{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:19:49Z","timestamp":1785284389399,"version":"3.55.0"},"reference-count":23,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,29]],"date-time":"2023-03-29T00:00:00Z","timestamp":1680048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation (DFG)","doi-asserted-by":"publisher","award":["DFG-GEPRIS 413535489"],"award-info":[{"award-number":["DFG-GEPRIS 413535489"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation (DFG)","doi-asserted-by":"publisher","award":["PI21\/00248"],"award-info":[{"award-number":["PI21\/00248"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation (DFG)","doi-asserted-by":"publisher","award":["779257"],"award-info":[{"award-number":["779257"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation (DFG)","doi-asserted-by":"publisher","award":["305444"],"award-info":[{"award-number":["305444"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Damp Stiftung","award":["DFG-GEPRIS 413535489"],"award-info":[{"award-number":["DFG-GEPRIS 413535489"]}]},{"name":"Damp Stiftung","award":["PI21\/00248"],"award-info":[{"award-number":["PI21\/00248"]}]},{"name":"Damp Stiftung","award":["779257"],"award-info":[{"award-number":["779257"]}]},{"name":"Damp Stiftung","award":["305444"],"award-info":[{"award-number":["305444"]}]},{"name":"Gutes tun\u201d foundation of the University Hospital Schleswig Holstein","award":["DFG-GEPRIS 413535489"],"award-info":[{"award-number":["DFG-GEPRIS 413535489"]}]},{"name":"Gutes tun\u201d foundation of the University Hospital Schleswig Holstein","award":["PI21\/00248"],"award-info":[{"award-number":["PI21\/00248"]}]},{"name":"Gutes tun\u201d foundation of the University Hospital Schleswig Holstein","award":["779257"],"award-info":[{"award-number":["779257"]}]},{"name":"Gutes tun\u201d foundation of the University Hospital Schleswig Holstein","award":["305444"],"award-info":[{"award-number":["305444"]}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["DFG-GEPRIS 413535489"],"award-info":[{"award-number":["DFG-GEPRIS 413535489"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI21\/00248"],"award-info":[{"award-number":["PI21\/00248"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["779257"],"award-info":[{"award-number":["779257"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["305444"],"award-info":[{"award-number":["305444"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union\u2019s Horizon 2020","award":["DFG-GEPRIS 413535489"],"award-info":[{"award-number":["DFG-GEPRIS 413535489"]}]},{"name":"European Union\u2019s Horizon 2020","award":["PI21\/00248"],"award-info":[{"award-number":["PI21\/00248"]}]},{"name":"European Union\u2019s Horizon 2020","award":["779257"],"award-info":[{"award-number":["779257"]}]},{"name":"European Union\u2019s Horizon 2020","award":["305444"],"award-info":[{"award-number":["305444"]}]},{"name":"European Union Seventh Framework Programme (FP7\/2007-2013)","award":["DFG-GEPRIS 413535489"],"award-info":[{"award-number":["DFG-GEPRIS 413535489"]}]},{"name":"European Union Seventh Framework Programme (FP7\/2007-2013)","award":["PI21\/00248"],"award-info":[{"award-number":["PI21\/00248"]}]},{"name":"European Union Seventh Framework Programme (FP7\/2007-2013)","award":["779257"],"award-info":[{"award-number":["779257"]}]},{"name":"European Union Seventh Framework Programme (FP7\/2007-2013)","award":["305444"],"award-info":[{"award-number":["305444"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Biallelic variants in the mitochondrial form of the tryptophanyl-tRNA synthetases (WARS2) can cause a neurodevelopmental disorder with movement disorders including early-onset tremor\u2013parkinsonism syndrome. Here, we describe four new patients, who all presented at a young age with a tremor\u2013parkinsonism syndrome and responded well to levodopa. All patients carry the same recurrent, hypomorphic missense variant (NM_015836.4: c.37T&gt;G; p.Trp13Gly) either together with a previously described truncating variant (NM_015836.4: c.797Cdel; p.Pro266ArgfsTer10), a novel truncating variant (NM_015836.4: c.346C&gt;T; p.Gln116Ter), a novel canonical splice site variant (NM_015836.4: c.349-1G&gt;A), or a novel missense variant (NM_015836.4: c.475A&gt;C, p.Thr159Pro). We investigated the mitochondrial function in patients and found increased levels of mitochondrially encoded cytochrome C Oxidase II as part of the mitochondrial respiratory chain as well as decreased mitochondrial integrity and branching. Finally, we conducted a literature review and here summarize the broad phenotypical spectrum of reported WARS2-related disorders. In conclusion, WARS2-related disorders are diagnostically challenging diseases due to the broad phenotypic spectrum and the disease relevance of a relatively common missense change that is often filtered out in a diagnostic setting since it occurs in ~0.5% of the general European population.<\/jats:p>","DOI":"10.3390\/genes14040822","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T03:17:35Z","timestamp":1680146255000},"page":"822","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7794-0282","authenticated-orcid":false,"given":"Martje","family":"Pauly","sequence":"first","affiliation":[{"name":"Institute of Neurogenetics, University of Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany"},{"name":"Institute of Systems Motor Science, University of Luebeck, 23562 Luebeck, Germany"},{"name":"Department of Neurology, University Hospital Schleswig Holstein, 23562 Luebeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Korenke","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, University Children\u2019s Hospital, Klinikum Oldenburg, 26133 Oldenburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sokhna","family":"Diaw","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Gr\u00f6zinger","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Cazurro-Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Research Group, Autonomous University of Barcelona, Hospital Universitari Vall d\u2019Hebron, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"P\u00e9rez-Due\u00f1as","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Research Group, Autonomous University of Barcelona, Hospital Universitari Vall d\u2019Hebron, 08035 Barcelona, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Neurology, Autonomous University of Barcelona, Hospital Universitari Vall d\u2019Hebron, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfons","family":"Macaya","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Research Group, Autonomous University of Barcelona, Hospital Universitari Vall d\u2019Hebron, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5471-8550","authenticated-orcid":false,"given":"Ana","family":"Serrano Ant\u00f3n","sequence":"additional","affiliation":[{"name":"Clinical Genetic Section, Pediatric Service, Hospital Clinico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7824-4978","authenticated-orcid":false,"given":"Borut","family":"Peterlin","sequence":"additional","affiliation":[{"name":"Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Bo\u017eovi\u0107","sequence":"additional","affiliation":[{"name":"Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ale\u0161","family":"Maver","sequence":"additional","affiliation":[{"name":"Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"M\u00fcnchau","sequence":"additional","affiliation":[{"name":"Institute of Systems Motor Science, University of Luebeck, 23562 Luebeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5121-1460","authenticated-orcid":false,"given":"Katja","family":"Lohmann","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1159\/000015196","article-title":"Assignment of the Human Mitochondrial Tryptophanyl-TRNA Synthetase (WARS2) to 1p13.3-->p13.1 by Radiation Hybrid Mapping","volume":"83","author":"Justesen","year":"1998","journal-title":"Cytogenet. Cell Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1080\/15476286.2017.1330245","article-title":"Human Aminoacyl-TRNA Synthetases in Diseases of the Nervous System","volume":"15","year":"2018","journal-title":"RNA Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/humu.23205","article-title":"Mutations of the Aminoacyl-TRNA-Synthetases SARS and WARS2 Are Implicated in the Etiology of Autosomal Recessive Intellectual Disability: MUSANTE ET AL","volume":"38","author":"Musante","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1002\/ajmg.a.38339","article-title":"Deficiency of WARS2, Encoding Mitochondrial Tryptophanyl TRNA Synthetase, Causes Severe Infantile Onset Leukoencephalopathy","volume":"173","author":"Theisen","year":"2017","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1002\/humu.23340","article-title":"Biallelic Variants in WARS2 Encoding Mitochondrial Tryptophanyl-TRNA Synthase in Six Individuals with Mitochondrial Encephalopathy","volume":"38","author":"Wortmann","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1111\/cge.13172","article-title":"Biallelic Mutations in Mitochondrial Tryptophanyl-TRNA Synthetase Cause Levodopa-Responsive Infantile-Onset Parkinsonism","volume":"93","author":"Burke","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s13023-018-0822-6","article-title":"Severe Hepatopathy and Neurological Deterioration after Start of Valproate Treatment in a 6-Year-Old Child with Mitochondrial Tryptophanyl-TRNA Synthetase Deficiency","volume":"13","author":"Vantroys","year":"2018","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e654","DOI":"10.1002\/mgg3.654","article-title":"Mutations in the Mitochondrial Tryptophanyl-tRNA Synthetase Cause Growth Retardation and Progressive Leukoencephalopathy","volume":"7","author":"Maffezzini","year":"2019","journal-title":"Mol. Genet. Genomic. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.mito.2019.02.006","article-title":"Targeted next Generation Sequencing Identifies Novel Pathogenic Variants and Provides Molecular Diagnoses in a Cohort of Pediatric and Adult Patients with Unexplained Mitochondrial Dysfunction","volume":"47","author":"Nogueira","year":"2019","journal-title":"Mitochondrion"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1177\/0883073819854604","article-title":"Expanding the Phenotype: Neurodevelopmental Disorder, Mitochondrial, With Abnormal Movements and Lactic Acidosis, With or Without Seizures (NEMMLAS) Due to WARS2 Biallelic Variants, Encoding Mitochondrial Tryptophanyl-TRNA Synthase","volume":"34","author":"Virdee","year":"2019","journal-title":"J. Child Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/mdc3.12855","article-title":"Mutation of the WARS2 Gene as the Cause of a Severe Hyperkinetic Movement Disorder","volume":"7","author":"Huppertz","year":"2020","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.parkreldis.2020.02.003","article-title":"Co-Occurring WARS2 and CHRNA6 Mutations in a Child with a Severe Form of Infantile Parkinsonism","volume":"72","author":"Martinelli","year":"2020","journal-title":"Park. Relat. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.parkreldis.2022.01.012","article-title":"A Relatively Common Hypomorphic Variant in WARS2 Causes Monogenic Disease","volume":"94","author":"Ilinca","year":"2022","journal-title":"Park. Relat. Disord."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.parkreldis.2021.11.030","article-title":"WARS2 Mutations Cause Dopa-Responsive Early-Onset Parkinsonism and Progressive Myoclonus Ataxia","volume":"94","author":"Skorvanek","year":"2022","journal-title":"Park. Relat. Disord."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1038\/s41431-021-00859-0","article-title":"Solve-RD: Systematic Pan-European Data Sharing and Collaborative Analysis to Solve Rare Diseases","volume":"29","author":"Zurek","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1038\/s41431-021-00852-7","article-title":"Solving Patients with Rare Diseases through Programmatic Reanalysis of Genome-Phenome Data","volume":"29","author":"Matalonga","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1038\/s41431-018-0115-5","article-title":"RD-Connect, NeurOmics and EURenOmics: Collaborative European Initiative for Rare Diseases","volume":"26","author":"Badowska","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: The Human Genomic Variant Search Engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A General Framework for Estimating the Relative Pathogenicity of Human Genetic Variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"W446","DOI":"10.1093\/nar\/gkab266","article-title":"MutationTaster2021","volume":"49","author":"Steinhaus","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Diaw, S.H., Ganos, C., Zittel, S., Pl\u00f6tze-Martin, K., Kulikovskaja, L., Vos, M., Westenberger, A., Rakovic, A., Lohmann, K., and Dulovic-Mahlow, M. (2022). Mutant WDR45 Leads to Altered Ferritinophagy and Ferroptosis in \u03b2-Propeller Protein-Associated Neurodegeneration. IJMS, 23.","DOI":"10.3390\/ijms23179524"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gr\u00fcnewald, A., Voges, L., Rakovic, A., Kasten, M., Vandebona, H., Hemmelmann, C., Lohmann, K., Orolicki, S., Ramirez, A., and Schapira, A.H.V. (2010). Mutant Parkin Impairs Mitochondrial Function and Morphology in Human Fibroblasts. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012962"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The Mutational Constraint Spectrum Quantified from Variation in 141,456 Humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/4\/822\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:06:11Z","timestamp":1760123171000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/4\/822"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,29]]},"references-count":23,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["genes14040822"],"URL":"https:\/\/doi.org\/10.3390\/genes14040822","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,29]]}}}