Infantile nystagmus (IN) is a common neuro-ophthalmological disorder that presents as early-onset involuntary oscillations of the eyes. Here, we report a novel genotype-phenotype correlation that associates sequence alterations in the calcium voltage-gated channel auxiliary subunit beta 3 (CACNB3) gene, encoding the CaVβ3 protein, with idiopathic infantile nystagmus (IIN). Linkage analysis, whole exome and Sanger sequencing identified a homozygous missense mutation (c.316G>C) in CACNB3 co-segregating with IIN. Our calcium imaging experiments suggest that the p.Gly106Arg mutation in the Src homology 3 domain of CaVβ3 may impair voltage-gated calcium channel function at the plasma membrane and may increase ligand-triggered inositol trisphosphate receptor mediated calcium release at the endoplasmic reticulum. Co-localization studies indicate reduced plasma membrane localization of the calcium channel. We propose CACNB3 to be a novel gene associated with IIN. Our findings point towards an important role of calcium-signalling in IIN and may contribute to deciphering its aetiology.

Background: Optical coherence tomography (OCT) and OCT angiography (OCTA) retinal imaging in inherited retinal dystrophies (IRD) has been limited to the posterior pole and central midperiphery (up to about 16.5x16.5 mm). Two novel commercially available swept-source (SS) OCT/-OCTA devices provide the possibility of wide-field (WF) evaluation of retinal and choroidal structures including the vasculature in a single examination. Methods: A limited series of 16 IRD patients could be examined with a BMizar (400kHz, 24x20 mm scan width) and a Dream OCT (200 kHz, 26x21 mm scan width) in addition to the normal clinical examination protocol. This series included patients with retinitis pigmentosa, cone-rod dystrophy, macular dystrophy and autosomal recessive bestrophinopathy. Results: WF-SS-OCT/-OCTA enabled the detection of retinal, choroidal and choriocapillaris alterations in the macular and midperiphery in a single examination session. Even small foveal lesions and a small silent macular neovascularization could be detected on WF screening. Regional alterations of choroidal and choriocapillaris flow patterns were identified. These were mostly in correspondence with areas that appeared clinically affected, but unexpected lesions were identified as well. Occlusion of peripheral retinal vessels was seen in retinitis pigmentosa, though flow could be detected in retinal vessel which were difficult to distinguish on fundus images. In one patient with nystagmus WF-SS-OCT/-OCTA could be performed, whereas standard OCT volume scan could not be obtained. Conclusions: Both WF-SS-OCT/-OCTA devices provide detailed insights in structural and vascular retinal and choroidal alterations in a single short examination. Larger series of IRD patients examined with WF-SS-OCT/-OCTA promise to provide novel insights into the pathology of IRDs and will help to understand differences in the development of IRDs between humans and research animals.

Background: Optical coherence tomography (OCT) and OCT angiography (OCTA) retinal imaging in inherited retinal dystrophies (IRD) has been limited to the posterior pole and central midperiphery (up to about 16.5 × 16.5 mm). Two novel commercially available swept-source (SS) OCT/-OCTA devices provide the possibility of wide-field (WF) evaluation of retinal and choroidal structures, including the vasculature, in a single examination. Methods: A limited consecutive series of 16 IRD patients were examined with a BMizar (400 kHz, 24 × 20 mm scan width) and a Dream OCT (200 kHz, 26 × 21 mm scan width) in addition to the normal clinical examination protocol. This series included patients with retinitis pigmentosa, cone-rod dystrophy, macular dystrophy and autosomal recessive bestrophinopathy. In addition, 12 healthy probands were examined. Results: WF-SS-OCT/-OCTA enabled the detection of retinal, choroidal and choriocapillaris alterations in the macular and midperiphery in a short, single examination session of up to 15 s. Even small foveal lesions and a small silent macular neovascularization were detected on WF screening. Regional alterations of choroidal and choriocapillaris flow patterns were identified. These were mostly in correspondence with areas that appeared clinically affected, but unexpected lesions were identified as well. Occlusion of peripheral retinal vessels was seen in retinitis pigmentosa, though flow was detected in retinal vessels, which were difficult to distinguish on fundus images. In one patient with nystagmus, WF-SS-OCT/-OCTA was performed, whereas standard OCT volume scan could not be obtained. The most frequent artifact were horizontal lines of misalignment, which did not interfere with the detection of pathologies. Conclusions: Both WF-SS-OCT/-OCTA devices provide detailed insights in structural and vascular retinal and choroidal alterations in a single, short examination. Larger series of IRD patients examined with WF-SS-OCT/-OCTA promise to provide novel insights into the pathology of IRDs.

Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration.

Inherited retinal diseases (IRDs) represent a heterogeneous group of genetically driven conditions that frequently lead to progressive vision loss. Due to their complexity and the limited therapeutic options available, they pose a significant challenge for ophthalmology. This article provides a comprehensive overview of current evidence-based therapeutic approaches, including pharmacological strategies, gene therapy, and stem cell therapy, as well as innovative developments such as optogenetics and retinal implants. While gene therapies like Luxturna for RPE65 -associated retinitis pigmentosa have paved the way for causal treatments, initial successes are also being observed in other retinal dystrophies, such as Stargardt disease and Usher syndrome. Rehabilitative measures and interdisciplinary care remain essential to improving the quality of life for affected individuals. Future research efforts focus on enhancing the efficacy and accessibility of therapies while addressing challenges such as inflammatory reactions, high costs, and genetic variability. The perspectives outlined highlight promising advancements in the treatment of genetic retinal diseases.

Inherited retinal dystrophies and optic neuropathies (IRD) are the most frequent cause for vision loss in the working age. The huge variability of phenotypes and initial clinical presentation frequently delay the ophthalmologic diagnosis. The most frequent phenotypes are retinitis pigmentosa, macular dystrophies, cone-rod dystrophies and syndromes associated with IRDs. Causative gene variants have been identified in more than 300 genes, with a frequency variation between different ethnicities. In this series of 1 914 patients seen in Germany between 1995 and 2024, in 47.4 % of families the genetic background could be solved. Even with a common genotype, the phenotype can be variable. Genetic diagnostic testing is important for the correct diagnosis, for patient selection for current or future therapies, but also from the patient perspective.

Inherited retinal dystrophies (IRD) are the most frequent cause for severe visual loss in the working age. The heterogeneous group of IRDs is associated with loss of visual function and has a severe impact on personal and familial life. Early diagnosis is of high relevance for patients and their families, to facilitate possible therapies and professional help for the individual situation. This review summarizes a diagnostic protocol for an efficient diagnosis of IRD including non-invasive retinal imaging, functional and molecular genetic testing as well as examination in specialized centers for IRD.

Objectives: To evaluate the patient-reported impact of retinitis pigmentosa (RP) in a large patient cohort to identify relevant disease-related disadvantages as key aspects for the improvement of ophthalmic and social care. Methods: Consecutive patients with molecularly confirmed RP older than 18 years of age were identified in two tertiary care centers in Germany. Patients were contacted to participate in an anonymized patient query regarding the impact of RP on their vocational training, professional career, and social, familial, and personal life, as well as their experience with ophthalmologic care. Results: Out of 241 contacted patients, 162 responded (67.2%; 52.5% female, 67.3% younger than 50 years of age). While the impact of RP on vocational training was limited, professional careers were frequently disrupted with early retirement rates of 39.8% (≥40 years of age) to 50% (≥50 years of age). Most respondents felt restricted in their participation in public life (66.3%). One-fifth complained about financial restrictions; however, one-third of this number did not obtain financial help. A negative impact on familial life (21.4%) was less frequently reported compared to personal impairments, especially anxiety (74.5%) and depression (24.2%). Most respondents considered their ophthalmic care as adequate; however, a delayed diagnosis (≥two years: 28.6%) and initial misdiagnosis (24.0%) were frequent. Insufficient psychological support was the major complaint about professional care. Conclusions: RP affects the lives of patients in multiple aspects. Ophthalmic and social care providers should focus on the acceleration of the diagnostic process, as well as easy access to financial assistance and psychological support, as key areas for improvement. Improvements in these areas are expected to reduce challenges for patients. They should have an impact on rehabilitation, participation in public life, and quality of life.

The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ~30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent de novo variants in the U4 RNA, transcribed from the RNU4-2 gene, and in at least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited and de novo heterozygous variants in RNU4-2 (n.18_19insA and n.56T>C) and in four out of the five RNU6 paralogues (n.55_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5' stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants in RNU4-2 and in RNU6 paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders and uncovers pleiotropy in RNU4-2, where different variants underlie neurodevelopmental disorder and RP.

ZusammenfassungExogen bedingte Retinopathien werden am häufigsten durch externe Stimulanzien, seltener durch unerwünschte Arzneimittelwirkungen systemisch oder intravitreal eingesetzter Medikamente und noch seltener durch Impfungen oder die Einwirkung von Lichtstrahlung verursacht. Die Kenntnis exogener Ursachen und ihre mögliche Symptomatik ist zur Prophylaxe oder zur Früherkennung schädigender Wirkungen und zur adäquaten Beratung der Patienten wichtig.

BACKGROUND:Paediatric ophthalmological care is suffering from a thinning care network. Two (of several) possible causes are the increasing number of new forms of organisation (large contract medical facilities in terms of number of patients, doctors and locations) and medical care centres (MVZ) in non-physician ownership. METHODS:In a network of large ophthalmological care facilities, paediatric ophthalmological care activities per provider were surveyed for 2019 for all providers according to the proportion of the number of cases and structural characteristics (number of locations with orthoptists and sites with paediatric surgery), evaluated overall and in the subgroups according to ownership (non-physician or physician ownership) and compared with specialist group-related comparative data. RESULTS:With the one exception of a physician ownership provider, all providers (total n = 15, 12 of which were physician-owned) treated children < 6 years. In 2019, a total of 90,461 statutory health insurance (SHI) cases of children < 6 years were treated (9.3%of all SHI cases in children < 6 years in Germany). In the entire cohort, their share of all SHI cases was 3.7% (physician ownership: 4.8%, non-physician ownership: 3.2%). For the specialist group of all ophthalmologists in Germany, the average was 3.2% (difference not significant). Orthoptists worked at a total of 98 locations (58 physician ownership, 40 non-physician ownership, difference significant [p = 0.03]). Outpatient and inpatient paediatric surgery were offered by all non-physician owned providers and some physician owned providers. CONCLUSIONS:In this first large study on paediatric ophthalmic care in relation to the provider, the contribution of the newer types of organisation was evaluated. In comparison to traditional practices, there was no systematically different orientation - either for the whole study group or for any type of provider, as based on the relative proportion of children with SHI insurance or structural indicators (orthoptists or, outpatient or inpatient surgical care).

Retinitis pigmentosa (RP) is a genetically mediated degenerative retinal disease that leads to progressive photoreceptor degeneration and, ultimately, blindness. Oxidative stress plays a central role in the pathogenesis of RP. This study examines the effect of N-acetylcysteine (NAC), an antioxidant and glutathione precursor, on the disease progression in RP patients. NAC can reduce oxidative stress in the retina and has shown potential neuroprotective effects in preclinical models. Initial clinical studies indicate improvements in visual acuity and macular function with NAC therapy, though no structural changes have yet been demonstrated. The ongoing multicentre Phase III trial "NAC Attack" aims to evaluate the long-term efficacy and safety of NAC in RP.

Objective: The clinical presentation of inherited retinal dystrophies associated with pathogenic variants in PRPH2 is highly variable. Here we present bilateral sector macular dystrophy as a novel clinical phenotype. Methods and analysis: Ophthalmologic examination, detailed retinal imaging with optical coherence tomography (OCT), OCT-angiography, fundus and near-infrared autofluorescence and molecular genetic testing were performed on a 30-year-old female. Results: The patient reported the onset of subjective visual disturbances 4.5 months prior to our first examination. Clinical examination and retinal imaging revealed bilateral sharply demarcated paracentral lesions in the temporal lower macula and otherwise normal retinal findings. Patient history revealed no medication or other possible causes for these unusual retinal lesions. Molecular genetic testing revealed a heterozygous c.623G>A variation (p.(Gly208Asp)) in the PRPH2 gene. Conclusions: Bilateral sectoral macular dystrophy has not been reported previously in any inherited retinal dystrophy. This feature adds to the wide spectrum of PRPH2-associated clinical presentations.

Objectives: To identify patient-reported key disease-related challenges of macular and cone–rod dystrophies (MDs/CRDs) in a large consecutive cohort of individuals with molecularly confirmed diagnoses. Methods: Out of the 281 patients contacted, 194 (69.0%; 55.2% female) responded to an anonymized survey exploring the effects of MD/CRD on vocational training, professional careers, social participation, family life, personal well-being, and experience with ophthalmologic care. Results: While vocational training was generally less affected, professional careers were frequently disrupted, with 20.6% of patients aged ≥ 50 retiring early. A majority (54.7%) reported feeling restricted in public life. Financial constraints were noted by 20%. A negative impact on familial life (12.3%) was less frequently reported compared to anxiety (74.2%) and depression (15.8%). Diagnostic delays (≥2 years) were common (34.2%), along with a notable rate of initial misdiagnoses (22.1%). The lack of adequate psychological support was a major complaint in professional care. Conclusions: Compared to a previous study in retinitis pigmentosa, MD/CRD patients reported differing patterns of burden, especially in early retirement and family impact. Our findings underscore the need for ophthalmic and social care providers to accelerate the diagnostic process and enhance access to financial assistance and psychological support as key areas to improve patient care.

Inherited retinal diseases (IRDs) represent a heterogeneous group of genetically driven conditions that frequently lead to progressive vision loss. Due to their complexity and the limited therapeutic options available, they pose a significant challenge for ophthalmology. This article provides a comprehensive overview of current evidence-based therapeutic approaches, including pharmacological strategies, gene therapy, and stem cell therapy, as well as innovative developments such as optogenetics and retinal implants. While gene therapies like Luxturna for RPE65-associated retinitis pigmentosa have paved the way for causal treatments, initial successes are also being observed in other retinal dystrophies, such as Stargardt disease and Usher syndrome. Rehabilitative measures and interdisciplinary care remain essential to improving the quality of life for affected individuals. Future research efforts focus on enhancing the efficacy and accessibility of therapies while addressing challenges such as inflammatory reactions, high costs, and genetic variability. The perspectives outlined highlight promising advancements in the treatment of genetic retinal diseases.