{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:03:36Z","timestamp":1787504616511,"version":"build-2736575974"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T00:00:00Z","timestamp":1640131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Innovation, Madrid, Spain","award":["PMP15_00025"],"award-info":[{"award-number":["PMP15_00025"]}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI18\/01374"],"award-info":[{"award-number":["PI18\/01374"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Autosomal dominant mutations in the TWNK gene, which encodes a mitochondrial DNA helicase, cause adult-onset progressive external ophthalmoplegia (PEO) and PEO-plus presentations. In this retrospective observational study, we describe clinical and complementary data from 25 PEO patients with mutations in TWNK recruited from the Hospital 12 de Octubre Mitochondrial Disorders Laboratory Database. The mean ages of onset and diagnosis were 43 and 63 years, respectively. Family history was positive in 22 patients. Ptosis and PEO (92% and 80%) were the most common findings. Weakness was present in 48%, affecting proximal limbs, neck, and bulbar muscles. Exercise intolerance was present in 28%. Less frequent manifestations were cardiac (24%) and respiratory (4%) involvement, neuropathy (8%), ataxia (4%), and parkinsonism (4%). Only 28% had mild hyperCKemia. All 19 available muscle biopsies showed signs of mitochondrial dysfunction. Ten different TWNK mutations were identified, with c.1361T&gt;G (p.Val454Gly) and c.1070G&gt;C (p.Arg357Pro) being the most common. Before definitive genetic confirmation, 56% of patients were misdiagnosed (36% with myasthenia, 20% with oculopharyngeal muscle dystrophy). Accurate differential diagnosis and early confirmation with appropriately chosen complementary studies allow genetic counseling and the avoidance of unnecessary treatments. Thus, mitochondrial myopathies must be considered in PEO\/PEO-plus presentations, and particularly, TWNK is an important cause when positive family history is present.<\/jats:p>","DOI":"10.3390\/jcm11010022","type":"journal-article","created":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T10:24:52Z","timestamp":1640168692000},"page":"22","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Clinical, Histological, and Genetic Features of 25 Patients with Autosomal Dominant Progressive External Ophthalmoplegia (ad-PEO)\/PEO-Plus Due to TWNK Mutations"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8349-715X","authenticated-orcid":false,"given":"Laura","family":"Bermejo-Guerrero","sequence":"first","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Pablo","family":"de Fuenmayor-Fern\u00e1ndez de la Hoz","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5661-7574","authenticated-orcid":false,"given":"Pablo","family":"Serrano-Lorenzo","sequence":"additional","affiliation":[{"name":"Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Mitochondrial Disorders Laboratory, Clinical Biochemistry Department, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6479-3615","authenticated-orcid":false,"given":"Alberto","family":"Bl\u00e1zquez-Encinar","sequence":"additional","affiliation":[{"name":"Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Mitochondrial Disorders Laboratory, Clinical Biochemistry Department, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1391-754X","authenticated-orcid":false,"given":"Gerardo","family":"Guti\u00e9rrez-Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Infanta Sof\u00eda, 28703 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0622-7380","authenticated-orcid":false,"given":"Laura","family":"Mart\u00ednez-Vicente","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Cl\u00ednico San Carlos, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Gal\u00e1n-D\u00e1vila","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Cl\u00ednico San Carlos, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Garc\u00eda-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Neurology, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaqu\u00edn","family":"Arenas","sequence":"additional","affiliation":[{"name":"Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Mitochondrial Disorders Laboratory, Clinical Biochemistry Department, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Muelas","sequence":"additional","affiliation":[{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Neuromuscular Unit, Department of Neurology, Hospital Universitari I Polit\u00e8cnic La Fe, 46026 Valencia, Spain"},{"name":"Neuromuscular and Ataxias Research Group, Instituto de Investigaci\u00f3n Sanitaria La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelio","family":"Hern\u00e1ndez-La\u00edn","sequence":"additional","affiliation":[{"name":"Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain"},{"name":"Department of Neuropathology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5151-988X","authenticated-orcid":false,"given":"Cristina","family":"Dom\u00ednguez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"},{"name":"Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4741-772X","authenticated-orcid":false,"given":"Miguel A.","family":"Mart\u00edn","sequence":"additional","affiliation":[{"name":"Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain"},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Mitochondrial Disorders Laboratory, Clinical Biochemistry Department, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.bbadis.2017.02.017","article-title":"Mitochondrial DNA Maintenance Defects","volume":"1863","author":"Craigen","year":"2017","journal-title":"Biochim. 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