AccScience Publishing / JBM / Online First / DOI: 10.14440/jbm.2024.0113
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REVIEW

Extraocular features of Leber hereditary optic neuropathy: A scoping review

Layla Ali1 ,  Iyawnna Hazzard1 ,  Niloufar S. Tehrani1 ,  Ubaid Ansari1† ,  Adam Ali1† ,  Preyasi Kumar1 ,  Nadia Ali2 ,  Gurkiranjeet Gakhal1 ,  Forshing Lui1*
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1 Office of Research, College of Medicine, California Northstate University, Elk Grove, California 95757, United States of America
2 Department of Translational Science, Rush University Medical Center, Chicago, Illinois 60612, United States of America
JBM, e99010055 https://doi.org/10.14440/jbm.2024.0113
Submitted: 12 November 2024 | Revised: 16 February 2025 | Accepted: 18 February 2025 | Published: 14 May 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Background: Leber hereditary optic neuropathy (LHON) is a rare inherited mitochondrial disease that leads to mitochondrial dysfunction, resulting in optic nerve damage and vision loss. Systemic involvement has been reported in several LHON cases, referred to as LHON+ disorders. However, the causes and presentations of such conditions have been poorly studied. It is suggested that 90% of mitochondrial dysfunction is caused by one of three primary point mutations in mitochondrial DNA that affect respiratory complex I (referred to as mtDNA LHON), with unresolved cases of LHON being caused by other variants, known as autosomal recessive LHON. The cardiac, musculoskeletal, neurological, and auditory systems are commonly affected in LHON. For example, hypertrophic cardiomyopathy and sudden cardiac death have been linked to specific mutations. Neurological effects – such as dystonia, epilepsy, polyneuropathy, and ataxia – as well as hearing loss, have also been observed in patients with specific mitochondrial mutations. These findings highlight the need for a more comprehensive evaluation beyond standard ophthalmic assessments. LHON is typically diagnosed based on a combination of ophthalmic imaging, patient age and gender, clinical course (bilateral, rapidly progressive, and sequential visual loss), family history, maternal inheritance, and fundus appearance. However, the advent of genetic testing has significantly expanded the recognized phenotype. In terms of treatment, idebenone is the only FDA-approved therapy for LHON; however, intravitreal gene therapy yields promising improvement, especially for the most common m.11778G>A mutation, which accounts for 70% of causative mutations. At present, these therapies are confined to ocular treatment. Objective: This review highlights the importance of recognizing systemic manifestations of LHON, which are frequently overlooked in clinical practice. Conclusion: Early detection of these systemic manifestations, especially in cardiac and neurological systems, could help with prompt intervention and improve patient outcomes. Further research into gene therapy and mitochondrial replacement techniques holds promising potential for developing more effective treatment strategies.

Keywords
Genetics
Leber hereditary optic neuropathy
Systemic involvement
Treatment
Funding
None.
Conflict of interest
The authors declare they have no competing interests.
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