8db9db3cfcaade3105ea04d333e218f9 pmc_10137540.pdf 8237d7f42ed7a6788d3a00d5d78f1a7fda49cfee pmc_10137540.pdf 2c359b267371ae4a512cf8e34d7e42c9a68eb51a63c6310f37a4a67a00a643b2 pmc_10137540.pdf Title: The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant Subject: Biallelic variants in the mitochondrial form of the tryptophanyl-tRNA synthetases (WARS2) can cause a neurodevelopmental disorder with movement disorders including early-onset tremor–parkinsonism syndrome. Here, we describe four new patients, who all presented at a young age with a tremor–parkinsonism syndrome and responded well to levodopa. All patients carry the same recurrent, hypomorphic missense variant (NM_015836.4: c.37T>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>T; p.Gln116Ter), a novel canonical splice site variant (NM_015836.4: c.349-1G>A), or a novel missense variant (NM_015836.4: c.475A>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. Keywords: WARS2; tremor; parkinsonism; levodopa Author: Martje G. Pauly, G. Christoph Korenke, Sokhna Haissatou Diaw, Anne Grözinger, Ana Cazurro-Gutiérrez, Belén Pérez-Dueñas, Victoria González, Alfons Macaya, Ana Teresa Serrano Antón, Borut Peterlin, Ivana Babić Božović, Aleš Maver, Alexander Münchau and Katja Lohmann Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Mar 29 12:58:34 2023 CEST ModDate: Wed Mar 29 13:08:29 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 11 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1729523 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- LVYGFQ+URWPalladioL-Bold Type 1 Custom yes yes no 10 0 KRGPUP+URWPalladioL-Roma Type 1 Custom yes yes no 15 0 HTPEWW+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 OWBXTL+URWPalladioL-BoldItal Type 1 Custom yes yes no 23 0 ZZTQUO+VnURWPalladioL-Bold Type 1 Custom yes yes no 27 0 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FPLRVR+PalatinoLinotype CID TrueType Identity-H yes yes yes 191 0 FHBIOA+VnURWPalladioL Type 1 Custom yes yes no 209 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-08-08 02:25:29 CEST RepresentationInformation: pmc_10137540.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-08-01 02:31:39 CEST Size: 1729523 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 361 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Identification of Variants and Additional Patients Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Collection of Biosamples Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Sanger Sequencing and Sequencing of cDNA Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Staining of the Mitochondrial Network Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Western Blotting of MT-CO2 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Children: Item: Title: Case Reports Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: Patient 1 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Patient 2 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Patient 3 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Patient 4 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Characterization of WARS2 Variants Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Mitochondrial Integrity Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Respiratory Chain and WARS2 Level Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Info: Title: The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant Author: きちひぴなづ〠ぇ〮〠ぐちふぬべ〬〠ぇ〮〠ぃとひどびぴはばと〠かはひづのにづ〬〠こはにとのち〠えちどびびちぴはふ〠いどちぷ〬〠ぁののづ〠ぇひヶぺどのでづひ〬〠ぁのち〠ぃちぺふひひは〭ぇふぴどラひひづぺ〬〠あづぬラの〠ぐラひづぺ〭いふづヱちび〬〠ざどっぴはひどち〠ぇはのぺメぬづぺ〬〠ぁぬてはのび〠きちっちべち〬〠ぁのち〠ごづひづびち〠こづひひちのは〠ぁのぴンの〬〠あはひふぴ〠ぐづぴづひぬどの〬〠ぉぶちのち〠あちぢどㅜ〰㝜〰〠あはㅾはぶどㅜ〰㝜〰〬〠ぁぬづㅡ〠きちぶづひ〬〠ぁぬづへちのつづひ〠きーのっとちふ〠ちのつ〠かちぴなち〠がはとねちのの Subject: Biallelic variants in the mitochondrial form of the tryptophanyl-tRNA synthetases (WARS2) can cause a neurodevelopmental disorder with movement disorders including early-onset tremor parkinsonism syndrome. Here, we describe four new patients, who all presented at a young age with a tremor parkinsonism syndrome and responded well to levodopa. All patients carry the same recurrent, hypomorphic missense variant (NM_015836.4: c.37T>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>T; p.Gln116Ter), a novel canonical splice site variant (NM_015836.4: c.349-1G>A), or a novel missense variant (NM_015836.4: c.475A>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. 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