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@ARTICLE{Synofzik:138570,
      author       = {Synofzik, Matthis and Smets, Katrien and Mallaret, Martial
                      and Di Bella, Daniela and Gallenmüller, Constanze and
                      Baets, Jonathan and Schulze, Martin and Magri, Stefania and
                      Sarto, Elisa and Mustafa, Mona and Deconinck, Tine and
                      Haack, Tobias and Züchner, Stephan and Gonzalez, Michael
                      and Timmann, Dagmar and Stendel, Claudia and Klopstock,
                      Thomas and Durr, Alexandra and Tranchant, Christine and
                      Sturm, Marc and Hamza, Wahiba and Nanetti, Lorenzo and
                      Mariotti, Caterina and Koenig, Michel and Schöls, Ludger
                      and Schüle, Rebecca and de Jonghe, Peter and Anheim,
                      Mathieu and Taroni, Franco and Bauer, Peter},
      title        = {{SYNE}1 ataxia is a common recessive ataxia with major
                      non-cerebellar features: a large multi-centre study.},
      journal      = {Brain},
      volume       = {139},
      number       = {5},
      issn         = {1460-2156},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2020-04892},
      pages        = {1378-1393},
      year         = {2016},
      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     = {Adult / Aged / Brain: metabolism / Cerebellar Ataxia:
                      diagnosis / Cerebellar Ataxia: diagnostic imaging /
                      Cerebellar Ataxia: genetics / Cerebellar Ataxia:
                      physiopathology / Cytoskeletal Proteins / Evoked Potentials,
                      Motor: physiology / Female / Genes, Recessive /
                      Heredodegenerative Disorders, Nervous System: diagnosis /
                      Heredodegenerative Disorders, Nervous System: diagnostic
                      imaging / Heredodegenerative Disorders, Nervous System:
                      genetics / Heredodegenerative Disorders, Nervous System:
                      physiopathology / High-Throughput Nucleotide Sequencing /
                      Humans / Magnetic Resonance Imaging / Male / Middle Aged /
                      Muscles: metabolism / Mutation, Missense / Nerve Tissue
                      Proteins: genetics / Nerve Tissue Proteins: metabolism /
                      Neuroimaging / Nuclear Proteins: genetics / Nuclear
                      Proteins: metabolism / Phenotype / Positron-Emission
                      Tomography / Young Adult / Cytoskeletal Proteins (NLM
                      Chemicals) / Nerve Tissue Proteins (NLM Chemicals) / Nuclear
                      Proteins (NLM Chemicals) / SYNE1 protein, human (NLM
                      Chemicals)},
      cin          = {AG Gasser 1 / Ext LMU Klinik / AG Höglinger 1 / Clinical
                      Dementia Research München / AG Schöls 1 / AG Maetzler},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)5000049 /
                      I:(DE-2719)1110002 / I:(DE-2719)1111016 / I:(DE-2719)5000005
                      / I:(DE-2719)5000024},
      pnm          = {345 - Population Studies and Genetics (POF3-345) / 344 -
                      Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-345 / G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:27086870},
      pmc          = {pmc:PMC6363274},
      doi          = {10.1093/brain/aww079},
      url          = {https://pub.dzne.de/record/138570},
}