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

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 KaiyrzhanovMie Rizig, Henry Houlden, Juliane Winkelmann, Vincenzo Bonifati, Michael Zech, Robert Jech

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)54-61
Number of pages8
JournalParkinsonism and Related Disorders
Volume94
Early online date2 Dec 2021
DOIs
Publication statusPublished - 1 Jan 2022

Bibliographical note

Funding Information:
This work was supported by the Slovak Grant and Development Agency [ APVV-18-0547 ] and the Operational Programme Integrated Infrastructure , funded by the ERDF [ ITMS2014+:313011V455 ] to MS, VH, ZG, MO, KK, AL, and PP. It was also funded by a research grant from the Else Kröner-Fresenius-Stiftung and by in-house institutional funding from Technische Universität München, Munich, Germany , Helmholtz Zentrum München, Munich, Germany , and Charles University, Prague, Czech Republic [ PROGRES Q27 ]. This study was also funded by the Czech Ministry of Health [ AZV: NV19–04–00233 ], and by the Stichting ParkinsonFonds (The Netherlands, research grants to VB and WM). JW and MZ received research support from the German Research Foundation [DFG; WI 1820/14-1 ; ZE 1213/2-1 ].

Funding Information:
This work was supported by the Slovak Grant and Development Agency [APVV-18-0547] and the Operational Programme Integrated Infrastructure, funded by the ERDF [ITMS2014+:313011V455] to MS, VH, ZG, MO, KK, AL, and PP. It was also funded by a research grant from the Else Kr?ner-Fresenius-Stiftung and by in-house institutional funding from Technische Universit?t M?nchen, Munich, Germany, Helmholtz Zentrum M?nchen, Munich, Germany, and Charles University, Prague, Czech Republic [PROGRES Q27]. This study was also funded by the Czech Ministry of Health [AZV: NV19?04?00233], and by the Stichting ParkinsonFonds (The Netherlands, research grants to VB and WM). JW and MZ received research support from the German Research Foundation [DFG; WI 1820/14-1; ZE 1213/2-1].

Publisher Copyright:
© 2021 Elsevier Ltd

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