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.

1st Department of Neurology Faculty of Medicine St Anne's University Hospital and CEITEC Masaryk University Brno Czech Republic

Department of Neurology Charles University 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Department of Neurology P J Safarik University Kosice Slovak Republic; Department of Neurology University Hospital of L Pasteur Kosice Slovak Republic

Department of Pediatrics and Adolescent Medicine Division of General Pediatrics Medical University of Graz Graz Austria

Division of Pediatric Neurology and Metabolic Medicine Centre for Child and Adolescent Medicine University Hospital Heidelberg Heidelberg Germany

Division of Pediatric Neurology University Children's Hospital Zurich Zurich Switzerland

Erasmus MC University Medical Center Rotterdam Department of Clinical Genetics Rotterdam Netherlands

Expertise Center Movement Disorders Groningen University Medical Center Groningen University of Groningen Groningen Netherlands

Institute of Human Genetics Technical University of Munich Munich Germany

Institute of Human Genetics Technical University of Munich Munich Germany; Lehrstuhl für Neurogenetik Technische Universität München Munich Germany; Munich Cluster for Systems Neurology SyNergy Munich Germany

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany; Institute of Human Genetics Technical University of Munich Munich Germany

University College London Institute of Neurology Department of Neuromuscular Disorders Queen Square WC1N 3BG London UK

Parkinsonism Relat Disord. 2022 Jan;94:129-131. doi: 10.1016/j.parkreldis.2022.01.012. PubMed

Citace poskytuje Crossref.org

Central European Group on Genetics of Movement Disorders

Challenges in Establishing the Diagnosis of PRRT2-Related Dystonia: Recurrent Pathogenic Variants in a Homopolymeric Stretch