Orphanet Journal of Rare Diseases最新文献

{"title":"Distribution of perivascular spaces distribution and relate to the clinical features of SCA3.","authors":"Xinyuan Chen, Yanhua Lian, Wei Lin, Xiaoyue Xia, Lin Zhang, Zhuoying Huang, Maolin Cui, Ruying Yuan, Mengcheng Li, Ziqiang Huang, Naping Chen, Yuqing Tu, Jianping Hu, Ning Wang, Qunlin Chen, Shirui Gan","doi":"10.1186/s13023-025-03954-3","DOIUrl":"10.1186/s13023-025-03954-3","url":null,"abstract":"<p><strong>Background: </strong>Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative condition. Prior research has established perivascular spaces (PVS) expansion has been implicated in the pathogenesis and prognosis of various neurodegenerative diseases. To examine PVS changes in SCA3 by comparing patients and matched healthy controls and to identify potential connection of PVS for clinical features.</p><p><strong>Methods: </strong>We conducted MRI scans on 91 SCA3 patients and 64 healthy controls. We utilized visual semi-quantitative methods to assess PVS in various brain regions, including the center of the semiovale (CSO), basal ganglia (BG), and midbrain-pons, as well as combinations (BG + CSO, BG + CSO + midbrain-pons). To differentiate SCA3 patients from healthy controls, we compared the area under the curve (AUC) of the receiver operating characteristic curve between the two groups. Additionally, we employed Pearson's correlation coefficient to examine the relationship between PVS scores in each brain region and clinical indicators among SCA3 patients.</p><p><strong>Results: </strong>In the SCA3 group, we observed higher levels of PVS in the BG, CSO + BG, and three brain regions compared to the healthy control group. PVS in the CSO and CSO + BG also showed positive correlations with age and disease duration, and negative correlations with the number of CAG repeats. Furthermore, PVS in three brain regions exhibited negative correlation with the number of CAG repeats.</p><p><strong>Conclusions: </strong>This study represents an initial investigation into the relationship between PVS and SCA3 disease. Our findings suggest that PVS might indicate the degree of cerebellar ataxia to a certain extent.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"423"},"PeriodicalIF":3.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient experience in retinitis pigmentosa and Choroideremia- a concept elicitation study in 17 patients based on qualitative interviews.","authors":"Elke Rometsch, Per-Olof Thuresson, Noémie Hurst, Eckhart Eule, Isabel Bachmeier, Benoit Blanchard, José-Alain Sahel, Isabelle Audo","doi":"10.1186/s13023-025-03713-4","DOIUrl":"10.1186/s13023-025-03713-4","url":null,"abstract":"<p><strong>Background: </strong>Retinitis pigmentosa (RP) and Choroideremia (CHM) are rare inherited retinal diseases (IRDs) that can lead to severe visual impairment or blindness. Despite different underlying genetic pathways, they have many progression patterns in common, first affecting the more peripheral retina and later advancing toward the central retina. Early symptoms of both diseases include night blindness, difficulty adjusting to changing levels of light, and difficulty seeing in poor contrast. This is followed by progressive loss of the peripheral visual field in daylight, and eventually blindness. Currently, hardly any studies based on interviews that describe symptom experience and impact exist. In this concept elicitation study, we conducted qualitative interviews to identify the symptoms experienced by RP (n = 12) and CHM (n = 5) patients, and to understand the impact of symptoms on patients' lives.</p><p><strong>Results: </strong>Among the 14 symptoms reported, poor night vision/night blindness, difficulty seeing in bright light, and difficulty seeing in low/dim light were experienced by all participants. Over 50% of participants in either condition reported difficulty adapting from bright to dark and vice versa, poor peripheral vision, poor contrast sensitivity, poor distance vision, and poor visual acuity. Symptoms had a significant impact on activities of daily living. Most commonly impacted were the ability to navigate and the use of digital screens (n = 17/17, 100%) as well as physical functioning and work/school-related activities (n = 16/17, 94.1%). These impacts were often exacerbated by environmental factors. For instance, all participants reported this for navigation. Additionally, most participants (n = 13/17, 76.5%) reported impacts on emotional well-being. Concept saturation was shown for the RP sample (n = 12) and the combined sample (n = 17), i.e., all concepts reported were spontaneously mentioned in the first 3 sets of interviews. This suggests that further interviews would be unlikely to yield any new symptom concepts.</p><p><strong>Conclusion: </strong>The patient interviews provided insight into the patient experience of RP and CHM and formed the basis for developing a combined conceptual model of RP and CHM disease experience, suitable to serve as basis for future patient reported and performance outcome measures. Testing in larger samples, especially in CHM, is recommended to further evaluate content validity of these preliminary findings.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"418"},"PeriodicalIF":3.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12337473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ocular and confocal manifestations of Mainland Chinese with Fabry disease: a cross-sectional controlled study.","authors":"Yao Xu, Yingjie Chen, Jiali Fan, Sasa Kou, Xinyu Zhuang, Bingyuan Zhou, Xiaofeng Zhang","doi":"10.1186/s13023-025-03940-9","DOIUrl":"10.1186/s13023-025-03940-9","url":null,"abstract":"<p><strong>Background: </strong>This cross-sectional controlled study aims to characterize ocular manifestations and corneal microstructure via in vivo confocal microscopy (IVCM) in mainland Chinese patients with Fabry disease (FD). We evaluated 30 FD patients (mean age: 38 ± 14.41 years; range: 10-60 years), divided equally into enzyme replacement therapy (ERT)-treated and untreated groups, alongside 30 age- and gender-matched healthy controls. Slit-lamp examinations assessed ocular manifestations, while IVCM was employed to analyze corneal microstructure.</p><p><strong>Results: </strong>Eighteen FD patients presented with corneal verticillata (CV) opacities. High-reflective intracellular inclusions were identified in the corneal basal epithelial cells in the majority of FD patients (22 out of 30). IVCM detected increased dendritic cells (DCs) in three FD patients. The nerve fiber layer showed an increased corneal nerve tortuosity coefficient (P < 0.001), decreased nerve fiber density (NFD) (P = 0.033), decreased nerve fiber length (NFL) (P = 0.012), and reduced fractal dimension (P = 0.010) in FD patients compared to healthy controls. Reduced transparency of the anterior corneal stroma and the presence of visible microdots were observed in 11 out of 30 FD patients. Endothelial morphological parameters in FD patients showed no obvious differences compared to healthy controls. α-galactosidase A (α-Gal A) activity was negatively correlated with Mainz Severity Score Index (MSSI) scores (P = 0.001), whereas plasma globotriaosylsphingosine (lyso-Gb3) levels and posterior capsular opacification exhibited a direct correlation with MSSI scores(P = 0.002). None of these changes showed significant differences in FD patients, regardless of ERT.</p><p><strong>Conclusions: </strong>This study substantially enhances our understanding of FD-associated ocular alterations in the mainland Chinese demographic. The presence of CV opacities, posterior capsular opacification, or distinct changes observed in IVCM offers the potential for early detection of FD. Additionally, there is a notable increase in DCs and a positive correlation between posterior capsular opacification and MSSI scores. These findings support the integration of ocular biomarker screening into standardized FD diagnostic protocols to facilitate pre-symptomatic interventions, particularly in familial risk cohorts.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"417"},"PeriodicalIF":3.5,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12337376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA-binding proteins regulate immune-related alternative splicing in inherited salt-losing tubulopathies.","authors":"Fuhui Ma, Yanrong Ma, Mayinu Yusufu, Reziwanguli Wusiman, Shuqing Xing, Xiangxin Song, Suli Li, Yanying Guo","doi":"10.1186/s13023-025-03972-1","DOIUrl":"10.1186/s13023-025-03972-1","url":null,"abstract":"<p><strong>Background: </strong>Inherited salt-losing tubulopathies (SLT) are rare disorders caused by gene mutations that disrupt renal tubular ion transport. However, the molecular mechanisms underlying SLT pathogenesis remain unclear. This study aims to elucidate the functional genes and potential regulatory mechanisms associated with SLT.</p><p><strong>Methods: </strong>We established a study cohort comprising inherited SLT patients, age-matched patients with acquired hypokalemia, and healthy volunteers. Clinical characteristics were compared among the groups. RNA sequencing (RNA-seq) was performed to obtain transcriptomic profiles, followed by analysis of gene expression patterns and alternative splicing events (ASEs). Key findings were validated using RT-qPCR.</p><p><strong>Results: </strong>SLT patients exhibited a higher prevalence of recurrent viral infections (65%, P = 0.004) and autoimmune thyroid disorders (30%, P = 0.022) compared to healthy controls. RNA-seq analysis identified 2,611 differentially expressed genes (DEGs) in SLT patients, including 1,236 upregulated and 1,375 downregulated genes. These DEGs were primarily enriched in innate immune responses and adaptive immunity pathways. Additionally, significant alterations in gene expression related to viral defense and stress responses were observed. Notably, we identified several RNA-binding proteins (RBPs) that may contribute to SLT pathogenesis by regulating ASEs of immune-related genes.</p><p><strong>Conclusion: </strong>Our findings highlight the critical role of RBPs in SLT pathogenesis and provide novel insights into the immune profiles and gene expression dynamics in SLT. This study lays the foundation for future research into targeted therapies and personalized treatment strategies for SLT management.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"416"},"PeriodicalIF":3.5,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibrous dysplasia/McCune-Albright syndrome: state-of-the-art advances, pathogenesis, and basic/translational research.","authors":"Biagio Palmisano, Camryn Berry, Alison Boyce, Julia F Charles, Michael T Collins, Alessandro Corsi, Fernando A Fierro, Anne-Marie Heegaard, Hanne van der Heijden, Charles S Hoffman, Chelsea Hopkins, Jaymin Upadhyay, Paul M Wehn, Kelly L Wentworth, Yingzi Yang, Xuefeng Zhao, Edward C Hsiao, Mara Riminucci","doi":"10.1186/s13023-025-03909-8","DOIUrl":"10.1186/s13023-025-03909-8","url":null,"abstract":"<p><p>Fibrous dysplasia/McCune Albright syndrome (FD/MAS) is a rare genetic disease caused by postzygotic activating variants in the GNAS gene, encoding the α subunit of stimulatory G protein (Gα_s). Although multiple organs may be involved, skeletal lesions usually represent the most severe and least treatable expression of the disease, leading to bone deformities, spontaneous fractures, and chronic pain that severely reduce patients' quality of life.The recognition of the causative Gα_s variants and the consequent ligand-independent activation of the adenylyl cyclase/cAMP/PKA pathway has provided a clear molecular explanation to most extra-skeletal pathologies of FD/MAS, leading to the development of effective therapeutic approaches. In contrast, a detailed understanding of the cellular and molecular mechanisms that act downstream of the Gα_s pathway to generate FD bone lesions and clinical expression thereof remain elusive. Multiple key issues remain to be addressed, including some questions that have recently emerged such as the interaction between mutated and non-mutated cells and the role of the latter in the development of the fibrotic tissue.In this review, we provide a summary of the proof-of-concept, preclinical data, and experimental tools that have emerged to date from basic and translational studies on FD and represent the background for future research on the pathogenesis and treatment of this rare disease.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"414"},"PeriodicalIF":3.5,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural history of SPTBN4-related neurodevelopmental disorder with hypotonia, neuropathy, and deafness.","authors":"Hanan AlQudairy, Mohammad A AlMuhaizea, Mohamed Tohary, Maissa Alfuraih, Aisha Alnafisah, Aljouhra AlHargan, Anoud Albader, Hadeel Jaber, Rawan Almass, Albandary Albakheet, Terfa Alsheddi, Eman AlObeid, Maha M Alrasheed, Ali Al-Odaib, Hamad AlZaidan, Moeenaldeen D AlSayed, Namik Kaya","doi":"10.1186/s13023-025-03810-4","DOIUrl":"10.1186/s13023-025-03810-4","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in SPTBN4 have been linked to autosomal recessive \"neurodevelopmental disorder with hypotonia, neuropathy, and deafness\" (MIM# 617519) known as NEDHND. The disorder is highlighted with neuropathy, muscle weakness, and infrequent appearance of seizures in the affected individuals. This study aims to investigate the natural history of the disease, present genetic and clinical appearance of the syndrome in a highly consanguineous population, Saudi Arabia, and finally provide an overview of the reported cases, their clinical features, and disease-causing variants.</p><p><strong>Methods: </strong>The study started with a search through neurology clinics and local databases and utilized genetic testing records after diagnosing a patient with NEDHND at our hospital (King Faisal Specialist Hospital and Research Centre, KFSHRC). Based on the search we have identified additional patients (in total, n = 10) with the disease and performed genetic testing using whole exome sequencing and confirmatory Sanger sequencing. We performed RT-PCR on RNA extracted from lymphoblastoid cell line from a patient who found to have an aberrant splicing variant. Finally, we comprehensively reviewed current literature and available data related to the disease.</p><p><strong>Results: </strong>We present natural history of SPTBN4-associated neurodevelopmental disorder with hypotonia, neuropathy, and deafness in addition to four Saudi families with ten affected individuals who share clinical features of NEDHND. We report three known mutations and one novel nonsense variant, highlight atypical clinical features related to cerebellar involvement, confirm the pathogenicity of a splicing variant by RT-PCR, and review the findings of previously reported patients.</p><p><strong>Conclusion: </strong>Our study defines the clinical phenotype of a cohort of NEDHND in detail including the evolution of patients' clinical features, compares them to previously reported cases, and utilizes the existing data on the disease to direct development of a better prevention plan by means of genetic and preimplantation counseling. Our study may help and enable future clinical trials focusing on NEDHND in our country.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"415"},"PeriodicalIF":3.5,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Wechsler intelligence scale for children, fourth and fifth editions perform comparably in children with Batten disease.","authors":"Heather R Adams, Erika F Augustine, Kristen Bonifacio, Alyssa Collins, Amy E Vierhile, Jonathan W Mink","doi":"10.1186/s13023-025-03923-w","DOIUrl":"10.1186/s13023-025-03923-w","url":null,"abstract":"<p><strong>Background: </strong>The neuronal ceroid lipofuscinoses (Batten disease) are rare neurodegenerative lysosomal storage diseases principally of childhood onset and an autosomal recessive inheritance pattern. Cognitive regression is a hallmark of the disease, and has been characterized as part of the University of Rochester Batten Center's prospective longitudinal natural history. The objective of the present study was to establish convergent validity of the two most recent versions of the Wechsler Intelligence Scale for Children in this population (WISC-IV, 2003; WISC-V, 2014) due to anticipated eventual obsolescence of WISC-IV. 18 children and young adults (12 males, 6 females) with a genetically confirmed NCL diagnosis were administered selected subtests from the WISC-IV and WISC-V. We used bivariate correlations and repeated measures ANOVA between matching subtests across these two WISC versions to determine convergence of the measures.</p><p><strong>Results: </strong>WISC-IV and WISC-V verbal subtests were strongly correlated with one another and mean age-adjusted scores for comparable subtests on WISC-IV vs. WISC-V were not significantly different from one another.</p><p><strong>Conclusions: </strong>Overall, the minimal performance differences on the two measures supports combining WISC-IV and WISC-V datasets for larger-scale analyses of the neurocognitive natural history of NCL disorders.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"413"},"PeriodicalIF":3.5,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic evaluation of five patients with ROHHAD-NET using whole genome sequencing and optical genome mapping.","authors":"N van Engelen, H M van Santen, F van Dijk, M M Kleisman, J H M Merks, A Y N Schouten-van Meeteren, E J Kamping, K Neveling, A Hoischen, M C J Jongmans, R P Kuiper","doi":"10.1186/s13023-025-03938-3","DOIUrl":"10.1186/s13023-025-03938-3","url":null,"abstract":"<p><strong>Background: </strong>Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation (ROHHAD) and neuroendocrine tumor (NET) is a very rare condition with an unknown etiology. While various potential causes have been hypothesized, including genetic and paraneoplastic autoimmune mechanisms, no definitive cause has been identified to date. This study aimed to explore whether patients with ROHHAD-NET share an underlying heritable genetic etiology.</p><p><strong>Results: </strong>We identified five female patients clinically suspected of having ROHHAD(-NET); among them in two patients a NET was found: a ganglioneuroma and a low grade cerebellar ganglion cell tumor with BRAF mutation. To identify potential pathogenic germline genomic variants, whole genome sequencing (WGS) was performed on germline DNA from all five patients, including four patient-parent trios. Furthermore, optical genome mapping (OGM) was performed for two patients to detect germline structural variants (SVs). Rare single nucleotide variants (SNVs) and small insertions/deletions (InDels) were identified through WGS and rare SVs affecting (non)-coding or regulatory regions were analyzed using both WGS and OGM. We explored a de novo, inherited autosomal dominant and autosomal recessive inheritance scenario. However, no candidate variants in a recurrently affected gene locus or genomic region were identified in two or more patients.</p><p><strong>Conclusion: </strong>Our comprehensive genome-wide data analysis did not reveal evidence of a monogenetic cause for ROHHAD-NET. Whereas these findings do not exclude a genetic etiology for ROHHAD-NET, they strengthen the hypothesis of an autoimmune origin for symptoms of ROHHAD.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"412"},"PeriodicalIF":3.5,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation and study of adverse reactions to imiglucerase based on the FAERS database.","authors":"Pan Hong, Qingbo Zhou","doi":"10.1186/s13023-025-03934-7","DOIUrl":"10.1186/s13023-025-03934-7","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to evaluate the adverse drug reactions associated with imiglucerase in the treatment of Gaucher disease by analyzing data from the FDA Adverse Event Reporting System (FAERS) database.</p><p><strong>Methods: </strong>A comprehensive analysis was conducted on 166,800,135 adverse event reports from the FAERS database, covering the period from the first quarter of 2004 to the fourth quarter of 2023. The data were processed using R software and analyzed using multiple disproportionality methods, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS). These methodologies were applied to identify significant adverse reaction signals across various System Organ Classes (SOCs) and Preferred Terms (PTs).</p><p><strong>Results: </strong>The analysis revealed significant adverse reaction signals in multiple SOCs, including general disorders and administration site conditions, injury, poisoning and procedural complications, infections and infestations, and nervous system disorders. Notably, general disorders and injury-related conditions had the highest number of reports. At the PT level, the term \"Gaucher disease\" yielded the highest statistical signal. This was identified as a critical reporting artifact, likely representing perceived treatment failure or disease progression, rather than a true adverse reaction. After accounting for this artifact, other significant adverse event signals included increased chitotriosidase, elevated acid phosphatase, and bone infarction, with musculoskeletal and connective tissue disorders being a key area of concern. A comparative analysis against other Gaucher therapies suggests this strong skeletal signal likely reflects confounding by indication rather than a drug-specific risk.</p><p><strong>Conclusion: </strong>The findings underscore the importance of ongoing pharmacovigilance to monitor the safety of imiglucerase, especially among vulnerable populations such as pregnant women, long-term users, and those with comorbid hepatobiliary or skeletal conditions.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"406"},"PeriodicalIF":3.5,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Juvenile Paget disease with unique compound heterozygous sequence variants in the TNFRSF11B gene.","authors":"Jana Horackova, Renata Taslerova, Milan Bayer, Jana Nekvindova, Ladislava Pavlikova, Jan M Horacek, Vladimir Palicka","doi":"10.1186/s13023-025-03804-2","DOIUrl":"10.1186/s13023-025-03804-2","url":null,"abstract":"<p><strong>Background: </strong>Juvenile Paget disease (JPD) is a rare autosomal recessive bone disease characterized by escalated bone metabolism leading to skeletal deformities, susceptibility to fractures, and some extraskeletal findings. This genetic disease is associated with changes in the TNFRSF11B gene encoding osteoprotegerin, an important regulator of osteoresorption. Most published JPD cases have been found to carry homozygous TNFRSF11B variants, while compound heterozygous variants in this gene have been reported only twice.</p><p><strong>Methods and results: </strong>We report the first case of JPD diagnosed in the Czech Republic, who presented with a mild phenotype of this disease. The first bone fractures, appeared at 3 years of age. Other clinical manifestations included typical skeletal deformities, macrocephaly, arched chest, lower extremity valgosity, lateral bowing of the thighs, and anterior bowing of the shins. Minor mixed hearing impairment, angioid stripes of the choroidea, and temporary immunodeficiency were present among extra-skeletal findings. Sanger sequencing was performed on both the patient and the parents to test for the presence of TNFRSF11B sequence variants. Molecular genetic analysis showed unique compound heterozygous sequence variants in TNFRSF11B: a paternally inherited variant c.30 + 5G > A, p.(?) and a maternally inherited variant c.329G > T, p.(Gly110Val). Both of the variants were analyzed by several in silico predictive tools indicating, for their strongly supported pathogenicity according to American College of Medical Genetics and Genomics standards. Furthermore, we present diagnostic findings, their treatment, and follow-up care.</p><p><strong>Conclusion: </strong>The newly described variants of TNFRSF11B extend knowledge of this very rare disease. Early diagnosis and antiresorption treatment prevent further fractures and deformity progression, and improve the patient's quality of life. This example of osteoprotegerin deficiency may help us better understand its role in skeletal and non-skeletal systems.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"409"},"PeriodicalIF":3.5,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}