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

M. Skorvanek, I. Rektorova, W. Mandemakers, M. Wagner, R. Steinfeld, L. Orec, V. Han, P. Pavelekova, A. Lackova, K. Kulcsarova, M. Ostrozovicova, Z. Gdovinova, B. Plecko, T. Brunet, R. Berutti, DJS. Kuipers, V. Boumeester, P. Havrankova, MAJ....

. 2022 ; 94 (-) : 54-61. [pub] 20211202

Language English Country Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22019583

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.

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$a Skorvanek, Matej $u Department of Neurology, P.J. Safarik University, Kosice, Slovak Republic; Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic. Electronic address: mskorvanek@gmail.com
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$a WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia / $c M. Skorvanek, I. Rektorova, W. Mandemakers, M. Wagner, R. Steinfeld, L. Orec, V. Han, P. Pavelekova, A. Lackova, K. Kulcsarova, M. Ostrozovicova, Z. Gdovinova, B. Plecko, T. Brunet, R. Berutti, DJS. Kuipers, V. Boumeester, P. Havrankova, MAJ. Tijssen, R. Kaiyrzhanov, M. Rizig, H. Houlden, J. Winkelmann, V. Bonifati, M. Zech, R. Jech
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$a 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.
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$a Rektorova, Irena $u First Department of Neurology, Faculty of Medicine, St. Anne's University Hospital, and CEITEC, Masaryk University, Brno, Czech Republic
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$a Mandemakers, Wim $u Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, Rotterdam, Netherlands
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$a Wagner, Matias $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University of Munich, Munich, Germany
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$a Steinfeld, Robert $u Division of Pediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland
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$a Orec, Laura $u Division of Pediatric Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
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$a Han, Vladimir $u Department of Neurology, P.J. Safarik University, Kosice, Slovak Republic; Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic
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$a Ostrozovicova, Miriam $u Department of Neurology, P.J. Safarik University, Kosice, Slovak Republic; Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic
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$a Gdovinova, Zuzana $u Department of Neurology, P.J. Safarik University, Kosice, Slovak Republic; Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic
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$a Plecko, Barbara $u Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria
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$a Brunet, Theresa $u Institute of Human Genetics, Technical University of Munich, Munich, Germany
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$a Berutti, Riccardo $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University of Munich, Munich, Germany
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$a Kuipers, Demy J S $u Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, Rotterdam, Netherlands
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$a Boumeester, Valerie $u Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, Rotterdam, Netherlands
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$a Havrankova, Petra $u Department of Neurology, Charles University, First Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic
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$a Tijssen, M A J $u Expertise Center Movement Disorders Groningen, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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$a Winkelmann, Juliane $u Institute of Human Genetics, Technical University of Munich, Munich, Germany; Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany; Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
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$a Bonifati, Vincenzo $u Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, Rotterdam, Netherlands
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$a Zech, Michael $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University of Munich, Munich, Germany
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