AMIA Annu Symp Proc. 2025 May 22;2024:1275-1283. eCollection 2024.

ABSTRACT

Large language models (LLMs) have shown great promise in clinical medicine, but their adoption in real-world settings has been limited by their tendency to generate incorrect and sometimes even toxic statements. This study presents a reliable rare disease intelligent agent called RDguru, which incorporates authoritative and reliable knowledge sources and tools into the reasoning and response of LLMs. In addition to answering questions about rare diseases more accurately, RDguru can conduct medical consultations to provide differential diagnosis decision support for clinical users. The DQN-based multi-source fusion diagnostic model integrates three diagnostic recommendation strategies, GPT-4, PheLR, and phenotype matching. Testing on 238 real rare disease cases showed that RDguru's top 10 list of recommended diagnoses was able to recall 69.1% of real diagnoses, the top 5 recommended diagnoses were able to recall 63.6% of real diagnoses, and the top ranked diagnosis was able to achieve an accuracy rate of 41.9%.

PMID:40417483 | PMC:PMC12099370

Drug Des Devel Ther. 2025 May 20;19:4201-4220. doi: 10.2147/DDDT.S506112. eCollection 2025.

ABSTRACT

OBJECTIVE: This study analyzes the current research landscape and trends in orphan drug development, providing insights for future advancements in the field.

METHODS: Gathering pertinent material from the China National Knowledge Infrastructure (CNKI) and Web of Science databases. Microsoft Office Excel 2017, VOSview 1.6.20, and CiteSpace 6.3R2 were utilised to summarise the present research state and offer insights into research hotspots in the domain of orphan drugs.

RESULTS: A total of 3598 research papers were included, with Chinese research showing a continuous upward trend, while international research has entered a slow development stage. The field of orphan drug research has formed a sizable research team, and cooperation between international institutions is relatively mature. Meanwhile, the United States and the United Kingdom have strong influence in this research field, while China lacks international cooperation. The research focus in this field mainly involves the development and clinical application of orphan drugs, and domestic and foreign research also has its own emphasis. Maintain consistency in clinical trials and medication support for orphan drugs both domestically and internationally; And foreign research has obvious advantages in the development of orphan drugs. Keyword emergence research indicates that the clinical accessibility and regulatory approval of orphan drugs have become a prominent issue of interest both nationally and globally.

CONCLUSION: This study systematically summarises and examines the current research status and emerging trends in the global orphan drug sector by analysing relevant literature from 2000 to 2024 through bibliometric methods. It further delineates the similarities and differences in orphan drug research domestically and internationally, offering valuable references for future investigations in this domain.

PMID:40416799 | PMC:PMC12103199 | DOI:10.2147/DDDT.S506112

Genome Med. 2025 May 22;17(1):58. doi: 10.1186/s13073-025-01467-z.

ABSTRACT

BACKGROUND: Only half of individuals with suspected rare diseases receive a genetic diagnosis following genomic testing. A genetic diagnosis allows access to appropriate care, restores reproductive confidence and reduces the number of potentially unnecessary interventions. A major barrier is the lack of disease agnostic functional tests suitable for implementation in routine diagnostics that can provide evidence supporting pathogenicity of novel variants, especially those refractory to RNA sequencing.

METHODS: Focusing on mitochondrial disease, we describe an untargeted mass-spectrometry based proteomics pipeline that can quantify proteins encoded by > 50% of Mendelian disease genes and > 80% of known mitochondrial disease genes in clinically relevant sample types, including peripheral blood mononuclear cells (PBMCs). In total we profiled > 90 individuals including undiagnosed individuals suspected of mitochondrial disease and a supporting cohort of disease controls harbouring pathogenic variants in nuclear and mitochondrial genes. Proteomics data were benchmarked against pathology accredited respiratory chain enzymology to assess the performance of proteomics as a functional test. Proteomics testing was subsequently applied to individuals with suspected mitochondrial disease, including a critically ill infant with a view toward rapid interpretation of variants identified in ultra-rapid genome sequencing.

RESULTS: Proteomics testing provided evidence to support variant pathogenicity in 83% of individuals in a cohort with confirmed mitochondrial disease, outperforming clinical respiratory chain enzymology. Freely available bioinformatic tools and criteria developed for this study ( https://rdms.app/ ) allow mitochondrial dysfunction to be identified in proteomics data with high confidence. Application of proteomics to undiagnosed individuals led to 6 additional diagnoses, including a mitochondrial phenocopy disorder, highlighting the disease agnostic nature of proteomics. Use of PBMCs as a sample type allowed rapid return of proteomics data supporting pathogenicity of novel variants identified through ultra-rapid genome sequencing in as little as 54 h.

CONCLUSIONS: This study provides a framework to support the integration of a single untargeted proteomics test into routine diagnostic practice for the diagnosis of mitochondrial and potentially other rare genetic disorders in clinically actionable timelines, offering a paradigm shift for the functional validation of genetic variants.

PMID:40400026 | DOI:10.1186/s13073-025-01467-z

Curr Rheumatol Rep. 2025 May 21;27(1):24. doi: 10.1007/s11926-025-01189-6.

ABSTRACT

PURPOSE OF THIS REVIEW: Rare diseases, although individually infrequent, collectively impact a substantial number of people. Collaborative translational research using biospecimens is essential for advancing our understanding of the diverse characteristics and pathophysiology of rare diseases. Biobanks play a pivotal role in this endeavor by collecting, processing, transporting, and storing biospecimens, thereby serving as invaluable resources for medical research. In this review, we explore currently available biobanks, with a specific focus on those dedicated to rare rheumatic diseases. We also examine accessible best practice guidelines for establishing and maintaining high-quality biobanks, discuss the limitations and propose future directions for enhancing biobanking efforts in rare disease research.

RECENT FINDINGS: Advances in molecular and genomic technologies have expanded the role of biobanks, enhancing biomarker discovery and precision medicine. However, despite growth in biobanking capabilities, key challenges persist concerning ethics, interoperability, and biospecimen exchange, prompting active responses by various regulatory and governing bodies. Biobanking has transformed rare disease research. Strengthening national and international collaborations is essential for driving progress in this field and accelerating the development of novel therapeutic and precision medicine approaches.

PMID:40397074 | DOI:10.1007/s11926-025-01189-6

Dtsch Med Wochenschr. 2025 Jun;150(12):703-712. doi: 10.1055/a-2145-7495. Epub 2025 May 19.

ABSTRACT

Bronchiectasis is a worldwide inflammatory disease with different epidemiology and heterogenous etiology. The disease burden is high for patients and economic costs can be immense. So far there are no special disease modifying drugs available for patients with bronchiectasis other than cystic fibrosis. With rising numbers of newly diagnosed patients (prevalence 120/100000 in Germany) due to different reasons (idiopathic, postinfectious, genetic, asthma, COPD etc.) the awareness for this once called orphan disease should rise - not only among pulmonologists but also among general care practitioners. This article focuses on diagnostic algorithms and multimodal treatment options based on the latest studies and the recently published German bronchiectasis guideline from May 2024. It outlines what general care practitioners can do for their patients, what they should consider when treating an exacerbation and that special surveillance of these patients is needed in centers with expertise in this disease due to its complexity. With upcoming treatment options just as disease modifying drugs like DDP-1 inhibitors or inhaled antibiotics one can expect a change in disease treatment and outcome. Therefore, it is more and more important to raise awareness for bronchiectasis starting at the very basis when patients present at their general care practitioner with recurring productive cough, exacerbations, and further cardinal symptoms of bronchiectasis disease.

PMID:40388981 | DOI:10.1055/a-2145-7495

Am J Manag Care. 2025 May;31(5):240-244. doi: 10.37765/ajmc.2025.89673.

ABSTRACT

OBJECTIVES: To quantify the magnitude of altruism value as applied to a hypothetical new treatment for a rare, severe pediatric disease: Duchenne muscular dystrophy (DMD).

STUDY DESIGN: Prospective survey of individuals not planning to have children in the future.

METHODS: A survey was administered to US adults (aged ≥ 21 years) not intending to have a child in the future to elicit willingness to pay (WTP) for government insurance coverage for a new hypothetical DMD treatment that improves mortality and morbidity relative to the current standard of care. A multiple random staircase design was used to identify an indifference point between status quo government insurance coverage and coverage with additional cost in taxes that would cover the treatment if unrelated individuals had a child with DMD. Altruism value was calculated as respondents' mean WTP.

RESULTS: Among 215 respondents, 54.9% (n = 118) were aged 25 to 44 years and 80.0% (n = 172) were women. Mean WTP for insurance coverage of the hypothetical DMD treatment for others was $80.01 (95% CI, $41.64-$118.37) annually, or $6.67 monthly, after adjustment to account for disease probability overestimation. The adjusted altruism value was higher than the ex ante per-person value using traditional cost-effectiveness approaches ($45.30/year). Without adjusting, individuals were willing to pay $799.11 annually ($66.59 monthly).

CONCLUSIONS: Despite no possibility of accruing health benefits directly for themselves or their children, individuals had a high WTP for government insurance coverage of a novel treatment for this rare, severe pediatric disease.

PMID:40387711 | DOI:10.37765/ajmc.2025.89673

Biotechnol Lett. 2025 May 17;47(3):56. doi: 10.1007/s10529-025-03596-2.

ABSTRACT

Orphan diseases comprise a range of disorders that individually affect a small percentage of people, but collectively impact millions of people worldwide. Patients with this disorder often face significant challenges in diagnosis, treatment, and access to care due to their rare nature and limited understanding and treatment options. In recent years, significant advancements have been made in the global healthcare in addressing the accessibility of essential treatments and medicines, but still challenges persist particularly related to orphan drugs (to treat rare diseases) in the developing world. The accessibility of orphan drugs remains a major challenge, where patients face barriers such as high costs, limited availability, and inadequate healthcare infrastructure. The high cost associated with orphan drugs presents a barrier to affordability for both patients and healthcare systems, causing disparities in access to life-saving treatments. The molecular farming approach utilizing plant-based production systems for recombinant protein production offers a hope for overcoming barriers to orphan drug access in resource-constrained settings. Molecular farming has the potential to produce a wide range of therapeutic proteins and biologics for the treatment of various rare diseases. The FDA approval of plant-derived proteins for the treatment of Gaucher disease (Elelyso) and Fabry disease (Elfabrio) highlights the potential of plant-based expression systems for the development of suitable drugs targeting niche and orphan diseases. This review examines the potential of the plant system in producing orphan drugs and also highlights the opportunities and challenges related to orphan drug manufacturing.

PMID:40381123 | DOI:10.1007/s10529-025-03596-2

Stud Health Technol Inform. 2025 May 15;327:1270-1274. doi: 10.3233/SHTI250602.

ABSTRACT

Electronic Health Records (EHRs) provide valuable longitudinal data for tracking disease progression, especially in rare diseases like ciliopathies which often involve chronic renal decline. While important biomarkers are available in structured databases, crucial information such as external lab tests and detailed disease history may only be found in clinical narratives. This study aims to enrich structured datasets with unstructured clinical text and assess its impact on estimating chronic kidney disease progression in ciliopathy patients. Our results demonstrate that data enrichment increased the number of eligible patients for longitudinal analysis by 73.5%, expanded available measurements by 189%, and significantly extended the median follow-up duration from 3.2 to 6.6 years. Using linear mixed regression to model individual estimated glomerular filtration (eGFR) rate trajectories over age, we found that data enrichment reduced standard errors by 30%, indicating a substantial increase in precision and reliability. These findings underscore the value of EHR data enrichment for longitudinal analysis in rare disease research.

PMID:40380706 | DOI:10.3233/SHTI250602

Stud Health Technol Inform. 2025 May 15;327:123-127. doi: 10.3233/SHTI250286.

ABSTRACT

Rare diseases, while individually rare, cumulatively affect a large population, and patients often undergo long and arduous diagnostic odysseys. Toward the goal of supporting earlier diagnosis of rare diseases, we developed generalizable methods of extracting rare diseases and phenotypes from structured electronic health records and clinical notes. We analyzed the distributions of the age of onset of phenotypes per disease to identify disease-phenotype associations, producing a dataset with over 500 thousand associations covering 2300 rare diseases. Disease-phenotype associations are characterized by disease prevalence and mean age of onset of the phenotype to aid phenotype selection according to the priorities of the clinical decision support task.

PMID:40380398 | DOI:10.3233/SHTI250286

Stud Health Technol Inform. 2025 May 15;327:32-36. doi: 10.3233/SHTI250268.

ABSTRACT

Rare diseases are challenging to diagnose and collectively affect a large fraction of the population. This work sought to develop an approach to generate models for probabilistic reasoning focused on the presence of a specified phenotypic abnormality. The approach generates a Bayesian network, a graphical AI model that uses probability to reason under uncertainty, that includes all diseases that can cause the specified abnormality as well as all phenotypic abnormalities caused by those diseases. The approach efficiently computes the probabilities of the possible diagnoses and evaluates the impact of additional evidence. One can use the model to identify the observations that yield the greatest information to reduce uncertainty. An example model for diagnosis of a finding of enlarged kidney is presented to demonstrate the feasibility and advantages of the approach. Further work includes incorporation of age of onset and inheritance pattern of the diseases, hierarchical relationships among diseases and phenotypic abnormalities to allow diagnosis based on information at varying levels of granularity, and user interfaces to simplify interaction with the models.

PMID:40380380 | DOI:10.3233/SHTI250268

Recenti Prog Med. 2025 May;116(5):310-321. doi: 10.1701/4495.44951.

ABSTRACT

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a rare disease that causes a progressive loss of muscle function in males, presenting at the age of two years, and involving respiratory and heart function starting from teenage years. This retrospective observational study has identified patients potentially affected by DMD and described their utilization of healthcare resources and direct healthcare costs charged to the Italian National Healthcare Service (INHS).

METHODS: From the Foundation Ricerca e Salute (ReS), through a specific algorithm based only on administrative healthcare data of 5.4 million inhabitants in 2021 (index date), male patients aged <30 years potentially affected by DMD were identified. Comorbidities at baseline, and utilization of healthcare resources and direct healthcare costs charged to the INHS during the year following index date, were described.

RESULTS: In 2021, 120 male patients aged <30 years were identified as potentially affected with DMD (2.2/100,000 inhabitants; 16.1/100,000 males aged <30 years). Chronic airway disease and cardiomyopathy were found in 19.2% and 15.0% of patients, respectively. During follow-up: 41.7% of patients were treated with deflazacort, 2.5% with ataluren and about one third with cardiac drugs; 29.2% and 42.5% were admitted to overnight and day hospitalization, respectively, mainly due to neurological, cardiac, and respiratory diseases; 12.5% accessed the emergency department, mainly for traumatisms and fractures; 70.8% received local outpatient specialist care, half of which were specialist visits, and about 15% cardiac diagnostics. On average, the per capita annual total cost charged to the -INHS was € 6713; ataluren accounted for more than half of this expenditure. After having excluded the dispensation of ataluren during follow-up, the mean per capita total cost was € 2548, more than half of which due to hospitalizations.

CONCLUSIONS: This study of administrative data has identified patients potentially affected by DMD, a rare disease, from a large sample of INHS beneficiaries, and assessed their healthcare pathway. This is useful for regulatory purposes and for improved access to emerging innovative therapies.

PMID:40376903 | DOI:10.1701/4495.44951

Fam Process. 2025 Jun;64(2):e70041. doi: 10.1111/famp.70041.

ABSTRACT

Parents caring for children with rare diseases are more impaired regarding health-related quality of life (HRQoL) and mental health than healthy controls and norm data. To address the research gap in psychological care for these parents, this study evaluates the effectiveness of two family-based interventions. The children affected by rare disease and their families network (CARE-FAM-NET) study is a multicenter randomized controlled 2 × 2 factorial trial for affected families with children (0-21 years). This paper focuses on evaluating the impact of two interventions, one face-to-face (CARE-FAM) and one online (WEP-CARE), on the HRQoL and mental health of parents. One thousand, one hundred sixty-eight parents participated: TAU = 291, CARE-FAM = 296, WEP-CARE = 300, and CARE-FAM + WEP-CARE combined = 281. Data were collected at four time points over a period of 18 months using standardized questionnaires. The results had to be interpreted exploratively. The results indicate that there are no clinically relevant differences in the parents' HRQoL and mental health between the treatment groups. However, time-dependent differences in the intervention effects for WEP-CARE were observed. Although the results did not show clear relevant differences between conditions, trends in improvement in HrQoL and mental health were identified. CARE-FAM shows a greater reduction in parental distress and WEP-CARE shows a greater distortion of distress, particularly at T3 and T4. Given the exploratory nature of this study, it highlights the urgent need for further confirmatory research in this area.

PMID:40375458 | DOI:10.1111/famp.70041

Orphanet J Rare Dis. 2025 May 15;20(1):231. doi: 10.1186/s13023-025-03692-6.

ABSTRACT

BACKGROUND: Genomic newborn screening (gNBS) offers the potential to detect genetic conditions early, enhancing outcomes through timely treatment. It can serve as an additional tool to identify conditions that are not detectable via metabolic screening. The Screen4Care project seeks to develop a systematic approach for selecting treatable rare diseases (RDs) for inclusion in gNBS through the creation of the TREAT-panel.

METHODS: A set of six selection criteria containing treatability, clinical validity, age of onset, disease severity, penetrance, and genetic feasibility was applied to a comprehensive list of gene-disease pairs. Genes meeting a defined threshold score were included in the TREAT-panel. This automated scoring process was complemented by expert review from clinicians and patient representatives to ensure clinical relevance and adherence to current medical guidelines.

RESULTS: The initial gene list, derived from multiple data sources, included 484 gene-disease pairs. After applying the scoring system and two rounds of expert curation, a final list of 245 genes was selected. These genes predominantly represent disorders in metabolic, neurological, and immunological categories, with treatability and early disease onset as key inclusion factors.

CONCLUSION: The Screen4Care TREAT-panel provides a curated, scientifically robust gene set for gNBS, focusing on treatable RDs with early onset and clinical actionability. The panel will be tested in a European pilot project involving approximately 20,000 newborns, contributing to the growing body of evidence for the implementation of next-generation sequencing (NGS) in newborn screening programs.

PMID:40375093 | DOI:10.1186/s13023-025-03692-6

Orphanet J Rare Dis. 2025 May 15;20(1):230. doi: 10.1186/s13023-025-03674-8.

ABSTRACT

The traditional process of intercultural adaptation, while suitable for one or a few target languages, is not optimal for developing instruments for rare connective tissue diseases (CTDs) in multiple languages simultaneously. The European Reference Network ReCONNET presents the protocol for a novel methodology for cross-cultural adaptation of instruments for research and care in the context of rare CTDs (ReCONNET-CROSSADAPT). It is initiated by the identification of 'key-terms' that are crucial for maintaining the original meaning of the source document. Each language group, led by a senior member and two collaborators, independently assesses the existence and equivalence of these key terms in target languages. Reconciliation meetings are held to establish agreed-upon terms for consistent usage across translations when difficulties arise with key-terms. Subsequently, each language group translates the source document, followed by a reconciliation meeting involving one CTD patient in each group. The purpose of this meeting is to address potential discrepancies among translations, ensuring a comprehensive assessment from a linguistic, cultural and patient perspective. Collective feedback and consensus-based decision-making guide the resolution process. This methodology eliminates the need for backward translation, optimizing time and cost utilization. This new ReCONNET-CROSSADAPT methodology ensures linguistic accuracy, cultural relevance, and contextual appropriateness for the cross-cultural adaptation of instruments for research and care in the context of rare CTDs.

PMID:40375068 | DOI:10.1186/s13023-025-03674-8

Eur J Hum Genet. 2025 May 15. doi: 10.1038/s41431-025-01863-4. Online ahead of print.

ABSTRACT

WD40 and SOCS box protein-2 (WSB2), a member of the large family of suppressor of cytokine signaling (SOCS)-box proteins, has recently been identified as a substrate receptor of cullin 5 E3 ligase that plays an important role in proteomic regulation through substrate ubiquitination and proteasomal degradation. Here we report five patients from four unrelated families presenting with neurodevelopmental delay, dysmorphic features, brain structural abnormalities with or without growth restriction, hypotonia, and microcephaly, all of whom are homozygous for extremely rare and predicted loss-of-function (pLoF) or missense variants in WSB2, inherited from consanguineous parents. The Wsb2-mutant mice exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina. Our findings suggest that homozygous LoF WSB2 variants cause a novel neurodevelopmental disorder in humans with similar neurologic and developmental findings seen in Wsb2-mutant mouse models.

PMID:40374945 | DOI:10.1038/s41431-025-01863-4

Fam Syst Health. 2025 Mar;43(1):173. doi: 10.1037/fsh0000910.

ABSTRACT

This short 55-word story highlights a clinical psychology doctoral student's work in therapy with individuals diagnosed with rare diseases. Upon diagnosis, clients may experience a range of emotions and feel isolated. Connection with a social network and support can increase hope and promote well-being. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

PMID:40372839 | DOI:10.1037/fsh0000910

Int J Mol Sci. 2025 Apr 25;26(9):4072. doi: 10.3390/ijms26094072.

ABSTRACT

The growing availability of protein structural data from experimental methods and accurate predictive models provides the opportunity to investigate the molecular origins of rare diseases (RDs) reviewed in the Orpha.net database. In this study, we analyzed the topology of 5728 missense mutation sites involved in Mendelian RDs (MRDs), forming the basis of our structural bioinformatics investigation. Each mutation site was characterized by side-chain position within the overall 3D protein structure and side-chain orientation. Atom depth quantitation, achieved by using SADIC v2.0, allowed the classification of all the mutation sites listed in our database. Particular attention was given to mutations where smaller amino acids replaced bulky, outward-oriented residues in the outer structural layers. Our findings reveal that structural features that could lead to the formation of void spaces in the outer protein region are very frequent. Notably, we identified 722 cases where MRD-associated mutations could generate new surface pockets with the potential to accommodate pharmaceutical ligands. Molecular dynamics (MD) simulations further supported the prevalence of cryptic pocket formation in a subset of drug-binding protein candidates, underscoring their potential for structure-based drug discovery in RDs.

PMID:40362311 | DOI:10.3390/ijms26094072

Int J Mol Sci. 2025 May 4;26(9):4367. doi: 10.3390/ijms26094367.

ABSTRACT

The scarcity of robust models and therapeutic options for rare diseases continues to hamper their preclinical investigation. Traditional animal models and two-dimensional cell cultures are limited in their ability to replicate human heredity-associated traits and complex pathological features. Organoids-on-a-chip approaches open up new frontiers in rare-disease research via the integration of organ chips and organoid technology. This integrative strategy offers immense opportunities for the mimicry of disease-related traits, the clarification of the mechanisms underlying disease, and the prediction of treatment responses in a highly human-related manner. This forward-looking perspective suggests organoids on chips are transformative tools for parsing rare-disease pathogenesis, accelerating therapeutic discovery, and bridging the gap between basic research and precision medicine.

PMID:40362604 | DOI:10.3390/ijms26094367

Nat Commun. 2025 May 13;16(1):4449. doi: 10.1038/s41467-025-59478-8.

ABSTRACT

Artificial intelligence applications in oncology imaging often struggle with diagnosing rare tumors. We identify significant gaps in detecting uncommon thyroid cancer types with ultrasound, where scarce data leads to frequent misdiagnosis. Traditional augmentation strategies do not capture the unique disease variations, hindering model training and performance. To overcome this, we propose a text-driven generative method that fuses clinical insights with image generation, producing synthetic samples that realistically reflect rare subtypes. In rigorous evaluations, our approach achieves substantial gains in diagnostic metrics, surpasses existing methods in authenticity and diversity measures, and generalizes effectively to other private and public datasets with various rare cancers. In this work, we demonstrate that text-guided image augmentation substantially enhances model accuracy and robustness for rare tumor detection, offering a promising avenue for more reliable and widespread clinical adoption.

PMID:40360460 | DOI:10.1038/s41467-025-59478-8

Orphanet J Rare Dis. 2025 May 10;20(1):222. doi: 10.1186/s13023-025-03751-y.

ABSTRACT

PURPOSE: Patients with rare diseases often undergo a long diagnostic odyssey. However, there is little empirical evidence on the cost incurred during the diagnostic pathway for patients with suspected rare diseases. This study provides a comprehensive analysis of healthcare costs and utilization during the diagnostic pathway for a heterogeneous sample of patients with suspected rare diseases but unclear diagnosis.

METHODS: Using claims data from five German statutory health insurance organizations for the years 2014-2019, we analyzed costs and healthcare utilization of 1,243 patients (aged 0 to 82 years) with suspected rare diseases referred to a rare disease center. A control cohort was assigned using 1:75 exact matching on age, sex and place of residence.

RESULTS: In the years prior to referral to an expert center, healthcare utilization of patients with suspected rare diseases was, on average, substantially and significantly higher compared to a matched control cohort during the same observation period - e.g. in terms of the number of hospitalizations (3.1 (95%CI: 2.9-3.4) vs. 0.5 (95%CI: 0.5-0.5)), different diagnoses (50.0 (95%CI: 48.1-51.9) vs. 26.4 (95%CI: 26.2-26.5)), different active substances prescribed (12.7 (95%CI: 12.2-13.3) vs. 8.2 (95%CI: 8.2-8.3)) and the number of genetic tests (14.7 (95%CI: 12.6-16.7) vs. 0.3 (95%CI: 0.3-0.3)). We found evidence of heterogeneity in utilization by age and sex. On average, direct costs (inpatient, outpatient and prescription drug costs) of patients with suspected rare diseases during the diagnostic pathway were 7.6-fold higher than the costs of matched controls (€26,999 (95%CI: €23,751 - 30,247) vs. €3,561 (95% CI: € 3,455-3,667)). Inpatient costs were the main cost component, accounting for 62.5% of total costs.

CONCLUSIONS: The diagnostic odyssey of patients with suspected rare diseases is associated with extensive healthcare utilization and high cost. Against this background, new ways to shorten the diagnostic journey have a high potential to decrease the financial burden related to rare diseases.

PMID:40349051 | DOI:10.1186/s13023-025-03751-y