Prognostic impact of hyperreflective foci in nonsyndromic retinitis pigmentosa.

PURPOSE: To evaluate the prognostic impact of hyperreflective foci (HRF) on spectral-domain optical coherence tomography (SD-OCT) in nonsyndromic retinitis pigmentosa (RP). METHODS: Retrospective, single-center cohort study including genetically-tested RP patients with a minimum follow-up of 24 months. Clinical data including demographics, genetic results and best-corrected visual acuity (BCVA) at baseline and follow-up were collected. Horizontal and vertical SD-OCT scans were analyzed by 2 independent graders. Outer nuclear layer (ONL) thickness and ellipsoid zone (EZ) width were manually measured in horizontal and vertical scans. HRF were classified according to location: outer retinal layers within the central 3mm (central-HRF), outer retinal layers beyond the central 3mm (perifoveal-HRF), and choroid (choroidal-HRF). Central macular thickness (CMT), central point thickness (CPT) and choroidal thickness (CT) at baseline and follow-up were also recorded. RESULTS: A total of 175 eyes from 94 RP patients (47.9% female, mean age 50.7±15.5 years) were included, with a mean follow-up of 29.24±7.17 months. Mean ETDRS (early treatment diabetic retinopathy study) BCVA decreased from 61.09±23.54 to 56.09±26.65 (p=0.082). At baseline, 72 eyes (41.1%) showed central-HRF, 110 eyes (62.9%) had perifoveal-HRF and 149 eyes (85.1%) exhibited choroidal-HRF. Central-HRF and perifoveal-HRF were associated with worse final BCVA, as well as greater BCVA deterioration (all p<0.0029). Only central-HRF were associated with a worse final CMT (p<0.001). Shorter EZ widths were associated with all types of HRF (p<0.05). Perifoveal and choroidal-HRF predicted smaller final EZ areas (p<0.01). CONCLUSION: HRF are highly prevalent in RP patients and appear to have a negative prognostic impact in visual function and EZ area.

The socioeconomic epidemiology of inherited retinal diseases in Portugal.

BACKGROUND: Inherited retinal diseases (IRDs) are a group of rare degenerative disorders of the retina that can lead to blindness from birth to late middle age. Knowing the target population and its resources is essential to better plan support measures. The aim of this study was to evaluate the socioeconomic characteristics of regions in Portugal where IRD patients reside to inform the planning of vision aid and rehabilitation intervention measures. RESULTS: This study included 1082 patients from 973 families, aged 3 to 92 years, with a mean age of 44.8 ± 18.1 years. Patients living with an IRD were identified in 190 of the 308 municipalities. According to this study, the estimated IRD prevalence in Portugal was 10.4 per 100,000 inhabitants, and by municipalities, it ranged from 0 to 131.2 per 100,000 inhabitants. Overall, regions with a higher prevalence of IRD have a lower population density (r=-0.371, p < 0.001), a higher illiteracy rate (r = 0.404, p < 0.001) and an overall older population (r = 0.475, p < 0.001). Additionally, there is a lower proportion of doctor per capita (r = 0.350, p < 0.001), higher social security pensions beneficiaries (r = 0.439, p < 0.001), worse water quality for human consumption (r=-0.194, p = 0.008), fewer audiences at the cinema (r=-0.315, p < 0.001) and lower proportion of foreign guests in tourist accommodations (r=-0.287, p < 0.001). CONCLUSION: The number of identified patients with IRD varied between regions. Using data from national statistics (PORDATA), we observed differences in socioeconomic characteristics between regions. Multiple targeted aid strategies can be developed to ensure that all IRD patients are granted full clinical and socioeconomic support.

Mutational spectrum and deep phenotyping in Pseudoxanthoma Elasticum: Findings from a Portuguese cohort.

INTRODUCTION: Pseudoxanthoma Elasticum (PXE) is a rare autosomal recessive disorder originated by disease-causing variants in ABCC6 gene. The purpose of this study was to characterize the genetic landscape, phenotypic spectrum and genotype-phenotype correlations in a Portuguese cohort of PXE patients. METHODS: Multicentric cross-sectional study conducted in patients with a clinical and genetic diagnosis of PXE. Patients were identified using the IRD-PT registry (www.retina.com.pt). Genotypes were classified into 3 groups: (1) two truncating variants, (2) two non-truncating variants, or (3) mixed variants. Deep phenotyping comprised a comprehensive ophthalmologic and systemic evaluation using the updated Phenodex Score (PS). RESULTS: Twenty-seven patients (23 families) were included. Sixteen different ABCC6 variants were identified, 7 of which are novel. The most prevalent variant was the nonsense variant c.3421C > T p.(Arg1141*) with an allele frequency of 18.5%. All patients exhibited ocular manifestations. Cutaneous manifestations were present in most patients (88.9%, n = 24/27). A PS score > E2 was strongly associated with worse visual acuity (B = -29.02; p = 0.001). No association was found between genotypic groups and cutaneous, vascular or cardiac manifestations. CONCLUSIONS: This study describes the genetic spectrum of patients with PXE for the first time in a Portuguese cohort. A total of 16 different variants in ABCC6 were found (7 of which are novel), thus highlighting the genotypic heterogeneity associated with this condition and expanding its mutational spectrum. Still, no major genotype-phenotype associations could be established.

Evolutionary and functional characterization of lagomorph guanylate-binding proteins: a story of gain and loss and shedding light on expression, localization and innate immunity-related functions.

Guanylate binding proteins (GBPs) are an evolutionarily ancient family of proteins that are widely distributed among eukaryotes. They belong to the dynamin superfamily of GTPases, and their expression can be partially induced by interferons (IFNs). GBPs are involved in the cell-autonomous innate immune response against bacterial, parasitic and viral infections. Evolutionary studies have shown that GBPs exhibit a pattern of gene gain and loss events, indicative for the birth-and-death model of evolution. Most species harbor large GBP gene clusters that encode multiple paralogs. Previous functional and in-depth evolutionary studies have mainly focused on murine and human GBPs. Since rabbits are another important model system for studying human diseases, we focus here on lagomorphs to broaden our understanding of the multifunctional GBP protein family by conducting evolutionary analyses and performing a molecular and functional characterization of rabbit GBPs. We observed that lagomorphs lack GBP3, 6 and 7. Furthermore, Leporidae experienced a loss of GBP2, a unique duplication of GBP5 and a massive expansion of GBP4. Gene expression analysis by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and transcriptome data revealed that leporid GBP expression varied across tissues. Overexpressed rabbit GBPs localized either uniformly and/or discretely to the cytoplasm and/or to the nucleus. Oryctolagus cuniculus (oc)GBP5L1 and rarely ocGBP5L2 were an exception, colocalizing with the trans-Golgi network (TGN). In addition, four ocGBPs were IFN-inducible and only ocGBP5L2 inhibited furin activity. In conclusion, from an evolutionary perspective, lagomorph GBPs experienced multiple gain and loss events, and the molecular and functional characteristics of ocGBP suggest a role in innate immunity.

[Evaluation of the Scientific Production in the Field of General Practice and Family Medicine in Portugal]. / Avaliação da Produção Científica na Área da Medicina Geral e Familiar em Portugal.

INTRODUCTION: The Portuguese publications in the field of General Practice and Family Medicine have not yet been assessed in bibliometric studies. The aim of this study was to analyze that production between 2012 and 2022. METHODS: The Web of Science Core Collection was used to gather the number of articles, journals and citations obtained; the Journal Citation Reports to obtain the Impact Factor and quartile of journals; and Scimago Journal & Country Rank, for the comparison of data with other European countries. The search was based on the following query: "usf OR unidade de Saude Familiar OR centro de Saude OR ACeS OR medicina geral familiar OR Gen Practice Family SAME Portugal", and a time window between 2012 and 2022 was defined. The study considered the following quantitative indicators: total number of publications, typology, language, affiliation, co-authors, geographical distribution, thematic areas, and the number of publications/inhabitant and publications/physician from European countries; the qualitative indicators selected were the Impact Factor (IF), the quartile and the number of citations. RESULTS: Between 2012 and 2022, the national scientific production had an average annual growth rate of 36.6%. Of 389 publications, 73.8% were 'Articles' and 11.8% were 'Review Articles', predominantly in English (88.4%). The fields of 'General Internal Medicine' (24.7%) and 'Public Environmental Health' (14.9%) had the highest publication rates among the journals. The 389 publications received 5354 citations, for an average of 13.76 citations per article, and the average yearly citation growth was 115%. According to IF, 22.5% of the 222 journals belonged to Q4, 27.5% to Q3, 29.7% to Q2 and 20.3% to Q1, and therefore no significant bias regarding the journals where Portuguese doctors publish was observed. CONCLUSION: The bibliometric analysis allowed us to examine the evolution of the scientific production in the field of Portuguese General Practice and Family Medicine by observing an increasing publication trend and with a high potential for publication growth.

Introdução: As publicações portuguesas da área de Medicina Geral e Familiar ainda não foram alvo de estudos bibliométricos. Pretendeu-se analisar tal produção no período entre 2012 e 2022. Métodos: Usou-se a Web of Science Core Collection para obter o número de artigos, as revistas de publicação e as respetivas citações; o Journal Citation Reports para obter o Fator de Impacto e o quartil das revistas; e o Scimago Journal & Country Rank para a comparação de dados com outros países europeus. Utilizou-se a equação de pesquisa "usf OR unidade de Saude Familiar OR centro de Saude OR ACeS OR medicina geral familiar OR Gen Practice Family SAME Portugal", e selecionaram-se os resultados obtidos no período entre 2012 e 2022. Os indicadores quantitativos selecionados foram o total de publicações, tipologia, idioma, afiliação, coautorias, distribuição geográfica, áreas temáticas e o número de publicações/habitante e de publicações/médico em países europeus. Como indicadores qualitativos escolheu-se o Fator de Impacto (FI), o quartil das revistas e o número de citações. Resultados: Entre 2012 e 2022, a produção científica nacional teve uma taxa de crescimento médio anual de 36,6%. Em 389 publicações, 73,8% foram de 'Article' e 11,8% de 'Review Article', predominando a publicação em língua inglesa (88,4%). As revistas com maior publicação pertencem às áreas 'General Internal Medicine' (24,7%) e 'Public Environmental Health' (14,9%). As 389 publicações tiveram 5354 citações, com uma média de 13,76 citações por artigo e a taxa de crescimento médio anual de citações foi de 115%. Em função do FI, das 222 revistas, 22,5% pertenciam ao Q4, 27,5% ao Q3, 29,7% ao Q2 e 20,3% ao Q1, não se observando por isso nenhum viés assinalável relativamente às revistas onde os médicos portugueses publicam. Conclusão: A análise bibliométrica permitiu avaliar a evolução e o estado da produção científica da área da Medicina Geral e Familiar por investigadores portugueses, observando-se uma tendência de publicação crescente, e com forte potencial de crescimento.

Genetic profile of syndromic retinitis pigmentosa in Portugal.

PURPOSE: Retinitis pigmentosa (RP) comprises a genetically and clinically heterogeneous group of inherited retinal degenerations, where 20-30% of patients exhibit extra-ocular manifestations (syndromic RP). Understanding the genetic profile of RP has important implications for disease prognosis and genetic counseling. This study aimed to characterize the genetic profile of syndromic RP in Portugal. METHODS: Multicenter, retrospective cohort study. Six Portuguese healthcare providers identified patients with a clinical diagnosis of syndromic RP and available genetic testing results. All patients had been previously subjected to a detailed ophthalmologic examination and clinically oriented genetic testing. Genetic variants were classified according to the American College of Medical Genetics and Genomics; only likely pathogenic or pathogenic variants were considered relevant for disease etiology. RESULTS: One hundred and twenty-two patients (53.3% males) from 100 families were included. Usher syndrome was the most frequent diagnosis (62.0%), followed by Bardet-Biedl (19.0%) and Senior-Løken syndromes (7.0%). Deleterious variants were identified in 86/100 families for a diagnostic yield of 86.0% (87.1% for Usher and 94.7% for Bardet-Biedl). A total of 81 genetic variants were identified in 25 different genes, 22 of which are novel. USH2A and MYO7A were responsible for most type II and type I Usher syndrome cases, respectively. BBS1 variants were the cause of Bardet-Biedl syndrome in 52.6% of families. Best-corrected visual acuity (BCVA) records were available at baseline and last visit for 99 patients (198 eyes), with a median follow-up of 62.0 months. The mean BCVA was 56.5 ETDRS letters at baseline (Snellen equivalent ~ 20/80), declining to 44.9 ETDRS letters (Snellen equivalent ~ 20/125) at the last available follow-up (p < 0.001). CONCLUSION: This is the first multicenter study depicting the genetic profile of syndromic RP in Portugal, thus contributing toward a better understanding of this heterogeneous disease group. Usher and Bardet-Biedl syndromes were found to be the most common types of syndromic RP in this large Portuguese cohort. A high diagnostic yield was obtained, highlighting current genetic testing capabilities in providing a molecular diagnosis to most affected individuals. This has major implications in determining disease-related prognosis and providing targeted genetic counseling for syndromic RP patients in Portugal.

Presumed Autoimmune Pigmented Paravenous Retinochoroidal Atrophy in a Female Patient Aged 69 Years.

This case report describes a diagnosis of presumed autoimmune pigmented paravenous retinochoroidal atrophy in a 69-year-old patient who presented with slowly progressive vision loss and nyctalopia.

Idiopathic acute exudative polymorphous vitelliform maculopathy: the importance of multimodal imaging, systemic workup and genetic testing.

The authors describe a case of acute exudative polymorphous vitelliform maculopathy (AEPVM) in an otherwise healthy man in his 60s complaining of subacute bilateral blurred vision. At examination, best-corrected visual acuity was 20/32 in the right eye and 20/40 in the left eye. Bilateral central large serous detachments with inferior meniscus-like deposition of a vitelliform-like material were observed at funduscopy and confirmed by spectral-domain optical coherence tomography. Small vitelliform-like lesions along the temporal superior vascular arcades were also seen. The lesions with vitelliform appearance appeared hyperautofluorescent on fundus autofluorescence. A complete systemic workup and genetic testing were performed and the diagnosis of idiopathic AEPVM was established. Six months later, a complete resolution of the lesions was observed.

Mutational Spectrum, Ocular and Olfactory Phenotypes of CNGB1-Related RP-Olfactory Dysfunction Syndrome in a Multiethnic Cohort.

CNGB1 gene mutations are a well-known cause of autosomal recessive retinitis pigmentosa (RP), which was recently associated with olfactory dysfunction. The purpose of this study was to report the molecular spectrum and the ocular and olfactory phenotypes of a multiethnic cohort with CNGB1-associated RP. A cross-sectional case series was conducted at two ophthalmic genetics referral centers. Consecutive patients with molecularly confirmed CNGB1-related RP were included. All patients underwent a complete ophthalmological examination complemented by psychophysical olfactory evaluation. Fifteen patients (10 families: 8 Portuguese, 1 French, and 1 Turkish), mean aged 57.13 ± 15.37 years old (yo), were enrolled. Seven disease-causing variants were identified, two of which are reported for the first time: c.2565_2566del and c.2285G > T. Although 11/15 patients reported onset of nyctalopia before age 10, diagnosis was only established after 30 yo in 9/15. Despite widespread retinal degeneration being present in 14/15 probands, a relatively preserved visual acuity was observed throughout follow-up. Olfactory function was preserved in only 4/15 patients, all of whom carried at least one missense variant. Our study supports previous reports of an autosomal recessive RP-olfactory dysfunction syndrome in association with certain disease-causing variants in the CNGB1 gene and expands the mutational spectrum of CNGB1-related disease by reporting two novel variants.

Self-reported visual function and psychosocial impact of visual loss in EYS-associated retinal degeneration in a Portuguese population.

PURPOSE: To evaluate self-reported visual function and the psychosocial impact of visual loss EYS-associated retinal degeneration (EYS-RD) using two patient-reported outcome (PRO) measures: Michigan Retinal Degeneration Questionnaire (MRDQ) and Michigan Vision-related Anxiety Questionnaire (MVAQ). METHODS: Cross-sectional, single-center study conducted at a tertiary care hospital in Portugal. Patients with biallelic EYS variants were invited to participate. Clinical data including demographics, ETDRS best-corrected visual acuity (BCVA) in the better-seeing eye and genetic testing results were collected. Interviews were carried out during clinic visits or by phone between November 2021 and February 2022. A blind grader used horizontal and vertical spectral domain optical coherence tomography (SD-OCT) scans to manually measure ellipsoid zone (EZ) width in the nasal, temporal, superior and inferior macular quadrants to calculate the EZ area. RESULTS: Forty-nine patients (53.1% males; mean age 53 ± 14 years) were included. A positive correlation (p < .05) was found between age and most MRDQ domain scores (central vision, color vision, contrast sensitivity, scotopic function, photopic peripheral vision and mesopic peripheral vision). A negative correlation was found between both BCVA and EZ area across all MRDQ domains. In MVAQ, SD-OCT EZ area negatively correlated with both rod function and cone function-related anxiety. Neither age, BCVA or gender correlated with MVAQ domains. CONCLUSIONS: This study provides strong evidence supporting a correlation between PRO measures and both functional and structural clinician-reported outcomes. The use of MRDQ and MVAQ adds a new dimension to our understanding of EYS-RD and establishes both PRO measures as important disease outcome measures.

Current Management of Patients with RPE65 Mutation Associated Inherited Retinal Degenerations in Europe: Results of a 2-Year Follow-Up Multinational Survey.

INTRODUCTION: The aim of this study was to evaluate the current management of RPE65 biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) in Europe since market authorization of voretigene neparvovec (VN, LuxturnaTM) in 2018. By July 2022, over 200 patients have been treated outside the USA, of whom about 90% in Europe. We conducted among all centers of the European Vision Institute Clinical Research Network (EVICR.net) and health care providers (HCPs) of the European Reference Network dedicated to Rare Eye Diseases (ERN-EYE) the second multinational survey on management of IRDs in Europe elaborated by EVICR.net with a special focus on RPE65-IRD. METHODS: An electronic survey questionnaire with 48 questions specifically addressing RPE65-IRD (2019 survey 35) was developed and sent by June 2021 to 95 EVICR.net centers and 40 ERN-EYE HCPs and affiliated members. Of note, 11 centers are members of both networks. Statistical analysis was performed with Excel and R. RESULTS: The overall response rate was 44% (55/124); 26 centers follow RPE65 biallelic mutation-associated IRD patients. By June 2021, 8/26 centers have treated 57 RPE65-IRD cases (1-19/center, median 6) and 43 planned for treatment (range 0-10/center, median 6). The overall age range was 3-52 years, and on average 22% of the patients did not (yet) qualify for treatment (range 2-60%/center, median 15%). Main reasons were too advanced (range 0-100, median 75%) or mild disease (range 0-100, median 0). Eighty-three percent of centers (10/12) that follow RPE65 mutation-associated IRD patients treated with VN participate in the PERCEIVE registry (EUPAS31153, http://www.encepp.eu/encepp/viewResource.htm?id=37005). Quality of life and full-field stimulus test improvements had the highest scores of the survey-reported outcome parameters in VN treatment follow-up. CONCLUSION: This second multinational survey on management of RPE65-IRD by EVICR.net centers and ERN-EYE HCPs in Europe indicates that RPE65-IRD might be diagnosed more reliably in 2021 compared to 2019. By June 2021, 8/26 centers reported detailed results including VN treatment. Main reasons for non-treatment were too advanced or mild disease, followed by absence of 2 class 4 or 5 mutations on both alleles or because of a too young age. Patient satisfaction with treatment was estimated to be high by 50% of the centers.

Recurrent optic disc pit maculopathy due to Valsalva's maneuver.

PURPOSE: We report a patient with recurrent optic disc pit maculopathy after Valsalva's maneuver and discuss its pathophysiology. We also hypothesize the role of Valsalva's maneuver in its genesis. METHOD: Case report of one patient, male, 12 years old. RESULTS: Serous retinal detachment may occur in association with the optic disc pit, a developmental anomaly of the optic nerve head. Histopathologically, it consists of a dysplastic retina herniation into a pocket extending posteriorly through a defect in the lamina cribrosa into the subarachnoid space. These three different compartments - intraocular space, optic nerve head and subarachnoid space - and the dynamic interactions among them should be understood as the key factors for the occurrence of optic disc pit-related serous retinal detachment. CONCLUSION: Based on the possibility that serous retinal detachment secondary to the ODP could be related to the Valsalva's maneuver, we strongly recommend that patients with ODP be advised to avoid intense physical or work activities that may increase abdominal, thoracic and cerebral pressure, and to refrain from playing wind instruments in order to avoid pre, per and post treatment intercurrences.

Eyes Shut Homolog-Associated Retinal Degeneration: Natural History, Genetic Landscape, and Phenotypic Spectrum.

PURPOSE: To describe the natural history, genetic landscape, and phenotypic spectrum of Eyes shut homolog (EYS)-associated retinal degeneration (EYS-RD). DESIGN: Retrospective, single-center cohort study complemented by a cross-sectional examination. SUBJECTS: Patients with biallelic EYS variants were recruited at an inherited RD referral center in Portugal. METHODS: Every patient underwent a cross-sectional examination comprising a comprehensive ophthalmic examination including best-corrected visual acuity (BCVA), dilated slit-lamp anterior segment, and fundus biomicroscopy; ultrawide-field color fundus photography and fundus autofluorescence imaging; and spectral domain-OCT. In the setting of a retinitis pigmentosa (RP) diagnosis, every patient was classified as typical or atypical RP according to imaging criteria. Baseline demographics, age at onset of symptoms, family history, history of consanguinity, symptoms, age at diagnosis, BCVA at baseline and throughout follow-up, and EYS variants were collected from each individual patient file. MAIN OUTCOME MEASURES: Clinical/demographic, genetic, multimodal imaging data, and BCVA variation were compared between typical and atypical RP. Additionally, BCVA variation during follow-up was used as an endpoint to describe EYS-RD natural history. RESULTS: Fifty-eight patients (59% men; mean age 52 ± 14 years) from 48 White families of Portuguese ancestry were included. Twenty distinct EYS variants were identified, 8 of which are novel. In 32.8% of patients, onset of symptoms was in early adulthood (21-30 years). A clinical diagnosis of RP was established in 57 patients and cone-rod dystrophy in 1 patient. Regarding RP, 75.0% of the patients were graded as typical and 25.0% as atypical. Atypical EYS-RP commonly presents with inferior crescent-shaped macular atrophy with superior midperipheral sparing. In EYS-RD, a negative correlation was found between age and BCVA (r = -0.50; P < 0.001), with an average loss of 1.45 letters per year. When stratifying for RP phenotype, lower average loss of letters per year (P < 0.001), higher BCVA (P < 0.001), and larger ellipsoid zone widths (P < 0.001) were found in atypical RP. CONCLUSIONS: This study expands the genetic spectrum of EYS-RD by reporting 8 novel variants. A high frequency of atypical phenotypes was identified. These patients have better BCVA and larger ellipsoidal zone widths, thus presenting an overall better prognosis. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Current Management of Inherited Retinal Degeneration Patients in Europe: Results of a 2-Year Follow-Up Multinational Survey by the European Vision Institute Clinical Research Network - EVICR.net.

INTRODUCTION: An increasing number of gene-specific therapies are being developed for inherited retinal degenerations (IRDs). Identification of well-characterized patients is an emerging need. We conducted the second multinational survey among the EVICR.net and ERN-EYE members to understand the management and treatment of IRDs in Europe and compared it to the 2019 survey. METHODS: An electronic survey questionnaire was developed and sent to 124 clinical centers (25 countries) by June/July 2021. Statistical analysis was performed with Excel and R. RESULTS: The overall response rate was 44% but varied among countries. Only 9% of responding centers do not see IRD patients (2019 survey 14%), 42% follow at least 200 patients per year, 18% follow 500-999, and 2% more than 1,000. Databases exist in 86% of the centers (local 86%; national web based 12%). IRD patients are referred to EVICR.net and ERN-EYE centers mainly by general ophthalmologists, patient self-referral, or medical retina specialists. Most IRD patients are first seen as adults. Signs and symptoms depend on age of onset: in infancy, nystagmus; at older age, night blindness and reduced visual field; reduced visual acuity is described at any age. Comprehensive ophthalmic examination always includes visual acuity and almost always visual field multimodal retinal imaging, electrophysiology, color vision testing, and refraction. Identification of genotypes is successful in 72% of centers in 40-80% of cases (2019 survey 69% of centers). The time for confirmation of the genetic diagnosis varies from 2-4 weeks to 24 months (2019 survey >4 weeks ≤10 years). Genetic testing is covered by public health service in 83%, private health insurance in 29%, research funds in 24%; 5% do not have access to genetic testing (2019 survey 15%). The most striking result is the high increase in the involvement of centers in natural history and gene therapy trials that more than doubled for the latter. DISCUSSION: This second multinational survey on management of IRDs in Europe highlights persistent important differences in the number of IRD patients managed per center, comparable diagnostic work-up, and increasing genotyping in diagnostic laboratories. The important increase in involvement of centers in natural history and gene therapy trials reflects the rapidly evolving field of gene therapy development. The survey provides important follow-up data for researchers, clinicians, caregivers, patient advocate groups, pharmaceutical companies, and investors.

GenEye24: Novel rapid screening test for the top-3 Leber's Hereditary Optic Neuropathy pathogenic sequence variants.

Leber's Hereditary Optic Neuropathy (LHON) has been mainly (90-95 %) associated to one of three variants: m.3460G>A, m.11778G>A, m.14484T>C. Herein, a screening method was developed for its detection, supporting clinical/therapeutics decision. It relies on real-time PCR with High-Resolution Melting (HRM) analysis. Variant classification is made using HRM Software and quality controls. A total of 101 samples were analyzed. All samples were correctly assigned: 58 wild-type, 35 positive for m.11778G>A, 6 positive for m.14484T>C, 2 positive for m.3460G>A. Results presented sensitivity = 1, specificity = 1, Positive Predictive Value = 1 and Negative Predictive Value = 1. A new Real-Time PCR/HRM screening method cost-efficient, simple, robust and quick, detecting LHON's top-3 is described.