Leber Hereditary Optic Neuropathy

Clinical characteristics.

Leber hereditary optic neuropathy (LHON) is characterized by bilateral, painless, subacute visual failure that develops during young adult life. Males are four to five times more likely than females to be affected. Affected individuals are usually entirely asymptomatic until they develop visual blurring affecting the central visual field in one eye; similar symptoms appear in the other eye an average of two to three months later. In about 25% of cases, visual loss is bilateral at onset. Visual acuity is severely reduced to counting fingers or worse in the majority of cases, and visual field testing shows an enlarging dense central or centrocecal scotoma. After the acute phase, the optic discs become atrophic. Significant improvement in visual acuity is rare and most persons qualify for registration as legally blind (visual acuity ≤20/200). Neurologic abnormalities such as postural tremor, peripheral neuropathy, nonspecific myopathy, and movement disorders have been reported to be more common in individuals with LHON than in the general population. Some individuals with LHON, usually women, may also develop a multiple sclerosis-like illness.

Diagnosis/testing.

The diagnosis of LHON is established in a proband with bilateral, painless, subacute visual failure that develops during young adult life and/or by the identification of one of three common mtDNA pathogenic variants (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4, or m.14484T>C in MT-ND6) on molecular genetic testing.

Management.

Treatment of manifestations: Management of affected individuals is largely supportive, with the provision of visual aids, help with occupational rehabilitation, and registration with the relevant social services. ECG may reveal a pre-excitation syndrome in individuals harboring a mtDNA LHON-causing pathogenic variant; referral to cardiology can be considered and treatment for symptomatic individuals is the same as that in the general population. A multidisciplinary approach for those affected individuals with extraocular neurologic features (ataxia, peripheral neuropathy, nonspecific myopathy, and movement disorders) should be considered to minimize the functional consequences of these complications.

Prevention of primary manifestations: Treatment for raised intraocular pressure in individuals who have a LHON-causing pathogenic variant.

Agents/circumstances to avoid: Individuals harboring a mtDNA LHON-causing pathogenic variant should be strongly advised to moderate their alcohol intake and not to smoke. Avoiding exposure to other putative environmental triggers for visual loss, in particular industrial toxins and drugs with mitochondrial-toxic effects, also seems reasonable.

Genetic counseling.

Leber hereditary optic neuropathy is caused by pathogenic variants in mtDNA and transmitted by mitochondrial (maternal) inheritance. Genetic counseling for LHON is complicated by the gender- and age-dependent penetrance of the primary mtDNA LHON-causing pathogenic variants. The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. In most cases a history of visual loss affecting maternal relatives at a young age is present, but up to 40% of cases are simplex (i.e., occur in a single individual in a family). A male (affected or unaffected) with a primary LHON-causing mtDNA pathogenic variant cannot transmit the variant to any of his offspring. A female (affected or unaffected) with a primary LHON-causing mtDNA pathogenic variant transmits the variant to all of her offspring. Prenatal diagnosis for mitochondrial pathogenic variants is possible if the variant in a family is known; however, accurate interpretation of a positive prenatal test result is difficult because the mtDNA mutational load in amniocytes and chorionic villi may not correspond to that of other fetal or adult tissues, and the presence of the mtDNA pathogenic variant does not predict the occurrence of disease, age of onset, severity, or rate of disease progression.

Suggestive Findings

Leber hereditary optic neuropathy (LHON) should be suspected in individuals with the following ophthalmologic, extraocular, neuroimaging, biochemical, and family history findings:

Ophthalmologic

• Bilateral, painless subacute visual failure that develops during young adult life
  • Visual acuity is severely reduced to counting fingers or worse in the majority of cases.
  • Visual field testing by kinetic or static perimetry shows an enlarging dense central or centrocecal scotoma.
• Disk hyperemia, edema of the peripapillary retinal nerve fiber layer, retinal telangiectasia, and increased vascular tortuosity
  Note: Approximately 20% of affected individuals show no fundal abnormalities in the acute stage.
• Optic disc atrophy
• Electrophysiologic studies (pattern electroretinogram and visual evoked potentials) demonstrating optic nerve dysfunction and the absence of retinal disease

Extraocular

• Neurologic abnormalities
  • Postural tremor
  • Peripheral neuropathy
  • Movement disorders
  • Multiple sclerosis-like illness
• Nonspecific myopathy
• Cardiac arrhythmias

Neuroimaging. Magnetic resonance imaging (MRI) is often normal, but may reveal white matter lesions and/or a high signal within the optic nerves [Matthews et al 2015].

Biochemical studies show respiratory chain defect that is more subtle than that seen in other mitochondrial genetic disorders. The m.3460G>A pathogenic variant in MT-ND1 is associated with the most severe biochemical phenotype (see Table 1).

Family history of similarly affected individuals is seen in up to 60% of probands. Note: Absence of a family history of LHON does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of LHON is established in a proband with the ocular manifestations listed in Suggestive Findings and/or by the identification of one of three common mtDNA pathogenic variants on molecular genetic testing (see Table 2).

Molecular testing approaches can include targeted testing, a multigene panel, or complete mtDNA sequencing.

Targeted testing. Three common mtDNA pathogenic variants account for 90%-95% of LHON. Targeted analysis for one of these three variants should be performed first.

• m.3460G>A in MT-ND1
• m.11778G>A in MT-ND4, present in 70% of affected individuals of northern European descent and 90% of affected individuals of Asian descent [Mackey et al 1996, Mashima et al 1998, Jia et al 2006]
• m.14484T>C in MT-ND6, commonly found among French Canadians due to a founder effect [Mackey et al 1996, Macmillan et al 1998, Chinnery et al 2001, Yu-Wai-Man et al 2003]

A multigene panel that includes the mitochondrial genes that encode subunits of NADH dehydrogenase, MT-ND1, MT-ND2, MT-ND4, MT-ND4L, MT-ND5, and MT-ND6, which are known to cause LHON (see Table 5 [pdf]) and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and the sensitivity of multigene panels vary by laboratory and over time.

Complete mtDNA sequencing may be considered if use of targeted testing and/or a multigene panel did not identify a pathogenic variant, clinical suspicion remains high, and there is no evidence of paternal transmission.

Interpretation of test results. Heteroplasmy, a mixture of mutated and wild type mtDNA in leukocytes, occurs in approximately 10%-15% of individuals with LHON [Smith et al 1993, Yu-Wai-Man et al 2003].

• Heteroplasmy does not influence the sensitivity of molecular genetic testing for LHON because affected individuals generally have more than 70% mutated mtDNA in leukocytes, which is easily detected by standard techniques.
• It is likely that the level of heteroplasmy may have a bearing on the risk of developing LHON in the asymptomatic individual and on the risk for transmission [Chinnery et al 2001]; however, no rigorous prospective studies have been performed to clarify this possibility.

Clinical Description

Leber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral, painless, subacute visual failure. The peak age of onset in LHON is in the second and third decades of life, with 95% of those who lose their vision doing so before age 50 years. Very rarely, individuals first manifest LHON in the seventh and eighth decades of life [Dimitriadis et al 2014]. Males are four to five times more likely to be affected than females, but neither gender nor mutational status significantly influences the timing and severity of the initial visual loss.

In the presymptomatic phase, fundal abnormalities including peripapillary telangiectatic vessels and variable degrees of retinal nerve fiber layer edema have been previously documented; these can vary with time [Nikoskelainen 1994]. Using optical coherence tomography imaging, thickening of the temporal retinal nerve fiber layer was confirmed in clinically unaffected individuals with a LHON-causing mtDNA pathogenic variant, providing further evidence that the papillomacular bundle is particularly vulnerable in LHON [Savini et al 2005]. On more detailed investigation, some individuals with a LHON-causing mtDNA pathogenic variant can also exhibit subtle impairment of optic nerve function including: (a) loss of color vision affecting mostly the red-green system, (b) reduced contrast sensitivity, and (c) subnormal electroretinogram and visual evoked potential [Sadun et al 2006].

Affected individuals are usually entirely asymptomatic until they develop visual blurring affecting the central visual field in one eye (acute phase); similar symptoms appear in the other eye an average of two to three months later, so that both eyes are affected in the majority of cases within six months. Unilateral optic nerve involvement in LHON is exceptionally rare; if it is present, another underlying pathologic process should be actively excluded. In about 25% of cases, visual loss is bilateral at onset. The most characteristic feature is an enlarging central or centrocecal scotoma and as the field defect increases in size and density, visual acuity deteriorates to the level of counting fingers or worse. Following the nadir, visual acuity may improve; such improvement is more likely in individuals with the m.14484T>C pathogenic variant than in those with the m.11778G>A or m.3460G>A pathogenic variant (see Genotype-Phenotype Correlations).

Other positive prognostic factors have been identified including an earlier age of onset (<10 years), a subacute presentation with slow visual deterioration, and a relatively large optic disc [Barboni et al 2006, Ramos et al 2009].

The atrophic phase is characterized by optic atrophy (which typically develops within six weeks of the onset of visual loss) and a dense central or centrocecal scotoma. Most persons remain severely visually impaired and are within the legal requirements for blind registration [Kirkman et al 2009].

Other neurologic features associated with LHON. Some neurologic abnormalities (e.g., postural tremor, peripheral neuropathy, nonspecific myopathy, movement disorders, and Leigh syndrome) have been reported to be common in individuals with LHON [McFarland et al 2007, Martikainen et al 2016].

Some individuals with LHON, usually women, may develop a progressive multiple sclerosis (MS)-like illness. The pattern of visual loss in LHON-MS appears distinct from classic LHON, being marked by recurrent episodes of visual loss that can be associated with ocular pain, but with incomplete visual recovery and progression to legal blindness in half of all affected persons [Pfeffer et al 2013]. In addition to a severe bilateral optic neuropathy, these individuals manifest disseminated central nervous system demyelination, with characteristic periventricular white matter lesions and unmatched cerebrospinal fluid oligoclonal bands [Bhatti & Newman 1999, Horváth et al 2000, Palace 2009].

Cardiac conduction defects and LHON. A Finnish study showed an increased incidence of cardiac arrhythmias secondary to accessory pathways in association with LHON [Nikoskelainen 1994]; this finding has not been replicated in other populations [Bower et al 1992].

Genotype-Phenotype Correlations

Some broad categorization can be made with regard to specific LHON-causing pathogenic variants:

• m.3460G>A is associated with the worst impairment in visual function.
• m.11778G>A has an intermediate phenotype.
• m.14484T>C is associated with the best long-term visual outcome.

It must be emphasized that recovery of visual function in LHON, if it does occur, is usually incomplete. Reported visual recovery rates among persons with LHON are summarized in Table 3; the lifetime risk for visual failure in individuals with a homoplasmic primary LHON-causing pathogenic variant by sex and age is summarized in Table 4.

A multiple sclerosis-like illness has been reported in association with all three primary mtDNA LHON-causing pathogenic variants (m.3460G>A, m.11778G>A, and m.14484T>C), but with a female bias [Pfeffer et al 2013].

Penetrance

LHON-causing mtDNA pathogenic variants are characterized by reduced penetrance. An individual can only develop LHON if a pathogenic mtDNA LHON-causing variant is present, but approximately 50% of males and 90% of females who harbor a primary LHON-causing mtDNA pathogenic variant do not develop blindness. It must be stressed that penetrance can vary markedly in different branches of the same family and between families harboring the same LHON-causing mtDNA pathogenic variants, which complicates genetic counseling at the individual level. Additional environmental and genetic factors interact with the primary mtDNA pathogenic variant and determine whether an individual ultimately develops optic nerve dysfunction and visual failure. The two most important risk factors for visual loss are sex and age (see Table 4) [Yu-Wai-Man et al 2009].

• Age-related penetrance of LHON. The penetrance of LHON is age specific. The 95th centile for age at onset is 50 years for all three primary pathogenic variants. Thus, a clinically unaffected male age 50 years has less than a 1/20 chance of losing his vision [Yu-Wai-Man et al 2003].
• Heteroplasmy. Many mitochondria (and thus many mtDNA molecules) are present in each cell. Some individuals with a pathogenic LHON-causing mtDNA variant have a mixture of mutated and wild type species of mtDNA, a finding referred to as heteroplasmy. Heteroplasmy is present in 10%-15% of individuals with a LHON-causing mtDNA variant. In one study, individuals with a m.11778G>A pathogenic variant load of less than 75% in their leukocytes were unaffected [Smith et al 1993]. In a retrospective analysis of 17 families heteroplasmic for the m.11778G>A pathogenic variant, males with a mutational load greater than 60% in their leukocytes had an increased frequency of optic neuropathy than did those with lower mutational loads [Chinnery et al 2001]. However, quantifying the level of heteroplasmy for the purpose of presymptomatic testing is limited as the majority of individuals with a LHON-causing mtDNA variant are homoplasmic.

Anticipation

Anticipation has not been seen in LHON.

Nomenclature

In the past, LHON was sometimes referred to as Leber hereditary optic neuroretinopathy; this term is outdated and should not be used.

Prevalence

In the North East of England, 1:8,500 individuals were found to harbor a pathogenic LHON-causing variant; 1:31,000 had experienced visual loss as a result of LHON [Yu-Wai-Man et al 2003, Gorman et al 2015]. Fairly similar figures have been reported in other northern European populations, with a disease prevalence of 1:39,000 in the Netherlands and 1:50,000 in Finland [Spruijt et al 2006, Puomila et al 2007].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Leber hereditary optic neuropathy (LHON), the following evaluations are recommended:

• Measurement of best corrected visual acuity
• Assessment of visual fields with static or kinetic perimetry
• ECG. Although a relatively rare finding, an ECG may reveal a pre-excitation syndrome in both symptomatic and asymptomatic individuals who have a LHON-causing mtDNA variant. Even when present, such an ECG finding does not necessitate further intervention in the absence of cardiac symptoms.
• Screening for possible associated neurologic complications, which can further compound the visual impairment among individuals with LHON
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Management of affected individuals is supportive and includes provision of visual aids, occupational rehabilitation, and registration with the relevant local social services.

A minority of individuals with LHON develop neurologic features including ataxia, peripheral neuropathy, nonspecific myopathy, and movement disorders. This group of affected individuals should be managed by a multidisciplinary team of physicians and allied professionals to minimize the functional consequences of these neurologic complications.

In those individuals who are found to have pre-excitation syndrome on ECG, referral to a cardiologist can be considered; treatment for symptomatic individuals with pre-excitation syndrome is the same as in the general population.

Prevention of Primary Manifestations

There is evidence that raised intraocular pressure could be a risk factor triggering visual loss in individuals at risk for developing LHON. Until further evidence becomes available, it is reasonable to set a lower threshold for initiating treatment for raised intraocular pressure in individuals with a LHON-causing variant given the possible deleterious consequences of raised intraocular pressure on mitochondrial function and retinal ganglion cell survival [Thouin et al 2013].

Surveillance

Ongoing surveillance of asymptomatic individuals harboring LHON-causing mtDNA variants is not necessary; however, they should be advised to seek immediate medical attention should they experience any visual disturbance.

The frequency of follow-up for affected individuals varies depending on the individual's personal circumstances and the availability of health care locally.

Agents/Circumstances to Avoid

Individuals harboring established LHON-causing mtDNA variants should be strongly advised not to smoke and to moderate their alcohol intake, avoiding binge-drinking episodes. Although based largely on anecdotal evidence, avoidance of other environmental factors that have been implicated in precipitating visual loss in LHON (e.g., head trauma, industrial toxins, drugs with mitochondrial toxic effects) would seem reasonable.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Idebenone. Small case series have reported that oral administration of idebenone (a short-chain synthetic benzoquinone; 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone) and/or vitamin supplementation (B₁₂ and C) can accelerate visual recovery and improve final visual outcome in patients with LHON [Mashima et al 2000, Carelli et al 2001]. A subsequent report of two individuals with LHON showed no visual benefit from idebenone and multivitamin supplementation [Barnils et al 2007].

To address these conflicting anecdotal findings, a Phase II double-blind randomized placebo-controlled trial was conducted to investigate the efficacy, safety, and tolerability of oral idebenone in LHON: RHODOS (Rescue of Hereditary Optic Disease Outpatient Study). In total, 85 affected individuals harboring one of the three primary mtDNA LHON-causing variants (m.3460G>A, m.11778G>A, and m.14484T>C) were successfully enrolled in this multicenter study [Klopstock et al 2013]. Research subjects were assigned in a two-to-one randomization ratio to receive either idebenone (at a dose of 300 mg/3x/day) or placebo. This dose of idebenone was found to be safe with no significant drug-related adverse events. Affected individuals with discordant visual acuities (defined as a difference of >0.2 LogMAR between the two eyes) and at highest risk for further visual loss in the least affected eye were more likely to benefit from treatment with idebenone [Klopstock et al 2011].

In the follow-up study (RHODOS-OFU), the beneficial effect of six months of treatment with idebenone appeared to persist despite discontinuation of the active medication at the end of the trial [Klopstock et al 2013]. In a large retrospective study involving 103 individuals with LHON, 44 with visual loss of one year's duration or less were treated with idebenone and followed up for at least five years. A greater proportion of those in the treated group recovered vision compared with the untreated group, and the most consistent factor associated with visual recovery was an early initiation of treatment during the acute phase of the disease process [Carelli et al 2011]. It must be stressed that idebenone will not completely reverse the significant damage already sustained to the optic nerve, but in those affected individuals who do respond, there is an increased rate and likelihood of visual recovery compared with the known natural history.

There is no evidence to support the prophylactic use of idebenone among asymptomatic individuals with LHON-causing mtDNA variants.

EPI-743. In an open-label study of five individuals with acute LHON treated within 90 days of disease conversion, the antioxidant α-tocotrienol-quinone (EPI-743), a vitamin E derivative, has shown early promise [Sadun et al 2012]. An adequately powered, double-blind, randomized placebo-controlled trial is needed to confirm the visual benefit of this agent in both acute and chronic LHON [Sadun et al 2012].

Gene therapy. Targeted gene therapy for LHON is being actively explored for affected individuals harboring the m.11778G>A pathogenic variant [Qi et al 2003, Qi et al 2004, Qi et al 2007, Ellouze et al 2008, Lam et al 2010]. Promising pre-clinical data based on in vitro and rodent models have resulted in the recent launch of pivotal clinical trials for affected individuals with the m.11778G>A pathogenic variant involving the intravitreal injection of a modified adeno-associated virus (AAV2) vector carrying the replacement MTND4 subunit (see ClinicalTrials.gov).

Hormone therapy. The marked male bias in LHON could reflect a protective influence of female sex hormones, and this hypothesis was recently investigated using LHON cybrid cell lines. Treatment with estrogens was found to reduce reactive oxygen species levels in these LHON cybrids, with increased activity of the antioxidant enzyme superoxide dismutase. These beneficial estrogenic effects translated into more efficient mitochondrial oxidative phosphorylation [Giordano et al 2011]. Further research is needed to determine whether females with a LHON-causing variant are at increased risk for visual loss in the perimenopausal period and following the onset of menopause.

Mitochondrial replacement. In vitro fertilization (IVF) techniques aimed at preventing the maternal transmission of mtDNA pathogenic variants from mother to child are being developed. Pronuclear transfer and metaphase II spindle transfer are the two approaches that are being investigated, and further experimental work to validate the safety and potential clinical applicability of these IVF strategies is currently ongoing [Tachibana et al 2009, Craven et al 2010, Chinnery et al 2014].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.