Therapeutic advances in rare disease最新文献

{"title":"Evaluation of muscle microvascular perfusion in primary mitochondrial disease by contrast-enhanced ultrasound: Feasibility study.","authors":"Laith R Sultan, Trudy A Morgan, Daniel E McGinn, Kassa Darge, Liya Gendler, Jie Nguyen, Elizabeth Brennan, Julie A Brother, Rui Xiao, Marni J Falk, Vinay Nadkarni, Harry Ischiropoulos, Jose A Adams, Zarazuela Zolkipli Cunningham","doi":"10.1177/26330040261486870","DOIUrl":"10.1177/26330040261486870","url":null,"abstract":"<p><strong>Background: </strong>Primary mitochondrial disease (PMD) are genetic disorders characterized by impaired oxidative metabolism and microvascular abnormalities that contribute to the myopathy.</p><p><strong>Objectives: </strong>This study evaluates the feasibility and utility of contrast-enhanced ultrasound (CEUS) for quantifying skeletal muscle perfusion in patients with PMD. In addition, we assessed exercise-induced changes following cardiopulmonary exercise testing (CPET) to characterize dynamic vascular responses.</p><p><strong>Design: </strong>Prospective pilot feasibility study.</p><p><strong>Methods: </strong>We enrolled genetically confirmed PMD and healthy control participants with ability to complete the CPET protocol. CEUS of the vastus lateralis muscle was performed at rest and following CPET. Imaging parameters were standardized across all CEUS scans, with a fixed mechanical index of 0.13. Perfusion parameters, including perfusion index (PI), peak enhancement (PE), and area under the curve (AUC) were quantified using delta projection analysis, and compared between PMD and control participants, and within each group, pre- and post-exercise.</p><p><strong>Results: </strong>A total of 5 PMD and 5 control participants were evaluated. At rest, CEUS demonstrated a trend in higher muscle perfusion in PMD as compared to control participants on comparing PI (13.7 ± 2.7 vs. 10.7 ± 3.2; p = 0.42), PE (24.9 ± 11.5 vs. 14.3 ± 6.8; p = 0.22), and AUC (95,253.4 ± 35,072.8 vs. 73,591.2 ± 32,820.6; p = 0.31), which did not reach statistical significance, likely in part due to the small cohort size. Following CPET, PMD participants demonstrated exaggerated percentage increases in PI (+21.1% vs. +16.0%), PE (+11.2% vs. +7.6%), and AUC (+20.2% vs. +12.5%) as compared to control participants. Within group analysis revealed a significant post-exercise increase in AUC among PMD participants (p = 0.01) but did not reach significance in control participants.</p><p><strong>Conclusion: </strong>This is the first study to demonstrate the feasibility and utility of conducting CEUS to assess skeletal muscle perfusion in ambulatory PMD patients. The distinct perfusion patterns and exaggerated exercise-induced responses observed in PMD as compared to control participants suggest that reactive hyperemia occurs in PMD at rest and is further exaggerated by exercise. CEUS may serve as a sensitive tool for detecting microvascular alterations in PMD.</p>","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"7 ","pages":"26330040261486870"},"PeriodicalIF":0.0,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13554588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148922163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Addressing unmet needs in rare diseases: A patient-centred vision through INFORM-RD.","authors":"Kenji Demesure, Lien Beckers, Wendy Vansteenkiste, Ruxanda Berlinschi, Alessandra Blonda, Fabienne Dobbels, Elja Eskes, Marion Delcroix, Isabelle Huys","doi":"10.1177/26330040261486869","DOIUrl":"10.1177/26330040261486869","url":null,"abstract":"<p><p>Rare diseases collectively affect approximately 6% of the global population, yet 95% of affected individuals lack access to effective treatments. Beyond this persistent therapeutic gap, patients and caregivers face a broad spectrum of unmet needs, spanning psychosocial challenges, access to reliable diagnostic information, care coordination, and long-term follow-up, which remain poorly characterised in both clinical and policy contexts. Three interrelated challenges underpin this problem. First, validated instruments capable of systematically capturing unmet needs across diverse patient groups, including adults, minors, and caregivers, are largely absent. Second, even when patient data are collected, they are rarely integrated into clinical trial design, regulatory evaluation, or reimbursement deliberations in a structured and reproducible manner. Third, the responsible governance of rare disease data, particularly across institutional and national boundaries, faces unresolved ethical, legal, and organisational barriers. This perspective paper outlines the conceptual foundations of the INFORM-RD research project (a patient-informed clinical platform to inform patient-centred decision-making for rare diseases), embedded at KU Leuven, Leuven Institute for Rare Diseases and University Hospitals Leuven, Belgium. Drawing on the KCE NEED framework and leveraging a cohort of over 30,000 people with rare diseases, INFORM-RD aims to: 1) develop and validate a scalable methodology for unmet need data collection, 2) translate these data into actionable decision-support tools for clinicians, regulators, and payers, and 3) establish an ethical and legal governance architecture enabling responsible and scalable data sharing at national and international levels. By positioning patients, including underrepresented groups such as children and persons with cognitive limitations, as co-creators throughout the research process, INFORM-RD offers a transferable blueprint for need-driven rare disease care across Europe.</p>","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"7 ","pages":"26330040261486869"},"PeriodicalIF":0.0,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13554637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148922203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial-mitochondrial coupling in mitochondrial disease: A systematic review and quantitative synthesis of vascular, biochemical, and oxidative bioenergetic dysfunction.","authors":"Jose A Adams, Tiffany Ko, Laith R Sultan, Tejas Sarna, Daniel McGinn, Arkady Uryash, Jose R Lopez, Vinay Nadkarni, Rui Xiao, Marni J Falk, Harry Ischiropoulos, Zarazuela Zolkipli-Cunningham","doi":"10.1177/26330040261480132","DOIUrl":"10.1177/26330040261480132","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Mitochondrial diseases are multisystem disorders in which defects in oxidative phosphorylation disrupt cellular bioenergetics and redox signaling across the vasculature and heart. Because mitochondrial function is closely linked to endothelial nitric oxide (NO) production, we hypothesized that mitochondrial diseases manifest as a NO-deficiency endotheliopathy affecting conduit and microvascular function. To evaluate this, we performed a systematic review with quantitative synthesis of human studies reporting vascular reactivity, biochemical NO production, or myocardial metabolic imaging, aiming to define the magnitude of impairment and responsiveness to NO-precursor therapy (l-arginine or l-citrulline).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Following PRISMA 2020 guidelines, we conducted a comprehensive search (inception-October 2025) identifying clinical studies of genetically or clinically confirmed mitochondrial disease with quantitative endothelial or bioenergetic endpoints. Eligible measures included flow-mediated dilation (FMD), reactive hyperemia index (RHI), passive-leg-movement (PLM) hyperemia, absolute synthesis rate of NO metabolites (ASR NOm), and positron emission tomography (PET)-derived myocardial oxidative indices (&lt;i&gt;k&lt;/i&gt; &lt;sub&gt;&lt;i&gt;mono&lt;/i&gt;&lt;/sub&gt; , DP/&lt;i&gt;k&lt;/i&gt; &lt;sub&gt;&lt;i&gt;mono&lt;/i&gt;&lt;/sub&gt; ). Quantitative synthesis used Hedges g for between-group comparisons and standardized mean change (SMC) for within-subject responses. Risk of bias was evaluated using ROBINS-I and a modified Newcastle-Ottawa Scale.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Seven studies met these inclusion criteria, comprising 76 mitochondrial-disease subjects and 81 controls (ages 8-63 years). Across all vascular and metabolic domains, mitochondrial disease was associated with marked endothelial and bioenergetic impairment. Macro- and microvascular dysfunction, reflected by reduced FMD, RHI, and PLM hyperemia, demonstrated severe endothelium-specific abnormalities. Biochemical assays showed diminished NO synthesis. Myocardial PET imaging revealed reduced oxidative rate constants and increased energetic inefficiency despite preserved perfusion. Nitric oxide synthesis-precursor therapy was associated with improved endothelial reactivity (increased FMD, RHI, and ASR NOm) and significant, modest improvements in myocardial oxidative metabolism, consistent with partial restoration of endothelial NO signaling. Effect sizes collectively supported a reversible NO-deficiency endotheliopathy. The risk-of-bias assessment indicated moderate-to-good methodological quality, with limitations primarily related to small sample sizes and nonrandomized designs.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Mitochondrial disease is characterized by significant impairments in vascular reactivity, NO signaling, and myocardial bioenergetics. Improvements in endothelial function and NO synthesis following l-arginine or l-citrulline supplementation are consistent with a role for impair","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"7 ","pages":"26330040261480132"},"PeriodicalIF":0.0,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progress and perspectives in primary mitochondrial myopathy: Highlights from the 2025 mitochondrial medicine masterclass with a focus on TK2 deficiency.","authors":"Austin Larson, Jared Goettemoeller, Ken Goettemoeller, Linda Goettemoeller, Amy Goldstein, Nikki Huggan, Amel Karaa, Megan Leahey, Fernando Scaglia, Philip Yeske, Zarazuela Zolkipli-Cunningham, Michio Hirano","doi":"10.1177/26330040261478640","DOIUrl":"10.1177/26330040261478640","url":null,"abstract":"<p><p>The inaugural United Mitochondrial Disease Foundation (UMDF) Mitochondrial Medicine 2025 Masterclass focused on primary mitochondrial diseases (PMDs) especially primary mitochondrial myopathies (PMMs) and thymidine kinase 2 deficiency (TK2d). The Masterclass featured leading US experts in the field, providing the latest scientific and clinical knowledge, as well as patients and caregivers sharing their lived experience of mitochondrial diseases. In this report, we summarize the key highlights of each presentation. An overview of PMM featuring the etiologies of different PMMs and key features of notable PMMs, was followed by a presentation discussing the practical clinical processes of diagnosing PMM, how the roles of clinicians have evolved as diagnostic technology has improved, and actions clinicians can take to maximize the chances of an early, accurate diagnosis. Real-world case studies highlighted variations in disease presentation among the wide range of PMMs, which was followed by an in-depth review of clinical assessments and symptom management for PMM across organ systems. Multisystemic disorders like PMM require multidisciplinary management, in both a chronic and acute setting, and two experts discussed the practical workflow for clinicians to build a multidisciplinary model of care at their hospitals, the roles and responsibilities of the lead coordinator and each subspecialist, and practical steps that clinicians can take to manage acute care coordination and decrease acute care utilization. A hypothetical case study of TK2d (based on real patients) brought together the different aspects of PMM discussed during the Masterclass, while the patient perspective presentations allowed patients and caregivers to discuss the real-world impact that the diagnostic and care journey had on them and their families. This Educational Masterclass provided detailed knowledge of PMM designed to provide the next generation of clinicians and investigators with practical, actionable guidance and resources they could utilize to make a difference in the lives of patients with PMM.</p>","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"7 ","pages":"26330040261478640"},"PeriodicalIF":0.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13546419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148901626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interim analysis of an international multi-site prospective natural history study evaluating the clinical presentation and progression of Leigh syndrome spectrum disorders.","authors":"Laura E MacMullen, Katelynn D Stanley, John Christodoulou, Bruce H Cohen, Matthew Demczko, Amy C Goldstein, Richard Haas, Mary Kay Koenig, Maria Poblete, Alyssa Rice, Ian Rossman, Carolina Ruiz, S Nicholas Russo, David R Thorburn, Eloise Uebergang, Jennifer H Yang, Zarazuela Zolkipli-Cunningham, Marni J Falk","doi":"10.1177/26330040261476231","DOIUrl":"10.1177/26330040261476231","url":null,"abstract":"<p><strong>Background: </strong>Leigh Syndrome Spectrum (LSS) is the most common pediatric mitochondrial disease syndromic presentation. However, its natural history has not been well-characterized, particularly across diverse populations.</p><p><strong>Objectives: </strong>Information obtained through robust, prospective natural history studies (NHSs) in LSS will be foundational to accurately counsel newly diagnosed families, develop effective therapeutics, and identify outcome measures for future clinical trials.</p><p><strong>Design: </strong>We describe an ongoing multi-site, international, patient advocacy group funded, observational NHS in LSS. We employed a multi-site international federated design with local regulatory review coupled with central regulatory and coordinator support. To date, NHS outcome measures have been collected on LSS participants across 5 sites every 3 to 6 months for up to 3.8 years.</p><p><strong>Methods: </strong>Objective and subjective outcome measures were carefully selected by the international LSS outcome measure working group. Study data across sites were anonymized and combined for cleaning and analysis at the Data Coordinating Center (Children's Hospital of Philadelphia). Descriptive statistics of the study cohort and inter-measure correlations were analyzed across NHS assessments.</p><p><strong>Results: </strong>Preliminary analysis of the first 74 participants was completed to characterize demographics, symptomatology, and clinical history. The average age at enrollment was 10.7 years, ranging from 0 to 50 years. The most common gene disorders were <i>MT-ATP6</i> (22%, n=16), <i>MT-ND5</i> (8%, n=6) and <i>SURF1</i> (8%, n=6). No statistically significant between-group differences were detected by sex or genetic etiology. High inter-measure correlation between all the outcome measures and \"gold standard\" outcomes provides justification for future use of these assessments in both NHSs and clinical trials.</p><p><strong>Conclusion: </strong>We have demonstrated the feasibility of prospectively collecting robust international-site LSS NHS data through multi-site collaboration. These LSS community data will be critical for informing therapeutic development, outcome measure selection and clinical trial design, and providing baseline comparator evidence for development of future therapeutic interventions.</p>","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"7 ","pages":"26330040261476231"},"PeriodicalIF":0.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13519198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148842375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2000-2025: Emerging therapies in primary mitochondrial disease: A structured review, horizon scan, and roadmap for the future.","authors":"Amel Karaa, Maria Isabel G Lopez Sanchez, Clare Stuart, Luca Bolliger, Kate Murray, Maria E O'Hanlon, Brian Tseng, Philip Yeske, Sean Murray","doi":"10.1177/26330040261473291","DOIUrl":"10.1177/26330040261473291","url":null,"abstract":"<p><p>Primary mitochondrial diseases (PMD) are ultra-rare, genetically diverse disorders that impair cellular energy metabolism and typically present with multisystemic symptoms. Over the past decades, the therapeutic landscape of PMD has evolved substantially. Early trials of non-specific antioxidant and metabolic therapies produced largely negative or mixed results, providing important methodological lessons for the field. More recent studies have adopted improved outcome measures, natural history-informed designs, and precision therapeutic approaches, including gene therapy and nucleoside therapy, which have shown encouraging clinical and regulatory progress. Regulatory agencies have only recently begun approving disease-modifying therapies for selected mitochondrial disorders. The European Medicines Agency (EMA) approved idebenone for Leber Hereditary Optic Neuropathy (LHON) in 2015 but only recently, in 2025 did the Food and Drug Administration (FDA) in the US approve a treatment for Barth syndrome and thymidine kinase 2 deficiency (TK2d). Friedreich's ataxia received regulatory approval in 2023 from both the EMA and FDA, marking another milestone in mitochondria-related disorders. To comprehensively review clinical and regulatory developments in PMD over the past two decades, we conducted a structured scoping review and horizon scan of published clinical trials and regulatory approvals in PMD from January 2000 to November 2025. Data sources included PubMed, Embase, https://ClinicalTrials.gov, and regulatory agency websites. Recent accelerated and full FDA approvals validate the feasibility of tailored evidence packages, but sustaining this momentum will require more rigorous alignment of trial design with molecular biology, strengthening of natural history infrastructure, deployment of sensitive biomarkers, and adoption of innovative statistical approaches. Early regulatory engagement and robust patient-community partnerships will be key.</p>","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"7 ","pages":"26330040261473291"},"PeriodicalIF":0.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148802644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First bone marrow transplantation for mucopolysaccharidosis type I in Vietnam: a case report.","authors":"Le Nguyen-Ngoc-Quynh, Ngoc Can-Thi-Bich, Duong Dang-Anh, Ha Dang-Thi, Thoa Ta-Thi, Binh Nguyen-Thanh, Dung Vu-Chi, Dien Tran-Minh, Tung Cao-Viet","doi":"10.1177/26330040261469199","DOIUrl":"10.1177/26330040261469199","url":null,"abstract":"<p><p>Mucopolysaccharidosis type I (MPS-I) is an inherited lysosomal storage disorder characterized by alpha-L-iduronidase deficiency, leading to progressive multi-organ damage and fatal complications. Early treatment is crucial to improve outcomes, particularly in patients with severe phenotypes. We present the first case of successful allogeneic bone marrow transplantation (BMT) for MPS-I in Vietnam. A 10-month-old girl experienced coarse facial features, congenital dermal melanocytosis spots, kyphoscoliosis developmental delay. Laboratory analyses revealed reduced alpha-L-iduronidase activity and elevated urinary glycosaminoglycans, genetic mutations identified two heterozygous mutations in the <i>IDUA</i> gene, confirmed the diagnosis of MPS-I. At 3 years old, she underwent allogeneic BMT from an HLA-matched sibling donor following conditioning regimen with busulfan, cyclophosphamide, antithymocyte globulin. Neutrophil engraftment was achieved on day +24, and platelet engrafted on day +32. The post-transplant course was complicated by respiratory deterioration requiring 5 days of mechanical ventilation, which was promptly managed and resolved. No graft-versus-host disease occurred. Post-transplant chimerism showed 95.77% donor-derived cells on day +30 and remained stable at 100% from 2 months. The patient demonstrated improvement in clinical symptoms, accompanied by alpha-L-iduronidase activity returned to normal range, urinary glycosaminoglycan levels decreased and remained stable during follow-up. At 12 months, she demonstrated complete immune reconstitution. This case suggests that allogeneic BMT may be a therapeutic approach for patients with MPS-I in resource-limited settings.</p>","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"7 ","pages":"26330040261469199"},"PeriodicalIF":0.0,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13434929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148674909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer prevalence in primary mitochondrial disease patients and their families.","authors":"Shrey Dalwadi, Nicole M Engelhardt, Colleen C Muraresku, Kelsey Keith, Kathleen D Valverde, Katherine L Nathanson, Marni J Falk","doi":"10.1177/26330040261471914","DOIUrl":"10.1177/26330040261471914","url":null,"abstract":"<p><strong>Background: </strong>While somatic mitochondrial dysfunction occurs in diverse cancers, the association between oncogenesis and germline mitochondrial gene pathogenic variants remains unclear. Further, few clinical observations have been reported of cancer occurring in primary mitochondrial disease (PMD) patients.</p><p><strong>Objectives: </strong>To improve understanding of the potential modulating role for PMD gene disorders in cancer prevalence.</p><p><strong>Design: </strong>727 individuals, including 100 with PMD, from 97 unrelated families were retrospectively surveyed to assess their history of individual cancer occurrence.</p><p><strong>Methods: </strong>We evaluated survey responses by characterizing the cancer prevalence among the study cohort and comparing to the general U.S. population via the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database. Odds ratio calculation was performed to determine the association of survey responses and cancer prevalence.</p><p><strong>Results: </strong>Although overall cancer prevalence in PMD probands and their families was elevated compared to the NCI SEER rate (8800 vs 5600 cases per 100,000), odds ratio calculation determined that PMD did not significantly increase the likelihood of developing cancer, with a non-significant trend observed toward less cancer occuring in PMD that needs to be explored in further studies. Cancer prevalence was significantly correlated with advanced age. Significantly reduced prevalence of prostate cancer was seen across the entire cohort. Surprisingly, while low absolute prevalence (<i>n</i> = 3), a 9-fold increased odds ratio of cancer was seen in <i>POLG</i> patients relative to those with other causes of PMD.</p><p><strong>Conclusion: </strong>No evidence of increased cancer odds was identified in a cohort of PMD patients and their close relatives. Interestingly, a possible inverse association, which did not reach statistical significance, was suggested between mitochondrial disease status and cancer odds. Future prospective investigations in larger PMD kindreds are warranted to validate and evaluate potential mechanistic relations between cancer prevalence and PMD.</p>","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"7 ","pages":"26330040261471914"},"PeriodicalIF":0.0,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13424766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148655342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment outcomes maintained in Hunter syndrome patients: a case series on switching from idursulfase to idursulfase beta in Belarus.","authors":"Anna Kulpanovich","doi":"10.1177/26330040261470451","DOIUrl":"10.1177/26330040261470451","url":null,"abstract":"<p><p>Hunter syndrome (Mucopolysaccharidosis type II, MPS II) is a rare X-linked lysosomal storage disorder caused by iduronate-2-sulfatase deficiency, leading to glycosaminoglycan accumulation. Enzyme replacement therapy (ERT) with idursulfase is a standard treatment, although supply shortages may disrupt continuity of care. This retrospective case series describes clinical and biochemical outcomes in seven patients with Hunter syndrome in Belarus who were switched from idursulfase (Elaprase®) to idursulfase beta (Hunterase®). Patients were evaluated before and after the switch using urinary GAG levels, 6-minute walking test (6MWT), liver and spleen size, and safety parameters. Following the transition, patients maintained or improved clinical outcomes, with continued reductions in urinary GAG levels, stable or improved 6MWT performance, and further decreases in organ enlargement. No new safety concerns were identified. These findings suggest that switching to idursulfase beta may preserve therapeutic benefits and support treatment continuity in real-world settings.</p>","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"7 ","pages":"26330040261470451"},"PeriodicalIF":0.0,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13416002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148623096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patients' lived experience of thymidine kinase 2 deficiency: the online survey-based assessment of TK2d patient perspectives study.","authors":"Amel Karaa, Asha Hareendran, Katie Waller, Philip Yeske, Alexandra Morrison, Marnie Ross, Cristy Balcells","doi":"10.1177/26330040261469197","DOIUrl":"10.1177/26330040261469197","url":null,"abstract":"<p><strong>Background: </strong>Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial disease characterized by progressive myopathy.</p><p><strong>Objectives: </strong>To understand patient experiences and the impact of TK2d on patient quality of life (QoL), and to explore support needs.</p><p><strong>Design: </strong>A cross-sectional international online survey.</p><p><strong>Methods: </strong>The survey for the Assessment of TK2d Patient Perspectives (ATP) study, co-created with patient advocates, included multiple-choice questions, verbal rating scales, and open free-text questions. Patients of all ages with a self-reported genetic diagnosis of TK2d were eligible to participate, either directly or through a caregiver proxy. The patient, caregiver proxy, or bereaved caregiver proxy answered questions on demographics, signs/symptoms, impacts on health-related QoL (HRQoL), support needs, healthcare resource use, and overall experience of living with TK2d. Quantitative data were summarized with descriptive statistics. Qualitative data were analyzed using inductive thematic analysis.</p><p><strong>Results: </strong>Responses for 32 patients (24 patient and 8 caregiver proxy responses) were collected between September 2023 and February 2024. All patients experienced myopathic symptoms. The most frequently reported impact of TK2d was on patients' ability to perform basic activities of daily living (26/32), including difficulties in walking (22/32), eating/swallowing (19/32), and breathing (25/32). The proportions of patients reporting a moderate or severe impact of breathing and walking difficulties on HRQoL, and the proportions requiring medical devices, were higher for those with an earlier age of TK2d symptom onset (⩽2, vs >2 to ⩽12, or >12 years). For most patients, TK2d also had a negative impact on mood, social and leisure activities, and employment/education. Progressive loss of abilities, increasing dependency on others, and medical equipment use contributed to mental and emotional burdens.</p><p><strong>Conclusion: </strong>These quantitative and qualitative analyses of patients' lived experiences highlight the substantial, progressive, and wide-ranging burden of TK2d.</p>","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"7 ","pages":"26330040261469197"},"PeriodicalIF":0.0,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13389147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148564071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}