Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Skorvanek, M; Rektorova, I; Mandemakers, W; Wagner, M; Steinfeld, R; Orec, L; Han, V; Pavelekova, P; Lackova, A; Kulcsarova, K; Ostrozovicova, M; Gdovinova, Z; Plecko, B; Brunet, T; Berutti, R; Kuipers, DJS; Boumeester, V; Havrankova, P; Tijssen, MAJ; Kaiyrzhanov, R; Rizig, M; Houlden, H; Winkelmann, J; Bonifati, V; Zech, M; Jech, R.
WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.
Parkinsonism Relat Disord. 2021; 94: 54-61.
Doi: 10.1016/j.parkreldis.2021.11.030
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PubMed
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- Co-Autor*innen der Med Uni Graz
- Plecko Barbara
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- 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.
- Find related publications in this database (Keywords)
- WARS2
- Early onset parkinsonism
- Progressive myoclonus ataxia
- Whole exome sequencing