Genes (Basel). 2025 May 22;16(6):614. doi: 10.3390/genes16060614.

ABSTRACT

Background/Objectives: Rare diseases are predominantly genetic in etiology and characterized by a prolonged 'diagnostic odyssey'. Advances in genetic testing (GT) have helped shorten the time to diagnosis for rare/undiagnosed conditions. We aimed to synthesize the evidence on psychosocial factors related to GT for rare diseases to inform more person-centered approaches to care. Methods: We conducted a systematic literature search in six databases using structured terms (September 2024). Retrieved articles underwent independent dual review. Data were extracted and collated in tables for analysis. Thematic analysis was used to identify promoters/barriers to GT for patients and families. Findings were validated by a patient advocate and were reported using PRISMA-ScR guidelines. Synthesized findings were mapped to the Theory of Planned Behavior to inform intervention development. Results: Of 1730 retrieved articles, 32 were included for data extraction/synthesis. Studies employed qualitative (n = 19), quantitative (n = 10), and mixed-methods (n = 3) approaches. Nearly all (29/32, 91%) were non-interventional, reporting on decision-making cognitions/processes (19/32, 59%), attitudes/preferences (15/32, 47%), psychosocial impact (6/32, 19%), and knowledge/awareness (4/32, 8%) of pre-conception/prenatal/diagnostic GT and carrier screening. Promoters included understanding GT, ending the diagnostic odyssey, actionable outcomes, personal/family history, altruism, and reproductive decision-making. Barriers included logistical (e.g., distance, cost), psychological burden, perceived lack of benefit, and discrimination/social stigma concerns. Conclusions: Some psychosocial factors related to GT for rare diseases overlap with those in literature on GT for common conditions. Identified factors represent targets for theory-informed, person-centered interventions to support high-quality GT decisions that are informed and aligned with patient/family values and preferences.

PMID:40565506 | DOI:10.3390/genes16060614

Med Sci (Basel). 2025 Jun 9;13(2):75. doi: 10.3390/medsci13020075.

ABSTRACT

Background: Next-generation sequencing (NGS), particularly whole-exome sequencing (WES), has become a powerful diagnostic tool for rare genetic conditions. However, its success rate varies based on the underlying genetic etiology and the population studied. Methods: This retrospective study evaluated the diagnostic yield of NGS in a cohort of 137 pediatric patients with suspected rare genetic disorders in Bulgaria, a setting where such testing is not reimbursed and must be self-funded. The patients underwent either WES or targeted gene panel testing based on clinical presentation, family history, and genetic evaluation. Results: The overall diagnostic yield was 45.99%, with WES achieving 51.25% and targeted testing achieving 38.60%. The highest yield was observed in patients presenting with both dysmorphic features and neurodevelopmental delays (62.5%), while the lowest was observed among those with isolated neurodevelopmental issues (10%). A significant portion of the identified variants (35.9%) were novel. Eight patients were diagnosed with copy number variants (CNVs) detected only through WES. Conclusions: Our findings illustrate the value of WES as a first-line test and highlight the impact of deep phenotyping on diagnostic success. This study also emphasizes the need for a population-specific reference genome and equal access to genomic diagnostics in all European countries.

PMID:40559233 | DOI:10.3390/medsci13020075

Front Integr Neurosci. 2025 Jun 9;19:1574758. doi: 10.3389/fnint.2025.1574758. eCollection 2025.

ABSTRACT

There is increasing interest in the utility of electrophysiological measures such as resting EEG and evoked potential (EPs) to serve as biomarkers to facilitate therapeutic development for rare genetic neurodevelopmental disorders (NDDs). Research on this topic thus far has been encouraging, but has also revealed the necessity for unique methods when acquiring EEG and EPs in children with genetic NDDs. Details of these methods are typically beyond the scope of research publications, yet are crucial to the quality and ultimately, usability of the data. In the current manuscript, we detail the methods that we have developed for acquiring EEG and EPs as part of multi-site studies with participants with Rett syndrome, CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome. By making our methods accessible, we hope to support other groups interested in acquiring EEG and/or EPs as part of clinical trials or research studies with individuals with genetic NDDs, including groups without prior experience with EEG/EP acquisition. The paper is presented as step-by-step procedures followed by a discussion of issues that may arise during acquisition and ways to troubleshoot these issues. We then discuss considerations for choosing EEG equipment and study paradigms and briefly, considerations for data analysis.

PMID:40552096 | PMC:PMC12183233 | DOI:10.3389/fnint.2025.1574758

Hosp Pract (1995). 2025 Feb;53(1):2520743. doi: 10.1080/21548331.2025.2520743. Epub 2025 Jun 22.

ABSTRACT

BACKGROUND: Porphyria is an orphan disease classified as a genetic disorder caused by a partial or high-grade deficiency of enzymes involved in the synthesis of heme, an essential component of hemoglobin. This deficiency results in the accumulation of porphyrins (ALAS1 and PBG), intermediates in the heme metabolic pathway. This accumulation triggers porphyria attacks. In Colombia the Heme Arginate and Human Hematin are the therapeutics alternatives for the management of porphyria Attacks.

OBJECTIVE: To evaluate the comparative effectiveness of heme arginate versus human hemin for treating porphyria attacks in hospitalized patients across three institutions in Medellin, Colombia.

METHODS: An observational and analytical study was conducted to compare the outcomes of treatment with human hematin versus heme arginate in clinical episodes of patients diagnosed with porphyria between 2015-2021.

RESULTS: In episodes treated with heme arginate (ArgH), 75% achieved pain control or reduction, 41.6% showed a reduction in opioid dosage, and 88.8% achieved resolution of the Porphyria attack. For episodes treated with human hematin (HH), 85.3% achieved pain control or reduction, 53.6% showed a reduction in opioid dosage, and 90.2% achieved resolution of the attack. When evaluating the effectiveness of both treatments, no statistically significant differences were observed across the three predefined effectiveness outcomes of the study.

CONCLUSIONS: This study provides a comparative evaluation of heme arginate (ArgH) and human hematin (HH) in the management of Porphyria attacks, demonstrating that both treatments are similarly effective in achieving pain control, reducing opioid use, and resolving clinical attacks.

PMID:40545748 | DOI:10.1080/21548331.2025.2520743

Skelet Muscle. 2025 Jun 20;15(1):17. doi: 10.1186/s13395-025-00382-6.

ABSTRACT

BACKGROUND: Dystrophin-deficient zebrafish larvae are a small, genetically tractable vertebrate model of Duchenne muscular dystrophy that is well suited for early-stage therapeutic development. However, current approaches for evaluating their mobility, a physiologically relevant therapeutic outcome, yield data of low resolution and high variability that provides minimal insight into potential mechanisms responsible for their abnormal locomotion.

METHODS: To address these issues, we used high speed videography and deep learning-based markerless motion capture to quantify escape response (ER) swimming kinematics of two dystrophic zebrafish strains (sapje and sapje-like). Each ER was partitioned into an initiating C-start, a subsequent power stroke, and a final burst of undulatory swimming activity.

RESULTS: Markerless motion capture provided repeatable, high precision estimates of swimming kinematics. Random forest and support vector machine prediction models identified overall ER distance and peak speed, the instantaneous speed conferred by the power stroke, and the average speed and distance covered during burst swimming as the most predictive biomarkers for differentiating dystrophic from wild-type larvae. For each of these predictors, mutant and wild-type larvae differed markedly with effect sizes ranging from 2.4 to 3.7 standard deviations. To identify mechanisms underlying these performance deficits, we evaluated the amplitude and frequency of propulsive tail movements. There was little evidence that tail stroke amplitude was affected by the absence of dystrophin. Instead, temporal aspects of tail kinematics, including tail maximal angular velocity during the C-start and power stroke and tail stroke frequency during burst swimming, were slowed in mutants. In fact, tail kinematics were as effective as direct, non-survival in vitro assessments of tail muscle contractility in differentiating mutant from wild-type larvae.

CONCLUSIONS: ER kinematics can be used as precise and physiologically relevant biomarkers of the dystrophic phenotype, may serve as non-lethal proxies for skeletal muscle dysfunction, and reveal new insights into why mobility is impaired in the absence of dystrophin. The approach outlined here opens new possibilities for the design and interpretation of studies using zebrafish to model movement disorders.

PMID:40542412 | DOI:10.1186/s13395-025-00382-6

J Med Internet Res. 2025 Jun 18;27:e69929. doi: 10.2196/69929.

ABSTRACT

BACKGROUND: Diagnosing rare diseases remains challenging due to their inherent complexity and limited physician knowledge. Large language models (LLMs) offer new potential to enhance diagnostic workflows.

OBJECTIVE: This study aimed to evaluate the diagnostic accuracy of ChatGPT-4o and 4 open-source LLMs (qwen2.5:7b, Llama3.1:8b, qwen2.5:72b, and Llama3.1:70b) for rare diseases, assesses the language effect on diagnostic performance, and explore retrieval augmented generation (RAG) and chain-of-thought (CoT) reasoning.

METHODS: We extracted clinical manifestations of 121 rare diseases from China's inaugural rare disease catalog. ChatGPT-4o generated a primary and 5 differential diagnoses, while 4 LLMs were assessed in both English and Chinese contexts. The lowest-performing model underwent RAG and CoT re-evaluation. Diagnostic accuracy was compared via the McNemar test. A survey evaluated 11 clinicians' familiarity with rare diseases.

RESULTS: ChatGPT-4o demonstrated the highest diagnostic accuracy with 90.1%. Language effects varied across models: qwen2.5:7b showed comparable performance in Chinese (51.2%) and English (47.9%; χ²1=0.32, P=.57), whereas Llama3.1:8b exhibited significantly higher English accuracy (67.8% vs 31.4%; χ²1=40.20, P<.001). Among larger models, qwen2.5:72b maintained cross-lingual consistency considering the odds ratio (OR; Chinese: 82.6% vs English: 83.5%; OR 0.88, 95% CI 0.27-2.76,P=1.000), contrasting with Llama3.1:70b's language-dependent variation (Chinese: 80.2% vs English: 90.1%; OR 0.29,95% CI 0.08-0.83, P=.02). Cross-model comparisons revealed Llama3.1:8b underperformed qwen2.5:7b in Chinese (χ²1=13.22,P<.001) but surpassed it in English (χ²1=13.92,P<.001). No significant differences were observed between qwen2.5:72b and Llama3.1:70b (English: OR 0.33, P=.08; Chinese: OR 1.5, 95% CI 0.48-5.12,P=.07); qwen2.5:72b matched ChatGPT-4o's performance in both languages (English: OR 0.33, P=.08; Chinese: OR 0.44, P=.09); Llama3.1:70b mirrored ChatGPT-4o's English accuracy (OR 1, P=1.000) but lagged in Chinese (OR 0.33; P=.02). RAG implementation enhanced qwen2.5:7b's accuracy to 79.3% (χ²1=31.11, P<.001) with 85.9% retrieval precision. The distilled model Deepseek-R1:7b markedly underperformed (9.9% vs qwen2.5:7b; χ²1=42.19, P<.001). Clinician surveys revealed significant knowledge gaps in rare disease management.

CONCLUSIONS: ChatGPT-4o demonstrated superior diagnostic performance for rare diseases. While Llama3.1:8b demonstrates viability for localized deployment in resource-constrained English diagnostic workflows, Chinese applications require larger models to achieve comparable diagnostic accuracy. This urgency is heightened by the release of open-source models like DeepSeek-R1, which may see rapid adoption without thorough validation. Successful clinical implementation of LLMs requires 3 core elements: model parameterization, user language, and pretraining data. The integration of RAG significantly enhanced open-source LLM accuracy for rare disease diagnosis, although caution remains warranted for low-parameter reasoning models showing substantial performance limitations. We recommend hospital IT departments and policymakers prioritize language relevance in model selection and consider integrating RAG with curated knowledge bases to enhance diagnostic utility in constrained settings, while exercising caution with low-parameter models.

PMID:40532199 | DOI:10.2196/69929

HGG Adv. 2025 Jun 12;6(3):100468. doi: 10.1016/j.xhgg.2025.100468. Online ahead of print.

ABSTRACT

Incontinentia pigmenti (IP) is caused by loss-of-function variants in IKBKG, with molecular genetic diagnosis complicated by a pseudogene. We describe seven individuals from three families with IP but negative clinical genetic testing in whom long-read sequencing identified causal variants, including one family with the common exon 4-10 deletion not identified by conventional clinical genetic testing. Concurrent methylation analysis explained disease severity in one individual who died from neurologic complications, identified a mosaic variant in an individual with an atypical presentation, and confirmed skewed X chromosome inactivation in an XXY individual.

PMID:40515401 | DOI:10.1016/j.xhgg.2025.100468

Eur J Hum Genet. 2025 Jun 14. doi: 10.1038/s41431-025-01891-0. Online ahead of print.

ABSTRACT

Structural variants (SVs) of the nebulin gene (NEB), including intragenic duplications, deletions, and copy number variation of the triplicate region, are an established cause of recessively inherited nemaline myopathies and related neuromuscular disorders. Large deletions have been shown to cause dominantly inherited distal myopathies. Here we provide an overview of 35 families with muscle disorders caused by such SVs in NEB. Using custom Comparative Genomic Hybridization arrays, exome sequencing, short-read genome sequencing, custom Droplet Digital PCR, or Sanger sequencing, we identified pathogenic SVs in 35 families with NEB-related myopathies. In 23 families, recessive intragenic deletions and duplications or pathogenic gains of the triplicate region segregating with the disease in compound heterozygous form, together with a small variant in trans, were identified. In two families the SV was, however, homozygous. Eight of these families have not been described previously. In 12 families with a distal myopathy phenotype (of which 10 are previously unpublished), eight unique, large deletions encompassing 52-97 exons in either heterozygous (n = 10) or mosaic (n = 2) state were identified. In the families where inheritance was recessive, no correlation could be made between the types of variants and the severity of the disease. In contrast, all patients with large dominant deletions in NEB had milder, predominantly distal muscle weakness. For the first time, we establish a clear and statistically significant association between large NEB deletions and a form of distal myopathy. In addition, we provide the hitherto largest overview of the spectrum of SVs in NEB.

PMID:40517164 | DOI:10.1038/s41431-025-01891-0

Methods Mol Biol. 2025;2921:31-56. doi: 10.1007/978-1-0716-4502-4_2.

ABSTRACT

Despite the transformation of genomics and genetics, DNA- and RNA-based information provides only a partial view of disease etiology and pathogenesis. This has increased awareness that genetic and gene expression data must be integrated with downstream product activity and cellular metabolite regulation to understand disease processes fully.By simultaneously analyzing the genome, transcriptome, proteome, and metabolome, crucial molecular pathways and novel biomarkers associated with various genetic diseases have been identified using multi-omics approaches. A more comprehensive understanding of the complex interactions between genetic factors (genotype) and disease development (phenotype) has been enabled by these approaches.This chapter describes multi-omics protocols for genetic diseases, emphasizing metabolomics and proteomics approaches.

PMID:40515983 | DOI:10.1007/978-1-0716-4502-4_2

Front Endocrinol (Lausanne). 2025 May 29;16:1543991. doi: 10.3389/fendo.2025.1543991. eCollection 2025.

ABSTRACT

BACKGROUND: Satoyoshi syndrome (also known as Komuragaeri disease ) is a rare disorder of unknown etiology, with progressive muscle spasms, whole-body hair loss, and diarrhea as its main symptoms, particularly progressive skeletal muscle spasms and pain. Because of the lack of a clear etiology and pathogenesis of Satoyoshi syndrome, Western medicine lacks established effective therapies, and the long-term prognosis of the treatment of this disease is poor, unable to improve multiple symptoms simultaneously and prevent the recurrence of the disease. In recent years, acupuncture has been increasingly explored as a complementary treatment for autoimmune diseases. It is believed to exert its effects by modulating the neuroendocrine-immune network, enhancing immune cell function, and restoring homeostatic pathways. These mechanisms enable acupuncture to provide immune modulation, ultimately achieving a holistic and bidirectional regulatory effect.

CASE DESCRIPTION: We report the case of a 54-year-old male police officer who had Satoyoshi syndrome for more than five years. After six months of acupuncture treatment, the patient's chronic diarrhea completely disappeared, and the occasional painful muscle cramps and insomnia significantly improved. After six months of follow-up, the patient's condition was stable.

CONCLUSION: In this study, we believe that acupuncture therapy is of great significance for the improvement of diarrhea, immediate and long-term analgesia, and stabilization of the Satoyoshi syndrome.

PMID:40510477 | PMC:PMC12158676 | DOI:10.3389/fendo.2025.1543991

Int J Mol Sci. 2025 May 30;26(11):5297. doi: 10.3390/ijms26115297.

ABSTRACT

Single-cell transcriptomics data are analyzed using two popular tools, Seurat and Scanpy. Multiple separate tools are used downstream of Seurat and Scanpy cell annotation to study cell differentiation and communication, including cell proportion difference analysis between conditions, pseudotime and trajectory analyses to study cell transition, and cell-cell communication analysis. To automate the integrative cell differentiation and communication analyses of single-cell RNA-seq data, we developed a single-cell RNA-seq downstream analysis pipeline called "scDown". This R package includes cell proportion difference analysis, cell-cell communication analysis, pseudotime analysis, and RNA velocity analysis. Both Seurat and Scanpy annotated single-cell RNA-seq data are accepted in this pipeline. We applied scDown to a published dataset and identified a unique, previously undiscovered signature of neuronal inflammatory signaling associated with a rare genetic neurodevelopmental disorder. These findings were not identified with a simple implementation of Seurat differential gene expression analysis, illustrating the value of our pipeline in biological discovery. scDown can be broadly utilized in downstream analyses of scRNA-seq data, particularly in rare diseases.

PMID:40508102 | DOI:10.3390/ijms26115297

bioRxiv [Preprint]. 2025 May 31:2025.05.30.656844. doi: 10.1101/2025.05.30.656844.

ABSTRACT

Elucidating the role of somatic mutations in cancer, healthy tissues, and aging depends on methods that can accurately characterize somatic mosaicism across different cell types, as well as assay their impact on cellular function. Current technologies to study cell-type-specific somatic mutations within tissues are low-throughput. We developed Duplex-Multiome, incorporating duplex consensus sequencing to accurately identify somatic single-nucleotide variants (sSNV) from the same nucleus simultaneously analyzed for single-nucleus ATAC-seq (snATAC-seq) and RNA-seq (snRNA-seq). By introducing strand-tagging into the construction of snATAC-seq libraries, duplex sequencing reduces sequencing error by >10,000-fold while eliminating artifactual mutational signatures. When applied to 98%/2% mixed cell lines, Duplex-Multiome identified sSNVs present in 2% of cells with 92% precision and accurately captured known sSNV mutational spectra, while revealing unexpected subclonal lineages. Duplex-Multiome of > 51,400 nuclei from postmortem brain tissue captured sSNV burdens and spectra across all major brain cell types and subtypes, including those difficult to assay by single-cell whole-genome sequencing (scWGS). This revealed for the first time that diverse neuronal and glial cell types show distinct rates and patterns of age-related mutation, while also directly discovering developmental cell lineage relationships. Duplex-Multiome identified clonal sSNVs occurring at increased rates in glia of certain aged brains, as well as clonal sSNVs that correlated with changes in expression of nearby genes, in both neurotypical and autism spectrum disorder (ASD) individuals, directly demonstrating that somatic mutagenesis can contribute to gene expression phenotypes. Duplex-Multiome can be easily adopted into the 10X Multiome protocol and will bridge somatic mosaicism to a wide range of phenotypic readouts across cell types and tissues.

PMID:40502142 | PMC:PMC12154604 | DOI:10.1101/2025.05.30.656844

Orphanet J Rare Dis. 2025 Jun 12;20(1):303. doi: 10.1186/s13023-025-03818-w.

ABSTRACT

BACKGROUND: People with a rare disease find it difficult to obtain a diagnosis and access appropriate services. Evidence suggests that this can lead to health inequity amongst the rare disease community, i.e. systemic, unfair and avoidable differences in health opportunities and outcomes. This scoping review aims to identify and describe evidence on health inequities experienced by the rare disease community with regards to receipt of a diagnosis and access to health and social care services.

METHODS: We searched ASSIA, CINAHL, Embase, HMIC, MEDLINE and Social Policy and Practice for relevant studies. Studies were double screened at title and abstract and full-text using pre-specified inclusion criteria. As this research was commissioned by the UK National Institute for Health and Care Research Policy Research Programme, primary studies were limited to UK settings. These were supplemented with international systematic reviews. We also applied a 2010 date limit. Relevant data were extracted and presented narratively and tabulated.

RESULTS: One hundred thirty-six studies met the inclusion criteria, including 96 primary studies and 40 systematic reviews. The most frequently occurring rare diseases were motor neurone disease, cystic fibrosis and sickle cell disease. Seventeen types of inequity were identified: delayed diagnosis, lack of knowledge amongst clinicians, lack of information provision, limited services provision (across six different services), limited services for undiagnosed conditions, lack of care co-ordination; in addition, inequity was identified relating to place of residence, race/ethnicity, gender, socioeconomic status, age and disability.

CONCLUSION: This review has drawn attention to experiences of the rare disease community with respect to receipt of a diagnosis and access to services which are different to experiences in the general population, and within the rare disease community itself. Some of these experiences are clearly attributable to factors which are unfair, avoidable and systemic, particularly those which relate to specific groups in the rare disease community. Experiences relating to delayed diagnosis, lack of knowledge, information, care co-ordination and access to various services, also appeared to indicate inequity. These issues are less likely to be encountered with respect to more common diseases experienced in the general population.

PMID:40506782 | DOI:10.1186/s13023-025-03818-w

Pediatr Neurol. 2025 May 16;169:105-114. doi: 10.1016/j.pediatrneurol.2025.05.017. Online ahead of print.

ABSTRACT

BACKGROUND: SYNGAP1 is a heterogeneous genetic disorder associated with intellectual disability, infantile-onset seizures, and other neurological and somatic symptoms. Clinical trial design for SYNGAP1 would benefit from a disease concept model-i.e., enumerating and ranking symptoms based on their impact on affected individuals and their caregivers.

METHODS: We developed a disease concept model for SYNGAP1 via five exercises: a scoping review of clinical features, semistructured interviews with caregivers, a survey of caregivers, a survey of clinical experts, and a review of charts of individuals with SYNGAP1 at one center (Weill Cornell Medicine). We provide a narrative summary of the key findings.

RESULTS: We reviewed 19 articles, conducted 16 interviews with caregivers, received survey responses from 90 caregivers and 15 clinical experts, and reviewed seven charts. Integrating findings from these exercises indicates that both caregivers and providers consider seizures/epilepsy, intellectual disability, and emotional regulation to be the most important therapeutic targets. Caregivers also place a high priority on the ability of individuals with SYNGAP1 to communicate. Chart review revealed that some symptoms discussed in the caregiver interviews (i.e., lack of danger awareness, heat/cold intolerance, lack of satiety) are not found in clinicians' notes.

CONCLUSIONS: Seizures, intellectual disability, communication, and emotional regulation are the four most meaningful clinical outcomes to target for investigating clinical interventions for SYNGAP1, according to caregivers and providers.

PMID:40494056 | DOI:10.1016/j.pediatrneurol.2025.05.017

J Neuromuscul Dis. 2025 Jun 10:22143602251339369. doi: 10.1177/22143602251339369. Online ahead of print.

ABSTRACT

BACKGROUND: Congenital myopathies are a group of neuromuscular disorders that typically present at birth or early childhood with hypotonia and non-progressive or slowly progressive muscle weakness. They are classically subclassified by characteristic structural changes and histopathological findings in skeletal muscle. Variants in over 40 genes have been described to date in patients with various forms of congenital myopathy with overlapping phenotypic and histological features, which poses a challenge for laboratories and clinicians in interpreting genetic findings.

OBJECTIVE: The purpose of this study was to evaluate the evidence supporting each gene-disease relationship and provide an expert-reviewed classification for the clinical validity of genes involved in congenital myopathies.

METHODS: The ClinGen Neurological Disorders Clinical Domain Working Group assembled the Congenital Myopathies Gene Curation Expert Panel (CongenMyopathy-GCEP), a group of clinicians and geneticists with expertise in congenital myopathies tasked to perform evidence-based curation of 50 gene-disease relationships using the ClinGen semiquantitative framework to assign clinical validity.

RESULTS: Our curation effort resulted in 35 (70%) Definitive, eight (16%) Moderate, six (12%) Limited, and one (2%) Disputed disease relationship classifications. The summary of each curation is made publicly available on the ClinGen website.

CONCLUSIONS: Expert-reviewed assignment of gene-disease relationships by the CongenMyopathy-GCEP facilitates accurate molecular diagnoses for congenital myopathies and can allow genetic testing to focus on genes with a validated role in disease.

PMID:40491337 | DOI:10.1177/22143602251339369

Medicine (Baltimore). 2025 Jun 6;104(23):e42807. doi: 10.1097/MD.0000000000042807.

ABSTRACT

RATIONALE: This study investigates the clinical, imaging, and pathological features of fibroblastic reticular cell tumors (FRCTs) through a retrospective analysis of a patient with FRCT, along with a review of relevant literature.

PATIENT CONCERNS: A 49-year-old male was admitted to our hospital because of swelling and discomfort in the right eye, occasionally accompanied by double vision, for more than 3 months. Physical examination revealed an obliquely downward right eye, ptosis, and a palpable medium-hard tumor at the supraorbital rim of the orbit.

DIAGNOSES: An orbital B-type ultrasound, orbital computed tomography, and orbital contrast-enhanced magnetic resonance imaging were performed, and the findings suggested a diagnosis of right orbital hemangioma.

INTERVENTIONS: Following imaging studies, the tumor was surgically excised. Microscopic pathological examination revealed that the lesion was composed of lymphatic follicles and spindle cells. Immunohistochemistry revealed that: the tumor is mainly composed of spindle fibroblastic cells, accompanied by the formation of lymphoid follicles. Immunohistochemical staining shows that the lymphoid follicles express CD20 positively, while the Ki67 positive index of the spindle tumor cells is lower. Based on these findings, the pathologists believed that the lesion was consistent with an FRCT.

OUTCOMES: The patient refused subsequent treatment and was discharged. Postoperative imaging (computed tomography and magnetic resonance imaging) conducted at 4 and 24 weeks revealed no recurrence of the tumor.

LESSONS: FRCTs are exceedingly rare in clinical practice, This is the first case report of an orbital FRCT. The main clinical manifestation is a painless orbital mass, and the imaging findings are nonspecific; therefore, the diagnosis mainly depends on the pathology and immune phenotype of the tumor. Currently, there are no detailed data regarding the effects of postoperative adjuvant therapy. With more reports and studies on patients with FRCT, the diagnostic accuracy for this disease can be increased, and more accurate and personalized treatment plans can be developed.

PMID:40489805 | DOI:10.1097/MD.0000000000042807

Hepatol Commun. 2025 Jun 9;9(7):e0746. doi: 10.1097/HC9.0000000000000746. eCollection 2025 Jul 1.

NO ABSTRACT

PMID:40489760 | DOI:10.1097/HC9.0000000000000746

Mol Ther Methods Clin Dev. 2025 Apr 24;33(2):101479. doi: 10.1016/j.omtm.2025.101479. eCollection 2025 Jun 12.

ABSTRACT

Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss of function of the lysosomal channel transient receptor potential mucolipin-1, TRPML1, and is associated with an early brain phenotype consisting of glial reactivity, hypomyelination, and lysosomal abnormalities. Although the field is approaching the first translationally relevant therapy, we currently lack a molecular signature of disease that can be used to detect therapeutic efficacy. Here, we analyzed 7,322 proteins in the plasma proteome from 17 MLIV patients and 37 controls and compared protein profiles with clinical measures of disease severity (motor function, muscle tone, and age). We found a decrease in neuronal proteins and an increase in muscle proteins in MLIV, consistent with neuronal dysfunction and muscle pathology observed in patients. Reduced synaptic proteins (e.g., GABARAP) best correlated with disease severity. Comparing the MLIV plasma proteome to the brain proteome from the MLIV mouse model identified shared alterations in 45 proteins, including upregulated proteins related to lysosomal function (e.g., ACTN2, GLB1) and downregulated proteins related to myelination (e.g., TPPP3, CNTN2). These data indicate that peripheral blood plasma protein signatures mirror changes found in the MLIV brain.

PMID:40486934 | PMC:PMC12141561 | DOI:10.1016/j.omtm.2025.101479

Orphanet J Rare Dis. 2025 Jun 6;20(1):282. doi: 10.1186/s13023-025-03796-z.

ABSTRACT

BACKGROUND: Rare diseases present a substantial patient burden, but the impact on non-professional caregivers is poorly understood. We explored the health-related quality of life (HRQoL) and productivity burden on caregivers of adults with rare diseases.

METHODS: We analysed physician- and caregiver-reported real-world data from France, Germany, Italy, Spain, the United Kingdom, and the United States of America collected July 2017-March 2021 via Adelphi Disease Specific Programmes™ in amyotrophic lateral sclerosis (ALS), eosinophilic esophagitis (EoE), graft versus host disease (GvHD), Huntington's disease (HD), myasthenia gravis (MG), and progressive supranuclear palsy (PSP). Non-professional caregivers completed the EQ-5D-5L and Work Productivity and Activity Impairment questionnaire. Multivariate regression analysis modelled the relationship of care recipient/caregiver characteristics with caregiver HRQoL and productivity.

RESULTS: Data were provided by 365 caregivers; 114, 89, 75, 32, 29 and 26 in GvHD, PSP, ALS, MG, EoE and HD, respectively. Care recipients' mean (standard deviation [SD]) age was 58.7 (15.6) years, 59% were male and 23% had both professional and non-professional caregivers. Patients' mean (SD) EuroQol visual analogue scale (EQ VAS) score was 50.9 (23.3) and mean EQ-5D utility was 0.460 (0.350). Caregivers' mean age was 55.8 (13.8) years, 66% were female. Caregivers' EQ-5D-5L indicated their greatest problems in anxiety/depression. Overall, 45% of caregivers were employed, mostly part-time. In the past 7 days, mean (SD) caregiver absenteeism was 5.2% (13.1%), presenteeism was 28.0% (23.7%), and activity impairment was 43.1% (27.2%). Regressions identified multiple significant associations with caregivers' HRQoL and productivity. Caregivers' HRQoL (EQ-5D utility and EQ VAS) was associated with care recipients' EQ-5D utility and caregivers' age. Outcomes relating to caregivers' employment and productivity (hours spent caring, employment status, hours in employment, hours of employment missed, absenteeism, presenteeism, work impairment and activity impairment) were most frequently associated with care recipients' EQ-5D utility, caregivers' age and sex, caregiver living with the care recipient, the presence of a professional caregiver, and the care recipient having HD.

CONCLUSIONS: The substantial burden of providing non-professional caregiving to adults with rare diseases is associated with multiple factors. Interventions improving care recipient HRQoL could enhance caregiver HRQoL and productivity.

PMID:40481583 | DOI:10.1186/s13023-025-03796-z

IUBMB Life. 2025 Jun;77(6):e70031. doi: 10.1002/iub.70031.

ABSTRACT

Over 7000 rare diseases have been described, collectively affecting 350 million people worldwide. Most of these conditions result from nonsense mutations, representing approximately 10% of all genetic mutations associated with human inherited diseases. Nonsense mutations convert a sense codon into a premature termination codon (PTC), leading to premature translation termination and the production of truncated, nonfunctional proteins. This results in a loss-of-function phenotype in many genetic disorders, contributing to the disease's severity and progression. The molecular mechanisms of PTC formation involve various genetic alterations, including single-nucleotide changes, frameshifts, and splicing mutations. The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs containing premature termination codons (PTCs). In contrast, 25% of PTC mRNAs, depending on the PTC position and cellular context, can evade NMD, resulting in the synthesis of truncated proteins. A termination codon during translation is essential for proper protein synthesis, and translational readthrough-a process in which the ribosome bypasses the PTC and reaches the natural stop codon-may restore some level of protein function. The effectiveness of readthrough depends on the surrounding genetic context and the type of amino acid incorporated at the PTC position. This review aims to explore the molecular characteristics of nonsense-related diseases (NRDs), including cystic fibrosis, hemophilia, Fabry disease, choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and certain hereditary neuropathies and cancers.

PMID:40474765 | DOI:10.1002/iub.70031