Orphanet Journal of Rare Diseases最新文献

{"title":"Lessons learned from a muscle study in nail-patella syndrome.","authors":"Luisa Paul, Anne Schänzer, Christel Depienne, Andreas Hentschel, Nicolai Kohlschmidt, Ulrike Schara-Schmidt, Christopher Jannik Nelke, Andreas Roos, Heike Kölbel","doi":"10.1186/s13023-025-03911-0","DOIUrl":"https://doi.org/10.1186/s13023-025-03911-0","url":null,"abstract":"<p><strong>Background: </strong>Nail-patella (NPS) syndrome is an autosomal dominant disorder caused by mutations in the LMX1B gene and manifests with involvement of kidneys, nails, eyes as well as skeletal musculature. NPS shows some clinical similarities with Emery-Dreifuss muscular dystrophy. However, thus far human muscle tissue has not been analysed in the context of NPS to precisely clarify the muscular involvement in this multi-systemic disease.</p><p><strong>Methods: </strong>To study the effects of a missense variant in LMX1B on human skeletal muscle, histological, immunofluorescence and ultra-structural studies were performed on a deltoid muscle biopsy performed at the age of 2 aiming to analyse potential pathologies in muscle fibres in addition to unbiased proteomic profiling to identify dysregulated proteins.</p><p><strong>Results: </strong>Microscopic work-up of the muscle biopsy revealed no striking pathologies, except for some atrophic fibres. The proteomic analyses unveiled a clustered number of dysregulated keratin proteins among the downregulated proteins.</p><p><strong>Conclusion: </strong>Although NPS can also present with a muscular phenotype indicated by muscular weakness of the upper extremities, elevated CK levels and contractures of the elbow joint, there is no evidence of primary muscular involvement due to expression of mutant LMX1B. The examination of human skeletal muscle tissue confirmed the findings from the animal models showing that the skeletal muscle symptoms of NPS may be the result of a developmental disorder of the extremities that leads to impaired muscle mobilisation.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"384"},"PeriodicalIF":3.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiogenesis-related genes and immune microenvironment in moyamoya disease: a transcriptomic and functional analysis.","authors":"Zhenyu Zhou, Hongchuan Niu, Shaoqi Xu, Junze Zhang, Yutong Liu, Chengxu Lei, Shihao He, Yuanli Zhao","doi":"10.1186/s13023-025-03945-4","DOIUrl":"https://doi.org/10.1186/s13023-025-03945-4","url":null,"abstract":"<p><strong>Background: </strong>Moyamoya disease (MMD) is a chronic, progressive occlusive cerebrovascular disease. It causes recurrent cerebrovascular stroke due to vascular closure and proliferation. An unclear pathophysiological mechanism is the most significant obstacle in the diagnosis and treatment of MMD.</p><p><strong>Method: </strong>This study prospectively included 10 MMD and 3 HC (healthy controls) participants in the discovery cohort. GSE189993 and GSE157628 were downloaded from the Gene Expression Omnibus (GEO) as validation cohorts, which included 32 patients with MMD and 20 HC. Angiogenesis-related genes were downloaded from GENECARD. Hub genes were selected by differential analysis and weighted correlation network analysis. Functional enrichment, immune infiltration, and metabolic pathway analyses and drug prediction mapping (Connectivity Map [CMap]) were performed.</p><p><strong>Result: </strong>Through differential analysis identified, 198 differentially expressed genes (DEGs), including 85 upregulated genes and 113 downregulated genes. In total, 238 angiogenesis -related genes were identified using WGCNA. Four hub genes were identified: TBC1 domain family member 9B (TBC1D9B), Phosphatidylinositol transfer protein beta (PITPNB), The ANK repeat and PH domain-containing protein 3 (ARAP3), and Ubiquitin-conjugating enzyme E2 E1 (UBE2E1). Four potential drugs were selected: calyculin A, H-9, parbendazole, and velnacrine. The results of multiple immune infiltration analyses collectively depicted the immune microenvironment characteristics of MMD.</p><p><strong>Conclusion: </strong>This study is the first to explore the mechanism by which angiogenesis related genes are involved in intimal hyperplasia in Moyamoya disease. TBC1D9B and ARAP3 may promote the pathological development of moyamoya disease through immune response, metabolism.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"385"},"PeriodicalIF":3.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unmet needs in hereditary angioedema: an international survey of physicians.","authors":"Thomas Buttgereit, Felix Aulenbacher, Adil Adatia, Carolina Vera Ayala, Maryam Ali Al-Nesf, Sabine Altrichter, Mohamed Abuzakouk, Mona Al-Ahmad, Ramzy Mohammed Ali, Alejandro Berardi, Isabelle Boccon-Gibod, Laurence Bouillet, Luisa Brussino, Marko Barešić, Paula J Busse, Stephen D Betschel, Herberto Chong-Neto, Oscar Calderón Llosa, Timothy J Craig, Anthony D Dorr, Sérgio Duarte Dortas Junior, Daria Fomina, Henriette Farkas, Jie Shen Fok, Anete S Grumach, Jens Greve, Mar Guilarte, Margarida Gonçalo, Vesna Grivcheva-Panovska, Michihiro Hide, Roman Hakl, Ankur Jindal, Constance H Katelaris, Shailajah Kamaleswaran, Tamar Kinaciyan, Elena Latysheva, José Ignacio Larco Sousa, Ramón Lleonart Bellfill, Hassan Mobayed, Martin Metz, Iman Nasr, Natasa T Mitrevska, Stefania Nicola, Claudio Alberto Salvador Parisi, Grzegorz Porebski, Jonny Peter, Mariana Paes Leme Ferriani, Nelson Rosario Filho, Bülent Enis Şekerel, Faradiba Sarquis Serpa, Marcin Stobiecki, Susanne Trainotti, Anna Valerieva, Chamard Wongsa, Jane C Y Wong, Esra Yucel, Yinglei Li, Chiara Nenci, Marcus Maurer, Markus Magerl, Philip H Li","doi":"10.1186/s13023-025-03739-8","DOIUrl":"https://doi.org/10.1186/s13023-025-03739-8","url":null,"abstract":"<p><strong>Background: </strong>Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by unpredictable attacks of angioedema. MENTALIST (UnMEt Needs in herediTAry angioedema-a gLobal physIcian perSpecTive) is the first international survey uncovering unmet needs and identifying barriers to optimal management in HAE following the latest update of the World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) HAE guidelines.</p><p><strong>Methods: </strong>This web-based survey comprised 24 questions on HAE management and unmet needs. HAE-expert physicians from the Angioedema Centers of Reference and Excellence network ranked unmet needs according to their own perspectives and their patients' perspectives, using a 10-point Likert scale ranging from 0 (not a challenge/unmet need at all) to 10 (huge challenge/unmet need).</p><p><strong>Results: </strong>Of 64 respondents from 32 countries, most (91%) had > 5 years of experience in managing HAE. Overall, 48% of respondents (n = 31/64) reported that < 50% of their patients had achieved the WAO/EAACI HAE treatment goals of total disease control and \"normalization\" of life at the time of the survey. Implementation of consensus recommendations was found to be inconsistent across regions. Gaps in non-HAE-expert physician knowledge, treatment costs, and reimbursement for long-term prophylaxis were the highest-priority challenges according to the respondents. Burden of disease remains a challenge among patients, as reported by their physicians.</p><p><strong>Conclusions: </strong>The MENTALIST findings highlight a need for removal of barriers to HAE treatment goals and propose a call to action to improve access to treatments, for greater provision of education for physicians and patients, critical collaboration with patient organizations and industry stakeholders and ultimately to optimize HAE care.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"383"},"PeriodicalIF":3.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A composite measurement concept for monitoring cardiac function in Fabry disease.","authors":"Pooja Nandi, Robert Ellis, Jennifer Hiros, Paul Howard, Biliana O Veleva-Rotse","doi":"10.1186/s13023-025-03895-x","DOIUrl":"https://doi.org/10.1186/s13023-025-03895-x","url":null,"abstract":"<p><strong>Background: </strong>Fabry disease (FD) is an X-linked, multisystemic, progressive lysosomal disorder caused by GLA variants resulting in alpha-galactosidase A deficiency. Although cardiovascular disease is the leading cause of death in people with FD, the progression of cardiac dysfunction remains poorly understood, mainly due to a lack of clinical measurement tools for predicting cardiac progression risk over relevant timescales. New, accessible tools are needed to measure cardiac functional change and predict event risk over shorter timescales. Digital tools allow at-home, frequent data collection that could help detect elevated cardiac event risk, inform treatment and management, and support novel therapy development. Digital measures are designed, developed, and validated using recognized frameworks. We present a novel composite measurement concept aligned to established guidance that utilizes digital tools to improve the monitoring of cardiac function in FD.</p><p><strong>Methods: </strong>A targeted literature search, patient advisory board, and clinician advisory board were conducted to identify important FD signs and symptoms and the most suitable cardiac patient-reported outcomes and digital tools for concurrent remote collection of subjective and objective data.</p><p><strong>Results: </strong>The literature search highlighted a lack of FD-specific cardiac digital monitoring tools. Patient advisory board discussions and survey responses highlighted pain, gastrointestinal issues, and fatigue as important FD symptoms, and participants expressed a desire to understand how cardiac manifestations impacted these symptoms. The clinician advisory board noted a lack of specific diagnostic, monitoring, and prognosis (especially cardiac) tools in FD. The composite measurement concept was developed to capture the signs and symptoms most important to people living with FD, alongside heart-rate variability, electrocardiograms, blood pressure, and quality of life as relevant measures within the cardiac domain that can be staged in a progression model with clear group boundaries.</p><p><strong>Conclusions: </strong>Based on work completed to date, developing a composite measurement concept that utilizes digital tools to improve the measurement of cardiac function in FD is conceptually possible and aligns with the evidentiary framework for designing and building a monitoring biomarker. This composite measurement concept could be used for future analytical validation, usability, and clinical validation, seeking to capture progressing cardiac dysfunction in people living with FD.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"382"},"PeriodicalIF":3.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proactive identification of rare diseases: lessons from hereditary angioedema diagnosis using electronic medical records.","authors":"Xue Wang, Huizhen Jiang, Ziyang Huang, Chao Dong, Weiguo Zhu, Shuyang Zhang, Yuxiang Zhi","doi":"10.1186/s13023-025-03882-2","DOIUrl":"https://doi.org/10.1186/s13023-025-03882-2","url":null,"abstract":"<p><strong>Background: </strong>Diagnosing rare diseases traditionally requires patients to endure lengthy and challenging journeys to find specialists familiar with their conditions. This study advocates a paradigm shift in rare disease diagnosis, moving from patients seeking physicians to physicians actively identifying patients. Using hereditary angioedema (HAE) as an example, we demonstrate how this approach, supported by electronic medical records (EMRs), enables proactive care for patients with rare diseases. Our EMR system incorporates a free-text search engine to screen for patients with potential HAE based on clinical symptoms and laboratory tests. Search terms include recurrent skin edema, abdominal pain, laryngeal edema, and/or decreased C4 levels. Suspected cases are followed up by telephone calls from trained physicians, inviting patients to undergo confirmatory C1-INH and C4 testing and genetic testing to ensure accurate diagnosis and appropriate treatment.</p><p><strong>Results: </strong>Of 2,689 patients who met the screening criteria, 3,441 records were analyzed. Ninety-five patients had already been diagnosed with HAE. After excluding those with a known etiology for edema or characteristics inconsistent with HAE, three patients with unexplained cutaneous edema, abdominal pain, and/or laryngeal edema were included in the final screening. Laboratory tests confirmed HAE in all three, highlighting the effectiveness of this proactive approach.</p><p><strong>Conclusions: </strong>This study underscores the transformative potential of EMRs in diagnosing rare diseases. By shifting the responsibility of identifying rare diseases from patients to healthcare professionals, we expedite diagnosis and exemplify the spirit of service in medicine, ensuring patients with rare diseases receive timely and effective care.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"386"},"PeriodicalIF":3.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Missense variants in SLC9A6 cause partial epilepsy without neurodevelopmental delay.","authors":"Jun-Ping Jiao, Hong-Wei Zhang, Xi-Zhong Zhou, Shu-Juan Tian, Li Gao, Bing-Mei Li, Jun-Xia Luo, Jie Wang, Song Lan, Bin Li, Wei-Ping Liao","doi":"10.1186/s13023-025-03924-9","DOIUrl":"https://doi.org/10.1186/s13023-025-03924-9","url":null,"abstract":"<p><strong>Background: </strong>The SLC9A6 gene encodes a monovalent sodium-selective sodium/hydrogen exchanger that is essential in regulating endosomal PH and volume. SLC9A6 variants are associated with Christianson Syndrome, a severe neurodevelopmental disorder that is accompanied by seizures. It is unknown whether SLC9A6 variants are associated with milder phenotypes.</p><p><strong>Method: </strong>Trio-based whole-exome sequencing was performed in unrelated cases (families) with epilepsy without acquired causes. Previously reported SLC9A6 variants were reviewed to analyze the mechanism underlying phenotype variations.</p><p><strong>Results: </strong>Five hemizygous variants, including three null and two missense variants, were identified in five males. All the variants were absent in the gnomAD-all populations and the missense variants were predicted to be damaging by multiple in silico tools. The three patients with null variants presented with refractory epilepsies and severe developmental delay; one patient with missense variant in the transmembrane region showed refractory epilepsies and speech delay; and one patient harboring missense variant located in the loop region achieved seizure-free with favorable outcome. Further analysis revealed that the proportions of brain atrophy, microcephaly, and movement disorders in patients with missense variants were significantly lower than that of patients with null variants, suggesting a genotype-phenotype correlation. Additionally, previously reported missense variants in the pore/transmembrane region led to Christianson Syndrome, whereas variants outside these regions were associated with milder phenotype, suggesting a sub-regional effect.</p><p><strong>Conclusion: </strong>Missense variants in SLC9A6 are associated with mild partial epilepsies. The genotype-phenotype correlation and molecular sub-regional effect of SLC9A6 help in explaining the mechanisms underlying phenotypic variations.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"380"},"PeriodicalIF":3.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of cholic acid in Smith-Lemli-Opitz syndrome (SLOS): real-world patient outcomes.","authors":"Edwin Ferren, Paul R Hillman, Amy Kritzer, Joseph Ray, Alvaro Serrano, Hope Northrup, Paige Roberts, Rana Dutta, Tiziano Pramparo, Pamela Vig, Robert D Steiner","doi":"10.1186/s13023-025-03914-x","DOIUrl":"https://doi.org/10.1186/s13023-025-03914-x","url":null,"abstract":"<p><strong>Background: </strong>Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by biallelic pathogenic variants in DHCR7, which encodes the enzyme 7-dehydrocholesterol reductase (DHCR7). SLOS is a multisystemic disorder affecting various aspects of health, including growth, development, behavior, and quality of life, underscoring the need for safe, efficacious interventions that limit disease burden. DHCR7 enzyme deficiency leads to a \"metabolic block\" resulting in decreased cholesterol production and accumulation of its precursor 7-dehydrocholesterol and the secondary isomer 8-dehydrocholesterol. Reduced cholesterol synthesis, in turn, leads to decreased levels of cholic acid (CA), an endogenous bile acid synthesized from cholesterol and essential for cholesterol absorption. Dietary cholesterol supplementation is standard therapy. Bile acid supplementation with CA has been shown to improve dietary cholesterol absorption and raise plasma cholesterol levels. However, there is a paucity of patient-level data regarding the utility of CA as a treatment for SLOS. The purpose of this case series is to address the lack of comprehensive patient data through documentation of the outcomes of a company-sponsored CA patient experience program. A retrospective chart review was conducted for these individuals while on CA plus cholesterol supplementation. Data for demographics and key clinical/laboratory parameters were captured with a standardized data collection tool.</p><p><strong>Results: </strong>Eight genetically confirmed individuals with SLOS (age range 1 to 20 years) with median plasma cholesterol levels at baseline ≤ 125 mg/dL were treated with CA at 10-15 mg/kg/d for 30 to 450 days. Exogenous CA administration improved cholesterol levels in the majority of patients. Growth improved after CA initiation and trended toward age-appropriate growth percentiles. Reports from the patient, parent/caregiver, and/or healthcare professional noted positive behavioral changes leading to increased social interaction, cognitive engagement, and improved communication skills. Improvements in biochemical parameters and quality of life were also observed in several patients after CA treatment. CA supplementation was well tolerated with minimal adverse events.</p><p><strong>Conclusions: </strong>The cumulative experiences of eight patients provide a compelling narrative supporting the potential utility of CA treatment in SLOS while underscoring the safety of CA in this patient population. Larger longitudinal studies of CA in patients with SLOS are warranted.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"381"},"PeriodicalIF":3.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of retrospective natural history data collected from patients with SYNGAP1-related disorders: a preliminary examination of the Citizen database.","authors":"Matthew R Scott, Albert Misko, Yang Liu, Oleksandr Sverdlov","doi":"10.1186/s13023-025-03918-7","DOIUrl":"https://doi.org/10.1186/s13023-025-03918-7","url":null,"abstract":"<p><strong>Background: </strong>SYNGAP1-related disorder (SRD) is a rare neurodevelopmental disorder caused by genetic variants. A major challenge is the characterization of SRD, which requires assessment of several outcomes. We considered natural history data from the Citizen database on 65 patients with SRD in eight data domains: demographics, genetics, growth parameters, standardized clinical scales, developmental skills, neurological examinations, hospitalizations, and seizures. Exploratory analysis tools such as visualizations, summary statistics, and non-parametric statistical modeling were utilized.</p><p><strong>Results: </strong>Age at SRD diagnosis (median [IQR] = 3 [2, 5] years; [min, max] = [1, 17] years) was similar by sex. No evidence of a high frequency allele change in SYNGAP1 was found, indicating no dominant variant in this patient population. Growth parameters of SRD children appeared normal in terms of height, weight, and head circumference. Developmental data were indicative of delayed development and language reversion. Standardized assessment data were largely sparse. Neurological exam data demonstrated ataxia and muscle tone issues. Hospitalization data highlighted substantial healthcare burden, largely due to seizures; absence, atonic, and myoclonic seizures were the most common types.</p><p><strong>Conclusion: </strong>Citizen data provide important insights into the natural course of SRD. Our findings not only provide utility in clinical practice of SRD but also contribute valuable insights to guide the development of SRD clinical trials. Limitations to our analysis include sparsity of standardized clinical scales data, crude statistical methodology, and bias induced by patients with older ages of diagnoses.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"379"},"PeriodicalIF":3.5,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arthrogryposis Multiplex Congenita (AMC) and counselling before and during pregnancy: a questionnaire study.","authors":"Arda Arduç, Julia Slootbeek, Johanna I P de Vries, Maria B Tan-Sindhunata, Femke Stoelinga, Bonita Sawatzky, Isabel Filges, Ingeborg H Linskens","doi":"10.1186/s13023-025-03913-y","DOIUrl":"https://doi.org/10.1186/s13023-025-03913-y","url":null,"abstract":"<p><strong>Background: </strong>Pre-pregnancy counselling in women with Arthrogryposis Multiplex Congenita (AMC) is not implemented as standard care. Prior surveys revealed that the majority of adults with AMC live independently with or without support, are working, and engage in social actifities. Although many of them underwent pregnancies, literature is scarce concerning women with AMC and pregnancies. This study enquires information of women with AMC and their preferences to optimize counselling and guidance concerning aspects related to (pre-)pregnancy, childbirth and parenthood. Women with AMC, being members of an international AMC patient support group or Canadian register, were invited anonymously via newsletter in mail or announcement on social media.</p><p><strong>Results: </strong>A total of 53 women with confirmed AMC participated in this questionnaire study. Pregnancies were reported in 64.2% (34/53) of the women and 26 women had multiple pregnancies and delivered in total 45 children. A third (15/45) of the children were born vaginally and the remaining per caesarean section. None of the children had AMC. Four women reported on complications during application of local analgesia in labour and in 3 while positioning on the operating table. Of the 47 women who answered this question, 95.7% (45/47) expressed a wish for standard pre-pregnancy counselling. As optimal circumstances they prefer counselling at or above 18 years of age, by a gynaecologist, at the outpatient clinic and for those with a relationship together with their partner. The importance of multidisciplinary team of physicians was emphasized as well as information from peer support groups and websites. Women expressed concerns about lack of knowledge on AMC in healthcare workers, discontinuity in care and attitude towards treatment and acknowledged the importance of this study.</p><p><strong>Conclusions: </strong>This study provides unique insights from women with AMC regarding pregnancy and parenthood. Participants emphasized the importance of tailored care. Their preferences strongly advocate for implementing pre-pregnancy counselling from the age of 18, ideally by a multidisciplinary team including a gynecologist. Incorporating these perspectives is essential to improve reproductive care.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"378"},"PeriodicalIF":3.4,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety findings from the phase 1/2 MOSAIC study of miransertib for patients with PIK3CA-related overgrowth spectrum or Proteus syndrome.","authors":"Whitney Eng, Ionela Iacobas, Jonathan Perkins, Giuseppe Zampino, Chiara Leoni, Paola Sabrina Buonuomo, Alessandra Simonetti, Himanshu Goel, Michael Briones, Mo Huang, Gregory Goldmacher, Danny Liaw, Adrienne Hammill","doi":"10.1186/s13023-025-03831-z","DOIUrl":"10.1186/s13023-025-03831-z","url":null,"abstract":"<p><strong>Background: </strong>PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome are associated with mosaic tissue overgrowth of varying severity that commonly presents in childhood. The multicenter, open-label, phase 1/2 MOSAIC study (NCT03094832) was designed to evaluate the clinical efficacy and safety of the selective pan-AKT inhibitor miransertib for participants with PROS or Proteus syndrome.</p><p><strong>Methods: </strong>Participants ≥ 2 years of age with PROS with documented somatic PIK3CA mutations or Proteus syndrome with documented somatic AKT1 mutations were enrolled to receive oral miransertib at a starting dose of 15 mg/m² every day for the first 3 cycles (1 cycle = 28 days) and miransertib 25 mg/m² every day thereafter, provided no clinically significant drug-related toxicities were observed. The initial primary objective of the study was to assess clinical response to miransertib. Due to study design and data collection limitations, evaluating efficacy was no longer considered feasible and the primary objective was updated in 2021 to evaluate the safety and tolerability of miransertib.</p><p><strong>Results: </strong>Between May 16, 2017 and January 25, 2021, 49 participants were enrolled and received ≥ 1 dose of study drug, comprising the safety analysis population. Forty-five participants had a diagnosis of PROS and four had a diagnosis of Proteus syndrome. The median (range) age at enrollment was 7 years (2-41). Median (range) duration of treatment was 20.5 months (9.9-45.6). A total of 23 (46.9%) participants had a drug-related adverse event, most commonly decreased neutrophil count (n = 6, 12.2%), increased blood insulin (n = 5, 10.2%), and stomatitis (n = 5, 10.2%). One (2.0%) participant experienced a grade 3 drug-related adverse event (deep vein thrombosis). No drug-related adverse events led to early study discontinuation or death. Laboratory assessment values remained generally stable throughout the study.</p><p><strong>Conclusion: </strong>Miransertib was safe and tolerable in participants with a confirmed diagnosis of PROS or Proteus syndrome. Future investigations are needed to determine whether patients receive measurable clinical benefit from miransertib.</p><p><strong>Trial registration: </strong>NCT03094832 registered Mar 28, 2017, https://clinicaltrials.gov/ct2/show/NCT03094832 .</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"375"},"PeriodicalIF":3.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}