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

Parkinsonism Relat Disord. 2022 Jan:94:54-61. doi: 10.1016/j.parkreldis.2021.11.030. Epub 2021 Dec 2.


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.

Keywords: Early onset parkinsonism; Progressive myoclonus ataxia; WARS2; Whole exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia
  • Dihydroxyphenylalanine
  • Humans
  • Mutation
  • Myoclonus*
  • Parkinsonian Disorders* / drug therapy
  • Parkinsonian Disorders* / genetics
  • Phenotype
  • Spinocerebellar Degenerations*
  • Tremor
  • Tryptophan-tRNA Ligase* / genetics


  • Dihydroxyphenylalanine
  • Tryptophan-tRNA Ligase