Orphanet Journal of Rare Diseases最新文献

{"title":"Illness cognition, illness perception and related factors in patients with lymphangioleiomyomatosis.","authors":"Liting Huang, Lulu Yang, Ruoyun Ouyang, Siying Ren","doi":"10.1186/s13023-025-03566-x","DOIUrl":"10.1186/s13023-025-03566-x","url":null,"abstract":"<p><strong>Purpose: </strong>To explore the self-perceived illness cognition and perception status, as well as the relevant factors among lymphangioleiomyomatosis (LAM) patients.</p><p><strong>Methods: </strong>A web-based questionnaire survey was conducted in September 2023. A total of 121 LAM patients participated (including 16 patients with TSC-LAM), and the survey collected general demographic information, responses to a disease cognition questionnaire, and a simplified disease perception questionnaire.</p><p><strong>Results: </strong>LAM patients have a higher level of negative illness cognition and a lower level of positive illness cognition, specifically characterized by helplessness (15.74 ± 4.68 points), acceptance (16.00 ± 3.28 points), and perceived benefits (16.92 ± 3.86 points). Single-factor analysis of variance found significant correlations between cultural level, age, family average monthly income, use of rapamycin, use of home oxygen therapy, hospitalization frequency, disease duration, severity of respiratory distress, activity limitation, and the helplessness score of LAM patients (p ≤ 0.05); the number of children was significantly associated with acceptance scores of LAM patients (p ≤ 0.05); and whether surgery had been performed was significantly associated with acceptance and perceived benefits scores of LAM patients (p ≤ 0.05). Disease duration and activity limitation entered the regression equation for helplessness dimension, while whether surgery had been performed entered the regression equation for perceived benefits dimension, but no factor entered the regression equation for acceptance dimension. Applying the same analysis to disease perception, we found that the average score of the Illness Perception Questionnaire was 45.43 ± 8.97, with lower scores in the reverse-scored items of individual control, treatment, and understanding.</p><p><strong>Conclusions: </strong>LAM patients exhibit higher levels of helplessness, particularly among those with longer disease duration and greater activity limitations, leading to a more negative perception of the disease. Additionally, patients who have undergone surgical procedures tend to perceive fewer benefits. Furthermore, there is a significant correlation between illness perception and factors such as rapamycin usage, home oxygen therapy, disease duration and activity limitations caused by LAM. This indicates that clinical healthcare providers should pay more attention to LAM patients and their associated groups, providing both informational and psychological support.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"78"},"PeriodicalIF":3.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458748","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":"Bone disease and oromaxillofacial disorders: a cross- sectional study in a Tanzanian pediatric population.","authors":"Elias Isaack Mashala, Lluís Brunet-Llobet, Anastasiya Lapitskaya, Sol Balsells-Mejía, Ombeni Mrina, Jaume Miranda-Rius","doi":"10.1186/s13023-025-03563-0","DOIUrl":"10.1186/s13023-025-03563-0","url":null,"abstract":"<p><strong>Background: </strong>Certain bone diseases of congenital origin are associated with dental alterations and with oromaxillofacial (OMF) disorders. The objective of this study was to evaluate and compare the OMF alterations presented by patients affected by bone pathology with respect to a healthy population from the same geographical environment.</p><p><strong>Material & methods: </strong>A cross-sectional study was carried out at Mount Meru Regional Referral Hospital and Kaloleni secondary school in Arusha, Tanzania. The patients with bone pathologies (n = 60) were consecutively recruited from the hospital, while the controls (n = 581) comprised a population of healthy students from the school, which was located in the same neighbourhood as the hospital. In the case group, the different bone pathologies were divided into two subgroups: (i) disorders in cellular metabolism (DCM); and (ii) disorders of bone growth/deformity (DGD). Musculoskeletal and oral clinical examinations were performed in both groups.</p><p><strong>Results: </strong>The case group presented significantly higher values of moderate and severe inflammation on the Löe & Silness Gingival Index (GI 2: 65%, GI 3: 25%) than the control group (p < 0.001), where mild inflammation predominated (GI 1: 88%). The case group also had higher scores for decayed, missing and filled teeth. Dental fluorosis was reported in 75.2% of controls and in only 26.6% of cases, the differences being clearly significant (p < 0.001). Significant differences for fluorosis were also reported between the two subgroups (p < 0.001), with a higher incidence for the DCM subgroup (43.8%). Twenty-two patients (36.7%) in the case group displayed clinical absence of teeth: the rate was significantly higher in the DGD subgroup (n = 15, 50%) than in the DCM subgroup (n = 8, 25%) (p = 0.045). In relation to the type of dental occlusion, the group with bone pathology presented a significant predominance of Angle class II - III malocclusions (p < 0.001). Craniofacial abnormalities were more frequent in the DGD subgroup, although the difference was not significant. The spine was normal in 41 patients (68.3%) and the differences between subgroups were not significant. Pathological fractures were significantly more frequent in the DGD subgroup (50% vs. 6.3%; p < 0.001). Assessing whether there was a relationship between malocclusion and skeletal deformities (spine and upper limb) in the case group, subjects with upper limb deformity (n = 16) presented significant differences for inverted overjet (p = 0.031).</p><p><strong>Conclusion: </strong>Patients with bone disease had worse oral health and more severe dental malocclusion than controls. The results presented here may help to raise awareness among orthopedic and pediatric professionals of abnormalities related to OMF conditions in childhood.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"77"},"PeriodicalIF":3.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441574","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":"Health outcomes and drug utilisation in children with Noonan syndrome: a European cohort study.","authors":"Michele Santoro, Ingeborg Barisic, Alessio Coi, Joachim Tan, Ester Garne, Maria Loane, Ljubica Odak, Maria Valentina Abate, Elisa Ballardini, Clara Cavero-Carbonell, Miriam Gatt, Mika Gissler, Kari Klungsøyr, Nathalie Lelong, David Tucker, Diana Wellesley, Joan K Morris","doi":"10.1186/s13023-025-03594-7","DOIUrl":"10.1186/s13023-025-03594-7","url":null,"abstract":"<p><strong>Background: </strong>Noonan Syndrome (NS) is a rare multisystemic disorder with heterogeneous phenotypic manifestations. The aim of this study was to analyse rates of survival, hospitalisation, surgeries and prescriptions in children born with NS in the first 10 years of life.</p><p><strong>Methods: </strong>This is a multi-centre population-based cohort study. Data on 175 liveborn children diagnosed with NS from 11 EUROCAT congenital anomaly registries were linked to healthcare databases. Each registry applied a common data model to standardise data and run common syntax scripts to produce aggregated results which were pooled using random effects meta-analyses.</p><p><strong>Results: </strong>Mortality rates were high in the first year of life with 5.4% (95%CI 1.5%-10.1%) of children dying before the age of 1 year with a further 2% dying up to age 5. In the first year, 87.9% (95%CI 75.3%-94.3%) of children were hospitalized and the median Length Of hospital Stay (LOS) was 15.3 days (95%CI 9.3-21.2). After the first year, the proportion of children hospitalized remained higher than 70%, but the LOS decreased to 1.3 days per year. In the first 5 years, 65.2% of children underwent a median of two surgical procedures. The median age at first surgery was 29 weeks. The proportion of children with an antibiotic prescription increased from 53.6% at age 1 to 62.4% yearly until 4 years of age.</p><p><strong>Conclusions: </strong>Children with NS have high mortality and morbidity not only in the first year of life but also up to five years of age. This study evaluated the health burden of NS and provided information for clinicians, health-care providers and families.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"76"},"PeriodicalIF":3.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441576","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 healthcare burden of pulmonary alveolar proteinosis (PAP).","authors":"Elinor Lee, Ali Ataya, Cormac McCarthy, Erica Godart, John Cosenza, Alysse King, Brian Robinson, Tisha Wang","doi":"10.1186/s13023-024-03478-2","DOIUrl":"10.1186/s13023-024-03478-2","url":null,"abstract":"<p><strong>Introduction: </strong>Pulmonary alveolar proteinosis (PAP) is a rare lung syndrome characterized by the accumulation of surfactant in the alveoli. Using a longitudinal claims database, we compared measures of clinical and economic burden between a sample of diagnosed PAP patients and non-PAP matched controls.</p><p><strong>Methods: </strong>PAP patients were identified leveraging IPM.ai's longitudinal U.S. claims database spanning January 1, 2009, through May 1, 2022. PAP patients were selected based on the presence of ICD-10: J84.01 or ICD-9: 516.0 in their claims history and were indexed for observation. An age, gender, and geographically matched control cohort was created (ratio of 1:4) for comparison. A third cohort, consisting of likely undiagnosed PAP patients, was identified using a machine learning model. The PAP and control cohorts were tracked longitudinally, depending on individual index dates, from January 1, 2018, through May 1, 2023. Inclusion criteria required evidence of continual claims activity 12 months prior to and after the index date, which reduced the total number of diagnosed PAP and control patients in the analysis. Demographics, comorbidities, procedures, medication use, annual healthcare resource utilization (HCRU), and costs were calculated for eligible PAP and control patients and were compared 12 months prior to, and 12 months after each patient's index date.</p><p><strong>Results: </strong>After inclusion criteria were applied, 2312 confirmed PAP patients and 9247 matched controls were included in the analysis. Compared with matched controls, PAP patients had significantly higher rates of diagnosed conditions at baseline as defined by the Charlson Comorbidity Index (CCI). During the follow-up period, PAP patients had higher rates of diagnosed conditions, procedures, medication use, and cost-of-care compared with controls. PAP patients also had higher rates of emergency room visits (35% vs. 14%; P < 0.001), outpatient visits (87% vs. 56%; P < 0.001), inpatient visits (20% vs. 5%; P < 0.001) and had longer lengths of stay for inpatient hospitalizations (2.8 days vs. 0.56 days; P < 0.001), respectively.</p><p><strong>Conclusion: </strong>This study represents the largest dataset of PAP patients and matched controls to be analyzed to date. Findings indicate that PAP patients have higher rates of diagnosed conditions, procedures, medication use, HCRU, and costs compared with non-PAP patients.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"73"},"PeriodicalIF":3.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425896","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":"Real-world evidence for Pompe disease remains fragmented. Comment on \"A rare partnership: patient community and industry collaboration to shape the impact of real-world evidence on the rare disease ecosystem\" by Klein et al.","authors":"Michelle E Kruijshaar, Tiffany House, Benedikt Schoser, Pascal Laforêt, Maudy T M Theunissen, Stephan Wenninger, Thomas Hundsberger, Jordi Diaz-Manera, Ans T van der Ploeg, Nadine A M E van der Beek","doi":"10.1186/s13023-025-03552-3","DOIUrl":"10.1186/s13023-025-03552-3","url":null,"abstract":"<p><p>In a recent publication by Klein et al., the need for real-world data on rare diseases is highlighted. We strongly support this need, and the collaboration with the patient community to collect data, as promoted in this publication. Our concern, however, is that this paper may be misunderstood as suggesting that the Sanofi-run Rare Disease Registries (RDRs) are sufficient to provide the datasets needed to evaluate current and future therapies. Industry-driven registries focus on their own product(s) and, therefore, do not provide the opportunity to compare products from different companies. Today, multiple companies produce treatments for all diseases included in the RDRs. Each company will have to run its own registry for regulatory purposes. This will lead to data fragmentation, which is prohibitive of truly understanding the effects of the various treatment options for these rare diseases. Therefore, independently funded and owned registries are essential to generate real-world evidence (RWE) unrelated to specific products. We discuss options for this for Pompe disease, including the International Pompe Survey, which has collected patient-reported outcomes independently from industry since 2002. This letter aims to raise awareness of the problem of siloed data and advocate for a new way forward where independent registries provide post-marketing surveillance data.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"74"},"PeriodicalIF":3.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425766","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":"Rates of mental health concerns among individuals assessed at the GoodHope Ehlers-Danlos Syndrome Clinic.","authors":"P Maxwell Slepian, Kristina Axenova, Molly McCarthy, Rachel Siegal, Keisha Gobin, Aliza Weinrib, Stephanie Buryk-Iggers, Daniel Santa Mina, Laura McGillis, Nimish Mittal, Joel Katz, Hance Clarke","doi":"10.1186/s13023-025-03550-5","DOIUrl":"10.1186/s13023-025-03550-5","url":null,"abstract":"<p><p>Past research has indicated that individuals with Ehlers-Danlos Syndromes (EDS) and Generalized Hypermobililty Spectrum Disorder (G-HSD) report psychological and psychiatric symptoms, particularly anxiety disorders and depressive symptoms, at much greater rates than the general population. However, these studies have been primarily conducted in small samples at European centres. We report a retrospective chart review from 1035 consecutive patients (88% female) assessed for EDS/G-HSD at the GoodHope EDS Clinic at Toronto General Hospital between June 2019 and June 2021. Prior to assessment, all patients completed self-reported mental health screening questions, the Inventory of Depressive and Anxiety Symptoms - Dysphoria scale, and the Borderline Symptom List-23. The majority of patients reported current or past anxiety or depressive symptoms (53-87%), and a substantial minority reported significant mental health concerns, including Posttraumatic Stress Disorder (4.7-34.8%), disordered eating (19%), self-harm (3-29.2%), and suicidal behaviour (7.8-18.6%). Patients did not differ by diagnostic category on self-report measures of dysphoria or borderline symptoms. Individuals with G-HSD reported higher rates of anxiety and depression in clinical interview than those diagnosed with non-hypermobile EDS, and endorsed a higher rate of having \"struggled with anxiety or depression\" on the mental health screening questionnaire than individuals not diagnosed with EDS/G-HSD. No other differences emerged across diagnostic groups. These findings highlight the need for psychological support for individuals with EDS or G-HSD.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"75"},"PeriodicalIF":3.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425758","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":"How does a preference-based generic health-related quality of life measure perform in patients with a rare disease? Measurement properties of the EQ-5D-Y proxy version among underage patients with neurofibromatosis type 1.","authors":"Wanxian Liang, Shihuan Cao, Yusi Suo, Lining Zhang, Lujia Yang, Hanfei Wang, Han Wang, Xuejing Jin","doi":"10.1186/s13023-025-03590-x","DOIUrl":"10.1186/s13023-025-03590-x","url":null,"abstract":"<p><strong>Background: </strong>EQ-5D-Y is a pediatric preference-based health-related quality of life (HRQL) measure that is recommended in health economic evaluation according to China's guidelines. However, there is limited evidence regarding how the EQ-5D-Y perform in patients with rare diseases in the country. Neurofibromatosis type 1 (NF1) is a rare disease that affects the growth and development of underage patients. This study aimed to examine the performance of EQ-5D-Y proxy version among underage NF1 patients in China.</p><p><strong>Methods: </strong>Data from a nationwide cross-sectional survey from Nov 2022 to Jan 2023 was used. A total of 154 caregivers for underage NF1 patients who completed the EQ-5D-Y proxy version, PedsQL 4.0 Generic Core Scales (PedsQL GCS) proxy version, and Zarit Burden Interview (ZBI-22) were included. The performance of the EQ-5D-Y was assessed by response pattern (ceiling and floor effects), convergent validity against the PedsQL GCS, known-groups validity, and Shannon (H') and Shannon evenness (J') indices.</p><p><strong>Result: </strong>Data from 154 caregivers were analyzed. The mean age of caregivers was 38.23 (6.02) years, and 78.57% of them were mothers of NF1 patients. The mean age of NF1 patients was 8.38 (3.34) years, with 51.30% being females. The ceiling effect of EQ-5D-Y was 30.52%, and floor effect was 0%. Moderate to strong correlations were found between EQ-5D-Y and PedsQL GCS dimensions that share similar constructs (rho - 0.42 to -0.60, all p values < 0.001). The hypotheses of known-groups defined by different PedsQL GCS and ZBI scores were validated. The EQ-5D-Y exhibited the strongest informativity and discriminatory power of the \"feeling worried, sad or unhappy\" dimension and weakest for the \"mobility\" dimension (H'_(mobility) = 0.60, J'_(mobility) = 0.38; H'_{(feeling worried, sad or unhappy)} = 1.23, J'_{(feeling worried, sad or unhappy)} = 0.78).</p><p><strong>Conclusions: </strong>EQ-5D-Y is acceptable for measuring HRQL of underage NF1 patients in China. More evidence for using EQ-5D-Y in rare diseases is awaited.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"71"},"PeriodicalIF":3.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414736","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":"Whole-exome sequencing identifies distinct genomic aberrations in eccrine porocarcinomas and poromas.","authors":"Maya Puttonen, Henrikki Almusa, Tom Böhling, Virve Koljonen, Harri Sihto","doi":"10.1186/s13023-025-03586-7","DOIUrl":"10.1186/s13023-025-03586-7","url":null,"abstract":"<p><strong>Background: </strong>Eccrine porocarcinoma (EPC) is a rare malignant skin tumor arising from the eccrine gland. Investigations into the genomic landscape of EPC have uncovered potential drivers of its development and progression. However, there is limited information on the discrepancies between EPC and its benign counterpart, eccrine poroma (EP).</p><p><strong>Methods: </strong>Formalin-fixed paraffin-embedded (FFPE) samples from 15 EPCs and 5 EPs were retrieved from Helsinki Biobank and Finnish Clinical Biobank Tampere. One EPC was found to be digital papillary adenocarcinoma in review of diagnoses. Whole-exome sequencing was used to conduct a comprehensive analysis to elucidate the genomic features of EPCs and EPs.</p><p><strong>Results: </strong>There was general heterogeneity within EPCs and EPs, with discrepancies such as exclusive TP53, NCOR1, and CDKN2A mutations in EPCs and a higher mutational load in EPCs than in EPs. Furthermore, we identified alterations in pathways associated with cell adhesion and the extracellular matrix in EPCs, while pathways associated with ketone body and amino acid metabolism were altered in EPs. The MAPK and Ras signaling pathways were enriched in genes mutated only in EPCs.</p><p><strong>Conclusions: </strong>EPCs and EPs are generally heterogeneous tumor entities with a few distinct discrepancies from each other. The findings from this study emphasize the need to further verify the roles of disrupted genes and pathways in the initiation and progression of EPCs and EPs.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"70"},"PeriodicalIF":3.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414710","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":"Functional evaluation of novel compound heterozygous variants in SLC12A3 of Gitelman syndrome.","authors":"Na Wang, Yuanxing Yang, Xiong Tian, Hongjun Fu, Shuaishuai Chen, Juping Du, Mengyi Xu, Haixia He, Bo Shen, Jiaqin Xu","doi":"10.1186/s13023-025-03577-8","DOIUrl":"10.1186/s13023-025-03577-8","url":null,"abstract":"<p><strong>Background: </strong>Gitelman syndrome (GS) is an inherited renal tubular disorder characterized by hypokalemic alkalosis and hypomagnesemia, due to biallelic pathogenic variants in the solute carrier family 12 member 3 (SLC12A3) gene encoding a sodium-chloride (Na-Cl) cotransporter (NCC). This work aimed at identifying SLC12A3 variants in the GS pedigree and reveal the effect of the mutations on protein structure and function.</p><p><strong>Methods: </strong>Whole-exome sequencing (WES) and Sanger sequencing were performed in the pedigree. Configuration prediction of two mutant NCC proteins were achieved using SWISS-MODEL. The SLC12A3 missense mutants were generated by site-specific mutagenesis, and the protein expression, location and Na⁺ uptake activity were assessed by using the HEK293T cell line.</p><p><strong>Results: </strong>Genetic analysis identified novel compound heterozygous SLC12A3 variants (c.718G > A/p.E240K and c.2675T > C/p.L892P) in the patient with typical GS phenotype. Both of her parents, elder brother and her son carried the heterozygous p.L892P variant, but only the elder brother exhibited mild hypokalemia. Bioinformatics tools predicted that both mutations were highly species conserved and pathogenic. The prediction of mutant protein indicated that p.E240K and p.L892P altered protein's secondary and three-dimensional (3D) structure and stability. Functional experiments revealed decreased protein expression and Na⁺ uptake activity caused by these two variants, especially the p.L892P variant.</p><p><strong>Conclusion: </strong>Our study presents the genetic and functional evidence for the novel compound heterozygous loss-of-function variants in SLC12A3 that may synergistically cuase GS, and expands the mutation spectrum of SLC12A3 variants in patients with GS.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"66"},"PeriodicalIF":3.4,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11816502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399688","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 patient experience of CHAPLE disease: results from interviews conducted as part of a clinical trial for an ultra-rare condition.","authors":"Leighann Litcher-Kelly, Ahmet Ozen, Sarah Ollis, Hagit Baris Feldman, Andrew Yaworsky, Paolo Medrano, Voranush Chongsrisawat, Lorah Perlee, Marisa Walker, Sharanya Pradeep, Diane M Turner-Bowker, Alina Kurolap, Orly Eshach Adiv, Michael J Lenardo, Olivier A Harari, Jessica J Jalbert","doi":"10.1186/s13023-024-03436-y","DOIUrl":"10.1186/s13023-024-03436-y","url":null,"abstract":"<p><strong>Background: </strong>CD55 deficiency with hyper-activation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) disease is a newly identified condition with an estimated worldwide prevalence of < 100 patients. Patient interviews can ensure that what is important to patients is assessed in a clinical trial program. Due to the rare and potentially fatal nature of CHAPLE disease, interviews were conducted as part of the pozelimab clinical trial, rather than in a separate study before the trial. The aim of the interviews was to identify the key disease-related signs, symptoms, and health-related quality-of-life (HRQoL) impacts that are important and relevant to patients with CHAPLE disease.</p><p><strong>Methods: </strong>Interviews were conducted with patients and/or caregivers at two timepoints (screening and Week 24) during the pozelimab trial to document the signs/symptoms and HRQoL impacts of CHAPLE disease, and document the most bothersome sign/symptom at screening. At Week 24, interviews gathered additional information on the patient experience from caregivers and patients (note: the impact of pozelimab treatment was also collected, though these results are presented elsewhere).</p><p><strong>Results: </strong>Ten patients, aged 3-19 years, were enrolled in the trial; caregivers contributed to nine interviews. Thirty-one signs‌/symptoms and 65 HRQoL impacts were reported during the interviews. Abdominal pain, diarrhea, facial and peripheral edema/‌swelling, nausea, and vomiting emerged as the core signs/‌symptoms of CHAPLE disease (i.e., experienced by ≥ 90% of patients prior to treatment). The remaining 25 signs/symptoms were experienced by four or fewer (n ≤ 4, ≤ 40.0%) patients, and 15 were only reported by one patient each. Abdominal pain and facial edema were reported as the most bothersome signs/‌symptoms (n = 9, 90.0% and n = 1, 10.0%, respectively). The most frequently reported (i.e., ≥ 80% of interviews) HRQoL impacts were restricted diet (n = 10, 100.0%), sleep disruptions (n = 10, 100.0%), missing school (n = 9, 90.0%), ability to get dressed independently (n = 8, 80.0%), and difficulty engaging in play activities (n = 8, 80.0%).</p><p><strong>Conclusions: </strong>The main finding from these patient interviews is the identification of six core signs/symptoms of CHAPLE disease: abdominal pain, diarrhea, facial edema/swelling, peripheral edema/swelling, nausea, and vomiting. The severity of the core signs/symptoms leads to substantial impacts on patients' lives.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT04209634. Registered 20 December 2019 https://classic.</p><p><strong>Clinicaltrials: </strong>gov/ct2/show/NCT04209634 .</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"68"},"PeriodicalIF":3.4,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11817392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399458","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}