Clinical manifestations

Presentation and course

Leber hereditary optic neuropathy is a maternally inherited optic neuropathy typically characterized by rapid visual loss, progressing over days to weeks in one eye and days to months later in the other eye. Acute bilateral disease is seen in about one fourth of patients (30). There may be disparity in visual function between the two eyes. Although Leber hereditary optic neuropathy is usually painless, some patients may have discomfort reminiscent of optic neuritis (30).

The typical vision loss pattern is decreased visual acuity, with most patients seeing 20/200 or worse (68; 67), a visual field defect involving the blind spot and central fixation (cecocentral scotoma). In the acute stage, there is a characteristic pseudoedema of the optic disc, which does not leak on fluorescein angiography. Fine telangiectatic vessels are often present at the disc margins.

One of the most peculiar features of Leber hereditary optic neuropathy is that the expected relative afferent pupillary defect (Marcus-Gunn pupil) is not as prominent in patients with unilateral disease. This may reflect preservation of W-like retinal ganglion cells, which are thought to mediate the pupillary response, whereas the X-like and Y-like ganglion cells responsible for visual processing are affected by the disease (34; 93). Another possible explanation is relative sparing of the intrinsically photosensitive retinal ganglion cells that contribute significantly to a sustained component of the pupillary light reflex independent of rod and cone pathways. 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 (62).

As clinical experience with the disease has increased and genetic testing is more readily available, it has become apparent that many patients may lack the clinical features described above (95). For example, the visual loss may be indolent. Instead of disc swelling, there may simply be optic atrophy, or even cupping (35; 75). The visual fields may be atypical, eg, bitemporal hemianopsia (95).

Prognosis and complications

The prospect for visual improvement in Leber hereditary optic neuropathy is low, with the specific rate highly dependent on which mitochondrial DNA mutation is present (38). The most dismal prognosis is for patients with the 11778 mutation. In a natural history study of 44 patients enrolled at varying time points since symptom onset, 15% of eyes had improvement, 7% had worsening, and the remainder were stable in one or more eyes (49). All improvement occurred within 36 months after onset, and all worsening occurred within 12 months of onset. A metaanalysis revealed that ultimate visual acuities of better than 20/200 are rare (66). 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 (79). 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 (89). Some clinical characteristics associated with better visual recovery include young age of onset and better visual acuity at nadir. Presence of peripapillary telangiectasia and optic disc hyperemia may indicate poor visual prognosis (61). 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 (92).

With improved knowledge in Leber hereditary optic neuropathy, it has become apparent that other neurologic abnormalities may be associated with it as part of Leber hereditary optic neuropathy plus syndromes. Most commonly, patients have a syndrome indistinguishable from multiple sclerosis (31; 22; 73; 36), particularly in female patients (29). Neuropathologic examination of one such patient with 1448 mutation showed extensive frontal lobe demyelination mixed with cavitary necrosis and CD8-positive T-cell predominant inflammatory infiltrates. Several pathophysiologic possibilities are discussed, one being that Leber hereditary optic neuropathy somehow activates an autoimmune process in the central nervous system with some features of multiple sclerosis (47).

There are also reports of Leber hereditary optic neuropathy with positive aquaporin-4-antibody (20) and, more recently, myelin oligodendrocyte glycoprotein antibody (05).

Other specific neurologic associations include cerebellar ataxia (23; 63), tremor (70), spastic dystonia (59), peripheral neuropathy (70), thoracic kyphosis (70), and primary degeneration of spinal cord dorsal columns (37). 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 MELAS syndrome (88). The 14459 mutation is characterized by hereditary dystonia (41; 42). Patients with the mitochondrial mutation at np 14484 have associated migraine with or without aura commonly, possibly as a manifestation of abnormal oxidative phosphorylation that has been demonstrated in migraineurs (16). 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 (92).

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 can occur in up to 9% of Leber hereditary optic neuropathy patients in Finland or Japan (71; 56). Prolongation of the corrected QT interval may also occur (75). The Danish national cohort study reported increased rate ratios for affected Leber hereditary optic neuropathy subjects compared with the general population for all heart disease, atherosclerosis, and stroke, but not ischemic heart disease, heart failure, or arrythmia (92).

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 couple of months after 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 the next day. At a subsequent optometry visit a week later, he was told his eyes were normal. An orbit MRI with and without gadolinium revealed normal orbits. 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 to count fingers in the right eye and 20/500 of the left eye and was unable to perform color vision and full visual fields to confrontation. The pupil exam showed a trace relative afferent pupillary defect. The anterior segment showed no signs of infection or inflammation. The ocular motility was normal, and there was no misalignment. His fundus exam showed pale optic discs, diminished peripapillary arteries, and normal macula in each eye.

Ophthalmic imaging. Optos scanning laser ophthalmoscopy demonstrated bilateral optic atrophy.

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. It is clinically consistent with Leber hereditary optic neuropathy, and he has 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 maternal, consistent with a mitochondrial genome abnormality as the cause (65). Each mitochondrion contains 2 to 10 copies of a closed circular double-stranded DNA coding for 13 of the 67 proteins making up the mitochondrial respiratory chain, as well as the transfer RNA and ribosomal RNA needed for mitochondrial protein synthesis. In most pedigrees, mutations at positions 11778, 3460, or 14484 of the mitochondrial genomes are found, and these mutations are not found in pedigrees of unaffected individuals. 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).

In a minority of cases, other mutations have been described including over seven in the mitochondrial DNA ND6 gene at A14495G and 14568 (14; 21) and at 11253 in the ND4 gene (53). In addition, a mutation at position 14459 is in association with hereditary spastic dystonia with wide variability of clinical expression (41; 42; 85; 25; 91). A mutation was found at G13513 and at 3376 (G> A) in the MTND1 gene with MELAS overlap syndromes (77; 06). These are called primary mutations.

Male predominance is strong in Leber hereditary optic neuropathy, the degree depending on the specific mutation. The genetic basis for this is controversial.

Although most patients with Leber hereditary optic neuropathy are homoplasmic for a primary mitochondrial DNA mutation, some patients (4% to 14%) may have heteroplasmy or a variable proportion of mutant and wild-type mitochondrial DNA (30; 58). The degree of heteroplasmy probably influences the likelihood of developing symptomatic Leber hereditary optic neuropathy (86; 30; 58; 90), but not necessarily the degree of visual loss (86). In an analysis of 17 independent pedigrees harboring the G117678A mutation, it was found that the frequency of blindness in males was related to the mutation load in blood cells and that 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 in the blood (13).

Mitochondrial dysfunction. Studies of the effects of mitochondrial DNA mutations on mitochondrial function suggest an oxidative phosphorylation defect resulting from the genetic defect. In general, mutations at the 11778 position result in minor changes in oxidative phosphorylation but may affect binding of complex I to ubiquinone (17). Mutations at the 3460 position result in greatly decreased complex I activity (55; 87; 15). There is some evidence that nuclear genome variation alters the expression of mitochondrial complex I expression in persons bearing the 3460 mitochondrial mutation (15). Mutations at the 14484 position result in decreased complex I electron transfer activity and ATP synthesis (74).

Oxidative stress. It has been presumed that abnormal energy production 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 (80). 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; thus, it remains the subject of active laboratory investigation.

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 (40; 48). Caporali and colleagues provide an excellent review on this topic (08).

Kirkman and colleagues have shown that oxidative stress is strongly associated with the onset of symptomatic vision loss in a study of 196 affected and 206 unaffected members of 125 pedigrees that harbor one of the three primary mitochondrial DNA mutations (44). They 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 but 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. 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 (72). Another study found that increase in cellular mtDNA content may protect against symptomatic conversions in individuals with heteroplasmic 11778 and 3460 mutations (04).

Asymptomatic manifestations. In a psychophysical study of 18 asymptomatic carriers of the 11778 mutation versus 18 control subjects, Gualtieri and colleagues demonstrated abnormally high contrast discrimination thresholds among the carriers as compared with normal control subjects (26). This 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 over time (27).

Microvasculopathy. The advent of optical coherence tomography angiography has 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 (03). Microvascular attenuation was also reported in the macular region corresponding with papillomacular bundle (07). These microvascular changes may play an integral part of Leber hereditary optic neuropathy pathophysiology.

Epidemiology

Leber hereditary optic neuropathy is an uncommon cause of optic neuropathy. Its prevalence is highly dependent on the population studied, as well as which mutation is being analyzed. In Australia 2% of those disabled by blindness have Leber hereditary optic neuropathy as a cause (54).

The 11778 is the most prevalent mutation, with the proportion varying depending on population. In Japan, approximately 80% to 90% of patients with Leber hereditary optic neuropathy have the 11778 mutation, whereas 40% to 85% of non-Japanese patients have that mutation (64; 34).

The age of onset is usually in the second or third decade but has been reported as early as 4 years of age (60) and as late as 73 years of age (01), with many cases over 60 years of age at time of symptom onset described in the literature (76; 18). The age of onset does not differ significantly between the different mutations (30).

Male predominance is strong in patients with Leber hereditary optic neuropathy (67), the degree depending on the specific mutation. In a European population, there were male-to-female ratios of 3.7:1 with the 11778 mutation, 4.3:1 with the 3460 mutation, and 7.7:1 with the 14484 mutation (30). In a study comparing 16 women and 66 men with Leber hereditary optic neuropathy, it was found that women were older at presentation (average 31.3 vs. 24.3 years), had more severe vision loss, less tendency to recover vision, and a much higher rate of having an affected mother than did affected men (52).

The likelihood that those genetically at risk will develop visual loss depends on gender. The likelihood of symptomatic disease affecting matrilineal first-degree relatives of affected individuals is approximately 20% to 46% for male relatives and 4% to 10% for female relatives (54; 30).

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 are maternally inherited, it can be expected that 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 or not an individual relative has the relevant mutation.

No prophylaxis has been convincingly shown to be of value in preventing development of 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 suggest that their patients take vitamin C, vitamin E, coenzyme Q10, or other antioxidants. For similar reasons, many 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 has demonstrated a strong influence of environmental risk factors in the development of phenotypic disease, particularly smoking (82). Other forms of smoke, such as grilling, and campfires were also identified as toxic agents that may produce or exacerbate Leber hereditary optic neuropathy (84).

Differential diagnosis

Confusing conditions

Leber hereditary optic neuropathy is often confused with other optic neuropathies and may even be misdiagnosed as functional visual loss. The presence of a family history, especially in the maternal lineage, is helpful in making the diagnosis but is not always known or present. Instead, certain clinical observations may help in distinguishing Leber hereditary optic neuropathy from other optic neuropathies.

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 (35). Recessive optic atrophy is a severe, usually congenital hereditary optic neuropathy associated with visual acuity worse than 20/200, nystagmus, and achromatopsia. The 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 ocular discomfort aggravated by eye movement, which is only occasionally seen in Leber hereditary optic neuropathy (30). Recovery of vision from optic neuritis usually begins after 1 or 2 weeks, and substantial improvement is often seen by 6 weeks, unlike the usually persistent visual loss of Leber hereditary optic neuropathy. High signal abnormalities on T2-weighted MRI images of the deep white matter are often seen in patients with optic neuritis, but a multiple sclerosis-like syndrome with corresponding neuroimaging findings can also be seen in Leber hereditary optic neuropathy (31; 29; 22; 73; 36).

Nonarteritic anterior ischemic optic neuropathy produces rapid painless visual loss but is uncommon in patients less than 50 years old and is frequently associated with altitudinal visual field defects corresponding to segmental disc edema. Arteritic anterior ischemic optic neuropathy is seen in elderly patients with symptoms, signs, and laboratory evidence of giant cell arteritis. There is usually pallid disc edema and severe visual loss.

Orbital lesions that compress the optic nerve (eg, extraocular muscle enlargement from Graves disease or orbital tumors), infiltrative disease of the optic nerve (eg, lymphoma, metastatic carcinoma, sarcoid, etc.), or infections of the optic nerve (eg, Cryptococcus or cytomegalovirus) may cause disc edema and visual loss. The time course of these processes is usually less rapid than that of Leber hereditary optic neuropathy, but in some cases, they may overlap. Associated clinical findings, such as proptosis, a history of immunosuppression, or the presence of a known primary cancer, suggest one of these etiologies. However, in some cases the history and examination do not aid in distinguishing these optic neuropathies, and neuroimaging, laboratory studies, and sampling of cerebrospinal fluid are required.

The differential diagnosis of bilateral Leber hereditary optic neuropathy is different. When disc elevation is present without severe visual loss, the possibility of papilledema (ie, disc edema secondary to increased intracranial pressure) should be considered. In papilledema, the visual acuity is initially normal, and the visual field either 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, absence of spontaneous venous pulsation at the disc) 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, bilateral presentation of a retrobulbar optic neuropathy, low-tension glaucoma (50; 57), and occult retinal dystrophy, particularly a cone dystrophy. All of these may demonstrate decreased visual acuity and central visual field loss. Optic disc pallor may develop late in optic neuropathies and may only be present on the temporal disc, where it may be hard to distinguish from normal variation in color. Cone dystrophies may only be detected by electroretinography.

Finally, functional visual loss is a diagnosis of exclusion in a patient with vision loss, no relative afferent pupillary defect, and relatively normal discs. Patients with relatively symmetric vision loss from bilateral optic neuropathy will not have a relative afferent pupillary defect because this test compares conduction in both optic nerves. Because the optic disc pallor of Leber hereditary optic neuropathy may occur late or be difficult to detect, patients should not be diagnosed as having factitious visual loss without considering other possibilities. In some patients, the presence of a constricted "tubular" field (best demonstrated at the tangent screen) instead of the cecocentral scotoma of Leber hereditary optic neuropathy may help in making this diagnosis.

Diagnostic workup

In a symptomatic patient presenting with optic neuropathy, the most reliable way to determine the likelihood of Leber hereditary optic neuropathy is to analyze the patient's mitochondrial DNA for the presence of one of the primary mutations. A saliva, buccal mucosa, or peripheral blood sample can be sent to a laboratory. Results usually take weeks to return.

To make a clinical diagnosis, visual acuity and visual field testing can identify if the pattern of vision loss is typical of Leber hereditary optic neuropathy. In the acute setting, ophthalmoscopic examination can identify the typical pseudoedema and peripapillary telangiectasias. Fluorescein angiography may help determine whether disc elevation represents true edema or the pseudoedema of Leber hereditary optic neuropathy. In the former, but not in the latter, there is leakage of fluorescein from the disc during the late phase of the angiogram. In the chronic stage, ophthalmoscopic examination and ophthalmic imaging will show optic atrophy.

Management

Options for effective treatment of Leber hereditary optic neuropathy have been a long time coming. In a review, the treatments for Leber hereditary optic neuropathy were classified as mutation-independent and mutation-specific (11). The former included idebenone, brimonidine, cyclosporin A, elamipretide, visomitin, and vitamin supplements, as well as several mutation-independent gene therapies. The successful launch of the antioxidant idebenone, followed by its introduction into clinical practice across Europe, was an important step forward. Several pharmaceutical agents, acting on different molecular pathways, are currently under development (02).

Idebenone is a synthetic benzoquinone that crosses the blood-brain barrier and mitochondrial membranes. The proposed benefit stems from idebenone’s ability to pass electrons to complex III, bypassing defective complex I in the mitochondrial electron transport chain. In a retrospective study of 103 patients with one of the three main mitochondrial gene mutations in Leber hereditary optic neuropathy, 44 were treated with idebenone in doses ranging from 270 to 675 mg/day, but treatment was initiated within the first year of visual loss onset in all (09). Benefit of treatment reached statistical significance only in the group with the 11778 mutation, probably because of the higher rate of spontaneous visual improvement in those with the 14484 mutation.

A prospective, randomized, placebo-controlled trial involved treatment of 84 patients with Leber hereditary optic neuropathy and one of the three primary mitochondrial gene mutations (45). Fifty-five patients were treated with idebenone 900 mg/day, and 30 patients received placebo. Treatment was carried on for 6 months and was initiated at various times in the course of the disease, sometimes years after first vision loss. This study failed to reach statistical significance for its primary endpoint—best recovery of visual acuity—but did reach significance in some secondary endpoints and subgroup analyses.

An open-label, multicenter, retrospective, noncontrolled analysis of long-term visual acuity and safety in 111 patients with Leber hereditary optic neuropathy treated with idebenone (900 mg/day) demonstrated the benefit of idebenone treatment in recovering vision loss and maintaining residual vision (10). The authors suggested that idebenone treatment should be initiated early and be maintained more than 24 months to maximize efficacy. The safety profile was consistent with known data.

Karanjia and colleagues provide an excellent review of current therapeutic studies (43). Nonetheless, 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 (19).

EPI-743 is a third-generation ubiquinone that has been shown to exhibit approximately 1000 times greater in vitro activity as 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 (83). Significant objective and subjective stabilization and improvement of various visual parameters occurred in four of the five patients. These encouraging results have prompted the authors to develop an international multicenter prospective controlled trial using EPI-743 to treat patients with Leber hereditary optic neuropathy. Other compounds are currently being studied.

Mutation-specific therapies included gene therapy with allotopic expression and mitochondrial targeted AAV. A radically different approach to management via gene therapy may be on the horizon for patients who have already lost vision in one or both eyes as well as for those who have one of the primary mitochondrial gene mutations but have not lost the vision of either eye. Koilkonda and Guy provide a comprehensive and thoughtful overview of this prospect in their important review article (46). Although exogenous genes have been injected into the nuclear genome to reverse genetic mutation effects, this has not been possible to do with the mitochondrial genome. To bypass this difficulty, these workers used a process called allotopic expression.

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 (28). 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 ND-4 gene and transport of the gene product into the mitochondria that are still homoplasmic for G11778A mutant mtDNA (78). The late Dr. John Guy also envisioned direct mitochondrial targeting.

RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial that 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 (69). 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 (96). 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. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. 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.

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 (69). One hundred (14.4%) patients reported vision recovery, although idebenone use in some studies could not be excluded. The m.11778G>A mutation of severe visual loss with rare or poor recovery from nadir still holds true for most affected individuals. In patients aged 15 years or older, meaningful visual recovery occurred in 23 of 204 (11.3%) and ultimate visual acuities of better than 20/200 were rare. Patients younger than 12 years of age portended a better visual prognosis and a different natural history of visual loss progression and recovery.

In an editorial, Drs. John Chen and Tariq Bhatti suggested that a placebo-controlled trial with randomized treatment versus true sham without treatment in either eye may be necessary to clarify the question on the efficacy of allotropic gene therapy for Leber hereditary optic neuropathy (12).