{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T13:09:04Z","timestamp":1764940144330,"version":"3.46.0"},"reference-count":19,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Reports"],"abstract":"<jats:p>Background and Clinical Significance: Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder characterized by acute or subacute bilateral central vision loss, typically in young males. Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are immune-mediated demyelinating diseases that may present with optic neuritis and myelitis. Although distinct in etiology, recent evidence suggests that mitochondrial dysfunction and neuroinflammation can overlap, giving rise to combined phenotypes such as LHON-MS (also known as Harding\u2019s disease). Case Presentation: We report a 42-year-old man who initially presented in 2018 with right-eye pain and severe visual loss diagnosed as idiopathic optic neuritis. Despite corticosteroid and plasma-exchange therapy, visual recovery was poor, and he was maintained on azathioprine. One year later, he developed visual flashes and left-eye visual loss with bilateral optic nerve thinning on OCT. Genetic testing revealed a pathogenic MT-ND4 (m.11778G&gt;A) mutation, confirming LHON. In 2021, he presented with ascending lower-limb numbness and bladder urgency. MRI demonstrated a central thoracic cord lesion at T11, consistent with acute transverse myelitis, while serum AQP4 and MOG antibodies were negative. CSF showed five unique oligoclonal bands. The diagnosis of LHON-MS overlap was established, and he was treated with corticosteroids followed by rituximab with clinical stability thereafter. Conclusions: This case highlights the diagnostic challenges of LHON with atypical optic neuritis initially followed by the development of demyelinating disease. Red flags such as poor visual recovery, bilateral or sequential optic neuropathy, and steroid-refractory episodes should prompt genetic testing to rule out LHON. Recognition of the mitochondrial\u2013immune overlap is essential for accurate diagnosis, counseling, and an appropriate therapeutic strategy.<\/jats:p>","DOI":"10.3390\/reports8040258","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T10:50:38Z","timestamp":1764931838000},"page":"258","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial\u2013Immune Overlap in Leber Hereditary Optic Neuropathy: A Case Report and Lessons Learned"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6096-3667","authenticated-orcid":false,"given":"Hind","family":"Alnajashi","sequence":"first","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, King Abdulaziz University, Jeddah P.O. Box 80200, Saudi Arabia"},{"name":"Department of Neurology, King Abdulaziz University Hospital, Jeddah P.O. Box 80200, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walid","family":"Eltantawi","sequence":"additional","affiliation":[{"name":"International Medical Centre, Jeddah P.O. Box 80200, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s004150070153","article-title":"Mitochondrial mutations of Leber\u2019s hereditary optic neuropathy: A risk factor for multiple sclerosis","volume":"247","author":"Vanopdenbosch","year":"2000","journal-title":"J. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rahimi, G., Silverman, M., Lucas, M., Kazerooni, L., Yousuf, M.M., Jafarpour, S., and Santoro, J.D. (2025). Leber\u2019s hereditary optic neuropathy and multiple sclerosis: Overlap between mitochondrial disease and neuroinflammation. Front. 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