Orphanet Journal of Rare Diseases最新文献

{"title":"Comprehensive review on Fanconi anemia: insights into DNA interstrand cross-links, repair pathways, and associated tumors.","authors":"Chenyan Fang, Zhoujun Zhu, Jun Cao, Jun Huang, Yipeng Xu","doi":"10.1186/s13023-025-03896-w","DOIUrl":"https://doi.org/10.1186/s13023-025-03896-w","url":null,"abstract":"<p><p>Fanconi anemia (FA) is a rare genetic disorder caused by defects in the repair of DNA interstrand crosslinks (ICLs)-highly toxic lesions that impede essential processes like DNA replication and transcription, leading to severe genome instability. Clinically, FA presents with a broad spectrum of symptoms, including progressive bone marrow failure, congenital abnormalities, and an elevated predisposition to various malignancies, particularly acute myeloid leukemia and squamous cell carcinomas. This review provides a comprehensive overview of both the endogenous and exogenous sources of ICLs and the DNA repair pathways responsible for their resolution, with a primary focus on the FA pathway. We also discuss the tumorigenic consequences of FA pathway deficiencies, highlighting the molecular mechanisms that contribute to the heightened cancer risk observed in FA patients.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"389"},"PeriodicalIF":3.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753960","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":"Cholic acid as a treatment for cerebrotendinous xanthomatosis: a comprehensive review of safety and efficacy.","authors":"Gary Pasternack, Jeff Courtney, Gurdyal Kalsi","doi":"10.1186/s13023-025-03889-9","DOIUrl":"10.1186/s13023-025-03889-9","url":null,"abstract":"<p><p>Cerebrotendinous xanthomatosis (CTX) is a rare treatable bile acid disorder caused by homozygous or compound heterozygous variants in CYP27A, a gene that encodes the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1). CYP27A1 facilitates the production of both cholic acid (CA) and chenodeoxycholic acid (CDCA). Deficiencies in CYP27A1 limit the production of both CA and CDCA, leading to multisystemic cholestanol deposition in membranes, including those of neurons, smooth muscle cells, tendons, and the eye. Because of increased concentrations of cholestanol, a byproduct of cholesterol metabolism, in the brain, cognitive decline develops as a hallmark of CTX. First-line treatment approaches for CTX include off-label prescribed CDCA to reduce serum cholestanol levels. Despite its effectiveness, the success of CDCA administration relies on early diagnosis and low disability scores at the time of initiation. Administration when neurological symptoms arise late in the diagnostic process can lead to worse outcomes, including higher mortality. US Food & Drug Administration-approved CA represents an alternative treatment for CTX. CA reduced cholestanol levels in CSF and blood while also reducing bile acid synthesis and excretion of bile alcohols in the urine. Importantly, outcomes with CA therapy are indistinguishable from those mediated by CDCA therapy and are associated with significantly fewer adverse effects. CA is used as an alternative therapy in patients who cannot tolerate CDCA due to its negative effects. Data from studies on CA strongly support the improvement of liver function, which is likely to be at the crux of secondary pathology, including neurological dysfunction. Because no consensus has been published on the treatment of CTX, Stelten et al (Orphanet J Rare Dis 16:353, 2021) a need exists for a direct comparison of the two approaches.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"387"},"PeriodicalIF":3.5,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12305907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743481","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":"Osteoporosis in Wilson's disease: A large cohort study highlighting age, sex and skeletal symptoms as key risk factors for clinical surveillance.","authors":"Ling Zhu, Bin Song, Yun Xu, Yu-Long Zhu, Lei Hua, Na Nian, Long Zhang, Quan Sun, Ben-Chun Xue, Yin Xu, Yong-Sheng Han","doi":"10.1186/s13023-025-03910-1","DOIUrl":"https://doi.org/10.1186/s13023-025-03910-1","url":null,"abstract":"<p><strong>Background: </strong>Wilson's disease (WD) is a rare disorder affecting copper metabolism that is characterized by multiple organ system damage, including the liver, brain, and eyes. Patients with WD are at risk for decreased bone mineral density (BMD). Only a few studies have investigated the relationship between WD and BMD, and there are discrepancies in the data. Therefore, we investigated the BMD status of patients with WD and analyzed the risk factors affecting the bone mass change.</p><p><strong>Methods: </strong>This retrospective cohort study selected 426 patients with WD who were admitted to a neurological hospital in Hefei, China, from January 2018 to August 2024 as study subjects. The enrolled patients were divided into the osteoporosis group (13 patients), osteopenia group (99 patients), and normal bone mass group (314 patients). The rates of prevalence of osteoporosis and osteopenia were calculated, and the risk factors of osteoporosis and osteopenia were analyzed by multivariate ordered logistic regression.</p><p><strong>Results: </strong>The prevalence of osteoporosis and osteopenia in patients with WD was 3.1% and 23.2%, respectively. Multivariate ordered logistic regression analysis demonstrated that age, male sex, and the presence of skeletal symptoms during the course of the disease were independent risk factors for osteoporosis and osteopenia in patients with WD, with odds ratio (OR) (95% confidence interval [CI]) values of 1.103 (1.074-1.134), 2.292 (1.216-4.320), and 2.675 (1.395-5.131), respectively.</p><p><strong>Conclusions: </strong>Patients with WD with older age, male sex, and skeletal symptoms during the course of the disease are prone to osteoporosis and osteopenia changes. BMD monitoring and early intervention of such patients should be strengthened clinically.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"388"},"PeriodicalIF":3.5,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743482","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":"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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306095/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306060/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306030/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306134/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306071/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12305939/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306108/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}