{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:01:08Z","timestamp":1787166068426,"version":"build-2736575974"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T00:00:00Z","timestamp":1726704000000},"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>Leber\u2019s Hereditary Optic Neuropathy (LHON) is a maternally inherited optic nerve disease primarily caused by mutations in mitochondrial DNA (mtDNA). The peak of onset is typically between 15 and 30 years, but variability exists. Misdiagnosis, often as inflammatory optic neuritis, delays treatment, compounded by challenges in timely genetic diagnosis. Given the availability of a specific treatment for LHON, its early diagnosis is imperative to ensure therapeutic appropriateness. This work gives an updated guidance about LHON differential diagnosis to clinicians dealing also with multiple sclerosi and neuromyelitis optica spectrtum disorders-related optic neuritis. LHON diagnosis relies on clinical signs and paraclinical evaluations. Differential diagnosis in the acute phase primarily involves distinguishing inflammatory optic neuropathies, considering clinical clues such as ocular pain, fundus appearance and visual recovery. Imaging analysis obtained with Optical Coherence Tomography (OCT) assists clinicians in early recognition of LHON and help avoiding misdiagnosis. Genetic testing for the three most common LHON mutations is recommended initially, followed by comprehensive mtDNA sequencing if suspicion persists despite negative results. We present and discuss crucial strategies for accurate diagnosis and management of LHON cases.<\/jats:p>","DOI":"10.3389\/fneur.2024.1466275","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T11:55:24Z","timestamp":1726746924000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Recognizing Leber\u2019s Hereditary Optic Neuropathy to avoid delayed diagnosis and misdiagnosis"],"prefix":"10.3389","volume":"15","author":[{"given":"Chiara","family":"La Morgia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Lucia","family":"Cascavilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"De Negri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Romano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Canalini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Centonze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Filippi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1126\/science.3201231","article-title":"Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy","volume":"242","author":"Wallace","year":"1988","journal-title":"Science"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.preteyeres.2003.10.003","article-title":"Mitochondrial dysfunction as a cause of optic neuropathies","volume":"23","author":"Carelli","year":"2004","journal-title":"Prog Retin Eye Res"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e42242","DOI":"10.1371\/journal.pone.0042242","article-title":"Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy","volume":"7","author":"Achilli","year":"2012","journal-title":"PLoS One"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e138267","DOI":"10.1172\/JCI138267","article-title":"Impaired complex I repair causes recessive Leber's hereditary optic neuropathy","volume":"131","author":"Stenton","year":"2021","journal-title":"J Clin Invest"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"521","DOI":"10.3390\/genes12040521","article-title":"Mcat mutations cause nuclear Lhon-like optic neuropathy","volume":"12","author":"Gerber","year":"2021","journal-title":"Genes (Basel)"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.preteyeres.2010.11.002","article-title":"Mitochondrial optic neuropathies \u2013 disease mechanisms and therapeutic strategies","volume":"30","author":"Yu-Wai-Man","year":"2011","journal-title":"Prog Retin Eye Res"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"2159","DOI":"10.1016\/j.ajhg.2021.09.015","article-title":"Establishing risk of vision loss in Leber hereditary optic neuropathy","volume":"108","author":"Lopez Sanchez","year":"2021","journal-title":"Am J Hum Genet"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.ajhg.2022.11.013","article-title":"Low disease risk and penetrance in Leber hereditary optic neuropathy","volume":"110","author":"Watson","year":"2023","journal-title":"Am J Hum Genet"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.ajhg.2022.11.014","article-title":"Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?","volume":"110","author":"Mackey","year":"2023","journal-title":"Am J Hum Genet"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1136\/practneurol-2015-001254","article-title":"Mimics and chameleons of optic neuritis","volume":"16","author":"Weerasinghe","year":"2016","journal-title":"Pract Neurol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1097\/WNO.0000000000000570","article-title":"International consensus statement on the clinical and therapeutic management of leber hereditary optic neuropathy","volume":"37","author":"Carelli","year":"2017","journal-title":"J Neuroophthalmol"},{"key":"ref12","article-title":"Idebenone summary of product characteristics","year":"2022"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/s40265-020-01428-3","article-title":"Therapeutic options in hereditary optic neuropathies","volume":"81","author":"Amore","year":"2021","journal-title":"Drugs"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1016\/s0161-6420(96)30665-9","article-title":"Ophthalmologic findings in Leber hereditary optic neuropathy, with special reference to Mtdna mutations","volume":"103","author":"Nikoskelainen","year":"1996","journal-title":"Ophthalmology"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.1093\/brain\/awq155","article-title":"Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies","volume":"133","author":"La Morgia","year":"2010","journal-title":"Brain"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"4471","DOI":"10.1167\/iovs.12-11137","article-title":"The pupil light reflex in Leber's hereditary optic neuropathy: evidence for preservation of melanopsin-expressing retinal ganglion cells","volume":"54","author":"Moura","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1001\/archopht.1982.01030040575003","article-title":"Ophthalmoscopic findings in Leber's hereditary optic neuropathy. I. Fundus findings in asymptomatic family members","volume":"100","author":"Nikoskelainen","year":"1982","journal-title":"Arch Ophthalmol"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1186\/s40064-016-2540-7","article-title":"A retrospective analysis of characteristics of visual field damage in patients with Leber's hereditary optic neuropathy","volume":"5","author":"Ran","year":"2016","journal-title":"Springerplus"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1097\/WNO.0b013e31829d1f5b","article-title":"Evaluation of fixation pattern and Reading ability in patients with Leber hereditary optic neuropathy","volume":"33","author":"Altpeter","year":"2013","journal-title":"J Neuroophthalmol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1167\/tvst.10.12.31","article-title":"Benefit of stimulus size V Perimetry for patients with a dense central scotoma from Leber's hereditary optic neuropathy","volume":"10","author":"Mejia-Vergara","year":"2021","journal-title":"Transl Vis Sci Technol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.ophtha.2004.09.033","article-title":"Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber's hereditary optic neuropathy mutations","volume":"112","author":"Savini","year":"2005","journal-title":"Ophthalmology"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"7608","DOI":"10.1167\/iovs.12-10452","article-title":"Mathematically modeling the involvement of axons in Leber's hereditary optic neuropathy","volume":"53","author":"Pan","year":"2012","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1016\/j.ophtha.2009.07.026","article-title":"Natural history of Leber's hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography","volume":"117","author":"Barboni","year":"2010","journal-title":"Ophthalmology"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1001\/archopht.1983.01040020061011","article-title":"Ophthalmoscopic findings in Leber's hereditary optic neuropathy. II. The fundus findings in the affected family members","volume":"101","author":"Nikoskelainen","year":"1983","journal-title":"Arch Ophthalmol"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1666","DOI":"10.1167\/iovs.08-2695","article-title":"Association of optic disc size with development and prognosis of Leber's hereditary optic neuropathy","volume":"50","author":"Ramos Cdo","year":"2009","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1136\/bjophthalmol-2015-307326","article-title":"Macular nerve fibre and ganglion cell layer changes in acute Leber's hereditary optic neuropathy","volume":"100","author":"Balducci","year":"2016","journal-title":"Br J Ophthalmol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s40942-015-0005-8","article-title":"A review of optical coherence tomography angiography (octa)","volume":"1","author":"de Carlo","year":"2015","journal-title":"Int J Retina Vitreous"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1001\/archopht.1973.01000050351002","article-title":"Ocular fundus in acute Leber optic neuropathy","volume":"90","author":"Smith","year":"1973","journal-title":"Arch Ophthalmol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1001\/archopht.1977.04450060055002","article-title":"The early phase in Leber hereditary optic atrophy","volume":"95","author":"Nikoskelainen","year":"1977","journal-title":"Arch Ophthalmol"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/s0005-2728(98)00163-7","article-title":"Clinical, biochemical and molecular genetic features of Leber's hereditary optic neuropathy","volume":"1410","author":"Chalmers","year":"1999","journal-title":"Biochim Biophys Acta"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.preteyeres.2017.11.003","article-title":"Optical coherence tomography angiography","volume":"64","author":"Spaide","year":"2018","journal-title":"Prog Retin Eye Res"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e290","DOI":"10.1111\/aos.13621","article-title":"Factors associated with deep circulation in the peripapillary chorioretinal atrophy zone in normal-tension glaucoma with myopic disc","volume":"96","author":"Kiyota","year":"2018","journal-title":"Acta Ophthalmol"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1111\/ceo.13326","article-title":"Peripapillary vessel density changes in Leber's hereditary optic neuropathy: a new biomarker","volume":"46","author":"Balducci","year":"2018","journal-title":"Clin Experiment Ophthalmol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.mito.2017.03.002","article-title":"Optical coherence tomography angiography of the peripapillary retina and optic nerve head in dominant optic atrophy","volume":"36","author":"Balducci","year":"2017","journal-title":"Mitochondrion"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1080\/01658107.2016.1275703","article-title":"Optical coherence angiographic demonstration of retinal changes from chronic optic neuropathies","volume":"41","author":"Chen","year":"2017","journal-title":"Neuroophthalmology"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1016\/s0002-9394(14)76784-4","article-title":"The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation","volume":"111","author":"Newman","year":"1991","journal-title":"Am J Ophthalmol"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1097\/WNO.0000000000000621","article-title":"MRI of the optic nerves and chiasm in patients with Leber hereditary optic neuropathy","volume":"38","author":"Blanc","year":"2018","journal-title":"J Neuroophthalmol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1001\/archopht.121.4.577","article-title":"Chiasmal enlargement and Optic nerve enhancement on magnetic resonance imaging in Leber hereditary optic neuropathy","volume":"121","author":"Phillips","year":"2003","journal-title":"Arch Ophthalmol"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"e94","DOI":"10.1212\/WNL.0000000000004760","article-title":"Teaching neuroimages: leber hereditary optic neuropathy masquerading as neuromyelitis optica","volume":"90","author":"Kassa","year":"2018","journal-title":"Neurology"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"e2585","DOI":"10.1212\/WNL.0000000000207979","article-title":"Pearls & oy-Sters: Leber hereditary optic neuropathy-plus masquerading as neuromyelitis optica spectrum disorder in a 2-year-old child","volume":"101","author":"Sunshine","year":"2023","journal-title":"Neurology"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1097\/WNO.0b013e318225247b","article-title":"Leber hereditary optic neuropathy mimicking neuromyelitis optica","volume":"31","author":"McClelland","year":"2011","journal-title":"J Neuroophthalmol"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1093\/brain\/115.4.979","article-title":"Occurrence of a multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation","volume":"115","author":"Harding","year":"1992","journal-title":"Brain"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1136\/jnnp-2014-308186","article-title":"MRI in Leber's hereditary optic neuropathy: the relationship to multiple sclerosis","volume":"86","author":"Matthews","year":"2015","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"e2021","DOI":"10.1038\/cddis.2015.364","article-title":"Cigarette toxicity triggers Leber's hereditary optic neuropathy by affecting MtDNA copy number, oxidative phosphorylation and ROS detoxification pathways","volume":"6","author":"Giordano","year":"2015","journal-title":"Cell Death Dis"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1016\/S1474-4422(22)00200-9","article-title":"Diagnosis and classification of optic neuritis","volume":"21","author":"Petzold","year":"2022","journal-title":"Lancet Neurol"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1080\/01658107.2019.1604764","article-title":"The utility of fundus fluorescein angiography in neuro-ophthalmology","volume":"43","author":"Littlewood","year":"2019","journal-title":"Neuroophthalmology"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1007\/s11910-024-01343-0","article-title":"Maculopapillary bundle degeneration in optic neuropathies","volume":"24","author":"Lambiri","year":"2024","journal-title":"Curr Neurol Neurosci Rep"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"101437","DOI":"10.1016\/j.xcrm.2024.101437","article-title":"Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: the LEROS nonrandomized controlled trial","volume":"5","author":"Yu-Wai-Man","year":"2024","journal-title":"Cell Rep Med"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1007\/s40123-022-00611-x","article-title":"Indirect comparison of lenadogene nolparvovec gene therapy versus natural history in patients with Leber hereditary optic neuropathy carrying the m.11778G>a MT-ND4 mutation","volume":"12","author":"Carelli","year":"2023","journal-title":"Ophthalmol Ther"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2024.1466275\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T11:55:26Z","timestamp":1726746926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2024.1466275\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,19]]},"references-count":49,"alternative-id":["10.3389\/fneur.2024.1466275"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2024.1466275","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,19]]},"article-number":"1466275"}}