A Rare Coincidence of Three Inherited Diseases in a Family with Cardiomyopathy and Multiple Extracardiac Abnormalities.

A genetic diagnosis of primary cardiomyopathies can be a long-unmet need in patients with complex phenotypes. We investigated a three-generation family with cardiomyopathy and various extracardiac abnormalities that had long sought a precise diagnosis. The 41-year-old proband had hypertrophic cardiomyopathy (HCM), left ventricular noncompaction, myocardial fibrosis, arrhythmias, and a short stature. His sister showed HCM, myocardial hypertrabeculation and fibrosis, sensorineural deafness, and congenital genitourinary malformations. Their father had left ventricular hypertrophy (LVH). The proband's eldest daughter demonstrated developmental delay and seizures. We performed a clinical examination and whole-exome sequencing for all available family members. All patients with HCM/LVH shared a c.4411-2A>C variant in ALPK3, a recently known HCM-causative gene. Functional studies confirmed that this variant alters ALPK3 canonical splicing. Due to extracardiac symptoms in the female patients, we continued the search and found two additional single-gene disorders. The proband's sister had a p.Trp329Gly missense in GATA3, linked to hypoparathyroidism, sensorineural deafness, and renal dysplasia; his daughter had a p.Ser251del in WDR45, associated with beta-propeller protein-associated neurodegeneration. This unique case of three monogenic disorders in one family shows how a comprehensive approach with thorough phenotyping and extensive genetic testing of all symptomatic individuals provides precise diagnoses and appropriate follow-up, embodying the concept of personalized medicine. We also present the first example of a splicing functional study for ALPK3 and describe the genotype-phenotype correlations in cardiomyopathy.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Charting a course for global progress in PIDs by 2030 - proceedings from the IPOPI global multi-stakeholders' summit (September 2023).

The International Patient Organisation for Primary Immunodeficiencies (IPOPI) held its second Global Multi-Stakeholders' Summit, an annual stimulating and forward-thinking meeting uniting experts to anticipate pivotal upcoming challenges and opportunities in the field of primary immunodeficiency (PID). The 2023 summit focused on three key identified discussion points: (i) How can immunoglobulin (Ig) therapy meet future personalized patient needs? (ii) Pandemic preparedness: what's next for public health and potential challenges for the PID community? (iii) Diagnosing PIDs in 2030: what needs to happen to diagnose better and to diagnose more? Clinician-Scientists, patient representatives and other stakeholders explored avenues to improve Ig therapy through mechanistic insights and tailored Ig preparations/products according to patient-specific needs and local exposure to infectious agents, amongst others. Urgency for pandemic preparedness was discussed, as was the threat of shortage of antibiotics and increasing antimicrobial resistance, emphasizing the need for representation of PID patients and other vulnerable populations throughout crisis and care management. Discussion also covered the complexities of PID diagnosis, addressing issues such as global diagnostic disparities, the integration of patient-reported outcome measures, and the potential of artificial intelligence to increase PID diagnosis rates and to enhance diagnostic precision. These proceedings outline the outcomes and recommendations arising from the 2023 IPOPI Global Multi-Stakeholders' Summit, offering valuable insights to inform future strategies in PID management and care. Integral to this initiative is its role in fostering collaborative efforts among stakeholders to prepare for the multiple challenges facing the global PID community.

Societal Preferences in Health Technology Assessments for Rare Diseases and Orphan Drugs: A Systematic Literature Review of New Analytic Approaches.

OBJECTIVES: This systematic literature review aimed to explore experiences worldwide of societal preferences integration into health technology assessments (HTAs) for rare diseases (RDs) and orphan drugs (ODs) through the implementation of multicriteria decision analysis (MCDA), discrete choice experiments (DCEs), and person trade-off (PTO) methods, among others. METHODS: A systematic search of the literature was conducted in April 2021 using PubMed, Cochrane, Embase, and Scopus databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach was used for the review phases. Finally, the Promoting Action on Research Implementation in Health Services framework was used to discuss the implementation of these instruments in the RD context. RESULTS: A total of 33 articles met the inclusion criteria. The studies measured societal preferences for RD and OD as part of HTA using MCDA (n = 17), DCE (n = 8), and PTO (n = 4), among other methods (n = 4). These found that patients and clinicians do not prioritize funding based on rarity. The public is willing to allocate funds only if the OD demonstrates effectiveness and improves the quality of life, considering as relevant factors disease severity, unmet health needs, and quality of life. Conversely, HTA agency experts preferred their current approach, placing more weight on cost-effectiveness and evidence quality, even though they expressed concern about the fairness of the drug review process. CONCLUSIONS: MCDA, PTO, and DCE are helpful and transparent methods for assessing societal preferences in HTA for RD and OD. However, their methodological limitations, such as arbitrary criteria selection, subjective scoring methods, framing effects, weighting adaptation, and value measurement models, could make implementation challenging.

A comprehensive review on the current status of CRISPR based clinical trials for rare diseases.

A considerable fraction of population in the world suffers from rare diseases. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and its related Cas proteins offer a modern form of curative gene therapy for treating the rare diseases. Hereditary transthyretin amyloidosis, hereditary angioedema, duchenne muscular dystrophy and Rett syndrome are a few examples of such rare diseases. CRISPR/Cas9, for example, has been used in the treatment of ß-thalassemia and sickle cell disease (Frangoul et al., 2021; Pavani et al., 2021) [1,2]. Neurological diseases such as Huntington's have also been focused in some studies involving CRISPR/Cas (Yang et al., 2017; Yan et al., 2023) [3,4]. Delivery of these biologicals via vector and non vector mediated methods depends on the type of target cells, characteristics of expression, time duration of expression, size of foreign genetic material etc. For instance, retroviruses find their applicability in case of ex vivo delivery in somatic cells due to their ability to integrate in the host genome. These have been successfully used in gene therapy involving X-SCID patients although, incidence of inappropriate activation has been reported. On the other hand, ex vivo gene therapy for ß-thalassemia involved use of BB305 lentiviral vector for high level expression of CRISPR biological in HSCs. The efficacy and safety of these biologicals will decide their future application as efficient genome editing tools as they go forward in further stages of human clinical trials. This review focuses on CRISPR/Cas based therapies which are at various stages of clinical trials for treatment of rare diseases and the constraints and ethical issues associated with them.

Clinical Benefit and Revenues of Drugs Affected by Rare Pediatric Disease Priority Review Vouchers, 2017-2023.

OBJECTIVE: To determine the clinical benefit of drugs that earned or redeemed rare pediatric disease priority review vouchers from 2017 through 2023, and the revenues generated by such drugs. STUDY DESIGN: In this cohort study, Federal Register documents, publicly available health technology agency (HTA) assessments, and financial filings were used to identify drugs that were issued or redeemed using a rare pediatric disease priority review voucher from 2017 through 2023, and to assess their added therapeutic benefit and drug-specific global revenues. RESULTS: Among the 36 drugs whose approval resulted in issuance of a rare pediatric priority review voucher, therapeutic benefit ratings were available for 17 (47%), with 9 (53%) rated as high by at least one organization. Mean annual global revenues were $363 million (year 1), $621 million (year 2), and $850 million (year 3). The median annual list price for drugs issued a voucher was $788,705. Vouchers were then redeemed for 15 different drugs; out of 13 drugs with therapeutic benefit ratings, 4 (31%) were high value. CONCLUSIONS: Drugs that treat rare pediatric diseases generate similar revenues compared with other brand drugs, and drugs with high therapeutic benefit tend to generate more revenue than those with low therapeutic benefit. Drugs that earned the rare pediatric disease priority review voucher for their manufacturer generate significant revenues and the voucher may not be necessary to incentivize drug development in the rare pediatric disease space.

The Role of the European Reference Network for Rare Bone Diseases (ERN BOND) and European Registries for Rare Bone and Mineral Conditions (EuRR-Bone) in the Governance of the Management of Rare Bone and Mineral Diseases.

Rare diseases (RDs) bear a significant challenge to individuals, healthcare systems, and societies. The European reference network on Rare BONe diseases (ERN BOND) is committed to improving multidisciplinary, patient-centred care for individuals with rare bone and mineral diseases (RBMDs). Its affiliated project, the European registries for rare bone and mineral conditions (EuRR-Bone) collects data using two different platforms, an electronic surveillance system (e-REC) that captures the occurrence of RBMDs and the Core Registry, a platform with the infrastructure for collecting Core data fields and longitudinal generic and condition-specific information. With emerging registries and the overlap with other ERNs, it is key to maintain the capability of the platforms to adapt to the needs of the network and the community whilst adhering to quality and FAIR (findable, accessible, interoperable, and reusable) principles. This binomial ensures long-term sustainability and potential advances in the care pathway of RBMDs whilst promoting good practice standards within Europe and beyond.

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.

Inaugural Patient-Reported Registry of Pediatric Opsoclonus-Myoclonus-Ataxia Syndrome: Presentation, Diagnosis, and Treatment of 194 Patients.

BACKGROUND: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare neuroimmune disease with peak onset at 18 months, associated with neural crest tumors in 50% of patients. In part due to its rarity, misdiagnosis at onset is common, can delay treatment, and may contribute to adverse outcomes. Patient-reported registries may overcome some of these challenges in rare disease research. In this context, the OMSLife Foundation collaborated with the National Organization of Rare Diseases to create a patient-reported registry in OMAS. METHODS: Retrospective analysis was performed of data entered by parents of patients with OMAS into nine online surveys assessing demographics, symptoms at onset, triggers, time of diagnosis, treatment, and additional therapies. RESULTS: A total of 194 patients were enrolled. There was a female predominance (54%) and high rate of parental autoimmunity (31%). Age at onset peaked between 12 and 18 months overall. The age of onset was older in female patients (median [interquartile range]: females 22 [15 to 31] vs males 18 [14 to 23], P = 0.0223, P = 0.0223). Symptoms at onset most commonly included ataxia (84%) and were typically severe. Initial misdiagnosis occurred in nearly 50% and tumor discovery was delayed in 18 patients, but overall median time to correct diagnosis was 25 days. Most patients (56%) received combination immunomodulatory therapies, and nearly all underwent supportive therapies. CONCLUSIONS: Patient- and parent-powered research is feasible in OMAS and created the second largest published cohort of pediatric patients with OMAS. Results were similar to other large cohorts and also validated findings from prior case reports and smaller case series.