Orphanet Journal of Rare Diseases最新文献

{"title":"Co-segregation of the c.489+3A>G variant with p.Cys1400Ter pathogenic CFTR mutation in Cyprus: prevalence and clinical implications.","authors":"Panayiotis K Yiallouros, Pinelopi Anagnostopoulou, Panayiotis Kouis, Andreas Μ Matthaiou, Tonia Adamidi, Phivos Ioannou, George Christopoulos, Constantina Costi, Leonidas A Phylactou, Pavlos Fanis, Vassos Neocleous","doi":"10.1186/s13023-025-03714-3","DOIUrl":"https://doi.org/10.1186/s13023-025-03714-3","url":null,"abstract":"<p><strong>Background: </strong>The high variety of mutations found in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene is responsible for the clinical heterogeneity observed in people with Cystic Fibrosis (CF) and the atypical manifestations in CFTR-related disorders (CFTR-RD). The intronic c.489+3A>G (c.621+3A>G) variant has been reported to have questionable pathogenicity, although its alleged severity was probably due to its co-segregation in cis with another undetected mutation, as previously reported from countries in the Mediterranean region. In the island of Cyprus, several rare CFTR variants have been previously identified, among them the c.489+3A>G in co-segregation with the pathogenic p.Cys1400Ter (cDNA name = c.4200_4201del or legacy name = 4332delTG) mutation. We aimed to investigate the prevalence of these variants in Cyprus and describe their clinical impact in patients and carriers.</p><p><strong>Results: </strong>The intronic variant c.489+3A>G has been so far identified to co-segregate with the pathogenic p.Cys1400Ter mutation in the same allele in six unrelated Cypriot families and in total of 20 subjects. Three of them were diagnosed with CF, presenting with persistent respiratory symptoms, pancreatic insufficiency and a second CF-causing mutation. Two were diagnosed with CFTR-RD, presenting with bronchiectasis, intermediate sweat test and a second mutation known to cause CFTR-RD. Also, four carriers had a high suspicion of CFTR-RD, with bronchiectasis or emphysema and intermediate sweat test, although due to the lack of another CFTR mutation and a second functional test, definite diagnosis has not been made. Haplotype analysis provided evidence of a common haplotype in all individuals with co-segregation of the c.489+3A>G variant with p.Cys1400Ter mutation.</p><p><strong>Conclusion: </strong>The intronic c.489+3A>G variant co-segregates extensively with p.Cys1400Ter in Cyprus as an ancestral combination due to a possible founder effect. Before providing genetic counselling to subjects identified through population screening to harbour the c.489+3A>G variant, extensive analysis of CFTR including gene rearrangements should be performed to identify possible other mutations in cis, especially in Mediterranean countries where this complex allele is probably common. Further research is warranted to fully delineate the clinical implications of the in cis co-segregation of p.Cys1400Ter with c.489+3A>G, even in the absence of pathogenic variants in the other CFTR allele.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"205"},"PeriodicalIF":3.4,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026673","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 features and risk factors of thrombotic thrombocytopenic purpura in systemic lupus erythematosus.","authors":"Hang Ma, Yujie He, Shanshan Li, Yingchao Yang, Liubin Huo, Tianfang Li","doi":"10.1186/s13023-025-03741-0","DOIUrl":"https://doi.org/10.1186/s13023-025-03741-0","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate clinical features and risk factors for the development of thrombotic thrombocytopenic purpura (TTP) in systemic lupus erythematosus (SLE) patients.</p><p><strong>Methods: </strong>A cohort of 32 SLE-TTP patients in the first affiliated hospital of Zhengzhou University from 2017 to 2023 were included, and 128 SLE patients without TTP admitted to the hospital during the same period were randomly selected as the control group. The demographic data, clinical and laboratory findings of these patients were statistically analyzed. Stepwise regression and logistic regression were used to identify the risk factors related to TTP development. The SLE-TTP patients were divided into two groups based on treatment outcomes, and the differences between the clinical data were compared between the two groups. Independent risks of short-term death in SLE-TTP patients were determined by logistic regression analysis.</p><p><strong>Results: </strong>Our study demonstrated that independent risk factors associated with the occurrence of TTP in patients with SLE included higher SLEDAI-2K score (OR = 1.96; 95%CI: 1.197-3.211; P = 0.007), high baseline total cholesterol (T-CHO) levels (OR = 8.19; 95%CI: 0.98-68.48; P = 0.048), and renal involvement (OR = 14.73; 95%CI: 1.250-173.64; P = 0.033). Multivariate logistic regression analysis showed that older age (OR = 1.02;95%CI: 0.94-1.119; P = 0.05) and non-nulliparous female (OR = 8.12; 95%CI: 0.484-136; P = 0.017) were independent risks factor for short-term death for SLE-TTP patients.</p><p><strong>Conclusion: </strong>SLE patients with higher SLEDAI-2K score, high baseline T-CHO levels, and renal involvement were predisposed to TTP development. The short-term mortality is increased for SLE-TTP patients of advanced age and in non-nulliparous females. Close monitoring and active treatments of these patients are needed for this life-threatening situation.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"203"},"PeriodicalIF":3.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034340","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":"Clinical features of hereditary transthyretin amyloidosis-polyneuropathy with transthyretin Ala97Ser(p.Ala117Ser) mutation in South Mainland China.","authors":"Yeli Zhu, Jingxian Fan, Xiying Zhu, Wei Li, Zhaoyong Zhang, Hui Zheng, Zhihua Zhou, Lingchao Meng, Ruxu Zhang, Haishan Jiang","doi":"10.1186/s13023-025-03733-0","DOIUrl":"https://doi.org/10.1186/s13023-025-03733-0","url":null,"abstract":"<p><strong>Objective: </strong>Our study aimed to report the clinical features and epidemiological characteristics of hereditary transthyretin amyloidosis-polyneuropathy(ATTRv-PN) with TTR Ala97Ser(p.Ala117Ser) mutation from South Mainland China.</p><p><strong>Methods: </strong>We identified 21 patients from 20 families diagnosed with Ala97Ser ATTRv-PN based on strict clinical and electrophysiological criteria from three centers. Clinical and laboratory data were retrospectively retrieved for analysis.</p><p><strong>Results: </strong>A gender imbalance was noted with a male-to-female ratio of 18:3. All patients showed late onset, with the age of onset at 56.5 ± 7.2 years. The predominant initial symptom, reported by 15 patients (71.4%), was numbness. Paraesthesia was present in all patients. Eighteen patients (85.7%) had autonomic dysfunction. Cardiac, renal, and ocular dysfunctions were noted in 17 (80.9%), 4(19.0%), and 4(19.0%) patients, respectively. Nerve conduction studies have shown axonal-type sensorimotor polyneuropathy. The decline in sensory nerve action potentials was more noticeable than in compound muscle action potentials. The nerve damage present in the lower limbs was more severe than that in the upper limbs. Nerve biopsy revealed positive Congo red staining in 11/15 patients (73.3%).</p><p><strong>Conclusion: </strong>ATTRv-PN appears relatively rare in South Mainland China, with our study providing the largest cohort of Ala97Ser mutation cases to date. We found a significant founder effect by combining the clinical and demographic characteristics. That helps us understand the gene's transmission pathway and lays the foundation for carrier screening and tertiary prevention and control. We also propose a new scoring model and demonstrate that this model allows the profiling of different genotypes of ATTRv-PN, facilitating early clinical detection and diagnosis.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"202"},"PeriodicalIF":3.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031042","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":"Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review.","authors":"Didier Bessis, Dominique Vidaud, Pierre Meyer, Laurence Pacot, de La Villeon G, Adeline Alice Bonnard, Yline Capri, Christine Coubes, Fanchon Herman, Didier Lacombe, Nicolas Molinari, Laura Poujade, Agathe Roubertie, Julien Van Gils, Alain Verloes, David Geneviève, Hélène Cavé, Marjolaine Willems","doi":"10.1186/s13023-025-03706-3","DOIUrl":"https://doi.org/10.1186/s13023-025-03706-3","url":null,"abstract":"<p><strong>Background: </strong>Data on clinical manifestations of neurofibromatosis-Noonan syndrome (NF-NS) remain heterogeneous, with limited validated descriptions.</p><p><strong>Methods: </strong>This study aims to better define the clinical and molecular features of NF-NS and compare them with existing literature. Secondary objectives include evaluating inter-rater diagnostic agreement among experienced clinicians and assessing the utility of deep-learning algorithms (Face2Gene^® [F2G]). Additionally, we assess the prevalence of congenital heart malformations (CHM) in NF-NS compared to 'classic' neurofibromatosis type 1 (NF1). A 9-year, prospective, monocentric study was conducted, involving patients with NF1 pathogenic variants (PVs) and Noonan syndrome-like facial phenotype (NSLFP).</p><p><strong>Results: </strong>Twenty-six patients were enrolled. NSLFP was categorized as 'suggestive' in 69% of cases and 'typical' in 31%. The presence of at least two facial abnormalities (e.g., low-set ears, downslanted palpebral fissures, hypertelorism, and ptosis) was consistently observed in 'typical' cases. Inter-rater concordance was substantial (0.65 [95% CI = 0.56; 0.74]), while concordance between clinicians and F2G was almost perfect at (0.821 [CI 95% = 0.625; 1.000]). Missense NF1 PVs were observed in 38.5% of cases. Apart from NSLP and a high frequency of pectus excavatum (62.5%), no significant differences in anthropometric, dermatological, neurological, skeletal, or ocular clinical features were observed between NF-NS and 'classic' NF1. CHM were found in 19.2% of NF-NS patients, with pulmonic stenosis present in 7.7%.</p><p><strong>Conclusion: </strong>NF-NS is a distinct phenotypic variant of NF1, marked by NSLP with consistent facial features -, and frequent pectus excavatum. F2G demonstrated high diagnostic concordance, reinforcing its clinical utility. Given the elevated risk of CHM, especially pulmonic stenosis, proactive cardiovascular assessment similar to other RASopathies is recommended for NS-NF patients, regardless of NF1 PV type.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"201"},"PeriodicalIF":3.4,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063823","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":"Perspectives on the current diagnostic and treatment paradigms in secondary hemophagocytic lymphohistiocytosis (HLH).","authors":"Leonard Naymagon, Philip Roehrs, Michelle Hermiston, James Connelly, Jeffrey Bednarski, Jaap-Jan Boelens, Shanmuganathan Chandrakasan, Blachy Dávila Saldaña, Michael M Henry, Prakash Satwani, Anish Ray, Kelly Walkovich, David Teachey, Edward M Behrens, Scott W Canna, Ashish Kumar","doi":"10.1186/s13023-025-03698-0","DOIUrl":"https://doi.org/10.1186/s13023-025-03698-0","url":null,"abstract":"<p><p>Improved awareness of hemophagocytic lymphohistiocytosis (HLH) among clinicians has led to an increase in its diagnosis. Often diagnosis is made based on the HLH- 2004 criteria. While these criteria have considerable strengths, they lack specificity and may be fulfilled in the setting of many pro-inflammatory disorders. Genetic defects affecting cellular cytotoxicity cause familial (primary) HLH. On the other hand, secondary HLH is more a pathophysiologic process common to many conditions, rather than a singular disease entity. Improved genetic, immunologic, and functional testing have changed not only the way we diagnose HLH, but also how we treat it. In 2004, there were few active agents and regimens. In 2024, there are multiple safe and effective targeted therapies. We have begun to understand that routine and immediate use of etoposide-based therapy in secondary HLH is likely not appropriate, and emerging cytokine-directed therapies may be more rational interventions. Moreover, it is recognized that identifying and treating the driver of secondary HLH is at least as important as treating the cytokine storm and immune dysregulation. Unfortunately, over-reliance on, and narrow interpretation of, the HLH- 2004 criteria can lead to overdiagnosis, misdiagnosis, and unneeded exposure to drugs that can be harmful. It is important that clinicians understand the limitations of the current diagnostic paradigms for secondary HLH, and the shortcomings of reflexive use of etoposide-based therapy. Herein we will discuss the pros and cons of the current paradigm for the recognition, diagnosis, and treatment of secondary HLH.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"200"},"PeriodicalIF":3.4,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034338","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":"Initial Psychometric Evaluation of the Barth Syndrome Symptom Assessment (BTHS-SA) for Adolescents and Adults in a Phase 2 Clinical Study.","authors":"Chad Gwaltney, Alan Shields, Emily Love, Sarah Ollis, Jonathan Stokes, Iyar Mazar, Ethan Arenson, Anthony Aiudi, R J Wirth, Carrie Houts","doi":"10.1186/s13023-025-03693-5","DOIUrl":"https://doi.org/10.1186/s13023-025-03693-5","url":null,"abstract":"<p><strong>Background: </strong>Barth syndrome (BTHS) is a rare, X-linked disorder that stems from mutations in the TAFAZZIN (TAZ) gene with varying disease severity among patients. The Barth Syndrome Symptom Assessment (BTHS-SA) is a patient-reported outcome questionnaire developed to assess BTHS symptom severity. The current study reflects the first exploration of the assessment's psychometric performance.</p><p><strong>Methods: </strong>The BTHS-SA was administered in TAZPOWER, a phase 2, randomized, double-blind, placebo-controlled crossover study to evaluate daily subcutaneous injections of elamipretide in subjects with genetically confirmed BTHS. Descriptive and correlational analyses were used to assess the score distributions, reliability, and construct-related validity of BTHS-SA items and domains including a two-item (2 FS), three-item (3 FS), and four-item (4 FS) fatigue score, and a five-item myopathy score (5MS).</p><p><strong>Results: </strong>Among the N = 12 white males (M age = 19.5, SD = 7.7) participating in the TAZPOWER trial, overall symptoms were rated as mild (n = 5, 41.7%), moderate (n = 5, 41.7%), severe (n = 1, 8.3%), or very severe (n = 1, 8.3%). Descriptive statistics for the BTHS-SA scores indicate variability of symptom severity both within symptom cluster and across patients. Promising results were found for both internal consistency (α = 0.67, 0.72, and 0.66 for the 3 FS, 4 FS, and 5MS, respectively) and test-retest reliability (ICC values ranging from 0.79 to 0.94 across two test-retest intervals). Correlational analyses showing moderate to strong relationships to other patient reports of fatigue (e.g., r = 0.59, 0.76, 0.68, and 0.61 between the PROMIS Fatigue SF and the 2 FS, 3 FS, 4 FS, and 5MS, respectively) and symptom severity (e.g., r = 0.60, 0.62, 0.56, 0.53 between a patient global rating and the 2 FS, 3 FS, 4 FS, and 5MS, respectively) support the measure's convergent validity. A similar pattern of relationships was observed when correlating changes in BTHS-SA scores to reference measures, including moderate to strong relationships between the BTHS-SA and direct patient reports of change (r = 0.81, 0.79, 0.82, and 0.80 between a global impression of change score and the 2 FS, 3 FS, 4 FS, and 5MS, respectively).</p><p><strong>Conclusion: </strong>Though the small sample size limits strong conclusions, this analysis suggests the BTHS-SA can produce reliable scores upon which valid inferences may be drawn. The BTHS-SA may be a useful tool to evaluate treatment benefits in this underserved population.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier, NCT03098797. Registered 05 May 2017, https://www.</p><p><strong>Clinicaltrials: </strong>gov/study/NCT03098797 .</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"199"},"PeriodicalIF":3.4,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972515","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":"Analysis of genomic ancestry and characterization of a new variant in MPS type VII.","authors":"Andreza Juliana Moreira da Costa, Isabel Cristina Neves de Souza, Raimunda Helena Feio, Laurent Ketlen Leão Viana, Mislene Cisz, Célio Luiz Rafaelli, Franciele Barbosa Trapp, Maira Graeff Burin, Kristiane Michelin-Tirelli, Ana Carolina Brusius-Facchin, Alice Brinckmann Oliveira Netto, André Salim Khayat, Ney Pereira Carneiro Dos Santos, Roberto Giugliani, Luiz Carlos Santana-da-Silva","doi":"10.1186/s13023-025-03593-8","DOIUrl":"https://doi.org/10.1186/s13023-025-03593-8","url":null,"abstract":"<p><strong>Background: </strong>Mucopolysaccharidosis (MPS) type VII is a storage disorder of autosomal recessive origin that is caused by a deficiency in a lysosomal enzyme that results in the accumulation of glycosaminoglycans and causes secondary metabolic pathway problems. It has systemic symptoms that mainly include progressive skeletal dysplasia, cardiovascular manifestations, hepatosplenomegaly, coarse facies, and many other manifestations, and cognitive decline is observed in most cases. A significant proportion of patients may present with foetal hydrops. Allelic variations in specific ethnic groups explain the higher incidence in some groups due to founder effects and/or endogamy. In Brazil, the most common variant is p.Leu176Phe. This study aimed to investigate GUSB gene expression in a patient with MPS VII with a new mutation (p.Leu292Pro). Additionally, this study investigated the ancestry of 5 patients with MPS VII from Brazil to understand the Amerindian, African, and European contributions.</p><p><strong>Results: </strong>The analysis revealed varying proportions of ancestry markers in the sample of patients with MPS VII. The European contribution was more prominent and significantly different (p = 0.0031) from the African contribution. Relative expression analysis by the 2^-ΔCT method revealed greater expression of the GUSB gene in the patient with MPS VII than in the control group (CG). However, some samples from the CG group presented higher expression than did the samples from the patient with the new mutation. Relative to the comparison among threshold cycles, 2/20 samples presented significantly different CT values for the patient with MPS VII when the numbers of amplification cycles were compared. The parents of the patient also presented different values (p < 0.05) for the amplification cycles. The in silico prediction of the new variant indicated that it affects function by modifying a highly conserved region.</p><p><strong>Conclusions: </strong>The p.Leu176Phe mutation may have originated in Europe, as suggested in this study. There is a discrepancy between the mRNA levels of GUSB and the amount of beta-glucuronidase synthesized. The expression of the GUSB gene variant from the patient with MPS VII was within the range of the control group's distribution in this study. The p.Leu292Pro mutation is pathogenic, but its impact on the MPS VII phenotype still needs to be fully elucidated.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"198"},"PeriodicalIF":3.4,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974405","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":"Using chanarin-dorfman syndrome patient fibroblasts to explore disease mechanisms and new treatment avenues.","authors":"Mor Angel, Yuval Kleinberg, Tanmoy Newaz, Victoria Li, Rinat Zaid, Keren Oved, Orly Dorot, Edward Pichinuk, Emily Avitan-Hersh, Ann Saada, Karin Weiss, Vanina Zaremberg, Galit Tal, Einat Zalckvar","doi":"10.1186/s13023-025-03711-6","DOIUrl":"https://doi.org/10.1186/s13023-025-03711-6","url":null,"abstract":"<p><strong>Background: </strong>Chanarin-Dorfman syndrome (CDS) is a multisystemic autosomal recessive rare disorder. CDS is caused by variants in the abhydrolase domain containing 5 (ABHD5) encoding gene (CGI-58), which ultimately leads to excessive lipid storage, and therefore a high abundance of cellular lipid droplets (LDs). Although the molecular etiology of the disease was described many years ago, no treatment for CDS is currently available.</p><p><strong>Results: </strong>To further characterize the molecular basis of the disease and to uncover new treatment avenues, we used skin fibroblasts originating from a young patient diagnosed with CDS due to a homozygous nonsense mutation. We show that dysfunctional ABHD5 does not only affect LDs, but also influences other metabolic-related organelles; the mitochondria and peroxisomes. Additionally, we found that expressing functional ABHD5 in CDS patient cells reduced LD number. Finally, we developed and applied a high content-based drug repurposing screen based on a collection of ∼2500 FDA approved compounds, yielding several compounds that affected LD total area and size.</p><p><strong>Conclusions: </strong>Our findings enhance the understanding of the dysfunction underlying CDS and propose new avenues for the treatment of CDS patients.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"195"},"PeriodicalIF":3.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006031","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":"Newborn screening facilitates early theranostics and improved spinal muscular atrophy outcome: five-year real-world evidence from Taiwan.","authors":"Chen-Hua Wang, Ting-Rong Hsu, Mei-Ying Liu, Li-Yun Wang, I-Jun Chou, Wang-Tso Lee, Wen-Chen Liang, Inn-Chi Lee, Hsiao-Jan Chen, Shu-Min Kao, Hui-Chen Ho, Dau-Ming Niu, Kwang-Jen Hsiao, Ming-Yuh Chang, Hui-Min Hsieh, Yuh-Jyh Jong","doi":"10.1186/s13023-025-03697-1","DOIUrl":"https://doi.org/10.1186/s13023-025-03697-1","url":null,"abstract":"<p><strong>Background: </strong>Recent findings indicate that infants with spinal muscular atrophy (SMA) treated early through newborn screening (NBS) have better outcomes. This study aimed to investigate the long-term outcomes of a 5-year SMA NBS program in Taiwan.</p><p><strong>Results: </strong>From September 2017 to August 2022, two NBS centers screened patients for SMN1 homozygous deletion using quantitative real-time polymerase chain reaction (RT-PCR) or the Sequenom MassARRAY platform and subsequently confirmed the findings using multiplex ligation-dependent probe amplification (MLPA). Implementation of SMA NBS using RT-PCR or MassARRAY platform efficiently led to the detection of neonates with homozygous survival motor neuron 1 (SMN1) deletions at a median age of 9 (range 4-14) days. Among the 446,966 newborns screened, 22 were detected to have a homozygous deletion of SMN1, followed by MLPA confirmation. One patient initially showed negative screening results but was later confirmed to have a compound heterozygous mutation. Among the 23 confirmed cases, 8 patients had two SMN2 copies (all classified as SMA type 1), 11 patients had three SMN2 copies (including 4 with SMA type 1, 2 with SMA type 2, 3 with SMA type 3, and 2 asymptomatic cases), and 4 patients had four SMN2 copies (all asymptomatic). The mean (median) follow-up duration for 19 survivors was 4.2 (5.0) years. All patients with two SMN2 copies developed symptoms within 62 days; those with three SMN2 copies experienced disease onset within 1 year. After diagnosis, most patients were on a watch and wait to receive disease-modifying therapy (DMT) due to initial lack of insurance coverage and limitations on indications after coverage was granted. Of the 19 children who received DMT, the outcomes included 12 walkers, 1 walker requiring support, 3 sitters, 1 non-sitter, and 2 patients with SMA type 1b with two SMN2 copies who succumbed to acute respiratory failure.</p><p><strong>Conclusions: </strong>This 5-year SMA NBS study using RT-PCR or the MassARRAY platform, along with an extended follow-up, demonstrates that early diagnosis and prompt treatment can enhance SMA clinical outcomes and change its natural progression in the therapeutic era. Infants with NBS who received presymptomatic DMT had better clinical outcomes than those who received symptomatic DMT.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"197"},"PeriodicalIF":3.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030348","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":"Revealing shared molecular and mechanistic signatures between intracranial aneurysms and abdominal aortic aneurysms: a comprehensive genomic analysis.","authors":"Xiao Liu, Zhenjun Li, Hongzhen Xu, Wangqing He, Lei Wu, Bin Ji, Nuerzhati Nuermaimaiti, Guangnan Ao, Yuhang Feng, Xuying He","doi":"10.1186/s13023-025-03689-1","DOIUrl":"https://doi.org/10.1186/s13023-025-03689-1","url":null,"abstract":"<p><p>Intracranial aneurysms (IAs) and abdominal aortic aneurysms (AAAs) are both vascular diseases that are closely linked. However, the pathogenesis underlying the co-occurrence of IAs and AAAs remains poorly understood. This study aims to identify key biomarkers that shed light on the molecular mechanisms connecting these two diseases using bioinformatics analysis. Gene expression profiles (GSE122897, GSE237229) were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) common to both IAs and AAAs were identified and subjected to functional enrichment analysis. The Cytoscape cytoHubba plugin was used to identify hub genes, and their predictive ability was evaluated using the receiver operating characteristic (ROC) curve. Additionally, immune infiltration analyses and single-gene gene set enrichment analysis (GSEA) were conducted for the hub genes. A total of 46 DEGs were identified, including 40 upregulated genes and 6 downregulated genes. The common DEGs were found to be involved in extracellular matrix structural constituents, collagen fibril organization, and regulation of basic cellular processes. ITGA11 was identified as a key gene implicated in the comorbidity of IAs and AAAs, with its upregulation strongly associated with plasma cells. Furthermore, in both IAs and AAAs, glycosaminoglycan biosynthesis of extracellular matrix components and immune-related diseases were significantly linked to the high expression of ITGA11. Our findings suggest that the comorbidity of IAs and AAAs may be driven by shared inflammatory and immune response mechanisms, with ITGA11 emerging as a potential biomarker for this co-occurrence.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"196"},"PeriodicalIF":3.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009123","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}