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Primary mitochondrial disorders (PMDs) are an extraordinarily complex group of rare disorders caused by impairment of the mitochondrial electron transport chain, or respiratory chain. Studying genotype-phenotype relationships in PMDs is a complex task. The clinical variability is large even in individuals with the same genotype, and the statistical power is low in single-center studies because of their rarity. To better define the clinical phenotypes associated with PMDs, in the last 15 years a significant multicenter effort has led to nation-wide studies on large cohorts of patients. Many national registries of mitochondrial patients have been developed in recent years, and now there is a strong effort towards international (and even global) registries. This review will revise the notable advances obtained with such studies in recent years, and will discuss the actual developments and future perspectives., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rare diseases affect 6%-8% of the population and present diagnostic challenges, particularly for historically marginalized ethnic and racial groups. The Undiagnosed Diseases Network (UDN) aims to enhance diagnosis rates and research participation among such minoritized groups. A retrospective review was conducted from 2015 to 2023, analyzing 2235 UDN participants to evaluate its progress toward this objective. Data on demographics, disease phenotypes, diagnostic outcomes, and socioeconomic factors were collected and statistical analyses assessed differences among ethnic and racial groups. This demonstrated that Hispanic and Black non-Hispanic groups were underrepresented, while White non-Hispanic participants were overrepresented in the UDN compared to the US population. Individuals whose primary language was not English were also significantly underrepresented. Diagnosis rates varied, with the highest rates among Asian non-Hispanic (39.5%) and Hispanic (35.3%) groups and the lowest rate in the White non-Hispanic group (26.8%) (p < 0.001). Binomial logistic regression found, however, that only participant age and disease phenotype predicted the likelihood of receiving a diagnosis (p < 0.001). Persistent ethnic and racial disparities in UDN participation appear to be associated with major differences in application rates. Under-enrollment of historically marginalized ethnic and racial groups may be due to economic hardships and language barriers. No differences in the diagnostic yield among ethnic and racial groups were observed after controlling for other factors. This work highlights the value of comprehensive genetic evaluations for addressing healthcare disparities and suggests priorities for advancing inclusion in rare disease research., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Temporal trends demonstrate improved survival for many types of common pediatric cancer. Studies have not examined improvement in very rare pediatric cancers or compared these improvements to more common cancers. In this cohort study of the Surveillance, Epidemiology, and End Results (SEER) registry, we examined patients from 1975 to 2016 who were 0-19 years of age at the time of diagnosis. Cancers were grouped by decade of diagnosis and 3 cancer frequency groups: Common, Intermediate, and Rare. Trends in mortality across decades and by cancer frequency were compared using Kaplan-Meier curves and adjusted Cox proportional hazards models. A total of 50,222 patients were available for analysis, with the top 10 cancers grouped as Common (67%), 13 cancers grouped with Intermediate (24%), and 37 cancers as Rare (9%). Rare cancers had higher rates of children who were older and Black. 5-year survival increased from 63% to 86% across all cancers from the 1970s to the 2010s. The hazard ratio (HR) for mortality decreased from the reference point of 1 in the 1970s to 0.27 (95% CI: 0.25-0.30) in the 2010s in Common cancers, while the HR only dropped to 0.60 (0.49-0.73) over that same period for rare cancers. Pediatric oncology patients have experienced dramatic improvement in mortality since the 1970s, with mortality falling by nearly 75% in common cancers. Unfortunately, rare pediatric cancers continue to lag behind more common and therefore better studied cancers, highlighting the need for a renewed focus on research efforts for children with these rare diseases.

Background: As the survival proportions for rare cancers are on average worse than for common cancers, assessing the expected remaining life years in good health becomes highly relevant. This study aimed to estimate the healthy life expectancy (HLE) of a subset of rare and common cancer survivors, and to assess the determinants of poor perceived health in rare cancer survivors., Methods: To calculate HLE, survival data from the population-based Netherlands Cancer Registry of survivors of a rare cancer (i.e., ovarian cancer, thyroid cancer, Hodgkin lymphoma, non-Hodgkin lymphoma) (n=21,376) and a common cancer (i.e., colorectal cancer (CRC)) (n=76,949) were combined with quality of life (QoL) data from the PROFILES registry on a random sample of the rare (n=1025) and common cancer (n=2400) survivors. A flexible parametric relative survival model was used to estimate life expectancy (LE) and years of life lost, and multivariate logistic regression was applied to determine factors related to reported poor perceived health., Results: Patients previously diagnosed with a rare cancer had an average LE of 8-36 years and were expected to spend ≥67 % of their remaining life in good health. CRC survivors had an average LE of 10 years with approximately 65 % of their remaining life expected to spend in good health. For all cancer types, those aged ≥65 years or with stage IV had the lowest HLE. Low socioeconomic status, advanced stage, and having received radiotherapy only were important predictors of poor perceived health among rare cancer survivors., Conclusion: HLE can provide meaningful perspective for patients and practitioners for all cancer types, including rare cancers. Yet, data on QoL for rare cancers should be routinely collected, as such will serve as an indicator for monitoring and improving cancer care, and for enabling HLE measurements in cancer survivors., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Despite advancements in early diagnosis and effective medications in last decade, most heterozygous familial hypercholesterolemia (heFH) patients still fail to achieve their low-density lipoprotein cholesterol (LDL-C) goals and remain at residual cardiovascular disease risk. We present recent data from the regional FH registry in Poland, highlighting the challenges and real-life clinical management of FH patients., Methods: The registry is held at the Regional Centre for Rare Diseases, founded in 2016, at the 2nd largest, supraregional hospital in Poland, where >80 different rare diseases in patients from all over Poland are diagnosed and treated, including phenotypically or genetically diagnosed FH patients. Our analysis focused on both children and adult FH patients, excluding those treated with inclisiran due to a small sample size (n = 5)., Results: We studied 173 consecutive heFH patients, median age for adult population was 40 years (range: 27-57), of whom 56.14 % were women. Among the population, 82.1 % were adults (n = 142), and 31 were children (17.92 %; median age 9 (8-13), females 58.16 %). Children exhibited lower total cholesterol and triglyceride levels compared to adults, with no significant differences in LDL-C and high-density lipoprotein cholesterol (HDL-C) levels. Molecular diagnosis in the whole population revealed that 76.6 % had an LDL receptor (LDLR) mutation, while 23.4 % had an apolipoprotein B (APOB) mutation. Risk assessment categorized patients into high (70.7 %), very high (22.1 %), and extremely high (7.1 %) risk groups. Triple therapy achieved treatment goals in 61.76 % of adults and 70.97 % of children. At baseline, 36.62 % of adult patients were not using statins. High-intensity statin therapy combined with ezetimibe was initiated for the remaining patients. Only 3.33 % of patients avoided statins due to complete intolerance. Ezetimibe was used in 57.27 % of patients (mostly in combination therapy), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were prescribed for 28.17 % FH patients. In adults receiving statin and ezetimibe therapy, median achieved LDL-C was 141 mg/dl (107-184). For triple therapy, median achieved LDL-C was 52.5 mg/dL (32-86.5). Overall median achieved LDL-C in the study population was 99.5 mg/dl (57.5-145.4). PCSK9 inhibitors reduced LDL-C by 165.6 mg/dl. Combination therapy did not significantly alter baseline lipoprotein(a) (Lp(a)) levels (p = 0.134), and PCSK9 inhibitors led to a mean Lp(a) reduction of 18.66 mg/dl (45 % reduction; p = 0.013). Multivariable regression analysis identified key factors for achieving LDL-C targets in FH patients: DLCN total score, DLCN category, ezetimibe use, and PCSK9 inhibitors., Conclusions: In Poland, FH patients are often diagnosed too late (usually over 40 years of age), and many still do not reach their LDL-C goals. Combination LLT double or triple therapy significantly increases the likelihood of achieving LDL-C targets - even up to fivefold. Therefore, unrestricted access to PCSK9 inhibitors for all FH patients is crucial, without the current limitations imposed by drug reimbursement programs like B101., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Lewek has received a speaker's fee from Amgen, Novartis, Sanofi; Dr. Banach has received research grant(s)/support from Amgen, Daiichi Sankyo, Sanofi and Viatris, and has served as a consultant/received speaker's fee for Amgen, Daiichi-Sankyo, Esperion, Kogen, KRKA, Menarini, MSD, Mylan/Viatris, Novartis, Novo-Nordisk, Polpharma, Sanofi, Servier, Teva, and Zentiva; all other author have nothing to declare in relation to the results of this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Rare cancers correspond to approximately 200 clinical entities, which can be grouped into 12 families. Updated data are available for childhood and haematological cancers, ie, for only two of the 12 families of rare cancer. We provide incidence and survival for the remaining ten families of rare adult solid cancers (RAC), across 29 EU Member States and over time. We also evaluate the association between resources invested in health and survival from RACs., Methods: We used the EUROCARE-6 database, which includes data from 108 cancer registries from 29 countries. We calculated incidence rates (IR) and 5-year relative survival (RS) for cases diagnosed during 2006-2013. We calculated 5-year RS in the follow-up period 2010-2014 using the period approach (last follow-up: December 31, 2014). We estimated changes in 5-year RS and IR over the period 2000-2013. We used a forest plot to report the differences in RS among countries with the highest and lowest health spending., Results: RACs are heterogeneous in terms of incidence, survival, sex, and age distribution. Several RACs (eg, those of the hypopharynx, small intestine, and trachea) still have a 5-year RS < 30 %, which is not improving. Survival differs among European countries and is higher in countries with the greatest investments in health. The incidence of smoking-related RACs is decreasing but rising in HPV-related RACs., Conclusion: Investments in health and healthcare networks at national and European level can help increase the survival of RACs, especially those requiring centralisation of care (eg, bone sarcomas, penile cancer). These investments are critical considering that survival from RACs is not significantly improving. Our results unmask the heterogeneity of RACs, which needs to be considered in clinical trial design. Finally, our findings support the importance of prevention strategies for known risk factors such as smoking., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: The availability of drugs and national public policies for patients with rare cancers, including sarcomas, varies in different parts of the world., Methods: In this manuscript, we have conducted a comprehensive analysis to evaluate rare cancer policies in Latin American countries' national policy documents. Additionally, we have reviewed the approvals for sarcoma drugs in selected Latin American countries and compared them with US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals., Results: The documents reviewed showed a lack of explicit focus on rare cancers, with no mention in 70% of the countries analyzed. Drug approval data reveal that in the last 15 years, the FDA and EMA have approved 19 and 13 drugs for sarcoma, whereas their Latin American counterparts, namely ANVISA, ANMAT, and COFEPRIS, approved six, eight, and seven drugs, respectively., Conclusion: Our data suggest that improving rare cancer and sarcoma care in Latin America requires enhanced collaboration for better rare cancer policies.

Rare kidney diseases encompass a wide range of congenital, inherited and acquired conditions. Two million Europeans are affected by rare kidney diseases. The European Rare Kidney Disease Reference Network (ERKNet) aims to improve the clinical management of patients with these diseases. ERKNet encompasses 95 highly specialized adult and pediatric nephrology units at 72 sites in 24 European Union (EU) member states, as well as a group of patient advocates (European Patient Advocacy Group, ePAG). ERKNet centers care for more than 65,000 rare kidney disease patients and pursues a variety of activities. An online consultation service helps improve the management of complex cases. Expert working groups develop clinical practice guidelines for individual groups of rare kidney diseases. In a 3-year postgraduate program, junior physicians at ERKNet centers are trained by experts in the diagnosis and treatment of rare kidney diseases through webinars and case-based eLearning modules. Information brochures and online texts on rare kidney diseases for patients, relatives and the general public are produced and disseminated. Clinical research is supported by a European Registry for Rare Kidney Diseases (ERKReg), which provides important information on demographics and disease progression and facilitates the identification of patient cohorts for therapeutic studies. In addition, the registry provides clinical performance statistics of reference centers and allows benchmarking to promote the harmonization and standardization of care for rare kidney disease patients across Europe., Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: T. Wlodkowski, S. Haeberle und F. Schaefer geben an, dass kein Interessenkonflikt besteht. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patient/-innen zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern/Vertreterinnen eine schriftliche Einwilligung vor., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Purpose: Research on rare diseases and atypical health care demographics is often slowed by high interparticipant heterogeneity and overall scarcity of data. Synthetic data (SD) have been proposed as means for data sharing, enlargement, and diversification, by artificially generating real phenomena while obscuring the real patient data. The utility of SD is actively scrutinized in health care research, but the role of sample size for actionability of SD is insufficiently explored. We aim to understand the interplay of actionability and sample size by generating SD sets of varying sizes from gradually diminishing amounts of real individuals' data. We evaluate the actionability of SD in a highly heterogeneous and rare demographic: adolescents and young adults (AYAs) with cancer., Methods: A population-based cross-sectional cohort study of 3,735 AYAs was subsampled at random to produce 13 training data sets of varying sample sizes. We studied four distinct generator architectures built on the open-source Synthetic Data Vault library. Each architecture was used to generate SD of varying sizes on the basis of each aforementioned training subsets. SD actionability was assessed by comparing the resulting SD with their respective real data against three metrics-veracity, utility, and privacy concealment., Results: All examined generator architectures yielded actionable data when generating SD with sizes similar to the real data. Large SD sample size increased veracity but generally increased privacy risks. Using fewer training participants led to faster convergence in veracity, but partially exacerbated privacy concealment issues., Conclusion: SD is a potentially promising option for data sharing and data augmentation, yet sample size plays a significant role in its actionability. SD generation should go hand-in-hand with consistent scrutiny, and sample size should be carefully considered in this process.

Functional annotation and interpretation of genetic variants are a critical step in genetic diagnosis, as it may lead to personalized therapeutic options and genetic counseling. While the number of confirmed pathogenic genetic variants in an individual is relatively low, the number of variants of uncertain significance (VOUS) can be considerably higher, increasing the number of potential carriers of genetic disorders. Thus, reducing uncertainty and assessing the real effect of VOUS are crucial for clinical and medical genetics. In this study, we evaluated the efficacy of genetic screening technologies in accurately predicting pathogenic variants and their corresponding disease prevalence in a cohort of over 6000 healthy individuals involved in assisted reproduction programs. Using data from 305 genes associated with recessive disorders, we determined the frequency of carriers of pathogenic variants and VOUS in our dataset and compared the predicted prevalence based on this information with reported population prevalence data. The higher predicted prevalence in some disorders when considering VOUS suggests a mostly benign effect., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

Purpose and Scope: The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times., Methods of Statement Development: A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute., Results and Conclusions: We identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The Australian Paediatric Surveillance Unit (APSU), established in 1993 to address the paucity of national data on rare childhood disorders, has become an invaluable research resource. It facilitates prospective, active surveillance for a variety of rare disorders, with monthly reporting by ~1500 paediatricians, who are invited to notify incident cases and provide demographic and clinical data. APSU is highly collaborative (used by >400 individuals/organisations), patient-informed and productive (>300 publications). In 30 years, 72 studies have been initiated on rare infections, and genetic, psychological and neurological disorders, and injuries. Return rates of monthly report cards were >90% for 30 years and paediatricians have provided data for >90% of notified cases. Although there are limitations, including case underascertainment in remote regions, APSU often provides the only available national data. APSU has assisted the government in reporting to the WHO, developing national strategies, informing inquiries and investigating disease outbreaks. APSU data have informed paediatrician education, practice, policy, and service development and delivery. APSU was integral in establishing the International Network of Paediatric Surveillance Units (INoPSU) and supporting development of other units. APSU's expanded remit includes one-off surveys, hospital audits, systematic reviews, studies on the impacts of rare disorders on families, surveillance evaluations, and joint studies with INoPSU members. Paediatricians value the APSU, reporting that APSU data inform their practice. They must be congratulated for an outstanding collective commitment to the APSU, in providing unique data that contribute to our understanding of rare disorders and support optimal, evidence-based care and improved child health outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Rare infectious diseases of poverty (rIDPs) involve more than hundreds of tropical diseases, which dominantly affect people living in impoverished and marginalized regions and fail to be prioritized in the global health agenda. The neglect of rIDPs could impede the progress toward sustainable development. This study aimed to estimate the disease burden of rIDPs in 2021, which would be pivotal for setting intervention priorities and mobilizing resources globally., Methods: Leveraging data from the Global Burden of Disease Study 2021, the study reported both numbers and age-standardized rates of prevalence, mortality, disability-adjusted life-years (DALYs), years lived with disability, and years of life lost of rIDPs with corresponding 95% uncertainty intervals (UIs) at global, regional, and national levels. The temporal trends between 1990 and 2021 were assessed by the joinpoint regression analysis. A Bayesian age-period-cohort model was used to project the disease burden for 2050., Results: In 2021, there were 103.76 million (95% UI: 102.13, 105.44 million) global population suffered from rIDPs with an age-standardized DALY rate of 58.44 per 100,000 population (95% UI: 42.92, 77.26 per 100,000 population). From 1990 to 2021, the age-standardized DALY rates showed an average annual percentage change of - 0.16% (95% confidence interval: - 0.22, - 0.11%). Higher age-standardized DALY rates were dominated in sub-Saharan Africa (126.35 per 100,000 population, 95% UI: 91.04, 161.73 per 100,000 population), South Asia (80.80 per 100,000 population, 95% UI: 57.31, 114.10 per 100,000 population), and countries with a low socio-demographic index. There was age heterogeneity in the DALY rates of rIDPs, with the population aged under 15 years being the most predominant. Females aged 15-49 years had four-times higher age-standardized DALY rates of rIDPs than males in the same age. The projections indicated a slight reduction in the disease burden of rIDPs by 2050., Conclusions: There has been a slight reduction in the disease burden of rIDPs over the past three decades. Given that rIDPs mainly affect populations in impoverished regions, targeted health strategies and resource allocation are in great demand for these populations to further control rIDPs and end poverty in all its forms everywhere., Competing Interests: Declarations Ethics approval and consent to participate The protocol of the GBD 2021 has been approved by the research ethics board at the University of Washington. The GBD 2021 shall be conducted in full compliance with University of Washington policies and procedures, as well as applicable federal, state, and local laws. The study was carried out in the public domain secondary database, without any nominal identity, hence, the ethical approval was exempted. Consent for publication Not applicable. Competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024. The Author(s).)

Background: The Brazilian Policy for Comprehensive Care for People with Rare Diseases was implemented in 2014; however, national epidemiological data on rare diseases (RDs) are scarce and mainly focused on specific disorders. To address this gap, University Hospitals, Reference Services for Neonatal Screening, and Reference Services for Rare Diseases, all of which are public health institutions, established the Brazilian Rare Diseases Network (RARAS) in 2020. The objective of this study was to perform a comprehensive nationwide epidemiological investigation of individuals with RDs in Brazil. This retrospective survey collected data from patients receiving care in 34 healthcare facilities affiliated with RARAS in 2018 and 2019., Results: The survey included 12,530 participants with a median age of 15.0 years, with women representing 50.5% of the cohort. Classification according to skin color demonstrated that 5044 (47.4%) participants were admixed. Most had a confirmed diagnosis (63.2%), with a predominance of phenylketonuria (PKU), cystic fibrosis (CF), and acromegaly. Common clinical manifestations included global developmental delay and seizures. The average duration of the diagnostic odyssey was 5.4 years (± 7.9 years). Among the confirmed diagnoses, 52.2% were etiological (biochemical: 42.5%; molecular: 30.9%), while 47.8% were clinical. Prenatal diagnoses accounted for 1.2%. Familial recurrence and consanguinity rates were 21.6% and 6.4%, respectively. Mainstay treatments included drug therapy (55.0%) and rehabilitation (15.6%). The Public Health System funded most diagnoses (84.2%) and treatments (86.7%). Hospitalizations were reported in 44.5% of cases, and the mortality rate was 1.5%, primarily due to motor neuron disease and CF., Conclusion: This study marks a pioneering national-level data collection effort for rare diseases in Brazil, offering novel insights to advance the understanding, management, and resource allocation for RDs. It unveils an average diagnostic odyssey of 5.4 years and a higher prevalence of PKU and CF, possibly associated with the specialized services network, which included newborn screening services., (© 2024. The Author(s).)

Background: An ongoing challenge with rare diseases is limited data and, consequently, limited knowledge about the collective prevalence and impact of these conditions on individuals, families, and the health system, particularly in rural and regional areas. Using existing datasets, this project aimed to examine the epidemiology of and hospital activity for Tasmanians with rare diseases., Methods: Rare diseases were defined as non-infectious diseases with a prevalence of less than 1 in 2000. An initial resource set of 1028 ICD-10-AM diagnostic codes was used to identify a cohort of Tasmanians with rare diseases in Tasmanian Health datasets (1 January 2007 until 31 December 2020). Validating the resource set using a small group with known rare diseases revealed limitations in ascertainment, and so an expanded set of 1940 ICD-10-AM diagnostic codes was developed by cross-referencing ICD-10-AM codes with Orphanet data. Cohort hospital activity and admission costs were compared to statewide data for the final year of the study, 01 January 2020 to 31 December 2020., Results: Using the resource set of 1028 ICD-10-AM diagnostic codes, the period prevalence of rare diseases in Tasmania across all age groups was estimated at 3.5%, with a point prevalence of 1.5% in December 2020. In 2020, 3384 individuals within the Tasmanian rare disease cohort, representing 0.6% of the Tasmanian population, accessed the public hospital system and accounted for 5.6% of all admissions. The mean length of stay for rare disease-related hospital admissions was 5.0 days, compared to 3.3 days for non-rare disease-related admissions. The mean cost per admission for the rare disease cohort was AUD$11,310, compared to AUD$6475 for all admissions statewide. In 2020, using the expanded resource set, the total cost of public hospital admissions in Tasmania was estimated to be AUD$979 million, with rare disease-related hospital admissions accounting for 9.1% of this cost, increasing to 19.0% when the costs for all admissions for the rare disease patients were included., Conclusions: Patients with rare diseases had more admissions, longer length of stay, and a higher average cost per admission. Patients with rare diseases have a disproportionate impact on statewide hospital activity and costs in Tasmania., (© 2024. Crown.)

Introduction: In patients with Hereditary Angioedema (HAE) related to primary C1 inhibitor deficiency (C1INH), the defective clearance of immune complexes and apoptotic materials along with impairment of normal humoral response potentially leads to autoimmunity. Few studies report evidence on autoimmune diseases in C1INH-HAE, but no large population studies focus on rare connective tissue diseases (RCTDs). We aim at evaluating for the first time prevalence and distribution of RCTDs - Systemic Lupus Erytematosus (SLE), primary Sjogren Syndrome (SjS), primary antiphospholipid syndrome (APS), Systemic Sclerosis (SSc), and mixed connective tissue diseases (MCTD) in a large Italian cohort of C1INH-HAE patients., Methods: A multicenter observational study includes C1INH-HAE patients from ITACA Centers throughout Italy (time frame Sept 2023-March 2024). Inclusion criteria are i. a defined diagnosis of type I or type II C1INH-HAE; ii. age ≥15 years (puberty already occurred); iii. enrollment in the ITACA Registry. The diagnosis of SLE, primary SjS, primary APS, SSc, and MCTD are made in accordance with international classification criteria., Results: Data are collected from a total of 855 C1INH-HAE patients referring to 15 ITACA Centers. Patients with concomitant RCTDs were 18/855 (2.1%) with F:M ratio 3.5 and a prevalent type I C1INH-HAE diagnosis (87.2%). A diagnosis of SLE results in 44.5% of cases (n=8) while the remaining diagnoses are primary SjS (22.2%, n=4), primary APS (16.6%, n=3), SSc (11.2%, n=2), and a single case of MCTD (5.5%). The female gender is prevalent in all the RCTDs. Patients on long term prophylaxis (LTP) are significantly prevalent in RCTDs group than in the whole C1INH-HAE population (p<0.01)., Conclusions: A relevant prevalence of RCTDs is documented in C1INH-HAE patients, mainly SLE. Patients with RCTDs are on LTP in a significant proportion supporting the idea of a bidirectional link between C1INH-HAE and autoimmunity., Competing Interests: PT received speaker/consultancy fees from CSL Behring and Takeda. RS was consultant for Biocryst and Takeda, and received travel grants from Takeda, Biocryst, CSL Behring, Alk Abello and Novartis. FA received consultancy fees or research grants from CSL Behring and Takeda. MG received speaker fees from CSL Behring. DF received speaking fees or research grants from CSL-Behring and Takeda. AZ received speaker/consultancy fees from and/or was a member of advisory boards for BioCryst, CSL Behring, KalVista, Pharming, Pharvaris, and Takeda. MC received travel grants from CSL Behring, Menarini, Novartis, and Shire-Takeda, and consultancy fees from Biocryst, CSL Behring, and Shire-Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision, (Copyright © 2024 Triggianese, Senter, Perego, Gidaro, Petraroli, Arcoleo, Brussino, Giardino, Rossi, Bignardi, Quattrocchi, Brancaccio, Cesoni Marcelli, Accardo, Lo Sardo, Cataudella, Guarino, Firinu, Bergamini, Spadaro, Zanichelli and Cancian.)

Rare genetic diseases (RGDs) affect a significant number of individuals, particularly in pediatric populations. This study investigates the efficacy of identifying RGD diagnoses through electronic health records (EHRs) and natural language processing (NLP) tools, and analyzes the prevalence of identified RGDs for potential underdiagnosis at Cincinnati Children's Hospital Medical Center (CCHMC). EHR data from 659,139 pediatric patients at CCHMC were utilized. Diagnoses corresponding to RGDs in Orphanet were identified using rule-based and machine learning-based NLP methods. Manual evaluation assessed the precision of the NLP strategies, with 100 diagnosis descriptions reviewed for each method. The rule-based method achieved a precision of 97.5% (95% CI: 91.5%, 99.4%), while the machine-learning-based method had a precision of 73.5% (95% CI: 63.6%, 81.6%). A manual chart review of 70 randomly selected patients with RGD diagnoses confirmed the diagnoses in 90.3% (95% CI: 82.0%, 95.2%) of cases. A total of 37,326 pediatric patients were identified with 977 RGD diagnoses based on the rule-based method, resulting in a prevalence of 5.66% in this population. While a majority of the disorders showed a higher prevalence at CCHMC compared with Orphanet, some diseases, such as 1p36 deletion syndrome, indicated potential underdiagnosis. Analyses further uncovered disparities in RGD prevalence and age of diagnosis across gender and racial groups. This study demonstrates the utility of employing EHR data with NLP tools to systematically investigate RGD diagnoses in large cohorts. The identified disparities underscore the need for enhanced approaches to guarantee timely and accurate diagnosis and management of pediatric RGDs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Spinocerebellar ataxia type 7 (SCA7) is a rare genetic disease characterized by progressive cerebellar syndrome and macular degeneration. In a previous study, we clinically and genetically characterized a group of Mexican patients, which represented one of the largest cohorts of SCA7 patients worldwide and demonstrated that all patients had a unique genetic origin. Our laboratory developed a program for the diagnosis, medical care, and long-term follow-up of these patients living in Veracruz State, and in this report, we present an update to this research, covering 2013 to 2024. So far, we identified 172 SCA7 carriers, with a few cases outside Veracruz, and our data support that the length of the CAG repeat tract mainly determines disease severity and life expectancy, and accordingly, we define three different phenotypes, early-onset (EO), classical-onset (CO), and late-onset (LO), with EO patients showing the lowest life expectancy. Furthermore, we found that parental transmission of mutant alleles leads to increased CAG repeat instability, compared to maternal ones. Interestingly, a haplotype analysis revealed that patients outside Veracruz may have different genetic origins. In conclusion, longitudinal observations of SCA7 patients provide insight into the natural history of SCA7 and help to design strategies for diagnosis, genetic counseling, physical rehabilitation, and therapeutic alternatives.

The present study aimed to compare the prevalence of oral problems between individuals with rare genetic diseases that affect skeletal development and individuals without rare diseases. A cross-sectional study was conducted with 210 individuals between two and fifty-four years of age: 105 with rare genetic diseases (27 with mucopolysaccharidosis [MPS] and 78 with osteogenesis imperfecta [OI]) and 105 without rare diseases. The rare genetic disease group was recruited from hospital units that provide care for patients with MPS and OI in five states of Brazil, and the other group was recruited from the same location. The participants were examined with regards to malocclusion, dental anomalies, dental caries, and gingivitis. A questionnaire was administered addressing individual, sociodemographic, and behavioral characteristics as well as dental history. A descriptive analysis was performed, followed by unadjusted and adjusted binary logistic regression analyses. The mean age was 14.1 ± 12.2 years. Individuals with a rare disease were 12.9-fold more likely to have some type of oral problem (95% CI: 3.7-44.7) compared to the group without rare diseases. The prevalence of oral problems was higher among Brazilians with MPS and OI compared to normotypical individuals.

Background: The Pareto Principle asserts that a large portion of results can be achieved with a small amount of effort. Wakap et al. found that around 80% of individuals with rare diseases (RD) suffer from one of 149 specific rare diseases. A significant challenge in the RD domain is the lack of information, compounded by the fact that most RD are not specifically codifiable in the ICD-10, leading to a deficit in reliable epidemiological data. Additionally, time constraints in medical education hinder the comprehensive teaching of all RD, contributing to the diagnostic odyssey problem through failure of recognizing diseases. We identified the most and second most prevalent RD (prevalences of 1-5/10,000 and 1-9/100,000, respectively) from the Orphanet Epidemiology File, totaling 454 diseases. We investigated the feasibility of specific coding using ICD-10-GM and whether these diseases were explicitly listed in the subject catalog (GK) of the second state examination in human medicine in Germany. A two-sided chi-square test was employed to identify statistically significant differences between prevalence groups., Results: Out of 454 diseases, a total of 34% could be specifically coded in ICD-10-GM, with 49% of diseases in the 1-5/10,000 prevalence range (153 RD) and 26% in the 1-9/100,000 range (301 RD) having specific codes. Approximately 15% of all investigated diseases were part of the GK, with 25% of the most prevalent and 10% of the second most prevalent RD group, respectively. Statistically significant differences were observed between prevalence groups concerning the presence of a specific ICD-10-GM code and inclusion in the GK., Conclusion: Only 49% of the most prevalent RD can be specifically coded, highlighting the challenge of limited epidemiological data on RD. In Germany, the Alpha-ID was introduced in addition to ICD-10 in the inpatient setting to obtain more valid epidemiological data on RD. Recognizing the Pareto Principle's applicability, the study emphasizes the importance of including the most common rare diseases in medical education. While recognizing the limitations, especially in covering ultra-rare diseases, the study underscores the potential benefits of enhancing medical curricula to improve rare disease awareness and diagnostic accuracy., (© 2024. The Author(s).)

Background: Initiatives aiming to assess the impact of rare diseases on population health might be hampered due to the complexity of disability-adjusted life years (DALYs) estimation. This study aimed to give insight into the epidemiological data sources and methodological approaches used in studies that estimated DALYs for chronic non-communicable rare diseases (CNCRD), and compare its results., Methods: A literature strategy was developed for peer-review search in Embase and Medline, and also performed on grey literature databases and population health and/or rare disease-focused websites. We included studies that determined the burden of CNCRD listed on the Orphanet's and/or the Genetic and Rare Diseases information center (GARD) websites. We excluded communicable and occupational diseases, rare cancers, and cost-effectiveness/benefit studies. Two researchers independently screened the identified records and extracted data from the final included studies. We used the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) statement to assess the quality of reporting of the included studies. The data synthesis depicted the studies' characteristics, their distribution by geographic coverage and the group of disease(s) they focused on, the methods and data input sources used and estimated DALY per case., Results: In total, 533 titles were screened, and 18 studies were included. These studies covered 19 different CNCRDs, of which most fell in the disease category "Diseases of the nervous system". Diverse methodological approaches and data input sources were observed among burden of CNCRD studies. A wide range of DALY per case was observed across the different studies and diseases included., Conclusions: A low number of burden of CNCRD studies was observed and most estimates resulted from multi-country studies, underlining the importance of international cooperation to further CNCRD research. This study revealed a lack of epidemiological data and harmonization of methods which hampers comparisons across burden of CNCRD studies., (© 2024. The Author(s).)

Rare diseases (RDs) are individually rare but collectively common, affecting an estimated 1 in 15 individuals in South Africa (SA). Patients with an RD often face a long diagnostic odyssey (>5 years on average) and many obstacles in accessing healthcare. A scoping review was conducted to assess the impact of the COVID-19 pandemic on the SA RD community. Fourteen studies met the inclusion criteria and were explored using thematic analysis, which showed that RD patients were further marginalised during the pandemic, particularly in access to healthcare. Increased inclusivity in policy creation and integrated community-based healthcare are recommended to ensure that RD patients are not an afterthought in future crises.

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.

Timely diagnosis is one of the most serious challenges faced by people living with a rare disease (PLWRD), and this study estimates that in Europe, the average total diagnosis time (TDT) is close to 5 years. We investigated the duration of the TDT for PLWRD in Europe, the difficulties associated with their diagnosis odyssey and the main determinants of diagnosis delays for all rare diseases (RD). We conducted a survey of PLWRD and their families using Rare Barometer, the survey initiative of EURORDIS-Rare Diseases Europe. In geographical Europe, we surveyed 6507 people living with 1675 RD in 41 countries. We then performed a descriptive analysis and ordinal logistic regressions to identify the main determinants of diagnosis delays. Average TDT is 4.7 years. 56% of respondents were diagnosed more than 6 months after a first medical contact. The main determinants of diagnosis delays are symptom onset before 30 years of age, especially during childhood (OR = 3.11; 95% CI: 2.4-4.0) and adolescence (OR = 4.79; 95% CI: 3.7-6.2), being a woman (OR = 1.22; 95% CI:1.1-1.4), living in Northern Europe (OR = 2.15; 95% CI:1.8-2.6) or Western Europe (OR = 1.96; 95% CI:1.6-2.3), the number of healthcare professionals consulted (OR = 5.15; 95% CI:4.1-6.4), misdiagnosis (OR = 2.48; 95% CI:2.1-2.9), referral to a centre of expertise (OR = 1.17; 95% CI:1.0-1.3), unmet needs for psychological support (OR = 1.34; 95% CI:1.2-1.5) and financial support (OR = 1.16; 95% CI:1.0-1.3), having a genetic disease (OR = 1.33; 95% CI:1.1-1.5) and a family history of an RD (OR = 1.36; 95% CI:1.1-1.6). These determinants can inform policies and actions to improve access to diagnosis for all PLWRD., (© 2024. The Author(s).)

Background: Rare diseases (RDs) affect millions of individuals collectively worldwide, contributing to significant burdens on patients and families in various aspects. However, there is a lack of evidence on the underlying patterns of burdens among diverse RDs for informing targeted social and health policies to address the unmet needs of this vulnerable population., Objective: This study aimed to examine the underlying patterns of the health and economic burden of 33 different RDs in China and identify the potential determinants., Methods: A nationwide internet-based cross-sectional survey was conducted in China between 2019 and 2020. Physical and mental health burden was measured by health-related quality of life. Economic burden was evaluated based on the proportions of direct medical, direct nonmedical, and indirect costs relative to household income. We used cluster analysis to identify patterns of health and economic burdens and conducted multinomial logistic regression to explore potential predictors of cluster membership., Results: The study included 8454 adults and 8491 children affected by 33 RDs. The following 3 clusters were identified: "extremely high burden" (representing 92/8454, 1.1% and 19/8491, 0.2% of adult and pediatric patients, respectively), "overall high burden" (5933/8454, 70.2% and 4864/8491, 57.3%, respectively), and "overall low burden" (2429/8454, 28.7% and 3608/8491, 42.5%, respectively). Wilson disease, Marfan syndrome, and Langerhans cell histiocytosis more likely resulted in an "extremely high burden" than others. Poverty was significantly associated with being in this extremely high burden group. Diseases causing neuromuscular symptoms and requiring long-term treatment (eg, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Dravet syndrome) were prevalent in the "overall high burden" group. Key predictors of this group included older age, lower socioeconomic status, diagnostic delay, and comorbidity., Conclusions: This study provides novel and valuable evidence on the burden of RDs in developing regions like China. The findings reveal significant disparities in the impact of RDs, emphasizing the need for targeted health care interventions and policies., (©Jiazhou Yu, Shanquan Chen, Huanyu Zhang, Shuyang Zhang, Dong Dong. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 27.08.2024.)

REHem-AR was created in 2013. The progressive implementation of neonatal screening for haemoglobinopathies in Spanish autonomous communities where the registry had not been implemented, as well as the addition of new centres during this period, has considerably increased the sample of patients covered. In this study, we update our previous publication in this area, after a follow-up of more than 5 years. An observational, descriptive, multicentre and ambispective study of adult and paediatric patients with haemoglobinopathies and rare anaemias registered in REHem was performed. The data are from a cross-sectional analysis performed on 1 June, 2023. The study population comprised 1,756 patients, of whom 1,317 had SCD, 214 had thalassaemia and 224 were diagnosed with another condition. Slightly more than one third of SCD patients (37%) were diagnosed based on neonatal bloodspot screening, and the mean age at diagnosis was 2.5 years; 71% of thalassaemia patients were diagnosed based on the presence of anaemia. Vaso-occlusive crisis and acute chest syndrome continue to be the most frequent complications in SCD. HSCT was performed in 83 patients with SCD and in 50 patients with thalassaemia. Since the previous publication, REHem-AR has grown in size by more than 500 cases. SCD and TM are less frequent in Spain than in other European countries, although the data show that rare anaemias are frequent within rare diseases. REHem-AR constitutes an important structure for following the natural history of rare anaemias and enables us to calculate investment needs for current and future treatments., (© 2024. The Author(s).)

Rare cancers are defined by low incidence rates, and may lack evidence that supports uniform standards of care and relevant clinical guidelines. Rare cancers may represent up to 24% of all cancers, yet remain understudied and underappreciated in terms of their clinical and ultimately societal impact. The PLOS Rare Cancer Collection brings together a broad range of research endeavors that are being undertaken in rare cancers research ranging from basic biological evaluations to therapeutic drug development. This Overview presents a brief background to the Collection and highlights the contributions of included articles., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mitesh J. Borad. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: With the advancement of next-generation sequencing, clinicians are now able to detect ultra-rare mutations that are barely encountered by the majority of physicians. Ultra-rare and rare diseases cumulatively acquire a prevalence equivalent to type 2 diabetes with 80% being genetic in origin and more prevalent among high consanguinity communities including Saudi Arabia. The challenge of these diseases is the ability to predict their prevalence and define clear phenotypic features., Methods: This is a non-interventional retrospective multicenter study. We included pediatric patients with a pathogenic variant designated as ultra-rare according to the National Institute for Clinical Excellence's criteria. Demographic, clinical, laboratory, and radiological data of all patients were collected and analyzed using multinomial regression models., Results: We included 30 patients. Their mean age of diagnosis was 16.77 months (range 3-96 months) and their current age was 8.83 years (range = 2-15 years). Eleven patients were females and 19 were males. The majority were of Arab ethnicity (96.77%). Twelve patients were West-Saudis and 8 patients were South-Saudis. SCN1A mutation was reported among 19 patients. Other mutations included SZT2, ROGDI, PRF1, ATP1A3, and SHANK3. The heterozygous mutation was reported among 67.86%. Twenty-nine patients experienced seizures with GTC being the most frequently reported semiology. The mean response to ASMs was 45.50% (range 0-100%)., Conclusion: The results suggest that ultra-rare diseases must be viewed as a distinct category from rare diseases with potential demographic and clinical hallmarks. Additional objective and descriptive criteria to detect such cases are needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Muthaffar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Rare cancers collectively account for a significant proportion of the overall cancer burden in Japan. We aimed to describe and examine the incidence of each rare cancer and the temporal changes using the internationally agreed rare cancer classification. Cancer cases registered in regional population-based cancer registries from 2011 to 2015 and the National Cancer Registry (NCR) from 2016 to 2018 were classified into 18 families, 68 Tier-1 cancer groupings, and 216 single cancer entities based on the RARECAREnet list. Crude incidence rates and age-standardized incidence rates (ASR) were calculated for Tier-1 and Tier-2 cancers. The annual percent change and the 95% and 99% confidence limits for annual ASR for each of the 68 Tier-1 cancers were estimated using the log-linear regression of the weighted least squares method. The differences in ASRs between 2011 and 2018 were evaluated as an absolute change. A total of 5,640,879 cases were classified into Tier-1 and Tier-2 cancers. The ASRs of 18 out of 52 Tier-1 cancers in the rare cancer families increased, whereas the ASR for epithelial tumors of gallbladder decreased. The ASRs of 6 out of the 16 Tier-1 cancers in the common cancer families increased, whereas those of epithelial tumors of stomach and liver decreased. There was no significant change in the incidence of the other 40 Tier-1 cancers. The incidence of several cancers increased due to the dissemination of diagnostic concepts, improved diagnostic techniques, changes in coding practice, and the initiation of the NCR., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Rare diseases affect over 300 million people worldwide and are gaining recognition as a global health priority. Their inclusion in the UN Sustainable Development Goals, the UN Resolution on Addressing the Challenges of Persons Living with a Rare Disease, and the anticipated WHO Global Network for Rare Diseases and WHO Resolution on Rare Diseases, which is yet to be announced, emphasise their significance. People with rare diseases often face unmet health needs, including access to screening, diagnosis, therapy, and comprehensive health care. These challenges highlight the need for awareness and targeted interventions, including comprehensive education, especially in primary care. The majority of rare disease research, clinical services, and health systems are addressed with specialist care. WHO Member States have committed to focusing on primary health care in both universal health coverage and health-related Sustainable Development Goals. Recognising this opportunity, the International Rare Diseases Research Consortium (IRDiRC) assembled a global, multistakeholder task force to identify key barriers and opportunities for empowering primary health-care providers in addressing rare disease challenges., Competing Interests: Declaration of interests PC is an employee of Medcan. HG receives grants or contracts from the European Commission and German Ministries for Health and Research; holds a leadership and fiduciary role as management team coordinating panel on rare neurological diseases, European Academy of Neurology; is a board member of association of German Centres for Rare Diseases; and is the chair of coordinators’ group of European Reference Networks. AG is an employee of Sanofi. SG is a volunteer and a board member of Every Life Foundation. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease with significant impact on morbidity, mortality, and quality of life. This study aimed to evaluate epidemiology, healthcare needs and related costs of pSS patients from the Italian National Health Service perspective., Methods: From the Fondazione Ricerca e Salute's database (∼5 million inhabitants/year), pSS prevalence in 2018 was calculated. Demographics, mean healthcare consumptions and direct costs at one year following index date (first in-hospital diagnosis/disease waiver claim) were analysed through an individual direct matched pair case-control analysis (age, sex, residency)., Results: In Italy, 3.8/10,000 inhabitants were identified as affected by pSS (1,746 case: 1,746 controls) in 2018. In the year following index date, 53.7% of cases and 42.7% of controls received ≥1 drug (p<0.001); mean per capita cost was €501 and €161, respectively (p<0.01). At least one hospitalization occurred to 7.8% of cases and 3.9% of controls (p<0.001) with mean per capita costs of €416 and €129, respectively (p = 0.46). At least one outpatient specialist service was performed in 49.8% of cases and 30.6% of controls (p<0.001); mean per capita costs were €200 and €75, respectively (p<0.01). Overall, mean annual costs were €1,171 per case and €372 per control (p < 0.01)., Conclusion: According to results of this population-based study, the prevalence of pSS in Italy appears to be consistent with the definition of rare disease. Patients with pSS have higher pharmacological, in-hospital and outpatient specialist care needs, leading to three-times higher overall cost for the INHS, compared to the general population., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Due to the COVID-19 pandemic, France underwent several lockdown periods during 2020. Our aim was to evaluate its clinical and social impact on lung transplant (LT) patients treated at Strasbourg University Hospital, by comparing three periods: first lockdown (T1: March-May 2020), end of the first lockdown (T2: May-October 2020), and second lockdown (T3: November-December 2020) and the incidence of COVID-19 infections. A cohort of patients with rare lung disease (RLD) was also studied during T2., Methods: We used clinical and paraclinical data collected during routine follow-up. A questionnaire was submitted to each patient at each period to assess their lifestyle, adherence to protective measures against COVID-19, contacts with their family and friends, and contagion risk. The incidence of new COVID-19 cases was also assessed., Results: Overall, 283 LT and 57 RLD patients were included. We observed only eight COVID-19 cases over the three periods (n = 4 during T1, n = 0 during T2, and n = 4 during T3) in LT patients, with 37.5 % of patients hospitalized, no ICU transfers, and 100 % favorable outcomes. No case of COVID-19 was diagnosed in the RLD cohort. When comparing the three periods in the LT group, fewer patients limited their out-of-home activities during T2 (p < 0.0001). The frequency of these activities increased after the first lockdown, for the purchase of basic necessities (p < 0.0001), and professional activity continued (p = 0.008). We observed a significant increase in unscheduled medical consultations and in the prescription of anti-infective treatments during the end of the lockdown (p = 0.0002 and p = 0.005, respectively). Adherence to lockdown and to protective measures was high in both groups of patients., Conclusion: COVID-19 incidence remained low in both groups and there were significant lifestyle evolutions in LT patients and in those with RLD between first and second lockdown., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Rare diseases (RD) are those that have a low prevalence in the population; ≈80% have a genetic origin, and to diagnose them it takes from 5 to 10 years, and they require evaluations from ≈10 specialists. There is no international consensus on the definition and number of RDs, which affects the availability of resources for their diagnosis, treatment, and research., Objective: To determine the prevalence of RDs in the Medical Genetics Service of a regional general hospital belonging to the Mexican Institute for Social Security (IMSS), in Puebla, Mexico., Material and Methods: The patients' records who were evaluated by the above-mentioned service from January 2019 to June 2022 were reviewed. Those patients with a diagnosis of a RD were identified, and the prevalence was obtained by using the formula: total number of cases of the disease/number of people in the population at that moment in time., Results: A total of 798 medical records were reviewed and a prevalence of RDs of 27% was obtained. Those diseases with a prevalence of 1 case per 2000 inhabitants were considered, being 118 different RD. Considering only the 20 rare diseases registered in Mexico in 2022, 11 of these were detected, distributed in 35 patients, with an estimated prevalence of 4.3%., Conclusion: The prevalence of RDs differs according to the criteria implemented. In Mexico, several diseases that fall within the definition of a RD based on their prevalence were not considered as such until 2022, so the recent recognition of rare diseases included by the World Health Organization will benefit affected patients., (Licencia CC 4.0 (BY-NC-ND) © 2024 Revista Médica del Instituto Mexicano del Seguro Social.)

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts., Competing Interests: Declaration of competing interest Adeline Vanderver and Laura Adang have received research support from IONIS pharmaceuticals, Takeda, Sanofi, Eli Lilly, Boehringer Ingelheim, Affinia and Orchard Therapeutics. In addition, Dr. Vanderver has received research support from Illumina, Sana, Passage Bio, Homology and PMD foundation. Dr. Adang from Biogen, MSD Foundation, Don't Forget Morgan, Legacy of Angels and Orphan Disease Center. Dr. Vanderver and Dr. Adang hold the license for the AGS Severity Scale and Dr. Vanderver the patent of ASO in TUBB4A. Dr. Vanderver participates on the advisory board of ELA and United Leukodystrophy Foundation. Dr. Adang is the scientific advisor for CureMLD, MLD Foundation, Don't Forget Morgan, Yaya Foundation and MLDi. Dr. Vanderver is a site Principal Investigator (PI) for Takeda Pharmaceutical's clinical trial for Metachromatic Leukodystrophy NCT03771898 and is an advisor to Passagebio. Dr. Adang also serves as an advisor to Biogen. Dr. Vanderver, Dr. Adang, Dr. Fatemi, Dr. Eichler, Dr. Bonkowsky, Dr. Fraser, Dr. Keller, Dr. Emrick and Dr. Van Haren are recipients of NIH funding through the NINDS (National Institute of Neurological Disorders and Stroke) and/or NCATS (National Center for Advancing Translational Sciences). Dr. Eichler is a recipient of grants through Kennedy Krieger Institute Inc. and Children's Hospital Corporation dba Boston Children's Hospital, and has <1% equity in Swan Bio, and royalties from AAV9 license for AMN. Dr. Eichler receives consulting fees from Leal Therapeutics, Swan Bio, Ionis, Minoryx, UptoDate, Origen, Takeda Therapeutics and Third Rock Ventures. Dr. Eichler is the founder and consultant of Swan Bio, is the ALD connect chair, and serves on the chair on the advisory board of European Leukodystrophy Association, board member at United Leukodystrophy Foundation, and as a scientific advisor for National Tay Sachs and Allied Diseases Association. Dr. Fatemi is a PI for Viking Therapeutics and Minoryx Therapeutics and receives research support from CureLBSL, Brian's Hope Foundation, SwanBio, Autobahn Therapeutics, Poxel Therapeutics, Vertex Pharmaceuticals, and Maryland Stem Cell Research Fund. Also, Dr. Fatemi was former Data and Safety Monitoring Board (DSMB) member for BlueBird Bio, and serves as the ALD Connect Board member. Dr. Fatemi co-invented a patent currently licensed to Ashvattha. All other authors have no conflicts of interest. Dr. Bonkowsky receives research support through grant from European Leukodystrophy Association, and consults for Ionis, Sanofi, Autobahn, Denali, Passage Bio, Bluebird, Calico. He also serves on the ALD connect board. Dr. Keller is the site PI for Ionis Pharmaceuticals Alexander Disease trial and Biomarin Pharmaceuticals Brineura extension study. Dr. Keller consults for Veristat and serves on United Leukodystrophy Foundation and Leukodystrophy Care Network Certified Center. Dr. Emrick serves on the advisory board for Ionis pharmaceuticals. Dr. Van Haren receives research support from United Leukodystrophy Foundation and Stanford MCHRI. He consults for Bluebird Bio, Poxel, Autobahn Therapeutics and Viking, and has participated in the Calico Board. He also serves in the leadership capacity at ALD connect, United Leukodystrophy Foundation and Global Leukodystrophy Alliance. All other authors have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Children's rare lung diseases are a heterogeneous group of rare lung diseases with significant morbidity and mortality. There is very limited information on the incidence and prevalence of children's rare lung diseases in Asia. We investigated the nationwide incidence, prevalence, and pattern of medical service utilization of children's rare lung diseases in Korea., Methods: We studied patients who were diagnosed with rare lung diseases coded per International Statistical Classification of Diseases and Related Health Problems, 10th Edition and registered in the national rare diseases database of confirmed patients. Data was extracted from the Korean National Health Insurance Service Claims database over 2019-2021., Results: Average incidence rate was 12.9 new cases per million children per year, and average prevalence rate was 60.2 cases per million children during the study period of 2019-2021. We found that more than 65% of new cases were diagnosed before 2 years of age. ChILD, primary ciliary dyskinesia, and cystic fibrosis were usually diagnosed after 6 years of age. Congenital airway and lung anomalies were often diagnosed before 2 years of age. Busan and Gyeongsangnam-do residents tended to visit hospitals near their place of residence, while residents of other areas tended to visit hospitals in Seoul regardless of their area of residence., Conclusions: We examined the epidemiology of rare lung diseases in children in South Korea. Our estimation of the incidence and prevalence could be used for sustainable health care and equitable distribution of health care resources., (© 2024 Wiley Periodicals LLC.)

Illnesses that afflict a tiny number of individuals are referred to as rare diseases (RDs), sometimes called orphan diseases. The local healthcare systems are constantly under financial, psychological, and medical strain due to low incidence rates, unusual presentations, flawed diagnostic standards, and a lack of treatment alternatives for these RDs. The effective management of the once widely spread viral hepatitis B and C has altered the spectrum of liver diseases in Egypt during the last several years. The detection of uncommon disorders such as autoimmune, cholestatic, and hereditary liver diseases has also been made easier by the increasing knowledge and greater accessibility of specific laboratory testing. Finally, despite Egypt's large population, there are more uncommon liver disorders than previously thought. This review article discusses the clinical and epidemiological characteristics of a few uncommon liver disorders and the information currently accessible concerning these illnesses in Egypt., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Purpose: In rare diseases, real-world evidence (RWE) generation is often restricted due to small patient numbers and global geographic distribution. A federated data network (FDN) approach brings together multiple data sources harmonized for collaboration to increase the power of observational research. In this paper, we review how to increase reproducibility and transparency of RWE studies in rare diseases through disease-specific FDNs., Method: To be successful, a multiple stakeholder scientific FDN collaboration requires a strong governance model in place. In such a model, each database owner remains in full control regarding the use of and access to patient-level data and is responsible for data privacy, ethical, and legal compliance. Provided that all this is well documented and good database descriptions are in place, such a governance model results in increased transparency, while reproducibility is achieved through data curation and harmonization, and distributed analytical methods., Results: Leveraging the OHDSI community set of methods and tools, two rare disease-specific FDNs are discussed in more detail. For multiple myeloma, HONEUR-the Haematology Outcomes Network in Europe-has built a strong community among the data partners dedicated to scientific exchange and research. To advance scientific knowledge in pulmonary hypertension (PH) an FDN, called PHederation, was established to form a partnership of research institutions with PH databases coming from diverse origins., (© 2024 Actelion Pharmaceuticals Ltd. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Rare genetic diseases affect 5-8% of the population but are often undiagnosed or misdiagnosed. Electronic health records (EHR) contain large amounts of data, which provide opportunities for analysing and mining. Data mining, in the form of cluster analysis and visualisation, was performed on a database containing deidentified health records of 1.28 million patients across 3 major hospitals in Singapore, in a bid to improve the diagnostic process for patients who are living with an undiagnosed rare disease, specifically focusing on Fabry Disease and Familial Hypercholesterolaemia (FH). On a baseline of 4 patients, we identified 2 additional patients with potential diagnosis of Fabry disease, suggesting a potential 50% increase in diagnosis. Similarly, we identified > 12,000 individuals who fulfil the clinical and laboratory criteria for FH but had not been diagnosed previously. This proof-of-concept study showed that it is possible to perform mining on EHR data albeit with some challenges and limitations., (© 2024. The Author(s).)

Background: Lipodystrophy is a relatively rare, complex disease characterised by a deficiency of adipose tissue and can present as either generalised lipodystrophy (GLD) or partial lipodystrophy (PLD). The prevalence of this disease varies by region. This study aimed to identify the genetic variations associated with lipodystrophy in the southern part of Saudi Arabia., Methodology:  We conducted a retrospective study by recruiting nine patients from six families, recruiting the proband whole exome sequencing results or any other genetic test results, screening other family members using Sanger sequencing and analysing the carrier status of the latter. These patients were recruited from the Endocrinology and Diabetes Clinic at Jazan General Hospital and East Jeddah Hospital, both in the Kingdom of Saudi Arabia., Result: Eight patients were diagnosed with GLD, and one was diagnosed with PLD. Of the six families, four were consanguineously married from the same tribe, while the remaining belonged to the same clan. The majority of GLD patients had an AGPAT2 c.158del mutation, but some had a BSCL2 c.942dup mutation. The single PLD case had a PPARG c.1024C > T mutation but no family history of the disease. In all families evaluated in this study, some family members were confirmed to be carriers of the mutation observed in the corresponding patient., Conclusion:  Familial screening of relatives of patients with rare, autosomal recessive diseases, such as lipodystrophy, especially when there is a family history, allows the implementation of measures to prevent the onset or reduced severity of disease and reduces the chances of the pathogenic allele being passed onto future generations. Creating a national registry of patients with genetic diseases and carriers of familial pathogenic alleles will allow the assessment of preventive measures and accelerate disease intervention via gene therapy., (© 2024. The Author(s).)

Background: With more than 103 million cases and 1.1 million deaths, the COVID-19 pandemic has had devastating consequences for the health system and the well-being of the entire US population. The Rare Diseases Clinical Research Network funded by the National Institutes of Health was strategically positioned to study the impact of the pandemic on the large, vulnerable population of people living with rare diseases (RDs)., Objective: This study was designed to describe the characteristics of COVID-19 in the RD population, determine whether patient subgroups experienced increased occurrence or severity of infection and whether the pandemic changed RD symptoms and treatment, and understand the broader impact on respondents and their families., Methods: US residents who had an RD and were <90 years old completed a web-based survey investigating self-reported COVID-19 infection, pandemic-related changes in RD symptoms and medications, access to care, and psychological impact on self and family. We estimated the incidence of self-reported COVID-19 and compared it with that in the US population; evaluated the frequency of COVID-19 symptoms according to self-reported infection; assessed infection duration, complications and need for hospitalization; assessed the influence of the COVID-19 pandemic on RD symptoms and treatment, and whether the pandemic influenced access to care, special food and nutrition, or demand for professional psychological assistance., Results: Between May 2, 2020, and December 15, 2020, in total, 3413 individuals completed the survey. Most were female (2212/3413, 64.81%), White (3038/3413, 89.01%), and aged ≥25 years (2646/3413, 77.53%). Overall, 80.6% (2751/3413) did not acquire COVID-19, 2.08% (71/3413) acquired it, and 16.58% (566/3413) did not know. Self-reported cases represented an annual incidence rate of 2.2% (95% CI 1.7%-2.8%). COVID-19 cases were more than twice the expected (71 vs 30.3; P<.001). COVID-19 was associated with specific symptoms (loss of taste: odds ratio [OR] 38.9, 95% CI 22.4-67.6, loss of smell: OR 30.6, 95% CI 17.7-53.1) and multiple symptoms (>9 symptoms vs none: OR 82.5, 95% CI 29-234 and 5-9: OR 44.8, 95% CI 18.7-107). Median symptom duration was 16 (IQR 9-30) days. Hospitalization (7/71, 10%) and ventilator support (4/71, 6%) were uncommon. Respondents who acquired COVID-19 reported increased occurrence and severity of RD symptoms and use or dosage of select medications; those who did not acquire COVID-19 reported decreased occurrence and severity of RD symptoms and use of medications; those who did not know had an intermediate pattern. The pandemic made it difficult to access care, receive treatment, get hospitalized, and caused mood changes for respondents and their families., Conclusions: Self-reported COVID-19 was more frequent than expected and was associated with increased prevalence and severity of RD symptoms and greater use of medications. The pandemic negatively affected access to care and caused mood changes in the respondents and family members. Continued surveillance is necessary., (©Maurizio Macaluso, Marc E Rothenberg, Thomas Ferkol, Pierce Kuhnell, Henry J Kaminski, David W Kimberlin, Michael Benatar, Mirna Chehade, The Principal Investigators of the Rare Diseases Clinical Research Network – Cycle 4. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 14.02.2024.)

Every year on February 28, the global community comes together to observe Rare Disease Day, a day dedicated to raising awareness and understanding for the millions of individuals who live with rare disorders. While individual rare diseases may seem uncommon, their collective impact is significant, affecting the lives of countless families and communities worldwide. This day serves as a crucial platform to amplify the voices of those affected, advocate for increased research and support, and inspire hope for a future where rare diseases can be prevented, diagnosed earlier, and effectively treated., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)