bims-curels Biomed News
on Leigh syndrome
Issue of 2025–11–23
fourteen papers selected by
Cure Mito Foundation
  1. Expanding research and care for Leigh syndrome: efforts of a patient-led advocacy organization.
  2. Hypocitrullinemia as an Early Diagnostic Biomarker for MT-ATP6 Mitochondrial Diseases.
  3. Mitochondrial transplantation restores mitochondrial content and function in SSBP1-related mitochondrial DNA depletion syndrome.
  4. Fontaine progeroid syndrome with neonatal mitochondrial disease.
  5. Study Designs and Crafting Endpoints for Gene Therapy Development Programs in Rare Disease: A Narrative Review.
  6. A Checklist for Involving Patients in Educational Activities.
  7. Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.
  8. From engagement to evidence: a scoping review of qualitative and quantitative measures of adult patient engagement in research.
  9. Mitochondrial transfer from human embryonic stem cell-derived mature cardiomyocytes to mesenchymal stem cells.
  10. Patient-based evidence for amyotrophic lateral sclerosis prognostic health communication: "the clock is ticking…how long do I have?"
  11. Six ways to get a grip on co-creating curriculum with patients.
  12. Exploring Patient Preference Information in Clinical Research and Decision Models: An Investigative Survey.
  13. Rare disease education in medical schools: patient-centered and innovative strategies.
  14. An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice.
  1. Res Involv Engagem. 2025 Nov 20. 11(1): 137
    Expanding research and care for Leigh syndrome: efforts of a patient-led advocacy organization.
    Sophia Zilber, Melinda Burnworth, Titilola Afolabi, Jonathan R Brestoff, Michal Minczuk, Alejandro Rodriguez Luis, Qinglan Ling, Alessandro Prigione, Isabella Tolle, Ibrahim Elsharkawi, Ethan Perlstein, Danielle Boyce, Simon Johnson, Kasey Woleben.
      
    Keywords:  Gene therapy; Leigh syndrome; Mitochondrial disease; Patient advocacy; Rare disease
    DOI:  https://doi.org/10.1186/s40900-025-00808-x
  2. J Mol Neurosci. 2025 Nov 19. 75(4): 154
    Hypocitrullinemia as an Early Diagnostic Biomarker for MT-ATP6 Mitochondrial Diseases.
    Yingxue Li, Dongjuan Wang, Maobin Zhou, Haoxuan Sun, Siqi Hong, Li Jiang, Yi Guo.
      MT-ATP6 mitochondrial diseases are a group of disorders inherited from the maternal lineage caused by pathogenic variants in the MT-ATP6 gene, which encodes the a subunit of mitochondrial complex V (ATP synthase) in the electron transport chain. In this study, statistical analysis of 69 mitochondrial disease patients with complete blood metabolic screening at our center demonstrated that hypocitrullinemia exhibited 58% sensitivity (7/12) and 100% specificity (57/57) for diagnosing MT-ATP6 mitochondrial diseases. For detecting the m.8993T > G variant, the diagnostic sensitivity reached 78% (7/9) with maintained 100% specificity (60/60). Among the 7 patients with hypocitrullinemia, one had mtDNA large segment deletion syndrome involving MT-ATP6, and the other 6 had MT-ATP6 mitochondrial diseases due to the m.8993T > G variant. Hypocitrullinemia was initially detected in 3 patients during newborn screening and persisted in follow-up evaluations. A literature review identified 42 cases with MT-ATP6 variants exhibiting hypocitrullinemia, of whom 21 were diagnosed with decreased citrulline during newborn screening. We propose that hypocitrullinemia may serve as an early, characteristic serum biomarker for MT-ATP6 mitochondrial diseases, particularly aiding in the early diagnosis of the m.8993T > G variant. It also exhibits high specificity for diagnosing MT-ATP6 mitochondrial diseases and the m.8993T > G variant. Timely interventions, such as proactive diagnosis of pathogenic variants and administration of mitochondrial cofactors and citrulline, can mitigate the risk of decompensation and improve long-term prognosis.
    Keywords:   MT-ATP6 ; Biomarker; Hypocitrullinemia; Leigh syndrome; m.8993T > G
    DOI:  https://doi.org/10.1007/s12031-025-02440-6
  3. BMB Rep. 2025 Nov 20. pii: 6418. [Epub ahead of print]
    Mitochondrial transplantation restores mitochondrial content and function in SSBP1-related mitochondrial DNA depletion syndrome.
    Dohee Kim, Seo-Eun Lee, JuHyuen Cha, Jun Ho Lee, Young Cheol Kang, Sang-Yeon Lee.
      This study examined therapeutic potential of mitochondrial transplantation using PN-101, a mitochondria preparation derived from human umbilical cord mesenchymal stem cells (UCMSCs), to address SSBP1-related mitochondrial DNA (mtDNA) depletion syndrome. Patient-derived fibroblasts harboring a heterozygous SSBP1 mutation (c.272G＞A:p.Arg91Gln) were treated with PN-101. Its successful uptake and integration into these cells were confirmed. Subsequent analyses revealed that PN-101 treatment significantly increased mtDNA copy numbers in a time- and dose-dependent manner, elevated the expression of key oxidative phosphorylation proteins, and enhanced overall mitochondrial bioenergetics. Taken together, these results provide strong evidence that mitochondrial transplantation holds promise as a therapeutic strategy for primary mitochondrial diseases, including those involving SSBP1 mutations.
  4. Hum Genome Var. 2025 Nov 21. 12(1): 26
    Fontaine progeroid syndrome with neonatal mitochondrial disease.
    Mitsuhiko Riko, Daiki Kawamoto, Kentaro Hirayama, Tomoya Tsuchihashi, Takayuki Suzuki, Takuya Sugimoto, Yasushi Okazaki, Kei Murayama, Daisuke Tokuhara.
      Fontaine progeroid syndrome (FPS) is a rare condition characterized by abnormalities in SLC25A24. Some instances of FPS have been reported to be fatal early in life. Here we present the first case of mitochondrial disease diagnosed with FPS in Japan. The diagnosis was based on the presence of the heterozygous known pathogenic variant of SLC25A24, NM_013386.5: c.649C>T and decreased activity of mitochondrial respiratory chain enzyme activity.
    DOI:  https://doi.org/10.1038/s41439-025-00331-1
  5. Adv Ther. 2025 Nov 21.
    Study Designs and Crafting Endpoints for Gene Therapy Development Programs in Rare Disease: A Narrative Review.
    on behalf of the Rare Disease Clinical Outcome Assessment Consortium
      Gene therapies are emerging as a promising strategy for the treatment of rare genetic diseases, for which treatment options are often limited and do not address the underlying disease mechanisms. However, there are significant challenges for gene therapy programs, including defining a suitable first-in-human cohort and selecting endpoints with appropriate variability, sensitivity, reliability, and clinical meaningfulness; a systematic framework for the assessment and approval of these treatments is lacking. In this review, we share insights from 12 clinical development programs that culminated in recent approvals of gene therapies for rare genetic diseases (2016-2023). These approvals highlight useful strategies for navigating the unique challenges of gene therapy trials, including early and frequent engagement with regulatory bodies, incorporating the patient voice, selecting meaningful clinical outcome assessments and suitable controls, and leveraging well-matched real-world data to understand long-term efficacy, durability, and safety. By systematically documenting and analyzing detailed examples in this review, it becomes possible to derive data-driven solutions that can inform the design of future studies. Such solutions may diverge from prior assumptions or preconceptions but can provide a more evidence-based foundation for improving trial efficiency, and ultimately accelerate the development of urgently needed therapies for patients with rare genetic diseases.
    Keywords:  Clinical development; Clinical outcome assessments; Clinical trials; Endpoints; Gene therapy; Genetic disorders; Marketing authorization; Rare diseases; Regulatory approval; Study design
    DOI:  https://doi.org/10.1007/s12325-025-03385-3
  6. Clin Teach. 2025 Dec;22(6): e70282
    A Checklist for Involving Patients in Educational Activities.
    Mandy Young, Cathy Kline, Angela Towle.
      Teachers in the health professions increasingly see the benefits of involving patients in their educational activities and are looking for good practice guidelines on how best to do this, especially when they lack experience. Patient partners say that they often do not get the information they need in order to understand expectations and prepare effectively for their teaching role. In collaboration with patient partners, we developed a checklist in the form of a parallel document, one side for instructors and one side for patient partners. The checklist is in four parts and covers the things for teachers and patients to do before, during and after an educational activity. The checklist has been used by patient partners and instructors in a wide range of health professions at two institutions. It provides a concise and comprehensive reminder for instructors, empowers patients to ask for the information they need and is a template that can be customised for different contexts.
    DOI:  https://doi.org/10.1111/tct.70282
  7. Int Rev Immunol. 2025 Nov 17. 1-30
    Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.
    Thao Hoang Nhu Le, Van Thi Tuong Nguyen.
      Mitochondria serve as the powerhouses of living cells, supplying energy and essential building blocks for cellular activities. The immune system exhibits a dynamic and active characteristic within the body, wherein immune cells are constantly activated and primed for pathogens without causing harmful effects on the self-body. These characteristics necessitate that immune cells function effectively and correctly, supported by a sufficient energy supply and metabolism from the mitochondria. Mitochondrial dysfunction leads to immune dysregulation, resulting in inappropriate inflammation, autoimmunity, immunodeficiency, and hypersensitive responses, all of which contribute to the development of illness and disease. Recent studies on mitochondrial transfer in immune cells indicate that mitochondrial replacement could emerge as a promising tool for rectifying immune cell function. This review will emphasize the role of mitochondria in various immune cell types and explore how mitochondrial dysfunction can result in pathogenesis in different conditions. We also discuss the potential application of mitochondrial transfer and transplantation to- and from immune cells in the context of health and disease.
    Keywords:  Immunology; immunometabolism; mesenchymal stem cells; metabolism; mitochondria transfer
    DOI:  https://doi.org/10.1080/08830185.2025.2577986
  8. Res Involv Engagem. 2025 Nov 20. 11(1): 136
    From engagement to evidence: a scoping review of qualitative and quantitative measures of adult patient engagement in research.
    Maya Zreik, Ashley Redding, Sara Santarossa.
      
    Keywords:  Patient engagement; Psychometrics; Reliability; Scoping review; Stakeholder participation; Validity
    DOI:  https://doi.org/10.1186/s40900-025-00810-3
  9. BMB Rep. 2025 Nov 20. pii: 6458. [Epub ahead of print]
    Mitochondrial transfer from human embryonic stem cell-derived mature cardiomyocytes to mesenchymal stem cells.
    Ye Seul Jeong, Dasol Kim, Yoon Ji Jung, Jung Won Yoon, Yong Seong Kwon, Seong-Jang Kim, Jae Ho Kim.
      Mitochondria are crucial for energy metabolism and their dysfunction is implicated in the development of various human diseases. Direct mitochondrial transplantation has shown potential in reversing mitochondrial dysfunction in recipient cells. Mesenchymal stem cells (MSCs) present a promising approach as donor cells for such transplantation. We have previously demonstrated that tomatidine, a natural steroidal alkaloid, promotes the differentiation of human embryonic stem cells (hESCs) into mature cardiomyocytes by enhancing mitochondrial quantity and function. In this study, we assessed the capacity of hESCderived cardiomyocytes (hESC-CMs) and MSCs as donor cells for mitochondrial transplantation. Mitochondria were extracted from MSCs, immature hESC-CMs, and tomatidine-treated mature hESC-CMs. Treating MSCs with mitochondria derived from mature hESC-CMs led to a marked increase in mitochondrial protein levels, such as COX IV and MIC60, in the recipient MSCs, in comparison to those receiving mitochondria from immature hESC-CMs or MSCs. Transplantation of mature hESC-CM-derived mitochondria significantly enhanced the proliferation of recipient MSCs. These findings indicate that mature hESC-CMs are highly effective as donor cells for mitochondrial transplantation in addressing mitochondrial dysfunction.
  10. Amyotroph Lateral Scler Frontotemporal Degener. 2025 Nov 20. 1-11
    Patient-based evidence for amyotrophic lateral sclerosis prognostic health communication: "the clock is ticking…how long do I have?"
    Shelagh K Genuis, Westerly Luth, Brianna Adams, Wendy S Johnston.
      Objectives: Prognostic health communication is a critical challenge for amyotrophic lateral sclerosis (ALS) health-care professions, however patient-based evidence for best practice remains limited. We investigated how the experiences of ALS patients and caregivers can inform prognostic communication and whether patient-based evidence supports clinical use of predictive tools. Methods: Data were drawn from ALS Talk, an asynchronous, online focus group study. Patients and family caregivers were recruited from across Canada. Seven groups interacted in a threaded web-forum structure. Sixty-four participants shared experiences and perspectives on prognostic communication. Data were qualitatively analyzed using conventional content analysis and the constant-comparative approach. Results: Primary themes were prognostic communication as an ongoing, evolving conversation; prognostic heterogeneity; progression as an embodiment of prognosis; and functional prognosis. The theme, information needs/wants, contributed to the primary themes. Participants highlighted the importance of stepwise discussions of general and personalized prognosis; prognostic heterogeneity as a source of hope and a potential communication barrier; and how progression facilitates material understanding of prognosis, adaptation, and future planning. Further, participants wanted more information about functional prognosis and the impact of interventions/therapies on function and survival. Conclusions: We discuss participants' central questions: "how long" and "how well," and provide recommendations for patient-centred ALS prognostic communication. Participants' embodied understanding of prognosis and desire for information that anticipates functional change, informs disease management, and facilitates timely planning suggests that clinical application of ALS staging systems may meet patient and caregiver need. Testing in real-world clinical settings is needed to ensure the development of patient-centred predictive tools.
    Keywords:  Amyotrophic lateral sclerosis (ALS); disease progression; health communication; physician-patient relations; prognosis
    DOI:  https://doi.org/10.1080/21678421.2025.2589782
  11. Can Med Educ J. 2025 Nov;16(5): 73-76
    Six ways to get a grip on co-creating curriculum with patients.
    L Graves, E Soleas, J Turnnidge, N Cofie, M Jackson, J Mulder, P Karazivan, A Descôteaux, V Balounaïck-Arowas, R Van Hoorn, N Dalgarno.
      There is growing recognition of the value and importance of patient engagement in medical education. In this work, we reflect on both the literature on patient engagement and our experiences with a recent initiative focused on the co-creation of educational curricula with patient and healthcare professional partners and offer recommendations for educators and researchers interested in engaging in patient partnerships to develop medical education curriculum. We adopted a co-creation approach, in which patient and healthcare professional Subject Matter Experts (SMEs) were provided an opportunity to co-create curricular material. During the curricular development period, we experienced successes and challenges that allowed us to develop six recommendations to "get a grip" on adopting co-creation approaches to curriculum development in medical education. By applying these recommendations, medical educators can help foster meaningful and sustainable patient partnerships.
    DOI:  https://doi.org/10.36834/cmej.78711
  12. Patient Prefer Adherence. 2025 ;19 3541-3547
    Exploring Patient Preference Information in Clinical Research and Decision Models: An Investigative Survey.
    Martina Di Blasio, Zahra Bami, Matteo Bracco, Carmen Fava, Alessia Visconti, Ileana Baldi, Paola Berchialla.
       Purpose: Patient preferences are playing an increasingly pivotal role in defining care pathways, assessing care quality, and advancing healthcare technologies, but their current use remains unclear.
    Patients and Methods: We conducted an online survey collecting data from 46 experts in clinical research, pharmaceutical industry, regulatory affairs, and health technology assessment.
    Results: About 30% of our respondents are using patient preference information routinely, and 90% are willing to prioritize its integration in the future. This is despite challenges such as limited patient engagement, difficulty in obtaining reliable data, and reluctance to deviate from traditional practices.
    Conclusion: Here, we show a growing recognition of the potential benefits of integrating patient preference information, and that concerted efforts and investments are necessary to support wider adoption.
    Keywords:  decision-making; evidence synthesis; patient preference information; survey
    DOI:  https://doi.org/10.2147/PPA.S541040
  13. Orphanet J Rare Dis. 2025 Nov 20. 20(1): 596
    Rare disease education in medical schools: patient-centered and innovative strategies.
    Sharon Huynh, Eric L Wan, Angelette Pham, Robin Yoon, Scott Dorris, Nada Yazigi, Jessica M Jones.
       PURPOSE: Globally, approximately 300 million people live with a rare disease, while in the United States, nearly 30 million, or 1 in 10 Americans, have a rare disease or disorder (RD) (The Lancet Global Health. Lancet Glob Health 2024. https://doi.org/10.1016/S2214-109X(24)00244-0 ; National Center for Advancing Translational Sciences. Rare disease day at NIH 2024; 2024). Despite the prevalence of RDs, many physicians do not have adequate awareness of RDs or training to care for RD patients. RD advocates are focusing on undergraduate medical education to improve timely and quality care for RD patients. Thus, in 2023, the authors conducted an RD patient panel at their medical school and a scoping review of global medical schools' approaches to integrating RD education into their curricula. While the panel was implemented in a U.S. context, the scoping review revealed diverse approaches applicable worldwide, highlighting the need to prepare medical students for the global burden of RDs, which affect approximately 300 million people across WHO regions, with significant challenges in low- and middle-income countries (LMICs) (The Lancet Global Health. Lancet Glob Health 2024. https://doi.org/10.1016/S2214-109X(24)00244-0 ).
    METHOD: In 2023, the authors implemented an RD patient and caregiver panel for first-year medical students (n = 175) and Special Master's Program students (n =109). Pre- and post-panel surveys with ANOVA statistical analysis assessed attitudes toward and knowledge of RDs. The systematic scoping review from the databases MEDLINE, Embase, ERIC, and Web of Science sought international literature written in English discussing RD education in medical schools. From 11 relevant studies, the authors analyzed broad trends in RD education and their outcomes.
    RESULTS: Pre- and post-survey results from the patient panel demonstrated improved students' attitude, knowledge, and value of RDs. Confidence in caring for RD patients also increased significantly. From the scoping review, educational intervention types and content varied broadly among medical schools. Many institutions employed multiple interventions simultaneously, and all reported positive attitudes, higher knowledge from participants, or both. However, interventions lacked input from RD patients and caregivers.
    CONCLUSIONS: Patient panels improved students' understanding of the RD patient experience. Beyond patient panels, effective approaches in RD education in undergraduate medical curricula included lectures, case studies, role-playing simulations, artificial intelligence, and more. The authors hope medical schools will continue to implement RD education into their curricula.
    Keywords:  Medical Education; Patient Panel; Rare Diseases; Scoping Review; Undergraduate Medical Education
    DOI:  https://doi.org/10.1186/s13023-025-03771-8
  14. Nat Commun. 2025 Nov 20. 16(1): 10222
    An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice.
    Eloïse Marques, Stephen P Burr, Alva M Casey, Richard J Stopforth, Chak Shun Yu, Keira Turner, Dane M Wolf, Marisa Dilucca, Vincent Paupe, Suvagata Roy Chowdhury, Victoria J Tyrrell, Robbin Kramer, Yamini M Kanse, Chinmayi Pednekar, Chris A Powell, James B Stewart, Julien Prudent, Michael P Murphy, Michal Minczuk, Valerie B O'Donnell, Clare E Bryant, Patrick F Chinnery, Arthur Kaser, Alexander von Kriegsheim, Dylan G Ryan.
      Impaired mitochondrial bioenergetics in macrophages promotes hyperinflammatory cytokine responses, but whether inherited mtDNA mutations drive similar phenotypes is unknown. Here, we profiled macrophages harbouring a heteroplasmic mitochondrial tRNAAla mutation (m.5019A>G) to address this question. These macrophages exhibit combined respiratory chain defects, reduced oxidative phosphorylation, disrupted cristae architecture, and compensatory metabolic adaptations in central carbon metabolism. Upon inflammatory activation, m.5019A>G macrophages produce elevated type I interferon (IFN), while exhibiting reduced pro-inflammatory cytokines and oxylipins. Mechanistically, suppression of pro-IL-1β and COX2 requires autocrine IFN-β signalling. IFN-β induction is biphasic: an early TLR4-IRF3 driven phase, and a later response involving mitochondrial nucleic acids and the cGAS-STING pathway. In vivo, lipopolysaccharide (LPS) challenge of m.5019A>G mice results in elevated type I IFN signalling and exacerbated sickness behaviour. These findings reveal that a pathogenic mtDNA mutation promotes an imbalanced innate immune response, which has potential implications for the progression of pathology in mtDNA disease patients.
    DOI:  https://doi.org/10.1038/s41467-025-65023-4
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