SKORVANEK, Matej, Irena REKTOROVÁ, 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 and Robert JECH. WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia. PARKINSONISM & RELATED DISORDERS. OXFORD: ELSEVIER SCI LTD, 2022, vol. 94, January 2022, p. 54-61. ISSN 1353-8020. Available from: https://dx.doi.org/10.1016/j.parkreldis.2021.11.030.
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Basic information
Original name WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia
Authors SKORVANEK, Matej (guarantor), Irena REKTOROVÁ (203 Czech Republic, belonging to the institution), 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 and Robert JECH.
Edition PARKINSONISM & RELATED DISORDERS, OXFORD, ELSEVIER SCI LTD, 2022, 1353-8020.
Other information
Original language English
Type of outcome Article in a journal
Field of Study 30210 Clinical neurology
Country of publisher United Kingdom of Great Britain and Northern Ireland
Confidentiality degree is not subject to a state or trade secret
WWW URL
Impact factor Impact factor: 4.100
RIV identification code RIV/00216224:14110/22:00128075
Organization unit Faculty of Medicine
Doi http://dx.doi.org/10.1016/j.parkreldis.2021.11.030
UT WoS 000748987300009
Keywords in English WARS2; Early onset parkinsonism; Progressive myoclonus ataxia; Whole exome sequencing
Tags 14110127, podil, rivok
Tags International impact, Reviewed
Changed by Changed by: Mgr. Tereza Miškechová, učo 341652. Changed: 28/2/2023 14:12.
Abstract
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 myoclonusataxia 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 patientderived 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 tremordominant parkinsonism and progressive myoclonus-ataxia phenotypes.
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