{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:41:04Z","timestamp":1789522864638,"version":"build-2803163510"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["PI22\/01587"],"award-info":[{"award-number":["PI22\/01587"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["PI21\/00381"],"award-info":[{"award-number":["PI21\/00381"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Thymidine kinase 2 deficiency (TK2d) is an ultra\u2010rare autosomal recessive mitochondrial myopathy with variable presentations, including late\u2010onset forms beginning after age 12. Unlike early\u2010onset disease, the natural history of late\u2010onset TK2d remains poorly defined. We conducted a prospective, single\u2010centre natural history study of 11 untreated patients with late\u2010onset TK2d over 24\u2009months. The median age at symptom onset was 27.2\u2009years. Clinical phenotypes included progressive myopathy (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20097), chronic progressive external ophthalmoplegia plus (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20092), and exercise intolerance (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20092). Most patients (72%) required non\u2010invasive ventilation, and 70% showed axonal polyneuropathy. All patients carried biallelic pathogenic\n                    <jats:italic>TK2<\/jats:italic>\n                    variants, with p.Lys202del being the most common (13\/22 alleles). Muscle biopsies demonstrated mitochondrial DNA depletion and multiple deletions, and muscle MRI consistently showed selective involvement of the\n                    <jats:italic>sartorius<\/jats:italic>\n                    ,\n                    <jats:italic>gracilis<\/jats:italic>\n                    and\n                    <jats:italic>gluteus maximus<\/jats:italic>\n                    , whose fat fraction correlated with motor impairment. Functional assessments revealed a mean forced vital capacity of 70.4%, an NSAA score of 25.9, a six\u2010minute walk distance of 479.5\u2009m, and a 100\u2010m run time of 60.5\u2009s. Serum GDF15 levels were elevated (median 2747.5\u2009pg\/mL) and significantly correlated with motor and respiratory function. Over 2\u2009years, patients showed measurable clinical deterioration, with declines in NSAA (\u22122.65 points), FVC (\u22129.11%), and worsening 100\u2010meter run times (+6\u2009s). This study provides the first prospective longitudinal characterization of late\u2010onset TK2d and identifies clinically relevant, quantifiable outcomes that may inform future therapeutic trials targeting this underrepresented patient population. Moreover, these results are also relevant for the design of clinical trials in other mitochondrial myopathies.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70147","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T03:11:48Z","timestamp":1769137908000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring Outcome Measures for Mitochondrial Myopathies; Insights From a Longitudinal Study on\n                    <scp>TK2<\/scp>\n                    Deficiency"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6892-3632","authenticated-orcid":false,"given":"Paloma","family":"Mart\u00edn\u2010Jimenez","sequence":"first","affiliation":[{"name":"Neuromuscular Diseases Unit, Neurology Department Hospital Universitario 12 de Octubre  Madrid Spain"},{"name":"Medical\u2010Surgical Sciences Research, Faculty of Medicine Complutense University of Madrid  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Bermejo\u2010Guerrero","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Unit, Neurology Department Hospital Universitario 12 de Octubre  Madrid Spain"},{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019, Hospital Research Institute (imas12)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luz Edith","family":"Ochoa","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Unit, Neurology Department Hospital Universitario 12 de Octubre  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Navarro\u2010Riquelme","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019, Hospital Research Institute (imas12)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"Garrido\u2010Moraga","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019, Hospital Research Institute (imas12)  Madrid Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelio","family":"Hern\u00e1ndez\u2010La\u00edn","sequence":"additional","affiliation":[{"name":"Neuropathology Unit Hospital Universitario 12 de Octubre  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Hern\u00e1ndez\u2010Voth","sequence":"additional","affiliation":[{"name":"Pulmonology Department, Mechanical Ventilation and Neuromuscular Disorders Unit Hospital 12 de Octubre  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4011-362X","authenticated-orcid":false,"given":"Adri\u00e1n","family":"Gonz\u00e1lez Quintana","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019, Hospital Research Institute (imas12)  Madrid Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Bermejo\u2010Mori\u00f1igo","sequence":"additional","affiliation":[{"name":"Radiology Department Hospital Universitario 12 de Octubre  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Violeta","family":"Gonz\u00e1lez\u2010M\u00e9ndez","sequence":"additional","affiliation":[{"name":"Radiology Department Hospital Universitario 12 de Octubre  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2147-2811","authenticated-orcid":false,"given":"Cristina","family":"Mart\u00edn\u2010Arriscado Arroba","sequence":"additional","affiliation":[{"name":"Department of Statistics and Data Science Facultad de Estudios Estad\u00edsticos, Universidad Complutense de Madrid  Madrid Spain"},{"name":"Statistics Department Instituto de Investigaci\u00f3n Hospital Universitario 12 de Octubre (i+12)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrii","family":"Smirnov","sequence":"additional","affiliation":[{"name":"Jellyfish Bio, Inc., 1111B South Governors Avenue  Dover Delaware USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Konstantinovskiy","sequence":"additional","affiliation":[{"name":"Jellyfish Bio, Inc., 1111B South Governors Avenue  Dover Delaware USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaqu\u00edn","family":"Arenas","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019, Hospital Research Institute (imas12)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel \u00c1ngel","family":"Martin","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019, Hospital Research Institute (imas12)  Madrid Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER) Instituto de Salud Carlos III  Madrid Spain"},{"name":"Genetics Department Hospital Universitario  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6479-3615","authenticated-orcid":false,"given":"Alberto","family":"Bl\u00e1zquez","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019, Hospital Research Institute (imas12)  Madrid Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Dom\u00ednguez\u2010Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Unit, Neurology Department Hospital Universitario 12 de Octubre  Madrid Spain"},{"name":"Mitochondrial and Neuromuscular Research Group \u201812 de Octubre\u2019, Hospital Research Institute (imas12)  Madrid Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.07.009"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng751"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12860-020-00272-3"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1096-7192(03)00063-5"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn143"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm090"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000200138"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318248df2b"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.63.8.1122"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-019-1071-z"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.3233\/JND-210786"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2017-105012"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2018.04.012"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000213373"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr438"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2019-106649"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000210473"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000211173"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2020.100701"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-021-02030-w"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2022.07.399"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22115598"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25506"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2024.101879"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2025.109023"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-021-10957-0"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2018-0534"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.158.5.9710086"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awu279"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.3233\/JND-160145"},{"issue":"2","key":"e_1_2_12_32_1","first-page":"334","article-title":"Quantitative Muscle Magnetic Resonance Imaging as a Biomarker for Inclusion Body Myositis in Clinical Trials: Exploring the In Vivo Effects of Arimoclomol","volume":"43","author":"Salam S.","year":"2025","journal-title":"Clinical and Experimental Rheumatology"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1212\/CPJ.0000000000200229"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-66940-8"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2017.02.017"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-017-0027-5"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.50.6.1783"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2017.02.007"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/ptj\/pzac113"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.12220"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03304-z"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pdig.0000534"},{"key":"e_1_2_12_43_1","doi-asserted-by":"crossref","unstructured":"E.Mulligan B.McFarland andA.Lim \u201c37 Development of a Remote\u2010Use Scale for Monitoring Mitochondrial Disease in Patients \u201d2022 https:\/\/adc.bmj.com\/content\/107\/Suppl_2\/A217.2.","DOI":"10.1136\/archdischild-2022-rcpch.349"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.70147","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jimd.70147","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.70147","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:45:53Z","timestamp":1781743553000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jimd.70147"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/jimd.70147"],"URL":"https:\/\/doi.org\/10.1002\/jimd.70147","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2025-06-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70147"}}