Hereditary optic neuropathies, such as Leber’s hereditary optic neuropathy (LHON), remain a focus of active research. Diagnostic challenges and severe clinical consequences often result in atypical presentations, creating significant obstacles for neuro-ophthalmology. The field has garnered increased attention due to advances in molecular biology and genetic engineering. Pathogenic variants in mitochondrial DNA (mtDNA) and nuclear DNA disrupt oxidative phosphorylation, reduce adenosine triphosphate production, and increase reactive oxygen species generation, to which retinal ganglion cells are particularly vulnerable. Rare genetic variants have been identified in LHON and related mitochondrial disorders, including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and Leigh syndrome. Phenotypic heterogeneity, variable heteroplasmy levels, and limited sensitivity of targeted genetic testing complicate the detection and interpretation of rare variants. As a result, comprehensive next-generation sequencing is increasingly necessary for accurate molecular diagnosis and timely treatment initiation. Recent therapeutic interventions include genotype-specific approaches, such as adeno-associated virus serotype 2-mediated allotopic expression, and genotype-independent therapies, such as idebenone. Diagnostic standards for mitochondrial optic neuropathies have shifted from focusing solely on the three primary pathogenic mtDNA variants to a broader molecular diagnostic framework. Future research should prioritize mtDNA sequencing in cases with inconclusive diagnoses using conventional methods, incorporate mitochondrial and nuclear genomics, and leverage artificial intelligence-based approaches. Accurate identification and classification of rare variants, together with a deeper understanding of their phenotypic consequences, will facilitate the development of individualized therapeutic strategies to prevent further visual decline. This review outlines potential directions for multifaceted treatment strategies in patients with rare LHON-associated variants and critically evaluates current evidence regarding the clinical significance of rare mitochondrial and nuclear genetic variants in LHON and related mitochondrial optic neuropathies.
This study aims to investigate the neuroprotective efficacy of idebenone and citicoline in a rat model of traumatic optic neuropathy (TON), induced by controlled optic nerve (ON) crush injury. Forty male Wistar rats (250–300 g) were randomly assigned to four groups (n=10). TON was induced in Groups 1, 2 and 3 via right ON crush. Group 1 received no treatment; Group 2 received idebenone (50 mg/kg/day), and Group 3 received citicoline (1 g/kg/day) via a nasogastric tube, starting 24 h post-injury. Group 4 served as sham controls. Flash and pattern visual evoked potentials (fVEP, pVEP) were recorded at baseline, 48 h, and day 28. The flash and pattern VEP tests were performed using the MonPackONE device. Blood biomarkers (ischemia-modified albumin (IMA), total and native thiol) were analyzed, and histological evaluations included hematoxylin–eosin (H E) staining and glial fibrillary acidic protein (GFAP) monoclonal antibody immunohistochemistry. At day 2, VEP tests indicated delayed latency and decreased amplitude in Groups 1–3 versus the sham group. By day 28, Groups 2 and 3 showed significant VEP improvement over Group 1. Biochemical analysis demonstrated higher thiol levels in Group 3 compared to Group 2 on day 28; however, this difference was not statistically significant. GFAP staining in the retina and ON tissues was highest in Group 1 and lowest in Group 4. ON thickness was greater in Group 2 than in Group 3, but the difference was also not statistically significant. Although neither treatment demonstrated superiority over the other, both oral citicoline and idebenone provided neuroprotection in TON, as evidenced by improved electrophysiological function, greater retina ganglion cell survival, and elevated systemic antioxidant markers.
To report a patient with unilateral photophobia but unremarkable multimodal imaging, in whom a negative electroretinogram (ERG) indicated retinal bipolar cell dysfunction, and both the photophobia and the ERG later improved in part. Single case report. Examinations included best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, color fundus photography, optical coherence tomography (OCT), fundus autofluorescence (FAF), color vision testing, Goldmann and Humphrey perimetry, full-field ERG, multifocal ERG (mfERG), and photopic On–Off ERG, with 3-year follow-up. A 67-year-old man had a 3-year history of subacute photophobia and central blurring in the left eye that had remained undiagnosed at several institutions. At the initial visit to our hospital, BCVA was 1.2 in decimal in both eyes. Color fundus photography, OCT, FAF, color vision, and perimetry showed no relevant abnormality. Full-field ERG was normal in the right eye; the left eye showed a reduced dark-adapted (DA) 0.01 ERG, a negative DA 3 ERG with a preserved a-wave (b:a ratio = 0.53), mildly reduced oscillatory potentials, and severely reduced light-adapted (LA) 3 and LA 30 Hz ERGs. The mfERG was preserved centrally and reduced peripherally. At 4 years from onset, the photophobia improved, and the b:a ratio of the DA 3 ERG increased to 0.90, with slight recovery of the LA 30 Hz ERG. At 5 and 6 years from onset, the DA 0.01, LA 3, and LA 30 Hz ERGs showed slight further improvement, and the b:a ratio of the DA 3 ERG increased to 1.07 and 1.62, respectively, whereas the photophobia was unchanged. Unilateral On- and Off-bipolar cell dysfunction presenting as photophobia can show partial improvement. The ERG is essential for diagnosis and objective monitoring.
The objective of this study is to evaluate changes in the foveal avascular zone (FAZ), vascular density (VD), and electrophysiological parameters in patients with diabetic macular edema (DME) following intravitreal bevacizumab therapy. The study comprised 27 eyes of 22 patients with treatment-naive DME who received a loading phase of three consecutive monthly intravitreal bevacizumab injections, together with 30 eyes of 15 healthy controls. All participants underwent optical coherence tomography (OCT), OCT angiography (OCTA), pattern electroretinography (PERG) and visual evoked potentials (VEP) at baseline and at one and three months. As both eyes of some participants were included, all comparisons used generalized estimating equations clustered on subject, with cluster-robust variance estimation. Central retinal thickness decreased significantly after treatment, from 409.2 ± 105.9 µm at baseline to 368.4 ± 97.8 µm at 1 month (p = 0.007) and 352.6 ± 93.6 µm at 3 months (p < 0.001). Best-corrected visual acuity improved from 0.69 ± 0.47 to 0.57 ± 0.44 logMAR, but this change did not reach statistical significance (p = 0.166). FAZ measurements showed no significant change at either visit (all p > 0.57) and superficial VD remained stable (p = 0.404 and p = 0.185), whereas measured deep VD increased significantly at both 1 month (+ 1.02
