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Brain. 2016 May;139(Pt 5):1378-93. doi: 10.1093/brain/aww079. Epub 2016 Apr 17.

SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.

Author information

1
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.
2
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.
3
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.
4
Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
5
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.
6
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Germany.
7
Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany.
8
Neurogenetics Group, Department of Molecular Genetics, University of Antwerp, VIB Belgium Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
9
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.
10
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.
11
Department of Neurology, University of Duisburg-Essen, Essen, Germany.
12
Department of Neurology with Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany German Research Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
13
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.
14
Laboratoire de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, USTHB, Algiers, Algeria.
15
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.
16
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.
17
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.
18
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.

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.

KEYWORDS:

Nesprin 1; ataxia; genetics; hereditary spastic paraplegia; motor neuron disease

PMID:
27086870
DOI:
10.1093/brain/aww079
[Indexed for MEDLINE]

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