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WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia

Introduction - Sixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand th...

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Main Authors: Skorvanek, Matej (Author) , Rektorova, Irena (Author) , Mandemakers, Wim (Author) , Wagner, Matias (Author) , Steinfeld, Robert (Author) , Orec, Laura (Author) , Han, Vladimir (Author) , Pavelekova, Petra (Author) , Lackova, Alexandra (Author) , Kulcsarova, Kristina (Author) , Ostrozovicova, Miriam (Author) , Gdovinova, Zuzana (Author) , Plecko, Barbara (Author) , Brunet, Theresa (Author) , Berutti, Riccardo (Author) , Kuipers, Demy J. S. (Author) , Boumeester, Valerie (Author) , Havrankova, Petra (Author) , Tijssen, M. A. J. (Author) , Kaiyrzhanov, Rauan (Author) , Rizig, Mie (Author) , Houlden, Henry (Author) , Winkelmann, Juliane (Author) , Bonifati, Vincenzo (Author) , Zech, Michael (Author) , Jech, Robert (Author)
Format: Article (Journal)
Language:English
Published: January 2022
In: Parkinsonism & related disorders
Year: 2022, Volume: 94, Pages: 54-61
ISSN:1873-5126
DOI:10.1016/j.parkreldis.2021.11.030
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.parkreldis.2021.11.030
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1353802021004375
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Author Notes:Matej Skorvanek, Irena Rektorova, Wim Mandemakers, Matias Wagner, Robert Steinfeld, Laura Orec, Vladimir Han, Petra Pavelekova, Alexandra Lackova, Kristina Kulcsarova, Miriam Ostrozovicova, Zuzana Gdovinova, Barbara Plecko, Theresa Brunet, Riccardo Berutti, Demy J. S. Kuipers, Valerie Boumeester, Petra Havrankova, M. A. J. Tijssen, Rauan Kaiyrzhanov, Mie Rizig, Henry Houlden, Juliane Winkelmann, Vincenzo Bonifati, Michael Zech, Robert Jech
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Summary:Introduction - Sixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand the spectrum to later onset phenotypes including dopa-responsive early-onset parkinsonism and progressive myoclonus-ataxia. - Methods - Six individuals from four families underwent whole-exome sequencing within research and diagnostic settings. Following the identification of a genetic defect, in-depth phenotyping and protein expression studies were performed. - Results - A relatively common (gnomAD MAF = 0.0033) pathogenic p.(Trp13Gly) missense variant in WARS2 was detected in trans in all six affected individuals in combination with different pathogenic alleles (exon 2 deletion in family 1; p.(Leu100del) in family 2; p.(Gly50Asp) in family 3; and p.(Glu208*) in family 4). Two subjects presented with action tremor around age 10-12 years and developed tremor-dominant parkinsonism with prominent neuropsychiatric features later in their 20s. Two subjects presented with a progressive myoclonus-ataxia dominant phenotype. One subject presented with spasticity, choreo-dystonia, myoclonus, and speech problems. One subject presented with speech problems, ataxia, and tremor. Western blotting analyses in patient‐derived fibroblasts showed a markedly decreased expression of the full‐length WARS2 protein in both subjects carrying p.(Trp13Gly) and an exon-2 deletion in compound heterozygosity. - Conclusions - This study expands the spectrum of the disease to later onset phenotypes of early-onset tremor-dominant parkinsonism and progressive myoclonus-ataxia phenotypes.
Item Description:Version des Artikels 7 December 2021
Gesehen am 27.09.2022
Physical Description:Online Resource
ISSN:1873-5126
DOI:10.1016/j.parkreldis.2021.11.030

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