Skorvanek, M;
Rektorova, I;
Mandemakers, W;
Wagner, M;
Steinfeld, R;
Orec, L;
Han, V;
... Jech, R; + view all
(2022)
WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.
Parkinsonism & Related Disorders
, 94
pp. 54-61.
10.1016/j.parkreldis.2021.11.030.
Preview |
Text
Rizig_WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia_AAM.pdf Download (1MB) | Preview |
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: 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.
Archive Staff Only
 |
View Item |
