Multisystemic SYNE1 ataxia: confirming the high frequency and extending the mutational and phenotypic spectrum
| Autor: | Inès Mademan, Florian Harmuth, Ilaria Giordano, Dagmar Timmann, Stefania Magri, Tine Deconinck, Jens Claaßen, Daniel Jokisch, Gencer Genc, Daniela Di Bella, Silvia Romito, Rebecca Schüle, Stephan Züchner, Franco Taroni, Thomas Klockgether, Ludger Schöls, Peter De Jonghe, Peter Bauer, EOA Consortium, Jonathan Baets, Matthis Synofzik |
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| Přispěvatelé: | EOA Consortium |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Ataxia Cerebellar Ataxia DNA Mutational Analysis Medizin Biology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine non disponibile medicine Missense mutation Humans Clinical significance ddc:610 Amyotrophic lateral sclerosis Genetics Mutation Cerebellar ataxia Original Articles medicine.disease 030104 developmental biology Phenotype Human medicine Neurology (clinical) medicine.symptom Trinucleotide repeat expansion 030217 neurology & neurosurgery |
| Zdroj: | Brain 139(8), e46-e46 (2016). doi:10.1093/brain/aww115 Brain |
| ISSN: | 0006-8950 |
| DOI: | 10.1093/brain/aww115 |
| Popis: | Sir, We recently reported in Brain a large multi-centre study suggesting that truncating SYNE1 mutations are a recurrent cause of recessive ataxia also outside Quebec (23/434 = 5.3% of patients with unexplained early-onset ataxia) (Synofzik et al. , 2016). Moreover, this study indicated that SYNE1 ataxia might commonly present with complex multisystemic phenotypes rather than pure cerebellar ataxia, including in particular motor neuron and brainstem dysfunction (Synofzik et al. , 2016). However, confirmation of both the frequency estimate and the complex phenotypic spectrum is still lacking, raising the question whether these findings indeed represent systematic results rather than just exceptional or coincidental associations. Here, we now report the mutational and phenotypic findings on SYNE1 from a second, independent ataxia series of 116 patients. These findings not only confirm the high frequency of SYNE1 ataxia and extend both the mutational spectrum (seven novel index patients, 12 novel SYNE1 mutations) and the multisystemic phenotypic spectrum, including amyotrophic lateral sclerosis (ALS)-like motor neuron features, they also indicate that muscle immunohistochemistry might provide a valuable diagnostic biomarker for clarifying the pathogenic contribution of SYNE1 missense variants. This observation may have consequences for clinical SYNE1 diagnostics, as diagnostic tests are urgently needed for clarifying the role of the ubiquitous SYNE1 missense variants with unknown clinical significance (VUS), which are frequently found in neurological and non-neurological patients and controls (Synofzik et al. , 2016). Index subjects ( n = 116) with unexplained degenerative ataxia compatible with autosomal recessive inheritance (no ataxia in the parental generation) and negative for trinucleotide repeat expansions causing Friedreich’s ataxia (FRDA) were compiled from three sources: the Early Onset Ataxia Consortium ( n = 88), the ataxia centre Antwerp, Belgium ( n = 9), and the ataxia centre Milano, Italy ( n = 19). All subjects originated from European, Middle East or Mediterranean countries. This … |
| Databáze: | OpenAIRE |
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