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1. Prevalence and phenotypes associated with ALPK3 null variants in a large French multicentric cohort: Confirming its involvement in hypertrophic cardiomyopathy.

Author

Ader, Flavie, Jedraszak, Guillaume, Janin, Alexandre, Billon, Clarisse, Buisson, Nathalie Roux, Bloch, Adrien, Bensalah, Meriem, De Sandre‐Giovannoli, Anachiara, Goudal, Adeline, Marsili, Luisa, Cazeneuve, Cécile, Charron, Philippe, Millat, Gilles, and Richard, Pascale

Subjects
HYPERTROPHIC cardiomyopathy, NUCLEOTIDE sequencing, CHILD patients, GENETIC variation, GENETIC testing, EXOMES
Abstract

Biallelic disease‐causing variants in the ALPK3 gene were first identified in children presenting with a severe cardiomyopathy. More recently, it was shown that carriers of heterozygous ALPK3 null variants are at risk of developing hypertrophic cardiomyopathy (HCM) with an adult onset. Since the number of reported ALPK3 patients is small, the mutational spectrum and clinical data are not fully described. In this multi‐centric study, we described the molecular and clinical spectrum of a large cohort of ALPK3 patients. Genetic testing using targeted next generation sequencing was performed in 16 183 cardiomyopathy index cases. Thirty‐six patients carried at least one null ALPK3 variant. The five paediatric patients carried two ALPK3 variants, all presented an HCM phenotype with severe outcomes (one transplantation, one heart failure and one cardiac arrest). The 31 adult patients carried heterozygous variants and the main phenotype was HCM (n = 26/31); including 15% (n = 4) presented with an apical or a concentric form of hypertrophy. Reporting a large cohort of ALPK3 patients, this collaborative work confirmed a strong association with HCM and suggesting his screening in the context of idiopathic HCM. [ABSTRACT FROM AUTHOR]

Published
2024
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3. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Author

Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS

Subjects
Adult, Male, TDP-43, C9orf72, SLITRK2, amyotrophic lateral sclerosis, frontotemporal dementia, Nerve Tissue Proteins, Settore MED/03 - GENETICA MEDICA, Polymorphism, Single Nucleotide, Cohort Studies, Genes, X-Linked, 80 and over, Medicine, Dementia, Humans, Allele, Age of Onset, Polymorphism, Aged, Aged, 80 and over, biology, C9orf72 Protein, business.industry, Membrane Proteins, MESH: Frontotemporal Lobar Degeneration / epidemiology, Frontotemporal Lobar, Degeneration / genetics, Genes, X-Linked / genetics, Genome-Wide Association Study / methods, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, X-Linked, medicine.disease, Amyotrophic lateral sclerosis, Minor allele frequency, Genes, Immunology, Synaptophysin, biology.protein, Female, MESH: Adult, C9orf72 Protein / genetics, Frontotemporal Lobar Degeneration / diagnosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Neurology (clinical), MESH: Humans, Membrane Proteins / genetics, Nerve Tissue Proteins / genetics, Polymorphism, Single Nucleotide / genetics, Age of onset, Frontotemporal Lobar Degeneration, business, Frontotemporal dementia, Genome-Wide Association Study
Abstract

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Published
2021

4. Correction: Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Roux, Thomas, primary, Barbier, Mathieu, additional, Papin, Mélanie, additional, Davoine, Claire-Sophie, additional, Sayah, Sabrina, additional, Coarelli, Giulia, additional, Charles, Perrine, additional, Marelli, Cecilia, additional, Parodi, Livia, additional, Tranchant, Christine, additional, Goizet, Cyril, additional, Klebe, Stephan, additional, Lohmann, Ebba, additional, Van Maldergem, Lionel, additional, van Broeckhoven, Christine, additional, Coutelier, Marie, additional, Tesson, Christelle, additional, Stevanin, Giovanni, additional, Duyckaerts, Charles, additional, Brice, Alexis, additional, Durr, Alexandra, additional, Darios, Frédéric, additional, Forlani, Sylvie, additional, Site, Pitié-Salpêtrière, additional, Banneau, Guillaume, additional, Cazeneuve, Cécile, additional, Fontaine, Bertrand, additional, Azulay, Jean-Philippe, additional, Boesfplug-Tanguy, Odile, additional, Hannequin, Didier, additional, Hazan, Jamilé, additional, Burgo, Andrea, additional, Verny, Christophe, additional, Koenig, Michel, additional, Labauge, Pierre, additional, N’guyen, Karine, additional, Rodriguez, Diana, additional, Belarbi, Soraya, additional, Hamri, Abdelmadjid, additional, Tazir, Meriem, additional, Boesch, Sylvia, additional, Pandolfo, Massimo, additional, Laura, Jardim, additional, Guergueltcheva, Velina, additional, Tournev, Ivalo, additional, Pedraza Linarès, Olga Lucia, additional, Nielsen, Jørgen E., additional, Svenstrup, Kirsten, additional, Zaki, Maha, additional, Bauer, Peter, additional, Schöls, Lüdger, additional, Schüle, Rebecca, additional, Lossos, Alexander, additional, Bassi, Maria-Teresa, additional, Basso, Manuela, additional, Bertini, Enrico, additional, Brusco, Alfredo, additional, Casali, Carlo, additional, Casari, Giorgio, additional, Criscuolo, Chiara, additional, Filla, Alessandro, additional, Orsi, Laura, additional, Santorelli, Filippo M., additional, Valente, Enza Maria, additional, Vavla, Marinela, additional, Vazza, Giovanni, additional, Megarbane, André, additional, Benomar, Ali, additional, Kremer, Berry, additional, Van Roon-Mom, Willeke, additional, Roxburgh, Richard, additional, Erichsen, Anne Kjersti, additional, Tallaksen, Chantal, additional, Alonso, Isabel, additional, Coutinho, Paula, additional, Loureiro, José Léal, additional, Sequeiros, Jorge, additional, Salih, Mustapha, additional, Kostic, Vladimir S, additional, Rouco Axpe, Idoia, additional, Elsayed, Liena, additional, Paucar, Martin Arce, additional, Roumani, Samir, additional, Bing-Wen, Soong, additional, Reid, Evan, additional, Suran, Nethisinghe, additional, Warner, Thomas, additional, and Wood, Nicholas, additional

Published
2021
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5. Pharmacogenetic study in Hodgkin lymphomas reveals the impact of UGT1A1 polymorphisms on patient prognosis

Author

Ribrag, Vincent, Koscielny, Serge, Casasnovas, Olivier, Cazeneuve, Cecile, Brice, Pauline, Morschhauser, Franck, Gabarre, Jean, Stamatoullas, Aspasia, Lenoir, Gilbert, Salles, Gilles, and on Behalf from the Groupe d’Etude des Lymphomes agressifs group, Laboratoire de Génétique et de recherche translationnelle, and Institut Gustave Roussy

Published
2009
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7. Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes

Author

Tezenas du Montcel, Sophie, Durr, Alexandra, Bauer, Peter, Figueroa, Karla P., Ichikawa, Yaeko, Brussino, Alessandro, Forlani, Sylvie, Rakowicz, Maria, Schöls, Ludger, Mariotti, Caterina, van de Warrenburg, Bart P.C., Orsi, Laura, Giunti, Paola, Filla, Alessandro, Szymanski, Sandra, Klockgether, Thomas, Berciano, José, Pandolfo, Massimo, Boesch, Sylvia, Melegh, Bela, Timmann, Dagmar, Mandich, Paola, Camuzat, Agnès, Goto, Jun, Ashizawa, Tetsuo, Cazeneuve, Cécile, Tsuji, Shoji, Pulst, Stefan-M., Brusco, Alfredo, Riess, Olaf, Brice, Alexis, and Stevanin, Giovanni

Published
2014
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8. Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias:a frequent cause of predominant cognitive impairment

Author

Roux, Thomas, Barbier, Mathieu, Papin, Mélanie, Davoine, Claire Sophie, Sayah, Sabrina, Coarelli, Giulia, Charles, Perrine, Marelli, Cecilia, Parodi, Livia, Tranchant, Christine, Goizet, Cyril, Klebe, Stephan, Lohmann, Ebba, Van Maldergen, Lionel, van Broeckhoven, Christine, Coutelier, Marie, Tesson, Christelle, Stevanin, Giovanni, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, Darios, Frédéric, Forlani, Sylvie, Site, Pitié Salpêtrière, Banneau, Guillaume, Cazeneuve, Cécile, Fontaine, Bertrand, Azulay, Jean Philippe, Boesfplug-Tanguy, Odile, Hannequin, Didier, Hazan, Jamilé, Burgo, Andrea, Verny, Christophe, Koenig, Michel, Labauge, Pierre, N’guyen, Karine, Rodriguez, Diana, Belarbi, Soraya, Hamri, Abdelmadjid, Tazir, Meriem, Boesch, Sylvia, Nielsen, Jørgen E., Svenstrup, Kirsten, Roux, Thomas, Barbier, Mathieu, Papin, Mélanie, Davoine, Claire Sophie, Sayah, Sabrina, Coarelli, Giulia, Charles, Perrine, Marelli, Cecilia, Parodi, Livia, Tranchant, Christine, Goizet, Cyril, Klebe, Stephan, Lohmann, Ebba, Van Maldergen, Lionel, van Broeckhoven, Christine, Coutelier, Marie, Tesson, Christelle, Stevanin, Giovanni, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, Darios, Frédéric, Forlani, Sylvie, Site, Pitié Salpêtrière, Banneau, Guillaume, Cazeneuve, Cécile, Fontaine, Bertrand, Azulay, Jean Philippe, Boesfplug-Tanguy, Odile, Hannequin, Didier, Hazan, Jamilé, Burgo, Andrea, Verny, Christophe, Koenig, Michel, Labauge, Pierre, N’guyen, Karine, Rodriguez, Diana, Belarbi, Soraya, Hamri, Abdelmadjid, Tazir, Meriem, Boesch, Sylvia, Nielsen, Jørgen E., and Svenstrup, Kirsten

Abstract

Purpose: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48). Methods: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance. Results: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease–like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) “second hits” in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects. Conclusion: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.

Published
2020

9. Who and Why? Requests for Presymptomatic Genetic Testing for Amyotrophic Lateral Sclerosis/Frontotemporal Dementia vs Huntington Disease

Author

Amador, Maria del Mar, primary, Gargiulo, Marcela, additional, Boucher, Christilla, additional, Herson, Ariane, additional, Staraci, Stéphanie, additional, Salachas, François, additional, Clot, Fabienne, additional, Cazeneuve, Cécile, additional, Le Ber, Isabelle, additional, and Durr, Alexandra, additional

Published
2020
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10. Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Roux, Thomas, primary, Barbier, Mathieu, additional, Papin, Mélanie, additional, Davoine, Claire-Sophie, additional, Sayah, Sabrina, additional, Coarelli, Giulia, additional, Charles, Perrine, additional, Marelli, Cecilia, additional, Parodi, Livia, additional, Tranchant, Christine, additional, Goizet, Cyril, additional, Klebe, Stephan, additional, Lohmann, Ebba, additional, Van Maldergem, Lionel, additional, van Broeckhoven, Christine, additional, Coutelier, Marie, additional, Tesson, Christelle, additional, Stevanin, Giovanni, additional, Duyckaerts, Charles, additional, Brice, Alexis, additional, Durr, Alexandra, additional, Darios, Frédéric, additional, Forlani, Sylvie, additional, Site, Pitié-Salpêtrière, additional, Banneau, Guillaume, additional, Cazeneuve, Cécile, additional, Fontaine, Bertrand, additional, Azulay, Jean-Philippe, additional, Boesfplug-Tanguy, Odile, additional, Hannequin, Didier, additional, Hazan, Jamilé, additional, Burgo, Andrea, additional, Verny, Christophe, additional, Koenig, Michel, additional, Labauge, Pierre, additional, N’guyen, Karine, additional, Rodriguez, Diana, additional, Belarbi, Soraya, additional, Hamri, Abdelmadjid, additional, Tazir, Meriem, additional, Boesch, Sylvia, additional, Pandolfo, Massimo, additional, Laura, Jardim, additional, Guergueltcheva, Velina, additional, Tournev, Ivalo, additional, Pedraza Linarès, Olga Lucia, additional, Nielsen, Jørgen E., additional, Svenstrup, Kirsten, additional, Zaki, Maha, additional, Bauer, Peter, additional, Schöls, Lüdger, additional, Schüle, Rebecca, additional, Lossos, Alexander, additional, Bassi, Maria-Teresa, additional, Basso, Manuela, additional, Bertini, Enrico, additional, Brusco, Alfredo, additional, Casali, Carlo, additional, Casari, Giorgio, additional, Criscuolo, Chiara, additional, Filla, Alessandro, additional, Orsi, Laura, additional, Santorelli, Filippo M., additional, Valente, Enza Maria, additional, Vavla, Marinela, additional, Vazza, Giovanni, additional, Megarbane, André, additional, Benomar, Ali, additional, Kremer, Berry, additional, Van Roon-Mom, Willeke, additional, Roxburgh, Richard, additional, Erichsen, Anne Kjersti, additional, Tallaksen, Chantal, additional, Alonso, Isabel, additional, Coutinho, Paula, additional, Loureiro, José Léal, additional, Sequeiros, Jorge, additional, Salih, Mustapha, additional, Kostic, Vladimir S., additional, Rouco Axpe, Idoia, additional, Elsayed, Liena, additional, Paucar, Martin Arce, additional, Roumani, Samir, additional, Bing-Wen, Soong, additional, Reid, Evan, additional, Suran, Nethisinghe, additional, Warner, Thomas, additional, and Wood, Nicholas, additional

Published
2020
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11. Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy

Author

Klebe, Stephan, Depienne, Christel, Gerber, Sylvie, Challe, Georges, Anheim, Mathieu, Charles, Perrine, Fedirko, Estelle, Lejeune, Elodie, Cottineau, Julien, Brusco, Alfredo, Dollfus, Hélène, Chinnery, Patrick F., Mancini, Cecilia, Ferrer, Xavier, Sole, Guilhem, Destée, Alain, Mayer, Jean-Michel, Fontaine, Bertrand, Seze, Jérôme de, Clanet, Michel, Ollagnon, Elisabeth, Busson, Philippe, Cazeneuve, Cécile, Stevanin, Giovanni, Kaplan, Josseline, Rozet, Jean-Michel, Brice, Alexis, and Durr, Alexandra

Published
2012
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12. Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes

Author

Millecamps, Stéphanie, Boillée, Séverine, Le Ber, Isabelle, Seilhean, Danielle, Teyssou, Elisa, Giraudeau, Marine, Moigneu, Carine, Vandenberghe, Nadia, Danel-Brunaud, Véronique, Corcia, Philippe, Pradat, Pierre-François, Le Forestier, Nadine, Lacomblez, Lucette, Bruneteau, Gaelle, Camu, William, Brice, Alexis, Cazeneuve, Cécile, LeGuern, Eric, Meininger, Vincent, and Salachas, François

Published
2012
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13. SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype–phenotype correlations

Author

Millecamps, Stéphanie, Salachas, François, Cazeneuve, Cécile, Gordon, Paul, Bricka, Bernard, Camuzat, Agnès, Guillot-Noël, Léna, Russaouen, Odile, Bruneteau, Gaëlle, Pradat, Pierre-François, Le Forestier, Nadine, Vandenberghe, Nadia, Danel-Brunaud, Véronique, Guy, Nathalie, Thauvin-Robinet, Christel, Lacomblez, Lucette, Couratier, Philippe, Hannequin, Didier, Seilhean, Danielle, Le Ber, Isabelle, Corcia, Philippe, Camu, William, Brice, Alexis, Rouleau, Guy, LeGuern, Eric, and Meininger, Vincent

Published
2010
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14. Parkinsonʼs disease-related LRRK2 G2019S mutation results from independent mutational events in humans

Author

Lesage, Suzanne, Patin, Etienne, Condroyer, Christel, Leutenegger, Anne-Louise, Lohmann, Ebba, Giladi, Nir, Bar-Shira, Anat, Belarbi, Soraya, Hecham, Nassima, Pollak, Pierre, Ouvrard-Hernandez, Anne-Marie, Bardien, Soraya, Carr, Jonathan, Benhassine, Traki, Tomiyama, Hiroyuki, Pirkevi, Caroline, Hamadouche, Tarik, Cazeneuve, Cécile, Basak, A. Nazli, Hattori, Nobutaka, Dürr, Alexandra, Tazir, Meriem, Orr-Urtreger, Avi, Quintana-Murci, Lluis, Brice, Alexis, Agid, Y., Bonnet, A.-M., Borg, M., Brice, A., Broussolle, E., Damier, Ph., Destée, A., Dürr, A., Durif, F., Lohmann, E., Martinez, M., Penet, C., Pollak, P., Rascol, O., Tison, F., Tranchant, C., Troiano, A., Vérin, M., Viallet, F., and Vidailhet, M.

Published
2010
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15. Efficacy of exome-targeted capture sequencing to detect mutations in known cerebellar ataxia genes

Author

Coutelier, Marie, Hammer, Monia B., Stevanin, Giovanni, Monin, Marie-Lorraine, Davoine, Claire-Sophie, Mochel, Fanny, Labauge, Pierre, Ewenczyk, Claire, Ding, Jinhui, Gibbs, J. Raphael, Hannequin, Didier, Melki, Judith, Toutain, Annick, Laugel, Vincent, Forlani, Sylvie, Charles, Perrine, Broussolle, Emmanuel, Thobois, Stéphane, Afenjar, Alexandra, Anheim, Mathieu, Calvas, Patrick, Castelnovo, Giovanni, De Broucker, Thomas, Vidailhet, Marie, Moulignier, Antoine, Ghnassia, Robert T., Tallaksen, Chantal, Mignot, Cyril, Goizet, Cyril, Le Ber, Isabelle, Ollagnon-Roman, Elisabeth, Pouget, Jean, Brice, Alexis, Singleton, Andrew, Durr, Alexandra, Belarabi, Soraya, Hamri, Abdelmadjid, Tazir, Meriem, Boesch, Sylvia, Pandolfo, Massimo, Ullmann, Urielle, Jardim, Laura, Guergueltcheva, Velina, Tournev, Ivalo, Soong, Bing-Wen, Linarès, Olga Lucia Pedraza, Nielsen, Jørgen E., Svenstrup, Kirsten, Zaki, Maha, Azulay, Jean-Philippe, Banneau, Guillaume, Boesfplug-Tanguy, Odile, Burgo, Andrea, Cazeneuve, Cécile, Darios, Frédéric, Depienne, Christel, Duyckaerts, Charles, Fontaine, Bertrand, Hazan, Jamilé, Koenig, Michel, Marelli, Cecilia, N'Guyen, Karine, Rodriguez, Diana, Sittler, Annie, Verny, Christophe, Bauer, Peter, Schöls, Lüdger, Schüle, Rebecca, Koutsis, Georgios, Lossos, Alexander, Antenora, Antonella, Bassi, Maria Teresa, Basso, Manuela, Bertini, Enrico, Brusco, Alfredo, Casali, Carlo, Casari, Giorgio, Criscuolo, Chiara, Filla, Alessandro, Lieto, Maria, Orsi, Laura, Santorelli, Filippo M., Valente, Enza Maria, Vavla, Marinela, Vazza, Giovanni, Megarbane, André, Benomar, Ali, Roxburgh, Richard, Erichsen, Anne Kjersti, Alonso, Isabel, Coutinho, Paula, Loureiro, José Léal, Sequeiros, Jorge, Salih, Mustapha, Kostic, Vladimir S., Axpe, Idoia Rouco, Roumani, Samir, Kremer, Berry, Van Roon-Mom, Willeke, Boukhris, Amir, Mhiri, Chokri, Karabay, Arzu, Nethisinghe, Suran, Okane, Cahir, Oliva, Megan, Reid, Evan, Warner, Thomas, Wood, Nicholas, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Université de Montpellier (UM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of New Haven [Connecticut], Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital de la Croix-Rousse [CHU - HCL], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Filière Neuromusculaire (FILNEMUS), UCL - SSS/DDUV/GEHU - Génétique, Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Coutelier, Marie, Hammer, Monia B., Stevanin, Giovanni, Monin, Marie-Lorraine, Davoine, Claire-Sophie, Mochel, Fanny, Labauge, Pierre, Ewenczyk, Claire, Ding, Jinhui, Gibbs, J. Raphael, Hannequin, Didier, Melki, Judith, Toutain, Annick, Laugel, Vincent, Forlani, Sylvie, Charles, Perrine, Broussolle, Emmanuel, Thobois, Stéphane, Afenjar, Alexandra, Anheim, Mathieu, Calvas, Patrick, Castelnovo, Giovanni, De Broucker, Thoma, Vidailhet, Marie, Moulignier, Antoine, Ghnassia, Robert T., Tallaksen, Chantal, Mignot, Cyril, Goizet, Cyril, Le Ber, Isabelle, Ollagnon-Roman, Elisabeth, Pouget, Jean, Brice, Alexi, Singleton, Andrew, Durr, Alexandra, Belarabi, Soraya, Hamri, Abdelmadjid, Tazir, Meriem, Boesch, Sylvia, Pandolfo, Massimo, Ullmann, Urielle, Jardim, Laura, Guergueltcheva, Velina, Tournev, Ivalo, Soong, Bing-Wen, Linarès, Olga Lucia Pedraza, Nielsen, Jørgen E., Svenstrup, Kirsten, Zaki, Maha, Azulay, Jean-Philippe, Banneau, Guillaume, Boesfplug-Tanguy, Odile, Burgo, Andrea, Cazeneuve, Cécile, Darios, Frédéric, Depienne, Christel, Duyckaerts, Charle, Fontaine, Bertrand, Hazan, Jamilé, Koenig, Michel, Marelli, Cecilia, N'Guyen, Karine, Rodriguez, Diana, Sittler, Annie, Verny, Christophe, Bauer, Peter, Schöls, Lüdger, Schüle, Rebecca, Koutsis, Georgio, Lossos, Alexander, Antenora, Antonella, Bassi, Maria Teresa, Basso, Manuela, Bertini, Enrico, Brusco, Alfredo, Casali, Carlo, Casari, Giorgio, Criscuolo, Chiara, Filla, Alessandro, Lieto, Maria, Orsi, Laura, Santorelli, Filippo M., Valente, Enza Maria, Vavla, Marinela, Vazza, Giovanni, Megarbane, André, Benomar, Ali, Roxburgh, Richard, Erichsen, Anne Kjersti, Alonso, Isabel, Coutinho, Paula, Loureiro, José Léal, Sequeiros, Jorge, Salih, Mustapha, Kostic, Vladimir S., Axpe, Idoia Rouco, Roumani, Samir, Kremer, Berry, Van Roon-Mom, Willeke, Boukhris, Amir, Mhiri, Chokri, Karabay, Arzu, Nethisinghe, Suran, Okane, Cahir, Oliva, Megan, Reid, Evan, Warner, Thoma, Wood, Nicholas, École Pratique des Hautes Études (EPHE), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
0301 basic medicine, Male, Candidate gene, [SDV]Life Sciences [q-bio], ataxia, exome sequencing, disease genes, spastic ataxia, oculomotor apraxia, Gene mutation, Whole Exome Sequencing, Cohort Studies, disease genes, 0302 clinical medicine, Oculomotor apraxia, Exome, Exome sequencing, Heat-Shock Proteins, Original Investigation, oculomotor apraxia, Nuclear Proteins, Metalloendopeptidases, Middle Aged, 3. Good health, Phenotype, Female, medicine.symptom, RNA Helicases, Adult, medicine.medical_specialty, Ataxia, Adolescent, Cerebellar Ataxia, Nerve Tissue Proteins, Consanguinity, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Cerebellar ataxia, business.industry, ataxia, DNA Helicases, Computational Biology, medicine.disease, Multifunctional Enzymes, Cytoskeletal Proteins, spastic ataxia, 030104 developmental biology, Mutation, ATPases Associated with Diverse Cellular Activities, Calcium Channels, Neurology (clinical), business, exome sequencing, 030217 neurology & neurosurgery
Abstract

International audience; Importance: Molecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion. Objectives: To assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence. Design, Setting, and Participants: Three hundred nineteen index patients with CA and without a history of dominant transmission were included in the this cohort study by the Spastic Paraplegia and Ataxia Network. Centralized storage was in the DNA and cell bank of the Brain and Spine Institute, Salpetriere Hospital, Paris, France. Patients were classified into 6 clinical groups, with the largest being those with spastic ataxia (ie, CA with pyramidal signs [n = 100]). Sequencing was performed from January 1, 2014, through December 31, 2016. Detected variants were classified as very probably or definitely causative, possibly causative, or of unknown significance based on genetic evidence and genotype-phenotype considerations. Main Outcomes and Measures: Identification of variants in genes broadly linked to CA, classified in pathogenicity groups. Results: The 319 included patients had equal sex distribution (160 female [50.2%] and 159 male patients [49.8%]; mean [SD] age at onset, 27.9 [18.6] years). The age at onset was younger than 25 years for 131 of 298 patients (44.0%) with complete clinical information. Consanguinity was present in 101 of 298 (33.9%). Very probable or definite diagnoses were achieved for 72 patients (22.6%), with an additional 19 (6.0%) harboring possibly pathogenic variants. The most frequently mutated genes were SPG7 (n = 14), SACS (n = 8), SETX (n = 7), SYNE1 (n = 6), and CACNA1A (n = 6). The highest diagnostic rate was obtained for patients with an autosomal recessive CA with oculomotor apraxia-like phenotype (6 of 17 [35.3%]) or spastic ataxia (35 of 100 [35.0%]) and patients with onset before 25 years of age (41 of 131 [31.3%]). Peculiar phenotypes were reported for patients carrying KCND3 or ERCC5 variants. Conclusions and Relevance: Exome capture followed by targeted analysis allows the molecular diagnosis in patients with highly heterogeneous mendelian disorders, such as CA, without prior assumption of the inheritance mode or causative gene. Being commonly available without specific design need, this procedure allows testing of a broader range of genes, consequently describing less classic phenotype-genotype correlations, and post hoc reanalysis of data as new genes are implicated in the disease.

Published
2018

16. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Author

Clot, Fabienne, Grabli, David, Cazeneuve, Cécile, Roze, Emmanuel, Castelnau, Pierre, Chabrol, Brigitte, Landrieu, Pierre, Nguyen, Karine, Ponsot, Gérard, Abada, Myriem, Doummar, Diane, Damier, Philippe, Gil, Roger, Thobois, Stéphane, Ward, Alana J., Hutchinson, Michael, Toutain, Annick, Picard, Fabienne, Camuzat, Agnès, Fedirko, Estelle, Sân, Chankannira, Bouteiller, Delphine, LeGuern, Eric, Durr, Alexandra, Vidailhet, Marie, and Brice, Alexis

Published
2009

20. Cystic fibrosis patients with the 3272-26A>G splicing mutation have milder disease than F508del homozygotes: a large European study

Author

Amaral, Margarida D, Pacheco, Paula, Beck, Sebastian, Farinha, Carlos M, Penque, Deborah, Nogueira, Paulo, Barreto, Celeste, Lopes, Beatriz, Casals, Teresa, Dapena, Javier, Gartner, Silvia, Vásquez, Carlos, Pérez-Frías, Javier, Olveira, Casilda, Cabanas, Rodrigo, Estivill, Xavier, Tzetis, Maria, Kanavakis, Emmanuel, Doudounakis, Stavros, Dörk, Thilo, Tümmler, Burkhard, Girodon-Boulandet, Emmanuelle, Cazeneuve, Cécile, Goossens, Michel, Blayau, Martine, Verlingue, Claudine, Vieira, Isabel, Féréc, Claude, Claustres, Mireille, Georges, Marie des, Clavel, Christine, Birembaut, Philippe, Hubert, Dominique, Bienvenu, Thierry, Adoun, Michèle, Chomel, Jean-Claude, De Boeck, Kris, Cuppens, Harry, and Lavinha, João

Published
2001

21. Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers

Author

Fournier, Clémence, Barbier, Mathieu, Camuzat, Agnè, Anquetil, Vincent, Lattante, Serena, Clot, Fabienne, Cazeneuve, Cécile, Rinaldi, Daisy, Couratier, Philippe, Deramecourt, Vincent, Sabatelli, Mario, Belliard, Serge, Vercelletto, Martine, Forlani, Sylvie, Jornea, Ludmila, Brice, Alexi, Auriacombe, Sophie, Blanc, Frédéric, Bouteleau-Bretonnière, Claire, Ceccaldi, Mathieu, Didic, Mira, Dubois, Bruno, Duyckaerts, Charle, Etcharry-Bouix, Frédérique, Golfier, Véronique, Hannequin, Didier, Lacomblez, Lucette, Le Ber, Isabelle, Levy, Richard, Michel, Bernard-Françoi, Pasquier, Florence, Thomas-Anterion, Catherine, Pariente, Jérémie, Sellal, Françoi, Benchetrit, Eve, Bertin, Hugo, Bertrand, Anne, Bissery, Anne, Bombois, Stéphanie, Boncoeur, Marie-Paule, Cassagnaud, Pascaline, Chastan, Mathieu, Chen, Yaohua, Chupin, Marie, Colliot, Olivier, Delbeucq, Xavier, Delmaire, Christine, Gerardin, Emmanuel, Hossein-Foucher, Claude, Habert, Marie-Odile, Lautrette, Géraldine, Lebouvier, Thibaud, Lehéricy, Stéphane, Le Toullec, Benjamin, Martineau, Kelly, Mackowiak, Marie-Anne, Monteil, Jacque, Petyt, Grégory, Pradat, Pierre-Françoi, Oya, Assi-Hervé, Rollin-Sillaire, Adeline, Salachas, Françoi, Sayah, Sabrina, Wallon, David, Leguern, Eric, Lattante, Serena (ORCID:0000-0003-2891-0340), Sabatelli, Mario (ORCID:0000-0001-6635-4985), Fournier, Clémence, Barbier, Mathieu, Camuzat, Agnè, Anquetil, Vincent, Lattante, Serena, Clot, Fabienne, Cazeneuve, Cécile, Rinaldi, Daisy, Couratier, Philippe, Deramecourt, Vincent, Sabatelli, Mario, Belliard, Serge, Vercelletto, Martine, Forlani, Sylvie, Jornea, Ludmila, Brice, Alexi, Auriacombe, Sophie, Blanc, Frédéric, Bouteleau-Bretonnière, Claire, Ceccaldi, Mathieu, Didic, Mira, Dubois, Bruno, Duyckaerts, Charle, Etcharry-Bouix, Frédérique, Golfier, Véronique, Hannequin, Didier, Lacomblez, Lucette, Le Ber, Isabelle, Levy, Richard, Michel, Bernard-Françoi, Pasquier, Florence, Thomas-Anterion, Catherine, Pariente, Jérémie, Sellal, Françoi, Benchetrit, Eve, Bertin, Hugo, Bertrand, Anne, Bissery, Anne, Bombois, Stéphanie, Boncoeur, Marie-Paule, Cassagnaud, Pascaline, Chastan, Mathieu, Chen, Yaohua, Chupin, Marie, Colliot, Olivier, Delbeucq, Xavier, Delmaire, Christine, Gerardin, Emmanuel, Hossein-Foucher, Claude, Habert, Marie-Odile, Lautrette, Géraldine, Lebouvier, Thibaud, Lehéricy, Stéphane, Le Toullec, Benjamin, Martineau, Kelly, Mackowiak, Marie-Anne, Monteil, Jacque, Petyt, Grégory, Pradat, Pierre-Françoi, Oya, Assi-Hervé, Rollin-Sillaire, Adeline, Salachas, Françoi, Sayah, Sabrina, Wallon, David, Leguern, Eric, Lattante, Serena (ORCID:0000-0003-2891-0340), and Sabatelli, Mario (ORCID:0000-0001-6635-4985)

Abstract

A (GGGGCC)n repeat expansion in C9orf72 gene is the major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The relations between the repeats size and the age at disease onset (AO) or the clinical phenotype (FTD vs. ALS) were investigated in 125 FTD, ALS, and presymptomatic carriers. Positive correlations were found between repeats number and the AO (p < 10e−4) but our results suggested that the association was mainly driven by age at collection (p < 10e−4). A weaker association was observed with clinical presentation (p = 0.02), which became nonsignificant after adjustment for the age at collection in each group. Importantly, repeats number variably expanded or contracted over time in carriers with multiple blood samples, as well as through generations in parent-offspring pairs, conversely to what occurs in several expansion diseases with anticipation at the molecular level. Finally, this study establishes that measure of repeats number in lymphocytes is not a reliable biomarker predictive of the AO or disease outcome in C9orf72 long expansion carriers.

Published
2018

23. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Author

Clot, Fabienne, Grabli, David, Cazeneuve, Cécile, Roze, Emmanuel, Castelnau, Pierre, Chabrol, Brigitte, Landrieu, Pierre, Nguyen, Karine, Ponsot, Gérard, Abada, Myriem, Doummar, Diane, Damier, Philippe, Gil, Roger, Thobois, Stéphane, Ward, Alana J., Hutchinson, Michael, Toutain, Annick, Picard, Fabienne, Camuzat, Agnès, Fedirko, Estelle, Sân, Chankannira, Bouteiller, Delphine, LeGuern, Eric, Durr, Alexandra, Vidailhet, Marie, Brice, Alexis, Clot, Fabienne, Grabli, David, Cazeneuve, Cécile, Roze, Emmanuel, Castelnau, Pierre, Chabrol, Brigitte, Landrieu, Pierre, Nguyen, Karine, Ponsot, Gérard, Abada, Myriem, Doummar, Diane, Damier, Philippe, Gil, Roger, Thobois, Stéphane, Ward, Alana J., Hutchinson, Michael, Toutain, Annick, Picard, Fabienne, Camuzat, Agnès, Fedirko, Estelle, Sân, Chankannira, Bouteiller, Delphine, LeGuern, Eric, Durr, Alexandra, Vidailhet, Marie, and Brice, Alexis

Abstract

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of l-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after l-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of l-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and rec

Published
2017

25. Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes

Author

du Montcel, Sophie Tezenas, Dürr, Alexandra, Cazeneuve, Cécile, Brice, Alexis, Stevanin, Giovanni, Forlani, Sylvie, Camuzat, Agnès, Bauer, Peter, Riess, Olaf, Figueroa, Karla Pattie, Pulst, Stefan Matthias, Ichikawa, Yaeko, Goto, Jun, Tsuji, Shoji, Brussino, Alessandro, Brusco, Alfredo, Rakowicz, Maria, Schöls, Lüdger, Mariotti, Caterina, van de Warrenburg, Bart P C, Orsi, Laura, Giunti, Paola, Filla, Alessandro, Szymanski, Sandra, Klockgether, Thomas, Berciano, José, Pandolfo, Massimo, Boesch, Sylvia, Melegh, Bela, Timmann, Dagmar, Mandich, Paola, Ashizawa, Tetsuo, du Montcel, Sophie Tezenas, Dürr, Alexandra, Cazeneuve, Cécile, Brice, Alexis, Stevanin, Giovanni, Forlani, Sylvie, Camuzat, Agnès, Bauer, Peter, Riess, Olaf, Figueroa, Karla Pattie, Pulst, Stefan Matthias, Ichikawa, Yaeko, Goto, Jun, Tsuji, Shoji, Brussino, Alessandro, Brusco, Alfredo, Rakowicz, Maria, Schöls, Lüdger, Mariotti, Caterina, van de Warrenburg, Bart P C, Orsi, Laura, Giunti, Paola, Filla, Alessandro, Szymanski, Sandra, Klockgether, Thomas, Berciano, José, Pandolfo, Massimo, Boesch, Sylvia, Melegh, Bela, Timmann, Dagmar, Mandich, Paola, and Ashizawa, Tetsuo

Abstract

Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases. © The Author (2014)., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2014

26. Phenotype difference between ALS patients with expanded repeats inC9ORF72and patients with mutations in other ALS-related genes

Author

Millecamps, Stéphanie, primary, Boillée, Séverine, additional, Le Ber, Isabelle, additional, Seilhean, Danielle, additional, Teyssou, Elisa, additional, Giraudeau, Marine, additional, Moigneu, Carine, additional, Vandenberghe, Nadia, additional, Danel-Brunaud, Véronique, additional, Corcia, Philippe, additional, Pradat, Pierre-François, additional, Le Forestier, Nadine, additional, Lacomblez, Lucette, additional, Bruneteau, Gaelle, additional, Camu, William, additional, Brice, Alexis, additional, Cazeneuve, Cécile, additional, LeGuern, Eric, additional, Meininger, Vincent, additional, and Salachas, François, additional

Published
2012
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28. Correction: Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females

Author

Depienne, Christel, primary, Bouteiller, Delphine, additional, Keren, Boris, additional, Cheuret, Emmanuel, additional, Poirier, Karine, additional, Trouillard, Oriane, additional, Benyahia, Baya, additional, Quelin, Chloé, additional, Carpentier, Wassila, additional, Julia, Sophie, additional, Afenjar, Alexandra, additional, Gautier, Agnès, additional, Rivier, François, additional, Meyer, Sophie, additional, Berquin, Patrick, additional, Hélias, Marie, additional, Py, Isabelle, additional, Rivera, Serge, additional, Bahi-Buisson, Nadia, additional, Gourfinkel-An, Isabelle, additional, Cazeneuve, Cécile, additional, Ruberg, Merle, additional, Brice, Alexis, additional, Nabbout, Rima, additional, and LeGuern, Eric, additional

Published
2009
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29. Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females

Author

Depienne, Christel, primary, Bouteiller, Delphine, additional, Keren, Boris, additional, Cheuret, Emmanuel, additional, Poirier, Karine, additional, Trouillard, Oriane, additional, Benyahia, Baya, additional, Quelin, Chloé, additional, Carpentier, Wassila, additional, Julia, Sophie, additional, Afenjar, Alexandra, additional, Gautier, Agnès, additional, Rivier, François, additional, Meyer, Sophie, additional, Berquin, Patrick, additional, Hélias, Marie, additional, Py, Isabelle, additional, Rivera, Serge, additional, Bahi-Buisson, Nadia, additional, Gourfinkel-An, Isabelle, additional, Cazeneuve, Cécile, additional, Ruberg, Merle, additional, Brice, Alexis, additional, Nabbout, Rima, additional, and LeGuern, Eric, additional

Published
2009
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32. Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations

Author

Mansour, Issam, primary, Delague, Valérie, additional, Cazeneuve, Cécile, additional, Dodé, Catherine, additional, Chouery, Eliane, additional, Pêcheux, Christophe, additional, Medlej-Hashim, Myrna, additional, Salem, Nabiha, additional, ElZein, Loubna, additional, Levan-Petit, Isabelle, additional, Lefranc, Gérard, additional, Goossens, Michel, additional, Delpech, Marc, additional, Amselem, Serge, additional, Loiselet, Jacques, additional, Grateau, Gilles, additional, Mégarbane, André, additional, and Naman, Roger, additional

Published
2001
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33. CAG repeat size in Huntingtin alleles is associated with cancer prognosis

Author

Thion, Morgane Sonia, Tézenas du Montcel, Sophie, Golmard, Jean-Louis, Vacher, Sophie, Barjhoux, Laure, Sornin, Valérie, Cazeneuve, Cécile, Bièche, Ivan, Sinilnikova, Olga, Stoppa-Lyonnet, Dominique, Durr, Alexandra, and Humbert, Sandrine

Abstract

The abnormal expansion of a ≥36 CAG unit tract in the Huntingtin gene (HTT) leads to Huntington's disease (HD), but has also been associated with cancer: the incidence of cancer is lower in HD patients than in age-matched controls, but HD-causing variants of HTT accelerate the progression of breast tumors and the development of metastases in mouse models of breast cancer. To investigate the relationship between HTT CAGs and cancer, data concerning 2407 women with BRCA1 or BRCA2 mutations that predispose to breast and ovarian cancers and 431 patients with breast cancer without family histories were studied; the size of the CAG expansions on both HTT alleles was determined in each subject. The proportion of individuals carrying a CAG expansion in a pathological range for HD was 10 times more frequent than previously reported in the literature. In carriers of BRCA2 mutations, the length of the HTT CAG tract was correlated with lower incidence of ovarian cancer. Among carriers of BRCA1 mutations who developed a breast cancer, its onset occurred 2.4 years earlier in individuals with intermediate HTT alleles (≥27) than in those with a CAG tract <27. Finally, in patients with sporadic HER2 breast cancer, metastasis increased by a factor of 11.10 per 10 additional CAG repeats in HTT. We concluded that whereas long CAG length could be associated with lower cancer incidence, it could also be paradoxically associated with cancer severity (age of apparition and metastasis development).

Published
2016
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34. Identification of MEFV-Independent Modifying Genetic Factors for Familial Mediterranean Fever

Author

Cazeneuve, Cécile, primary, Ajrapetyan, Hasmik, additional, Papin, Stéphanie, additional, Roudot-Thoraval, Françoise, additional, Geneviève, David, additional, Mndjoyan, Elizaveta, additional, Papazian, Marina, additional, Sarkisian, Ashot, additional, Babloyan, Ara, additional, Boissier, Brigitte, additional, Duquesnoy, Philippe, additional, Kouyoumdjian, Jean-Claude, additional, Girodon-Boulandet, Emmanuelle, additional, Grateau, Gilles, additional, Sarkisian, Tamara, additional, and Amselem, Serge, additional

Published
2000
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36. MEFV-Gene Analysis in Armenian Patients with Familial Mediterranean Fever: Diagnostic Value and Unfavorable Renal Prognosis of the M694V Homozygous Genotype—Genetic and Therapeutic Implications

Author

Cazeneuve, Cécile, primary, Sarkisian, Tamara, additional, Pêcheux, Christophe, additional, Dervichian, Michel, additional, Nédelec, Brigitte, additional, Reinert, Philippe, additional, Ayvazyan, Alexandre, additional, Kouyoumdjian, Jean-Claude, additional, Ajrapetyan, Hasmik, additional, Delpech, Marc, additional, Goossens, Michel, additional, Dodé, Catherine, additional, Grateau, Gilles, additional, and Amselem, Serge, additional

Published
1999
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37. CFTR Gene Mutations in Adults with Disseminated Bronchiectasis

Author

Girodon, Emmanuelle, primary, Cazeneuve, Cécile, additional, Lebargy, François, additional, Chinet, Thierry, additional, Costes, Bruno, additional, Ghanem, Nada, additional, Martin, Josiane, additional, Lemay, Sylvie, additional, Scheid, Philippe, additional, Housset, Bruno, additional, Bignon, Jean, additional, and Goossens, Michel, additional

Published
1997
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38. Correction: Clinical, neuropathological, and genetic characterization of STUB1variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Roux, Thomas, Barbier, Mathieu, Papin, Mélanie, Davoine, Claire-Sophie, Sayah, Sabrina, Coarelli, Giulia, Charles, Perrine, Marelli, Cecilia, Parodi, Livia, Tranchant, Christine, Goizet, Cyril, Klebe, Stephan, Lohmann, Ebba, Van Maldergem, Lionel, van Broeckhoven, Christine, Coutelier, Marie, Tesson, Christelle, Stevanin, Giovanni, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, Durr, Alexandra, Stevanin, Giovanni, Brice, Alexis, Darios, Frédéric, Forlani, Sylvie, Site, Pitié-Salpêtrière, Banneau, Guillaume, Cazeneuve, Cécile, Charles, Perrine, Duyckaerts, Charles, Fontaine, Bertrand, Azulay, Jean-Philippe, Boesfplug-Tanguy, Odile, Goizet, Cyril, Hannequin, Didier, Hazan, Jamilé, Burgo, Andrea, Verny, Christophe, Koenig, Michel, Labauge, Pierre, Marelli, Cecilia, N’guyen, Karine, Rodriguez, Diana, Belarbi, Soraya, Hamri, Abdelmadjid, Tazir, Meriem, Boesch, Sylvia, Pandolfo, Massimo, Laura, Jardim, Guergueltcheva, Velina, Tournev, Ivalo, Pedraza Linarès, Olga Lucia, Nielsen, Jørgen E., Svenstrup, Kirsten, Zaki, Maha, Bauer, Peter, Schöls, Lüdger, Schüle, Rebecca, Lossos, Alexander, Bassi, Maria-Teresa, Basso, Manuela, Bertini, Enrico, Brusco, Alfredo, Casali, Carlo, Casari, Giorgio, Criscuolo, Chiara, Filla, Alessandro, Orsi, Laura, Santorelli, Filippo M., Valente, Enza Maria, Vavla, Marinela, Vazza, Giovanni, Megarbane, André, Benomar, Ali, Kremer, Berry, Van Roon-Mom, Willeke, Roxburgh, Richard, Erichsen, Anne Kjersti, Tallaksen, Chantal, Alonso, Isabel, Coutinho, Paula, Loureiro, José Léal, Sequeiros, Jorge, Salih, Mustapha, Kostic, Vladimir S, Rouco Axpe, Idoia, Elsayed, Liena, Paucar, Martin Arce, Roumani, Samir, Bing-Wen, Soong, Reid, Evan, Suran, Nethisinghe, Warner, Thomas, and Wood, Nicholas

Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41436-020-01064-y

Published
2021
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40. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Author

Clot, Fabienne, Grabli, David, Cazeneuve, Cécile, Roze, Emmanuel, Castelnau, Pierre, Chabrol, Brigitte, Landrieu, Pierre, Nguyen, Karine, Ponsot, Gérard, Abada, Myriem, Doummar, Diane, Damier, Philippe, Gil, Roger, Thobois, Stéphane, Ward, Alana J., Hutchinson, Michael, Toutain, Annick, Picard, Fabienne, Camuzat, Agnès, Fedirko, Estelle, Sân, Chankannira, Bouteiller, Delphine, LeGuern, Eric, Durr, Alexandra, Vidailhet, Marie, Brice, Alexis, Clot, Fabienne, Grabli, David, Cazeneuve, Cécile, Roze, Emmanuel, Castelnau, Pierre, Chabrol, Brigitte, Landrieu, Pierre, Nguyen, Karine, Ponsot, Gérard, Abada, Myriem, Doummar, Diane, Damier, Philippe, Gil, Roger, Thobois, Stéphane, Ward, Alana J., Hutchinson, Michael, Toutain, Annick, Picard, Fabienne, Camuzat, Agnès, Fedirko, Estelle, Sân, Chankannira, Bouteiller, Delphine, LeGuern, Eric, Durr, Alexandra, Vidailhet, Marie, and Brice, Alexis

Abstract

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of l-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after l-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of l-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and rec

41. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Author

Clot, Fabienne, Grabli, David, Cazeneuve, Cécile, Roze, Emmanuel, Castelnau, Pierre, Chabrol, Brigitte, Landrieu, Pierre, Nguyen, Karine, Ponsot, Gérard, Abada, Myriem, Doummar, Diane, Damier, Philippe, Gil, Roger, Thobois, Stéphane, Ward, Alana J., Hutchinson, Michael, Toutain, Annick, Picard, Fabienne, Camuzat, Agnès, Fedirko, Estelle, Sân, Chankannira, Bouteiller, Delphine, LeGuern, Eric, Durr, Alexandra, Vidailhet, Marie, Brice, Alexis, Clot, Fabienne, Grabli, David, Cazeneuve, Cécile, Roze, Emmanuel, Castelnau, Pierre, Chabrol, Brigitte, Landrieu, Pierre, Nguyen, Karine, Ponsot, Gérard, Abada, Myriem, Doummar, Diane, Damier, Philippe, Gil, Roger, Thobois, Stéphane, Ward, Alana J., Hutchinson, Michael, Toutain, Annick, Picard, Fabienne, Camuzat, Agnès, Fedirko, Estelle, Sân, Chankannira, Bouteiller, Delphine, LeGuern, Eric, Durr, Alexandra, Vidailhet, Marie, and Brice, Alexis

Abstract

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of l-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after l-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of l-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and rec

42. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration.

Author

Barbier M, Camuzat A, Hachimi KE, Guegan J, Rinaldi D, Lattante S, Houot M, Sánchez-Valle R, Sabatelli M, Antonell A, Molina-Porcel L, Clot F, Couratier P, van der Ende E, van der Zee J, Manzoni C, Camu W, Cazeneuve C, Sellal F, Didic M, Golfier V, Pasquier F, Duyckaerts C, Rossi G, Bruni AC, Alvarez V, Gómez-Tortosa E, de Mendonça A, Graff C, Masellis M, Nacmias B, Oumoussa BM, Jornea L, Forlani S, Van Deerlin V, Rohrer JD, Gelpi E, Rademakers R, Van Swieten J, Le Guern E, Van Broeckhoven C, Ferrari R, Génin E, Brice A, and Le Ber I

Subjects
Adult, Age of Onset, Aged, Aged, 80 and over, Cohort Studies, Female, Frontotemporal Lobar Degeneration epidemiology, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, C9orf72 Protein genetics, Frontotemporal Lobar Degeneration diagnosis, Frontotemporal Lobar Degeneration genetics, Genes, X-Linked genetics, Genome-Wide Association Study methods, Membrane Proteins genetics, Nerve Tissue Proteins genetics
Abstract

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2021
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43. Questioning on the role of D amino acid oxidase in familial amyotrophic lateral sclerosis.

Author

Millecamps S, Da Barroca S, Cazeneuve C, Salachas F, Pradat PF, Danel-Brunaud V, Vandenberghe N, Lacomblez L, Le Forestier N, Bruneteau G, Camu W, Brice A, Meininger V, and LeGuern E

Subjects
Amino Acid Sequence, Amino Acid Substitution, Base Sequence, Conserved Sequence, DNA genetics, DNA Mutational Analysis, Exons, Female, Heterozygote, Humans, Male, Molecular Sequence Data, Mutation, Missense, Pedigree, Polymorphism, Single Nucleotide, Sequence Homology, Amino Acid, Species Specificity, Amyotrophic Lateral Sclerosis enzymology, Amyotrophic Lateral Sclerosis genetics, D-Amino-Acid Oxidase genetics, Genetic Variation
Published
2010
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44. The tumor necrosis factor alpha-dependent activation of the human mediterranean fever (MEFV) promoter is mediated by a synergistic interaction between C/EBP beta and NF kappaB p65.

Author

Papin S, Cazeneuve C, Duquesnoy P, Jeru I, Sahali D, and Amselem S

Subjects
Base Sequence, DNA Primers, HeLa Cells, Humans, CCAAT-Enhancer-Binding Protein-beta physiology, Familial Mediterranean Fever genetics, NF-kappa B physiology, Promoter Regions, Genetic, Tumor Necrosis Factor-alpha physiology
Abstract

MEFV is a gene expressed specifically in myeloid cells and whose mutations underlie an autosomal recessive auto-inflammatory disease, called familial Mediterranean fever (FMF), characterized by recurrent episodes of serosal inflammation. This gene, which encodes a protein with unclear physiological functions, has been shown to be up-regulated by the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha). However, the mechanism of this regulation is unknown, and the MEFV promoter is still to be characterized. Here, we show that 243 bp of the 5'-flanking region of the human MEFV gene are sufficient to direct high level expression of MEFV in TNFalpha-treated cells. The TNFalpha-induced expression of MEFV is dependent on both NFkappaB p65 and C/EBPbeta that bind to evolutionarily conserved sites located, in the human promoter, at positions -163 and -55, respectively. As shown by a series of transcription and gel shift assays performed with wild-type and mutated promoter sequences, these two transcription factors act differently on the TNFalpha-dependent transcription of MEFV: C/EBPbeta is the key regulatory factor required to confer cell responsiveness to TNFalpha, whereas NFkappaB p65 increases this response by means of a synergistic interaction with C/EBPbeta that is dependent on the integrity of the identified -55 C/EBP binding site. Given the phenotype of patients with FMF, this C/EBP-NFkappaB interaction may represent a key step in the control of an inflammatory response that is abnormally high in this disease. These data, which shed novel light on the pathophysiology of FMF, represent an unusual example of cross-talk between C/EBP and NFkappaB pathways in TNFalpha signaling.

Published
2003
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