Rev Salud Publica (Bogota). 2023 Jul 1;25(4):107594. doi: 10.15446/rsap.V25n4.107594. eCollection 2023 Aug.

ABSTRACT

OBJECTIVE: To analyze the reports of orphan diseases in Bogotá, in order to describe the epidemiological profile, based on the cases reported to the Public Health System (Sivigila), from January 2019 to March 2022.

METHODS: A descriptive and cross-sectional study was carried out in which the cases reported to Sivigila in Bogotá were analyzed in the period between January 2019 and March 2022. Absolute and relative frequencies, frequency distribution and prevalences and averages of different variables were calculated. notified in the notification sheets.

RESULTS: From January 2019 to March 2022, 10,399 patients with orphan diseases have been notified to Sivigila in Bogotá, of which 56.25% (5,849) are female and 43.75% (4,550) are female. male sex. 87.10% (9,060) of the cases belong to the contributory regime. The town with the highest number of reports was Suba with 15.85% (1,294). The most reported orphan diseases were: multiple sclerosis with 13.1% (1,363), amyotrophic lateral sclerosis with 4.04% (421) and Guillain-Barre syndrome with 3.6% (374). A patient with an orphan disease in Bogotá takes 61.3 months on average from the beginning of their symptoms to obtaining a diagnosis (SD 101.9).

CONCLUSIONS: From the notification to Sivigila in Bogotá, compared to the global prevalence, there is an under-registration of patients with orphan diseases and the delay in the diagnosis of these diseases is evident.

PMID:40098659 | PMC:PMC11648384 | DOI:10.15446/rsap.V25n4.107594

bioRxiv [Preprint]. 2025 Mar 8:2025.03.03.641186. doi: 10.1101/2025.03.03.641186.

ABSTRACT

Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) are common neurodegenerative disorders for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 429 neurons from three C9ORF72 ALS, six C9ORF72 FTD, seven AD, and twenty-three neurotypical control brains revealed significantly increased burdens in somatic single nucleotide variant (sSNV) and insertion/deletion (sIndel) in all three disease conditions. Mutational signature analysis identified a disease-associated sSNV signature suggestive of oxidative damage and an sIndel process, affecting 28% of ALS, 79% of FTD, and 65% of AD neurons but only 5% of control neurons (diseased vs. control: OR=31.20, p = 2.35×10-10). Disease-associated sIndels were primarily two-basepair deletions resembling signature ID4, which was previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Duplex sequencing confirmed the presence of sIndels and identified similar single-strand events as potential precursor lesions. TOP1-associated sIndel mutagenesis and resulting genome instability may thus represent a common mechanism of neurodegeneration.

PMID:40093130 | PMC:PMC11908196 | DOI:10.1101/2025.03.03.641186

bioRxiv [Preprint]. 2025 Mar 4:2025.03.03.641217. doi: 10.1101/2025.03.03.641217.

ABSTRACT

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is linked to exposure to repetitive head impacts (RHI), yet little is known about its pathogenesis. Applying two single-cell whole-genome sequencing methods to hundreds of neurons from prefrontal cortex of 15 individuals with CTE, and 4 with RHI without CTE, revealed increased somatic single-nucleotide variants in CTE, resembling a pattern previously reported in Alzheimer's disease (AD). Furthermore, we discovered remarkably high burdens of somatic small insertions and deletions in a subset of CTE individuals, resembling a known pattern, ID4, also found in AD. Our results suggest that neurons in CTE experience stereotyped mutational processes shared with AD; the absence of similar changes in RHI neurons without CTE suggests that CTE involves mechanisms beyond RHI alone.

PMID:40093089 | PMC:PMC11908173 | DOI:10.1101/2025.03.03.641217

bioRxiv [Preprint]. 2025 Mar 6:2025.03.05.641682. doi: 10.1101/2025.03.05.641682.

ABSTRACT

A mechanistic understanding of neurodevelopment requires us to follow the multiscale processes that connect molecular genetic processes to macroscopic cerebral cortical formations and thence to neurological function. Using magnetic resonance imaging of the brain of the ferret, a model organism for studying cortical morphogenesis, we create in vitro physical gel models and in silico numerical simulations of normal brain gyrification. Using observations of genetically manipulated animal models, we identify cerebral cortical thickness and cortical expansion rate as the primary drivers of dysmorphogenesis and demonstrate that in silico models allow us to examine the causes of aberrations in morphology and developmental processes at various stages of cortical ontogenesis. Finally, we explain analogous cortical malformations in human brains, with comparisons with human phenotypes induced by the same genetic defects, providing a unified perspective on brain morphogenesis that is driven proximally by genetic causes and affected mechanically via variations in the geometry of the brain and differential growth of the cortex.

PMID:40093050 | PMC:PMC11908256 | DOI:10.1101/2025.03.05.641682

Tunis Med. 2025 Feb 5;103(2):212-216. doi: 10.62438/tunismed.v103i2.5261.

ABSTRACT

INTRODUCTION: Lipoid pneumonia is a rare disease affecting adults' which frequency increases with age. Exogenous lipoid pneumonia results from the penetration, usually by inhalation, of oily substances into the pulmonary parenchyma.

AIM: To study the clinical and radiological features of exogenous lipoid pneumonia and to define therapeutic strategies.

METHODS: We performed a monocentric, retrospective study of patients followed in the Pneumology Department of the Hedi Chaker Hospital in Sfax between 2004 and 2023. The diagnosis of exogenous lipoid pneumonia was confirmed by bronchoalveolar lavage with positive Oil Red O staining or by biopsy with anatomopathological examination showing lipid-laden foamy histiocytes.

RESULTS: During this period, we collected nine patients with an average age of 46. Dyspnea and cough were the most frequent symptoms. Chest computed tomography revealed ground-glass opacity in five cases, parenchymal condensations in three cases and crazy paving in three cases. The frequent risk factors were occupational exposure to a lipid in five cases and consumption of a lipid product in four cases. In terms of treatment, four patients underwent occupational reclassification and a declaration of occupational disease. Systemic corticotherapy was indicated in six patients.

CONCLUSION: Exogenous lipoid pneumonia is a rare entity. This study highlights the difficulty of making a diagnosis, due to misleading clinico-radiological presentation in the absence of exposure.

PMID:40096721 | DOI:10.62438/tunismed.v103i2.5261

J Mol Cell Biol. 2025 Mar 17:mjaf009. doi: 10.1093/jmcb/mjaf009. Online ahead of print.

ABSTRACT

Calciphylaxis is a rare, progressive disorder characterized by subcutaneous adipose and dermal microvascular calcifications, microthrombi, and endothelial damage. It mainly affects patients with chronic kidney disease (CKD), which is also known as calcific uremic arteriolopathy. Skin biopsy is the gold standard for diagnosis, but it is an invasive procedure. Calciphylaxis frequently results in ischemic and nonhealing ulcerations with a high mortality rate. A multidisciplinary targeted approach is the primary treatment method. Vascular calcification, which is a common complication in patients with CKD, cannot completely explain the rapid progression of calciphylaxis. This article reviews the advances in the epidemiological characteristics, risk factors, and diagnosis, including non-uraemic calciphylaxis (NUC) and visceral calciphylaxis, pathogenesis, associated animal models, and treatment of calciphylaxis. The scarcity of animal models that mimic the clinical presentation of calciphylaxis hampers the understanding of its pathogenesis. The acute effects on progressive vascular injury, including the induction of severe ischemia and inflammatory responses, have been emphasized. Actively listening to the voices of patients and their families and building a multidimensional research system with artificial intelligence technologies based on the specific molecular makeup of calciphylaxis patients will help tailor regenerative treatment strategies. Mesenchymal stem cells (MSCs) may be proposed as a novel therapy for calciphylaxis because of their regenerative effects, inhibition of vascular calcification, anti-infection and immunomodulation properties, and improvement of hypercoagulability. Safe, effective, accessible, and economical MSC strategies guided by biomarkers deserve consideration for the treatment of this devastating disease.

PMID:40097288 | DOI:10.1093/jmcb/mjaf009

J Assoc Physicians India. 2025 Mar;73(3):11-12. doi: 10.59556/japi.73.0884.

ABSTRACT

Guillain-Barré syndrome (GBS) is a rare but common cause of acute flaccid paralysis globally.1 This syndrome, first described in 1916 by Georges Guillain, Jean Alexandre Barré, and André Strohl, has captured the interest of clinicians, researchers, and patients all over the world.2.

PMID:40087924 | DOI:10.59556/japi.73.0884

Skelet Muscle. 2025 Mar 15;15(1):7. doi: 10.1186/s13395-025-00376-4.

ABSTRACT

BACKGROUND: SELENON-Congenital Myopathy (SELENON-CM) is a rare congenital myopathy caused by mutations of the SELENON gene characterized by axial muscle weakness and progressive respiratory insufficiency. Muscle histopathology may be non-specific, but commonly includes multiminicores or a dystrophic pattern. The SELENON gene encodes selenoprotein N (SelN), a selenocysteine-containing redox enzyme located in the endo/sarcoplasmic reticulum membrane where it colocalizes with mitochondria-associated membranes. However, the molecular mechanism(s) by which SelN deficiency cause SELENON-CM remain poorly understood. A hurdle is the lack of cellular and animal models that show easily assayable phenotypes.

METHODS: Using CRISPR-Cas9 we generated three zebrafish models of SELENON-CM, which were then studied by spontaneous coiling, hatching, and activity assays. We also performed selenon coexpression analysis using a single cell RNAseq zebrafish embryo-atlas. SelN-deficient myoblasts were generated and assayed for glutathione, reactive oxygen species, carbonylation, and nytrosylation levels. Finally, we tested Selenon-deficient myoblasts' metabolism using a Seahorse cell respirometer.

RESULTS: We report deep-phenotyping of SelN-deficient zebrafish and muscle cells. SelN-deficient zebrafish exhibit changes in embryonic muscle function and swimming activity in larvae. Analysis of single cell RNAseq data in a zebrafish embryo-atlas revealed coexpression of selenon and genes involved in the glutathione redox pathway. SelN-deficient zebrafish and mouse myoblasts exhibit altered glutathione and redox homeostasis, as well as abnormal patterns of energy metabolism, suggesting roles for SelN in these functions.

CONCLUSIONS: These data demonstrate a role for SelN in zebrafish early development and myoblast metabolism and provide a basis for cellular and animal model assays for SELENON-CM.

PMID:40087793 | DOI:10.1186/s13395-025-00376-4

Orphanet J Rare Dis. 2025 Mar 14;20(1):125. doi: 10.1186/s13023-025-03614-6.

ABSTRACT

BACKGROUND: Clinical trials for rare diseases pose unique challenges warranting alternative approaches in demonstrating treatment efficacy. Such trials face challenges including small patient populations, variable onset of symptoms and rate of disease progression, and ethical considerations, particularly in neurodegenerative diseases. In this study, we present the retrospective clinical global impression (RCGI) severity and change (RCGI-S/C) scale on 27 patients with GM1 gangliosidosis, a post hoc clinician-rated outcome measure to evaluate natural history study participants as historical controls for comparisons with treated patients in a clinical trial.

METHODS: We conducted a systematic chart review of 27 GM1 gangliosidosis natural history participants across 95 total visits. RCGI-S was assessed at the first visit and rated 1 (normal) to 7 (among the most extremely ill). Each subsequent follow-up was rated on the RCGI-C scale from 1 (very much improved) to 7 (very much worse). We demonstrate scoring guidelines of both scales with examples and justifications for this pilot in GM1 gangliosidosis natural history participants. The convergent validity of the RCGI scales was explored through correlations with magnetic resonance imaging (MRI) and the Vineland Adaptive Behavioral Scales.

RESULTS: We found strong association between the RCGI-S scores with gray matter volume (r(14) = -0.81; 95% CI [-0.93, -0.51], p < 0.001), and RCGI-C scores significantly correlated with increases in ventricular volume (χ2(1) = 18.6, p < 0.001). Baseline RCGI-S scores also strongly correlated with Vineland adaptive behavioral composite scores taken at the same visit (r(14) = -0.72; 95% CI [-0.93, -0.17], p = 0.02).

CONCLUSION: RCGI-S/C scales, which use the clinical evaluation to assess the severity of disease of each patient visit over time, were consolidated into a single quantitative metric in this study. Longitudinal RCGI-C scores allowed us to quantify disease progression in our late-infantile and juvenile GM1 patients. We suggest that the retrospective CGI may be an important tool in evaluating historical data for comparison with changes in disease progression/mitigation following therapeutic interventions.

PMID:40087722 | DOI:10.1186/s13023-025-03614-6

BMC Bioinformatics. 2025 Mar 14;26(1):82. doi: 10.1186/s12859-025-06096-2.

ABSTRACT

BACKGROUND: Diagnosing Mendelian and rare genetic conditions requires identifying phenotype-associated genetic findings and prioritizing likely disease-causing genes. This task is labor-intensive for molecular and clinical geneticists, who must review extensive literature and databases to link patient phenotypes with causal genotypes. The challenge is further complicated by the large number of genetic variants detected through next-generation sequencing, which impacts both diagnosis timelines and patient care strategies. To address this, in silico methods that prioritize causal genes based on patient-derived phenotypes offer an effective solution, reducing the time involved in diagnostic case reviews and enhancing the efficiency of clinical diagnosis.

RESULTS: We developed the phenotype prioritization and analysis for rare diseases (PPAR) to rank genes based on human phenotype ontology (HPO) terms, with the specific goal of aiding the interpretation of genetic testing for Mendelian and rare diseases. PPAR leverages embeddings from a knowledge graph and incorporates knowledge from connections between genes, HPO terms, and gene ontology annotations. When applied on a clinical rare disease cohort and the publicly available deciphering developmental disorders (DDD) dataset. PPAR ranked the causal gene in the top 10 for 27% of cases in the clinical cohort and for 85% of cases in the DDD dataset, outperforming other established HPO-based methods.

CONCLUSION: Our findings demonstrate that PPAR, a method developed from the clinical knowledge graph, effectively ranks causal genes based on patient-derived HPO terms in rare and Mendelian disease contexts. PPAR has shown superior performance compared to other well-established HPO-only methods and provides an efficient, accessible solution for clinical geneticists. The Python-based tool is publicly available at https://github.com/dimi-lab/PPAR , offering a user-friendly platform for gene prioritization.

PMID:40087567 | DOI:10.1186/s12859-025-06096-2

Nat Commun. 2025 Mar 14;16(1):2500. doi: 10.1038/s41467-025-57695-9.

ABSTRACT

With ongoing improvements in the detection of complex genomic and epigenomic variations, long-read sequencing (LRS) technologies could serve as a unified platform for clinical genetic testing, particularly in rare disease settings, where nearly half of patients remain undiagnosed using existing technologies. Here, we report a simplified funnel-down filtration strategy aimed at enhancing the identification of small and large deleterious variants as well as abnormal episignature disease profiles from whole-genome LRS data. This approach detected all pathogenic single nucleotide, structural, and methylation variants in a positive control set (N = 76) including an independent sample set with known methylation profiles (N = 57). When applied to patients who previously had negative short-read testing (N = 51), additional diagnoses were uncovered in 10% of cases, including a methylation profile at the spinal muscular atrophy locus utilized for diagnosing this life-threatening, yet treatable, condition. Our study illustrates the utility of LRS in clinical genetic testing and the discovery of novel disease variation.

PMID:40087273 | DOI:10.1038/s41467-025-57695-9

Mol Genet Metab. 2025 Apr;144(4):109073. doi: 10.1016/j.ymgme.2025.109073. Epub 2025 Mar 1.

ABSTRACT

Rare diseases affect over 400 million people worldwide, with approved treatment available for less than 6 % of these diseases. Drug repurposing is a key strategy in the development of therapies for rare disease patients with large unmet medical needs. The process of repurposing drugs compared to novel drug development is a time-saving and cost-efficient method potentially resulting in higher success rates. To accelerate and ensure sustainability in therapy development for rare neurometabolic, neurological, and neuromuscular diseases, an international consortium SIMilarities in clinical and molecular PATHology (SIMPATHIC) has been established where we move away from the one drug one disease concept and move towards one drug targeting a pathomechanism shared between diseases, by applying parallel preclinical and clinical drug development. Here the consortium describes accelerators of drug repurposing pursued by the consortium, including 1) co-creation, 2) patient empowerment, 3) use of standardized induced pluripotent stem cell (iPSC)-derived disease models and cellular and molecular profiling, 4) high-throughput drug screening in neurons, 5) innovative clinical trial design, and 6) selection of appropriate exploitation and patient access models. In this way, a fast and effective drug repurposing pathway for several rare diseases will be established to reduce time from discovery to patient access.

PMID:40086177 | DOI:10.1016/j.ymgme.2025.109073

Front Public Health. 2025 Feb 27;13:1417771. doi: 10.3389/fpubh.2025.1417771. eCollection 2025.

ABSTRACT

Burnout among physicians has gained increasing attention in recent years. This issue arises not only from stressful working conditions and individual factors but also from the correlation between burnout and physicians' tolerance of uncertainty. This association could be particularly important in the context of rare diseases, which inherently present greater uncertainty. To date, no studies have explored this topic. Our exploratory study aimed to investigate the associations between uncertainty and burnout scores among physicians while considering secondary factors associated with rare diseases and COVID-related stress. Although not the primary focus, we included COVID-related stress due to its impact during the ongoing pandemic. We conducted an online survey using the Physicians' Reaction to Uncertainty Scale (PRU) and the Oldenburg Burnout Inventory (OLBI). Experience with rare diseases was quantified by assessing the weekly working hours devoted to patients with such conditions. We conducted a path analysis, initially using a fully recursive model and subsequently eliminating non-significant paths. 128 physicians (n = 73 female) participated in the survey, with 31% of them displaying significant burnout scores. Notably, significant associations were found between the PRU subscale anxiety and both dimensions of burnout, as well as between the PRU subscale disclosure to patients and the burnout dimension of exhaustion. COVID-related stress was also significantly associated with exhaustion, while experience with rare diseases was significantly associated with disengagement. No correlation was observed between experience with rare diseases and uncertainty scores. The model demonstrated an excellent fit (RMSEA = 0.055). Our results show that physician burnout is a pressing issue and confirm the association between anxiety due to uncertainty and increased burnout scores.

PMID:40084205 | PMC:PMC11903758 | DOI:10.3389/fpubh.2025.1417771

Front Public Health. 2025 Feb 26;13:1510818. doi: 10.3389/fpubh.2025.1510818. eCollection 2025.

ABSTRACT

BACKGROUND: Undiagnosed rare diseases (URDs) are a complex and multifaceted challenge, especially in low-and medium-income countries. They affect individuals with unique clinical features and lack a clear diagnostic label. Although the Undiagnosed Diseases Network International (UDNI) definition of URDs is not universally accepted, it is widely recognized.

METHODS: We surveyed UDNI members and participants from other countries to explore the challenges posed by URDs and identify possible solutions. Participation in the survey was completely voluntary.

RESULTS: The survey revealed a need for more consensus on a universally accepted definition for URDs. Still, the UDNI definition gained widespread recognition and serves as a valuable framework for understanding and addressing the challenges of URDs. In addition to national or international networks, fostering a more substantial engagement and resource-sharing ethos among member countries is critical. Despite advances in genomics and diagnostic tools, the diagnostic journey for people living with URDs (PLURDs) remains arduous and often inconclusive. The availability of specialized centers and the utilization of whole exome sequencing (WES) and whole genome sequencing (WGS) vary across countries, with disparities due to healthcare systems, economic status, and government policies. Advocacy groups play a crucial role in supporting PLURDs.

CONCLUSION: A unified commitment to prioritizing URDs on the global health agenda, paired with targeted funding, stipulated national strategies, and aligned international cooperation, is imperative to leveling the playing field for the diagnosis and management of URDs and capitalizing on the potential of Advocacy Groups as allies in this endeavor.

PMID:40078755 | PMC:PMC11897027 | DOI:10.3389/fpubh.2025.1510818

Rheumatology (Oxford). 2025 Mar 1;64(Supplement_1):i82-i84. doi: 10.1093/rheumatology/keae593.

ABSTRACT

Polyarteritis Nodosa (PAN), is the firstly described vasculitis and can be seen in paediatric and adult age. PAN has a heterozygous clinical picture including cutaneous, constitutional, musculoskeletal, gastrointestinal, and renal involvement. Description and splitting of other vasculitis, makes this medium vessel vasculitis, a very rare disease. Additionally, many subgroups of PAN have been defined and this effort let to move Hepatitis B virus-PAN to Vasculitis with probable aetiology. Anyhow, idiopathic PAN still exists and cohorts from various countries such as France, India, and Japan have been published. Rarity of PAN necessities global collaboration to highlight clinical features and genetics studies. GLOBAL-PAN is an ongoing collaborative project of EUVAS, VCRC and many national cohorts. This review covers the recent epidemiological data of PAN along with demographic and clinical characteristics of cohorts from all-over the world and GLOBAL-PAN.

PMID:40071408 | DOI:10.1093/rheumatology/keae593

Orphanet J Rare Dis. 2025 Mar 11;20(1):117. doi: 10.1186/s13023-025-03618-2.

ABSTRACT

BACKGROUND: The current development of gynecology services for children and adolescents seeks to meet needs both in the overall population and in patients with rare diseases. In France, the referral center for rare gynecological diseases specializes in four major types of conditions, namely, uterovaginal malformations, hereditary hemorrhagic diseases, rare benign breast diseases, and gynecological repercussions of rare chronic diseases.

OBJECTIVE: To describe consecutive patients who had a first visit in 2018-2023 at the referral center for rare gynecological diseases at the Necker Pediatric University Hospital in Paris, France, and who were diagnosed with a condition in any of the four categories listed above.

MATERIAL AND METHODS: For this single-center retrospective observational cohort study, data from the referral-center database were collected and reviewed. These data included year of birth, age at and reason for first gynecology visit, and rare chronic disease and referring rare-disease center for patients seen for gynecological repercussions of rare chronic diseases.

RESULTS: The 704 included patients had a median age of 15.2 years (interquartile range 3.8) at the first visit. Among them, 100 (14.2%) had uterovaginal malformations, 32 (4.6%) hereditary hemorrhagic diseases, 17 (2.4%) rare benign breast diseases, and 555 (78.8%) gynecological repercussions of rare chronic diseases. The leading reasons for the visit were dysmenorrhea (15.6%), menorrhagia (15.5%), uterovaginal malformations (15.2%), and irregular periods (14.9%).

CONCLUSION: Repercussions of rare chronic diseases managed at rare-disease referral centers were by far the leading reason for seeking gynecological expertise in rare diseases. In this complex situation, the underlying disease and its treatments interact with the gynecological manifestations and their treatment, requiring close collaboration among all specialists caring for each patient.

PMID:40069734 | DOI:10.1186/s13023-025-03618-2

Orphanet J Rare Dis. 2025 Mar 10;20(1):112. doi: 10.1186/s13023-024-03435-z.

ABSTRACT

BACKGROUND: Rare and complex diseases can have a significant impact on family life, and managing the reproductive aspects of patients of childbearing age with rare diseases is often difficult and complex. A European Reference Network (ERN) Transversal Working Group (WG) on Pregnancy and Family Planning was created to join forces to promote and address issues on these topics in rare and low-prevalence diseases.

OBJECTIVE: To outline the challenges and the good practices related to pregnancy and family planning in rare and complex diseases for healthcare professionals (HCPs).

METHODS: A survey on state of the art and unmet needs was created by a co-design group of both clinicians and patients' representatives from 20 ERNs. The survey was uploaded in English on the online platform "EU Survey" and disseminated by respective ERNs and learned societies. Seven transversal domains were explored in the survey by using closed and open-ended questions: fertility preservation, pre-conceptional counselling, family planning counselling, pre-implantation diagnosis, prenatal diagnosis, pregnancy monitoring and post pregnancy monitoring, lactation monitoring/counselling and newborn management. The questions investigated for each topic were the following: level of importance, activities performed by the centre, clinical challenges, good practice and educational activities.

RESULTS: A total of 197 answers were collected from 24 different countries. Unmet needs for HCPs included: the need to improve communication between different HCPs, the lack of predefined organizational pathways, the lack of availability of expert HCPs for some pregnancy-related issues and the need to streamline the care provided among different countries. In addition, the survey underlined the need to improve the educational activities provided to rare disease patients.

CONCLUSIONS: Physicians and patients need to be educated on the emerged unmet needs in order to standardize the information for both HCPs and patients with rare diseases. Educational activities should be considered to help to disseminate information.

PMID:40065363 | DOI:10.1186/s13023-024-03435-z

bioRxiv [Preprint]. 2025 Mar 1:2025.02.27.640588. doi: 10.1101/2025.02.27.640588.

ABSTRACT

Heterozygous loss-of-function (LoF) variants in RFX3, a transcription factor known to play key roles in ciliogenesis, result in autism spectrum disorder (ASD) and neurodevelopmental delay. RFX binding motifs are also enriched upstream of genes found to be commonly dysregulated in transcriptomic analyses of brain tissue from individuals with idiopathic ASD. Still, the precise functions of RFX3 in the human brain is unknown. Here, we studied the impact of RFX3 deficiency using human iPSC-derived neurons and forebrain organoids. Biallelic loss of RFX3 disrupted ciliary gene expression and delayed neuronal differentiation, while monoallelic loss of RFX3 did not. Instead, transcriptomic and DNA binding analyses demonstrated that monoallelic RFX3 loss disrupted synaptic target gene expression and diminished neuronal activity-dependent gene expression. RFX3 binding sites co-localized with CREB binding sites near activity-dependent genes, and RFX3 deficiency led to decreased CREB binding and impaired induction of CREB targets in response to neuronal depolarization. This study demonstrates a novel role of the ASD-associated gene RFX3 in shaping neuronal synaptic development and plasticity.

PMID:40060598 | PMC:PMC11888390 | DOI:10.1101/2025.02.27.640588

Orphanet J Rare Dis. 2025 Mar 7;20(1):107. doi: 10.1186/s13023-025-03634-2.

ABSTRACT

Rare disease prevalence rates are increasing rapidly worldwide, as are the cost of orphan indication drugs used to treat them, posing significant strain on many healthcare systems. In response, a set of tensions have arisen within academic, activist, advocacy, industry, and policy circles over orphan drug pricing. Yet there has to date been no unifying review of the literature engaging critically with these tensions. Addressing this gap, the article examines the narratives in circulation around orphan pricing, the traditions and epistemic bases they draw on, and their points of contestation/coalescence. It does so through a meta-narrative literature review, finding three core narratives. One involves dispute over outlay costs for developing new orphan drugs, often drawing on normative health economics with a base in practical idealism. It argues that (bio)pharmaceutical manufacturers misuse policy incentives to profit excessively through monopoly capitalism. A second narrative draws on both empirical and normative health economics (often steeped in empiricism paired with a utilitarian standpoint). It contends that high orphan drug prices signify a healthy market and justifiably support longer-term innovation while promoting wider equity of access. A third (midway) narrative draws on the sociology of health and innovation studies alongside normative health economics and health policy studies to suggest alternative models of innovation and valuation. As a unifying meta-narrative, the review finds a sustained call for reform, centred on welfare economics and resource allocation, where current incentives and regulations are held to be insufficient. Overall, the article recommends that regulators look to alternative models of innovation steeped in social science thinking to modify reviewing appraisal, coverage, and reimbursement processes for orphan drugs. Also, that greater patient inclusion and transparency would help include a wider range of intangible social factors that rare disease patients face in accessing high priced orphan drugs.

PMID:40055799 | DOI:10.1186/s13023-025-03634-2

EBioMedicine. 2025 Mar 5;114:105629. doi: 10.1016/j.ebiom.2025.105629. Online ahead of print.

ABSTRACT

BACKGROUND: First described in 1972, idiopathic subglottic stenosis (iSGS) is a serious chronic orphan disease characterised by recurrent scarring of the subglottis. Although the cause is unknown, iSGS is almost exclusively restricted to Caucasian females typically in their fourth to sixth decade. However, given its rare incidence (1:400,000), understanding the clinical trajectory and molecular factors associated with iSGS disease development and prognosis has been difficult. In the current study we sought to unravel the pathogenesis of iSGS at the clinical, transcriptional, and genetic level in a prospective cohort.

METHODS: We prospectively enrolled 126 patients with iSGS, 104 controls, and 13 patients with traumatic SGS. Within this cohort, we profiled 114 human epiglottis and 121 human subglottis biopsies across three different conditions: control, iSGS, and intubation-related traumatic stenosis using bulk and single nucleus RNA-sequencing. Whole exome sequencing for germline variants was performed for 70 controls and 75 patients with iSGS.

FINDINGS: Patients with iSGS received a median number of five (range 0-18) surgical dilations at a rate of 1.031 dilations (range: 0.12-6.2) per year. Older age at diagnosis and higher Cotton-Myers grade were associated with increased number of surgical dilations over time. Cohort-level bulk transcriptomics found that iSGS pathology was restricted within the subglottis and did not affect anatomically adjacent epiglottis, opposite to previous hypotheses. We further identified cellular subsets associated with iSGS prognosis and severity. Finally, patients with iSGS exhibit lower testosterone predicted using a polygenic score.

INTERPRETATION: Together, our data refines our understanding of laryngeal biology and provides insights into the clinical trajectory of subglottic stenoses. Future research should explore the role of testosterone in the development of iSGS.

FUNDING: This study was funded by a grant from the American Laryngology Association (#1082), an Academic Medical Organization of Southwestern Ontario innovation fund grant (INN21-016), grant support from the Departments of Otolaryngology-Head and Neck Surgery at University of Toronto and Western University. ACN was supported by the Wolfe Surgical Research Professorship in the Biology of Head and Neck Cancers Fund. PYFZ was supported by a Vanier Canada Graduate Scholarship and PSI foundation fellowship.

PMID:40048847 | DOI:10.1016/j.ebiom.2025.105629