title: SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.
abstract: Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal, including premature death due to respiratory dysfunction. With a relative frequency of ∼5%, SYNE1 is one of the more common recessive ataxias worldwide.
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany German Research Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Germany matthis.synofzik@uni-tuebingen.de.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, University of Antwerp, VIB Belgium Department of Neurology, Antwerp University Hospital, Belgium Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Smets
authors.affiliation: Department of Neurology, Hôpital de Hautepierre, Strasbourg, France Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Collège de France, 67404 Illkirch, France.
authors.forename: Martial
authors.initials: M
authors.lastname: Mallaret
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Di Bella
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany German Research Center for Neurodegenerative Diseases (DZNE), Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Gallenmüller
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, University of Antwerp, VIB Belgium Department of Neurology, Antwerp University Hospital, Belgium Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schulze
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Magri
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Sarto
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Mona
authors.initials: M
authors.lastname: Mustafa
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, University of Antwerp, VIB Belgium Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Haack
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: Department of Neurology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Timmann
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany German Research Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stendel
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany German Research Center for Neurodegenerative Diseases (DZNE), Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: APHP Genetic department and Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (ICM), UPMC University Paris VI, UMR975; CNRS UMR 7225; INSERM U975; University Hospital Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: Department of Neurology, Hôpital de Hautepierre, Strasbourg, France Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Collège de France, 67404 Illkirch, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Sturm
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, USTHB, Algiers, Algeria.
authors.forename: Wahiba
authors.initials: W
authors.lastname: Hamza
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Nanetti
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mariotti
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Collège de France, 67404 Illkirch, France Laboratoire de Genetique de Maladies Rares, EA 7402, Institut Universitaire de Recherche Clinique, Université et CHU de Montpellier, 34093 Montpellier cedex 5, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany German Research Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany German Research Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Germany Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, University of Antwerp, VIB Belgium Department of Neurology, Antwerp University Hospital, Belgium Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: de Jonghe
authors.affiliation: Department of Neurology, Hôpital de Hautepierre, Strasbourg, France Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Collège de France, 67404 Illkirch, France Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Anheim
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Taroni
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000378:metabolism; D002524:Cerebellar Ataxia / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D003598:Cytoskeletal Proteins; D019054:Evoked Potentials, Motor / Q000502:physiology; D005260:Female; D005808:Genes, Recessive; D020271:Heredodegenerative Disorders, Nervous System / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D059906:Neuroimaging; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D049268:Positron-Emission Tomography; D055815:Young Adult
chemical_list: D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C415465:SYNE1 protein, human
keywords: Nesprin 1; ataxia; genetics; hereditary spastic paraplegia; motor neuron disease