PuSH - Publikationsserver des Helmholtz Zentrums München: <em>WARS2</em> mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.

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Škorvánek, M.* ; Rektorová, I.* ; Mandemakers, W.* ; Wagner, M. ; Steinfeld, R.* ; Orec, L.* ; Han, V.* ; Pavelekova, P.* ; Lackova, A.* ; Kulcsarová, K.* ; Ostrozovičová, M.* ; Gdovinova, Z.* ; Plecko, B.* ; Brunet, T.* ; Berutti, R. ; Kuipers, D.J.S.* ; Boumeester, V.* ; Havránková, P.* ; Tijssen, M.A.J.* ; 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. 94, 54-61 (2022)

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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.

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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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