bims-curels Biomed News
on Leigh syndrome
Issue of 2026–02–22
sixteen papers selected by
Cure Mito Foundation
  1. Identifying NDUFA12 mutation in a Saudi family: An unusual presentation of mitochondrial Complex I deficiency mimicking as idiopathic intracranial hypertension in a patient with papilledema and visual loss.
  2. The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency.
  3. Phenotypic description and functional characterization of the mitochondrial disease associated with the SFXN4 gene.
  4. Best practices for the collection and analysis of patient experience data from social media for patient-focused drug development.
  5. Informing Dose for Pediatric Rare Diseases-A Survey of Recent Orphan Drugs Approvals.
  6. Neurodegenerative diseases need more mechanism-informed trials.
  7. Enhancing rare disease guideline development with real-world data: a method evaluation.
  8. Patients and Caregivers Leveraging AI to Improve Their Health Care Journey: Case Study and Lessons Learned.
  9. A misstep is not the end of the dance: embracing the challenges of reflective practice.
  10. Medicine Development and Access for Rare Diseases: Can We Do Better?
  11. Hydrogel-based mitochondrial therapies: A new frontier in disease treatment.
  12. Christopher Sharp: When a patient shared the story of her sister's death, an AI captured the clinical details-freeing physician Christopher Sharp to just be present.
  13. Scaling Genomic Reanalysis to Unlock Diagnoses and Transform Rare Disease Care.
  14. Artificial intelligence translation in healthcare: an urgent call for evidence-informed policy frameworks.
  15. "Velhotes" - Listening beyond the symptoms.
  16. Collaborating With a Biostatistician on Your Research Project.
  1. J Family Community Med. 2026 Jan-Mar;33(1):33(1): 47-52
    Identifying NDUFA12 mutation in a Saudi family: An unusual presentation of mitochondrial Complex I deficiency mimicking as idiopathic intracranial hypertension in a patient with papilledema and visual loss.
    Foziah J Alshamrani, Modhi S Alajmi, Nora I Almuslim, Muneerah M Alsubaie, Ghadeer M Fardan, Majed M Alabdali.
      Mitochondrial diseases are considered one of the most common groups of neurogenetic diseases. Complex I (CI) deficiency is the most encountered single enzyme deficiency of the mitochondrial diseases. The mutation of the NDUFA is linked to Leigh syndrome and CI defects. This article reports on a patient with mutation in NDUFA12 that was initially perceived as idiopathic intracranial hypertension, calling attention to the importance of considering NDUFA12 mutations in optic atrophy and dystonia diagnoses, particularly in young patients with new onset headache and progressive bilateral visual impairment. In addition, it emphasizes the need to explore other nonneurological features in diagnosing mitochondrial disease in those who do not fit into a defined syndrome. Further research on NDUFA12 variants is essential for a better understanding of their wide phenotypic spectrum.
    Keywords:  Blindness; Saudi Arabia; headache; mitochondrial disease; papilledema
    DOI:  https://doi.org/10.4103/jfcm.jfcm_322_25
  2. iScience. 2026 Feb 20. 29(2): 114717
    The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency.
    Meagan J McManus, Yi Zhu, Cesar Alves, Neha Kohli, Patricia Prada-Dacasa, Laura Sanchez-Benito, Elisenda Sanz, Irene Yee, Lozen Robinson, Malkah Sheldon, Walter J McHugh, Abhay Ranganathan, Jennie Meng, Nina Duncan, Alvar Grönberg, Douglas C Wallace, Sarah Piel, Michael Karlsson, Steven J Moss, Lee Webster, Magnus J Hansson, Eskil Elmér, Johannes K Ehinger, Albert Quintana, Todd J Kilbaugh.
      Leigh syndrome is a fatal pediatric neurodegenerative disease caused by mitochondrial dysfunction, which can be modeled in the Ndufs4 KO mouse with mitochondrial respiratory chain complex I (CI) deficiency. This study explores NV354, a prodrug of succinate with enhanced oral bioavailability and brain uptake, as a potential therapy to counteract this devastating condition. NV354 modulated whole-body respiration and metabolic flexibility, prevented late-stage motor dysfunction, delayed clinical ataxia scores, and improved body weight development, but had otherwise minimal effect on neurobehavior and lifespan of the animals. The succinate prodrug prevented development of the brain stem lesions pathognomonic for Leigh syndrome, attenuated neuronal loss in the brainstem, diminished activation of astrocytes, blocked hypertrophic microglial accumulation, and reduced reactive oxygen species (ROS) levels in the brain. NV354 also partially alleviated motor symptoms and metabolic decompensation in a rat model of Parkinson disease induced by the CI inhibitor rotenone. In conclusion, the succinate prodrug NV354 shows promise as a potential treatment of mitochondrial CI-related neurodegeneration.
    Keywords:  biochemistry; biological sciences; natural sciences; neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2026.114717
  3. Mitochondrion. 2026 Feb 17. pii: S1567-7249(26)00026-7. [Epub ahead of print] 102136
    Phenotypic description and functional characterization of the mitochondrial disease associated with the SFXN4 gene.
    Sarah Courtois, Chloé Angelini, Juliette Preud'homme, Mégane Le Quang, Elodie Dumon, Stéphanie Dulucq, Nathalie Aladjidi, Caroline Kannengiesser, Pascal Barat, Sophie Naudion, Caroline Espil, Marie-Laure Martin-Negrier, Aurélien Trimouille.
      Sideroflexin 4 (SFXN4) is a transmembrane protein located in the inner membrane of the mitochondria. SFXN4 is also thought to be involved in the formation of iron-sulphur centres. Deleterious bi-allelic variants of the SFXN4 gene have been reported in only 3 patients, with a phenotype including intellectual disability and macrocytic anaemia. We describe here a patient carrying pathogenic variants of SFXN4, associated with a non-anaemic sideroblastic macrocytosis and a complex I deficiency.
    Keywords:  Macrocytosis; Mitochondrial disease; SFXN4
    DOI:  https://doi.org/10.1016/j.mito.2026.102136
  4. Front Med (Lausanne). 2025 ;12 1703923
    Best practices for the collection and analysis of patient experience data from social media for patient-focused drug development.
    Philipp Cimiano, Nicole Brazda, Matthias Hartung, Cornelius Starke-Knäusel, Ana Lucia Schmidt, Maria Carmela De Vuono, Aditya Tyagi, Jürgen Gottowik, Raul Rodriguez-Esteban, Ben Collins, Krzysztof Wieckowski, Thierry Escudier.
      Patient experience data derived from social media captures the unsolicited conversations of patients and helps in understanding their subjective experiences with disease and treatments. By comparison, many other real-world datasets, such as electronic health records, have the drawback that they solely capture the perspective of health care practitioners. Regulators such as the FDA or EMA have recognized the potential of social media as a source of patient experience data that can inform patient-focused drug development. While social media has limitations, such as the reliance on patient or caregiver self-reporting, it allows us to understand the subjective perception and context of patients, how they experience their condition, its progression, existing treatments and how they manage these, which unmet needs they have, and how the disease affects their daily lives and activities. All this is crucial information that can inform drug development initiatives, and help substantiate relevant outcomes measured, both in clinical trials as well as in post-marketing evidence generation activities. This paper proposes best practices for Social Media Listening (SML) for the purpose of Real World Evidence generation along the following dimensions: purposes and objectives of a SML study, data collection, and data analysis. To illustrate how these best practices can be adopted, we showcase their application in a case study, aiming to unveil the key symptoms and comorbidities that diabetes type II patients face and how these affect their quality of life across an observation period of 24 months. We believe the proposed best practices will contribute to provide a rigorous methodological ground for the use of social media in generating patient experience data that can inform patient-focused drug development and could be accepted in regulatory processes.
    Keywords:  guideline development; patient experience data; patient-focused drug development; real world evidence; social media listening
    DOI:  https://doi.org/10.3389/fmed.2025.1703923
  5. Clin Transl Sci. 2026 Feb;19(2): e70503
    Informing Dose for Pediatric Rare Diseases-A Survey of Recent Orphan Drugs Approvals.
    Elimika Pfuma Fletcher, Chloe Kim, Hannah Mei, Bilal AbuAsal, Sherbet Samuels, Rajanikanth Madabushi, Anuradha Ramamoorthy.
      Collectively, pediatric rare diseases affect millions of children worldwide. Yet, treatment options are limited. Dose selection presents unique challenges in pediatric rare disease drug development. Traditional dose-finding approaches are impractical for these populations, and conventional pediatric dosing methods like exposure matching face limitations when insufficient adult data exists. Herein, we analyzed dosing strategies and study design characteristics used for new molecular entities (NMEs) for orphan indications approved between 2013 and 2022 that included a pediatric indication at initial approval. Among 63 evaluable products included in this analysis, initial pediatric dose selection was supported by adult data in the same indication (37%), adult healthy volunteer data (33%), nonclinical data only (14%), adult data from different indications (10%), and pediatric data from different indications (5%). The use of modeling and simulation to support initial dose selection was explicitly mentioned for 21% of products. Nearly half (48%) utilized multiple data sources for dose selection. Study design characteristics included multiple dose level evaluation (49%), intra-patient dose escalation (33%), interim pharmacokinetic evaluation (10%), pharmacokinetic/biomarker-driven dosing (5%), and age group staggering (5%). Multiple design features were incorporated in 17% of drugs. This analysis reveals diverse approaches to pediatric dose selection in rare diseases and the use of adaptive study design elements suggests recognition of the need for flexible approaches in these challenging populations. Utility of modeling and simulation, ability to leverage all available data sources, and increased implementation of adaptive trial designs could improve dose selection and optimization in pediatric rare disease drug development.
    Keywords:  dosing; pediatric; rare disease; study design
    DOI:  https://doi.org/10.1111/cts.70503
  6. Nat Med. 2026 Feb;32(2): 381
    Neurodegenerative diseases need more mechanism-informed trials.
      
    DOI:  https://doi.org/10.1038/s41591-026-04258-0
  7. BMC Med Res Methodol. 2026 Feb 14.
    Enhancing rare disease guideline development with real-world data: a method evaluation.
    Willemijn Irvine, Linde Margriet van der Kamp, Olivia Spivack, Alexandra Benachi, Carmen Mesas Burgos, Roel Bakx, Charlotte Gaasterland, Rene Wijnen.
      
    Keywords:  Guideline; Methodology; Rare diseases; Real-world data
    DOI:  https://doi.org/10.1186/s12874-026-02802-7
  8. J Particip Med. 2026 Feb 20. 18 e69790
    Patients and Caregivers Leveraging AI to Improve Their Health Care Journey: Case Study and Lessons Learned.
    Mary Beth Schoening, Dustin Cotliar.
       Unlabelled: Artificial intelligence (AI) is increasingly integrated into everyday life. Yet in health care, patients and families are challenged to understand how AI may be helpful. As a result, real-world patient stories remain scarce. Generative AI can serve as a learning partner to help patients interpret complex medical information, prepare for appointments, and navigate care decisions. A case study is presented from the perspective of a caregiver and a clinician colleague, describing how one family used generative AI (ChatGPT; OpenAI) to better understand test results, possible diagnoses and treatments, prepare for visits, and summarize and share information with an extended care team. This paper also shares tips and lessons learned with others navigating similar health care challenges. A first-hand account of family interactions with ChatGPT is described during a period between diagnostic imaging and surgical consultation. Real-world use of AI by a caregiver is showcased, including strategies used to understand and summarize health record data, querying AI using medical documents, and resulting actions taken by the family. Using the case study as a springboard, the authors provide a separate section to share lessons learned for patients and caregivers in their use of AI. The family reported benefits of AI, including the ability to comprehend health information by translating medical records into patient-friendly language; to emotionally process and prepare for visits; to research diagnoses and treatments; to streamline communication with care teams by using concise patient summaries; and to feel more empowered to take timely, informed action. Generative AI can serve as a valuable companion tool for patients and caregivers navigating complex medical information. By translating results, providing education about diagnoses and treatment options, and helping prepare for visits, AI may reduce care delivery delays and raise family confidence in decision-making. However, limitations exist, and patients and caregivers need to validate AI output to ensure accuracy and privacy.
    Keywords:  LLM; artificial intelligence; care journey; caregiver AI; generative AI; health literacy; healthcare communication; healthcare navigation; large language model; large language models; medical documentation; medical information translation; participatory medicine; patient AI; patient activation; patient education; patient efficacy; patient empowerment; patient engagement; patient experience; patient friendly; patient learning; patient-physician relationship; self efficacy; shared decision making
    DOI:  https://doi.org/10.2196/69790
  9. Educ Prim Care. 2026 Feb 16. 1-3
    A misstep is not the end of the dance: embracing the challenges of reflective practice.
    Tim Clement.
      There are a number of claims about reflective practice that ought to be confronting for clinical educators. For example, that models of reflection are often taught by unreflective teachers. Embracing these claims, the author resolved to use the practices of Intentional Noticing - a form of reflective practice - to improve his reflective capabilities. Using a worked example, this paper outlines the features of Intentional Noticing, beginning with the interrogation of the phrase, 'I've got one if you want to hear it', spoken by a colleague working with a group of clinical supervisors. The paper addresses the author's subsequent failure to make such an invitational comment when the opportunity arose; the challenge of acting congruently with one's pedagogical values in the heat of the moment; exploring the perceived tension between 'inquiry learning' and didactic teaching; and eventually finding a way of managing this tension. The example underscores that reflection is hard and that teaching is never completely successful, but a never-ending process of investigating and trying out. The author found Intentional Noticing to be a useful way of studying his practice over time, of confronting the challenges of unreflective doing and of discovering new ideas to try out in the future.
    Keywords:  Reflective practice; intentional noticing; professional development; sensemaking; teaching and learning
    DOI:  https://doi.org/10.1080/14739879.2026.2613406
  10. J Inherit Metab Dis. 2026 Mar;49(2): e70146
    Medicine Development and Access for Rare Diseases: Can We Do Better?
    Carla E M Hollak, Noa Rosenberg, Colinda Post, Nina Stolwijk, Evert Manders, Daphne Schoenmakers, Bart Penninx, Niels Reijnhout, Kathelijn Verdeyen, Roel Jonker, Annet M Bosch, Mirjam Langeveld, Vincent van der Wel, Saco de Visser, Sibren van den Berg.
      Recent advances in molecular biology and genomics have significantly enhanced our understanding of rare diseases. While enabling the development of highly targeted therapies, it also leads to complexity in the development, regulation, and accessibility of orphan medicines. Unmet need and great promise of new medicines, combined with high prices and uncertain effectiveness, highlight the shortcomings of the system, particularly evident for highly specialized treatment options, such as advanced therapy medicinal products and RNA-based treatments. While all stakeholders in this field must take responsibility, academic researchers and clinicians have a vital role which must be strengthened to improve access to and affordability of medicines. Regarding academia-driven orphan medicine development, academic contributions are predominantly concentrated in the early research phases, often lacking continuity throughout the full development pipeline. There is limited expertise in regulatory affairs and market access, and little involvement in medicine pricing or licensing negotiations. Recommendations include sustained academic engagement across all development stages, integration of regulatory and market access training into educational programs, and the implementation of socially responsible frameworks. Strategies promoting the rational use of orphan medicines should be embedded across the entire product lifecycle. Industry-driven development typically interacts primarily with regulatory agencies and payers, with academia playing a reactive and, at times, conflicted role. Independent academic-industry interaction is recommended, with early involvement in clinical trial design. Additionally, academia should proactively contribute to the evaluation of new therapies, development of controlled access models, and exploration of sustainable pricing frameworks. Establishing independent, multi-purpose disease registries would enhance post-authorization monitoring and evidence generation.
    DOI:  https://doi.org/10.1002/jimd.70146
  11. Biomaterials. 2026 Feb 11. pii: S0142-9612(26)00095-5. [Epub ahead of print]330 124071
    Hydrogel-based mitochondrial therapies: A new frontier in disease treatment.
    Zihua Tang, Yu Jiang, Huiling Ling, Yifei Shen, Xingbo Wu, Chun Hung Chu, Irene Shuping Zhao, Xueqi Gan.
      Mitochondria are essential for cell energy metabolism, redox homeostasis, and apoptosis. Meanwhile, numerous pathological conditions are linked with mitochondrial dysfunction, such as cardiovascular diseases, connective tissue disorders, chronic wounds, neurological disorders, and cancer. Mitochondria-targeted hydrogels (MTHs) have emerged for their ability to selectively deliver active agents to mitochondria, modulate mitochondrial function precisely, which plays a key role in improving treatment efficacy. Hydrogels offer unique advantages, including biocompatibility, structural tunability, and controlled drug release. With specific targeting ligands and stimuli-responsive mechanisms, hydrogels can achieve mitochondrial localization and therapeutic modulation. Recent advancements have demonstrated significant benefits of MTHs in reducing oxidative stress, promoting oxidative phosphorylation and restoring mitochondrial quality control across a variety of disease models. However, challenges remain, including optimizing targeting efficiency, as well as accuracy. Further exploration of therapeutic mechanisms and the integration of multi-dimensional targeting strategies are also essential for the clinical application of MTHs. The current review highlights the development of mitochondrial targeting strategies and specifically focuses on a series of applications of MTHs in mitochondrial-related diseases. Lastly, the discussion delves into the shortcomings of existing therapies and possible future research ideas.
    Keywords:  Hydrogel engineering; Mitochondria-related diseases; Mitochondria-targeted hydrogels; Mitochondrial quality control; Tissue regeneration
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124071
  12. Sci Am. 2026 Mar 01. 334(3): 26
    Christopher Sharp: When a patient shared the story of her sister's death, an AI captured the clinical details-freeing physician Christopher Sharp to just be present.
    Deni Ellis Béchard.
      
    DOI:  https://doi.org/10.1038/scientificamerican032026-5UUMfmDl6NMgUD2G03kBUp
  13. HGG Adv. 2026 Feb 18. pii: S2666-2477(26)00022-9. [Epub ahead of print] 100582
    Scaling Genomic Reanalysis to Unlock Diagnoses and Transform Rare Disease Care.
    Shira Rockowitz, Wanqing Shao, Courtney French, Tina K Truong, Jacob Hagen, Rylee McGonigle, Alexa Geltzeiler, Beth Sheidley, Lacey Smith, Alissa M D'Gama, Mira Irons, Janet Chou, Joan Stoler, Amy Kritzer, Lance Rodan, Akiko Shimamura, Olaf Bodamer, Stephanie Sacharow, Janet S Soul, Siddharth Srivastava, Amy Roberts Kennedy, Aya Abu-El-Haija, Abbe Lai, Heather Olson, Jane Juusola, Erin Ryan, Bethany Friedman, Anupama Singh, Cliff Li, Rittika Mallik, Gwendolyn Strickland, Gillian Prinzing, Alisa Mo, Anne O'Donnell-Luria, Jeff Bolton, Philip M Boone, William Brucker, Michael Duyzend, Sonal Mahida, David T Miller, Jacklyn Omorodion, Jeanette Petit, Jonathan Picker, Annapurna Poduri, Colleen Carlston, Monica H Wojcik, Piotr Sliz, Wendy K Chung.
      Genomic reanalysis can identify causative variants for rare diseases as patient phenotypes evolve and gene-disease knowledge expands. Despite its diagnostic value, routine reanalysis is limited by clinician capacity, lack of patient follow-up, data silos, cost, and lack of availability of clinical data to testing laboratories that are not obligated to conduct reanalysis. The Children's Rare Disease Collaborative at Boston Children's Hospital (BCH) has integrated genomic and phenotypic data from over 15,500 patients into a clinician-facing platform. Leveraging this infrastructure, we developed a Proactive Genomic Reanalysis (PGR) workflow at BCH for clinical sequencing data that is centralized, semi-automated and clinically integrated. Here, we report initial results and outline required resources and transferable insights applicable to other healthcare settings. Initial pilot implementation, applied to a subset of clinical sequencing patients' data, revealed practical challenges, notably clinician turnover and patient recontact difficulties. Of 42 patients' candidate variants discovered by the PGR bioinformatics pipeline and returned to treating clinicians, 33 were determined to have a high suspicion of disease causality and an additional 3 were determined to be candidate VUS. A process to generate reports and return results to patients was initiated when applicable. Though the initial pilot implementation was limited, the PGR bioinformatics pipeline is designed to be utilized iteratively, making reanalysis a continuing process. This work highlights the feasibility and impact of centralized PGR processes and the potential for healthcare institutions to scale genomic reanalysis.
    DOI:  https://doi.org/10.1016/j.xhgg.2026.100582
  14. BMJ Health Care Inform. 2026 Feb 18. pii: e102007. [Epub ahead of print]33(1):
    Artificial intelligence translation in healthcare: an urgent call for evidence-informed policy frameworks.
    Chukwuebuka Anyaegbuna, Natasha Steele, April Shichu Liang, Stephen P Ma, Ivan Lopez, Nymisha Chilukuri, Kavita Patel, Kevin Schulman, Jonathan H Chen.
      The deployment of artificial intelligence (AI) translation tools in healthcare is accelerating rapidly, yet regulatory frameworks lag dangerously behind clinical practice. Recent data reveal that 57% of US physicians are already using or planning to adopt AI translation services within the next year. This creates a critical policy vacuum where clinicians deploy tools with variable performance across languages, risking patient safety and deepening health inequities. We examine the fractured regulatory landscape, document performance disparities between well-resourced and digitally under-represented languages, and argue for an urgent, evidence-informed policy framework centred on patient comprehension rather than linguistic accuracy.We delineate a risk-stratified validation approach comprising two distinct tracks: a 'Streamlined Pathway' for tool-language combinations with robust existing evidence (eg, Spanish) and a 'Standard Pathway' requiring independent, prospective validation for digitally under-represented languages (eg, Haitian Creole). To ensure accountability, we propose establishing oversight bodies within the U.S. Department of Health and Human Services (HHS) or the Food and Drug Administration (FDA) to mandate pre-deployment validation and post-market monitoring. Without such action, AI translation risks creating a two-tier system where the 25.7 million Americans with non-English language preferences receive dramatically different care quality based solely on the language they speak.
    Keywords:  Artificial intelligence; Health Equity; Natural Language Processing; Patient Care
    DOI:  https://doi.org/10.1136/bmjhci-2025-102007
  15. Patient Educ Couns. 2026 Feb 12. pii: S0738-3991(26)00067-4. [Epub ahead of print]147 109534
    "Velhotes" - Listening beyond the symptoms.
    Beatriz Guedes Sardão.
      This reflective piece explores the impact of childhood experiences with elderly family members on the development of empathy. The author connects these formative experiences to her evolving role as a family physician, emphasizing the importance of presence, attentiveness, and emotional insight when caring for older patients. The reflection highlights how genuine communication extends beyond symptoms, offering connection and dignity in an often fast-paced healthcare environment.
    Keywords:  Aging; Doctor–patient communication; Family medicine; Narrative medicine; Reflective practice
    DOI:  https://doi.org/10.1016/j.pec.2026.109534
  16. Hosp Pediatr. 2026 Feb 20. pii: e2025008754. [Epub ahead of print]
    Collaborating With a Biostatistician on Your Research Project.
    Danielle Guffey, Kristen A Staggers, Xiaofan Huang, Charles G Minard.
      Collaborating with a statistician is critical to the success of medical research. Statisticians contribute their expertise to ensure methodological rigor during all stages of the research process from study design to data interpretation and dissemination. Involving a statistician early in the research process to help guide the development of research hypotheses, study design, randomization strategies, sample size, data types, and data management is essential to the success of clinical and scientific research. Ongoing collaboration helps maintain consistency throughout all stages of research to answer the research question. We hope to pass on the understanding that statisticians want to be a part of your team and strive to help create rigorous and clinically relevant research by describing the statistician's perspective and needs. This article aims to provide clinicians and researchers with the tools needed to successfully collaborate with a statistician.
    DOI:  https://doi.org/10.1542/hpeds.2025-008754
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