{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:18:11Z","timestamp":1777861091535,"version":"3.51.4"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T00:00:00Z","timestamp":1737072000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T00:00:00Z","timestamp":1737072000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171394"],"award-info":[{"award-number":["82171394"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301590"],"award-info":[{"award-number":["82301590"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371410"],"award-info":[{"award-number":["82371410"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023M742116"],"award-info":[{"award-number":["2023M742116"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2024MH231"],"award-info":[{"award-number":["ZR2024MH231"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2023QH106"],"award-info":[{"award-number":["ZR2023QH106"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Progressive external ophthalmoplegia (PEO) is a classic manifestation of mitochondrial disease. However, the link between its genetic characteristics and clinical presentations remains poorly investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analysed the clinical, pathological and genetic characteristics of a large cohort of patients with PEO, based on the type of their mtDNA variations. Eighty\u2010two PEO patients were enrolled and grouped into three categories: mtDNA single large\u2010scale deletions (SLDs), multiple deletions (MulDs) and the m.3243A\u2009&gt;\u2009G point variant. Patients in the SLD category were further divided into \u2018common deletion\u2019 and \u2018noncommon deletion\u2019 groups based on the presence or absence of a 4977\u2010bp deletion. The mutational load of deleted mtDNA of these patients was comprehensively detected by real\u2010time polymerase chain reaction (RT\u2010PCR).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SLD Patients showed the highest proportion of cytochrome C oxidase\u2010negative (COX\u2010n) fibres on muscle biopsy. The mutational load of deleted mtDNA exhibited an inverse relationship with deletion length and a direct relationship with the COX\u2010n fibre ratio. Compared with patients having noncommon deletions, those with common deletions tend to have other muscle involvement, lower body mass index (BMI) scores (17\u2009\u00b1\u20093 vs. 22\u2009\u00b1\u20094\u2009kg\/m\n                      <jats:sup>2<\/jats:sup>\n                      ), higher mutational load in muscle (63%\u2009\u00b1\u200922% vs. 46%\u2009\u00b1\u200924%), more COX\u2010n fibres (26% vs. 9%, interquartile range [IQR]: 15%\u201332% vs. 6%\u201326%) and higher growth and differentiation factor 15 (GDF15) levels (2583 vs. 1472, IQR: 1746\u20134081 vs. 924\u20132155\u2009pg\/mL). MulDs patients displayed milder symptoms, especially compared to patients with m.3243A\u2009&gt;\u2009G variant, as indicated by their later age of onset (31 vs. 13, IQR: 27\u201349 vs. 6\u201329\u2009years), higher BMI scores (24.0\u2009\u00b1\u20094 vs. 16.5\u2009\u00b1\u20093.4\u2009kg\/m\n                      <jats:sup>2<\/jats:sup>\n                      ), lower lactate (1.6\u2009\u00b1\u20091.1 vs. 6.3\u2009\u00b1\u20096.0\u2009mmol\/L) levels and lower proportion of ragged\u2010blue fibres (RBFs) (3 vs. 16, IQR: 1%\u20139% vs. 7%\u201327%).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The m.3243A\u2009&gt;\u2009G variant group exhibits more severe symptoms compared to other subgroups, particularly MulDs patients. In the SLD group, those with common deletions experience more severe clinical and pathological manifestations. These findings enhance our understanding of PEO, facilitating its diagnosis, prognosis and genetic counselling.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nan.70001","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T04:59:48Z","timestamp":1737089988000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genotype\u2013Phenotype Correlation in Progressive External Ophthalmoplegia: Insights From a Retrospective Analysis"],"prefix":"10.1111","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4279-2188","authenticated-orcid":false,"given":"Jiayin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University  Jinan Shandong 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Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Busu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University  Jinan Shandong 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