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000138570 0247_ $$2doi$$a10.1093/brain/aww079
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000138570 037__ $$aDZNE-2020-04892
000138570 041__ $$aEnglish
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000138570 1001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b0$$eFirst author$$udzne
000138570 245__ $$aSYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.
000138570 260__ $$aOxford$$bOxford Univ. Press$$c2016
000138570 264_1 $$2Crossref$$3online$$bOxford University Press (OUP)$$c2016-04-17
000138570 264_1 $$2Crossref$$3print$$bOxford University Press (OUP)$$c2016-05-01
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000138570 520__ $$aMutations 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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000138570 650_7 $$2NLM Chemicals$$aCytoskeletal Proteins
000138570 650_7 $$2NLM Chemicals$$aNerve Tissue Proteins
000138570 650_7 $$2NLM Chemicals$$aNuclear Proteins
000138570 650_7 $$2NLM Chemicals$$aSYNE1 protein, human
000138570 650_2 $$2MeSH$$aAdult
000138570 650_2 $$2MeSH$$aAged
000138570 650_2 $$2MeSH$$aBrain: metabolism
000138570 650_2 $$2MeSH$$aCerebellar Ataxia: diagnosis
000138570 650_2 $$2MeSH$$aCerebellar Ataxia: diagnostic imaging
000138570 650_2 $$2MeSH$$aCerebellar Ataxia: genetics
000138570 650_2 $$2MeSH$$aCerebellar Ataxia: physiopathology
000138570 650_2 $$2MeSH$$aCytoskeletal Proteins
000138570 650_2 $$2MeSH$$aEvoked Potentials, Motor: physiology
000138570 650_2 $$2MeSH$$aFemale
000138570 650_2 $$2MeSH$$aGenes, Recessive
000138570 650_2 $$2MeSH$$aHeredodegenerative Disorders, Nervous System: diagnosis
000138570 650_2 $$2MeSH$$aHeredodegenerative Disorders, Nervous System: diagnostic imaging
000138570 650_2 $$2MeSH$$aHeredodegenerative Disorders, Nervous System: genetics
000138570 650_2 $$2MeSH$$aHeredodegenerative Disorders, Nervous System: physiopathology
000138570 650_2 $$2MeSH$$aHigh-Throughput Nucleotide Sequencing
000138570 650_2 $$2MeSH$$aHumans
000138570 650_2 $$2MeSH$$aMagnetic Resonance Imaging
000138570 650_2 $$2MeSH$$aMale
000138570 650_2 $$2MeSH$$aMiddle Aged
000138570 650_2 $$2MeSH$$aMuscles: metabolism
000138570 650_2 $$2MeSH$$aMutation, Missense
000138570 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000138570 650_2 $$2MeSH$$aNerve Tissue Proteins: metabolism
000138570 650_2 $$2MeSH$$aNeuroimaging
000138570 650_2 $$2MeSH$$aNuclear Proteins: genetics
000138570 650_2 $$2MeSH$$aNuclear Proteins: metabolism
000138570 650_2 $$2MeSH$$aPhenotype
000138570 650_2 $$2MeSH$$aPositron-Emission Tomography
000138570 650_2 $$2MeSH$$aYoung Adult
000138570 7001_ $$aSmets, Katrien$$b1
000138570 7001_ $$aMallaret, Martial$$b2
000138570 7001_ $$aDi Bella, Daniela$$b3
000138570 7001_ $$0P:(DE-2719)9000092$$aGallenmüller, Constanze$$b4$$udzne
000138570 7001_ $$aBaets, Jonathan$$b5
000138570 7001_ $$aSchulze, Martin$$b6
000138570 7001_ $$aMagri, Stefania$$b7
000138570 7001_ $$aSarto, Elisa$$b8
000138570 7001_ $$aMustafa, Mona$$b9
000138570 7001_ $$aDeconinck, Tine$$b10
000138570 7001_ $$aHaack, Tobias$$b11
000138570 7001_ $$aZüchner, Stephan$$b12
000138570 7001_ $$aGonzalez, Michael$$b13
000138570 7001_ $$aTimmann, Dagmar$$b14
000138570 7001_ $$0P:(DE-2719)2812141$$aStendel, Claudia$$b15$$udzne
000138570 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b16$$udzne
000138570 7001_ $$0P:(DE-HGF)0$$aDurr, Alexandra$$b17
000138570 7001_ $$aTranchant, Christine$$b18
000138570 7001_ $$aSturm, Marc$$b19
000138570 7001_ $$aHamza, Wahiba$$b20
000138570 7001_ $$aNanetti, Lorenzo$$b21
000138570 7001_ $$aMariotti, Caterina$$b22
000138570 7001_ $$aKoenig, Michel$$b23
000138570 7001_ $$0P:(DE-2719)2810795$$aSchöls, Ludger$$b24$$udzne
000138570 7001_ $$0P:(DE-2719)2812018$$aSchüle, Rebecca$$b25$$udzne
000138570 7001_ $$ade Jonghe, Peter$$b26
000138570 7001_ $$aAnheim, Mathieu$$b27
000138570 7001_ $$aTaroni, Franco$$b28
000138570 7001_ $$aBauer, Peter$$b29
000138570 77318 $$2Crossref$$3journal-article$$a10.1093/brain/aww079$$b : Oxford University Press (OUP), 2016-04-17$$n5$$p1378-1393$$tBrain$$v139$$x1460-2156$$y2016
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000138570 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363274
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