Visual Outcomes in Leber Hereditary Optic Neuropathy Patients With the m.11778G>A (MTND4) Mitochondrial DNA Mutation : Journal of Neuro-Ophthalmology

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Visual Outcomes in Leber Hereditary Optic Neuropathy Patients With the m.11778G>A (MTND4) Mitochondrial DNA Mutation

Newman, Nancy J. MD; Carelli, Valerio MD, PhD; Taiel, Magali MD; Yu-Wai-Man, Patrick MD, PhD

Editor(s): Costello, Fiona MD, FRCP(C); Prasad, Sashank MD

Author Information
Journal of Neuro-Ophthalmology: December 2020 - Volume 40 - Issue 4 - p 547-557
doi: 10.1097/WNO.0000000000001045

Abstract

Leber hereditary optic neuropathy (LHON) is a maternally inherited, nonsyndromic, bilaterally blinding optic neuropathy caused by point mutations in the mitochondrial DNA (mtDNA) (1), affecting approximately 1 in 30,000 to 1 in 50,000 people, particularly young adult males (2). Three mtDNA point mutations affecting respiratory complex I subunits account for approximately 90% of all LHON cases, namely, m.3460G>A (MTND1), m.11778G>A (MTND4), and m.14484T>C (MTND6), with m.11778G>A being the most common mutation worldwide and accounting for about 75% of LHON cases in North America and Europe (3–5) and up to 90% in Asia (6).

The phenotypic expression of LHON shows variable penetrance with a male predominance of about 86% (1). Subjects typically experience a subacute painless loss of central vision, either simultaneously recognized in both eyes (25%–50% of the time), or in one eye followed by sequential impairment of he second eye with days, weeks or months (50%–75% of the time), with at least 97% of patients having bilateral involvement within 1 year (3). The visual outcome is generally poor, with most patients worsening to at least 20/200 visual acuity (VA) in both eyes.

The current treatment for LHON remains limited (7). Idebenone (Raxone, Santhera GmbH, Germany) was granted market authorization in the European Union for the treatment of LHON under exceptional circumstances (8). It is agreed that LHON is a seriously debilitating disease, and there is a continued unmet medical need for more efficacious therapies.

To accurately assess the therapeutic efficacy of any treatment, the natural history of this disorder must be fully understood. The m.11778G>A mutation is associated with a severe clinical form of LHON, with rare visual recovery and poor overall visual outcomes. We review the available natural history data of subjects expressing the disease due to the m.11778G>A mutation, with special attention to the reported visual recovery rates and outcomes.

LITERATURE SEARCH

Literature review was performed using MEDLINE through PubMed, Cochrane Reviews Library, and Orpha.net with search terms of “Leber hereditary optic neuropathy,” “LHON,” “ND4,” “G11778A,” “visual acuity,” “nadir,” “natural history,” and “registry.” All English-language, peer-reviewed publications with study cohorts of at least 5 LHON patients with the molecularly confirmed m.11778G>A mutation were included. Of particular interest was information regarding the course of the disease, nadir (i.e., lowest VA recorded), recovery after nadir, and final available measurements of VA. Data of subjects receiving treatment for LHON, including but not limited to idebenone, were excluded when known.

LHON Natural History—Key Issues to Address

To have usable data to make valid comparisons regarding the natural history of LHON, several key issues were addressed:

  1. What is the genetic status of the LHON patients? The mitochondrial genotype is a major prognostic factor, with the m.14484T>C (MTND6) mutation typically associated with better visual outcomes and the m.11778G>A (MTND4) mutation with poor visual outcomes (1,5,9,10). Only patients with the m.11778G>A mutation were included in our analyses.
  2. What is the age of the subject at the onset of the disease? The visual prognosis for LHON subjects, even with the m.11778G>A mutation, is reported as much more favorable among prepubertal patients (9,11,12).
  3. What are the visual function measures? High-contrast VA? If so, what is the VA scale—Early Treatment Diabetic Retinopathy Study (ETDRS) or Snellen? Were all VAs performed with best correction?
  4. Where along the curve of visual loss was the vision measured? The evolution of visual loss in the initial weeks/months of symptomatic LHON is subacute, with a timeframe of days/weeks/months (3). Within 4–6 months, VA stabilizes, reaching the so-called nadir (lowest VA), but clinical metrics such as visual fields (13,14) and OCT measurements may still evolve (15–18), usually plateauing within 1 year after disease onset. This phase from 6 to 12 months has been thus defined as “dynamic.” At about 12 months, there is a transition into the chronic stage of the disease, with all metrics reduced and stable (3).
  5. Do the studies assess visual function changes from baseline or from nadir or somewhere else along the curve of vision loss or was just the last VA reported?
  6. How was the baseline defined? What is the time period between the onset of vision loss and baseline data collection?
  7. What is the definition of recovery/improvement: 2 or 3 Snellen lines? 2 or 3 ETDRS lines? 10 or 15 ETDRS letter gain? From baseline? From nadir?
  8. Do the studies assess visual function changes in individual eyes or in one or both eyes of subjects?
  9. Do the studies report a continuous variable for VA: is the endpoint the mean response of the whole group of eyes' improvement? Alternatively, do the studies report responder analyses: how many eyes (or subjects) achieve a certain level of recovery/improvement? If that is the case, what are the criteria for recovery/improvement?
  10. Have the patients taken idebenone in the past or currently?
  11. Should we consider all studies, including both retrospective and prospective studies, but should we assume a higher standard and accuracy in those studies performed prospectively?

VISUAL OUTCOMES IN LHON SUBJECTS WITH THE M.11778G>A MUTATION—LITERATURE REVIEW RESULTS

Because data from this relatively rare disease are limited, we analyzed both retrospective and prospective “natural history” studies of LHON subjects harboring the m.11778G>A mutation to reach as large a total sample size as possible. Likewise, we chose to restrict our primary metric of visual function to VA but report multiple methods of analyzing VA, including change over time, change from baseline, change from nadir, final VA, and recovery/improvement rates at the eye and subject level (improvement in one or both eyes), whenever available. Unfortunately, most studies do not indicate whether the reported VAs were performed with standardized methods of best refractive correction, and most studies, especially those with retrospective analyses, typically report only the final VAs. When it was not clearly stated whether the patients were taking idebenone, we chose to include those patients in the natural history data analyses, bearing in mind that these data may therefore overestimate “spontaneous” recovery rates.

A summary of the results is reported in Table 1. For all LHON patients confirmed with the m.11778G>A mutation, irrespective of age, data on visual outcomes were available in some form for 695 patients, of which 100 subjects (14.4%) were said to have “recovered” vision, although definitions of “recovery” vary from study to study.

TABLE 1. - Literature review of the visual outcomes of LHON subjects with the m.11778G>A mutation (all ages)
Study No. of Patients m.11778G>A Population Definition of Recovery Follow-up VA: Baseline and Follow-up Responders
Retrospective
 Newman et al (5) 56 Age 8–60 years Final outcome VA better than 20/200 2% (2/109*) eyes (1 eye each in a 12-year-old and an 8-year-old) had a nadir VA better than 20/2004% (2/56) patients had a nadir VA better than 20/200 in 1 eye4 eyes in 3 patients (aged 9, 12, and 15 years) had subsequent improvement to 20/40 or better
 Stone et al (13) 136 Included 56 subjects from the study by Newman 1991 Final outcome VA ≥20/40 (+0.3 logMAR) Between several months and 6 years 4% (5/136) patients recovered several months up to 6 years after onsetAmong the 5 subjects who recovered, 3 (60%) were below the age of 15 years at vision loss onset
 Oostra et al (19) 79 Age 6–61 years Final outcome VA in the best seeing eye better than 20/200 or at least 20/40 19% (15/79) patients had VA (best seeing eye) > 20/200
9% (7/79) patients had VA (best seeing eye) ≥ 20/40
 Riordan-Eva et al (9) 24 Age 15–62 years Final outcome VA 20/80 or better in the better eye ≥24 months Subject responder: 25% (6/24 patients)
 Hotta et al (20) 90
Individual data for 77 patients
Age 7–59 years Final outcome VA >20/200 0–48 months Eye responders: 14% eyes (25/177) had a final VA >20/20021% patients (16/77) had a final VA >20/200 in at least 1 eye
 Nikoskelainen et al (11) 32 Age 6–58 years 27% eyes (17/64) had a final VA ≥20/20017% eyes (11/64) had a final VA ≥20/5025% patients (8/32) had a “favorable visual prognosis” (no criteria provided)
 Sadun et al (21) 20 Age from 10 to 41 years, with a mean of 26.1 ± 10 years Final outcome VA better than 20/200 From 0 to 64 years (unknown for 2 patients) Final mean VA of 2.046 ± 0.55 logMAR Eye responders: 0% (0/40) eyes
Subject responders: 0% (0/20) subjects
 Carelli et al (22) 43
No treatment
≤1 year since onset
Age ≥10 yearsInclusion of 2 children from 10 to 14 years [Valerio Carelli, MD PhD, personal communication, May 2020]
Gain from nadir of at least 2 lines of Snellen acuity or a change from off-chart to on-chart ≥5 years Final VA in responder eyes (n = 19) best eye: 0.648 (Snellen 20/32); worst eye: 0.316 (Snellen 20/63) Eye responders: 22% (19/86) eyesSubject responders: 23% (10/43)Interval from onset to recovery: 27.7 months“Noticeably, the untreated patients recovering vision were younger at disease onset than the others.”
 Romero et al (23) 21 Age from 3 to 53 years Final outcome VA better than 20/200 From 2 to 51 years (mean 13 years) Final mean VA: 1.8 logMAR Eye responders: 10% (4/42)Subject responders: 10% (2/21)

 Mashima et al (24)
61
(40 no treatment and 21 treated with idebenone)
All in the acute phase
Age: 9 to 65 years
Average age: 23.1 ± 12.1
Median age: 18 years
Final VA ≥20/100 3–10 years Subject responders: 20% (8/40) patients
 Silva et al (25) 61 Age 6–75 years CRR: Recovery from baseline or nadir: on-chart VA: ability to read ≥10 additional ETDRS letters (equivalent to −0.2 logMAR); off-chart VA: ability to read ≥5 letters “on-chart” (equivalent to at least 1.6 logMAR) 2.3–58.7 mo (median of 14.9 mo) CRR from baseline: Subject responders: 15% (9/61) patientsCRR from nadir: Subject responders: 28% (17/61) patients
 Moon et al (26) 28 Age from 5 to 63 years (all 40 LHON patients) Recovery from nadir: Gain of 3 lines or more From 12 to 206 months (average: 42.9 months) (all 40 LHON patients) Eye responders: 23% (13/56) eyesSubject responders: 25% (7/28) subjects
Prospective
 Klopstock 2011 (RHODOS—placebo arm); EPAR idebenone (27) 18
(placebo arm)
Duration of vision loss (mean): 24.6 (SD: 16.6) months CRR: Recovery from baseline or nadir: on-chart VA: ability to read ≥10 additional ETDRS letters (equivalent to −0.2 logMAR); off-chart VA: ability to read ≥5 letters “on-chart” (equivalent to at least 1.6 logMAR) 24 weeks Change from baseline: +0.009 (−0.111 to 0.129); 0 letters CRR from baseline: Subject responders: 0% (0/18) patientsCRR from nadir: Subject responders: 0% (0/18) patients
 Lam et al (28) 44
(15 on idebenone)
Acute ≤12 months (13 patients at baseline)
Chronic >12 months
Age 4–64 years
Recovery from baseline
On-chart: ≥−0.3 logMAR or
Off-chart: From off-chart to at least 3 lines on-chart
Varied between 6 and 36 months Stable mean VA (ETDRS scores):
Baseline: 23.3
12 months: 23.2
24 months: 18.6
36 months: 21.9
Eye responders: 15% (13/88) eyes
Subject responders: 18% (8/44) patients (4 on idebenone)
 Yang et al (31) 16 1–10 years of vision loss ≥−0.3 logMAR (off-chart included) 12 months Stable mean BCVA (logMAR)
Baseline: 1.417 ± 0.543 logMAR
12 months: 1.385 ± 0.545 logMAR
Improvement: 5 eyes in 4 patients
Decline: 3 eyes in 2 patients
*Data are not available for 3 eyes because of other intervening factors (traumatic injury, persistent hyperplastic primary vitreous/cataract, and visual loss still in initial stages at the time of publication).
BCVA, best-corrected visual acuity; CRR, clinically relevant response; EPAR, European public assessment report; ETDRS, Early Treatment Diabetic Retinopathy Study; LHON, Leber hereditary optic neuropathy; logMAR, logarithm of the minimum angle of resolution; VA, visual acuity.

Retrospective Studies

In 1991, Newman et al (5) reported that among 56 subjects (109 eyes) with age at onset ranging from 8 to 60 years, 2 eyes had a VA nadir better than 20/200 (1 eye each of subjects with the onset of vision loss at ages 8 and 12 years). Four other eyes in 3 patients had subsequent improvement to 20/40 in both eyes (onset age 9), 20/30 (onset age 15), and 20/20 (onset age 12) after several months, 1 year, and 2.5 years, respectively.

In 1992, Stone et al (13) noted a 4% spontaneous improvement rate (5/136 patients, with 3 of the numerator and 56 of the denominator being subjects reported in the study by Newman et al (5)), defined as a VA of at least 20/40 in at least 1 eye.

In 1994, Oostra et al (19) reported the final VAs in the better-seeing eye of 79 subjects aged from 6 to 61 years, with 15 (19%) having a final VA better than 20/200 and 7 (9%) having a final VA of 20/40 or better.

In 1995, Riordan-Eva et al (9) reported a median final VA later than 24 months from the onset of vision loss for 24 subjects with the m.11778G>A mutation aged 15–62 years of 1/60 (Snellen equivalent of 20/1,200) in the better-seeing eye and counting fingers in the worst seeing eye, with 73% of subjects qualifying for “partial sightedness” (20/200 or worse in the better eye) or “legal blindness” (worse than 20/400 in the better eye). Six of 24 (25%) subjects with the m.11778G>A mutation had a final VA of 20/80 or better in the better eye, but only one of these patients (4%) is described in their summary as having “recovery.”

In 1995, Hotta et al (20) reported a VA of 20/200 or worse in 152 (86%) of 177 eyes in patients aged from 7 to 59 years (average 23.4 years). The follow-up period ranged from 0 to 48 months (average 6.2 months).

In 1996, Nikoskelainen et al (11) reported final VAs in 32 subjects aged 6–58 years as worse than 20/200 in 73% of 64 eyes and 20/50 or better in 17% of eyes (11 eyes in 8 subjects, at least 2 of whom had an onset of vision loss at age less than 15 years).

In 2004, Sadun et al (21) studied a large Brazilian LHON pedigree, including 20 affected subjects with onset age from 10 to 41 years (mean 26.1 ± 10 years). The time since onset was variable (from less than 1 year in 2 patients to 64 years for 1 patient). No patient reported visual recovery, and central vision function was severely impaired in all eyes, with a mean final VA of 2.04 logarithm of the minimum angle of resolution (logMAR) (Snellen equivalent 20/2000 or counting fingers).

In 2011, Carelli et al (22) reported a visual recovery from nadir (defined as a gain of at least 2 lines of Snellen acuity or a change from off-chart to on-chart) for 23% of the 43 untreated subjects with the m.11778G>A mutation. This study population included 2 children less than 15 years, 1 of whom spontaneously improved and 1 who did not (Valerio Carelli, MD PhD, personal communication, May 2020).

In 2014, Romero et al (23) described 21 Chilean LHON mt.11778A>G patients (42 eyes), with age at onset ranging from 3 to 53 years and follow-up from 2 to 51 years (mean 13 years). Four eyes (10%) had a final VA better than 20/200, and the mean final VA was 1.8 logMAR (Snellen equivalent 20/1,200).

In 2017, Mashima et al (24) reported 61 LHON patients with the m.11778G>A mutation with a mean age of 23.1 ± 12.1 years at onset. Eight of the 40 patients (20%) had a recovery of their VA of ≥−0.2 logMAR.

In 2019, Silva et al (25) defined clinically relevant recovery (CRR) as an improvement of VA of ≥10 ETDRS letters (equivalent to −0.2 logMAR) if on-chart, or from off-chart to on-chart VA with the ability to read ≥5 ETDRS letters (equivalent to at least 1.6 logMAR). For their subgroup of 61 subjects with the m.11778G>A mutation, including children from the age of 6 years, a CRR of 15% and 28% of subjects was reported from baseline and from nadir, respectively. The proportion of children younger than 15 years was not provided. Observation time was 2.3–58.7 months with a median of 14.9 months.

In 2020, Moon et al (26) reported on a total of 40 LHON subjects, 16 of whom were treated with idebenone and 28 of whom had the m.11778G>A mutation. Visual recovery (defined as a gain of 3 or more lines of VA from nadir) was noted in 13 of 56 (23.2%) eyes in 7 patients with the m.11778G>A mutation, with 6 eyes (10.7%) in 3 patients achieving VAs of 20/40 or better.

Prospective Studies

The Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) was a prospective, double-blind, placebo-controlled trial that randomized 85 patients with LHON to either idebenone or placebo in a 2:1 ratio (27). The recruited patients carried 1 of the 3 primary mtDNA mutations, and duration of visual loss of up to 5 years was allowed. In the European Public Assessment Report submitted to the European Medicines Agency (EMA), none of the 18 patients in the placebo group with the m.11778G>A mutation had a spontaneous CRR at week 24 from baseline or from nadir. The mean change from baseline was +0.009 (95% confidence interval, −0.111 to 0.129) logMAR (8,27).

In the 2014 study by Lam et al (28), the largest and most rigorous prospective observational study to date, 44 patients with the m.11778G>A mutation were recruited from 2008 to 2012 and evaluated every 6 months for 36 months. Important information is provided in the 2014 article, its supplementary material, and subsequent unpublished poster presentations from national meetings (29,30).

The mean age at onset of vision loss was 23.9 years (range 4–61 years), and the mean time from the onset of vision loss to enrollment was 97.7 months. Fifteen of the total 44 patients, and 11 of the 19 patients recruited within 2 years of the onset of visual loss, were concurrently taking idebenone, but these individual subjects are not identified for the reader. For VA measurements, both eyes were averaged at each visit. At 36-month follow-up, 18 subjects had a mean ETDRS score of 21.9 (Snellen equivalent <20/320). For the overall population, and in subpopulations based on the duration of visual loss before enrollment, there was no improvement in the mean VA over time, and there was no visual improvement on any of the monitored parameters (Table 2).

TABLE 2. - Population of 44 LHON subjects with the m.11778G>A mutation followed up to 36 months
Characteristics Mean (SD)
Baseline Mo 12 Mo 24 Mo 36
Total number of subjects 44 40 31 18
Mean BCVA ETDRS score (SD) 14.9 (18.3) 14.4 (19.3) 14.1 (17.3) 15.9 (19.6)
No. of subjects with vision loss ≤12 mo 13 12 9 4
 Mean BCVA ETDRS score (SD) 23.3 (21.4) 23.2 (28.3) 18.6 (24.6) 21.9 (28.4)
No. of subjects with vision loss >12 mo 31 28 22 14
 Mean BCVA ETDRS score (SD) 11.3 (15.9) 10.6 (12.7) 12.2 (13.5) 14.1 (17.4)
Adapted from Lam et al (28). Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; LHON, Leber hereditary optic neuropathy.

Regarding responder analyses, in total, 18% (8/44) of patients had visual recovery, defined as an improvement of at least −0.3 logMAR for on-chart eyes or at least 3 lines read on the ETDRS chart for off-chart eyes. Among the 8 patients with recovery, half were treated with idebenone. The time to recovery after the onset of vision loss ranged from 8.3 to 71.5 months (median, 27.5 months) (see Supplemental Digital Content, Table E1, https://links.lww.com/WNO/A431) (29).

The study by Lam et al included several young-onset patients. Defining young patients as either <18 years or <15 years, the numbers of patients included were 12 and 8, respectively. When removing subjects with age at onset 4–14 years, the eye and subject responder rates were, respectively, 11% (8/72) eyes and 14% (5/36) patients (28).

Only 13 enrolled subjects had vision loss onset within 1 year of enrollment. Twelve of these subjects had 1-year follow-up, and only 4 had a follow-up at 36 months. Similar to the total study population, there was no improvement of VA over time (Table 2) (28). Among the 12 patients enrolled within 1 year with a follow-up at 12 months, 2 patients (subject #s 14 and 76) were younger than 15 years at the onset of the disease, reducing the sample size to 10 patients (20 eyes) (30). Among the 9 patients enrolled within 1 year with a follow-up at 24 months, 1 patient (#14) was younger than 15 years at the onset of the disease, reducing the sample size to 8 patients (16 eyes) (30). Three of the 10 patients aged 15 years or older who had at least 12 months of follow-up had improvement of at least 15 letters (5 eyes: 1 eye for patient #53; 2 eyes for patients #77 and #82): 2 of them at 12 months (#77 and #82) with no further follow-up and 1 of them at 24 months of follow-up (#53). Therefore, 3 of 10 (30%) patients or 5 of 20 (25%) eyes had improvement but with follow-up at 24 months for only one of these patients. From the available data, it is unknown whether these patients were treated with idebenone (see Supplemental Digital Content, Table E2, https://links.lww.com/WNO/A431) (29). In summary, Lam et al (28) concluded that “spontaneous improvement of visual acuity in patients with G11778A LHON is not common and is partial and limited when it occurs.”

In 2016, Yang et al (31) reported that among 16 patients with the m.11778G>A mutation, VA was relatively stable in 24 eyes, with mean visual acuities of 1.417 ± 0.543 and 1.385 ± 0.545 logMAR at baseline and 12 months, respectively. The VA of 8 eyes (4 patients) had changed significantly after 12 months; in 5 eyes (4 patients), the VA improved, with mean values of 1.600 ± 0.464 and 1.040 ± 0.688 at the first and second examinations, respectively. The VA of 3 eyes (2 patients) decreased, with mean values of 1.000 ± 0.000 and 1.733 ± 0.252 at the first and second examinations, respectively.

Visual Outcomes in Pediatric LHON Subjects With the m.11778G>A Mutation—Literature Review Results

LHON is predominantly a disease of young adults, with most cases having an age at onset between 15 and 35 years. However, LHON onset has now been proven in molecularly confirmed cases to range from age 2 years to age 87 years. In Table 3, we report the distribution of age at onset in published large cohorts of LHON subjects with molecular confirmation of the causative mtDNA mutation (5,9,12,20,32–35). Although the 1963 Van Senus (32) description of a large cohort of Dutch patients predates the molecular definition of the disease, we included the data available from 12 of his original pedigrees (representing 110 affected patients) that were subsequently molecularly confirmed to be positive for the m.11778G>A mutation (36). Of the 91 patients for whom there is information regarding age at onset (range 7–61 years), 64% lost vision between the ages of 15 and 35 years, with the onset age of less than 18 years in 35% (32/91) of patients and less than 15 years in 18% (16/91) (32).

TABLE 3. - Distribution of age at onset in the LHON population
First Author (Year) Study Population LHON Mutations Total No. of Patients Age at Disease Onset
Under 18 15–17 12–14 10–12 Under 10
Van Senus et al (1963) (32) Dutch m.11778G>A (post hoc mutation confirmation) 91 32 16 6 7 3
Newman et al (1991) (5) American m.11778G>A 72 15 8 3 2 2
Hotta et al (1995) (20) Japanese m.11778G>A 80 32 18 8 5 1
Riordan-Eva et al (1995) (9) British 3 primary
m.11778G>A
94
50
34a
NR
NR
NR
NR
NR
NR
NR
4
0
Barboni et al (2006) (33) Italian 3 primary
m.11778G>A
157
97
NR
NR
NR
NR
NR
NR
NR
NR
18
10
Jia et al (2006) (34) Chinese 3 primary
m.11778G>A
346
312
240b
225b
NR
NR
NR
NR
NR
NR
10
10
Li et al (2017) (35) Chinese 3 primary
m.11778G>A
89C
76C
NS
NR
NS
NR
51e
NR

NR
38
NR
Majander et al (2017) (12) British 3 primary
m.11778G>A
27d
13d
NS
NS
NS
NS
NS
NS
27f
13f
3 primary refers to primary LHON mutations (m.3460G>A, m.1178G>A, and m.14484T>C).
aActual age group 0-20 years old.
bActual age group 0–19 years old.
cPopulation studied had LHON onset <14 years old.
dPopulation studied had LHON onset ≤12 years old.
eDisease onset between 10 and 14 years old.
fDisease onset ≤ 12 years old.
LHON, Leber hereditary optic neuropathy; NR, not reported; NS, not studied.

Few studies provide age-at-onset–specific visual outcomes (5,12,20,32,36) (see Supplemental Digital Content, Tables E3–E5, https://links.lww.com/WNO/A431). Combining 2 studies of LHON patients with the m.11778G>A mutation (5,20), all spontaneous recoveries occurred in patients with age at onset of 15 years or less, and all 3 patients with onset below age 10 years had a good outcome (defined as VA better than 20/200 in at least 1 eye; see Supplemental Digital Content, Table E4, https://links.lww.com/WNO/A431). In the age range between 15 and 17 years, the visual prognosis was poor and similar to that of adults. In the 1994 Oostra et al (19) study's subgroup of m.11778A>G patients representing 15 Dutch pedigrees, 6 of which were originally described in the Van Senus article, the mean age at onset of 78 patients with the final VA of 20/200 or worse, at least 24 months from onset, was 27.8 years, whereas the mean age at onset of those patients with VA of 20/40 or better was 13.4 years.

In a study specifically investigating visual outcomes in the pediatric LHON population, Barboni et al (33) reported that patients aged 10 years or younger represented a total of 11.5% (18/157) of the entire cohort of molecularly confirmed primary mutation LHON patients and 10.3% (10/97) of the subgroup of patients with the m.11778G>A mutation. Among the 9 children of this subgroup for which there was information on the natural history, one had a bilateral acute onset indistinguishable from the usual form of onset in adults, 2 had acute onset in 1 eye alone, and 6 had a slowly progressive form of the disorder. Of the 5 patients with acute bilateral vision loss (1 of which had the m.11778G>A mutation), 4 had spontaneous recovery (3 bilaterally and 1 unilaterally). Among the 6 patients carrying the m.11778G>A mutation with the slowly progressive form of the disease, ultimate VAs were statistically significantly better when compared with those of children with acute onset (mean of 0.45 (20/45) worst eye and 0.67 (20/30) best eye compared with 0.1 (20/200) worst eye and 0.33 (20/60) best eye), and definitely better than those VAs reported in most older patients with the m.11778G>A mutation. Similarly, Spruijt et al (37) described a more gradual onset of vision loss in patients younger than 15 years, as did Majander et al (12) in 37% of their cases 12 years or younger (slowly progressive or insidious/subclinical).

In a meta-analysis, Majander et al (12) described the clinical manifestations and visual prognosis of childhood LHON, defined as visual loss onset at 12 years or younger and molecular confirmation of 1 of the 3 primary mtDNA mutations (using previously published data from 20 studies and adding 27 previously unpublished UK patients) (5,9,11,21,23,33,38–50). Among the entire cohort of 60 pediatric patients with the m.11778G>A mutation, the final VA was better than or equal to 20/400 in 68% of cases and better than or equal to 20/40 in 11% of cases (12). In the UK patient subgroup with the m.11778G>A mutation, 65% of eyes (17/26) had a final VA of at least 20/400 and 19% of eyes (5/26) had a final VA of at least 20/40 (see Supplemental Digital Content, Table E5, https://links.lww.com/WNO/A431).

In summary, LHON with the m.11778G>A mutation is not uncommon in the age group less than 18 years old, but within that group, it is most common among 15–17 year olds, in whom the visual prognosis appears indistinguishable from LHON patients with this specific mutation and older onset (mostly poor outcome). The visual prognosis for LHON patients with the m.11778G>A mutation and onset under the age of 12 years (and especially under the age of 10 years) is much better than that of LHON patients with the m.11778G>A mutation and older onset, and the natural course of the disorder is more often atypical (slowly progressive or insidious) (12,33), although even a typical acute onset in this age group does not preclude meaningful spontaneous recovery (33).

Because the visual outcome and the spontaneous recovery rates are different in children, we specifically analyzed those natural history studies from which data of subjects aged 15 years or older could be extracted to better assess the rate and extent of spontaneous recovery in the adult LHON population harboring the m.11778G>A mutation. Table 4 summarizes these results. Of 204 such designated subjects, only 23 (11.3%) had meaningful visual recovery in at least 1 eye, and some were likely treated with idebenone. However, we recognize that by excluding those large studies without age at onset information, we are dramatically reducing our sample size.

TABLE 4. - Meta-analysis of LHON subjects with the m.11778G>A mutation and age ≥15 years old at onset
Study Total Number of Subjects Subjects ≥15 Years Old Recovery
Criteria for Recovery Patients (n/N)—in at Least 1 Eye Eyes (n/N)
Retrospective
 Newman et al (5) 56 50 Final outcome VA better than 20/200 0% (0/50) 0% (0/98)*
 Riordan-Eva et al (9) 24 24 Final outcome VA 20/80 or better in the better eye 25% (6/24)
 Sadun et al (21) 20 14 Final outcome VA better than 20/200 0% (0/14) 0% (0/28)
 Carelli et al (22) 43
No treatment
41 [Valerio Carelli, MD PhD, personal communication, May 2020] Recovery from nadir: Gain of at least 2 lines of Snellen acuity or a change from off-chart to on-chart 22% (9/41) 21% (17/82)
 Romero et al (23) 21 16 Final outcome VA better than 20/200 6% (1/16) 6% (2/32)
Prospective
 Klopstock 2011 (RHODOS—placebo arm); EPAR idebenone (27) 18 18 (≥14 years old) CRR: Recovery from baseline or nadir: On-chart VA: ability to read ≥10 additional ETDRS letters (equivalent to −0.2 logMAR); Off-chart VA: ability to read ≥5 letters “on-chart” (equivalent to at least 1.6 logMAR) 0% (0/18) NA
 Lam et al (28) 44 36 (subjects may have been treated with idebenone) Improvement from baseline of at least 15 ETDRS letters 14% (5/36) 11% (8/72)
 Yang et al (31) 16 5 Improvement of at least −0.3 logMAR from baseline 40% (2/5) 20% (2/10)
*Data are not available for 2 eyes because of other intervening factors (traumatic injury in one case and visual loss still in initial stages at the time of publication in the other case).
CRR, clinically relevant response; EPAR, European public assessment report; ETDRS, Early Treatment Diabetic Retinopathy Study; LHON, Leber hereditary optic neuropathy; logMAR, logarithm of the minimum angle of resolution; VA, visual acuity.

CONCLUSIONS

In this review with meta-analyses, we attempted to better define the clinical presentation, age at onset, and natural history of visual function (as defined primarily by VA) of patients with LHON, specifically those harboring the most prevalent m.11778G>A mutation in MTND4. Although there have been many published studies addressing these issues, and the cumulative numbers of patients are sufficient for simple statistical analyses, the heterogeneity of these studies makes direct comparison and global inclusion of individual subjects problematic. Among these studies, methods vary considerably regarding the specific information collected regarding age at onset, use of idebenone, duration of vision loss at the time of data collection, duration of patient follow-up, mode of visual function measurement, definition of visual recovery, and the methods of data collection, be it retrospective or prospective.

The classic presentation of LHON visual loss with subacute simultaneous or rapidly sequential painless bilateral optic neuropathies with progression over several months and severe visual loss with rare or poor recovery from nadir, primarily in young adults, still holds true for most patients, especially for those with the m.11778G>A mutation. However, careful and systematic review of the literature, both retrospective and prospective studies, reveals that LHON may be more heterogeneous than assumed. The age at onset of visual loss clusters most prominently between the ages of 15 and 35 years, but the onset of visual loss in molecularly confirmed cases spans more than 8 decades of life. Although the most powerful predictor of visual outcome remains the mtDNA genotype (with the m.11778G>A mutation portending a poor prognosis), young age at onset (usually defined as age 12 years or less) carries the best chance for a good visual outcome. Among patients 15 years or older harboring the m.11778G>A mutation, however, recovery of vision from nadir likely occurs in less than 20% of patients, irrespective of how recovery is defined, and ultimate visual acuities of better than 20/200 are rare.

Perhaps the most disappointing conclusion of this review is that despite the many natural history studies performed on the LHON population since molecular diagnosis became available in the 1990s, adequate prospective studies with sufficient sample sizes of genotypically homogeneous untreated patients stratified by age, immediately enrolled when symptomatic, followed regularly for adequate periods of time with consistent measures of visual function, and analyzed with a standard definition of visual improvement are unfortunately still lacking. Going forward, the design of such a prospective study would likely necessitate a global multicentered effort, hampered in part by the large number of LHON patients currently prescribed or self-administering idebenone, and the compassionate use of gene therapy. However, future clinical trials for LHON therapies will most certainly require these data, either provided by new prospective natural history studies meeting these requirements or emanating from properly designed control arms of future clinical trials.

STATEMENT OF AUTHORSHIP

Category 1: a. Conception and design: N. J. Newman, V. Carelli, M. Taiel, and P. Yu-Wai-Man; b. Acquisition of data: N. J. Newman, V. Carelli, M. Taiel, and P. Yu-Wai-Man; c. Analysis and interpretation of data: N. J. Newman, V. Carelli, M. Taiel, and P. Yu-Wai-Man. Category 2: a. Drafting the manuscript: N. J. Newman, V. Carelli, M. Taiel, and P. Yu-Wai-Man; b. Revising it for intellectual content: N. J. Newman, V. Carelli, M. Taiel, and P. Yu-Wai-Man. Category 3: a. Final approval of the completed manuscript: N. J. Newman, V. Carelli, M. Taiel, and P. Yu-Wai-Man.

ACKNOWLEDGMENTS

The authors wish to thank Laure Blouin for her support in reviewing the relevant data in the pediatric section of the manuscript. N. J. Newman is supported in part by an ophthalmology department core grant from the NIH/NEI (P30-EY006360). VC is supported by grants from the Italian Ministry of Health (RF-2018-12366703), the Italian Ministry of Research (20172T2MHH), and Telethon-Italy (GUP15016). V. Carelli is also supported by patients' organizations MITOCON and IFOND, and patients' donations. P. Yu-Wai-Man is supported by a Clinician Scientist Fellowship Award (G1002570) from the Medical Research Council (UK), and also receives funding from Fight for Sight (UK), the Isaac Newton Trust (UK), the Addenbrooke's Charitable Trust, the National Eye Centre UK), the UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration, and the NIHR Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

REFERENCES

1. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AMS, Elsas LJ, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science. 1988;242:1427–1430.
2. Yu-Wai-Man P, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The epidemiology of Leber hereditary optic neuropathy in the north east of England. Am J Hum Genet. 2003;72:333–339.
3. Carelli V, Carbonelli M, de Coo IF, Kawasaki A, Klopstock T, Lagrèze WA, La Morgia C, Newman NJ, Orssaud C, Pott JWR, Sadun AA, van Everdingen J, Vignal-Clermont C, Votruba M, Yu-Wai-Man P, Barboni P. International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. J Neuroophthalmol. 2017;37:371–381.
4. Yu-Wai-Man P, Votruba M, Burté F, La Morgia C, Barboni P, Carelli V. A neurodegenerative perspective on mitochondrial optic neuropathies. Acta Neuropathol. 2016;132:789–806.
5. Newman NJ, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol. 1991;111:750–762.
6. Yamada K, Oguchi Y, Hotta Y, Nakamura M, Isashiki Y, Mashima Y. Multicenter study on the frequency of three primary mutations of mitochondrial DNA in Japanese pedigrees with Leber's hereditary optic neuropathy: comparison with American and British counterparts. Neuro-Ophthalmology. 1999;22:187–193.
7. Jurkute N, Harvey J, Yu-Wai-Man P. Treatment strategies for Leber hereditary optic neuropathy. Curr Opin Neurol. 2019;32:99–104.
8. EMA/480039/2015 Committee for Medicinal Products for Human Use (CHMP)—Assessment Report Raxone (Idebenone). 2015. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/raxone. Accessed June 17, 2020.
9. Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J, Harding AE. The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain. 1995;118:319–337.
10. Koilkonda RD, Guy J. Leber's hereditary optic neuropathy-gene therapy: from benchtop to bedside. J Ophthalmol. 2011;2011:179412.
11. Nikoskelainen EK, Huoponen K, Juvonen V, Lamminen T, Nummelin K, Savontaus ML. Ophthalmologic findings in Leber hereditary optic neuropathy, with special reference to mtDNA mutations. Ophthalmology. 1996;103:504–514.
12. Majander A, Bowman R, Poulton J, Antcliff RJ, Reddy MA, Michaelides M, Webster AR, Chinnery PF, Votruba M, Moore AT, Yu-Wai-Man P. Childhood-onset Leber hereditary optic neuropathy. Br J Ophthalmol. 2017;101:1505–1509.
13. Stone EM, Newman NJ, Miller NR, Johns DR, Lott MT, Wallace DC. Visual recovery in patients with Leber's hereditary optic neuropathy and the 11778 mutation. J Clin Neuro Ophthalmol. 1992;12:10–14.
14. Nakamura M, Yamamoto M. Variable pattern of visual recovery of Leber's hereditary optic neuropathy. Br J Ophthalmol. 2000;84:534–535.
15. Barboni P, Savini G, Valentino ML, Montagna P, Cortelli P, De Negri AM, Sadun F, Bianchi S, Longanesi L, Zanini M, de Vivo A, Carelli V. Retinal nerve fiber layer evaluation by optical coherence tomography in Leber's hereditary optic neuropathy. Ophthalmology. 2005;112:120–126.
16. Barboni P, Carbonelli M, Savini G, Ramos CDV, Carta A, Berezovsky A, Salomao SR, Carelli V, Sadun AA. Natural history of Leber's hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography. Ophthalmology. 2010;117:623–627.
17. Balducci N, Savini G, Cascavilla ML, La Morgia C, Triolo G, Giglio R, Carbonelli M, Parisi V, Sadun AA, Bandello F, Carelli V, Barboni P. Macular nerve fibre and ganglion cell layer changes in acute Leber's hereditary optic neuropathy. Br J Ophthalmol. 2016;100:1232–1237.
18. Moster SJ, Moster ML, Bryan MS, Sergott RC. Retinal ganglion cell and inner plexiform layer loss correlate with visual acuity loss in LHON: a longitudinal, segmentation OCT analysis. Invest Ophthalmol Vis Sci. 2016;57:3872–3883.
19. Oostra RJ, Bolhuis PA, Wijburg FA, Zorn-Ende G, Bleeker-Wagemakers EM. Leber's hereditary optic neuropathy: correlations between mitochondrial genotype and visual outcome. J Med Genet. 1994;31:280–286.
20. Hotta Y, Flitik K, Hayakawa M, Nakajima A, Kanai A, Mashima Y, Hiida Y, Shinoda K, Yamada K, Oguchi Y, Ishida M, Yanashima K, Wakakura M, Ishikawa S, Nakamura M, Sakai J, Yamamoto M, Hayashi T, Mitani I, Miyazaki S, Shimooku M, Imachi J, Kuniyoshi N, Nagataki S, Isashiki Y, Ohba N. Clinical features of Japanese Leber's hereditary optic neuropathy with 11778 mutation of mitochondrial DNA. Japa J Ophthalmol. 1995;39:96–108.
21. Sadun F, De Negri AM, Carelli V, Salomao SR, Berezovsky A, Andrade R, Moraes M, Passos A, Belfort R, Bastos Da Rosa A, Quiros P, Sadun AA. Ophthalmologic findings in a large pedigree of 11778/haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol. 2004;137:271–277.
22. Carelli V, La Morgia C, Valentino ML, Rizzo G, Carbonelli M, De Negri AM, Sadun F, Carta A, Guerriero S, Simonelli F, Sadun AA, Aggarwal D, Liguori R, Avoni P, Baruzzi A, Zeviani M, Montagna P, Barboni P. Idebenone treatment in Leber's hereditary optic neuropathy. Lett Ed Brain. 2011;134:1–5.
23. Romero P, Fernández V, Slabaugh M, Seleme N, Reyes N, Gallardo P, Herrera L, Peña L, Pezo P, Moraga M. Pan-American mDNA haplogroups in Chilean patients with Leber's hereditary optic neuropathy. Mol Vis. 2014;20:334–340.
24. Mashima Y, Kigasawa K, Shinoda K, Wakakura M, Oguchi Y. Visual prognosis better in eyes with less severe reduction of visual acuity one year after onset of Leber hereditary optic neuropathy caused by the 11,778 mutation. BMC Ophthalmol. 2017;17:192.
25. Silva M, Llòria X, Catarino C, Klopstock T. Natural history of Leber's hereditary optic neuropathy (LHON): findings from a large patient cohort. Poster Presented at: 45th Annual Meeting of the North American Neuro-Ophthalmology Society; March 16–21, 2019; Las Vegas, NV.
26. Moon Y, Kim US, Han J, Ahn H, Lim HT. Clinical and optic disc characteristics of patients showing visual recovery in Leber hereditary optic neuropathy. J Neuroophthalmol. 2020;40:15–21.
27. Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, Kernt M, Petraki D, Rummey C, Leinonen M, Metz G, Griffiths PG, Meier T, Chinnery PF. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain. 2011;134:2677–2686.
28. Lam BL, Feuer WJ, Schiffman JC, Porciatti V, Vandenbroucke R, Rosa PR, Gregori G, Guy J. Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy. JAMA Ophthalmol. 2014;132:428–436.
29. Lam BL, Feuer WJ, Schiffman JC, Porciatti V, Vandenbroucke R, Rosa PR, Gregori G, Guy J. Supplementary Online Content. Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy: preparation for gene therapy clinical trial. JAMA Ophthalmol. 2014;132:1–5.
30. Guy J, Feuer W, Davis JL, Porciatti V, Gonzales P, Koilkonda RD, Yuan H, Lam BL. ARVO poster 2019. Gene therapy for Leber hereditary optic Neuropathy an update of where we stand (Clinicaltrials.gov number: NCT02161380). Invest Ophthalmol Visual Sci. 2019;60:3602.
31. Yang S, Yang H, Ma SQ, Wang SS, He H, Zhao MJ, Li B. Evaluation of Leber's hereditary optic neuropathy patients prior to a gene therapy clinical trial. Medicine. 2016;95:40.
32. Van Senus AHC. Leber's disease in The Netherlands. Doc Ophthalmol. 1963;17:1–161.
33. Barboni P, Savini G, Valentino ML, La Morgia C, Bellusci C, De Negri AM, Sadun F, Carta A, Carbonelli M, Sadun AA, Carelli V. Leber's hereditary optic neuropathy with childhood onset. Invest Ophthalmol Vis Sci. 2006;47:5303–5309.
34. Jia X, Li S, Xiao X, Guo X, Zhang Q. Molecular epidemiology of mtDNA mutations in 903 Chinese families suspected with Leber hereditary optic neuropathy. J Hum Genet. 2006;51:851–856.
35. Li Y, Li Jie, Jia X, Xiao X, Li S, Guo X. Genetic and clinical analyses of DOA and LHON in 304 Chinese patients with suspected childhood-onset hereditary optic neuropathy. Plos One. 2017;12:e0170090.
36. Howell N, Oostra RJ, Bolhuis PA, Spruijt L, Clarke LA, Mackey DA, Preston G, Herrnstadt C. Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet. 2003;72:1460–1469.
37. Spruijt L, Kolbach DN, de Coo RF, Plomp AS, Bauer NJ, Smeets HJ, De die-Smulders CEM. Influence of mutation type on clinical expression of Leber hereditary optic neuropathy. Am J Ophthalmol. 2006;141:676–682.
38. Johns DR, Smith KH, Miller NR. Leber's hereditary optic neuropathy: clinical manifestations of the 3460 mutation. Arch Ophthalmol. 1992;110:1577–1581.
39. Johns DR, Heher KL, Miller NR. Smith KH Leber's hereditary optic neuropathy: clinical manifestations of the 14484 mutation. Arch Ophthalmol. 1993;111:495–498.
40. Moorman CM, Elston JS, Matthews P. Leber's hereditary optic neuropathy as a cause of severe visual loss in childhood. Pediatrics. 1993;91:988–989.
41. Pezzi PP, De Negri AM, Sadun F, Carelli V, Leuzzi V. Childhood Leber's hereditary optic neuropathy (ND1/3460) with visual recovery. Pediatr Neurol. 1998;19:308–312.
42. Thieme H, Wissinger B, Jandeck C, Christ-Adler M, Kraus H, Kellner U, Foerster MH. A pedigree of Leber's hereditary optic neuropathy with visual loss in childhood, primarily in girls. Graefes Arch Clin Exp Ophthalmol. 1999;237:714–719.
43. Leo-Kottler B, Christ-Adler M. Lebersche optikusneuropathie (LHON) bei frauen und kindern. Ophthalmologe. 1999;96:698–701.
44. Balayre S, Gicquel JJ, Mercie M, Dighiero P. Childhood Leber hereditary optic neuropathy. A case of a 6-year-old girl with loss of vision. J Fr Ophtalmol. 2003;26:1063–1066.
45. Kawasaki A, Borruat FX. Rapid onset of visual recovery following acute visual loss due to Leber's hereditary optic neuropathy. Rev Neurol (Paris). 2005;161:599–601.
46. Yu-Wai-Man P, Elliott C, Griffiths PG, Johnson IJ, Chinnery PF. Investigation of auditory dysfunction in Leber hereditary optic neuropathy. Acta Ophthalmol. 2008;86:630–633.
47. Bosley TM, Brodsky MC, Glasier CM, Abu-Amero KK. Sporadic bilateral optic neuropathy in children: the role of mitochondrial abnormalities. Invest Ophthalmol Vis Sci. 2008;49:5250–5256.
48. Zhou X, Zhang H, Zhao F, Ji Y, Tong Y, Zhang J, Zhang Y, Yang L, Qian Y, Lu F, Qu J, Guan MX. Very high penetrance and occurrence of Leber's hereditary optic neuropathy in a large Han Chinese pedigree carrying the ND4 G11778A mutation. Mol Genet Metab. 2010;100:379–384.
49. Liang M, Jiang P, Li F, Zhang J, Ji Y, He Y, Xu M, Zhu J, Meng X, Zhao F, Tong Y, Liu X, Sun Y, Zhou X, Mo JQ, Qu J, Guan MX. Frequency and spectrum of mitochondrial ND6 mutations in 1218 Han Chinese subjects with Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2014;55:1321–1331.
50. Jiang P, Liang M, Zhang J, Gao Y, He Z, Yu H, Zhao F, Ji Y, Liu X, Zhang M, Fu Q, Tong Y, Sun Y, Zhou X, Huang T, Qu J, Guan MX. Prevalence of mitochondrial ND4 mutations in 1281 Han Chinese subjects with Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2015;56:4778–4788.

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