Frequency and Genetic Spectrum of Inherited Retinal Dystrophies in a Large Dutch Pediatric Cohort: The RD5000 Consortium.

Purpose: Gene-based therapies for inherited retinal dystrophies (IRDs) are upcoming. Treatment before substantial vision loss will optimize outcomes. It is crucial to identify common phenotypes and causative genes in children. This study investigated the frequency of these in pediatric IRD with the aim of highlighting relevant groups for future therapy. Methods: Diagnostic, genetic, and demographic data, collected from medical charts of patients with IRD aged up to 20 years (n = 624, 63% male), registered in the Dutch RD5000 database, were analyzed to determine frequencies of phenotypes and genetic causes. Phenotypes were categorized as nonsyndromic (progressive and stationary IRD) and syndromic IRD. Genetic causes, mostly determined by whole-exome sequencing (WES), were examined. Additionally, we investigated the utility of periodic reanalysis of WES data in genetically unresolved cases. Results: Median age at registration was 13 years (interquartile range, 9-16). Retinitis pigmentosa (RP; n = 123, 20%), Leber congenital amaurosis (LCA; n = 97, 16%), X-linked retinoschisis (n = 64, 10%), and achromatopsia (n = 63, 10%) were the most frequent phenotypes. The genetic cause was identified in 76% of the genetically examined patients (n = 473). The most frequently disease-causing genes were RS1 (n = 32, 9%), CEP290 (n = 28, 8%), CNGB3 (n = 21, 6%), and CRB1 (n = 17, 5%). Diagnostic yield after reanalysis of genetic data increased by 7%. Conclusions: As in most countries, RP and LCA are the most prominent pediatric IRDs in the Netherlands, and variants in RS1 and CEP290 were the most prominent IRD genotypes. Our findings can guide therapy development to target the diseases and genes with the greatest needs in young patients.

Clinical and genetic characterization of patients with eye diseases included in the Spanish Rare Diseases Patient Registry.

BACKGROUND: The low prevalence of rare diseases poses a significant challenge in advancing their understanding. This study aims to delineate the clinical and genetic characteristics of patients with rare eye diseases (RED) enrolled in the Spanish Rare Diseases Patient Registry. METHODS: A total of 864 patients from the registry database were included. Diseases were categorized into inherited retinal dystrophies (n=688); anterior segment diseases (n=48); congenital malformations (n=27); and syndromic diseases with ocular involvement including muscular (n=46), neurological (n=34), or metabolic (n=13); inflammatory diseases (n=4); and tumors (n=4). Data on visual acuity (VA) and/or visual field (VF), symptoms and signs, concurrent diseases in syndromic cases, age of onset and at diagnosis, affected genes, disability rating, inability to work and dependency grade recognition were collected. RESULTS: A mean diagnostic delay of 7 years from symptom onset was observed. Commonly reported symptoms included photophobia, night blindness, and progressive vision loss (≥57% of patients). Cataract was the most prevalent secondary disease (46%), with pseudophakia being the most common ocular surgery (26%). Hearing loss and cardiovascular diseases were the most prevalent concurrent systemic diseases (≥13%). Certificates of disability, incapacity for work, and dependency were held by 87%, 42%, and 19% of patients, respectively. Among the 719 patients with available VA data, 193 (27%) were blind, and 188 (26%) had moderate to severe visual impairment. Over half of the patients (54%) exhibited VF defects, and 216 (25%) had concentric contraction ≤5° or abolished VF. Most had genetic diseases with autosomal recessive (55%), autosomal dominant (30%), X-linked (9%), and mitochondrial (6%) patterns. One patient had mutations in both recessive USH2A and dominant RHO genes simultaneously. Of the 656 patients (75.7%) who underwent genetic testing, only 461 (70.3%) received a positive result (pathogenic or likely pathogenic mutations explaining the phenotype). We found 62 new gene variants related to RED not previously reported in databases of genetic variants related to specific phenotypes. CONCLUSIONS: This study delineates the clinical and genotypic profiles of RED in Spain. Genetic diseases, particularly retinal disorders, predominate, but a significant proportion of affected patients remain genetically undiagnosed, hindering potential gene therapy endeavors. Despite notable improvements in reducing diagnosis delays, it is still remarkable. RED frequently lead to disability and blindness among young populations.

A systematic review of inherited retinal dystrophies in Pakistan: updates from 1999 to April 2023.

BACKGROUND: Inherited retinal degenerations (IRDs) are a group of rare genetic conditions affecting retina of the eye that range in prevalence from 1 in 2000 to 1 in 4000 people globally. This review is based on a retrospective analysis of research articles reporting IRDs associated genetic findings in Pakistani families between 1999 and April 2023. METHODS: Articles were retrieved through survey of online sources, notably, PubMed, Google Scholar, and Web of Science. Following a stringent selection criterion, a total of 126 research articles and conference abstracts were considered. All reported variants were cross-checked and validated for their correct genomic nomenclature using different online resources/databases, and their pathogenicity scores were explained as per ACMG guidelines. RESULTS: A total of 277 unique sequence variants in 87 distinct genes, previously known to cause IRDs, were uncovered. In around 70% cases, parents of the index patient were consanguineously married, and approximately 88.81% of the detected variants were found in a homozygous state. Overall, more than 95% of the IRDs cases were recessively inherited. Missense variants were predominant (41.88%), followed by Indels/frameshift (26.35%), nonsense (19.13%), splice site (12.27%) and synonymous change (0.36%). Non-syndromic IRDs were significantly higher than syndromic IRDs (77.32% vs. 22.68%). Retinitis pigmentosa (RP) was the most frequently observed IRD followed by Leber's congenital amaurosis (LCA). Altogether, mutations in PDE6A gene was the leading cause of IRDs in Pakistani families followed by mutations in TULP1 gene. CONCLUSION: In summary, Pakistani families are notable in expressing recessively inherited monogenic disorders including IRDs likely due to the highest prevalence of consanguinity in the country that leads to expression of rare pathogenic variants in homozygous state.

Spectrum of variants associated with inherited retinal dystrophies in Northeast Mexico.

BACKGROUND: Inherited retinal dystrophies are hereditary diseases which have in common the progressive degeneration of photoreceptors. They are a group of diseases with clinical, genetic, and allelic heterogeneity. There is limited information regarding the genetic landscape of inherited retinal diseases in Mexico, therefore, the present study was conducted in the northeast region of the country. METHODS: Patients with inherited retinal dystrophies were included. A complete history, full ophthalmological and medical genetics evaluations, and genetic analysis through a targeted NGS panel for inherited retinal dystrophies comprising at least 293 genes were undertaken. RESULTS: A total of 126 patients were included. Cases were solved in 74.6% of the study's population. Retinitis pigmentosa accounted for the most found inherited retinal disease. Ninety-nine causal variants were found, being USH2A and ABCA4 the most affected genes (26 and 15 cases, respectively). CONCLUSIONS: The present study documents the most prevalent causative genes in IRDs, as USH2A, in northeastern Mexico. This contrasts with previous reports of IRDs in other zones of the country. Further studies, targeting previously unstudied populations in Mexico are important to document the genetic background of inherited retinal dystrophies in the country.

Inherited Retinal Dystrophy in Southeastern United States: Characterization of South Carolina Patients and Comparative Literature Review.

Inherited retinal dystrophies (IRDs) are a group of rare diseases involving more than 340 genes and a variety of clinical phenotypes that lead to significant visual impairment. The aim of this study is to evaluate the rates and genetic characteristics of IRDs in the southeastern region of the United States (US). A retrospective chart review was performed on 325 patients with a clinical diagnosis of retinal dystrophy. Data including presenting symptoms, visual acuity, retinal exam findings, imaging findings, and genetic test results were compiled and compared to national and international IRD cohorts. The known ethnic groups included White (64%), African American or Black (30%), Hispanic (3%), and Asian (2%). The most prevalent dystrophies identified clinically were non-syndromic retinitis pigmentosa (29.8%), Stargardt disease (8.3%), Usher syndrome (8.3%), cone-rod dystrophy (8.0%), cone dystrophy (4.9%), and Leber congenital amaurosis (4.3%). Of the 101 patients (31.1%) with genetic testing, 54 (53.5%) had causative genetic variants identified. The most common pathogenic genetic variants were USH2A (n = 11), ABCA4 (n = 8), CLN3 (n = 7), and CEP290 (n = 3). Our study provides initial information characterizing IRDs within the diverse population of the southeastern US, which differs from national and international genetic and diagnostic trends with a relatively high proportion of retinitis pigmentosa in our African American or Black population and a relatively high frequency of USH2A pathogenic variants.

Clinical and visual electrophysiological characteristics of vitelliform macular dystrophies in the first decade of life.

Purpose: To evaluate patterns of pediatric vitelliform macular dystrophy (PVMD). Methods: This is a retrospective analysis of Indian children with vitelliform macular dystrophy (VMD) presenting within the first decade of life. Records were evaluated for clinical findings, family screening, and investigative findings including optical coherence tomography (OCT), fundus autofluorescence (FAF), full-field electroretinogram (ERG) and electrooculogram (EOG). Electrophysiology was scrutinized and audited for acquisition and interpretation errors. Findings on follow-up were also recorded. Results: 46 eyes of 24 patients were included. Mean age at presentation was 7.17 ± 2.17 years. Mean follow-up duration was 1.55 ± 1.69 years. Best disease was the commonest type of VMD detected (21 patients), while autosomal recessive bestrophinopathy was seen in three cases. Mean logMAR BCVA was 0.364 which decreased to 0.402 on follow-up. Hyperopia was noted in 29 out of 46 eyes (mean being +3.87 D, range ebing +0.75 to +8.75 D). Four eyes of four children had choroidal neovascular membrane at presentation, while another child developed while in follow-up. Solid type subretinal deposit was the commonest OCT finding (n = 29/38) and central hyper FAF was the commonest pattern (n = 18/32). EOG was available for review in 32 eyes, but was unreliable in 11 eyes. Seven eyes demonstrated complete absence of light rise on EOG. Conclusion: PVMD can present in advanced forms. Progression to complications with loss of visual acuity can happen within the first decade of life. EOG shows grossly suppressed waveforms in the light phase in a large number of such children.

Childhood-onset retinal dystrophies reduces life-time income by one third - an individual based socio-economic analysis.

BACKGROUND: The aim of this study was to evaluate lifetime income, educational level and workforce participation in patients with childhood-onset inherited retinal dystrophies (IRD). MATERIAL AND METHODS: The registry-based study using national, Danish databases on education, income, employment and social benefits in a cohort of 515 patients with childhood-onset IRD and without severe systemic comorbidities matched 1:4 to an age- and sex to a control sample of the Danish background population. Socio-economic status was modelled with focus on grade mark points after primary education, highest attained education at 30 years or age, employment and unemployment rate, disability pension and lifetime income. RESULTS: At 30 years of age, the proportion of those who had primary education as the highest achieved level was higher in the IRD group (35.4% versus 18.7%) and they were more likely to be receiving a disability pension (OR 11.77) or be unemployed (OR 6.63). Those at work had the same number of work hours as the control group, and the same proportion had obtained a Master or PhD degree (14%). At 30 years of age, income earnings were lower in the IRD group and the lifetime income was reduced by 30%. CONCLUSION: A few among those with childhood-onset IRD were able to obtain high educational levels, and many were assigned a disability pension from early adulthood or were unemployed, resulting in a markedly reduced lifetime income although grade mark points from primary education were comparable, suggesting that the difference was not explained by intellectual differences between the groups.

Clinical characteristics of comorbid retinal dystrophies and primary angle closure disease.

PURPOSE: To assess the clinical characteristics of comorbid retinal dystrophies and primary angle closure disease. DESIGN: Retrospective study from January 1992 to June 2020. METHODS: This descriptive study included 92 eyes of 46 patients with comorbid retinal dystrophies and primary angle closure disease (PACD) that included eyes with primary angle closure suspect, primary angle closure and primary angle closure glaucoma. Demographic profile, clinical characteristics of PACD and its association with retinal dystrophies are described. RESULTS: The study included 46 patients (92 eyes). Males were majority, 63%. Mean (± standard deviation) age when retinal dystrophy was diagnosed was 29.6 ± 9.4 years and PACD was diagnosed at 32.23 ± 7.92 years. Mean BCVA at presentation was 1.07 ± 0.87 log MAR [95% confidence interval (CI) 0.87, 1.26]. Mean Intraocular pressure at diagnosis of glaucoma was 27 ± 16 mmHg (95% CI 23.5, 31.5 mmHg). The most common retinal dystrophy associated with PACD was retinitis pigmentosa (RP) followed by RP with retinoschisis. The hospital-based prevalence of PACD among all patients with RP and retinoschisis was 0.19% and 0.15% respectively. Laser peripheral iridotomy was performed in 74 eyes (80.5%). Glaucoma was managed medically in majority of the eyes (58 eyes, 63.04%) and minority required surgical management with trabeculectomy (11, 11.9%). CONCLUSION: Retinitis pigmentosa is the most common retinal dystrophy associated with PACD. Comorbid PACD in eyes with retinal dystrophies was observed in second to third decade of life. This calls for screening for angle closure in eyes with retinal dystrophies from second decade onwards to identify the comorbid PACD and treat or refer them appropriately.

Prevalence and associated relating factors in patients with hereditary retinal dystrophy: a nationwide population-based study in Taiwan.

OBJECTIVE: To investigate the prevalence, incidence and relating factors that are associated with hereditary retinal dystrophy (HRD) in Taiwan from 2000 to 2013. DESIGN, SETTING AND PARTICIPANTS: This is a nationwide, population-based, retrospective case-control study using National Health Insurance Database. Study groups are patients with HRD as case group; age-matched patients without any diagnosis of HRD as control group. We enrolled 2418 study subjects, of which 403 were HRD patients. Important relating factors such as hypertension, diabetes, coronary artery disease, autoimmune disease, cancer, liver cirrhosis, chronic kidney disease, stroke, hyperlipidaemia, asthma, depression and dementia are also included. EXPOSURE: Patients diagnosed with HRD were retrieved from National Health Insurance Database. MAIN OUTCOMES AND MEASURES: OR calculated between the relating factors and HRD for objects and stratified by age and sex group between 2000 and 2013. RESULTS: Four hundred and three patients were included in the study group and 2015 in the control group. The incidence of HRD was 3.29/100 000, and the prevalence of HRD was 40.5/100 000 persons. The tendency of study group to have more cataract, cystoid macula oedema (CME) as compared with the control group. Among the subgroup with comorbidities, the relating factors such as hypertension, diabetes and chronic kidney disease was significantly higher among HRD patients with age 55 and above. CONCLUSIONS: 74% of the diagnosed HRD are retinitis pigmentosa. Population-based data suggested an increased incidence of cataract in younger patients, whereas older HRD patients are more susceptible to develop CME. Further work is needed to elucidate the mechanism between these ophthalmological disorders and HRD.

RPE65-Associated Retinopathies in the Italian Population: A Longitudinal Natural History Study.

Purpose: To investigate the course of inherited retinal degenerations (IRD) due to mutations in the RPE65 gene. Methods: This longitudinal multicentric retrospective chart-review study was designed to collect best corrected visual acuity (BCVA), Goldman visual field, optical coherence tomography (OCT), and electroretinography (ERG) measurements. The data, including imaging, were collected using an electronic clinical research form and were reviewed at a single center to improve consistency. Results: From an overall cohort of 60 Italian patients with RPE65-associated IRD, 43 patients (mean age, 27.8 ± 19.7 years) were included and showed a mean BCVA of 2.0 ± 1.0 logMAR. Time-to-event analysis revealed a median age of 33.8 years and 41.4 years to reach low vision and blindness based on BCVA, respectively. ERG (available for 34 patients) showed undetectable responses in most patients (26; 76.5%). OCT (available for 31 patients) revealed epiretinal membranes in five patients (16.1%). Central foveal thickness significantly decreased with age at a mean annual rate of -0.6%/y (P = 0.044). We identified 43 different variants in the RPE65 gene in the entire cohort. Nine variants were novel. Finally, to assess genotype-phenotype correlations, patients were stratified according to the number of RPE65 loss-of-function (LoF) alleles. Patients without LoF variants showed significantly (P < 0.05) better BCVA compared to patients with one or two LoF alleles. Conclusions: We described the natural course of RPE65-associated IRD in an Italian cohort showing for the first time a specific genotype-phenotype association. Our findings can contribute to a better management of RPE65-associated IRD patients.