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

Authors: Synofzik, Matthis  Smets, Katrien  Mallaret, Martial  Di Bella, Daniela  Gallenmüller, Constanze  Baets, Jonathan  Schulze, Martin  Magri, Stefania  Sarto, Elisa  Mustafa, Mona  Deconinck, Tine  Haack, Tobias  Züchner, Stephan  Gonzalez, Michael  Timmann, Dagmar  Stendel, Claudia  Klopstock, Thomas  Durr, Alexandra  Tranchant, Christine  Sturm, Marc  Hamza, Wahiba  Nanetti, Lorenzo  Mariotti, Caterina  Koenig, Michel  Schöls, Ludger  Schüle, Rebecca  de Jonghe, Peter  Anheim, Mathieu  Taroni, Franco  Bauer, Peter 
Citation: Synofzik M, etal., Brain. 2016 May;139(Pt 5):1378-93. doi: 10.1093/brain/aww079. Epub 2016 Apr 17.
Pubmed: (View Article at PubMed) PMID:27086870
DOI: Full-text: DOI:10.1093/brain/aww079

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.

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RGD Object Information
RGD ID: 13209001
Created: 2017-08-28
Species: All species
Last Modified: 2017-08-28
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.