Leber’s Hereditary Optic Neuropathy: An Overview and Future Therapeutics

Sadat Yazdouni 

Introduction

Leber’s Hereditary Optic Neuropathy (LHON) was first described in 1871 by Theodor Leber. It is a rare disease, with an estimated prevalence of 1 in 30,000 to 50,000 individuals in European populations (1). LHON predominantly affects males in their second or third decades of life. The disease’s hallmark is the rapid onset of central vision loss due to selective damage to RGCs and the optic nerve.

Genetic Basis

LHON is caused by point mutations in mtDNA, most commonly m.11778G>A in the MT-ND4 gene, m.14484T>C in the MT-ND6 gene, and m.3460G>A in the MT-ND1 gene (1,2). These mutations impair the function of complex I in the mitochondrial respiratory chain, leading to increased oxidative stress and reduced ATP production. Although the disease is maternally inherited, the incomplete penetrance suggests the involvement of environmental factors and nuclear genetic modifiers (3).

Clinical Features

The onset of LHON is usually acute or subacute. Patients initially experience painless central vision loss in one eye, followed by involvement of the second eye within weeks to months. Fundoscopic examination may reveal hyperaemia and swelling of the optic disc, peripapillary telangiectatic vessels, and absence of leakage on fluorescein angiography (4). Over time, optic atrophy becomes evident.

Diagnosis

The diagnosis of LHON is primarily clinical but is confirmed through genetic testing for mtDNA mutations. Optical coherence tomography (OCT) shows thinning of the retinal nerve fibre layer (RNFL), particularly in the papillomacular bundle. Visual field testing reveals central or cecocentral scotomas (5). Ancillary tests, such as electrophysiological studies, can help assess the extent of RGC dysfunction.

Management

Currently, there is no definitive cure for LHON. Management focuses on supportive care and genetic counselling. Idebenone, a short-chain benzoquinone, has shown promise in improving visual outcomes, particularly if administered early in the disease course (6). Other experimental therapies include gene therapy targeting mitochondrial mutations and antioxidant treatments to reduce oxidative stress (7).

Smoking and Alcohol Consumption and Disease Onset

Evidence suggests a significant relationship between alcohol consumption and the onset or exacerbation of symptoms in individuals predisposed to LHON. Alcohol is a known mitochondrial toxin that exacerbates oxidative stress and impairs mitochondrial function. It inhibits complex I of the mitochondrial respiratory chain, amplifying the dysfunction caused by LHON-associated mtDNA mutations (8). Additionally, alcohol increases the production of reactive oxygen species (ROS), leading to further damage to retinal ganglion cells and the optic nerve. This mechanism highlights the importance of avoiding alcohol in individuals with a genetic predisposition to LHON, as it may act as a critical environmental trigger for disease manifestation.

Future Therapeutics

Research into potential future therapeutics for LHON is ongoing, with several promising approaches being explored. These include:

  1. Gene Therapy: Gene replacement strategies aim to deliver functional copies of affected mitochondrial genes directly to retinal cells. One such approach involves an adeno-associated virus (AAV) vector carrying the wild-type ND4 gene, which has shown encouraging results in clinical trials (9).
  2. Stem Cell Therapy: Stem cell-based interventions are under investigation to replace damaged retinal ganglion cells and restore optic nerve function. Preliminary studies suggest that stem cell-derived exosomes may also have neuroprotective effects (10).
  3. Mitochondrial Replacement Therapy: Techniques such as mitochondrial transfer or replacement therapy are being evaluated to improve mitochondrial function in affected cells (11).
  4. Novel Antioxidants: Next-generation antioxidants, such as EPI-743 and elamipretide, are being studied for their ability to reduce oxidative damage and support mitochondrial integrity in LHON patients(12,13).
  5. Neuroprotective Agents: Emerging neuroprotective drugs aim to enhance the survival and function of RGCs by targeting apoptotic pathways and promoting cellular resilience (14).

Discussion

The pathogenesis of LHON highlights the critical role of mitochondrial dysfunction in optic neuropathies. Despite advances in understanding its genetic basis, the variable penetrance and expression of the disease remain poorly understood. Early diagnosis and intervention with idebenone may mitigate vision loss in some cases. Ongoing research into gene therapy, mitochondrial bioenergetics, and neuroprotective agents offers hope for future treatments.

Conclusion

Leber’s Hereditary Optic Neuropathy is a debilitating condition with significant implications for affected individuals and their families. Advances in genetic research and therapeutics are essential to improve outcomes and quality of life. Further studies are needed to elucidate the interplay between genetic and environmental factors in disease expression.

References

1.        Yu-Wai-Man P, Griffiths PG, Hudson G, Chinnery PF. Inherited mitochondrial optic neuropathies. J Med Genet [Internet]. 2009 Mar 1 [cited 2025 Jan 17];46(3):145–58. Available from: https://jmg.bmj.com/content/46/3/145

2.        Yu-Wai-Man P, Chinnery PF. Leber Hereditary Optic Neuropathy. GeneReviews® [Internet]. 2021 Mar 11 [cited 2025 Jan 17]; Available from: https://www.ncbi.nlm.nih.gov/books/NBK1174/

3.        Newman NJ, Biousse V. Hereditary optic neuropathies. Eye 2004 18:11 [Internet]. 2004 Nov 8 [cited 2025 Jan 17];18(11):1144–60. Available from: https://www.nature.com/articles/6701591

4.        Huoponen K. Leber hereditary optic neuropathy: Clinical and molecular genetic findings. Neurogenetics [Internet]. 2001 May 16 [cited 2025 Jan 17];3(3):119–25. Available from: https://link.springer.com/article/10.1007/s100480100115

5.        Hedges TR, Gobuty M, Manfready RA, Erlich-Malona N, Monaco C, Mendoza-Santiesteban CE. The Optical Coherence Tomographic Profile of Leber Hereditary Optic Neuropathy. Neuro-Ophthalmology [Internet]. 2016 May 3 [cited 2025 Jan 17];40(3):107–12. Available from: https://www.tandfonline.com/doi/abs/10.3109/01658107.2016.1173709

6.        Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain [Internet]. 2011 [cited 2025 Jan 17];134(9):2677. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC3170530/

7.        Shamsnajafabadi H, MacLaren RE, Cehajic-Kapetanovic J. Current and Future Landscape in Genetic Therapies for Leber Hereditary Optic Neuropathy. Cells [Internet]. 2023 Aug 1 [cited 2025 Jan 17];12(15):2013. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10416882/

8.        Rabenstein A, Catarino CB, Rampeltshammer V, Schindler D, Gallenmüller C, Priglinger C, et al. Smoking and alcohol, health-related quality of life and psychiatric comorbidities in Leber’s Hereditary Optic Neuropathy mutation carriers: a prospective cohort study. Orphanet J Rare Dis [Internet]. 2021 Dec 1 [cited 2025 Jan 17];16(1):1–12. Available from: https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01724-5

9.        Wan X, Pei H, Zhao MJ, Yang S, Hu WK, He H, et al. Efficacy and Safety of rAAV2-ND4 Treatment for Leber’s Hereditary Optic Neuropathy. Scientific Reports 2016 6:1 [Internet]. 2016 Feb 19 [cited 2025 Jan 17];6(1):1–10. Available from: https://www.nature.com/articles/srep21587

10.     Mohana Devi S, Abishek Kumar B, Mahalaxmi I, Balachandar V. Leber’s hereditary optic neuropathy: Current approaches and future perspectives on Mesenchymal stem cell-mediated rescue. Mitochondrion. 2021 Sep 1;60:201–18.

11.      Wong RCB, Lim SY, Hung SSC, Jackson S, Khan S, Van Bergen NJ, et al. Mitochondrial replacement in an iPSC model of Leber’s hereditary optic neuropathy. Aging [Internet]. 2017 Apr 29 [cited 2025 Jan 17];9(4):1341–50. Available from: https://www.aging-us.com/article/101231

12.     Sadun AA, Chicani CF, Ross-Cisneros FN, Barboni P, Thoolen M, Shrader WD, et al. Effect of EPI-743 on the Clinical Course of the Mitochondrial Disease Leber Hereditary Optic Neuropathy. Arch Neurol [Internet]. 2012 Mar 12 [cited 2025 Jan 17];69(3):331–8. Available from: https://jamanetwork.com/journals/jamaneurology/fullarticle/1108018

13.     Karanjia R, Sadun AA. Elamipretide Topical Ophthalmic Solution for the Treatment of Subjects with Leber Hereditary Optic Neuropathy: A Randomized Trial. Ophthalmology [Internet]. 2024 Apr 1 [cited 2025 Jan 17];131(4):422–33. Available from: http://www.aaojournal.org/article/S0161642023008023/fulltext

14.     Ghelli A, Zanna C, Porcelli AM, Schapira AHV, Martinuzzi A, Carelli V, et al. Leber’s Hereditary Optic Neuropathy (LHON) Pathogenic Mutations Induce Mitochondrial-dependent Apoptotic Death in Transmitochondrial Cells Incubated with Galactose Medium. Journal of Biological Chemistry. 2003 Feb 7;278(6):4145–50.

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