Leber's Hereditary Optic Neuropathy Research Articles

Hereditary Optic Neuropathies: A Systematic Review on the Interplay between Biomaterials and Induced Pluripotent Stem Cells.

Hereditary optic neuropathies (HONs) such as dominant optic atrophy (DOA) and Leber Hereditary Optic Neuropathy (LHON) are mitochondrial diseases characterized by a degenerative loss of retinal ganglion cells (RGCs) and are a cause of blindness worldwide. To date, there are only limited disease-modifying treatments for these disorders. The discovery of induced pluripotent stem cell (iPSC) technology has opened several promising opportunities in the field of HON research and the search for therapeutic approaches. This systematic review is focused on the two most frequent HONs (LHON and DOA) and on the recent studies related to the application of human iPSC technology in combination with biomaterials technology for their potential use in the development of RGC replacement therapies with the final aim of the improvement or even the restoration of the vision of HON patients. To this purpose, the combination of natural and synthetic biomaterials modified with peptides, neurotrophic factors, and other low- to medium-molecular weight compounds, mimicking the ocular extracellular matrices, with human iPSC or iPSC-derived cell retinal progenitors holds enormous potential to be exploited in the near future for the generation of transplantable RGC populations.

The yin and the yang of molecular decompensation in LHON

Leber hereditary optic neuropathy (LHON) remains an incompletely understood disease. Reduced penetrance and male prevalence are two active areas of investigation. In fact, the presence of a homoplasmic LHON‐related mtDNA missense mutation, affecting all individuals along a maternal line, is the necessary genetic factor predisposing to develop LHON, but in most individuals it is not sufficient as they remain unaffected lifelong. Other genetic or environmental factor are assumed to play a role. The other point of investigation is the catastrophic nature of disease onset and progression, which defines LHON as a subacute disease.The application of iPSCs technology has advanced our understanding of LHON, refining the understanding of which mechanisms may be crucial to maintain cells compensated or prime them to degeneration. This presentation will focus on the balance between mitochondrial biogenesis and autophagic removal of mitochondria (mitophagy) as the emerging key mechanism priming individuals carrying the LHON mutation to become affected or to remain unaffected, possibly lifelong. This balance can be targeted by therapeutic strategies, opening new avenues to cure LHON.

Genotipske, fenotpiske i biohemijske karakteristike Leberove hereditarne optičke neuropatije

Leber hereditary optic neuropathy (LHON) is a mitochondrial neurodegenerative disease presented as a painless, acute, or subacute, usually sequential, loss of central visual acuity. The other eye is typically affected in a few weeks or months (on average in 6 to 8 weeks), while in about 25% of cases, the disease is simultaneously bilateral. Although individual unilateral cases have been reported, in 97% of cases, both eyes are affected within a year. Detailed genetic analysis is crucial in the process of diagnosing LHON. Between 75 - 90% of all the recorded LHON cases occur due to one of the three common mutations in mitochondrial DNA (mtDNA), located on nucleotides 11778, 14484, and 3460, although other, rare mutations with familial occurrence have been associated with LHON as well. More recently, the so-called autosomal recessive LHON has been described, which occurs due to a mutation in the DNAJC30 gene and presents with identical clinical features, but a better visual prognosis compared to mtLHON. This short review aims to present relevant information on the phenotype, genotype, and biochemical characteristics of LHON.

LHON spectrum disorder: Phenotype and genes

Leber hereditary optic neuropathy (LHON) is an inherited optic neuropathy primarily affecting young male with subacute bilateral visual loss. Clinically it is characterized by central scotoma, discromatopsia, and usually permanent central visual loss.This disease has a typical optic disc appearance at fundus examination of pseudoedema and microangiopathy which characterize the asymptomatic and subacute phases of the disease. Optic disc atrophy follows in the chronic phase.When the disease manifests, the preferential involvement of papillomacular fibres and macular retinal ganglion cell (RGC) damage are evident. These clinical features combined with the ophthalmoscopic pattern create the framework that make the disease unique.Primary point mutations of mitochondrial DNA (mtDNA) have been described as the genetic cause of the disease in about 90% of cases. Recently, new autosomal recessive DNA mutations have been reported in patients affected by subacute visual loss associated with a clinical picture resembling LHON.We herein describe the phenotype of 6 patients in which whole‐exome sequencing identified variants in the MECR gene in 2 probands of the same pedigree, in the NDUFAF4 gene in one patient, and mutation in the nuclear gene DNAJC30 in 3 patients. The 3 male probands with DNAJC30 mutation presented the typical LHON clinical picture with subacute loss of vision at an adult age in 2 cases and at a childhood age in one case. The pattern of visual loss with central scotoma and discromatopsia was associated with pseudoedema and microangiopathy at fundus appearance. Optical coherence tomography (OCT) analysis showed in both acute and asymptomatic family members the swelling of fibres while in the dynamic and chronic stages a progressive thinning of fibres. Visual recovery was detected in the younger patient and, partially, in one of adult patient.The 3 other patients carrying the MECR and NDUFAF4 gene variants showed a particular course of the disease characterized by a childhood onset of visual loss followed by a recurrence of visual loss at an adult age. The childhood onset was insidious in one case and subacute in the other 2 cases (about 6 years of age).OCT analysis demonstrated in the insidious case the temporal thinning of fibres and the macular RGC atrophy followed by swelling of fibres during the recurrence.In the differential diagnosis of inherited optic neuropathies with clinical presentation resembling LHON we should take into consideration the recessive form with mutations in the DNAJC30 gene which appears to overlap the mtDNA LHON disease. Moreover, clinical patterns resembling LHON with recurrence of visual loss represent another form of LHON with unique clinical presentation associated with variants in the MECR and the NDUFAF4 genes. These new clinical and genetic patterns enlarge the spectrum of LHON disease.

Leber hereditary optic neuropathy. The Dutch approach

Aims/Purpose: To share the structure of care for patients with Leber Hereditary Optic neuropathy (LHON) in the Netherlands. This includes the role of Expertise centers in coordinating rapid diagnosis and start of treatment, as well at the introduction of a specific database to track data of patients with LHON.Methods: Dutch LHON Expertise centres are organized to act as central points for patient referrals from regional hospitals with the aim to speed up the diagnostics and treatment of LHON patients. The database of Dutch LHON patients has been created and is online today, to provide demographical, epidemiological, clinical characteristics and effects of treatment with Idebenone on disease progression.Results: Three LHON Expertise centers provide fast diagnostic, coaching and treatment services in the whole of the Netherlands. Patient referral is done easily due to the small geography. A DNA test on primary and non‐primary mtDNA mutations is performed as standard, including the DNAJC30 gen. Additional parameters are obtained to monitor disease progression: Visual Acuity Score by ETDRS letters chart, HRR colour tests, OCT of ganglion cell layer and retinal neurofibral layer, Visual field by Goldmann kinetic perimetry or Humphry static perimetry. All patients have access to a social worker. They are provided with a flyer about LHON disease and contact details of the relevant patient association.Conclusion: A thoroughly organized clinical path for LHON patients provides rapid diagnostics and start of treatment. Patients referrals is done easily and treatment delay minimized. The centralization of Dutch LHON patients in three expertise centres enables us to maintain a central database with important clinical and epidemiological data. This information is relevant to optimize current therapy options with Idebenone and also for supporting future studies on novel therapy options.

Natural history of mitochondrial optic neuropathies

Mitochondrial optic neuropathies (MON) may occur as a single organ disease (non‐syndromic MON) or in the context of a multisystem mitochondrial disorder (syndromic MON). By far the most frequent MON are Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA). LHON is in most cases caused by mitochondrial DNA (mtDNA) mutations m.11778G>A, m.3460G>A or m.14484T>C, while ADOA is most frequently due to mutations in the OPA1 gene. As therapy trials have been performed, are ongoing or are planned for LHON and ADOA, it is important to know about the natural history of these disorders which may help to design trials or may serve as an external comparator.In LHON, an international observational retrospective registry (REALITY) analysed the visual course and outcome in 44 LHON patients, and found (after an average follow‐up time of 32.5 months) the mean best‐corrected visual acuity (BCVA) to be 1.46 LogMAR in m.11778G>A, 1.52 LogMAR in m.3460G>A, and 0.97 LogMAR in m.14484T>C mutations carriers. In line with previous findings, children below age 12 years at onset had the best visual prognosis. Since 25 of the 44 patients had taken idebenone at some point, this work does not qualify as a natural history study, though.A meta‐analysis of 12 retrospective and 3 prospective studies included data from 695 LHON patients with the m.11778G>A mutation. This meta‐analysis was hampered by the poor and variable definition of recovery among studies, and by the fact that idebenone use could not always be excluded. Main findings were some degree of recovery in 14.4% of patients, and 11.3% in those above age 15 years. Final BCVA of better than 1.0 logMAR was rare.In an own study of 83 LHON patients (73.5% with m.11778G>A mutation), BCVA at last observation was better than 1.0 logMAR in 18.1%, between 1.0 and 1.68 logMAR in 33.7% and worse than 1,68 logMAR (off‐chart) in 48.2%. Spontaneous recovery by at least 0.2 logMAR occurred in 16.3% of patients.In OPA1‐ADOA, a retrospective analysis of data from 64 affected patients showed a mean age at visual failure onset of 7.0 years (range 1.0–16.0 years), and a mean BCVA at last observation of 1.02 LogMAR. Longitudinal data in 43 OPA1 patients with a mean follow‐up duration of 18.0 years showed on average a slow visual decline of 0.032 LogMAR/year, but some patients deteriorated much faster (range 0–0.171 LogMAR/year).In conclusion, currently available data on the natural history of MON are hampered by retrospective analysis, low sample sizes, unsystematic phenotyping, variable definitions of key outcomes (eg, recovery) and often incomplete information on the administration of idebenone or other drugs. Large multicenter studies on natural history are needed but are more and more difficult to perform with the advent and sometimes even approval of disease‐modifying treatments.

Long‐term efficacy of idebenone in patients with Leber hereditary optic neuropathy in the LEROS study: Analysing change in visual acuity over time according to age at symptom onset

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to progressive, bilateral vision loss. Childhood‐onset LHON has a relatively good prognosis, suggesting that age at onset influences disease progression and potential response to treatment. In LEROS, a Phase IV, open‐label interventional study (ClinicalTrials.gov NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment (IDE) were compared to those of a Natural History (NH) cohort.Methods: LEROS included patients aged ≥12 years with a disease onset ≤5 years prior. Data from 181 patients were compared to retrospective data from a NH cohort (N = 372), matched by time since symptom onset. Here, we compare the difference in least squares‐mean VA change, or delta VA, from baseline to Month 24 in treated eyes versus those in the NH cohort (a negative value favours IDE). Eyes were stratified by time since symptom onset at baseline: subacute/dynamic (≤1 year) and chronic (>1 year) phase, and by age at symptom onset (<18 years, ≥18 years).Results: In treated subacute/dynamic eyes from the <18 years group (n = 22 IDE), delta VA was +0.38 logMAR (p = 0.020) relative to the NH cohort (n = 22). In the chronic phase, delta VA was −0.08 logMAR (n = 16 IDE vs n = 37 NH eyes; p = 0.405). In subacute/dynamic eyes from the ≥18 years group, delta VA was −0.18 logMAR (n = 99 IDE vs n = 53 NH; p = 0.060). In the chronic phase, delta VA was −0.21 logMAR (n = 100 IDE vs n = 56 NH; p < 0.001).Conclusions: In eyes of patients ≥18 years at symptom onset, VA improvement at Month 24 was greater in idebenone‐treated versus untreated NH eyes. Treatment benefit was particularly apparent in the chronic phase, corresponding to >10 additional letters on the ETDRS chart. In subacute/dynamic eyes, spontaneous VA recovery was unexpectedly high in the NH cohort. In chronic eyes from patients <18 years, a non‐significant trend favouring idebenone was observed.

Long‐term efficacy of idebenone in patients with Leber hereditary optic neuropathy in the LEROS study: Analysing change in visual acuity according to causative mutation and disease phase

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a mitochondrial disease resulting in severe vision loss. The causative mitochondrial DNA (mtDNA) mutation impacts disease progression and prognosis. In LEROS, a Phase IV, open‐label interventional study (Clinicaltrials.gov NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment (IDE) were compared to those of an external Natural History (NH) cohort. Here, we compare VA change from baseline to Month 24 according to primary mtDNA mutation and disease stage.Methods: Eyes of patients with LHON and either a m.G11778A, m.T14484C or m.G3460A, mtDNA mutation were stratified by time since onset: subacute/dynamic (≤1 year) and chronic (>1 but ≤5 years). Data from 181 patients were compared to retrospective data from the NH cohort (N = 372), matched by time since symptom onset at baseline. We compare the difference in least squares‐mean VA change, or delta VA, from baseline to Month 24 in IDE versus NH eyes (a negative value favours IDE).Results: In treated subacute/dynamic m.G11778A eyes (n = 60 IDE), delta VA was −0.32 logMAR (p = 0.002) versus the NH cohort (n = 47). In chronic m.G11778A eyes, delta VA was −0.11 logMAR (n = 82 IDE vs n = 51 NH; p = 0.043). In subacute/dynamic m.T14484C eyes, delta VA was +0.20 logMAR (n = 35 IDE vs n = 10 NH; p = 0.285). In chronic m.T14484C eyes, delta VA was −0.52 logMAR (n = 11 IDE vs n = 18 NH; p < 0.001). In subacute/dynamic m.G3460A eyes, delta VA was +0.53 logMAR (n = 26 IDE vs n = 18 NH; p = 0.001). In chronic m.G3460A eyes, delta VA was −0.13 logMAR (n = 23 IDE vs n = 24 NH; p = 0.162).Conclusions: Idebenone improved VA in a large proportion of eyes; this benefit manifested to varying degrees depending on disease stage and mtDNA mutation. m.G11778A eyes saw a consistent benefit regardless of disease stage. m.T14484C and m.G3460A results should be interpreted with caution in some cases due to the relatively low number of eyes; further study is warranted.

Optic nerve head dimension as biomarker in Leber hereditary optic neuropathy

Aims/Purpose: To study the optic nerve head (ONH) dimension in symptomatic and asymptomatic patients with Leber hereditary optic neuropathy (LHON) and to correlate ONH parameters with genotype and clinical phenotype.Methods: Seventy‐eight affected patients, 175 asymptomatic carriers, and 29 age‐matched healthy controls were enrolled in the study. All patients underwent ONH optical coherence tomography (OCT) measurements by DRI OCT Triton (Topcon, Japan) and were analysed with the Orion custom software (Volexeron, CA, USA). The following parameters were obtained for each eye: disc area, horizontal and vertical diameter; retinal nerve fibre layer (RNFL) and ONH volume. For the comparison of the different parameters the ANOVA with Bonferroni post‐hoc test was performed.Results: LHON‐affected patients appeared to have smaller ONH size parameters compared to control cases, but only the vertical disc diameter of patients with mutations 11 778 and 14 484 were statistically significant. Also, carrier patients with the mutation 11 778 presented a statistical significantly smaller vertical disc diameter compared to controls, instead 14 484 carriers presented a bigger diameter. ONH volume of all affected patients was significantly smaller. Moreover, asymptomatic 11 778 carriers older than 35 years were significantly smaller. Linear regression sustained the relationship between age, volume, and RNFL, unlike between age and disc area.Conclusions: This study exposed the differences of ONH size in LHON‐affected and ‐carrier patients with different mutations: smaller disc in 11 778 affected and unaffected patients and larger disc in 14 484 carriers. A strong correlation was found between ONH volume both in affected patients and carriers older than 35 years old. These results highlight the importance of the 3D ONH structure as a potential biomarker to support clinicians in the characterization of symptomatic LHON patients and possibly at‐risk mutation carriers with different genetic mutations and clinical course.

Long‐term efficacy of idebenone in patients with Leber hereditary optic neuropathy according to age at symptom onset and disease phase: Results from the LEROS study

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a mitochondrial disease resulting in bilateral vision loss. Childhood‐onset LHON has a relatively good prognosis, suggesting that age influences disease progression and, potentially, treatment response. In LEROS, a Phase IV, open‐label interventional study (Clinicaltrials.gov NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment (IDE) were compared to those of an external Natural History (NH) cohort.Methods: LEROS included patients aged ≥12 years with a disease onset ≤5 years prior. Data from 181 patients were compared to retrospective data from a NH cohort (N = 372), matched by time since symptom onset. Here, we compare clinically relevant recovery (CRR) and clinically relevant worsening (CRW) from baseline to Month 24 in IDE eyes versus NH eyes, stratified by time since symptom onset at baseline: subacute/dynamic (≤1 year) and chronic (>1 year) phase, and by age at symptom onset (<18 years, ≥18 years).Results: In patients aged <18 years, VA outcomes were observed, in IDE versus NH eyes, as follows: CRR: subacute/dynamic 31.8% (7/22) vs 59.1% (13/22), p = 0.048; chronic 31.3% (5/16) vs 21.6% (8/37), p = 0.241; CRW: subacute/dynamic 26.3% (5/19) vs 21.4% (3/14), p = 0.558; chronic 8.3% (1/12) vs 19.2% (5/26), p = 0.078. In patients aged ≥18 years, the following VA outcomes were observed: CRR: subacute/dynamic 51.5% (51/99) vs 22.6% (12/53), p = 0.001; chronic 32.0% (32/100) vs 12.5% (7/56), p < 0.001; CRW: subacute/dynamic 25.7% (19/74) vs 62.9% (22/35), p < 0.001; chronic 1.8% (1/56) vs 20.6% (7/34), p = 0.003.Conclusions: Idebenone improved the ratio of positive to negative VA outcomes. Treatment benefit was particularly pronounced in patients ≥18 years at onset, with only non‐significant positive trends observed in chronic patients <18 years. Results in subacute/dynamic patients aged <18 years were limited by an unusually high recovery rate in the NH cohort, warranting further study.

New insights into idebenone therapy in relation to NQO1

Idebenone is the only approved treatment for Leber's hereditary optic neuropathy (LHON).It promotes recovery of visual function in up to 50% of patients, but, based on the current knowledge, we can neither predict nor understand the non‐responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing complex I affected in LHON.We explored the possibility that genetic variant in the NQO1 enzyme can impact on idebenone response. We found that two polymorphic variants drastically reduce NQO1 protein levels, when homozygous or in compound heterozygote combination affecting idebenone reduction. In its oxidized form idebenone inhibits complex I, decreasing respiratory function in cells. We also retrospectively analysed a large cohort of LHON treated patients, classified by their response to therapy, demonstrating that patients homozygous or compound heterozygote for the NQO1 variants are characterized by the worst therapy response, particularly if carrying the m.3460G>A/MT‐ND1 LHON mutation.In summary, these results support the concept that the response to idebenone therapy may be influenced by the NQO1 genotype and the different mitochondrial DNA mutations.

Current status & outcomes of the Welsh national cohort of patients with leber's hereditary optic neuropathy treated with idebenone

Aims/Purpose: To assess the real‐world effectiveness of idebenone in a heterogenous group of patients with LHON treated with idebenone in Wales. This provides insight into the national outcomes of.Methods: Patients were identified from the ophthalmic genetics service based at Cardiff Eye Unit. Clinical notes were reviewed and details were collated on: demographics of patients, genetic mutation ascribed to be causative of LHON, visual acuity from diagnosis through to March 2023. Visual acuity was analysed for clinically relevant recovery (CRR) defined as improvement from “off‐chart” to at least 5 letters “on‐chart” or “on‐chart” improvement of at least 10 letters.Results: 11 patients with LHON were identified as being treated with Idebenone 300 mg TDS. Currently 45.9 ± 20.3 years of age (range 22–73). 8 male and 3 female patients. 6 patients had the m11778G > A mutation and 4 patients had the m14484T>C. Disease duration at treatment onset ranged from 2 to 216 months with a mean of 35.8 months. Patients had a mean duration of treatment of 14 months (range 6–20). 2 eyes in one patient demonstrated CRR improving from a nadir of 6/60 and counting fingers acuity to 6/6 and 6/7.5 respectively. All other patients demonstrated no CRR at the time of data collection.Conclusions: Idebenone has mixed results in a heterogenous group of patients with LHON providing significant benefit for one patient out of a cohort of 12, meanwhile others demonstrated limited improvements, albeit prior to a full two‐year course of treatment. It remains to be seen what the long‐term outcomes will be with sustained treatment with idebenone.

What OPA1 models teach us about potential therapy

Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy, affecting approximately 1 in 25 000 people. DOA has an insidious onset in early childhood. It presents typically with bilateral central painless vision loss, dyschromatopsia, and optic disc pallor due to gradual retinal ganglion cell (RGC) loss and optic nerve degeneration. 60%–70% of genetically confirmed DOA cases are associated with variants in OPA1. OPA1 is an ubiquitously expressed GTPase that regulates mitochondrial homeostasis through coordination of inner membrane fusion, maintenance of cristae structure, and maintenance of bioenergetic output. Over 250 known pathogenic variants in OPA1 have been reported, with missense variants within the GTPase domain associated with an increased susceptibility to developing DOA plus (DOA+), a multisystemic syndromic form of the disease with extraocular features, including sensorineural hearing loss and ataxia. Current therapeutic options to treat DOA are limited. Idebenone has been shown to protect against visual loss in Leber's hereditary optic neuropathy (LHON). In DOA off ‐label retrospective series show some promise in some patients.Animal models for OPA1 DOA, have been reported, including Drosophila, C elegans, Danio rerio and mouse models. They have cast light on some potential therapeutic modalities. Despite limitations, murine models of DOA are currently indispensable for understanding pathophysiology of disease, drug testing and development. They replicate many symptoms and signs of human disease. However, there are caveats. Chemically induced Complex I deficits are very toxic. Genetic models of mitochondrial mutation affect protein integrity and function and can cause severe pathologies. This is made more problematic if there is a need for aging the mouse to bring out the full phenotype. We shall review the mouse models and describe some features that aid or our understanding of pathophysiological mechanisms. Our research has characterized the earliest morphological changes as a progressive loss of synapses, dendrite retraction and RGC remodelling and loss of connectivity. In the DOA mouse Opa1+/− mouse (B6;C3‐Opa1Q285STOP), heterozygous Opa1+/− mice develop visual defects, on psychophysics (optokinetic response) and electrophysiology (VEP, PhNR), consistent with RGC dysfunction. There is depressed mitochondrial Complex I and IV activity. Visible structural changes and disrupted axon morphology in the optic nerve are seen. We have carried out a randomized, placebo‐controlled trial of the benzoquinone idebenone in our ADOA mouse, which revealed a limited therapeutic effect on RGC dendropathy and visual function.It is apparent that there are large differences between the rodent and primate visual system. The fovea of the retina, a critical component for central vision is one of the only primate‐specific components of the mammalian nervous system and is thus, not found in rodent. For these reasons, there is a strong case to use human cells. We shall review data on induced human pluripotent stem cell (hiPSC) with OPA1 mutation, with or without differentiation to RGCs, as models, and on CRISPRCas9 correction of patient‐derived OPA1 iPSC lines.

Management of LHON ‐ An update

Leber hereditary optic neuropathy (LHON) is a devastating cause of blindness that predominantly affects young adult men. Over 90% of patients harbour one of three mitochondrial DNA point mutations, namely, m.3460G>A (MT‐ND1), m.11778G>A (MT‐ND4) and m.144484T>C (MT‐ND6). Idebenone is the only approved treatment for LHON. New evidence has refined the management guidelines for idebenone, in particular the duration of treatment and the therapeutic window of opportunity. Gene therapy using allotopic expression is an attractive strategy for LHON as it corrects the underlying mitochondrial DNA defect. Promising results have been obtained for the m.1178G>A (MT‐ND4) mutation for patients treated within 1 year of disease onset with an intravitreal injection of a modified adeno‐associated viral vector carrying the replacement gene.

The ganglion cell complex thickness and visual function in leber hereditary optic neuropathy

Purpose: To evaluate the ganglion cell complex (GCC) thickness using the Iowa Reference Segmentation Algorithm in individuals with chronic Leber hereditary optic neuropathy (LHON) and to assess its relation to visual acuity, visual field sensitivity, and Estermann score.Methods: In this study, a total of 17 patients (34 eyes) aged 16–72 with chronic LHON were enrolled. Visual acuity, visual fields, and Optic coherence tomography (OCT) were performed. Visual fields was evaluated with Estermann and a custom central 30‐degree test, both performed monocularly with the Octopus 900 Haag‐Streit Diagnostics. OCT imaging was performed using a Canon OCT HS‐100 to measure the retinal ganglion cell complex (GCC) thickness. The raw OCT images were exported to IOWA Reference Algorithm and the GCC segmentation was rechecked and manually recorrected if needed. The thickness obtained from the Iowa Reference Algorithms was analysed and compared against the automated segmentation provided by the OCT's inbuilt segmentation algorithm. The correlation between the GCC thickness from 9 ETDRS sectors and the visual function were analysed.Results: On average the automated segmentation overestimated GCC thickness by 23.8 μm for all sectors. Macular central GCC correlated significantly with both visual field sensitivity and Estermann points missed (r = −0.486 and −0.396 respectively). Macular middle sector GCC thickness correlated significantly with visual acuity and visual field sensitivity (r = −0.586 and −0.396 respectively). GCC thickness in outer macular sector correlated significantly only with visual acuity (r = −0.471).Conclusions: In patients with chronic LHON, GCC thickness in central and middle sectors of macula correlates well with the visual function. OCT imaging and precise ganglion cell thickness evaluations in the macula can provide useful information about the structural damage and level of visual impairment in chronic LHON patients.

Gene therapy for mitochondrial disorders.

In this review, we detail the current state of application of gene therapy to primary mitochondrial disorders (PMDs). Recombinant adeno-associated virus-based (rAAV) gene replacement approaches for nuclear gene disorders have been undertaken successfully in more than ten preclinical mouse models of PMDs which has been made possible by the development of novel rAAV technologies that achieve more efficient organ targeting. So far, however, the greatest progress has been made for Leber Hereditary Optic Neuropathy, for which phase 3 clinical trials of lenadogene nolparvovec demonstrated efficacy and good tolerability. Other methods of treating mitochondrial DNA (mtDNA) disorders have also had traction, including refinements to nucleases that degrade mtDNA molecules with pathogenic variants, including transcription activator-like effector nucleases, zinc-finger nucleases, and meganucleases (mitoARCUS). rAAV-based approaches have been used successfully to deliver these nucleases in vivo in mice. Exciting developments in CRISPR-Cas9 gene editing technology have achieved in vivo gene editing in mouse models of PMDs due to nuclear gene defects and new CRISPR-free gene editing approaches have shown great potential for therapeutic application in mtDNA disorders. We conclude the review by discussing the challenges of translating gene therapy in patients both from the point of view of achieving adequate organ transduction as well as clinical trial design.

Long‐term response to idebenone treatment in a patient with advanced Leber hereditary optic neuropathy

Aims/Purpose: To present a case with advanced LHON and its response to 2‐year‐treatment with idebenone, which was prescribed 13 years after the onset of the disease.Methods: A 40‐year‐old Caucasian male patient with a history of bilateral painless visual loss since the age of 28 was examined at our Ophthalmology department. His brother had also suffered similar visual loss. At presentation ETDRS best corrected visual acuity (BCVA) was counting fingers (CF) in both eyes (BE). Fundoscopy revealed pale optic discs bilaterally. Visual fields (30‐2) showed central scotomas in BE. During OCT/OCTA imaging of the optic disc RNFL and GCC thickness were decreased bilaterally. In electrophysiological assessment with flash visual evoked potentials a reduction in amplitude was recorded in BE but with normal latency. Full‐field ERG was within normal limits in BE. At the genetic test, a mitochondrial point mutation m. 3460 G>A at MT‐ND1 gene was detected, which was compatible with LHON. The patient was prescribed 300 mg idebenone per os three times/day for 24 months. Follow‐up visits were scheduled at 6, 12, 18 and 24 months.Results: At 6‐ and 12‐month follow‐up visits visual acuity, fundoscopic findings and OCT‐RNFL imaging remained unchanged. However, the patient reported subjective visual improvement bilaterally, with greater improvement in the visual field of the left eye. At 18 months following initiation of treatment an improvement of the visual field was documented in BE. No change of the GCC thickness was noted. At 2‐year follow‐up his condition remained improved.Conclusions: Delayed treatment with idebenone in advanced LHON can lead to subjective visual improvement. Moreover, an improvement in visual fields can also be documented even after 18 to 24 months of the initiation of the treatment.

MRI Findings in Leber’s Hereditary Optic Neuropathy: A case report

Background: Leber’s hereditary optic neuropathy (LHON) is a rare genetic condition which is mainly presented with painless, sub-acute central unilateral vision loss followed by contralateral vision loss after few weeks to months. Young adults are typically affected with men preponderance. Relatively, it is a common cause of blindness as a result of mutation in mitochondrial DNA (mtDNA). Case report: We reported the case of two brothers, who had recent history of vision loss. Fundoscopy examination revealed bilateral optic nerve atrophy along with vessel narrowing and absent macular reflex. We performed MRI bilateral orbits with contrast which revealed abnormal signals and atrophy of the optic nerves suggesting optic neuritis. Conclusion: Whenever young males develop bilateral sequential vision loss with a positive family history, the diagnosis of Leber’s hereditary optic neuropathy should be suspected. Ophthalmological examination may reveal signs suggestive of Leber’s hereditary optic neuropathy. MRI may demonstrate edema signals in both optic nerve along with thinning of nerve fibers suggesting nerve atrophy. MRI is considered an useful tool to show optic nerve abnormality and optic neuritis.

DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients.

Leber hereditary optic neuropathy (LHON) is a rare disorder causing a sudden painless loss of visual acuity in one or both eyes, affecting young males in their second to third decade of life. The molecular background of the LHON is up to 90%, genetically defined by a point mutation in mitochondrial DNA. Recently, an autosomal recessive form of LHON (LHONAR1, arLHON) has been discovered, caused by biallelic variants in the DNAJC30 gene. This study provides the results of the DNAJC30 gene analysis in a large group of 46 Polish patients diagnosed with LHON, together with the clinical characterization of the disease. The c.152A>G (p.Tyr51Cys) substitution in the DNAJC30 gene was detected in all the patients as homozygote or compound heterozygote. Moreover, we identified one novel variant, c.293A>G, p.(Tyr98Cys), as well as two ultra-rare DNAJC30 variants: c.293A>C, p.(Tyr98Ser), identified to date only in one individual affected with LHONAR1, and c.130_131delTC (p.Ser44ValfsTer8), previously described only in two patients with Leigh syndrome. The patients presented here represent the largest group of subjects with DNAJC30 gene mutations described to date. Based on our data, the autosomal recessive form of LHON caused by DNAJC30 gene mutations is more frequent than the mitochondrial form in Polish patients. The results of our study suggest that Sanger sequencing of the single-exon DNAJC30 gene should be a method of choice applied to identify a molecular background of clinically confirmed LHON in Polish patients. This approach will help to reduce the costs of molecular testing.

Correlation between Residual Sensitivity in the Central Inferior Nasal Visual Field and Visual Function in Chronic Leber Hereditary Optic Neuropathy Patients

Introduction: Leber hereditary optic neuropathy (LHON) is a maternally inherited, acute or subacute, optic neuropathy. The typical symptoms include reduced visual acuity and central scotoma. Despite the presence of deep central scotoma, some patients with LHON are able to perform daily activities. This study aimed to investigate the correlation between the residual visual field and visual acuity, critical flicker frequency, and fixation ellipse in patients with chronic LHON. Methods: Residual visual function (defined as sensitivity points where patients sensed the size V stimulus) of both eyes was evaluated in 10 patients with LHON carrying the m.11778 mitochondrial DNA mutation and with median age of onset and disease duration of 29 and 16.5 years, respectively. The central visual field was measured as static perimetry using the Humphrey visual field testing 30-2 program with the size III or V stimulus. Moreover, best-corrected visual acuity, critical flicker frequency, and the correlation between fixation ellipse and residual central visual fields were determined. The analysis was performed through a linear mixed-effects model. Results: The residual visual sensitivity in the inferior nasal visual field was significantly correlated with the logMAR (p < 0.05). The fixation ellipse fell within the residual visual field region with higher sensitivity. Conclusions: Patients with chronic LHON tended to retain the sensitivity detectable with the size V stimulus at the central inferior nasal visual field regions, where the fixation ellipse fell. Visual acuity, which influences daily activity, was spatially correlated with residual visual sensitivity.