Leber's Hereditary Optic Neuropathy Patients Research Articles

Poor visual prognosis of Asian patients with 3460 mitochondrial DNA mutation in Leber's hereditary optic neuropathy

BackgroundAmong the 3 primary mutations of Leber's hereditary optic neuropathy (LHON), the incidence of LHON with a mutation at nucleotide position 3460 is the lowest in Asians. Therefore, information about the clinical manifestations of LHON mutations in Asians with the 3460 mutation is limited. ObjectiveTo determine the clinical manifestations including visual prognosis of Asians with the LHON 3460 mutation. MethodsWe performed a retrospective study of 5 Korean LHON patients with the 3460 mutation. ResultsAll patients were male, and the age of onset for visual impairment varied from 17 to 35 years, with an average of 25.4 ± 7.16 years. Among the 10 affected eyes, only 1 eye of 1 patient showed visual improvement to 20/50 at 2 years after onset. The remaining patients had a visual acuity of worse than 20/200. ConclusionThe visual prognosis of Korean patients with the LHON 3460 mutation was generally poor. Further studies regarding Asian patients with the LHON 3460 mutation are necessary.

Electroretinographic oscillatory potentials in Leber hereditary optic neuropathy.

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. 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 100Hz low cutoff frequencies were applied to isolate high-frequency components from the original ERG signals. 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 (75Hz 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 100Hz low-cutoff frequency filter was applied. 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.

Variant and clinical landscape of Leber hereditary optic neuropathy based on 1516 families with mtDNA variants in a tertiary centre

AimsTo investigate the clinical characteristics of Leber hereditary optic neuropathy (LHON) with mtDNA primary mutations to better understand features associated with prognosis.MethodsThis study enrolled 1540 LHON patients from 1516 unrelated...

Epigenetic regulation of the nuclear genome associated with mitochondrial dysfunction in Leber’s hereditary optic neuropathy (LHON)

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial hereditary disease in which visual loss affects complex 1 activity of the electron transport chain of mitochondria. It first manifests as painless dulling or blurry in one or even both eyes, and as it develops, sharpness and color perception are lost. In addition to primary mitochondrial DNA (mtDNA) mutations, there are also other environmental and epigenetic factors involved in the pathogenesis of LHON. One of the most common locations for deadly pathogenic mutations in humans is the human complex I accessory NDUFS4 subunit gene. The iron-sulfur clusters of the electron input domain were distorted in the absence of NDUFS4, which reduced complex I function and elevated the production of reactive oxygen species. Therefore, here, we studied the epigenetic alterations of NDUFS4 by focusing on histone activation and repressive markers. We isolated peripheral blood mononuclear cells (PBMCs) from LHON patients and healthy individuals and examined epigenetic modifications in ND4 mutant cells and control cells. Chromatin immunoprecipitation-qRT PCR (ChIP-qRT PCR) assays were performed to investigate the modifications of histones. In comparison to their controls, both LHON patients and ND4 mutant cells exhibited a significant enrichment in activation and repressive markers. This finding indicates that these modifications might mitigate the impact of LHON mutations on complex 1 and aid in elucidating the mechanism underlying the progression 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.

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.

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.

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

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. 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. 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. 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.

Elamipretide Topical Ophthalmic Solution for the Treatment of Subjects with Leber Hereditary Optic Neuropathy: A Randomized Trial

PurposeThe purpose of this study was to assess the safety, tolerability, and potential efficacy of topical elamipretide in patients affected with Leber’s Hereditary Optic Neuropathy (LHON). DesignThis Phase 2, prospective, randomized, vehicle controlled, single-center clinical trial involved administration of elamipretide (MTP-131) topical ophthalmic solution to LHON patients over a 52-week double-masked treatment period (DMTP), followed by an open extension label (OLE) for up to 108 additional weeks of treatment. SubjectsTwelve patients affected with LHON were included in this study. Patients between ages 18 and 50 with decreased vision, for at least one year and no more than ten years, and a genetically confirmed diagnosis of m.11778G>A LHON were eligible for this trial. MethodsFor the first 52 weeks of the study, patients were randomized to one of two arms, elamipretide in both eyes or elamipretide in one eye and vehicle in the other eye, followed by an OLE where both eyes were treated with elamipretide. Main outcome measuresThe primary outcome measure was the assessment of adverse events from the administration of topical elamipretide 1% and the primary efficacy endpoint was change in best corrected visual acuity (BCVA). Secondary outcome measures included changes in color vision, visual field mean deviation, and electrophysiological outcomes. ResultsElamipretide was well tolerated with the majority of treatment-emergent adverse events (TEAEs) being mild to moderate and resolving spontaneously. The change from baseline in BCVA in elamipretide-treated eyes was not significantly different from the vehicle eyes at any time point. Six of 12 subjects met the criteria for clinically relevant benefit (CRB). In the post-hoc analysis, change from baseline in mean deviation in the central visual field was significantly greater in elamipretide treated eyes versus the vehicle eyes. Compared to baseline, both treatment groups showed improvement in color discrimination and contrast sensitivity in the OLE. ConclusionsElamipretide treatment was generally well tolerated with no serious adverse events reported. Although this study did not meet its primary BCVA efficacy endpoint, improvements across assessments on visual function during the OLE, and the post-hoc findings of the HVF central region, were encouraging and require further exploration.

Leber Hereditary Optic Neuropathy Gene Therapy: Longitudinal Relationships Among Visual Function and Anatomical Measures

To assess longitudinal relationships among visual function and anatomical measures of gene therapy in G11778A Leber hereditary optic neuropathy (LHON). Phase 1 clinical trial. This was a single-institution study of patients with G11778A LHON. Patients with chronic bilateral visual loss >12 months (group 1, n=11), acute bilateral visual loss <12 months (group 2, n=9), or unilateral visual loss (group 3, n=8) were administered unilateral intravitreal AAV2(Y444,500,730F)-P1ND4v2 injection with low, medium, high, and higher doses to worse eye for groups 1 and 2 and better eye for group 3. Oucome measures were best-corrected visual acuity (BCVA), visual field mean deviation (VF MD), steady-state pattern electroretinogram (SS-PERG), optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness and ganglion cell+inner plexiform layer (GCIPL) thickness, and National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) scores. Mean follow-up was 33.6 months (range=18-36 months). Baseline SS-PERG amplitude was much reduced in both eyes of all groups including asymptomatic eyes of group 3, and showed no appreciable changes irrespective of disease stage and treatment. Significant and progressive GCIPL and RNFL thinning occurred in all eyes; BCVA and VF MD fluctuated in treated and fellow eyes, with some eyes having modest improvement that may be related to natural history or to gene therapy. Mean NEI-VFQ-25 scores declined in group 3 subjects (P=.023), CONCLUSION: Asymptomatic eyes in LHON patients with unilateral visual loss may be beyond the window of effective neuroprotection given reduced GCIPL and SS-PERG. Randomization of patients to an untreated control group would help to assess treatment effect by accounting for variable natural history. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Evaluation of Mitochondrial Dysfunction and Idebenone Responsiveness in Fibroblasts from Leber's Hereditary Optic Neuropathy (LHON) Subjects.

Leber's hereditary optic neuropathy (LHON) is a disease that affects the optical nerve, causing visual loss. The diagnosis of LHON is mostly defined by the identification of three pathogenic variants in the mitochondrial DNA. Idebenone is widely used to treat LHON patients, but only some of them are responders to treatment. In our study, we assessed the maximal respiration rate (MRR) and other respiratory parameters in eight fibroblast lines from subjects carrying LHON pathogenic variants. We measured also the effects of idebenone treatment on cell growth and mtDNA amounts. Results showed that LHON fibroblasts had significantly reduced respiratory parameters in untreated conditions, but no significant gain in MRR after idebenone supplementation. No major toxicity toward mitochondrial function and no relevant compensatory effect in terms of mtDNA quantity were found for the treatment at the tested conditions. Our findings confirmed that fibroblasts from subjects harboring LHON pathogenic variants displayed impaired respiration, regardless of the disease penetrance and severity. Testing responsiveness to idebenone treatment in cultured cells did not fully recapitulate in vivo data. The in-depth evaluation of cellular respiration in fibroblasts is a good approach to evaluating novel mtDNA variants associated with LHON but needs further evaluation as a potential biomarker for disease prognosis and treatment responsiveness.

Abnormal cerebral blood flow in patients with Leber's hereditary optic neuropathy.

The study aimed to unravel abnormal cerebral blood flow (CBF) in patients with Leber's hereditary optic neuropathy (LHON) using arterial spin labeling (ASL) and to investigate the associations among disrupted CBF, disease duration, and neuro-ophthalmological impairment. ASL perfusion imaging data was collected from 20 patients with acute LHON, 29 patients with chronic LHON, and 37 healthy controls. We used a one-way analysis of covariance to test the intergroup differences in CBF. Linear and nonlinear curve fit models were applied to explore the associations among CBF, disease duration, and neuro-ophthalmological metrics. Brain regions differed in LHON patients, including the left sensorimotor and bilateral visual areas (p < 0.05, cluster-wise family-wise error correction). Acute and chronic LHON patients demonstrated lower CBF in bilateral calcarine than the healthy controls. Chronic LHON had lower CBF in the left middle frontal gyrus and sensorimotor cortex, and temporal-partial junction than the healthy controls and acute LHON. A significant logarithmic negative correlation was shown between CBF of left middle frontal gyrus and disease duration. A significant linear positive correlation was found between retinal nerve fiber layer thickness and CBF in left middle frontal gyrus, and negative correlations between loss of variance and CBF in left middle frontal gyrus and sensorimotor cortex (p < 0.05, Bonferroni correction). LHON patients exhibited reduced CBF in the visual pathway, sensorimotor and higher-tier cognitive areas. Disease duration and neuro-ophthalmological impairments can influence the metabolism of non-visual areas.

Photoreceptor changes in Leber hereditary optic neuropathy with m.G11778A mutation.

To evaluate the functional and structural changes of photoreceptors in patients and asymptomatic carriers with Leber hereditary optic neuropathy (LHON) using full-field electroretinography (FERG) and optical coherence tomography (OCT). Individuals diagnosed with LHON at the Renmin Hospital of Wuhan University and their family members were included in this cross-sectional observational study. The FERG a-wave amplitude of affected patients and asymptomatic carriers was analyzed. The thickness of the outer nuclear layer (ONL), inner and outer segment (IS/OS) and total photoreceptors in the macular fovea and parafovea were measured. This study included 14 LHON patients (mean age: 20.00±9.37y), 12 asymptomatic carriers (mean age: 39.83±6.48y), and 14 normal subjects (mean age: 24.20±1.52y). The FERG results showed that the dark-adapted 3.0 electroretinography and light-adapted 3.0 electroretinography a-wave amplitudes of patients and carriers were significantly decreased (P<0.001). The ONL and photoreceptors layers were slightly thicker in patients than in normal subjects (P<0.05), whereas they were thinner in carriers (P<0.05). There were no differences in IS/OS thickness among the groups (P>0.05). Photoreceptors function is significantly impaired in LHON-affected patients and asymptomatic carriers. Meanwhile, photoreceptors morphology is slightly altered, mainly manifesting as a change in ONL thickness.

Non-Pharmaceutical Interventions against COVID-19 Causing a Lower Trend in Age of LHON Onset.

Leber hereditary optic neuropathy (LHON) is a monogenic but multifactorial disease vulnerable to environmental triggers. Little is known about how LHON onset changed during the COVID-19 pandemic and how non-pharmaceutical interventions (NPHIs) against COVID-19 impact LHON onset. One hundred and forty-seven LHON patients with the m.11778G>A mutation complaining of vision loss were involved between January 2017 and July 2022. The onset time points, age of onset, and possible risk factors were evaluated. Analyses were conducted among 96 LHON patients in the Pre-COVID-19 group and 51 in the COVID-19 group. The median (IQR) age of onset decreased significantly from 16.65 (13.739, 23.02) in pre-COVID-19 to 14.17 (8.87, 20.29) during COVID-19. Compared with the Pre-COVID-19 group, the COVID-19 group exhibited bimodal distribution with an additional peak at six; the first quarter of 2020 also witnessed a relatively denser onset, with no subsequent second spike. NPHIs against COVID-19 significantly changed patients' lifestyles, including higher secondhand smoke exposure (p < 0.001), adherence to masks (p < 0.001), reduction in time spent outdoors for leisure (p = 0.001), and prolonged screen time (p = 0.007). Multivariate logistic regression revealed that secondhand smoke exposure and mask-wearing were independent risk factors of younger LHON onset. Lower age of onset of LHON appeared after the breakout of the COVID-19 pandemic, and novel risk factors were detected, including secondhand exposure and long mask-wearing. Carriers of LHON mtDNA mutations, especially teenagers or children, should be advised to avoid secondhand smoke exposure and there are possible adverse outcomes of longer mask-wearing.

Long-term Follow-up of m.11778G&gt;A MT-ND4-LHON Patients Treated with Lenadogene Nolparvovec Ocular Gene Therapy: the RESTORE Study (S12.004)

Long-term Follow-up of m.11778G&gt;A MT-ND4-LHON Patients Treated with Lenadogene Nolparvovec Ocular Gene Therapy: the RESTORE Study (S12.004)

Modeling mitochondrial DNA diseases: from base editing to pluripotent stem-cell-derived organoids.

Mitochondrial DNA (mtDNA) diseases are multi-systemic disorders caused by mutations affecting a fraction or the entirety of mtDNA copies. Currently, there are no approved therapies for the majority of mtDNA diseases. Challenges associated with engineering mtDNA have in fact hindered the study of mtDNA defects. Despite these difficulties, it has been possible to develop valuable cellular and animal models of mtDNA diseases. Here, we describe recent advances in base editing of mtDNA and the generation of three-dimensional organoids from patient-derived human-induced pluripotent stem cells (iPSCs). Together with already available modeling tools, the combination of these novel technologies could allow determining the impact of specific mtDNA mutations in distinct human cell types and might help uncover how mtDNA mutation load segregates during tissue organization. iPSC-derived organoids could also represent a platform for the identification of treatment strategies and for probing the in vitro effectiveness of mtDNA gene therapies. These studies have the potential to increase our mechanistic understanding of mtDNA diseases and may open the way to highly needed and personalized therapeutic interventions.

Choroidal vascularity index in hereditary optic neuropathies.

To assess the choroidal vascularity index (CVI) in patients affected by Leber hereditary optic neuropathy (LHON) compared to patients affected by dominant optic atrophy (DOA) and healthy subjects. In this retrospective study, we considered three cohorts: LHON eyes (48), DOA eyes (48) and healthy subjects' eyes (48). All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) acquisition. OCT parameters as subfoveal choroidal thickness (Sub-F ChT), mean choroidal thickness (ChT), total choroidal area (TCA), luminal choroidal area (LCA) were calculated. CVI was obtained as the ratio of LCA and TCA. Subfoveal ChT in LHON patients did not show statistically significant differences compared to controls, while in DOA a reduction in choroidal thickness was observed (p = 0.344 and p = 0.045, respectively). Mean ChT was reduced in both LHON and DOA subjects, although this difference reached statistical significance only in DOA (p = 0.365 and p = 0.044, respectively). TCA showed no significant differences among the 3 cohorts (p = 0.832). No changes were detected in LCA among the cohorts (p = 0.389), as well as in the stromal choroidal area (SCA, p = 0.279). The CVI showed no differences among groups (p = 0.898): LHON group was characterized by a similar CVI in comparison to controls (p = 0.911) and DOA group (p = 0.818); the DOA group was characterized by a similar CVI in comparison to controls (p = 1.0). CVI is preserved in DOA and LHON patients, suggesting that even in the chronic phase of the neuropathy the choroidal structure is not irreversibly compromised.

Psychometric Validity of the Visual Function Index in Leber Hereditary Optic Neuropathy.

The purpose of this study was to determine the psychometric validity of the Visual Function Index (VF-14) for use by patients with Leber hereditary optic neuropathy (LHON). Rasch analysis was conducted in two stages using data for 196 individuals (74.5% male) carrying one of the three primary LHON mutations and affected by vision loss. In stage 1, scale unidimensionality, scale-to-sample targeting, response category threshold ordering, item fit statistics, local dependency, and reliability were assessed. In stage 2, iterative post-hoc revisions of the VF-14 structure (VF-14R) were applied and psychometrically re-evaluated. Issues identified with the VF-14 included disordered response thresholds (12/14 items), local dependency (10/91 pairwise dependencies), and evidence of multidimensionality. However, the distribution of person estimates and item thresholds were fairly well matched, only one item showed misfit to the Rasch model, and there was good reliability (Person Separation Index 0.84). Rasch-informed VF-14 revisions included removing both driving items and the misfitting sports item, rescoring response options across all items by merging two response categories, and accounting for the dependency between two reading items. The VF-14R demonstrated improved psychometric validity. Clinicians and researchers using the VF-14 with LHON patients should be aware of its limitations. Compared to the original version, the proposed Rasch-based structure of the VF-14R appears to offer improved psychometric performance and interpretation of vision-related activity limitation. The original version of the VF-14 exhibits several limitations that undermines its psychometric validity as a patient-reported outcome measure for patients with LHON.

Aberrant neurovascular coupling in Leber's hereditary optic neuropathy: Evidence from a multi-model MRI analysis.

The study aimed to investigate the neurovascular coupling abnormalities in Leber's hereditary optic neuropathy (LHON) and their associations with clinical manifestations. Twenty qualified acute Leber's hereditary optic neuropathy (A-LHON, disease duration ≤ 1 year), 29 chronic Leber's hereditary optic neuropathy (C-LHON, disease duration > 1 year), as well as 37 healthy controls (HCs) were recruited. The neurovascular coupling strength was quantified as the ratio between regional homogeneity (ReHo), which represents intrinsic neuronal activity and relative cerebral blood flow (CBF), representing microcirculatory blood supply. A one-way analysis of variance was used to compare intergroup differences in ReHo/CBF ratio with gender and age as co-variables. Pearson's Correlation was used to clarify the association between ReHo, CBF, and neurovascular coupling strength. Furthermore, we applied linear and exponential non-linear regression models to explore the associations among ReHo/CBF, disease duration, and neuro-ophthalmological metrics. Compared with HCs, A_LHON, and C_LHON patients demonstrated a higher ReHo/CBF ratio than the HCs in the bilateral primary visual cortex (B_CAL), which was accompanied by reduced CBF while preserved ReHo. Besides, only C_LHON had a higher ReHo/CBF ratio and reduced CBF in the left middle temporal gyrus (L_MTG) and left sensorimotor cortex (L_SMC) than the HCs, which was accompanied by increased ReHo in L_MTG (p < 1.85e-3, Bonferroni correction). A-LHON and C-LHON showed a negative Pearson correlation between ReHo/CBF ratio and CBF in B_CAL, L_SMC, and L_MTG. Only C_LHON showed a weak positive correlation between ReHo/CBF ratio and ReHo in L_SMC and L_MTG (p < 0.05, uncorrected). Finally, disease duration was positively correlated with ReHo/CBF ratio of L_SMC (Exponential: Radj2 = 0.23, p = 8.66e-4, Bonferroni correction). No statistical correlation was found between ReHo/CBF ratio and neuro-ophthalmological metrics (p > 0.05, Bonferroni correction). Brain neurovascular "dyscoupling" within and outside the visual system might be an important neurological mechanism of LHON.