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Article Dans Une Revue Brain - A Journal of Neurology Année : 2016

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

Matthis Synofzik
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Katrien Smets
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Daniela Di Bella
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Constanze Gallenmüller
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Jonathan Baets
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Martin Schulze
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Stefania Magri
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Elisa Sarto
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Mona Mustafa
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Tine Deconinck
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Tobias B Haack
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Stephan Züchner
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Michael Gonzalez
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Dagmar Timmann
Claudia Stendel
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Thomas Klopstock
Marc Sturm
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Wahiba Hamza
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Lorenzo Nanetti
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Caterina Mariotti
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Ludger Schöls
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Rebecca Schüle
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Peter de Jonghe
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Franco Taroni
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Peter Bauer
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Résumé

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.

Dates et versions

hal-01871789 , version 1 (11-09-2018)

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Matthis Synofzik, Katrien Smets, Martial Mallaret, Daniela Di Bella, Constanze Gallenmüller, et al.. SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study. Brain - A Journal of Neurology , 2016, 139 (5), pp.1378 - 1393. ⟨10.1093/brain/aww079⟩. ⟨hal-01871789⟩
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