Leber hereditary optic neuropathy …

Lulu LCD Bursztyn MD

Neuro-Ophthalmology & Neuro-Otology

Updated 06.24.2024
Released 05.28.1997
Expires For CME 06.24.2027

Leber hereditary optic neuropathy

Author: Lulu LCD Bursztyn MD

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Editor: Jonathan D Trobe MD

Leber hereditary optic neuropathy

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Introduction

Overview

Leber hereditary optic neuropathy is a mitochondrial DNA disorder that typically causes severe bilateral consecutive vision loss in the two eyes. A maternally inherited disorder, it most frequently affects young males who present with subacute vision loss first in one eye, followed by vision loss in the fellow eye within days to months. The distinctive changes in the fundus appearance at various stages of the disease process assist in clinical diagnosis, which must be confirmed with genetic testing. Clinical trials have demonstrated some benefit of treatment with idebenone. The efficacy of gene therapy is still undetermined.

Key points

	• Leber hereditary optic neuropathy is primarily caused by various mutations in the mitochondrial genome, although certain nuclear DNA mutations have also been reported to cause Leber hereditary optic neuropathy.
	• Leber hereditary optic neuropathy usually manifests as bilateral sequential painless vision loss in young males; females are more often carriers.
	• The preferential involvement of retinal ganglion cells in the papillomacular bundle produces dense cecocentral scotomas on visual field examination with relative sparing of the peripheral visual field.
	• The optic disc appears mildly swollen in the acute phase but typically does not leak on fluorescein angiography.
	• Peripapillary telangiectasia is visible during the acute phase but regresses within days to weeks after onset of vision loss.

Historical note and terminology

In 1871, Theodor Leber (1840-1917), Professor of Ophthalmology at the University Göttingen, Germany, described 55 patients in 16 families with a hereditary optic neuropathy of rapid onset (52). Most of these patients were male, had visual loss beginning in the late teens or early 20s, and did not recover. Although this was not the first description of such patients, it was the most comprehensive report at that time. Ensuing decades saw the description of several pedigrees with similar clinical findings, almost all of which had a peculiar mode of inheritance from mother to affected son or mother to carrier daughter. Initially thought to be a sex-linked recessive disorder, the greater-than-expected occurrence in women and less-than-expected occurrence in maternal grandfathers of affected males suggested an alternative mechanism for transmission (84). In retrospect, many apparent cases of transmission from father to child were probably other hereditary optic neuropathies. Cytoplasmic transmission was suggested in 1936 (32), and the maternal inheritance of mitochondrial DNA (23) eventually led to the discovery that many cases of Leber hereditary optic neuropathy were due to a mutation at position 11778 of the mitochondrial genome (98). Subsequently, mutations at positions 3460 (31) and 14484 (38) were also demonstrated to be associated with Leber hereditary optic neuropathy.

Leber coined several eponymous disorders with similar names. Leber congenital amaurosis is a severe bilateral retinal dystrophy that is present at birth, transmitted as an autosomal recessive trait, and diagnosed by a persistent absence of retinal electrical activity. Leber congenital amaurosis is a severe bilateral retinal disease that is present at birth, transmitted as an autosomal recessive trait, and diagnosed by a permanent absence of retinal electrical activity. Leber idiopathic stellate neuroretinitis is an acute sporadic inflammation of the optic nerve and macula, characterized by both disc and macular edema, the resolution of the latter leading to a macular "star.” Leber miliary aneurysms are a milder variant of congenital retinal telangiectasia (Coats disease), a unilateral disease mostly affecting young boys. In that disorder, retinal vessels are telangiectatic and may have localized aneurysmal outpouchings. Exudative leakage from these abnormal vessels may lead to visual loss.

Clinical manifestations

Presentation and course

Leber hereditary optic neuropathy is a maternally inherited optic neuropathy typically characterized by subacute visual loss progressing over days to weeks in one eye, followed days to months later in the fellow eye. Leber hereditary optic neuropathy is usually painless, but some patients may have discomfort reminiscent of optic neuritis (29). Bilateral simultaneous onset occurs in about one fourth of patients, although there may be disparity in visual function between the two eyes (82).

The typical pattern of visual loss is decreased visual acuity to 20/200 or worse (69; 68), associated with a cecocentral scotoma extending from the physiologic blind spot to the point of fixation. In the acute stage, there is mild swelling of the optic disc that is concentrated at the disc margins. On fluorescein angiography, the optic disc does not leak dye, a feature that distinguishes this form of optic disc edema from that associated with many other causes. Fine telangiectatic vessels often surround the optic disc.

A peculiar feature of Leber hereditary optic neuropathy is that the relative afferent pupillary defect is less prominent than in other optic neuropathies. A pupillographic study comparing 10 severely affected Leber patients with 16 healthy age-matched controls demonstrated relative preservation of the pupillary light reflex in the patients with Leber hereditary optic neuropathy compared to controls, despite an estimated loss of over 90% of the retinal ganglion cells by optical coherence topography retinal nerve fiber layer thickness determination (63). This phenomenon may owe to impairment of the X-like and Y-like retinal ganglion cells but sparing of the W-like retinal ganglion cells, which have a major role in mediating the pupil constriction to light (33; 97). Another explanation for the diminished afferent pupil defect is relative sparing of the intrinsically photosensitive retinal ganglion cells that significantly contribute to a sustained component of the pupillary light reflex independent of rod and cone pathways. A third possibility is that at symptom onset in one eye, the apparently “unaffected” eye actually has some visual dysfunction, a feature that would weaken the relative afferent pupil defect.

As clinical experience with the disease has increased and genetic testing has become more readily available, the clinical spectrum of this disorder has broadened (99). For example, the visual loss may be indolent. At the time of initial diagnosis, optic disc pallor or even cupping may be present rather than edema (34; 77). The visual fields may display a pattern of bitemporal hemianopia (99).

Prognosis and complications

The prospect for visual improvement in Leber hereditary optic neuropathy is low and dependent on which mitochondrial DNA mutation is present (37). The most dismal prognosis is for patients with the 11778 mutation, which is also the most common. In a natural history study of 44 patients enrolled at varying time points after symptom onset, 15% of eyes had improvement, 7% had worsening, and the remainder were stable in one or more eyes (50). All improvement occurred within 36 months after onset, and all worsening occurred within 12 months of onset. A meta-analysis revealed that ultimate visual acuities better than 20/200 are rare (67). The best prognosis is for those with the 14484 mutation, in which partial or full recovery may be seen in as many as 71% of patients (82). An intermediate recovery rate of approximately 22% is seen with the 3460 mutation. In all of these mutations, there may be a latency period of months to years until visual improvement occurs (93). Clinical characteristics associated with better visual recovery include young age of onset and better visual acuity at nadir. Peripapillary telangiectasia and optic disc hyperemia may indicate poor visual prognosis (62). A nationwide cohort study in Denmark comparing 141 affected Leber hereditary optic neuropathy subjects, 297 carriers, and the general population found a rate ratio of 1.95 for mortality and 7.53 for alcohol-related disorders in Leber hereditary optic neuropathy subjects versus the general population with no difference between carriers and the general population (96).

Other neurologic abnormalities may be associated with Leber hereditary optic neuropathy, termed “Leber hereditary optic neuropathy plus” syndromes. Most commonly, patients have a syndrome indistinguishable from multiple sclerosis (30; 21; 75; 35), particularly in female patients (28). One explanation is that Leber hereditary optic neuropathy activates an autoimmune process (46). There are also reports of Leber hereditary optic neuropathy with positive aquaporin-4-antibody (19) and myelin oligodendrocyte glycoprotein antibody (04).

There are also reports of Leber hereditary optic neuropathy with positive aquaporin-4-antibody (19) and, more recently, myelin oligodendrocyte glycoprotein antibody (04).

Other specific neurologic associations include cerebellar ataxia (22; 64), tremor (72), spastic dystonia (61), peripheral neuropathy (72), thoracic kyphosis (72), and primary degeneration of spinal cord dorsal columns (36). The association of spastic dystonia and Leber hereditary optic neuropathy has been documented with a novel mitochondrial mutation, 3697G>A/ND1, a mutation that has also been associated with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome (92). The 14459 mutation is characterized by hereditary dystonia (40; 41). Patients with the mitochondrial mutation at 14484 commonly have associated migraine with or without aura, possibly as a manifestation of abnormal oxidative phosphorylation that has been demonstrated in migraineurs (14). The Danish national cohort study reported increased rate ratios for affected Leber hereditary optic neuropathy subjects compared with the general population for dementia, epilepsy, and neuropathy, but not migraine (96).

A relatively uncommon complication of Leber hereditary optic neuropathy is a cardiac pre-excitation syndrome, either Wolff-Parkinson-White or Lown-Ganong-Levine syndrome. This has been reported in up to 9% of Leber hereditary optic neuropathy patients in Finland and Japan (73; 58). Prolongation of the corrected QT interval may also occur (77). The Danish national cohort study reported increased rate ratios in affected Leber hereditary optic neuropathy subjects compared with the general population for nonischemic heart disease, atherosclerosis, and stroke, but not heart failure or arrhythmia (96).

Clinical vignette

History. A 34-year-old male with hypertension and obstructive sleep apnea presented with gradually worsening bilateral vision loss for the past 2 years. He reported noticing blurred vision in both eyes after waking up on a flight. He had a similar episode of blurred vision a few months later at a shooting range, where he could not see a small target with the left eye during nighttime shooting. He was unsure whether his right eye was affected at the time. He reported that this episode resolved spontaneously on the next day. At a subsequent consultation with an optometrist 1 week later, he was told that the examination was normal. An orbit MRI with and without gadolinium revealed no abnormalities. There was no family history of vision loss. He had recently started smoking and binge drinking due to emotional distress. Blood work for common treatable causes of optic neuropathy was negative, which included common infectious, inflammatory, and immunological causes, such as aquaporin-4 antibody and anti-myelin oligodendrocyte glycoprotein antibody.

Examination. He had decreased best-corrected visual acuity of counting fingers in the right eye and 20/500 in the left eye. Visual fields were full to confrontation. There was a trace right relative afferent pupillary defect. The anterior segment showed no signs of infection or inflammation. Ocular alignment and motility were normal. Ophthalmoscopy in both eyes disclosed pale optic discs, diminished peripapillary arteries, and a normal-appearing macular region.

Ophthalmic imaging. Wide-field scanning laser ophthalmoscopy demonstrated bilateral optic disc pallor. Optical coherence tomography demonstrated bilateral thinning of the retinal nerve fiber layer and ganglion cell complex.

Scanning laser ophthalmoscopy demonstrates bilateral optic disc pallor

(Contributed by Dr. Allison Liu.)
OCT retina nerve fiber layer and ganglion cell complex measurements

Optical coherence tomography retina nerve fiber layer measurements and ganglion cell complex measurements show thinning in both eyes. (Contributed by Dr. Allison Liu.)
Ganglion cell layer measurements

(Contributed by Dr. Allison Liu.)
Goldmann perimetry

Larger and brighter isopters (II4e to V4e) are relatively preserved. However, the smaller and dimmer isopters (I3e and I2e) show moderately to severely constricted visual fields. (Contributed by Dr. Allison Liu.)
Humphrey visual field 24-2

Bilateral severe visual field defects. Foveal threshold is also reduced at 16 dB in the right eye and 15 dB in the left eye. (Contributed by Dr. Allison Liu.)

Genetic testing. A homoplasmic pathogenic variant was identified in the mitochondrial MT-ND4 gene at m.11778.

Impression. This is a patient with bilateral optic atrophy and severe vision loss, clinically consistent with Leber hereditary optic neuropathy, with an associated mitochondrial gene mutation. Acute presentation was possibly triggered by metabolic stresses related to cigarette and alcohol consumption.

Biological basis

Etiology and pathogenesis

Genetics. Inheritance of Leber hereditary optic neuropathy susceptibility is prototypically maternal, consistent with a mitochondrial genome abnormality (66). Each mitochondrion contains 2 to 10 copies of a closed circular double-stranded DNA coding for 13 of the 67 proteins comprising the mitochondrial respiratory chain, as well as the transfer RNA and ribosomal RNA needed for mitochondrial protein synthesis. Up to 95% of Leber hereditary optic neuropathy cases are the result of three primary mitochondrial mutations: m.11778G> A, m.3460G> A, and m.14484T>C. However, at least 38 additional causative mtDNA variants have been identified (15). In general, these mutations involve mitochondrial DNA complex I, or NADH:ubiquinone oxidoreductase (ND) genes (G11778A in ND4, G3460A in ND1, and T14484C in ND6).

Seven mutations in the ND6 gene at A14495G and 14568 (12; 20) and at 11253 in the ND4 gene (54) have been reported. A mutation at position 14459 has been associated with hereditary spastic dystonia with wide variability of clinical expression (40; 41; 89; 24; 95). A mutation has been found at G13513 and at 3376 (G> A) in the MTND1 gene with MELAS overlap syndromes (80; 05).

Male predominance is strong in Leber hereditary optic neuropathy and varies depending on the specific mutation. The genetic basis for this predominance is unresolved. In one large study, the ratios of affected male to female patients were 2.5:1 (m.11778), 2:1 (m.3460), and 5.7:1 (m.14484) (82).

Although most patients with Leber hereditary optic neuropathy are homoplasmic for a primary mitochondrial DNA mutation, 4% to 14% have heteroplasmy or a variable proportion of mutant and wild-type mitochondrial DNA (29; 60). The degree of heteroplasmy probably influences the likelihood of developing symptomatic Leber hereditary optic neuropathy (90; 29; 60; 94), but not necessarily the degree of visual loss (90). In an analysis of 17 independent pedigrees harboring the G117678A mutation, the frequency of blindness in males was related to the mutation load in their blood cells. Mothers with 80% or less mutant mtDNA in their blood cells were less likely to have clinically affected sons than mothers with 100% mutant mtDNA (11).

Mitochondrial dysfunction. Studies of the effects of mitochondrial DNA mutations on mitochondrial function suggest an oxidative phosphorylation defect resulting from the genetic mutation. In general, mutations at the 11778 position result in minor changes in oxidative phosphorylation but may affect binding of complex I to ubiquinone (16). Mutations at the 3460 position result in greatly decreased complex I activity (57; 91; 13). There is some evidence that nuclear genome variation alters the expression of mitochondrial complex I expression in persons bearing the 3460 mitochondrial mutation (13). Mutations at the 14484 position result in decreased complex I electron transfer activity and ATP synthesis (76).

Oxidative stress. Abnormal energy production presumably leads to accumulation of reactive oxygen species in retinal ganglion cells that are responsible for the optic neuropathy, resulting in the clinical and pathological findings. Similarities between Leber hereditary optic neuropathy, vitamin B12 deficiency, and nutritional amblyopia have suggested that abnormalities of ATP levels might be causative (83). However, abnormalities of retinal ganglion cell energy production or free radicals have not been demonstrated in an in vitro or in vivo model of Leber hereditary optic neuropathy.

Penetrance determinants. Beyond contributions of secondary mutations and haplotypes discussed above, the fact that genetically identical monozygotic twins may be discordant for long periods of time for Leber hereditary optic neuropathy implies that epigenetic factors affect the susceptibility to the disease (39; 47; 07).

Oxidative stress is strongly associated with the onset of symptomatic vision loss, as evidenced by a study of 196 affected and 206 unaffected members of 125 pedigrees that harbor one of the three primary mitochondrial DNA mutations (43). The authors found a strong and consistent association between vision loss and smoking, with penetrance of 93% among males who smoked. There was a lesser trend toward increased vision loss with alcohol ingestion and only with very heavy intake.

Another factor affecting susceptibility to clinical manifestations may be the possibility of adaptive change in the mtDNA in the presence of point mutations. One study investigated the quantitative ratio of mtDNA to nuclear DNA in peripheral circulating leukocytes from 13 asymptomatic carriers and 18 family noncarriers related to 11 patients with Leber hereditary optic neuropathy due to the 14486 mutation (74). Significant increase in the mtDNA relative to nuclear DNA was found only in asymptomatic carriers, indicating that those who had not increased the mtDNA had become symptomatic. Another study found that increase in cellular mtDNA content may protect against symptomatic conversions in individuals with heteroplasmic 11778 and 3460 mutations (03).

Asymptomatic manifestations. A psychophysical study of 18 asymptomatic carriers of the 11778 mutation versus 18 control subjects demonstrated abnormally high contrast discrimination thresholds among the carriers as compared with normal control subjects (25). This result suggests that even in asymptomatic carriers, there are subtle abnormalities of visual processing that may be used to identify them. Decline in pattern electroretinogram measurements have been reported in asymptomatic carriers (26).

Microvasculopathy. Optical coherence tomographic angiography has allowed improved visualization and quantitative measurement of optic nerve and retinal microvasculature in Leber hereditary optic neuropathy. Peripapillary microvascular changes correlate with ganglion cell–inner plexiform layer loss and precede retinal nerve fiber layer thinning (02). Microvascular attenuation was also reported in the macular region corresponding with the papillomacular bundle (06). These microvascular changes may play an integral part in Leber hereditary optic neuropathy pathophysiology.

Prevention

The most important risk factor for development of Leber hereditary optic neuropathy is the presence of one of the primary mutations (11778, 3460, and 14484). As the mitochondrial DNA is maternally inherited, the children of an affected female, but not of an affected male, will harbor the mutation. Similarly, a cousin linked through a female lineage to an affected subject may be at risk, as would any similar relative. DNA testing can confirm whether a related individual has the mutation.

No prophylaxis has been convincingly shown to be of value in preventing Leber hereditary optic neuropathy in those genetically at risk. Because of the presumption that mutations in genes coding for respiratory chain subunits result in functional abnormalities of oxidative phosphorylation, some clinicians have prescribed vitamin C, vitamin E, coenzyme Q10, or other antioxidants. Patients are counseled to avoid use of tobacco or alcohol. Some suggest avoiding foods containing naturally occurring cyanide, which interferes with mitochondrial respiration. A systematic epidemiologic and neuro-ophthalmologic study of a large Brazilian pedigree with 11778 haplogroup J mutation demonstrated a strong influence of environmental risk factors in the development of phenotypic disease, particularly smoking (85). Other forms of smoke, such as grilling and campfires, were also identified as toxic agents that may produce or exacerbate Leber hereditary optic neuropathy (87).

Certain medications with detrimental effects on mitochondrial function, such as antimicrobials, could theoretically trigger or worsen Leber hereditary optic neuropathy in susceptible individuals by causing an increase in circulating reactive oxygen species. Potential offending antimicrobials include tetracyclines, aminoglycosides, linezolid, erythromycin, chloramphenicol, and ethambutol (45).

Differential diagnosis

Confusing conditions

Leber hereditary optic neuropathy is often confused with other optic neuropathies and may even be misdiagnosed as psychogenic visual loss. The presence of a family history, especially in the maternal lineage, is helpful in making the diagnosis but is not always present.

Other hereditary optic neuropathies may be distinguished based on a combination of clinical features and inheritance pattern. Kjer dominant optic atrophy has an autosomal dominant mode of inheritance mapped to chromosome 3q. Typically with onset from 4 to 8 years of age, it is slowly progressive and rarely results in visual acuity worse than 20/200. Although temporal disc cupping and a tritan (blue/yellow) color defect are typical, these findings may also be seen in Leber hereditary optic neuropathy (34). Recessive optic atrophy is a severe, usually congenital hereditary optic neuropathy associated with visual acuity worse than 20/200, nystagmus, and achromatopsia. The early age of onset usually distinguishes it from Leber hereditary optic neuropathy. Other hereditary optic neuropathies may be associated with neurodegenerative disorders, such as Charcot-Marie-Tooth disease and Friedreich ataxia.

It is often difficult to distinguish Leber hereditary optic neuropathy from other optic neuropathies when only one eye is involved. In these cases, the visual loss and disc elevation of Leber hereditary optic neuropathy may be mistaken for optic neuritis (papillitis), anterior ischemic optic neuropathy, or anterior compressive, infiltrative, or infective optic neuropathies. Optic neuritis is typically associated with periocular pain aggravated by eye movement, a feature uncommonly associated with Leber hereditary optic neuropathy (29). Recovery of vision from optic neuritis usually begins after 1 or 2 weeks, and substantial improvement is often seen within 6 weeks, unlike the usually persistent visual loss of Leber hereditary optic neuropathy. Enhancement and high T2 MRI signal abnormalities in the affected optic nerve and cerebral white matter are often seen in patients with optic neuritis but may also rarely be seen in Leber hereditary optic neuropathy (30; 28; 21; 75; 35).

Non-arteritic anterior ischemic optic neuropathy produces acute painless visual loss but is uncommon in patients less than 50 years of age and is frequently associated with altitudinal visual field defects corresponding to segmental optic disc edema. Arteritic anterior ischemic optic neuropathy is a disorder of patients aged 60 years or more who have constitutional manifestations and laboratory evidence of systemic inflammation. There is often pallid disc edema and severe visual loss.

Orbital lesions that compress the optic nerve (Graves disease, orbital tumors, idiopathic orbital inflammation), infiltrative disease of the optic nerve (lymphoma, metastatic carcinoma, sarcoid), and infections of the optic nerve (cryptococcus, cytomegalovirus) may cause optic disc edema and visual loss. Associated clinical findings, such as proptosis, a history of immunosuppression, and the presence of a known primary cancer, are distinctive. In other cases, laboratory studies and sampling of cerebrospinal fluid are required to exclude these entities.

When optic disc elevation is present in both eyes without severe visual loss, the possibility of papilledema should be considered. In papilledema, the visual acuity is initially normal, and the visual field is normal or demonstrates enlargement of the blind spot. Associated symptoms (headache, vomiting, tinnitus, transient obscurations of vision lasting a few seconds) and signs (unilateral or bilateral sixth nerve palsy) may suggest the diagnosis. Other causes of bilateral disc edema and visual loss include bilateral presentation of one of the optic neuropathies mentioned above and acute toxic optic neuropathies.

Bilateral Leber hereditary optic neuropathy without disc elevation should be differentiated from nutritional and toxic optic neuropathy and occult retinal dystrophy, particularly the cone dystrophy variant. In the presence of pathologic excavation of the optic discs, low-tension glaucoma must be a consideration (51; 59). The diagnosis of Leber hereditary optic neuropathy at a stage when both eyes were affected long ago is particularly challenging. The ophthalmic signs of temporal optic disc pallor could represent optic neuropathy of many causes, as well as cone dystrophy.

Dismissing psychogenic visual loss is difficult. There should be no relative afferent pupillary defect or optic disc pallor. However, patients with Leber hereditary optic neuropathy affecting both eyes will also lack a relative afferent pupillary defect because this test compares conduction in the two optic nerves. Moreover, normal-appearing optic discs may be present in Leber hereditary optic neuropathy. Thus, diagnosis of psychogenic vision loss depends heavily on discovering a “tunnel” visual field defect in which the borders of the constricted visual field do not expand with increasing test distance. However, demonstrating this field defect takes expertise.

Management

Management of Leber hereditary optic neuropathy is primarily supportive, with limited evidence for effective therapy. Treatment for Leber hereditary optic neuropathy can be classified as mutation-independent or mutation-specific (09). The former aims to improve mitochondrial function and enhance ganglion cell survival, whereas the latter uses gene editing to correct the underlying mutation. Mutation-independent therapies include idebenone, brimonidine, cyclosporin A, elamipretide, visomitin, and vitamin supplements, as well as potential gene therapies. Several pharmaceutical agents, acting on different molecular pathways, are under development (42; 01).

Idebenone is a synthetic hydrosoluble analogue of ubiquinone that crosses the blood-brain barrier and mitochondrial membranes. It facilitates production of ATP by transporting electrons directly to complex III, bypassing defective complex I in the mitochondrial electron transport chain. Several studies have demonstrated a modest benefit of idebenone to improve or stabilize vision in Leber hereditary optic neuropathy. Treatment with 900 mg/day should be initiated early, as the likelihood of visual recovery is highest when started less than 1 year after onset (09; 15). Treatment should continue for at least 24 months, particularly if visual recovery is noted within the first 12 months (08). Visual improvement may continue even after cessation of idebenone (44).

EPI-743 is a third-generation ubiquinone that exhibits approximately 1000 times greater in vitro activity than idebenone as an antioxidant. In an initial open-label study of five patients with vision loss from Leber hereditary optic neuropathy, treatment with oral EPI-743 was initiated at various intervals after onset of vision loss and was continued for at least a year in all (86). Significant objective and subjective stabilization and improvement of various visual parameters occurred in four of the five patients. These results are encouraging but require further prospective study.

On the basis of clinical experience suggesting that Leber hereditary optic neuropathy may occur in the setting of tobacco or ethanol abuse, many physicians advise their patients to stop smoking and drinking alcohol. Similarly, because the mitochondrial DNA mutations in this disorder affect subunits of the electron transport chain, some clinicians offer their patients the option of taking vitamin C, vitamin E, and coenzyme Q10. Good glucose control may be of help in patients with diabetes mellitus (18).

Mutation-specific therapeutic approaches include gene therapy with allotopic expression, mitochondrial targeted adeno-associated virus (AAV) vector, and mitochondrial base editing (48). These alternative approaches to gene therapy were developed to overcome the double membranes of the mitochondria, which impedes access to the mitochondrial genome. For example, allotopic expression delivers a nuclear-encoded version of the ND4 mitochondrial gene into the retinal ganglion cell nucleus, which is then transcribed into mRNA. The mRNA produces the ND4 protein, which is transported into the mitochondria, thereby improving mitochondrial function.

To study the effectiveness of allotopic expression, Guy and colleagues created transmitochondrial hybrid cell lines (cybrids) by fusing enucleated patient cells homoplasmic for wild type (11778G) or mutant (G11778A) mitochondrial DNA with neutral nucleated host cells that have permanently lost all mitochondrial DNA after exposure to ethidium bromide (27). They then showed that in transmitochondrial cybrids with G11778A mutated mitochondrial DNA, ATP synthesis dependent on complex I substrates was substantially reduced and that this deficiency in oxidative phosphorylation can be reversed using allotopic expression of the ND4 gene and transport of the gene product into the mitochondria that are still homoplasmic for G11778A mutant mtDNA (81). The late Dr. John Guy also envisioned direct mitochondrial targeting.

RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial that has evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy within 6 months of disease onset (70). Although the primary end point of best-corrected visual acuity in the treated eye compared with the sham eye was not met at 48 weeks, 1778G>A mutation carriers treated within 6 months after vision loss achieved comparable visual outcomes in the injected and sham eyes at 96 weeks after unilateral injection.

REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss due to Leber hereditary optic neuropathy (100). In comparison to the RESCUE trial, the REVERSE trial treated subjects between 6 to 12 months after the onset of vision loss. A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation were treated. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.

REFLECT is a randomized, double-masked, placebo-controlled phase 3 clinical trial that evaluated the efficacy of bilateral intravitreal injection of rAAV2/2-ND4 in subjects with 11778G>A within 12 months of vision loss (71). The first affected eye was treated with gene therapy, whereas the fellow eye received either gene therapy or placebo. After 1.5 years, there was a statistically significant improvement in BCVA from baseline in treated eyes, with 85.4% of bilaterally treated and 72% of unilaterally treated patients having one or both eyes on chart.

Overall assessment of the efficacy of treatment in Leber hereditary optic neuropathy is complicated by the poorly characterized natural history of the disease, with variable spontaneous improvement. The optimal timing of treatment has not been established. At the time of acute unilateral vision loss, there is already evidence of retinal ganglion cell dysfunction in the asymptomatic eye, suggesting a very narrow therapeutic window for treatment (48). Indeed, a trial of gene therapy for 11778G>A in asymptomatic fellow eyes failed to prevent vision loss, with all fellow eyes demonstrating progressive vision loss after treatment (48).

Outcomes

A meta-analysis of 12 retrospective and three prospective studies reviewed visual function of 695 Leber hereditary optic neuropathy patients with the m.11778G>A mutation (70). One hundred (14.4%) patients reported vision recovery, although idebenone use in some studies could not be excluded. The m.11778G>A mutation is associated with the most severe visual impairment. In patients aged 15 years or older, meaningful visual recovery occurred in only 23 of 204 (11.3%) patients and ultimate visual acuities of better than 20/200 were rare. Patients younger than 12 years of age had a better visual prognosis.

A placebo-controlled trial of randomized treatment versus true sham treatment in either eye may be necessary to clarify the question of efficacy of allotropic gene therapy for Leber hereditary optic neuropathy (10).

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References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Lulu LCD Bursztyn MD

Dr. Bursztyn of Western University has no relevant financial relationships to disclose.
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Editor

Jonathan D Trobe MD

Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.
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Former Authors

James Goodwin MD
Tanyatuth Padungkiatsagul MD
Heather E Moss MD PhD
Yin Allison Liu MD PhD
Leonard A Levin MD PhD (original author)

Patient Profile

Age range of presentation: Typical: 15 to 65 years

Atypical: 1 to 15 years and 65 to 99 years
Sex preponderance: male>female, >2:1
Heredity: heredity typical

heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Leber hereditary optic neuropathy: H47.2
ICD-11: Other specified mitochondrial myopathies: 8C73.Y
OMIM: Leber hereditary optic neuropathy: #535000

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Leber hereditary optic neuropathy

Associated Disorders

Dominant optic atrophy
Mitochondrial disorders
Toxic and metabolic optic neuropathies

Differential Diagnosis

Kjer dominant optic atrophy
Genetic optic neuropathy
Functional vision loss
Optic neuritis
Anterior ischemic optic neuropathy
- Compressive optic neuropathies
- Infiltrative optic neuropathies
- Infective optic neuropathies
- Graves disease
- Orbital tumors
- Lymphoma
- Sarcoidosis
- Nutritional optic neuropathy
- Toxic optic neuropathy
- Low-tension glaucoma
- Tobacco-alcohol amblyopia

Also Relevant

Amblyopia
Ischemic optic neuropathy
Mitochondrial disorders
Molecular diagnosis of neurogenetic disorders
Multiple sclerosis: presentation and course
- Optic neuritis
- Toxic and nutritional deficiency optic neuropathies

Clinical Categories

Neuro-Ophthalmology & Neuro-Otology

Leber hereditary optic neuropathy …

Leber hereditary optic neuropathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

NF2-related schwannomatosis

Common maculopathies

Toxic and nutritional deficiency optic neuropathies

Third nerve palsy

Nystagmus

Chronic progressive external ophthalmoplegia

Von Hippel-Lindau disease

Giant cell arteritis

Leber hereditary optic neuropathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

NF2-related schwannomatosis

Common maculopathies

Toxic and nutritional deficiency optic neuropathies

Third nerve palsy

Nystagmus

Chronic progressive external ophthalmoplegia

Von Hippel-Lindau disease

Giant cell arteritis

This is an article preview.
Start a Free Account
to access the full version.