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Updated Review of Leber Hereditary Optic Neuropathy

  • Neurologic Ophthalmology and Otology (R Shin and D Gold, Section Editors)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Abstract

Purpose of Review

We aim to present a comprehensive review of Leber hereditary optic neuropathy (LHON), detailing currently established practices for diagnosis and management, as well as emerging research on novel therapies.

Recent Findings

A randomized, placebo-controlled, double-masked trial demonstrated, in a post hoc analysis, that the anti-oxidant supplement idebenone may offer visual benefit in a subset of LHON patients early in the disease course. Several recent clinical trials have evaluated the safety and efficacy of gene therapy targeting the most common LHON mutation, m.11778/ND4. These trials unexpectedly reported bilateral visual improvement with monocular treatment, which prevented them from meeting their primary endpoints due to lack of the anticipated internal control (the untreated eye). However, when compared with previously published natural history studies, phase 3 clinical trials evaluating the gene therapy Lumevoq® (lenadogene nolparvovec) demonstrated sustained bilateral visual improvement, both with monocular and binocular treatment.

Summary

Studies of gene therapy for LHON have shown modestly promising results, and more studies are planned. As of April 2022, no gene therapy agents have received marketing approval from the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). For now, multidisciplinary support, with idebenone in some cases, remains the standard management for LHON patients, offering a means for functionality despite vision loss.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Wallace DC, Singh G. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. 1988;242:1427–30.

    CAS  Google Scholar 

  2. Chinnery PF, Johnson MA. The epidemiology of pathogenic mitochondrial DNA mutations. 2000;48:188–93.

    CAS  Google Scholar 

  3. Yu-Wai-Man P, et al. The epidemiology of Leber hereditary optic neuropathy in the North East of England. 2003;72:333–9.

    CAS  Google Scholar 

  4. Spruijt L, et al. Influence of mutation type on clinical expression of Leber hereditary optic neuropathy. 2006;141:676–82.

    Google Scholar 

  5. Yu-Wai-Man P, Chinnery PF. Leber hereditary optic neuropathy. 2000. https://www.ncbi.nlm.nih.gov/books/NBK1174/. Accessed April 27, 2022.

  6. Rosenberg T, et al. Prevalence and genetics of Leber hereditary optic neuropathy in the Danish population. 2016;57:1370–5.

    CAS  Google Scholar 

  7. Chinnery PF, et al. Leber hereditary optic neuropathy: does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? 2001;98:235–243.

  8. Jurkute N, et al. Clinical utility gene card for: inherited optic neuropathies including next-generation sequencing-based approaches. 2019;27:494–502.

    CAS  Google Scholar 

  9. Howell N. Leber hereditary optic neuropathy: respiratory chain dysfunction and degeneration of the optic nerve. 1998;38:1495–504.

    CAS  Google Scholar 

  10. Johns DR, et al. Leber’s hereditary optic neuropathy. Clinical manifestations of the 14484 mutation. 1993;111:495–498.

  11. Carelli V, et al. International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. 2017;37:371–81.

    Google Scholar 

  12. Newman NJ, et al. Visual outcomes in Leber hereditary optic neuropathy patients with the m.11778G>A (MTND4) mitochondrial DNA mutation. 2020;40:547–557.

  13. Kirkman MA, et al. Gene-environment interactions in Leber hereditary optic neuropathy. 2009;132:2317–26.

    Google Scholar 

  14. Yen M, et al. Leber’s hereditary optic neuropathy: a multifactorial disease. 2006;25:381–96.

    Google Scholar 

  15. Jacobson DM, et al. Relative afferent pupillary defects in patients with Leber hereditary optic neuropathy and unilateral visual loss. 1998;126:291–5.

    CAS  Google Scholar 

  16. Newman NJ. Walsh and Hoyt’s clinical neuro-ophthalmology. Baltimore: Lippincott Williams & Wilkins; 2005.

    Google Scholar 

  17. Ruijin R, et al. A retrospective analysis of characteristics of visual field damage in patients with Leber’s hereditary optic neuropathy. 2016;5:843.

    Google Scholar 

  18. Shemesh A, et al. Leber hereditary optic neuropathy (LHON). 2021. https://www.ncbi.nlm.nih.gov/books/NBK482499/. Accessed April 27, 2022.

  19. Nikoskelainen R, et al. The early phase in Leber hereditary optic atrophy. 1977;95:969–78.

    CAS  Google Scholar 

  20. Wang D, et al. Characterisation of thickness changes in the peripapillary retinal nerve fibre layer in patients with Leber’s hereditary optic neuropathy. 2021;105:1166–71.

    Google Scholar 

  21. Hedges TR, et al. The optical coherence tomographic profile of Leber hereditary optic neuropathy. 2016;40:107–12.

    Google Scholar 

  22. Matthews L, et al. MRI in Leber’s hereditary optic neuropathy: the relationship to multiple sclerosis. 2015;86:537–42.

    Google Scholar 

  23. Blanc C, et al. MRI of the optic nerves and chiasm in patients with Leber hereditary optic neuropathy. 2018;38:434–7.

    Google Scholar 

  24. Wallace SE, Bean LJH. Educational materials – genetic testing: current approaches. 2017. https://www.ncbi.nlm.nih.gov/books/NBK279899/#app5.Multigene_Panels. Accessed April 27, 2022.

  25. Sundaramurthy A, et al. Next-generation sequencing of the complete mitochonfrial genome in individual with Leber hereditary optic neuropathy negative for the common pathogenic mitochondrial DNA mutations. 2020;61:5183.

    Google Scholar 

  26. Newman NJ. Treatment of Leber hereditary optic neuropathy. 2011;134:2447–50.

    Google Scholar 

  27. Lyseng-Williamson KA. Idebenone: a review in Leber’s hereditary optic neuropathy. 2016;76:805–813.

  28. Klopstock T, et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy (RHODOS). 2011;134:2677–86.

    Google Scholar 

  29. Carelli V, et al. Idebenone treatment in Leber’s hereditary optic neuropathy. 2011;134:188.

    Google Scholar 

  30. Thouin A, et al. Raised intraocular pressure as a potential risk factor for visual loss in Leber hereditary optic neuropathy. 2013;8:63446.

    Google Scholar 

  31. Biousse V, Newman NJ. The NORD guide to rare disorders. Philadelphia: Lippincott Williams & Wilkins; 2003.

    Google Scholar 

  32. Bower SP, et al. Cardiac arrhythmia and Leber’s hereditary optic neuropathy. 1992;339:1427–8.

    CAS  Google Scholar 

  33. Mackey D, et al. A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology. 1991;51:1218–28.

    Google Scholar 

  34. Slone J, Huang T. The special considerations of gene therapy for mitochondrial diseases. 2020;5:7.

    Google Scholar 

  35. Sahel JA, et al. Gene therapies for the treatment of Leber hereditary optic neuropathy. 2021;61:195–208.

    Google Scholar 

  36. Guy J, et al. Gene therapy for Leber hereditary optic neuropathy: low- and medium- dose visual results. 2017;124:1621–34.

    Google Scholar 

  37. Lam BL, et al. Leber hereditary optic neuropathy gene therapy: adverse events and visual acuity results of all patient groups. Epub ahead of print. 2022.

  38. •• Yuan J, et al. Seven-year follow-up of gene therapy for Leber’s hereditary optic neuropathy. 2020;8:1125–1127. This review conducted in China built on the prior safety profile demonstrated by Guy et al. in 2017, again demonstrated a favorable safety profile of the rAAV2/ND4 intravenous gene therapy over a 7-year period.

  39. •• Yu-Wai-Man P, et al. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. 2020;12. The REVERSE trial was the first to directly measure efficacy of the rAAV2/ND4 intravenous gene therapy and demonstrated bilateral visual recovery after single eye injection. This suggested a crossing of the therapy to the fellow eye.

  40. •• Newman NJ, et al. Efficacy and safety of intravitreal gene therapy for Leber hereditary optic neuropathy treated within 6 months of disease onset. 2021;128:649–660. The RESCUE trial was similarly designed to REVERSE and demonstrated efficacy of the rAAV2/ND4 intravenous gene therapy in patients with less than 6 months of visual symptoms from LHON.

  41. •• Efficacy & safety study of bilateral IVT injection of GS010 in LHON subjects due to the ND4 mutation for up to 1 year. ClinicalTrials.gov. 2019. https://www.clinicaltrials.gov/ct2/show/study/NCT03293524. Accessed 27 Apr 2022. The REFLECT trial is currently awaiting conclusion and reporting of data in literature. This trial builds on REVERSE and RESCUE’s findings of bilateral visual improvement by studying the efficacy of rAAV2/ND4 intravenous gene therapy injections into both eyes.

  42. •• Biousse V, et al. Long-term follow-up after unilateral intravitreal gene therapy for Leber hereditary optic neuropathy: the RESTORE study. 2021;3:309–315. The RESTORE study demonstrated sustained treatment efficacy and safety of the rAAV2/ND4 intravenous gene therapy up from 96 weeks to 4.3 years.

  43. Yu-Wai-Man P, et al. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. 2020;573.

  44. Newman NJ. REFLECT trial: efficacy and safety of bilateral gene therapy for Leber hereditary optic neuropathy. In: NANOS 48th Annual Meeting On Demand Content. 2022. https://www.eventscribeapp.com/live/videoPlayer.asp?lsfp=N3ltTm9wUkFNVVErU1gxMk8rR3pqM3BUZTBBM3dYMDFJV201THFONzFwWT0=. Accessed April 27, 2022.

  45. Vignal-Clermont C, et al. Safety of intravitreal gene therapy for treatment of subjects with Leber hereditary optic neuropathy due to mutations in the mitochondrial ND4 gene: the REVEAL study. 2021;35:201–214.

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Authors and Affiliations

  1. Division of Neuro-Ophthalmology, Johns Hopkins University School of Medicine, Wilmer Eye Institute 600 N. Wolfe St., MD, 21287, Baltimore, USA

    Michael G. Carper MD & Amanda D. Henderson MD

  2. Department of Neurology, Johns Hopkins Hospital, 1800 Orleans St., Baltimore, MD, 21287, USA

    Amanda D. Henderson MD

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  1. Michael G. Carper MD
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Correspondence to Michael G. Carper MD.

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Michael G. Carper declares that he has no conflict of interest. Amanda D. Henderson declares that she has no conflict of interest.

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This article is part of the Topical Collection on Neurologic Ophthalmology and Otology

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Carper, M.G., Henderson, A.D. Updated Review of Leber Hereditary Optic Neuropathy. Curr Treat Options Neurol 24, 441–452 (2022). https://doi.org/10.1007/s11940-022-00729-0

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