Electroretinographic oscillatory potentials in Leber hereditary optic neuropathy.

PURPOSE: Leber hereditary optic neuropathy (LHON) affects retinal ganglion cells causing severe vision loss. Pattern electroretinogram and photopic negative response (PhNR) of the light-adapted (LA) full-field electroretinogram (ERG) are typically affected in LHON. In the present study, we evaluated dark-adapted (DA) and LA oscillatory potentials (OPs) of the flash ERG in genetically characterized LHON patients to dissociate slow from fast components of the response. METHODS: Seven adult patients (mean age = 28.4 ± 5.6) in whom genetic diagnosis confirmed LHON with mtDNA or nuclear DNAJC30 (arLHON) pathogenic variants were compared to 12 healthy volunteers (mean age = 35.0 ± 12.1). Full-field ERGs were recorded from both eyes. Offline digital filters at 50, 75 and 100 Hz low cutoff frequencies were applied to isolate high-frequency components from the original ERG signals. RESULTS: ERG a-waves and b-waves were comparable between LHON patients and controls, while PhNR was significantly reduced (p = 0.009) in LHON patients compared to controls, as expected. OPs derived from DA signals (75 Hz low cutoff frequency) showed reduced peak amplitude for OP2 (p = 0.019). LA OP differences between LHON and controls became significant (OP2: p = 0.047, OP3: p = 0.039 and OP4: p = 0.013) when the 100 Hz low-cutoff frequency filter was applied. CONCLUSIONS: Reduced OPs in LHON patients may represent disturbed neuronal interactions in the inner retina with preserved photoreceptoral (a-wave) to bipolar cell (b-wave) activation. Reduced DA OP2 and high-cutoff LA OP alterations may be further explored as functional measures to characterize LHON status and progression.

Nuclear modifier YARS2 allele correction restored retinal ganglion cells-specific deficiencies in Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted eye disease due to the degeneration of retinal ganglion cells (RGCs). Mitochondrial 11778G > A mutation is the most common LHON-associated mitochondrial DNA (mtDNA) mutation. Our recent studies demonstrated some LHON families manifested by synergic interaction between m.11778G > A mutation and YARS2 allele (c.572G > T, p.Gly191Val) encoding mitochondrial tyrosyl-tRNA synthetase. However, the RGC-specific effects of LHON-associated mtDNA mutations remain elusive and there is no highly effective therapy for LHON. Here, we generated patients-derived induced pluripotent stem cells (iPSCs) from fibroblasts derived from a Chinese LHON family (both m.11778G > A and c.572G > T mutations, only m.11778G > A mutation, and control subject). The c.572G > T mutation in iPSC lines from a syndromic individual was corrected by CRISPR/Cas9. Those iPSCs were differentiated into neural progenitor cells and subsequently induced RGC-like cells using a stepwise differentiation procedure. Those RGC-like cells derived from symptomatic individual harboring both m.11778G > A and c.572G > T mutations exhibited greater defects in neuronal differentiation, morphology including reduced area of soma, numbers of neurites and shortened length of axons, electrophysiological properties than those in cells bearing only m.11778G > A mutation. Furthermore, these RGC-like cells revealed more drastic reductions in oxygen consumption rates, levels of mitochondrial ATP and increasing productions of reactive oxygen species than those in other cell models. These mitochondrial dysfunctions promoted the apoptotic process for RGC degenerations. Correction of YARS2 c.572G > T mutation rescued deficiencies of patient-derived RGC-like cells. These findings provide new insights into pathophysiology of LHON arising from RGC-specific mitochondrial dysfunctions and step toward therapeutic intervention for this disease.

Longitudinal Study of Optic Disk Perfusion and Retinal Structure in Leber's Hereditary Optic Neuropathy.

Purpose: The purpose of this study was to evaluate optic disk perfusion and neural retinal structure in patients with subacute Leber's hereditary optic neuropathy (LHON) and LHON carriers, as compared with healthy controls. Methods: This study included 8 patients with LHON in the subacute stage, 10 asymptomatic carriers of a LHON-associated mitochondrial DNA mutation, and 40 controls. All subjects underwent measurement of the retinal nerve fiber layer (RNFL) thickness, the ganglion cell-inner plexiform layer (GCIPL) thickness using optical coherence tomography and optic disk microvascular perfusion (Mean Tissue [MT]) using laser speckle flowgraphy (LSFG). Patients were re-examined after a median interval of 3 months from the baseline visit. Results: LHON carriers had higher values of RNFL thickness, GCIPL thickness, and disk area than controls (P < 0.05), whereas MT was not different between the two groups (P = 0.936). Median MT and RNFL thickness were 32% and 15% higher in the early subacute stage of the disease than in controls (P < 0.001 and P = 0.001). MT declined below the values of controls during the late subacute stage (P = 0.024), whereas RNFL thickness declined later during the dynamic stage (P < 0.001). GCIPL thickness was lower in patients with LHON than in controls independently of the stage of the disease (P < 0.001). Conclusions: The high blood flow at the optic disk during the early subacute stage may be the consequence of vasodilation due to nitric oxide release as compensation to mitochondrial impairment. Optic disk perfusion as measured by LSFG is a promising biomarker for LHON diagnosis and monitoring as well as an objective outcome measure for assessing response to therapies.

Long-Term Follow-Up After Unilateral Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy: The RESTORE Study.

BACKGROUND: RESCUE and REVERSE were 2 Phase 3 clinical trials that assessed the efficacy and safety of intravitreal gene therapy with lenadogene nolparvovec (rAAV2/2-ND4) for the treatment of Leber hereditary optic neuropathy (LHON). RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials. METHODS: In RESCUE and REVERSE, 76 subjects with LHON because of the m.11778 G>A mutation in the mitochondrial gene ND4 received a single unilateral intravitreal injection of lenadogene nolparvovec. After 96 weeks, 61 subjects were enrolled in the long-term follow-up study RESTORE. The best-corrected visual acuity (BCVA) was assessed over a period of up to 52 months after onset of vision loss. A locally estimated scatterplot smoothing regression model was used to analyze changes in BCVA over time. Vision-related quality of life was reported using the visual function questionnaire-25 (VFQ-25). RESULTS: The population of MT-ND4 subjects enrolled in RESTORE was representative of the combined cohorts of RESCUE and REVERSE for mean age (35.1 years) and gender distribution (79% males). There was a progressive and sustained improvement of BCVA up to 52 months after the onset of vision loss. The final mean BCVA was 1.26 logarithm of the minimal angle of resolution 48 months after the onset of vision loss. The mean VFQ-25 composite score increased by 7 points compared with baseline. CONCLUSION: The treatment effect of lenadogene nolparvovec on BCVA and vision-related quality of life observed 96 weeks (2 years) after treatment in RESCUE and REVERSE was sustained at 3 years in RESTORE, with a maximum follow-up of 52 months (4.3 years) after the onset of vision loss.

Cross-Sectional Analysis of Baseline Visual Parameters in Subjects Recruited Into the RESCUE and REVERSE ND4-LHON Gene Therapy Studies.

OBJECTIVE: This report presents a cross-sectional analysis of the baseline characteristics of subjects with Leber hereditary optic neuropathy enrolled in the gene therapy trials RESCUE and REVERSE, to illustrate the evolution of visual parameters over the first year after vision loss. METHODS: RESCUE and REVERSE were 2 phase III clinical trials designed to assess the efficacy of rAAV2/2-ND4 gene therapy in ND4-LHON subjects. At enrollment, subjects had vision loss for ≤6 months in RESCUE, and between 6 and 12 months in REVERSE. Functional visual parameters (best-corrected visual acuity [BCVA], contrast sensitivity [CS], and Humphrey Visual Field [HVF]) and structural parameters assessed by spectral-domain optical coherence tomography were analyzed in both cohorts before treatment. The cross-sectional analysis of functional and anatomic parameters included the baseline values collected in all eyes at 2 different visits (Screening and Inclusion). RESULTS: Seventy-six subjects were included in total, 39 in RESCUE and 37 in REVERSE. Mean BCVA was significantly worse in RESCUE subjects compared with REVERSE subjects (1.29 and 1.61 LogMAR respectively, P = 0.0029). Similarly, mean CS and HVF were significantly more impaired in REVERSE vs RESCUE subjects (P < 0.005). The cross-sectional analysis showed that the monthly decrease in BCVA, ganglion cell layer macular volume, and retinal nerve fiber layer thickness was much more pronounced in the first 6 months after onset (+0.24 LogMAR, -0.06 mm3, and -6.00 µm respectively) than between 6 and 12 months after onset (+0.02 LogMAR, -0.01 mm3, and -0.43 µm respectively). CONCLUSION: LHON progresses rapidly in the first months following onset during the subacute phase, followed by relative stabilization during the dynamic phase.

Mild Leber hereditary optic neuropathy (LHON) in a Western European family due to the rare Asian m.14502T>C variant in the MT-ND6 gene.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is a mitochondrial neurodegenerative disease. The majority (>90%) is related to three primary mitochondrial DNA (mtDNA) variants: ND1 m.3460G>A, ND4 m.11778G>A and ND6 m.14484T>C. The remaining 10% is associated with >40 secondary variants with variable penetrance and incidence between different ethnic backgrounds. MATERIALS AND METHODS: Five sisters underwent an extensive ophthalmic workup including psychophysical, electrophysiological, multimodal brain imaging, biochemical testing and molecular screening. MT-ND6 protein modelling was performed. RESULTS: A 23-year-old woman presented with acute central visual loss to counting fingers in the right eye. She developed a central visual field scotoma, severe color vision deficiencies and impaired pattern visual evoked responses. Progressive optic atrophy ensued. The left eye was unremarkable, except for borderline thinning of the temporal retinal nerve fiber layer. Alcohol use and passive smoking were noted. MtDNA analysis revealed a rare variant, m.14502T>C in MT-ND6, exclusively known to cause optic neuropathy in an Asian population. Three sisters of the proband, two of whom reported tobacco and alcohol abuse, had bilateral temporal optic disc pallor without functional impact. A fourth non-smoker sister had a completely normal eye exam. CONCLUSIONS: The rare Asian m.14502T>C variant in the MT-ND6 gene was linked to a mild LHON phenotype in a Western European family. Penetrance in this family was likely triggered by alcohol and tobacco abuse. A full mtDNA sequencing is warranted in the case of high clinical suspicion of LHON when mutation analysis for the three common pathogenic variants is negative.

Brain functional MRI responses to blue light stimulation in Leber's hereditary optic neuropathy.

Melanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive photoreceptors contributing both to image and non-image-forming (NIF) functions of the eye. They convey light signal to the brain to modulate circadian entrainment, sleep, alertness, cognition, brightness perception and coarse vision. Given that rods and cones also contribute to all these impacts of light, isolating mRGC visual and NIF roles in humans is challenging so that mRGC functions remains to be fully characterized. Here, we evaluated light-driven visual and cognitive brain responses in Leber's Hereditary Optic Neuropathy (LHON), an inherited optic neuropathy that is characterized by a selective relative sparing of the melanopsin-expressing retinal ganglion cells (mRGCs). Twelve patients and twelve matched healthy controls (HC) were enrolled in a functional brain magnetic resonance imaging (fMRI) protocol including visual and visual-cognitive paradigms under blue (480 nm) and red (620 nm) light exposures. Primary visual cortex activation was detected in LHON patients; in particular higher occipital activation was found in response to sustained blue vs. red stimulation in LHON vs. HC. Similarly, brain responses to the executive task were larger under blue vs. red light in LHON over lateral prefrontal cortex. These findings are in line with the relative mRGC sparing demonstrated in LHON and support the mRGC contribution to both non-visual and visual brain functions, with potential implication for visual rehabilitation in hereditary optic neuropathy patients.

Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy.

BACKGROUND: Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse. METHODS: Open-label, multicenter, retrospective, noncontrolled analysis of long-term visual acuity and safety in 111 LHON patients treated with idebenone (900 mg/day) in an expanded access program. Eligible patients had a confirmed mitochondrial DNA mutation and had experienced the onset of symptoms (most recent eye) within 1 year before enrollment. Data on visual acuity and adverse events were collected as per normal clinical practice. Efficacy was assessed as the proportion of patients with either a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS) of visual acuity. In the case of CRR, time to and magnitude of recovery over the course of time were also assessed. RESULTS: At time of analysis, 87 patients had provided longitudinal efficacy data. Average treatment duration was 25.6 months. CRR was observed in 46.0% of patients. Analysis of treatment effect by duration showed that the proportion of patients with recovery and the magnitude of recovery increased with treatment duration. Average gain in best-corrected visual acuity for responders was 0.72 logarithm of the minimal angle of resolution (logMAR), equivalent to more than 7 lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Furthermore, 50% of patients who had a visual acuity below 1.0 logMAR in at least one eye at initiation of treatment successfully maintained their vision below this threshold by last observation. Idebenone was well tolerated, with most adverse events classified as minor. CONCLUSIONS: These data demonstrate the benefit of idebenone treatment in recovering lost vision and maintaining good residual vision in a real-world setting. Together, these findings indicate that idebenone treatment should be initiated early and be maintained more than 24 months to maximize efficacy. Safety results were consistent with the known safety profile of idebenone.

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

BACKGROUND: Leber hereditary optic neuropathy (LHON) is a maternally inherited bilaterally blinding optic neuropathy, predominantly affecting otherwise healthy young individuals, mostly men. The visual prognosis is generally poor, with most patients worsening to at least 20/200 visual acuity. The m.11778G>A (MTND4) mitochondrial DNA mutation is the most common cause of LHON and is associated with poor outcomes and limited potential for meaningful visual recovery. Treatments for LHON are limited, and clinical trials are hampered by inadequate data regarding the natural history of visual loss and recovery. In this article, we review the current literature specifically related to visual function of LHON patients with the m.11778G>A mutation. EVIDENCE ACQUISITION: 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. RESULTS: Meta-analysis of 12 retrospective and 3 prospective studies provided visual function information on 695 LHON patients with the m.11778G>A mutation, 100 (14.4%) of whom were reported to have "recovered" some vision, although definitions of "recovery" varied among studies and idebenone use could not always be excluded. When incorporating age at onset of visual loss into the analyses, and specifically addressing those patients aged 15 years or older, meaningful visual recovery occurred in 23 of 204 (11.3%) patients. A younger age at onset, especially less than 12 years, portends a better visual prognosis and a different natural history of visual loss progression and recovery than in adults. CONCLUSIONS: The classic presentation of LHON patients with the m.11778G>A mutation of severe visual loss with rare or poor recovery from nadir still holds true for most affected individuals. Among patients 15 years and older, recovery of meaningful vision 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. Adequate prospective studies with sufficient sample sizes of genotypically homogeneous untreated LHON 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 lacking. Future clinical trials for LHON will require more standardized reporting of the natural history of this disorder.

Therapeutic Effects of Idebenone on Leber Hereditary Optic Neuropathy.

Purpose: To characterize the potential therapeutic effects of idebenone on Leber hereditary optic neuropathy (LHON) in terms of visual acuity (VA), visual field (VF) defects, visual evoked potential (VEP) and retinal nerve fibre layer (RNFL) thickness using optical coherence tomography (OCT) measurements. Methods: This was a retrospective case-controlled study of the effect of idebenone (900 mg/d) on 30 patients with LHON due to m.3460 G > A, m.11778 G > A and m.14484 T > C mutations. The primary end-point was the recovery in VA after 3 and 6 mon. The main secondary end-point was the change in VF, VEP and RNFL thickness. The other secondary end-point was the correlation between visual changes after 6 mon and the VF, VEP and RNFL thickness at baseline of the groups. Results: Idebenone was shown to be safe and well tolerated. The primary end-point reached statistical significance. The VA in the idebenone group improved in both the best eye and worst eye. The mean defect of VF decreased and amplitude of VEP increased. There was no significant difference in latency and RNFL thickness between the groups. The treatment, together with the VA and amplitude at baseline, had a significant effect on the improvement in VA at 6 mon. Conclusion: This case-controlled study of LHON provides evidence that idebenone treatment may be beneficial in cases of LHON and that the influential factors governing outcomes are the VA and amplitude of the VEP at baseline.

Multilocus Mitochondrial Mutations Do Not Directly Affect the Efficacy of Gene Therapy for Leber Hereditary Optic Neuropathy.

PURPOSE: Clinical trials of gene therapy for Leber hereditary optic neuropathy (LHON) were conducted in 9 volunteers with the mitochondrial mutation, G11778A in ND4. The purpose of this study was to investigate whether multilocus mitochondrial mutations directly influence the efficacy of gene therapy for LHON. METHODS: Nine volunteers with LHON participated in a clinical trial with intravitreal injection of an adenoviral vector expressing wild-type ND4. Patients were subsequently divided into 2 groups: according to the differences in therapy efficacy and based on improvements in visual acuity. Full mitochondrial DNA sequences of the 2 groups of patients were generated and compared using PubMed, PolyPhen, and PROVEAN. Furthermore, the association between the detected mutations and clinical effects of gene therapy was analyzed. RESULTS: Best-corrected visual acuity (BCVA) significantly improved (≥0.3 log of minimum angle of resolution [logMAR]) in 7 patients 6 months after gene therapy, whereas there was no significant change in BCVA (<0.3 logMAR) of the remaining 2 patients. All 9 patients carried the G1178A mutation in addition to other nonsynonymous mutations. Among these mutations, some were predicted to be neutral and deleterious. Meanwhile, different mitochondrial mutations in the group in which treatment was ineffective, compared with those in responders, were at nucleotide positions 6569 (CO1; Patient 3), 9641 (CO3; Patient 3), and 4491 (ND2; Patient 5). CONCLUSIONS: Detection of the 3 primary mitochondrial mutations causing LHON is sufficient for screening before gene therapy; sequencing of the entire mitochondrial genome is unnecessary before treatment. Patients with LHON can respond to targeted gene therapy irrespective of additional multilocus mitochondrial mutations.

Clinical and Optic Disc Characteristics of Patients Showing Visual Recovery in Leber Hereditary Optic Neuropathy.

BACKGROUND: The visual prognosis in Leber hereditary optic neuropathy (LHON) is generally poor. However, some individuals can have spontaneous visual recovery (VR) in one or both eyes by a mechanism that is not yet clearly understood. The purpose of this study was to determine whether certain clinical and optic disc features are associated with VR in patients with LHON. METHODS: We retrospectively examined 80 eyes of 40 patients with LHON using clinical databases, fundus photographs, and high-definition spectral-domain optical coherence tomography (OCT) images. VR was defined as a gain of 3 or more lines of logarithm of the minimum angle of resolution (logMAR)-scaled visual acuity from nadir; this represents a doubling of the visual angle. Patients were divided into VR and nonrecovery (NR) groups. Using fundus photographs, we measured optic disc size and evaluated for the presence of optic disc features, including peripapillary telangiectasia, disc hyperemia, and swelling. We also measured the disc area, cup-to-disc ratio, and rim area of the optic disc using OCT. RESULTS: Twenty-one of 80 eyes (26%) had a VR. The VR occurred within 2 years after onset in 81% of cases. The VR group showed younger age at onset (21 vs 29 years, P = 0.017) and better visual acuity at the nadir (1.39 vs 2.16 logMAR, P < 0.001) compared with the NR group. Optic disc features, particularly peripapillary telangiectasia (P = 0.027) and disc hyperemia (P = 0.006), were more prominent in the NR group. The cup-to-disc ratio was significantly smaller (0.64 vs 0.71, P = 0.004) and the rim area was significantly greater (1.17 vs 0.85 mm, P < 0.001) in the VR group compared with the NR group. CONCLUSIONS: A younger age at onset and a less severe reduction of visual acuity at the nadir were associated with a higher probability of VR. Presence of peripapillary telangiectasia and optic disc hyperemia may serve as predictive factors for poor visual prognosis in patients with LHON.

Visual function in chronic Leber's hereditary optic neuropathy during idebenone treatment initiated 5 to 50 years after onset.

PURPOSE: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by a subacute and progressive impairment and subsequent degeneration of retinal ganglion cells (RGCs). In most cases, it results in optic nerve atrophy and permanently reduced visual acuity (VA). Idebenone has recently been approved in Europe for treating LHON. However, published clinical data has only focused on efficacy in patients within the first years after disease onset. The present study is the first to evaluate possible effects of idebenone treatment in patients with LHON when initiated after more than 5 years from disease onset. METHODS: Oral treatment with idebenone 300 mg tid was started in seven patients 5 to 51 years after LHON onset. All patients had genetically confirmed primary LHON mutations (m11778G>A, m14484T>C, and m13051G>A). Visual function of all fourteen eyes was tested every 3 months using logarithmic reading charts and automated static threshold perimetry. The obtained clinical data were analyzed retrospectively using a multivariate analysis for VA and the Wilcoxon signed-rank test for visual field data. RESULTS: Before treatment, VA was 0.78 ± 0.38 logMAR (range 0.24 to 1.50 logMAR). During the first year of therapy, VA improved significantly by an average of - 0.20 ± 0.10 logMAR or 10 ± 5 ETDRS letters (P = 0.002; VA range 0.06 to 1.30 logMAR). Seven of fourteen eyes showed an improvement of 2 or more lines. Visual field mean deviation increased from - 8.02 ± 6.11 to - 6.48 ± 5.26 dB after 12 months, but this change was not statistically significant (P = 0.056). CONCLUSIONS: The increase in VA of patients who have had LHON for more than 5 years observed soon after start of treatment may not constitute a coincidental spontaneous recovery. We hypothesize that the treatment response in chronic LHON was the result of a reactivated signal transduction in surviving dysfunctional RGCs. The results of this study indicate a beneficial effect of idebenone on improvement of visual function in LHON patients with established optic atrophy.

Three Cases of Leber's Hereditary Optic Neuropathy with Rapid Increase in Visual Acuity After Gene Therapy.

BACKGROUND: During the first few trials of gene therapy for Leber's hereditary optic neuropathy performed by our group, the visual acuity of the patients increased gradually over several months, or even years. However, in the current round of gene therapy for Leber's hereditary optic neuropathy, we noted that the visual acuity of three patients increased rapidly, within a few days after treatment. CASE PRESENTATION: Three patients who were diagnosed with mitochondrial gene 11778 mutation (associated with a G-to-A transition at Mt-11778 in the ND4 subunit gene of complex I of mitochondrial DNA that changes an arginine to histidine at amino acid 340) by genetic diagnosis were followed up three times before gene therapy, which lasted for 1 year, without spontaneous improvement of vision. Visual acuity in one or both eyes of each of the three patients increased rapidly after the initial gene therapy treatment. CONCLUSION: We suspect that in some patients with Leber's hereditary optic neuropathy, a portion of the retinal ganglion cells might remain in a "dormant" state for a certain period of time; these may be activated, within an optimal timeframe, during gene therapy for Leber's hereditary optic neuropathy.

Prognostic factors for visual acuity in patients with Leber's hereditary optic neuropathy after rAAV2-ND4 gene therapy.

IMPORTANCE: Factors affecting visual acuity prognosis after gene therapy in Leber's hereditary optic neuropathy (LHON) patients with mutation at site 11 778 are unknown. BACKGROUND: To analyse correlations between visual acuity prognosis and baseline characteristics of LHON after rAAV2-ND4 gene therapy. DESIGN: Retrospective study. PARTICIPANTS: Fifty-three LHON patients with a mutation at site 11 778. METHODS: Single-eye intravitreal injection of rAAV2-ND4. MAIN OUTCOME MEASURES: Sex, onset age, duration of disease, best-corrected visual acuity (BCVA), visual field index (VFI) and mean deviation (MD) were recorded for all patients at baseline. BCVA was recorded at 1- and 3-month follow-up visits after gene therapy. Correlations between BCVA prognosis and baseline characteristics were analysed by univariate analysis. Logistic regression analysis was performed on independent factors affecting BCVA prognosis. RESULTS: Univariate analysis showed significant differences in the VFI and MD of the injected eye between BCVA improvement and non-improvement groups after 3 months of treatment, with greater VFI and smaller absolute MD in the BCVA improvement group. Logistic regression showed that VFI and baseline BCVA were independent prognostic factors for visual acuity. The correlation between VFI and MD was statistically significant. CONCLUSIONS AND RELEVANCE: VFI and baseline BCVA were correlated with the visual acuity prognosis of LHON patients receiving gene therapy, with greater baseline VFI and better baseline BCVA predicting better visual acuity prognosis. MD was strongly correlated with VFI and might be correlated with gene therapy prognosis. This finding may form a basis for predicting the efficacy of gene therapy in these patients and guiding subsequent treatment.

Harding's disease: an important MS mimic.

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited disorder characterised by bilateral, painless visual loss which leads to severe optic atrophy. It can be associated with other conditions including multiple sclerosis (MS), movement disorders, epilepsy and cardiac arrhythmias. The association of LHON with an MS-like illness is often referred to as Harding's disease (or Harding's syndrome). We report two siblings, who both harbour the 11 778 mitochondrial DNA (mtDNA) mutation, but who manifest markedly different clinical phenotypes; a male with classical LHON and a female with an MS-like illness. LHON affects males four to five times more often than females. By contrast, Harding's disease is seen predominantly in females, in a pattern comparable to that seen in MS. The pathogenic basis behind the variation in penetrance and phenotype between genders and individual family members remains unclear.