A Nomogram for Predicting Overall Survival of Patients With Primary Spinal Cord Glioblastoma.

OBJECTIVE: Primary spinal cord glioblastoma (PSCGBM) is a rare malignancy with a poor prognosis. To date, no prognostic nomogram for this rare disease was established. Hence, we aimed to develop a nomogram to predict overall survival (OS) of PSCGBM. METHODS: Clinical data of patients with PSCGBM was retrospectively collected from the neurosurgery department of Soochow University Affiliated Second Hospital and the Surveillance Epidemiology and End Results database. Information including age, sex, race, tumor extension, extent of resection, adjuvant treatment, marital status, income, year of diagnosis and months from diagnosis to treatment were recorded. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors for PSCGBM. A nomogram was constructed to predict 1-year, 1.5-year, and 2-year OS of PSCGBM. RESULTS: A total of 132 patients were included. The 1-year, 1.5-year, and 2-year OS were 45.5%, 29.5%, and 18.9%, respectively. Four variables: age groups, tumor extension, extent of resection, and adjuvant therapy, were identified as independent prognostic factors. The nomogram showed robust discrimination with a C-index value for the prediction of 1-year OS, 1.5-year OS, and 2-year of 0.71 (95% confidence interval [CI], 0.61-0.70), 0.72 (95% CI, 0.62-0.70), and 0.70 (95% CI, 0.61-0.70), respectively. The calibration curves exhibited high consistencies between the predicted and observed survival probability in this cohort. CONCLUSION: We have developed and internally validated a nomogram for predicting the survival outcome of PSCGBM for the first time. The nomogram has the potential to assist clinicians in making individualized predictions of survival outcome of PSCGBM.

Synthetic datasets for open software development in rare disease research.

BACKGROUND: Globally, researchers are working on projects aiming to enhance the availability of data for rare disease research. While data sharing remains critical, developing suitable methods is challenging due to the specific sensitivity and uniqueness of rare disease data. This creates a dilemma, as there is a lack of both methods and necessary data to create appropriate approaches initially. This work contributes to bridging this gap by providing synthetic datasets that can form the foundation for such developments. METHODS: Using a hierarchical data generation approach parameterised with publicly available statistics, we generated datasets reflecting a random sample of rare disease patients from the United States (US) population. General demographics were obtained from the US Census Bureau, while information on disease prevalence, initial diagnosis, survival rates as well as race and sex ratios were obtained from the information provided by the US Centers for Disease Control and Prevention as well as the scientific literature. The software, which we have named SynthMD, was implemented in Python as open source using libraries such as Faker for generating individual data points. RESULTS: We generated three datasets focusing on three specific rare diseases with broad impact on US citizens, as well as differences in affected genders and racial groups: Sickle Cell Disease, Cystic Fibrosis, and Duchenne Muscular Dystrophy. We present the statistics used to generate the datasets and study the statistical properties of output data. The datasets, as well as the code used to generate them, are available as Open Data and Open Source Software. CONCLUSION: The results of our work can serve as a starting point for researchers and developers working on methods and platforms that aim to improve the availability of rare disease data. Potential applications include using the datasets for testing purposes during the implementation of information systems or tailored privacy-enhancing technologies.

Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis: A potential model for rare diseases.

Background: Neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments. Methods: Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts. Results: The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF. Conclusions: These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials.

The development of a set of key points to aid clinicians and researchers in designing and conducting n-of-1 trials.

INTRODUCTION: n-of-1 trials are undertaken to optimise the evaluation of health technologies in individual patients. They involve a single patient receiving treatments, both interventional and control, consecutively over set periods of time, the order of which is decided at random. Although n-of-1 trials are undertaken in medical research it could be argued they have the utility to be undertaken more frequently. We undertook the National Institute for Health Research (NIHR) commissioned DIAMOND (Development of generalisable methodology for n-of-1 trials delivery for very low volume treatments) project to develop key points to assist clinicians and researchers in designing and conducting n-of-1 trials. METHODS: The key points were developed by undertaking a stakeholder workshop, followed by a discussion within the study team and then a stakeholder dissemination and feedback event. The stakeholder workshop sought to gain the perspectives of a variety of stakeholders (including clinicians, researchers and patient representatives) on the design and use of n-of-1 trials. A discussion between the study team was held to reflect on the workshop and draft the key points. Lastly, the stakeholders from the workshop were invited to a dissemination and feedback session where the proposed key points were presented and their feedback gained. RESULTS: A set of 22 key points were developed based on the insights from the workshop and subsequent discussions. They provide guidance on when an n-of-1 trial might be a viable or appropriate study design and discuss key decisions involved in the design of n-of-1 trials, including determining an appropriate number of treatment periods and cycles, the choice of comparator, recommended approaches to randomisation and blinding, the use of washout periods and approaches to analysis. CONCLUSIONS: The key points developed in the project will support clinical researchers to understand key considerations when designing n-of-1 trials. It is hoped they will support the wider implementation of the study design.

Gene therapy - once just a dream, now a reality.

Gene therapy is gradually becoming a mainstream treatment modality and is no longer the preserve of large university departments whose laboratories master nucleic acid analytical procedures and whose clinical teams manage its administration. It was originally designed for genetic diseases that, because of their prevalence, were a group known as rare diseases. Gene therapy has so far been applied in children to act before the disease development. These new treatments have also begun to be applied for common diseases such as metabolic disorders (e. g. diabetes) and even for those that are increasingly affecting us, such as various malignancies and diseases of the central nervous system (e. g. Alzheimer's disease). The targets targeted by GT are genes, where pathogenic alterations in the form of pathogenic variants (formerly mutations) induce phenotypic disorders, and our aim is either to knock them out of function (e. g. haemoglobinopathies) or to replace them with genes with normal function, which we introduce into the genome using one of the appropriate vectors, such as viruses or liposomes. The process of GT can take place directly inside the patient's body (in vivo) or outside the body on isolated cells (ex vivo), which are usually stem cells (iPSCs, induced pluripotent stem cell). After treatment, these cells are returned to the patient's body to fulfil their "destiny". In a broader sense, GT can target the product of gene transcription, which is the messenger RNA, or the end product of gene function, such as functional proteins (eg. cystic fibrosis). Any of these approaches have been used successfully in various diseases, depending on their availability, which is determined, among other things, by the costs associated with GT or the accessibility of the target tissue. Ultimately, it is not only the validation of the efficacy and safety of GT, but also economic reasons that determine why GT has been slow to develop and is mostly undertaken only by large and wealthy institutions. Another decisive factor is that from initial experimental work through clinical trials, the whole process of its development normally takes up to a decade.

Fibrodysplasia Ossificans Progressiva: A Man Turned to Stone.

Fibrodysplasia ossificans progressiva (FOP) is an exceptionally rare genetic disorder, representing humans' most debilitating form of extraskeletal ossification. It is characterized by progressive postnatal heterotopic ossification of connective tissue and malformations of the big toes. In FOP, ectopic ossification usually begins in the upper paraspinal muscles and then spreads from axial to appendicular regions, cranial to caudal directions, and proximal to distal sites. The mean life expectancy for these patients is typically 40-50 years. Most patients need partial or complete assistance with walking by age 30, and common causes of death include thoracic insufficiency syndrome and pneumonia. We present the case of a patient with an advanced stage of FOP, highlighting its complex and progressive nature. The patient exhibits severe impairment of jaw mobility, swallowing difficulties, speech impediments, and hearing impairment. Additionally, severe kyphoscoliosis, heterotopic ossification of intercostal and paravertebral muscles, and ankylosis of the spine and all major joints of the upper and lower extremities, except the metacarpophalangeal and proximal interphalangeal joints, are evident. We discuss disease presentation, current management options, and rehabilitation challenges. To our knowledge, this is the first reported case of this rare disease from our country.

Overview of Research Status in Castleman Disease.

Castleman disease (CD) is characterized by the proliferation of lymphoid tissue and encompasses a range of disorders that vary in clinical presentation, histopathological features, and therapeutic approaches. This article presents a comprehensive review of the current state of CD research, emphasizing the etiology, pathogenesis, clinical manifestations, diagnostic criteria, treatment options, and prognostic factors. CD is a relatively rare condition infrequently encountered in clinical practice. Certain subtypes of CD progress rapidly and pose a significant threat to patient health. Consequently, a timely and accurate diagnosis is crucial. This article aimed to equip clinicians and researchers with an updated and detailed understanding of CD, thereby enhancing the management of this complex condition.

Peer support in adolescents and young adults with chronic or rare conditions in northern America and Europe: Targeted literature review.

PROBLEM: Adolescents and young adults with chronic or rare conditions face unique risks to their physical, social and emotional development. Research suggests that peer support improves their quality of life and reduces social isolation. However, there is a paucity of current information considering multiple intervention formats. ELIGIBILITY CRITERIA: A targeted literature review was conducted to identify peer support interventions and assess their feasibility, acceptability and efficacy for this population. Searches were conducted in MEDLINE, Embase and American Psychological Association PsycINFO for records reporting peer support interventions in young adults with chronic or rare conditions. Data were extracted from relevant publications and qualitatively evaluated. SAMPLE: Thirty studies were included, which assessed the use of peer support for young adults (aged 13-30 years) with chronic or rare conditions in Europe or North America. RESULTS: Peer support interventions had positive effects on social positivity, psychosocial development and medical outcomes, though significance was not always demonstrated. CONCLUSIONS: Peer support can enhance care for young adults with chronic or rare conditions. Current literature suggests that once-weekly virtual interventions are the most feasible and acceptable for patients, leading to multifaceted improvements in their well-being. IMPLICATIONS: This study is one of the first to discuss in-person, virtual and hybrid peer-based interventions for young adults with chronic and rare conditions. While all formats improved social, psychological and medical outcomes, virtual formats may be most accessible to participants. Interventions should be made available to this population, and guidelines for optimal implementation of peer support are needed.

Why are rare diseases underdiagnosed? A clinical management study on detection of primary biliary cholangitis in primary care.

Background: There are about 7,000 rare diseases that affect 10% of the world population. Primary biliary cholangitis, an autoimmune chronic liver disease of the interlobular bile ducts, is one of the most common causes of chronic cholestasis. However, it is a rare, often underdiagnosed and undertreated, disease which can lead to cirrhosis and liver failure. We aimed to assess the proportion of undetected primary biliary cholangitis patients in primary care through a clinical management process. Methods: We made two extractions of the clinical data concerning liver diseases, risk factors and laboratory tests from the databases of a sample of general practitioners, with a check and correction of mistakes. The clinical data of the patients without liver disease and major risk factors, and with serum Alkaline Phosphatase above the laboratory reference values, were re-evaluated by each general practitioner with an expert gastroenterologist. The patients with elevated Alkaline Phosphatase values and without evidence of intrahepatic or extrahepatic causes of cholestasis were considered suspected for primary biliary cholangitis and assessed for antimitochondrial antibodies test and specialist' s evaluation, according to present guidelines. Results: A total of 20,480 adults attending 14 general practitioners in the province of Brescia, Northern Italy, were included in the study. Nine patients had a prior primary biliary cholangitis diagnosis, with a prevalence of 43.9/100000. After excluding 2094 (10.2%) patient with liver diseases or other causes of cholestasis, 121 subjects with Alkaline Phosphatase above the reference values were re-evaluated by the general practitioners and gastroenterologist, and 27 patients without symptoms or signs of cholestasis were considered suspected for primary biliary cholangitis: 9 of them were tested for antimitochondrial antibodies, and three new primary biliary cholangitis cases were detected (+33%). Discussion and Conclusions: This study shows that there is a not negligible burden of undetected cases of adult rare diseases that can be diagnosed in primary care, through a disease management procedure, without modifying the routine clinical practice.

The Undiagnosed Diseases Network: Characteristics of solvable applicants and diagnostic suggestions for non-accepted ones.

PURPOSE: Can certain characteristics identify as solvable some undiagnosed patients who seek extensive evaluation and thorough record review, like by the Undiagnosed Diseases Network (UDN)? METHODS: The UDN is a national research resource to solve medical mysteries through team science. Applicants provide informed consent to access to their medical records. After review, expert panels assess if applicants meet inclusion and exclusion criteria to select participants. When not accepting applicants, UDN experts may offer suggestions for diagnostic efforts. Using minimal information from initial applications, we compare features in applicants not accepted with those accepted and either solved or still not solved by the UDN. The diagnostic suggestions offered to non-accepted applicants and their clinicians were tallied. RESULTS: Non-accepted applicants were more often female, older at first symptoms and application, and longer in review than accepted applicants. The accepted and successfully diagnosed applicants were younger in ages, shorter in review time, more often non-white, of Hispanic ethnicity, and presenting with nervous system features. Half of non-accepted applicants were given suggestions for further local diagnostic evaluation. A few seemed to have two major diagnoses or a provocative environmental exposure history. CONCLUSION: Comprehensive UDN record review generates possibly helpful advice.

The centrality of healthcare and education interactions - An Interpretive Phenomenological Analysis of experiences of parents of children with Ehlers-Danlos Syndrome.

BACKGROUND: Ehlers-Danlos Syndrome (EDS) is a rare group of connective tissue disorders and, as such, the diagnosis can often be delayed. While emerging research indicates that there may be adverse psychosocial consequences for the child, little is known about the processes behind such outcomes, including the psychosocial impact of this rare disease on family life. AIMS: To extend our understanding, we examined the lived experiences of parenting a child with EDS. METHODS: Four parents recruited from a specialist child development clinic participated in semi-structured interviews. Data were analysed using Interpretative Phenomenological Analysis RESULTS: Three superordinate themes were identified: (1) Challenges Associated with hEDS, (2) Interactions with Professionals and (3) "Pulling and Pacing": Life with EDS. DISCUSSION: This is one of the first qualitative studies to gain an insight into the lived experiences of parenting a child with EDS. Findings had systemic implications. Specifically, we demonstrate the need for raising awareness in health and educational professionals about how to better support families to support the child, as well as the importance of promoting effective advocacy skills in parents.

Molecular Origins of the Mendelian Rare Diseases Reviewed by Orpha.net: A Structural Bioinformatics Investigation.

The study of rare diseases is important not only for the individuals affected but also for the advancement of medical knowledge and a deeper understanding of human biology and genetics. The wide repertoire of structural information now available from reliable and accurate prediction methods provides the opportunity to investigate the molecular origins of most of the rare diseases reviewed in the Orpha.net database. Thus, it has been possible to analyze the topology of the pathogenic missense variants found in the 2515 proteins involved in Mendelian rare diseases (MRDs), which form the database for our structural bioinformatics study. The amino acid substitutions responsible for MRDs showed different mutation site distributions at different three-dimensional protein depths. We then highlighted the depth-dependent effects of pathogenic variants for the 20,061 pathogenic variants that are present in our database. The results of this structural bioinformatics investigation are relevant, as they provide additional clues to mitigate the damage caused by MRD.

Orphan drug policy analysis in China.

Rare diseases have various types, low incidence rates, complex conditions, and are often difficult to diagnose. Due to China's large population, there is a significant number of rare disease patients, but there is a shortage of orphan drugs. Consequently, these patients often find themselves in a situation where necessary medications are either unavailable or unaffordable. To address this urgent clinical need, China has implemented a series of orphan drug policies aimed at improving drug accessibility and affordability. In terms of drug accessibility, companies are encouraged to expedite drug development through the implementation of tax incentives, guidance for clinical research on rare diseases, and the provision of data protection periods of 6 years, along with market exclusivity periods limited to a maximum of 7 years. Moreover, exemptions for clinical trials, acceptance of overseas clinical trial data, and the creation of a list prioritizing clinically urgent new drugs from overseas have been introduced to expedite the drug registration application, review, inspection, and approval processes. In terms of drug affordability, the import value-added tax on rare disease drugs has been reduced by 3%, and various provinces and cities have established a representative rare disease protection model, which includes special funds, medical assistance programs, and serious disease insurance. The national medical insurance catalog has been adjusted to reduce the financial burden on rare disease patients, resulting in an increase in the number of orphan drugs covered by the catalog to 95 as of March 2024. By comparing orphan drug policies in the United States, the European Union, Japan, Australia, and other countries (or regions), we will provide relevant suggestions to further improve orphan drug policies in China, thus bringing more treatment options and hope to patients with rare diseases.

Advancements in Hematopoietic Stem Cell Gene Therapy: A Journey of Progress for Viral Transduction.

Hematopoietic stem cell (HSC) transduction has undergone remarkable advancements in recent years, revolutionizing the landscape of gene therapy specifically for inherited hematologic disorders. The evolution of viral vector-based transduction technologies, including retroviral and lentiviral vectors, has significantly enhanced the efficiency and specificity of gene delivery to HSCs. Additionally, the emergence of small molecules acting as transduction enhancers has addressed critical barriers in HSC transduction, unlocking new possibilities for therapeutic intervention. Furthermore, the advent of gene editing technologies, notably CRISPR-Cas9, has empowered precise genome modification in HSCs, paving the way for targeted gene correction. These striking progresses have led to the clinical approval of medicinal products based on engineered HSCs with impressive therapeutic benefits for patients. This review provides a comprehensive overview of the collective progress in HSC transduction via viral vectors for gene therapy with a specific focus on transduction enhancers, highlighting the latest key developments, challenges, and future directions towards personalized and curative treatments.

Retrieval-Based Diagnostic Decision Support: Mixed Methods Study.

BACKGROUND: Diagnostic errors pose significant health risks and contribute to patient mortality. With the growing accessibility of electronic health records, machine learning models offer a promising avenue for enhancing diagnosis quality. Current research has primarily focused on a limited set of diseases with ample training data, neglecting diagnostic scenarios with limited data availability. OBJECTIVE: This study aims to develop an information retrieval (IR)-based framework that accommodates data sparsity to facilitate broader diagnostic decision support. METHODS: We introduced an IR-based diagnostic decision support framework called CliniqIR. It uses clinical text records, the Unified Medical Language System Metathesaurus, and 33 million PubMed abstracts to classify a broad spectrum of diagnoses independent of training data availability. CliniqIR is designed to be compatible with any IR framework. Therefore, we implemented it using both dense and sparse retrieval approaches. We compared CliniqIR's performance to that of pretrained clinical transformer models such as Clinical Bidirectional Encoder Representations from Transformers (ClinicalBERT) in supervised and zero-shot settings. Subsequently, we combined the strength of supervised fine-tuned ClinicalBERT and CliniqIR to build an ensemble framework that delivers state-of-the-art diagnostic predictions. RESULTS: On a complex diagnosis data set (DC3) without any training data, CliniqIR models returned the correct diagnosis within their top 3 predictions. On the Medical Information Mart for Intensive Care III data set, CliniqIR models surpassed ClinicalBERT in predicting diagnoses with <5 training samples by an average difference in mean reciprocal rank of 0.10. In a zero-shot setting where models received no disease-specific training, CliniqIR still outperformed the pretrained transformer models with a greater mean reciprocal rank of at least 0.10. Furthermore, in most conditions, our ensemble framework surpassed the performance of its individual components, demonstrating its enhanced ability to make precise diagnostic predictions. CONCLUSIONS: Our experiments highlight the importance of IR in leveraging unstructured knowledge resources to identify infrequently encountered diagnoses. In addition, our ensemble framework benefits from combining the complementary strengths of the supervised and retrieval-based models to diagnose a broad spectrum of diseases.

Integrating Genetic Services in the Philippine Public Health Delivery System: The Value of Networks.

The delivery of genetic services in developing countries is faced with significant challenges, despite medical and technological advances globally. The Philippines, being an archipelago, faces even more challenges, with significant disparities in access to healthcare, and tertiary medical centers and specialists being concentrated in the major cities. The utilization of different networks for the integration of genetic services in the existing public health delivery system has been valuable. Using the well-established network of the national newborn screening program, genetic services have been successfully integrated into the delivery of healthcare, even at the grassroot level. Equitable access to healthcare, including genetic services, was highlighted and supported by the enactment of the Rare Disease Law in 2016. The support of the academe to assure the sustainability of services was evident in the establishment of a genetic counseling program to augment the work of a handful of clinical geneticists. Professional societies and support groups have been instrumental in identifying genetic conditions to be prioritized and lobbying for increased public awareness, leading to national programs and policies. This paper primarily discusses the value of networks in the delivery of genetic services, specifically newborn screening, programs for rare diseases, birth defects, and genetic counseling.

Artificial intelligence in drug repurposing for rare diseases: a mini-review.

Drug repurposing, the process of identifying new uses for existing drugs beyond their original indications, offers significant advantages in terms of reduced development time and costs, particularly in addressing unmet medical needs in rare diseases. Artificial intelligence (AI) has emerged as a transformative force in healthcare, and by leveraging AI technologies, researchers aim to overcome some of the challenges associated with rare diseases. This review presents concrete case studies, as well as pre-existing platforms, initiatives, and companies that demonstrate the application of AI for drug repurposing in rare diseases. Despite representing a modest part of the literature compared to other diseases such as COVID-19 or cancer, the growing interest, and investment in AI for drug repurposing in rare diseases underscore its potential to accelerate treatment availability for patients with unmet medical needs.

Should We Consider Routine Blood Work for Diplopia and Ptosis in a Primary Care Setting?

Myasthenia gravis (MG) is a rare disorder that most commonly presents with ocular symptoms. Despite the highly sensitive blood work that can be used to diagnose the disease, it is frequently misdiagnosed until the disease becomes systemic. Literature, however, shows that those who begin treatment with acetylcholinesterase inhibitors before systemic presentation have a better prognosis. We discuss the case of a patient who presented to the clinic with a chief complaint of diplopia that was subsequently referred to ophthalmology. It was not until lab work was done by a subspecialist that the diagnosis of MG was made. The patient quickly responded to an acetylcholinesterase inhibitor and has since had a great prognosis. Here, we are advocating for the inclusion of routine lab work in the evaluation of patients who present to the primary care setting with diplopia in the absence of red flag symptoms. This approach aids in deciphering the potential involvement of MG in diplopia or ptosis. While such symptoms justify referral to ophthalmology, logistical challenges often hinder a prompt evaluation. Early diagnosis with the incorporation of routine lab work offers the potential to expedite the diagnosis of a rare disease. In doing so, providers can improve prognosis and potentially mitigate additive medical consultations.

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.