Macarena Cabrera-Serrano1, Fabiola Mavillard1, Valerie Biancalana1, Eloy Rivas1, Bharti Morar1, Aurelio Hernández-Laín1, Montse Olive1, Nuria Muelas1, Eduardo Khan1, Alejandra Carvajal1, Pablo Quiroga1, Jordi Diaz-Manera1, Mark Davis1, Rainiero Ávila1, Cristina Domínguez1, Norma Beatriz Romero1, Juan J Vílchez1, David Comas1, Nigel G Laing1, Jocelyn Laporte1, Luba Kalaydjieva1, Carmen Paradas2. 1. From the Unidad de Enfermedades Neuromusculares, Department of Neurology (M.C.-S., C.P.), Instituto de Biomedicina de Sevilla (IBiS) (M.C.-S., F.M., C.P.), and Department of Pathology, Neuropathology Unit (E.R.), Hospital Universitario Virgen del Rocío, Sevilla, Spain; Laboratoire Diagnostic Génétique (V.B.), Faculté de Médecine-CHRU, Strasbourg; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (V.B., R.Á., J.L.), Illkirch, France; Harry Perkins Institute of Medical Research and Centre for Medical Research (B.M., N.G.L., L.K.), University of Western Australia, Nedlands; Department of Pathology (Neuropathology) (A.H.-L.), Hospital Universitario 12 de Octubre, Madrid Research Institute; Neuropathology Unit (M.O.), Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona; Department of Neurology and IIS La Fe (N.M., J.J.V.), Hospital Universitari i Politècnic La Fe, Valencia; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER) (N.M., J.D.-M., J.J.V.); Department of Neurology (E.K.), Consulta de Enfermedades Neuromusculares y Unidad de ELA, Hospital General Universitario Santa Lucía, Cartagena, Murcia; Department of Neurology (A.C.), Hospital Virgen de las Nieves, Granada; Department of Neurology (P.Q.), Hospital Torrecárdenas, Almería; Unidad de Enfermedades Neuromusculares (J.D.-M.), Department of Neurology, Universidad Autónoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Department of Diagnostic Genomics (M.D.), PathWest Laboratory Medicine WA, Perth, Australia; Department of Neurology (C.D.), Hospital 12 de Octubre, Madrid, Spain; Unité de Morphologie Neuromusculaire (N.B.R.), Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris; Université Sorbonne (N.B.R.), UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France; Department of Medicine (J.J.V.), Universitat de Valencia; Department of Experimental and Health Sciences (D.C.), Institute of Evolutionary Biology (CSIC-UPF), Universitat Pompeu Fabra, Barcelona, Spain; Centre National de la Recherche Scientifique (J.L.), UMR7104, Illkirch; and Institut National de la Santé et de la Recherche Médicale (J.L.), U964, Illkirch, France. 2. From the Unidad de Enfermedades Neuromusculares, Department of Neurology (M.C.-S., C.P.), Instituto de Biomedicina de Sevilla (IBiS) (M.C.-S., F.M., C.P.), and Department of Pathology, Neuropathology Unit (E.R.), Hospital Universitario Virgen del Rocío, Sevilla, Spain; Laboratoire Diagnostic Génétique (V.B.), Faculté de Médecine-CHRU, Strasbourg; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (V.B., R.Á., J.L.), Illkirch, France; Harry Perkins Institute of Medical Research and Centre for Medical Research (B.M., N.G.L., L.K.), University of Western Australia, Nedlands; Department of Pathology (Neuropathology) (A.H.-L.), Hospital Universitario 12 de Octubre, Madrid Research Institute; Neuropathology Unit (M.O.), Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona; Department of Neurology and IIS La Fe (N.M., J.J.V.), Hospital Universitari i Politècnic La Fe, Valencia; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER) (N.M., J.D.-M., J.J.V.); Department of Neurology (E.K.), Consulta de Enfermedades Neuromusculares y Unidad de ELA, Hospital General Universitario Santa Lucía, Cartagena, Murcia; Department of Neurology (A.C.), Hospital Virgen de las Nieves, Granada; Department of Neurology (P.Q.), Hospital Torrecárdenas, Almería; Unidad de Enfermedades Neuromusculares (J.D.-M.), Department of Neurology, Universidad Autónoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Department of Diagnostic Genomics (M.D.), PathWest Laboratory Medicine WA, Perth, Australia; Department of Neurology (C.D.), Hospital 12 de Octubre, Madrid, Spain; Unité de Morphologie Neuromusculaire (N.B.R.), Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris; Université Sorbonne (N.B.R.), UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France; Department of Medicine (J.J.V.), Universitat de Valencia; Department of Experimental and Health Sciences (D.C.), Institute of Evolutionary Biology (CSIC-UPF), Universitat Pompeu Fabra, Barcelona, Spain; Centre National de la Recherche Scientifique (J.L.), UMR7104, Illkirch; and Institut National de la Santé et de la Recherche Médicale (J.L.), U964, Illkirch, France. cparadas@us.es macabrera@us.es.
Abstract
OBJECTIVE: To describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified. METHODS: Patients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed. RESULTS: Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma. CONCLUSION: We have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.
OBJECTIVE: To describe a large series of BIN1patients, in which a novel founder mutation in the Roma population of southern Spain has been identified. METHODS:Patients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed. RESULTS: Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma. CONCLUSION: We have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.
Authors: K G Claeys; T Maisonobe; J Böhm; J Laporte; M Hezode; N B Romero; G Brochier; M Bitoun; R Y Carlier; T Stojkovic Journal: Neurology Date: 2010-02-09 Impact factor: 9.910
Authors: Johann Böhm; Valérie Biancalana; Edoardo Malfatti; Nicolas Dondaine; Catherine Koch; Nasim Vasli; Wolfram Kress; Matthias Strittmatter; Ana Lia Taratuto; Hernan Gonorazky; Pascal Laforêt; Thierry Maisonobe; Montse Olivé; Laura Gonzalez-Mera; Michel Fardeau; Nathalie Carrière; Pierre Clavelou; Bruno Eymard; Marc Bitoun; John Rendu; Julien Fauré; Joachim Weis; Jean-Louis Mandel; Norma B Romero; Jocelyn Laporte Journal: Brain Date: 2014-09-25 Impact factor: 13.501
Authors: Dirk Fischer; Muriel Herasse; Marc Bitoun; Héctor M Barragán-Campos; Jacques Chiras; Pascal Laforêt; Michel Fardeau; Bruno Eymard; Pascale Guicheney; Norma B Romero Journal: Brain Date: 2006-04-03 Impact factor: 13.501