Compound Heterozygous WARS2 Variants Including a Hypomorphic Allele Cause a Milder Phenotype of Complex Dopa Responsive Dystonia: Case Report and Review of the Literature

• Published in: Cerebellum (London, England) Vol. 23; no. 6; pp. 2616 - 2621
• Main Authors: Schneider, Vincent, Dupont, Gwendoline, Madinier, Guillaume, Ramond, Francis, Lesca, Gaetan, Thauvin-Robinet, Christel, Thomas, Quentin
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2024; Springer Nature B.V
• Subjects: Adult; Age; Alleles; Aminoacylation; Ataxia; Basal ganglia; Benzodiazepines; Biomedical and Life Sciences; Biomedicine; Brief Report; Case reports; Central nervous system diseases; Children; Dystonia; Dystonic Disorders - drug therapy; Dystonic Disorders - genetics; Genetics; Genomes; Genotype & phenotype; Genotypes; Hospitals; Humans; Literature reviews; Male; Movement disorders; Myoclonus; Neurobiology; Neurology; Neurosciences; Phenotype; Phenotypes; Rare diseases; Transfer RNA; Tryptophan-tRNA Ligase - genetics; Whole genome sequencing; Dopa-responsive dystonia; Early-onset parkinsonism; Genotype-phenotype correlation; Mild phenotype; Hypomorphic allele; WARS2
• ISSN: 1473-4230; 1473-4222; 1473-4230
• DOI: 10.1007/s12311-024-01725-7

Biallelic WARS2 pathogenic variants responsible for partial defect in aminoacylation, have recently been reported in subjects presenting with late-onset phenotypes combining dopa-responsive early-onset dystonia parkinsonism with altered DaTSCAN and progressive myoclonus ataxia. Here, we present the case of a 39-year-old male with childhood-onset progressive dopa-responsive dystonia parkinsonism, prominent psychiatric features and ataxia whose genome sequencing identified a p.(Arg36Ter) nonsense variant and a hypomorphic p.(Trp13Gly) missense variant, allowing the diagnosis of WARS2 -related disease. The p.(Trp13Gly) missense variant has previously been reported in individuals with less severe phenotypes than those carrying biallelic WARS2 loss-of-function variants. Among these individuals, two subjects had similar genetic backgrounds and almost identical clinical history to our patient. Our report brings additional proof that the p.(Trp13Gly) variant acts as a hypomorphic allele, offering insight on a genotype-phenotype correlation in WARS2 -related disorders.