films after the composition of the powders changed. It mentions patch tests found that N-(4-hydroxyphenyl)benzenesulfonamide (HPBS), an intermediate used in production of PET films, was responsible for the allergic contact dermatitis.
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- 2019
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36. Partial deletion of AFG3L2 causing spinocerebellar ataxia type 28
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Smets, Katrien, primary, Deconinck, Tine, additional, Baets, Jonathan, additional, Sieben, Anne, additional, Martin, Jean-Jacques, additional, Smouts, Iris, additional, Wang, Shuaiyu, additional, Taroni, Franco, additional, Di Bella, Daniela, additional, Van Hecke, Wim, additional, Parizel, Paul M., additional, Jadoul, Christina, additional, De Potter, Robert, additional, Couvreur, Francine, additional, Rugarli, Elena, additional, and De Jonghe, Peter, additional
- Published
- 2014
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37. De novo SCN1A mutations ara a major cause of severe myoclonic epilepsy of infancy
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Claes, L., Ceulemans, Berten, Audenaert, Dominique, Smets, Katrien, Löfgren, Ann, Del-Favero, Jurgen, Ala-Mello, S., Basel-Vanagaite, L., Plecko, B., Raskin, S., Thiry, P., Wolf, N.I., Van Broeckhoven, Christine, and De Jonghe, Peter
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- 2003
38. Loss of Function of Glucocerebrosidase GBA2 Is Responsible for Motor Neuron Defects in Hereditary Spastic Paraplegia
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Martin, Elodie, primary, Schüle, Rebecca, additional, Smets, Katrien, additional, Rastetter, Agnès, additional, Boukhris, Amir, additional, Loureiro, José L., additional, Gonzalez, Michael A., additional, Mundwiller, Emeline, additional, Deconinck, Tine, additional, Wessner, Marc, additional, Jornea, Ludmila, additional, Oteyza, Andrés Caballero, additional, Durr, Alexandra, additional, Martin, Jean-Jacques, additional, Schöls, Ludger, additional, Mhiri, Chokri, additional, Lamari, Foudil, additional, Züchner, Stephan, additional, De Jonghe, Peter, additional, Kabashi, Edor, additional, Brice, Alexis, additional, and Stevanin, Giovanni, additional
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- 2013
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39. TheSCN1Avariant database: a novel research and diagnostic tool
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Claes, Lieve RF, primary, Deprez, Liesbet, additional, Suls, Arvid, additional, Baets, Jonathan, additional, Smets, Katrien, additional, Van Dyck, Tine, additional, Deconinck, Tine, additional, Jordanova, Albena, additional, and De Jonghe, Peter, additional
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- 2009
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40. De novoSCN1Amutations are a major cause of severe myoclonic epilepsy of infancy
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Claes, Lieve, primary, Ceulemans, Berten, additional, Audenaert, Dominique, additional, Smets, Katrien, additional, Löfgren, Ann, additional, Del-Favero, Jurgen, additional, Ala-Mello, Sirpa, additional, Basel-Vanagaite, Lina, additional, Plecko, Barbara, additional, Raskin, Salmo, additional, Thiry, Paul, additional, Wolf, Nicole I., additional, Van Broeckhoven, Christine, additional, and De Jonghe, Peter, additional
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- 2003
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41. Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.
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Zee, Julie, Langenhove, Tim, Kovacs, Gabor, Dillen, Lubina, Deschamps, William, Engelborghs, Sebastiaan, Matěj, Radoslav, Vandenbulcke, Mathieu, Sieben, Anne, Dermaut, Bart, Smets, Katrien, Damme, Philip, Merlin, Céline, Laureys, Annelies, Broeck, Marleen, Mattheijssens, Maria, Peeters, Karin, Benussi, Luisa, Binetti, Giuliano, and Ghidoni, Roberta
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AMYOTROPHIC lateral sclerosis ,DEGENERATION (Pathology) ,BRAIN degeneration ,DEMENTIA ,NEUROMUSCULAR diseases ,ALLELES - Abstract
Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology. [ABSTRACT FROM AUTHOR]
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- 2014
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42. Partial deletion of AFG3L2causing spinocerebellar ataxia type 28
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Smets, Katrien, Deconinck, Tine, Baets, Jonathan, Sieben, Anne, Martin, Jean-Jacques, Smouts, Iris, Wang, Shuaiyu, Taroni, Franco, Di Bella, Daniela, Van Hecke, Wim, Parizel, Paul M., Jadoul, Christina, De Potter, Robert, Couvreur, Francine, Rugarli, Elena, and De Jonghe, Peter
- Abstract
To identify the genetic cause of autosomal dominant spinocerebellar ataxia type 28 (SCA28) with ptosis in 2 Belgian families without AFG3L2point mutations and further extend the clinical spectrum of SCA28 through the study of a brain autopsy, advanced MRI, and cell-based functional assays exploring the underlying disease mechanism.
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- 2014
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43. Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48)
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Hirst, Jennifer, Madeo, Marianna, Smets, Katrien, Edgar, James R, Schols, Ludger, Li, Jun, Yarrow, Anna, Deconinck, Tine, Baets, Jonathan, Van Aken, Elisabeth, De Bleecker, Jan, Datiles, Manuel B, Roda, Ricardo H, Liepert, Joachim, Züchner, Stephan, Mariotti, Caterina, De Jonghe, Peter, Blackstone, Craig, and Kruer, Michael C
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Clinical Medicine and Science ,Rare Diseases ,Clinical Research ,FOS: Clinical medicine ,FOS: Biological sciences ,Neurological ,Neurosciences ,Genetics ,2.1 Biological and endogenous factors ,Neurodegenerative ,1109 Neurosciences ,3. Good health - Abstract
OBJECTIVE: Biallelic mutations in the AP5Z1 gene encoding the AP-5 ζ subunit have been described in a small number of patients with hereditary spastic paraplegia (HSP) (SPG48); we sought to define genotype-phenotype correlations in patients with homozygous or compound heterozygous sequence variants predicted to be deleterious. METHODS: We performed clinical, radiologic, and pathologic studies in 6 patients with biallelic mutations in AP5Z1. RESULTS: In 4 of the 6 patients, there was complete loss of AP-5 ζ protein. Clinical features encompassed not only prominent spastic paraparesis but also sensory and motor neuropathy, ataxia, dystonia, myoclonus, and parkinsonism. Skin fibroblasts from affected patients tested positive for periodic acid Schiff and autofluorescent storage material, while electron microscopic analysis demonstrated lamellar storage material consistent with abnormal storage of lysosomal material. CONCLUSIONS: Our findings expand the spectrum of AP5Z1-associated neurodegenerative disorders and point to clinical and pathophysiologic overlap between autosomal recessive forms of HSP and lysosomal storage disorders.
44. Additional file 3: of STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations
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Hayer, Stefanie, Deconinck, Tine, Bender, Benjamin, Smets, Katrien, Züchner, Stephan, Reich, Selina, Schöls, Ludger, Schüle, Rebecca, Jonghe, Peter De, Baets, Jonathan, and Synofzik, Matthis
- Subjects
3. Good health - Abstract
Case vignettes. Detailed medical history and clinical examination data of the three STUB1 patients. (DOCX 14 kb)
45. Additional file 3: of STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations
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Hayer, Stefanie, Deconinck, Tine, Bender, Benjamin, Smets, Katrien, Züchner, Stephan, Reich, Selina, Schöls, Ludger, Schüle, Rebecca, Jonghe, Peter De, Baets, Jonathan, and Synofzik, Matthis
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3. Good health - Abstract
Case vignettes. Detailed medical history and clinical examination data of the three STUB1 patients. (DOCX 14 kb)
46. Hereditary spastic paraplegia type 5: Natural history, biomarkers and a randomized controlled trial
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Claudia Stendel, Tine Deconinck, Alessandro Filla, Jonathan Baets, Ingemar Björkhem, Dana M. Bis, Philip Höflinger, Christoph Meisner, Tim W. Rattay, Lisa Abreu, Peter Martus, Jonas Alex Morales Saute, Rebecca Schüle, Antonella Antenora, Stephan Züchner, Andrea Martinuzzi, Wilson Marques, Alessia Arnoldi, Peter Bauer, Laura Bannach Jardim, Thomas Klopstock, Matthew J. Fraidakis, Imma Fischer, Stefan Hauser, Chiara Criscuolo, Ludger Schöls, Peter De Jonghe, Katrien Smets, Martin Paucar, Sarah Wiethoff, Charles Marques Lourenço, Maria Teresa Bassi, Christine Jägle, Marina Scarlato, Schöls, Ludger, Rattay, Tim W., Martus, Peter, Meisner, Christoph, Baets, Jonathan, Fischer, Imma, Jägle, Christine, Fraidakis, Matthew J., Martinuzzi, Andrea, Saute, Jonas Alex, Scarlato, Marina, Antenora, Antonella, Stendel, Claudia, Höflinger, Philip, Lourenco, Charles Marque, Abreu, Lisa, Smets, Katrien, Paucar, Martin, Deconinck, Tine, Bis, Dana M., Wiethoff, Sarah, Bauer, Peter, Arnoldi, Alessia, Marques, Wilson, Jardim, Laura Bannach, Hauser, Stefan, Criscuolo, Chiara, Filla, Alessandro, Züchner, Stephan, Bassi, Maria Teresa, Klopstock, Thoma, De Jonghe, Peter, Björkhem, Ingemar, and Schüle, Rebecca
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0301 basic medicine ,Male ,Atorvastatin ,Steroid Hydroxylase ,therapeutic use [Atorvastatin] ,Gastroenterology ,Severity of Illness Index ,Induced Pluripotent Stem Cell ,law.invention ,0302 clinical medicine ,Randomized controlled trial ,law ,Interquartile range ,blood [Oxysterols] ,Spastic ,polycyclic compounds ,CYP7B1 protein, human ,blood [Biomarkers] ,cerebrospinal fluid [Oxysterols] ,genetics [Steroid Hydroxylases] ,Oxysterols ,Middle Aged ,drug therapy [Spastic Paraplegia, Hereditary] ,Clinical Trial ,3. Good health ,Pedigree ,cerebrospinal fluid [Biomarkers] ,Disease Progression ,lipids (amino acids, peptides, and proteins) ,Female ,Paraplegia ,Case-Control Studie ,medicine.drug ,Human ,Adult ,medicine.medical_specialty ,Oxysterol ,metabolism [Hydroxycholesterols] ,27-hydroxycholesterol ,Adolescent ,Hereditary spastic paraplegia ,25-hydroxycholesterol ,Induced Pluripotent Stem Cells ,Hydroxycholesterol ,Cytochrome P450 Family 7 ,Neurite ,Placebo ,SPG5 ,03 medical and health sciences ,Young Adult ,Double-Blind Method ,Internal medicine ,therapeutic use [Hydroxymethylglutaryl-CoA Reductase Inhibitors] ,genetics [Spastic Paraplegia, Hereditary] ,medicine ,Neurites ,Humans ,Family ,ddc:610 ,hereditary spastic paraplegia ,Atorvastatin Calcium ,Cell Proliferation ,Cross-Sectional Studie ,business.industry ,Spastic Paraplegia, Hereditary ,Biomarker ,medicine.disease ,Hydroxycholesterols ,nervous system diseases ,030104 developmental biology ,Cross-Sectional Studies ,Case-Control Studies ,metabolism [Spastic Paraplegia, Hereditary] ,Steroid Hydroxylases ,randomized controlled trial ,Mutation ,Physical therapy ,genetics [Cytochrome P450 Family 7] ,Human medicine ,Hydroxymethylglutaryl-CoA Reductase Inhibitor ,Neurology (clinical) ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
SPG5 is a rare subtype of Hereditary Spastic Paraplegia caused by mutations in the oxysterol-7 alpha-hydroxylase gene CYP7B1. Schols et al. study properties of lipid biomarkers in SPG5 and evaluate a treatment strategy targeting oxysterol accumulation in a randomized controlled trial (STOP-SPG5).Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7 alpha-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683-1113] to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.
- Published
- 2017
47. Exon-disrupting deletions ofNRXN1in idiopathic generalized epilepsy
- Author
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Møller, R.S., Weber, Y.G., Klitten, L.L., Trucks, H., Muhle, H., Kunz, W.S., Mefford, H.C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I.M., Wichmann, H.E., Ernst, J.P., Schurmann, C., Grabe, H.J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D.B., Lehesjoki, A.E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M.R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C.E., Kleefuß Lie, A.A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K.M., Reif, P.S., Oertel, W.H., Hamer, H.M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M.T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B.P.C., De Kovel, C., Lindhout, D., De Haan, G.J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., R. S. Møller, Y. G. Weber, L. L. Klitten, H. Truck, H. Muhle, W. S. Kunz, H. C. Mefford, A. Franke, M. Kautza, P. Wolf, D. Dennig, S. Schreiber, I. Rückert, H. Wichmann, J. P. Ernst, C. Schurmann, H. J. Grabe, N. Tommerup, U. Stephani, H. Lerche, H. Hjalgrim, I. Helbig, T. Sander, P. Tinuper, F. Bisulli, EPICURE Consortium, Suls, Arvid, Weckhuysen, Sarah, Claes, Godelieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Jordanova, Albena, Møller, R, Weber, Yg, Klitten, Ll, Trucks, H, Muhle, H, Kunz, W, Mefford, Hc, Franke, A, Kautza, M, Wolf, P, Dennig, D, Schreiber, S, Rückert, Im, Wichmann, He, Ernst, Jp, Schurmann, C, Grabe, Hj, Tommerup, N, Stephani, U, Lerche, H, Hjalgrim, H, Helbig, I, Sander, T, Epicure, Consortium, DEL GIUDICE, Ennio, Coppola, Antonietta, and YÜCESAN, EMRAH
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Male ,Idiopathic generalized epilepsy ,Neuronal ,Idiopathic Generalized Epilepsy ,1q21 ,1 Microdeletion ,Two-hit Hypothesis ,Nrxn1 ,Neuropsychological Tests ,Immunoglobulin E ,Cell Adhesion Molecules, Neuronal/genetics ,Adult, Age of Onset, Anticonvulsant ,Exon ,1q21.1 microdeletion ,Exons/genetics ,Odds Ratio ,Nerve Tissue Proteins/genetics ,Copy-number variation ,Valproic Acid/therapeutic use ,Age of Onset ,Neural Cell Adhesion Molecules ,genetics, DNA Copy Number Variations, Electroencephalography, Epilepsy ,Genetics ,biology ,Triazines ,Anticonvulsants/therapeutic use ,Electroencephalography ,genetics, Family, Female, Fructose ,Exons ,Middle Aged ,Settore MED/39 - Neuropsichiatria Infantile ,Pedigree ,therapeutic use, Valproic Acid ,Neurology ,Settore MED/26 - Neurologia ,Anticonvulsants ,Epilepsy, Generalized ,Female ,Adult ,Case-Control Studies ,Cell Adhesion Molecules, Neuronal ,DNA Copy Number Variations ,Family ,Fructose ,Gene Deletion ,Genotype ,Humans ,Infant ,Microarray Analysis ,Nerve Tissue Proteins ,Valproic Acid ,analogs /&/ derivatives/therapeutic use, Gene Deletion, Genotype, Humans, Infant, Male, Microarray Analysis, Middle Aged, Nerve Tissue Protein ,therapeutic use, Case-Control Studies, Cell Adhesion Molecule ,drug therapy/genetics/psychology, Exon ,genetics, Neuropsychological Tests, Odds Ratio, Pedigree, Triazine ,Lamotrigine ,NRXN1 ,Topiramate ,Epilepsy, Generalized/drug therapy ,medicine ,Allele ,Biology ,Gene ,Generalized ,Point mutation ,Calcium-Binding Proteins ,Odds ratio ,medicine.disease ,Triazines/therapeutic use ,Settore MED/03 - Genetica Medica ,therapeutic use ,biology.protein ,Fructose/analogs & derivatives ,Human medicine ,Neurology (clinical) ,Two-hit hypothesis - Abstract
Summary Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92–51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.
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- 2013
48. STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.
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Hayer SN, Deconinck T, Bender B, Smets K, Züchner S, Reich S, Schöls L, Schüle R, De Jonghe P, Baets J, and Synofzik M
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- Adult, Amino Acid Sequence, Female, Gonadotropin-Releasing Hormone genetics, Humans, Male, Middle Aged, Mutation, Neurodegenerative Diseases diagnostic imaging, Neurodegenerative Diseases pathology, Pedigree, Protein Domains, Ubiquitin-Protein Ligases genetics, Cerebellar Ataxia genetics, Gonadotropin-Releasing Hormone deficiency, Hypogonadism genetics, Neurodegenerative Diseases genetics, Ubiquitin-Protein Ligases metabolism
- Abstract
Background: CHIP, the protein encoded by STUB1, is a central component of cellular protein homeostasis and interacts with several key proteins involved in the pathogenesis of manifold neurodegenerative diseases. This gives rise to the hypothesis that mutations in STUB1 might cause a far more multisystemic neurodegenerative phenotype than the previously reported cerebellar ataxia syndrome., Methods: Whole exome sequencing data-sets from n = 87 index subjects of two ataxia cohorts were screened for individuals with STUB1 mutations. In-depth phenotyping by clinical evaluation and neuroimaging was performed in mutation carriers., Results: We identified four novel STUB1 mutations in three affected subjects from two index families (frequency 2/87 = 2.3%). All three subjects presented with a severe multisystemic phenotype including severe dementia, spastic tetraparesis, epilepsy, and autonomic dysfunction in addition to cerebellar ataxia, plus hypogonadism in one index patient. Diffusion tensor imaging revealed degeneration of manifold supra- and infratentorial tracts., Conclusions: Our findings provide clinical and imaging support for the notion that CHIP is a crucial converging point of manifold neurodegenerative processes, corresponding with its universal biological function in neurodegeneration. Further, our data reveal the second STUB1 family with ataxia plus hypogonadism reported so far, demonstrating that Gordon Holmes syndrome is indeed a recurrent manifestation of STUB1. However, it does not present in isolation, but as part of a broad multisystemic neurodegenerative process. This supports the notion that STUB1 disease should be conceptualized not by historical or clinical syndromic names, but as a variable multisystemic disease defined by disturbed function of the underlying STUB1 gene, which translates into a multidimensional gradual spectrum of variably associated clinical signs and symptoms.
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- 2017
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49. Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48).
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Hirst J, Madeo M, Smets K, Edgar JR, Schols L, Li J, Yarrow A, Deconinck T, Baets J, Van Aken E, De Bleecker J, Datiles MB 3rd, Roda RH, Liepert J, Züchner S, Mariotti C, De Jonghe P, Blackstone C, and Kruer MC
- Abstract
Objective: Biallelic mutations in the AP5Z1 gene encoding the AP-5 ζ subunit have been described in a small number of patients with hereditary spastic paraplegia (HSP) (SPG48); we sought to define genotype-phenotype correlations in patients with homozygous or compound heterozygous sequence variants predicted to be deleterious., Methods: We performed clinical, radiologic, and pathologic studies in 6 patients with biallelic mutations in AP5Z1., Results: In 4 of the 6 patients, there was complete loss of AP-5 ζ protein. Clinical features encompassed not only prominent spastic paraparesis but also sensory and motor neuropathy, ataxia, dystonia, myoclonus, and parkinsonism. Skin fibroblasts from affected patients tested positive for periodic acid Schiff and autofluorescent storage material, while electron microscopic analysis demonstrated lamellar storage material consistent with abnormal storage of lysosomal material., Conclusions: Our findings expand the spectrum of AP5Z1-associated neurodegenerative disorders and point to clinical and pathophysiologic overlap between autosomal recessive forms of HSP and lysosomal storage disorders.
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- 2016
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50. A detailed clinical analysis of 13 patients with AUTS2 syndrome further delineates the phenotypic spectrum and underscores the behavioural phenotype.
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Beunders G, van de Kamp J, Vasudevan P, Morton J, Smets K, Kleefstra T, de Munnik SA, Schuurs-Hoeijmakers J, Ceulemans B, Zollino M, Hoffjan S, Wieczorek S, So J, Mercer L, Walker T, Velsher L, Parker MJ, Magee AC, Elffers B, Kooy RF, Yntema HG, Meijers-Heijboer EJ, and Sistermans EA
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- Adult, Child, Child, Preschool, Cytoskeletal Proteins, Exons genetics, Female, Genetic Association Studies methods, Haploinsufficiency genetics, Humans, Infant, Male, Microcephaly genetics, Middle Aged, Mutation genetics, Phenotype, Sequence Deletion genetics, Syndrome, Transcription Factors, Young Adult, Intellectual Disability genetics, Mental Disorders genetics, Proteins genetics
- Abstract
Background: AUTS2 syndrome is an 'intellectual disability (ID) syndrome' caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children., Methods: We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist., Results: All patients have borderline to severe ID/developmental delay, 83-100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5' deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo., Conclusions: The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
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- 2016
- Full Text
- View/download PDF
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