Orphanet J Rare Dis. 2025 Apr 10;20(1):169. doi: 10.1186/s13023-025-03673-9.

ABSTRACT

BACKGROUND: Individuals living with rare congenital malformations and/or intellectual disability often face challenges in accessing appropriate healthcare. Clinical practice guidelines (CPGs) may serve as a tool to provide evidence-based care for rare diseases, but their development is complex, and the views of affected individuals and families often remain unknown.

METHODS: Patient advocates of the European Reference Network ITHACA (Intellectual disability, TeleHealth, Autism and Congenital Anomalies) participated in focus groups in which their experiences with and perspectives on CPG use and development were discussed.

RESULTS: Patient advocates considered CPGs relevant to address information and care needs and support advocacy efforts. Important characteristics included representation of heterogeneity within conditions, a holistic approach in which and how topics are addressed, user-friendly availability for individuals and families, and reliability of information. Guideline development and implementation were described as challenging, iterative processes in which effective partnership between clinicians, patient advocates, and other stakeholders is essential.

CONCLUSIONS: Understanding the perspectives of patient advocates is essential to develop CPGs that meet the life-long and complex care needs of individuals and families living with rare conditions. Identified challenges include balancing the urgency of information needs with thorough guideline development processes, as well as the integration and interpretation of different types of knowledge.

PMID:40205602 | DOI:10.1186/s13023-025-03673-9

Front Public Health. 2025 Mar 24;13:1531583. doi: 10.3389/fpubh.2025.1531583. eCollection 2025.

ABSTRACT

Rare diseases, also known as orphan diseases, are a group of disorders that affect a small percentage of the population. Despite individually affecting a small number of people, collectively, they impact millions worldwide. This is particularly significant in paediatric patients, highlighting the global scale of the issue. This review delves into the exact prevalence of rare diseases among children and adolescents and their diverse impact on the quality of life of patients and their families. The review sheds light on the complex interplay of genetic and environmental factors contributing to these conditions and the diagnostic challenges and delays often encountered in identifying and categorising these diseases. It is noted that although there have been significant strides in the field of genomic medicine and the development of orphan drugs, effective treatments remain limited. This necessitates a comprehensive, multidisciplinary approach to management involving various specialities working closely together to provide holistic care. Furthermore, the review addresses the psychosocial and economic burdens faced by families with paediatric patients suffering from rare diseases, highlighting the urgent need for enhanced support mechanisms. Recent technological and therapeutic advancements, including genomic sequencing and personalized medicine, offer promising avenues for improving patient outcomes. Additionally, the review underscores the role of policy and advocacy in advancing research, ensuring healthcare access, and supporting affected families. It emphasises the importance of increased awareness, education, and collaboration among healthcare providers, researchers, policymakers, and patient advocacy groups. It stresses the pivotal role each group plays in improving the diagnosis, treatment, and overall quality of life for paediatric patients with rare diseases.

PMID:40196857 | PMC:PMC11973084 | DOI:10.3389/fpubh.2025.1531583

Orphanet J Rare Dis. 2025 Apr 8;20(1):166. doi: 10.1186/s13023-025-03629-z.

ABSTRACT

BACKGROUND: Rare diseases (RDs) clinical care and research face several challenges. Patients are dispersed over large geographic areas, their number per disease is limited, just like the number of researchers involved. Current databases as well as biological collections, when existing, are generally local, of modest size, incomplete, of uneven quality, heterogeneous in format and content, and rarely accessible or standardised to support interoperability. Most disease phenotypes are complex corresponding to multi-systemic conditions, with insufficient interdisciplinary cooperation. Thus emerged the need to generate, within a coordinated, mutualised, secure and interoperable framework, high-quality data from national or international RD cohorts, based on deep phenotyping, including molecular analysis data, notably genotypic. The RaDiCo program objective was to create, under the umbrella of Inserm, a national operational platform dedicated to the development of RD e-cohorts. Its Information System (IS) is presented here.

MATERIAL AND METHODS: Constructed on the cloud computing principle, the RaDiCo platform was designed to promote mutualization and factorization of processes and services, for both clinical epidemiology support and IS. RaDiCo IS is based on an interoperability framework combining a unique RD identifier, data standardisation, FAIR principles, data exchange flows/processes and data security principles compliant with the European GDPR.

RESULTS: RaDiCo IS favours a secure, open-source web application in order to implement and manage online databases and give patients themselves the opportunity to collect their data. It ensures a continuous monitoring of data quality and consistency over time. RaDiCo IS proved to be efficient, currently hosting 13 e-cohorts, covering 67 distinct RDs. As of April 2024, 8063 patients were recruited from 180 specialised RD sites spread across the national territory.

DISCUSSION: The RaDiCo operational platform is equivalent to a national infrastructure. Its IS enables RD e-cohorts to be developed on a shared platform with no limit on size or number. Compliant with the GDPR, it is compatible with the French National Health Data Hub and can be extended to the RDs European Reference Networks (ERNs).

CONCLUSION: RaDiCo provides a robust IS, compatible with the French Data Hub and RDs ERNs, integrated on a RD platform that enables e-cohorts creation, monitoring and analysis.

PMID:40200372 | DOI:10.1186/s13023-025-03629-z

Orphanet J Rare Dis. 2025 Apr 8;20(1):163. doi: 10.1186/s13023-025-03704-5.

ABSTRACT

BACKGROUND: Rare neurological diseases (RNDs) result in severe health burdens worldwide. Data from China are limited. We aimed to investigate the health burden of 20 RNDs in Guangdong Province (GD), which contains two-thirds of the population of South China.

METHODS: The hospitalization data of 20 RNDs were described using hospital-based front sheet data from 3,037 hospitals of GD from 2016 to 2022. The 20 RNDs included amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth Disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, congenital myotonia, congenital myasthenic syndrome, Dravet syndrome, Fabry disease, hereditary spastic paraplegia, Huntington disease, Leber hereditary optic neuropathy, mitochondrial encephalopathy (ME), multi-focal motor neuropathy, myotonic dystrophy, primary hereditary dystonia, progressive muscular dystrophy (PMD), spinal and bulbar muscular atrophy, spinal muscular atrophy (SMA), spinocerebellar ataxia, Wilson disease (WD) and X-linked adrenoleukodystrophy. Age were presented as mean and standard deviation while length of hospital stay as median and interquartile range (25th and 75th percentiles). The other variables were described as number and percentage. The data were analyzed by Joinpoint regression.

RESULTS: There were 9,351 cases, including 330 ICU and 155 death cases. The average age was 33.7 ± 22.0 y, and 63.8% of patients were male. From 2016 to 2022, the number of RND (and juvenile RND) cases were 1034 (184), 1174 (293), 1443 (374), 1422 (320), 1331 (337), 1432 (409) to 1515 (515). ICU (and juvenile ICU) cases rose from 28 (3), 34 (6), 24 (4), 38 (11), 46 (13), 54 (24) to 106 (56). Joinpoint regression showed significant upward trend in percentages of juvenile and juvenile ICU cases (APC = 8.13, P< 0.05; APC = 28.42, P< 0.05). The fop five RNDs were WD, ASL, PMD, ME, and SMA, which accounted for 79.7% of all, 99.1% of ICU, and 94.8% of death cases.

CONCLUSIONS: We demonstrated that the increase in health burden of RNDs was mainly evident in juveniles in South China from 2016 to 2022. The top 5 RNDs accounted for majority of the critical patients.

PMID:40200352 | DOI:10.1186/s13023-025-03704-5

Neurology. 2025 Apr 8;104(7_Supplement_1):3899. doi: 10.1212/WNL.0000000000211311. Epub 2025 Apr 7.

ABSTRACT

OBJECTIVE: This study aims to evaluate condition-specific knowledge among patients with rare neuroimmune disorders.

BACKGROUND: Rare neuroimmune disorders (RNDs) include conditions such as neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD), acute disseminated encephalomyelitis (ADEM), idiopathic optic neuritis (ON) and transverse myelitis (TM). These conditions share significant phenotypic overlap, which makes communication of the diagnosis and relapse risk challenging for neurologists. This may predispose patients to have an incomplete understanding of their condition and long-term prognosis. In this study, we sought to understand the condition-specific knowledge in patients with RNDs.

DESIGN/METHODS: A questionnaire was developed to assess condition-specific knowledge in patients with RNDs by a group of neuroimmunologists. An initial version of the test was administered to five individuals with RNDs, who provided feedback via semistructured interviews. The final version of the test included fifteen questions covering localization, symptoms, etiology, and relapse risk. The test was administered virtually to subjects via a Redcap survey. Subjects also completed a demographic questionnaire, the Medical Term Recognition Test (METER) for health literacy assessment, and the Patient Determined Disease Steps (PDDS).

RESULTS: Ninety-two subjects completed the test of knowledge, and eighty-nine completed all procedures. The study population was largely female (73%), and 68% completed 16+ years of education. Individuals with MOGAD and NMOSD (n=45) scored higher on the test (median score 87%) compared to individuals with idiopathic conditions (n=45; median score 73%). Analysis for the correlation of test scores with age, duration since diagnosis, health literacy, and self-reported disability are ongoing.

CONCLUSIONS: Individuals with idiopathic conditions (TM, ON, ADEM) scored lower on our test when compared to the better-characterized conditions of NMOSD and MOGAD. Individuals with idiopathic conditions may benefit from targeted education about their diagnosis and relapse risk. Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff. Disclosure: Ms. Mahale has nothing to disclose. Dr. Sguigna has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Sguigna has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Sguigna has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Horizon Therapeutics. The institution of Dr. Sguigna has received research support from Genentech. The institution of Dr. Sguigna has received research support from Clene Nanomedicine. The institution of Dr. Sguigna has received research support from The International Progressive Multiple Sclerosis Alliance through the National Multiple Sclerosis Society. The institution of Dr. Sguigna has received research support from PCORI. The institution of Dr. Sguigna has received research support from DOD/CDMRP. The institution of Dr. Sguigna has received research support from Alexion. Dr. Sguigna has received intellectual property interests from a discovery or technology relating to health care. Dr. Tardo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Tardo has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for NeurologyLive. Dr. Tardo has received personal compensation in the range of $500-$4,999 for serving as a Panel member with CanDoMS. Dr. Tardo has a non-compensated relationship as a Tardo with The MOG Project that is relevant to AAN interests or activities. Dr. Nguyen has nothing to disclose. Dr. DeFiebre has received personal compensation for serving as an employee of Siegel Rare Neuroimmune Association. Dr. Blackburn has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics.

PMID:40194445 | DOI:10.1212/WNL.0000000000211311

Fam Cancer. 2025 Apr 7;24(2):35. doi: 10.1007/s10689-025-00462-y.

ABSTRACT

Recent updated management guidelines for Familial Adenomatous Polyposis (FAP) have been published by professional bodies internationally. These recommendations reflect the diverse needs and capabilities of varying health systems worldwide, including thresholds for intervention and population health priorities. Whilst guidelines are closely aligned in many regards, there are areas of disparity. However, alongside discrepancies in guideline recommendations, common challenges also face professional bodies across the globe. Generation of a robust evidence-base in the environment of limited data is difficult in rare diseases such as FAP, underscored by the fact that expert consensus opinion underpins virtually all guidelines. The presence of a wide phenotypic spectrum in FAP and the other hereditary gastrointestinal polyposis syndromes, whilst now well recognised, further complicates the creation of universal recommendations. In this review we draw comparison between the various international guidelines for the management of FAP, using examples to focus on thematic areas of agreement and divergence. However, beyond this, we also wish to highlight the persisting evidence gaps in clinical management, and any areas of ongoing debate among clinicians, where we are yet to establish the optimal approach.

PMID:40192835 | DOI:10.1007/s10689-025-00462-y

NAR Genom Bioinform. 2025 Apr 4;7(2):lqaf033. doi: 10.1093/nargab/lqaf033. eCollection 2025 Jun.

ABSTRACT

We describe FoundHaplo, an identity-by-descent algorithm that can be used to screen untyped disease-causing variants using single nucleotide polymorphism (SNP) array data. FoundHaplo leverages knowledge of shared disease haplotypes for inherited variants to identify those who share the disease haplotype and are, therefore, likely to carry the rare [minor allele frequency (MAF) ≤ 0.01%] variant. We performed a simulation study to evaluate the performance of FoundHaplo across 33 disease-harbouring loci. FoundHaplo was used to infer the presence of two rare (MAF ≤ 0.01%) pathogenic variants, SCN1B c.363C>G (p.Cys121Trp) and WWOX c.49G>A (p.E17K), which can cause mild dominant and severe recessive epilepsy, respectively, in the Epi25 cohort and the UK Biobank. FoundHaplo demonstrated substantially better sensitivity at inferring the presence of these rare variants than existing genome-wide imputation. FoundHaplo is a valuable screening tool for searching disease-causing variants with known founder effects using only SNP genotyping data. It is also applicable to nonhuman applications and nondisease-causing traits, including rare-variant drivers of quantitative traits. The FoundHaplo algorithm is available at https://github.com/bahlolab/FoundHaplo (DOI:10.5281/zenodo.8058286).

PMID:40191585 | PMC:PMC11970371 | DOI:10.1093/nargab/lqaf033

Eur J Pediatr. 2025 Apr 5;184(5):281. doi: 10.1007/s00431-025-06101-z.

ABSTRACT

The diagnosis and treatment of rare diseases present significant global challenges. This study aimed to identify the difficulties faced by specialists in the diagnosis and management of rare diseases, as well as to gather their recommendations for potential solutions. An expert committee specializing in inborn metabolic disease and genetics developed a comprehensive survey, which was then distributed online to professionals working with rare diseases. A total of 21 specialists actively engaged in the management of rare diseases participated in the survey. All participants acknowledged the substanstial significant diagnostic challenges associated with rare diseases, with 86% indicating that these diagnostic challenges negatively affect their clinical practice. The primary obstacles encountered in the diagnosis and follow-up of rare diseases were low awareness, a lack of a multidisciplinary approach, insufficient numbers of specialists and inadequate infrastructure, limited newborn screening programs, challenges in accessing treatment, and insufficient psychosocial support. All participants emphasized the need for a multidisciplinary approach in the management of rare diseases. Proposed solutions included enhanced training for healthcare professionals, the establishment of multidisciplinary teams and diagnostic algorithms, the regular convening of councils and meetings, and the establishment of robust registries. While all participants rated their own clinical experience as proficient in diagnosing and treating rare diseases, the establishment of multidisciplinary teams was the most frequently suggested area for improvement.

CONCLUSION: Addressing the challenges in the diagnosis, treatment, and monitoring of rare diseases requires a multifaceted approach, including raising awareness, enhancing patient services, developing robust research and improving the infrastructure, establishing multidisciplinary care frameworks, and implementing preventive medicine and social policies.

WHAT IS KNOWN: • It is estimated that over 300 million people globally are living with one or more rare diseases. The process of diagnosis, treatment, and follow-up of rare diseases involves significant global challenges.

WHAT IS NEW: • In our study, the difficulties encountered by specialists in the diagnosis and treatment of rare diseases in Türkiye and solution suggestions are presented. This is the first study on this subject in Türkiye.

PMID:40186762 | DOI:10.1007/s00431-025-06101-z

Front Public Health. 2025 Mar 20;13:1450625. doi: 10.3389/fpubh.2025.1450625. eCollection 2025.

ABSTRACT

INTRODUCTION: The role of public health has evolved from addressing infectious diseases to encompass non-communicable diseases. Individuals with genetic disorders and rare diseases constitute a particularly vulnerable population, requiring tailored public health policies, practical implementation strategies, and a long-term vision to ensure sustainable support. Given the prolonged duration and significant costs often associated with these conditions, comprehensive, patient-centered, and cost-effective approaches are essential to safeguard their physical and mental well-being.

AIMS: To summarize definitions and concepts related to health, public health, rare diseases, and to highlight the role of integrating public health interventions into routine care in improving patient outcomes. Hemophilia was selected as an exemplary rare disease due to its significant lifetime treatment costs and the recent approval and pricing of its gene therapy as the world's most expensive drug, highlighting the critical importance of public health policies in ensuring equitable access to care and treatment.

METHODS: A narrative literature review was conducted between July 2023 and December 2024, searching PubMed, Google Scholar, and Google for various topics related to rare diseases, public health, and hemophilia.

RESULTS: Public health can play an important role in improving the health outcomes of people with rare diseases by implementing conceptual and applied models to accomplish a set of objectives. Over the past two decades, legislative and regulatory support in high income countries (HICs) has facilitated the development and approval of diagnostics and treatments for several rare diseases leading to important advancements. In contrast, many low- and middle-income countries (LMICs) face obstacles in enacting legislation, developing regulations, and implementing policies to support rare disease diagnosis and treatment. More investment and innovation in drug discovery and market access pathways are still needed in both LMICs and HICs. Ensuring the translation of public health policies into regulatory measures, and in turn implementing, and regularly evaluating these measures to assess their effectiveness is crucial. In the case of hemophilia, public health can play a pivotal role.

CONCLUSION: Enhancing public health surveillance, policies, and interventions in hemophilia and other rare diseases can bridge data gaps, support access to equitable treatment, promote evidence-based care, and improve outcomes across the socioeconomic spectrum.

PMID:40182514 | PMC:PMC11965367 | DOI:10.3389/fpubh.2025.1450625

Pathologie (Heidelb). 2025 May;46(3):142-151. doi: 10.1007/s00292-025-01426-w. Epub 2025 Apr 3.

ABSTRACT

Molecular methods have improved the diagnosis of many rare tumors but have also revealed their limitations. Gene fusions that originally appeared specific occur "promiscuously" in biologically distinct mesenchymal and epithelial tumors, underscoring the importance of integrated morphologic-molecular diagnostics. By contrast, similar tumor biology-which is difficult to prove in rare tumors-supports the concept of entity-defining gene fusions for a spectrum of morphologically diverse tumors. Still other rare tumors have no diagnostically or prognostically helpful molecular profile, and their rarity and lack of authentic tumor models are obstacles to the use of, for example, new single-cell-based molecular or AI-assisted morphological methods and preclinical functional analyses. These peculiarities of rare tumors are illustrated by thymic, testicular, salivary gland, and soft tissue neoplasms.

PMID:40178563 | DOI:10.1007/s00292-025-01426-w

Neurogenetics. 2025 Apr 3;26(1):41. doi: 10.1007/s10048-025-00822-x.

ABSTRACT

Neurodevelopmental, jaw, eye, and digital syndrome (NEDJED) is a rare autosomal dominant condition that has demonstrated diverse phenotypes. This is the second case report published on this condition, covering the disease history of an 8 year old patient with a severe manifestation of the disease. The patient was born with hydrocephalus, and demonstrated major developmental delay as he aged. Whole-genome sequencing of the patient and his parents was conducted, detecting a de novo variant, NM_001378974.1:c.1220 A > T [p.Lys407Ile], located in the conserved WD4 region of the WD40 domain of FBXW11, which is consistent with all previously reported patients. The phenotype of the patient is presented with a focus on MRI and EEG features, including images and detailed description for both. While the patient's phenotype is overall consistent with previous findings, there are a number of major factors we believe are caused by the FBXW11 variant that have not been previously described, such as the patient's complete inability to walk.

PMID:40178747 | DOI:10.1007/s10048-025-00822-x

Brain Commun. 2025 Mar 17;7(2):fcaf113. doi: 10.1093/braincomms/fcaf113. eCollection 2025.

ABSTRACT

Somatic mosaic variants contribute to focal epilepsy, with variants often present only in brain tissue and not in blood or other samples typically assayed for genetic testing. Thus, genetic analysis for mosaic variants in focal epilepsy has been limited to patients with drug-resistant epilepsy who undergo surgical resection and have resected brain tissue samples available. Stereo-EEG (sEEG) has become part of the evaluation for many patients with focal drug-resistant epilepsy, and sEEG electrodes provide a potential source of small amounts of brain-derived DNA. We aimed to identify, validate, and assess the distribution of deleterious mosaic variants in epilepsy-associated genes in DNA extracted from trace brain tissue on individual sEEG electrodes. We enrolled a prospective cohort of 10 paediatric patients with drug-resistant epilepsy who had sEEG electrodes implanted for invasive monitoring. We extracted unamplified DNA and in parallel performed whole-genome amplification from trace brain tissue on each sEEG electrode. We also extracted DNA from resected brain tissue and blood/saliva samples where available. We performed deep sequencing (panel and exome) and analysis for candidate germline and mosaic variants. We validated candidate mosaic variants and assessed the variant allele fraction in amplified and unamplified electrode-derived DNA and across electrodes. We extracted unamplified DNA and performed whole-genome amplification from >150 individual electrodes from 10 individuals. Immunohistochemistry confirmed the presence of neurons in the brain tissue on electrodes. Deep sequencing and analysis demonstrated similar depth of coverage between amplified and unamplified DNA samples but significantly more potential mosaic variants in amplified samples. We validated four deleterious mosaic variants in epilepsy-associated genes in electrode-derived DNA in three patients who underwent laser ablation and did not have resected brain tissue samples available. Three of the four variants were detected in both amplified and unamplified electrode-derived DNA, with higher variant allele fraction observed in DNA from electrodes in closest proximity to the electrical seizure focus in one case. We demonstrate that mosaic variants can be identified and validated from DNA extracted from trace brain tissue on individual sEEG electrodes in patients with drug-resistant focal epilepsy, from both unamplified and amplified electrode-derived DNA. Our findings support a relationship between the extent of regional genetic abnormality and electrophysiology and suggest that with further optimization, this minimally invasive diagnostic approach holds promise for advancing precision medicine for patients with drug-resistant epilepsy as part of the surgical evaluation.

PMID:40177531 | PMC:PMC11961356 | DOI:10.1093/braincomms/fcaf113

J Health Popul Nutr. 2025 Apr 2;44(1):103. doi: 10.1186/s41043-025-00845-y.

ABSTRACT

Sturge-Weber Syndrome (SWS), is a rare neuro-oculo-cutaneous disorder that presents unique diagnostic and management challenges, particularly in resource-limited settings. This editorial reflects on a recent case of an undiagnosed SWS in an Ethiopian refugee patient in Sudan, highlighting systemic barriers to healthcare access during a time of war and the importance of clinical vigilance. We advocate for local and global initiatives to further enhance diagnostic capabilities, develop integrated care systems in recognition and management of such a rare and complex condition.

PMID:40176099 | DOI:10.1186/s41043-025-00845-y

Am J Ophthalmol. 2025 Mar 31:S0002-9394(25)00162-X. doi: 10.1016/j.ajo.2025.03.043. Online ahead of print.

ABSTRACT

OBJECTIVE: Neurotrophic keratopathy (NK) is a rare disease characterized by the loss of corneal innervation and increased vulnerability to injury. The diagnosis and treatment of NK can be challenging for pediatric patients and their caregivers. This study explores the experiences of caregivers navigating the diagnostic and treatment journey of pediatric patients with neurotrophic keratopathy.

DESIGN: This study is a qualitative study using semi-structured interviews.

SUBJECTS: Ten caregivers of pediatric patients with NK who had undergone corneal neurotization (CN) surgery.

METHODS: Caregivers were interviewed about their experiences related to the diagnostic process, treatment challenges, lifestyle changes, and the impact of CN surgery. Interviews were recorded, transcribed, and analyzed using an inductive-deductive approach to identify recurring themes.

MAIN OUTCOMES: Caregiver experiences and perceptions of diagnostic delays, information-seeking behaviors, lifestyle changes, and the effects of CN surgery on corneal health and quality of life.

RESULTS: Five key themes emerged from the analysis: (1) Delays in diagnosis due to insufficient specialist knowledge; (2) Caregivers' proactive efforts in seeking information; (3) Substantial lifestyle changes required by NK; (4) The impact of CN surgery on corneal health and quality of life; and (5) Variability in healthcare experiences, highlighting the need for effective communication. Caregivers expressed frustration with diagnostic delays and highlighted their reliance on external support networks.

CONCLUSIONS: This study illustrates the need for enhanced awareness among clinicians about NK and the benefits of narrative medicine in fostering caregiver-provider relationships. The challenges reported by families navigating NK inform strategies that may improve diagnosis and treatment of NK.

PMID:40174715 | DOI:10.1016/j.ajo.2025.03.043

Pediatr Blood Cancer. 2025 Apr 2:e31697. doi: 10.1002/pbc.31697. Online ahead of print.

ABSTRACT

Parents of children with complex vascular anomalies (VAs) struggle to locate credible information. We explored whether their perceptions of the adequacy of VA-related information were associated with caregiver burden, anxiety, child health, and their ability to navigate the healthcare system and seek information. We also examined how their perceptions of clinician knowledge and communication affect their perceptions of information adequacy. A total of 86 parents completed our online survey. Perceived information adequacy was associated with lower anxiety, greater ability to navigate the healthcare system, greater clinician knowledge, and better clinician communication. These data identify important communication barriers that future research studies should address.

PMID:40172173 | DOI:10.1002/pbc.31697

Biochemistry. 2025 Apr 15;64(8):1698-1719. doi: 10.1021/acs.biochem.4c00722. Epub 2025 Apr 1.

ABSTRACT

Rare diseases are a diverse group of disorders that, despite each individual condition's rarity, collectively affect a significant portion of the global population. Currently approximately 10,000 rare diseases exist globally, with 80% of these diseases being identified as having genetic origins. In this Review, we examine data from the CAS Content Collection to summarize scientific progress in the area of rare diseases. We examine the publication landscape in the area in an effort to provide insights into current advances and developments. We then discuss the evolution of key concepts in the field, genetic associations, as well as the major technologies and development pipelines of rare disease treatments. We focus our attention on three specific rare diseases: (i) amyotrophic lateral sclerosis, a terminal neurodegenerative disease affecting the central nervous system resulting in progressive loss of motor neurons that control voluntary muscles; (ii) Huntington's disease, another terminal neurodegenerative disease that causes progressive degeneration of nerve cells in the brain, with a wide impact on a person's functional abilities; and (iii) myasthenia gravis, a chronic autoimmune synaptopathy leading to skeletal muscle weakness. While the pathogenesis of these rare diseases is being elucidated, there is neither a cure nor preventative treatment available, only symptomatic treatment. The objective of the paper is to provide a broad overview of the evolving landscape of current knowledge on rare diseases and specifically on the biology and genetics of the three spotlighted diseases, to outline challenges and evaluate growth opportunities, an aim to further efforts in solving the remaining challenges.

PMID:40169538 | DOI:10.1021/acs.biochem.4c00722

Res Sq [Preprint]. 2025 Mar 20:rs.3.rs-5968078. doi: 10.21203/rs.3.rs-5968078/v1.

ABSTRACT

A time-release ion matrix (TRIM) restores damaged tissue following injury through local ion release to stimulate regenerative gene expression. Here we report the use of CoO-TRIM, an FDA-designated Rare Pediatric Disease Drug, to restore muscle function and structure in the context of debilitating muscle disease. We demonstrate in an established animal model of Duchenne Muscular Dystrophy (DMD), the D2.mdx mouse, that tibialis anterior (TA) muscles receiving a single injection of CoO-TRIM exhibit greater active force, myofiber size and regeneration through 70 days post-treatment compared to D2.mdx receiving vehicle alone. TRIM promoted upregulation of pro-angiogenic growth factor (vascular endothelial growth factor) and increased muscle microvasculature. These findings indicate that CoO-TRIM stimulates growth factors to promote the restoration of muscle structure and function of severely dystrophic mice in vivo without toxicity. We conclude that CoO-TRIM is a first-in-class therapeutic compound to combat soft tissue disease by restoring tissue integrity. Moreover, this novel treatment strategy could benefit both early and late-stage DMD patients.

PMID:40166018 | PMC:PMC11957216 | DOI:10.21203/rs.3.rs-5968078/v1

Orphanet J Rare Dis. 2025 Apr 1;20(1):150. doi: 10.1186/s13023-025-03656-w.

ABSTRACT

Diagnosing rare diseases is challenging due to their low prevalence, diverse presentations, and limited recognition, often leading to diagnostic delays and errors. This study evaluates the effectiveness of multiple large language models (LLMs) in identifying rare diseases, comparing their performance with that of human physicians using real clinical cases. We analyzed 152 rare disease cases from the Chinese Medical Case Repository using four LLMs: ChatGPT-4o, Claude 3.5 Sonnet, Gemini Advanced, and Llama 3.1 405B. Overall, the LLMs performed better than human physicians, and Claude 3.5 Sonnet achieved the highest accuracy at 78.9%, significantly surpassing the accuracy of human physicians, which was 26.3%. These findings suggest that LLMs can improve rare disease diagnosis and serve as valuable tools in clinical settings, particularly in regions with limited resources. However, further validation and careful consideration of ethical and privacy issues are necessary for their effective integration into medical practice.

PMID:40165285 | DOI:10.1186/s13023-025-03656-w

bioRxiv [Preprint]. 2025 Mar 10:2025.03.07.642063. doi: 10.1101/2025.03.07.642063.

ABSTRACT

BACKGROUND: Changes in RNA splicing over the course of evolution have profoundly diversified the functional landscape of the human genome. While DNA sequences proximal to intron-exon junctions are known to be critical for RNA splicing, the impact of distal intronic sequences remains underexplored. Emerging evidence suggests that inverted pairs of intronic Alu elements can promote exon skipping by forming RNA stem-loop structures. However, their prevalence and influence throughout evolution remain unknown.

RESULTS: Here, we present a systematic analysis of inverted Alu pairs across the human genome to assess their impact on exon skipping through predicted RNA stem-loop formation and their relevance to hominoid evolution. We found that inverted Alu pairs, particularly pairs of AluY-AluSx1 and AluSz-AluSx, are enriched in the flanking regions of skippable exons genome-wide and are predicted to form stable stem-loop structures. Exons defined by weak 3' acceptor and strong 5' donor splice sites appear especially prone to this skipping mechanism. Through comparative genome analysis across nine primate species, we identified 67,126 hominoid-specific Alu insertions, primarily from AluY and AluS subfamilies, which form inverted pairs enriched across skippable exons in genes of ubiquitination-related pathways. Experimental validation of exon skipping among several hominoid-specific inverted Alu pairs further reinforced their potential evolutionary significance.

CONCLUSION: This work extends our current knowledge of the roles of RNA secondary structure formed by inverted Alu pairs and details a newly emerging mechanism through which transposable elements have contributed to genomic innovation across hominoid evolution at the transcriptomic level.

PMID:40161837 | PMC:PMC11952303 | DOI:10.1101/2025.03.07.642063

bioRxiv [Preprint]. 2025 Mar 14:2025.03.12.642857. doi: 10.1101/2025.03.12.642857.

ABSTRACT

Therapeutic strategies for Duchenne Muscular Dystrophy (DMD) will likely require complementary approaches. One possibility is to explore genetic modifiers that improve muscle regeneration and function. The beneficial effects of the overexpression of Jagged-1 were described in escaper golden retriever muscular dystrophy (GRMD) dogs that had a near-normal life and validated in dystrophin-deficient zebrafish (1). To clarify the underlying biology of JAG1 overexpression in dystrophic muscles, we generated a transgenic mouse (mdx5cv-JAG1) model that lacks dystrophin and overexpresses human JAG1 in striated muscles. Skeletal muscles from mdx5cv-JAG1 and mdx5cv mice were studied at one, four, and twelve-month time points. JAG1 expression in mdx5cv-JAG1 increased by three to five times compared to mdx5cv. Consequently, mdx5cv-JAG1 muscles were significantly bigger and stronger than dystrophic controls, along with an increased number of myofibers. Proteomics data show increased dysferlin in mdx5cv-JAG1 muscles and an association of Nsd1 with the phenotype. Our data supports the positive effect of JAG1 overexpression in dystrophic muscles.

PMID:40161820 | PMC:PMC11952387 | DOI:10.1101/2025.03.12.642857