Leber Hereditary Optic Neuropathy

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Leber hereditary optic neuropathy (LHON) is a genetic disorder that causes optic neuropathy and can lead to severe visual disability. LHON was the first disease discovered to be caused by a point mutation in mitochondrial DNA, and recent de­velopments now make LHON the first mitochondrial disorder treatable with gene therapy.¹

Epidemiology

The prevalence of vision loss due to LHON has been estimated to be be­tween 1 in 30,000 and 1 in 65,000 in Northern Europe, Asia, and Australia. Between 70% and 90% of individuals with vision loss due to LHON are male, and the onset of vision loss in males typically occurs between the ages of 20 and 30 years. Women affected by LHON tend to be older. Although epidemiological data are limited, there are no known overt racial, ethnic, or geographic disparities.

Genetics and Pathophysiology

LHON is caused by mutations in mitochondrial DNA (mtDNA). More than 90% of LHON patients worldwide carry one of three primary mtDNA point mutations: G11778A, T14484C, or G3460A (approximately 70%, 13%, and 14% of cases, respectively). These mutations affect proteins located in mitochondrial membranes that are involved in cellular respiration through the process of oxidative phos­phorylation.

Intriguingly, only approxi­mately 50% of males and 10% of females who carry a LHON mu­tation manifest optic neuropathy. This incomplete penetrance and sex imbalance im­ply the presence of modulatory factors beyond mtDNA muta­tions that affect disease phenotype. It has been suggested that environmental factors or genetic factors encoded by nuclear DNA (possibly on the X-chro­mosome) play a role in disease patho­physiology. Another theory suggests that individuals with LHON mutations harbor variable percentages of unmu­tated mtDNA—known as heteroplasmy—and that a patient’s phenotype may be determined by the balance of nor­mal and mutated mtDNA.

Clinical Features, Presentation

Classic presentation. The classic presentation of LHON is a young adult male who develops acute or subacute, painless, severe unilateral vision loss, followed by similar vision loss in the fellow eye two or three months later (though rarely the delay may be much longer).

Less commonly, patients may be female or of older age, or they may present with simultaneous bilateral involvement.

LHON Plus. Occasionally, patients exhibit extraocular manifestations, including neurologic, psychiatric, and cardiac conduction abnormalities. Cases with such features are termed LHON Plus.

Disability varies. The severity of visual disability is widely variable, even within affected families and among patients who share the same causative genetic mutation. Because the cause of such marked phenotypic variability remains unclear, it is difficult to predict if, when, or how a genetically affected individual will manifest disease in their lifetime.

Diagnosis

Differential diagnosis. LHON should be considered in the differential di­agnosis of any case of painless, unex­plained optic neuropathy, regardless of laterality, patient sex, age, or family history. Other diagnoses to consider in the setting of acute unilateral or bilateral central vision loss with signs suggestive of acute optic neuropathy are optic neuritis, retrobulbar compres­sion due to an intracranial mass, and toxic or nutritional optic neuropathy. The differential diagnosis for chronic vision loss resulting in papillomacular retinal nerve fiber layer (RNFL) dam­age and temporal optic atrophy include late presentations of the diagnoses listed above as well as dominant optic atrophy. Patients with vision loss but no other overt examination findings may be initially misdiagnosed with functional vision loss disorder.

Diagnostic features. The exam, visual function testing, imaging, and genetic testing can help determine the diagnosis.

Exam signs. Certain exam signs favor a diagnosis of LHON (see “Early and Late Features of LHON,” below). Typically, a relative afferent pupillary defect is minimal or absent, which is unique among asymmetric optic neuropathies. Notably, pupillary light reflexes are largely preserved through­out the disease course, even after optic atrophy has occurred. It is thought that melanopsin-containing intrinsically photosensitive retinal ganglion cells—which contribute to the pupillary response—may be spared in LHON, and that their persistent activity may maintain pupillary responses.²

The optic disc in acute LHON classically exhibits “pseudoedema,” also described as “nerve fiber layer prom­inence” or “fullness.” The disc margin may be hyperemic with telangiectatic and tortuous vessels; together, these subtle vascular changes have been described as circumpapillary telangiec­tatic microangiopathy (Fig. 1).

Approximately six weeks after the onset of vision loss, disc pseudoedema and peripapillary vascular changes resolve, and the optic nerve takes on a more atrophic appearance. At this stage, temporal pallor of the optic disc is common, reflecting permanent loss of the papillomacular nerve fiber bundle (Fig. 2). As with other aspects of LHON, the fundus examination is inconsistent. In some patients, early exam signs may be evident preceding any vision changes, whereas others with active vision loss may initially have a fundus that appears normal.

Visual function testing. The tempo and course of vision loss is also an im­portant diagnostic feature. Visual dys­function typically progresses until a na­dir is reached three to six months after symptom onset. Visual function testing demonstrates a dense central vision defect with poor VA, typically 20/200 or worse. Extremely poor vision (e.g., light perception or worse) or only slightly decreased vision (except in very early disease) should prompt evaluation for alternate diagnoses. Typically, the ear­liest finding on visual field testing is a cecocentral scotoma, corresponding to early loss of the papillomacular nerve fiber bundle, which later evolves into a central scotoma. Dyschromatopsia in proportion to the decline in VA is almost invariably present.

Imaging. Ocular imaging in the diagnosis of LHON is of indirect utility but can be helpful to diagnose and follow patients. Classically, fluorescein angiography was used to prove optic nerve pseudoedema by demonstrating a lack of true disc leakage despite the presence of disc congestion on fun­dus exam. Early in the disease course, OCT of the RNFL may be normal or thickened in the setting of edema of retinal ganglion cells (RGCs). Later in the disease process, RGC axons atrophy and the RNFL thins. This thinning is typically evident earliest and most severely in the temporal quadrant along the course of the papillomacular RNFL bundle.³ OCT evaluation of the macu­lar RGC complex also shows thinning within a few weeks of presentation, a finding that usually precedes RNFL thinning. It may therefore be clini­cally useful to monitor both parame­ters. There are no reliable or specific findings with brain or orbital MRI, but neuroimaging may be necessary to exclude alternate diagnoses such as retrobulbar optic nerve compression by tumors or to evaluate for LHON Plus syndromes.

Genetic testing. Genetic testing for causative mtDNA mutations can provide definitive diagnosis in individ­uals with suggestive clinical features. In patients suspected to have LHON, it is recommended to first pursue a targeted mtDNA sequencing approach probing for the three most common mutations (approximately 90% of LHON pa­tients).⁴ If such targeted analysis is unrevealing, subsequent sequencing can be performed using a larger, more comprehensive multigene panel. If necessary, sequencing of the entire mi­tochondrial genome can be performed.

TYPICAL FUNDUS SIGNS. (1) Optic nerve pseudoedema and circumpapillary telangiectasias (arrows) in a LHON patient early in the disease process. (2) Optic nerve pallor and atrophy in the same patient late in the disease course.

Management

Current therapies. Idebenone, the only medication approved by the European Medicine Agency to treat LHON, is a synthetic form of coenzyme Q₁₀, a molecule that acts as an electron shuttle in the electron transport chain during mitochondrial respiration. No treat­ments have been approved for use in the United States. Other medications, including steroids, cyanide antagonists, brimonidine, cyclosporine, and hy­droxycobalamin, do not appear to be effective.

In 2011, a prospective, randomized clinical trial (RHODOS) randomized patients with LHON diagnosed within the previous five years to treatment with 24 weeks of daily oral ibedenone or placebo.⁵ While the initial trial did not meet its primary endpoint com­paring improvement in VA between the two groups, there was a trend toward a beneficial, protective effect. Despite a lack of proven efficacy, given the seemingly favorable risk/benefit ratio, idebenone was approved for use in Europe in 2015. Consensus guidelines suggest starting idebenone for LHON patients with vision loss of less than one year in duration.⁶ Studies of other potentially neuroprotective agents—including EPI-743, an investigational antioxidant that has shown promise in a small LHON cohort—are ongoing.⁷

Therapies in development. Gene therapy has emerged as one of the most promising approaches to treat inherited ophthalmic diseases. Multiple recent clinical trials have investigated treating LHON patients who have the G11778A mutation with a one-time intravit­real injection of viral-mediated gene therapy. The goal of this approach is for patients to be able to produce a fully functional mitochondrial ND4 protein, which is defective in the presence of the G11778A mutation.⁸ Three different therapeutics are currently in develop­ment. Trials that have reported safety data have shown the most common side effect of treatment to be mild, self-limiting ocular inflammation, and no serious ocular or systemic adverse effects have so far been observed through multiple years of follow-up. Treatment appears to promote a mod­est improvement in visual recovery compared to the natural history of the disorder.⁹ In general, younger patients and those treated more quickly follow­ing the onset of vision loss appear to respond best to treatment. Gene thera­py is currently only available within the context of a clinical trial, unless special approval is sought.

Many of these early clinical trials were designed for one eye to receive gene therapy and the other to receive sham treatment so that the sham-treat­ed eye could serve as an internal con­trol. Surprisingly, however, results have consistently shown that not only does the eye receiving gene therapy regain some vision, but also there is improve­ment in the sham-treated eye (albeit slightly less than the directly treated eye). It has been shown that viral vector DNA is capable of transferring from the treated eye to the contralateral nontreated eye in nonhuman primate experiments,¹⁰ providing a plausible mechanism for the bilateral treatment effect.

Early and Late Features of LHON

Prognosis

Natural history. Most LHON patients develop permanent bilateral central vision loss. However, even without treatment, at least partial spontaneous visual recovery is possible. Natural history studies have shown that among patients with the three most common mutations, patients with the T14484C mutation have the highest rate of spon­taneous improvement from visual nadir (35%-60% of patients), those with the G3460A mutation have an intermediate rate (approximately 20%), and patients with the G11778A mutation have the lowest rate of recovery (approximately 5%). Recovery typically begins as small islands of improved vision within the central defect and usually occurs within the first two years after vision loss. Final VA is widely variable. Gene therapy appears capable of increasing the in­cidence and degree of visual improve­ment in patients with the G11778A mutation.⁹

Patients should be counseled to avoid environmental toxins and heavy alcohol and tobacco use, which can exacerbate the existing mitochondrial optic neuropathy. Patients often benefit from referral to vision rehabilitation clinics and should be monitored for the development of comorbid depression, which is common in this population due to significant visual disability.

Genetic counseling. Affected patients should be offered formal genetic counseling. They can be counseled with certainty that mutations in mtDNA cannot be inherited paternally but will be passed down from an affected mother to all of her children. However, given the incomplete understanding of all the factors that impact LHON phe­notypes, there is significant prognostic uncertainty for individuals harboring a causative mutation.

Conclusion

LHON is a maternally inherited optic neuropathy caused by mutations in mtDNA. For reasons that are not yet clear, the disease exhibits incomplete penetrance and a widely variable phenotype. LHON most commonly presents in young adult males but should be considered in any case of undifferentiated, painless optic neurop­athy. Pharmacologic and gene therapy treatment approaches have been shown to be safe and possibly effective in pro­moting some visual recovery, though no treatment has been approved for use in the United States, and most patients still develop significant permanent bilateral vision loss.

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1 Sahel JA et al. Int Ophthalmol Clin. 2021;61(4):195-208.

2 Moura ALA et al. Invest Ophthalmol Vis Sci. 2013;54(7):4471-4477.

3 Barboni P et al. Ophthalmology. 2010;117(3):623-627.

4 Yu-Wai-Man P, Chinnery PF. Leber Hereditary Optic Neuropathy. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews. University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1174/. Accessed Sept. 1, 2022.

5 Klopstock T et al. Brain. 2011;134(Pt 9):2677-2686.

6 Carelli V et al. J Neuroophthalmol. 2017;37(4):371-381.

7 Hage R, Vignal-Clermont C. Front Neurol. 2021;12:651639.

8 Chi SC et al. Biomedicines. 2022;10(8):1930.

9 Newman NJ et al. Front Neurol. 2021;12:662838.

10 Yu-Wai-Man P et al. Sci Transl Med. 2020;12(573):eaaz7423.

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Dr. Grassmeyer is an ophthalmology resident at the Casey Eye Institute and Dr. Winges is a neu­ro-ophthalmologist at the Portland VA Medical Center, both in Portland, Ore. Relevant financial disclosures: None.

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