{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T08:43:22Z","timestamp":1787301802758,"version":"build-2736575974"},"reference-count":13,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T00:00:00Z","timestamp":1646697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Mutations in nuclear-encoded genes that are involved in mitochondrial DNA replication and maintenance (e.g., <jats:italic>POLG<\/jats:italic>) have been associated with chronic progressive external ophthalmoplegia (CPEO) phenotype. These nuclear genome mutations may lead to multiple mitochondrial DNA deletions or mitochondrial DNA depletion. On the other hand, primary genetic defects of mitochondrial DNA (such as single large-scale deletion or point mutations) have also been associated with the CPEO phenotype. Chronic progressive external ophthalmoplegia (CPEO) may be a manifestation of specific syndromes that, when clinically recognized, prompt clinicians to investigate specific genetic defects. Thus, CPEO, as part of Kearns Sayre syndrome, suggests the presence of a large-scale deletion of mitochondrial DNA. However, in pure CPEO or CPEO plus phenotypes, it is more difficult to know whether causative genetic defects affect the nuclear or mitochondrial DNA. Here, we present a patient with a long-standing history of CPEO plus phenotype, in whom the sequencing of mitochondrial DNA from skeletal muscle was normal, and no other genetic defect was suspected at first. At the time of our evaluation, the presence of polyneuropathy and neuropathic pain prompted us to investigate nuclear genetic defects and, specifically, mutations in the <jats:italic>POLG<\/jats:italic> gene. Thus, the sequencing of the <jats:italic>POLG<\/jats:italic> gene revealed p.Thr251Ile and p.Pro587Leu mutations in one allele, and p.Ala467Thr mutation in another allele. Although one would expect that mutations in <jats:italic>POLG<\/jats:italic> lead to multiple mitochondrial DNA deletions or depletion (loss of copies), the absence of mitochondrial DNA abnormalities in tissue may be explained by heteroplasmy, a lack or no significant involvement of biopsied tissue, or a sampling bias. So, the absence of secondary mitochondrial DNA alterations should not discourage clinicians from further investigating mutations in nuclear-encoded genes. Lastly, mitochondrial point mutations and single mitochondrial DNA deletions very rarely cause CPEO associated with polyneuropathy and neuropathic pain, and POLG-related disease should be considered in this scenario, instead.<\/jats:p>","DOI":"10.3389\/fneur.2022.846110","type":"journal-article","created":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T07:24:02Z","timestamp":1646724242000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Neuropathic Pain as Main Manifestation of POLG-Related Disease: A Case Report"],"prefix":"10.3389","volume":"13","author":[{"given":"Melanie","family":"Lang-Orsini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma","family":"Gonzalez-Perez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/s41582-018-0101-0","article-title":"POLG-related disorders and their neurological manifestations","volume":"15","author":"Rahman","year":"2019","journal-title":"Nat Rev Neurol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s11910-016-0652-7","article-title":"Progressive external ophthalmoplegia","volume":"16","author":"McClelland","year":"2016","journal-title":"Curr Neurol Neurosci Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1007\/s00415-015-7710-y","article-title":"Redefining phenotypes associated with mitochondrial DNA single deletion","volume":"262","author":"Mancuso","year":"2015","journal-title":"J Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1007\/s10038-008-0289-8","article-title":"Genotype and phenotype analyses in 136 patients with single large-scale mitochondrial DNA deletions","volume":"53","author":"Yamashita","year":"2008","journal-title":"J Hum Genet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1093\/brain\/awl088","article-title":"Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene","volume":"129","author":"Horvath","year":"2006","journal-title":"Brain."},{"key":"B6","doi-asserted-by":"publisher","first-page":"760","DOI":"10.4103\/0028-3886.293454","article-title":"Clinicogenetical variants of progressive external ophthalmoplegia-An especial review of non-ophthalmic manifestations","volume":"68","author":"Maghbooli","year":"2020","journal-title":"Neurol India."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3200","DOI":"10.1093\/brain\/awu279","article-title":"Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia","volume":"137","author":"Horga","year":"2014","journal-title":"Brain."},{"key":"B8","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1016\/j.nmd.2016.02.008","article-title":"\u201cMitochondrial neuropathies\u201d: a survey from the large cohort of the Italian Network","volume":"26","author":"Mancuso","year":"2016","journal-title":"Neuromuscul Disord."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e113","DOI":"10.1212\/NXG.0000000000000113","article-title":"Peripheral neuropathy in patients with CPEO associated with single and multiple mtDNA deletions","volume":"2","author":"Lehmann","year":"2016","journal-title":"Neurol Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/90034","article-title":"Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions","volume":"28","author":"Van Goethem","year":"2001","journal-title":"Nat Genet."},{"key":"B11","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1093\/brain\/awh410","article-title":"Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA","volume":"128","author":"Ferrari","year":"2005","journal-title":"Brain."},{"key":"B12","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.jns.2011.02.012","article-title":"Inherited mitochondrial neuropathy","volume":"304","author":"Finsterer","year":"2011","journal-title":"J Neurol Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/0960-8966(94)00080-S","article-title":"Chronic progressive external ophthalmoplegia with ragged-red fibers: clinical, morphological and genetic investigations in 43 patients","volume":"5","author":"Laforet","year":"1995","journal-title":"Neuromuscul Disord."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.846110\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T07:24:03Z","timestamp":1646724243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.846110\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,8]]},"references-count":13,"alternative-id":["10.3389\/fneur.2022.846110"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2022.846110","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,8]]},"article-number":"846110"}}