Acta Biochim Pol. 2025 Jul 14;72:14777. doi: 10.3389/abp.2025.14777. eCollection 2025.

ABSTRACT

Although there no single, widely accepted definition of a "rare disease," this group of disorders includes conditions that affect only a small fraction of the population. A large number of rare diseases is caused by defined molecular defects, predominantly the occurrence of pathogenic variant(s) of genes. Thus, they are classified as "genetic diseases," among which there are many neurodegenerative disorders. Despite a low incidence of each such disease, majority of them are severe and no effective treatment is available. This creates a battery of problems for millions of people suffering from these disease as well as to their relatives and caregivers. However, the set of problems is larger; therefore, in this narrative review we summarize and discuss various kinds of problems caused by rare disease, including severe symptoms of patients, everyday problems of patients and caregivers, loneliness and social exclusion, diagnostic difficulties, unavailability of effective therapies and economic difficulties in introducing orphan drugs, and a complexity of studies on rare diseases due to low availability of biological material and complicated pathomechanisms. The global picture of the complex problems caused by rare diseases is presented.

PMID:40726965 | PMC:PMC12301258 | DOI:10.3389/abp.2025.14777

Orphanet J Rare Dis. 2025 Jul 28;20(1):386. doi: 10.1186/s13023-025-03882-2.

ABSTRACT

BACKGROUND: Diagnosing rare diseases traditionally requires patients to endure lengthy and challenging journeys to find specialists familiar with their conditions. This study advocates a paradigm shift in rare disease diagnosis, moving from patients seeking physicians to physicians actively identifying patients. Using hereditary angioedema (HAE) as an example, we demonstrate how this approach, supported by electronic medical records (EMRs), enables proactive care for patients with rare diseases. Our EMR system incorporates a free-text search engine to screen for patients with potential HAE based on clinical symptoms and laboratory tests. Search terms include recurrent skin edema, abdominal pain, laryngeal edema, and/or decreased C4 levels. Suspected cases are followed up by telephone calls from trained physicians, inviting patients to undergo confirmatory C1-INH and C4 testing and genetic testing to ensure accurate diagnosis and appropriate treatment.

RESULTS: Of 2,689 patients who met the screening criteria, 3,441 records were analyzed. Ninety-five patients had already been diagnosed with HAE. After excluding those with a known etiology for edema or characteristics inconsistent with HAE, three patients with unexplained cutaneous edema, abdominal pain, and/or laryngeal edema were included in the final screening. Laboratory tests confirmed HAE in all three, highlighting the effectiveness of this proactive approach.

CONCLUSIONS: This study underscores the transformative potential of EMRs in diagnosing rare diseases. By shifting the responsibility of identifying rare diseases from patients to healthcare professionals, we expedite diagnosis and exemplify the spirit of service in medicine, ensuring patients with rare diseases receive timely and effective care.

PMID:40722186 | DOI:10.1186/s13023-025-03882-2

J Health Psychol. 2025 Jul 29:13591053251354906. doi: 10.1177/13591053251354906. Online ahead of print.

ABSTRACT

Women who complain of bladder pain and urinary urgency and frequency wait years to receive the label of interstitial cystitis (IC), an "orphan disease" which has no known cause or cure. The current research used phenomenological research methods to understand the experiences of women who have IC as they affect their sexualities. Ten women with IC participated in individual, semi-structured interviews. Nine themes emerged from the interviews. Findings indicated that women who have IC experienced severely limited sexual relationships, negative physician-patient interactions, the necessity for self-management of symptoms and diminished quality of life. Their accounts underscore the profound impact IC has on sexuality, revealing how sexual experiences are deeply intertwined with the emotional, physical and medical challenges of the condition. These findings contribute to a deepened understanding of the experiences of women who have IC and help to increase physicians' understanding and awareness of the sexual effects that accompany IC.

PMID:40727966 | DOI:10.1177/13591053251354906

Cancer Control. 2025 Jan-Dec;32:10732748251364041. doi: 10.1177/10732748251364041. Epub 2025 Jul 28.

ABSTRACT

IntroductionThe purpose of this study was to identify patterns and themes that support participant engagement in patient-partnered cancer genomics research.MethodsThe Osteosarcoma (OS) and Leiomyosarcoma (LMS) Projects of Count Me In allow any patient with OS and LMS in the US and Canada to contribute their health information, tumor samples, and lived experience to an aggregated, public research database. We conducted in-depth interviews with research partners, including patients, caregivers, and advocates, who were purposefully sampled to ensure inclusion of racial and ethnic minorities, those with less than college education, and adolescents (age 12-17). Coding and analysis were conducted by the research team using NVivo to identify themes that support engagement.ResultsTen patients, ten caregivers, and six advocates were interviewed. Seven themes were identified that support participant engagement: (a) motivation, (b) respect, (c) trust, (d) inclusivity, (e) relationship, (f) engagement, and (g) empowerment. Research partners were motivated to serve others, play a part in scientific discovery, and play a role in a novel initiative. Respect was supported through timeliness in communication or follow-up, an appropriate amount of time and information requested, and an acknowledgement that illness may prevent participation. Trust was developed through ensuring adequate privacy/confidentiality safeguards and demonstrating transparency. Inclusivity was demonstrated through showcasing broad representation and mitigating technical barriers. Research partners wanted to feel a relationship with, and engaged and empowered by, researchers. Adolescents reported their parents were more engaged than they were.ConclusionsResearch partners, including patients, caregivers, and advocates, have a strong desire to engage with researchers. We identified seven themes to support engagement. Researchers can optimize their communication and operations to support participant engagement in cancer genomics research.

PMID:40719570 | DOI:10.1177/10732748251364041

Dis Model Mech. 2025 Jul 1;18(7):dmm052401. doi: 10.1242/dmm.052401. Epub 2025 Jul 28.

ABSTRACT

Rare diseases collectively impact hundreds of millions worldwide, yet the genetic causes of many remain unknown or poorly understood. Model organisms (MOs) - such as yeast, fly, zebrafish and mouse - provide powerful experimental systems for functional validation of candidate genes and variants, elucidation of gene function and disease mechanisms, and identification of potential therapeutic targets and treatments. However, gaps persist between clinical gene discovery and MO-based research. The Canadian Rare Diseases: Models and Mechanisms (RDMM) Network was established in 2014 to address this gap by linking clinicians with MO researchers through a scientist registry and peer-reviewed funding process. Over the past decade, the RDMM Network has funded over 160 collaborative projects, enabled insights into numerous rare conditions, and led to sustained partnerships and external funding. The RDMM Registry software has been adopted internationally, forming a network of interoperable registries that enable cross-border collaborations and expand access to MO expertise worldwide. Going forward, the Canadian RDMM Network remains committed to sharing its tools, processes and experience to help establish new RDMM-like networks worldwide and invites the global research community to join efforts to accelerate rare disease research.

PMID:40719025 | DOI:10.1242/dmm.052401

AAPS PharmSciTech. 2025 Jul 23;26(7):197. doi: 10.1208/s12249-025-03159-8.

ABSTRACT

The present work focuses on investigating the potential of nanovesicular drug and gene delivery systems in addressing therapeutic challenges associated with rare ocular diseases, including Leber's congenital amaurosis, retinitis pigmentosa, and Stargardt disease. These inherited retinal disorders are characterized by a genetic origin, progressive vision loss, and a lack of effective treatment options. Traditional drug delivery methods are limited by multiple ocular barriers such as the corneal epithelium, blood-aqueous barrier, and blood-retinal barrier, which significantly restrict drug penetration and therapeutic efficacy. Nanovesicular systems, including liposomes, niosomes, ethosomes, exosomes, and ultradeformable vesicles, have emerged as promising strategies to overcome these challenges by enhancing drug stability, enabling controlled release, and improving targeted delivery to ocular tissues. These self-assembled nanoscale carriers offer sustained drug release, prolonged ocular retention, and reduced systemic side effects, making them highly suitable for treating rare ocular disorders. Advances in surface functionalization, ligand-based targeting, and hybrid nanocarrier development have further optimized their therapeutic potential. Additionally, exosome-based and lipid nanoparticle-mediated gene delivery systems have demonstrated the ability to transport nucleic acids, including plasmid DNA, siRNA, and CRISPR components, for precise genetic modulation in inherited retinal diseases. Despite their potential, clinical translation remains challenging due to issues such as stability, large-scale manufacturing, and regulatory hurdles. Future research should focus on optimizing formulation strategies, improving ocular penetration, and addressing long-term safety concerns to advance nanovesicular platforms from preclinical studies to clinical applications. By overcoming these challenges, nanovesicular drug and gene delivery systems hold great promise in revolutionizing treatments for rare ocular diseases, offering more effective, targeted, and minimally invasive therapeutic solutions for patients with currently limited options.

PMID:40702295 | DOI:10.1208/s12249-025-03159-8

Eur J Trauma Emerg Surg. 2025 Jul 21;51(1):255. doi: 10.1007/s00068-025-02918-3.

ABSTRACT

PURPOSE: Fracture non-union (FNU) is a rare complication of bone fractures where healing does not occur without surgical intervention. This paper aims to summarize the current knowledge on FNUs from an orphan disease perspective, and to provide an overview of existing and some emerging treatment options.

METHODS: Literature review.

RESULTS: Epidemiological data on FNUs are limited and vary by population and methodology. While previously an overall estimate of 5-10% of nonunion of fractures has been reported, large epidemiological studies performed in Spain, Germany, Scotland and USA, reported that the prevalence of FNUs is less than 5 cases per 10.000 inhabitants justifying the criteria for an orphan designation. There are no approved pharmacological treatments for FNUs, highlighting the need for effective therapies. Current methods rely on mechanical stabilization of FNUs using various instrumentation with or without autologous bone grafting. Combining mechanical intervention and autologous bone grafting raises healing rates from 60-70% to more than 80%, but graft harvesting causes additional injury at the donor site. Lately, a novel drug, OSTEOGROW-C combining rhBMP6 with the patient's own blood coagulum as a carrier, augmented by synthetic ceramics for biomechanical support has been developed for the treatment of FNU. Results of preclinical studies suggested that OSTEOGROW-C is superior to other OSTEOGROW formulations and commercially available products.

CONCLUSION: Due to its low prevalence, FNU can be considered a rare disease. A novel drug, OSTEOGROW-C, represents a promising and safe therapeutic solution for inducing FNU healing.

PMID:40691747 | DOI:10.1007/s00068-025-02918-3

JMIR Public Health Surveill. 2025 Jul 18;11:e72590. doi: 10.2196/72590.

ABSTRACT

BACKGROUND: Caring for individuals with rare diseases (RDs) presents unique challenges that can significantly impact caregivers' quality of life (QoL). The World Health Organization Quality of Life-BREF (WHOQOL-BREF) is a widely used tool for assessing QoL across different populations.

OBJECTIVE: This study examines the QoL of caregivers of individuals with RDs and evaluates the psychometric properties of the WHOQOL-BREF in this population.

METHODS: A self-administered, anonymous, computer-assisted web-based survey was conducted among family caregivers of individuals with RDs in Poland between March and August 2024. Due to the lack of a national registry of patients with RDs, participants were recruited through convenience sampling via associations, foundations, and organizations of patients with RDs. Eligibility criteria included being 18 years and older of age, speaking Polish, being a caregiver of a person with a confirmed RD diagnosis, and providing informed consent. The survey included sociodemographic questions and the Polish version of the WHOQOL-BREF, which assesses QoL across 4 domains: physical health, psychological health, social relationships, and environment. Internal consistency was assessed using Cronbach α, and confirmatory factor analysis was conducted to examine the instrument's structural validity.

RESULTS: A total of 942 caregivers of individuals with various RDs participated in the study. Confirmatory factor analysis supported the 4-domain structure, with further improvement in a finally modified WHOQOL-BREF model (χ2243=1043.0; P<.001; Comparative Fit Index=0.919; Tucker-Lewis Index=0.907; root-mean-square error of approximation=0.059). Internal consistency was satisfactory, with Cronbach α values ranging from 0.70 (social relationships) to 0.84 (psychological health). Mean domain scores on a scale of 0-100 were 50.2 (SE 0.59; physical health), 54.9 (SE 0.59; psychological health), 51.3 (SE 0.67; social relationships), and 52.1 (SE 0.56; environment), with minimal floor and ceiling effects (≤1.4%) across domains. Younger female caregivers reported significantly lower psychological health (eg, mean 43.6, SE 0.59 vs mean 59.9, SE 10.0 for younger male caregivers) and social relationships (mean 39.3, SE 3.34 vs mean 55.0, SE 4.75) well-being compared to other groups. Exactly 151 (16%) of caregivers rated their overall QoL as poor or very poor, and 289 (30.7%) were dissatisfied or very dissatisfied with their health, with female caregivers reporting more dissatisfaction (n=263, 32.4%) than male caregivers (n=26, 20%). Overall, our findings demonstrate the robust psychometric properties of the WHOQOL-BREF among caregivers of people with RDs and provide domain-specific normative data to guide future research and interventions.

CONCLUSIONS: The WHOQOL-BREF is a reliable and valid instrument for assessing QoL among caregivers of individuals with RDs, though the social relationship domain may require further refinement. Caregivers experience varying QoL outcomes depending on demographic factors, highlighting the need for targeted support interventions. Future research should explore cultural adaptations and potential supplementary modules to enhance the instrument's applicability in caregiver populations.

PMID:40680179 | DOI:10.2196/72590

Orphanet J Rare Dis. 2025 Jul 17;20(1):368. doi: 10.1186/s13023-025-03893-z.

ABSTRACT

Adeno-associated virus (AAV), renowned for its exceptionally low pathogenicity and significant efficacy in clinical gene therapy, has emerged as a leading delivery vector in the field of gene therapy. AAV can achieve stable gene expression in various tissues, which has made it a promising treatment for genetic disorders. To date, eight AAV-based gene therapies have been approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). This review summarizes clinical trials of AAV gene therapies for rare diseases, including ophthalmic diseases, nervous system disorders, hematological diseases, neuromuscular diseases, lysosomal storage diseases. We also explore potential side effects and toxicities associated with AAV therapies. Our objective is to provide valuable insights for researchers and clinicians working on AAV-based therapies, helping improve the safety and effectiveness of these treatments.

PMID:40676625 | DOI:10.1186/s13023-025-03893-z

Sci Rep. 2025 Jul 17;15(1):25929. doi: 10.1038/s41598-025-11567-w.

ABSTRACT

Generative Pre-trained Transformer (ChatGPT) is a web-based artificial intelligence assistant with the potential to provide information, answer questions, and make recommendations on various topics. Rare cardiovascular diseases (rCVD) are among the health problems that require specialized knowledge and attention, and web databases provide relatively limited information. In this study, we investigated the accuracy and reliability of ChatGPT's answers to patients' possible questions about rCVD. ChatGPT was asked forty questions about rCVD. Based on current guidelines and information, academicians who are experts in their fields evaluated ChatGPT's answers to these questions. The success of ChatGPT, which has been repeatedly evaluated in classical diseases, was lower in rCVD. The responses to various questions exhibited significant similarity, with some answers including redundant information. In addition, ChatGPT did not give the desired answers to some questions. However, although some answers were longer than necessary, there was very little incorrect information in the answers. Although ChatGPT is competent in obtaining information about rCVD, physicians should clarify the answers given by ChatGPT to patients. Therefore, ChatGPT should be used as an auxiliary information acquisition tool rather than as a primary resource for patients with rCVD.

PMID:40676128 | DOI:10.1038/s41598-025-11567-w

Proc Natl Acad Sci U S A. 2025 Jul 22;122(29):e2509622122. doi: 10.1073/pnas.2509622122. Epub 2025 Jul 17.

ABSTRACT

While it is widely accepted that somatic variants that activate the PI3K-mTOR pathway are a major cause of drug-resistant focal epilepsy, typically associated with focal cortical dysplasia (FCD) type 2, understanding the mechanism of epileptogenesis requires identifying genotype-associated changes at the single-cell level, which is technically challenging with existing methods. Here, we performed single-nucleus RNA-sequencing (snRNA-seq) of 18 FCD type 2 samples removed surgically for treatment of drug-resistant epilepsy, and 17 non-FCD control samples, and analyzed additional published data comprising >400,000 single nuclei. We also performed simultaneous single-nucleus genotyping and gene expression analysis using two independent approaches: 1) a method that we called genotyping of transcriptomes enhanced with nanopore sequencing (GO-TEN) that combines targeted cDNA long-read sequencing with snRNA-seq, 2) ResolveOME snRNA-seq and DNA genotyping. snRNA-seq showed similar cell identities and proportions between cases and controls, suggesting that mosaic pathogenic variants in PI3K-mTOR pathway genes in FCD exert their effect by disrupting transcription in conserved cell types. GO-TEN and ResolveOME analyses confirmed that pathogenic variant-carrying cells have well-differentiated neuronal or glial identities, with enrichment of variants in cells of the neuroectodermal lineage, pointing to cortical neural progenitors as possible loci of somatic mutation. Within FCD type 2 lesions, we identified upregulation of PI3K-mTOR signaling and related pathways in variant-carrying neurons, downregulation of these pathways in non-variant-carrying neurons, as well as associated changes in microglial activation, cellular metabolism, synaptic homeostasis, and neuronal connectivity, all potentially contributing to epileptogenesis. These genotype-specific changes in mosaic lesions highlight potential disease mechanisms and therapeutic targets.

PMID:40674414 | DOI:10.1073/pnas.2509622122

medRxiv [Preprint]. 2025 Jun 28:2025.06.26.25330266. doi: 10.1101/2025.06.26.25330266.

ABSTRACT

Tubulinopathies encompass a wide spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked de novo or dominantly inherited TUBA4A missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, hereditary spastic ataxia, and more recently, an isolated report of congenital myopathy, the full phenotypic and genotypic spectrum of TUBA4A-related disorders remains incompletely characterised. In this multi-centre study, we identified 13 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Remarkably, affected individuals in 17 families presented with a primary axial myopathy without any identified CNS involvement or history of such disease. In the remaining two families, we observed probands with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness, establishing the first documented association between TUBA4A variants and multisystem proteinopathy. Our cohort exhibited diverse genotypes and associated inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had homozygous TUBA4A variants, where the biallelic genotype was found to be associated with the disease, and the heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous TUBA4A variants were classified as "isolated-sporadic cases" where parental samples were unavailable. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. We observed a range of disease onset, from congenital to late adulthood. Creatine kinase levels were also variable, ranging from normal to highly elevated. Cardiac function remained preserved across the cohort. Muscle biopsies revealed a range of pathologies, including myofibre size variation, myofibre atrophy, nemaline bodies, core-like regions, internal nuclei, and endomysial fibrosis. Immunohistochemical staining showed evidence of proteinopathy, with autophagic features and TUBA4A accumulation in patient myofibres. Complementary in silico and in vitro investigations suggested that the identified TUBA4A substitutions cause significant protein abnormalities and may differentially impact microtubule dynamics. Our findings establish myo-tubulinopathies as distinct clinical entities, encompassing both primary myopathies and multisystem proteinopathies with muscle involvement. This study broadens the phenotypic and genotypic spectrum of TUBA4A-related disorders beyond autosomal dominant or de novo mechanisms and neurodegenerative presentations. These results underscore the importance of considering TUBA4A variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement.

PMID:40666348 | PMC:PMC12262762 | DOI:10.1101/2025.06.26.25330266

Orphanet J Rare Dis. 2025 Jul 16;20(1):365. doi: 10.1186/s13023-025-03875-1.

ABSTRACT

BACKGROUND: Rare bone diseases (RBDs) are an important group of conditions characterized by abnormalities in bone and cartilage. Their large number, individual rarity, and heterogeneity make accurate and timely diagnosis challenging. Establishing correlations between genotype and phenotype (mainly via imaging) is critical for diagnosing RBDs. Image recognition artificial intelligence (AI) has the potential to significantly improve the diagnostic process by assisting healthcare providers to identify and differentiate imaging patterns associated with various RBDs. This survey study sought to assess the interest of various healthcare providers worldwide in utilizing an AI-based assistant tool for the differential diagnosis of RBDs.

METHOD: Survey data were collected from March to September 2024. The survey was performed online and the link was disseminated via direct email, newsletters, and flyers at scientific talks and conferences.

RESULTS: We received 103 completed surveys, representing respondents from 27 different countries covering most global regions, but mostly from Europe, the United States, and Canada. The majority of the participants are physicians (n = 92, 89%) and primarily work at academic medical centers (n = 84, 81%). While each participant could select multiple specialties, the most frequent clinician types were medical geneticists, pediatricians, and endocrinologists, accounting for 71 (69%) of the respondents. Ninety-four (91%) of the respondents find imaging to be very or extremely important, and the majority (n = 84, 81%) consider X-rays to be the most important imaging modality. Although around half of the participants (n = 45) have concerns about AI-related errors and consider the explainability of AI algorithms to be very (42/103) or extremely (9/103) important, 81% of the respondents report that they are somewhat (n = 39) or extremely (n = 45) likely to consider integrating image recognition AI into their current diagnostic workflow.

CONCLUSIONS: Most survey participants are open to integrating image recognition AI into their RBD diagnostic workflow. However, concerns about AI-related errors, privacy, and model interpretability highlight the importance of transparent collaboration between developers and healthcare professionals throughout the development process to ensure that such technologies are clinically trustworthy and practically adoptable.

PMID:40671115 | DOI:10.1186/s13023-025-03875-1

Brief Bioinform. 2025 Jul 2;26(4):bbaf329. doi: 10.1093/bib/bbaf329.

ABSTRACT

Precision medicine tailors medical procedures to individual genetic overviews and offers transformative solutions for rare genetic conditions. Machine learning (ML) has enhanced genome-based precision medicine (GBPM) by enabling accurate diagnoses, customized treatments, and risk assessments. ML tools, including deep learning and ensemble methods, process high-dimensional genomic data and reveal discoveries in rare diseases. This review analyzes the ML applications in GBPM, emphasizing its role in disease classification, therapeutic optimization, and biomarker discovery. Key challenges, such as computational complexity, data scarcity, and ethical concerns, are discussed alongside advancements such as hybrid ML models and real-time genomic analysis. Security issues, including data breaches and ethical challenges, are addressed. This review identifies future directions, emphasizing the need for comprehensible ML models, increasing data-sharing frameworks, and global collaborations. By integrating the current research, this study provides a comprehensive perspective on the use of ML for rare genetic disorders, paving the way for transformative advancements in precision medicine.

PMID:40668553 | DOI:10.1093/bib/bbaf329

Eur J Cancer. 2025 Aug 26;226:115602. doi: 10.1016/j.ejca.2025.115602. Epub 2025 Jul 5.

ABSTRACT

BACKGROUND: Evidence on patient pathways, care coordination, and patient needs in rare cancers (RC) is limited but essential for optimising healthcare systems and resource allocation. Addressing these gaps requires country-specific data reflecting national healthcare structures and cultural differences. This is the first study in Germany to explore these dimensions.

METHODS: Using methodological triangulation, we combined a literature review, exploratory interviews, and a cross-sectional anonymous online survey. The survey assessed diagnostic intervals, journeys, care coordination (German Care Coordination Instrument [CCI]), and involvement in medical decision-making (adapted Control Preference Scale) among adult patients with cancer in Germany. Diagnostic intervals were analysed using Kaplan-Meier and Cox regressions methods, CCI predictors using multivariate models.

FINDINGS: Patients with RC (338 of 1254 participants) reported longer median times from symptom onset to treatment (109 [IQR: 35-326] vs. common cancers (CC): 70 [35-185] days) and from first consultation to diagnosis (28 [14-90] vs. CC: 14 [7-35] days), particularly in rural areas (21 [7-60] vs. urban: 14 [7-42] days) (p < 0.001). Patients with RC more often first consulted general practitioners (65.6 %, CC: 28.1 %), saw more office-based physicians before diagnosis (1.99 [SD: 1.23], CC: 1.66 [0.90]), and were more frequently diagnosed at university hospitals (33.3 %, CC: 11.2 %) (p < 0.001). Discrepancies in preferred levels of involvement in decision-making and higher information needs (RC: 62.9 %, CC: 55.9 %, p = 0.047) were reported. The CCI varied according to cancer types.

INTERPRETATION: Patients with RC in Germany experience longer diagnostic pathways and fragmented care, highlighting the need for targeted, cross-sectoral care coordination and greater patient empowerment.

PMID:40664162 | DOI:10.1016/j.ejca.2025.115602

Orphanet J Rare Dis. 2025 Jul 16;20(1):363. doi: 10.1186/s13023-025-03892-0.

ABSTRACT

Therapeutic development for rare diseases is difficult for pharmaceutical companies due to significant scientific challenges, extensive costs, and low financial returns. It is increasingly common for caregivers and patient advocacy groups to partner with biomedical professionals to finance and develop treatments for rare diseases. This case study illustrates the story of Terry Pirovolakis, a father who partnered with biomedical professionals to develop the novel gene therapy, Melpida, within 36 months of the diagnosis of his infant son. We identify the factors that led to the success of Melpida and analyze the business model of Elpida Therapeutics, a social purpose corporation founded by Pirovolakis to reproduce the success of Melpida for other rare diseases. We conclude with four lessons from Melpida to inform caregivers like Pirovolakis on developing novel gene therapies to save their loved ones.

PMID:40665386 | DOI:10.1186/s13023-025-03892-0

Neurol Genet. 2025 Jul 3;11(4):e200277. doi: 10.1212/NXG.0000000000200277. eCollection 2025 Aug.

ABSTRACT

BACKGROUND AND OBJECTIVES: Nemaline myopathy (NM) is a congenital myopathy with a wide severity spectrum, from severe, generalized muscle weakness and respiratory failure in the neonatal period to mild, distal weakness in young adulthood. Eleven genes have been definitively established to cause the condition. Although some recurrent variants have been identified, the overall correlation of genotype with clinical severity in NM remains poor. This poses challenges when counseling families about prognosis after a diagnosis of NM is made. Better clinical and molecular predictors of outcome are needed for clinical trial readiness.

METHODS: A retrospective cohort analysis of 275 patients with a histopathologic diagnosis of NM and/or pathogenic variants in NM-associated genes was performed to identify relationships between early clinical findings and long-term outcomes, including need for respiratory and feeding support.

RESULTS: Early clinical predictors of long-term outcomes were identified: patients with hypotonia at birth had increased odds of requiring gastrostomy tubes, and patients with respiratory distress at birth had increased odds of requiring both gastrostomy tubes and invasive ventilation. Individuals with ACTA1-NM were more likely to require feeding tubes and invasive ventilation in the first year of life compared with those with NEB-related NM, but the odds of requiring invasive ventilation were similar after the first year of age. Additional clinical information is presented by genotype and severity class.

DISCUSSION: Neonatal findings of individuals with NM are correlated with long-term clinical outcomes, and there are some relationships between genotype and disease severity. Prospective longitudinal studies are needed to confirm these findings and evaluate for additional early clinical predictors of prognosis.

PMID:40661861 | PMC:PMC12258819 | DOI:10.1212/NXG.0000000000200277

Neurosci Res. 2025 Jul 11:104940. doi: 10.1016/j.neures.2025.104940. Online ahead of print.

ABSTRACT

This study assessed whether asfotase alfa treatment in Akp2-/- mice (a model of hypophosphatasia) reversibly normalizes GABA and cystathionine in brain tissue to concentrations in wild-type mice. To do this metabolite concentrations were analyzed at postnatal days 10 and 48. The data showed that asfotase alfa treatment significantly increased GABA concentrations and significantly decreased cystathionine concentrations in Akp2-/- mice compared with vehicle-treated Akp2-/- mice (GABA: 1.28±0.03 vs 0.48±0.02 μmol/g [P<0.0001]; cystathionine: 0.06±0.00 vs 0.60±0.02 μmol/g [P<0.0001]). Concentrations post-treatment were similar to those in wild-type mice. Asfotase alfa withdrawal negated these effects. These analyses demonstrated that asfotase alfa restores GABA and cystathionine concentrations in a murine model of hypophosphatasia.

PMID:40653050 | DOI:10.1016/j.neures.2025.104940

Int J Mol Sci. 2025 Jun 26;26(13):6126. doi: 10.3390/ijms26136126.

ABSTRACT

Recent diagnostic advances reveal that lymphatic disease in Noonan syndrome (NS) and other NS-like RASopathies often stems from central conducting lymphatic anomalies (CCLAs). The RAS/MAPK-ERK pathway plays a central role in lymphangiogenesis. Targeting this pathway with MEK-inhibitor trametinib has emerged as a promising therapeutic strategy for managing CCLAs in patients with NS-like RASopathies. This case series assessed the clinical outcomes of trametinib therapy in eight patients with NS-like RASopathies and CCLA, each offering unique insights into the therapeutic efficacy of MEK inhibition. In infants, a lower dose of 0.01 mg/kg/day and earlier discontinuation of trametinib therapy effectively alleviated the symptoms of congenital chylothorax and rescued the lymphatic phenotype, compared to similar published cases. Moreover, four patients aged >11 y showed a slower response and did not achieve complete symptomatic recovery. In conclusion, it is advised to consider trametinib therapy for patients with severe, therapy-refractory CCLA in patients with NS-like RASopathies. However, individual responses to trametinib therapy may vary, with some patients demonstrating more favorable outcomes than others. Further investigation into potential enhancers and suppressors of the lymphatic phenotype is necessary for more accurate treatment predictions. While these factors are likely genetic, we cannot rule out other intrinsic or physiological factors.

PMID:40649904 | DOI:10.3390/ijms26136126

Int J Mol Sci. 2025 Jun 24;26(13):6069. doi: 10.3390/ijms26136069.

ABSTRACT

Zebrafish is a well-recognized model for studying human genetic disorders. Recently, we proposed the homozygous cdkl5sa21938 mutant zebrafish as a model of CDKL5 deficiency disorder (CDD), a developmental epileptic encephalopathy with diverse symptoms. This study aimed to explore Cdkl5-associated molecular mechanisms in zebrafish and assess their similarity to those in mammals. We conducted RNA sequencing on whole cdkl5-/- zebrafish and wild-type siblings at 5 and 35 days post-fertilization (dpf) to compare their gene expression profiles. Most significant differentially expressed genes (DEGs) were related to muscle, neuronal, and visual systems which are affected in CDD. Gene Ontology analysis revealed downregulated DEGs enriched in muscle development, extracellular matrix, and actin cytoskeleton functions at both stages, while upregulated DEGs were enriched in eye development functions at 35 dpf. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed enrichment of downregulated DEGs in focal adhesion and extracellular matrix (ECM)-receptor interaction pathways at both stages. Neuronal development DEGs were mainly downregulated at both stages, while synaptic signaling DEGs were upregulated at 35 dpf. Crossing cdkl5-/- mutants with the Hb9:GFP transgenic line showed fewer motor neuron cells with shorter axons compared to the wild type, which may explain the impaired motor phenotype observed in zebrafish and CDD patients. Moreover, we identified key downregulated DEGs related to cartilage development at both stages and bone development at 35 dpf, potentially explaining the skeletal defects seen in zebrafish and CDD individuals. In conclusion, Cdkl5 loss in zebrafish leads to dysregulation of genes involved in CDKL5-associated functions in mammals, providing new insights into its less studied functions and phenotypes.

PMID:40649845 | DOI:10.3390/ijms26136069