| Title: |
WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia |
| Authors: |
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 |
| Source: |
Parkinsonism & Related Disorders , 94 pp. 54-61. (2022) |
| Publisher Information: |
ELSEVIER SCI LTD |
| Publication Year: |
2022 |
| Collection: |
University College London: UCL Discovery |
| Description: |
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: 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. 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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10177995/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10177995/3/Rizig_WARS2%20mutations%20cause%20dopa-responsive%20early-onset%20parkinsonism%20and%20progressive%20myoclonus%20ataxia_AAM.pdf; https://discovery.ucl.ac.uk/id/eprint/10177995/ |
| Rights: |
open |
| Accession Number: |
edsbas.140FF4EE |
| Database: |
BASE |