bims-curels Biomed News
on Leigh syndrome
Issue of 2025–10–26
seven papers selected by
Cure Mito Foundation
  1. Severe Chemoradiotherapy Toxicity in a Pediatric Patient with Leigh Syndrome and Grade IV Isocitrate Dehydrogenase-Mutant Astrocytoma: A Case Report.
  2. Introducing PROSPECT: a novel process for prospectively tracking research engagement.
  3. Trial Readiness: Understanding the Natural History of Rare Diseases.
  4. Development of Two In Vitro ND1-LHON Models for Evaluating Gene Therapy Efficacy.
  5. Bridging Ontologies of Neurological Conditions: Towards Patient-centered Data Practices in Digital Phenotyping Research and Design.
  6. The Ethics of Digital Touch.
  7. On the Two-Step Hybrid Design for Augmenting Randomized Trials Using Real-World Data.
  1. Am J Case Rep. 2025 Oct 20. 26 e949191
    Severe Chemoradiotherapy Toxicity in a Pediatric Patient with Leigh Syndrome and Grade IV Isocitrate Dehydrogenase-Mutant Astrocytoma: A Case Report.
    Madison T Granberry, Tyler Severance, Gregory Biedermann, Carolyn Quinsey, Dana G Mazuru, Alicia Bach.
      BACKGROUND Leigh syndrome is a mitochondrial disorder that results in disruption of oxidative phosphorylation, leading to spongiform lesions throughout the brain, brainstem, and spinal cord. Grade 4 isocitrate dehydrogenase (IDH)-mutant astrocytomas are rare high-grade gliomas; however, IDH-mutant gliomas have relatively high survival rates and sensitivity to chemoradiotherapy. The Warburg effect involves gliomas switching from oxidative to glycolytic pathways. Damage to oxidative pathways caused by Leigh syndrome could lead to premature shifting to glycolytic pathways, in which case patients with mitochondrial disorders may have increased susceptibility to glioma progression. Additionally, chemotherapy and radiation therapy lead to mitochondrial dysfunction and the production of reactive oxygen species, which increases toxicity when these patients receive chemoradiotherapy for cancer treatment. CASE REPORT A 10-year-old boy with Leigh syndrome was diagnosed with a WHO grade 4 IDH-mutant anaplastic astrocytoma and received chemoradiotherapy. The patient experienced severe toxicity to the chemoradiotherapy, manifesting as refractory grade IV thrombocytopenia. Upon presentation to the emergency department for epistaxis and desaturations, the patient's clinical course rapidly declined. The patient developed hypovolemic shock, alveolar hemorrhage, acute respiratory distress syndrome, breakthrough seizures, central apnea, neutropenia, tumor recurrence, and possible radiation necrosis. Following loss of brainstem function, the patient was compassionately extubated. CONCLUSIONS This is the first reported case of both Leigh syndrome and an IDH-mutant astrocytoma in a pediatric patient. The patient's unusual clinical course is likely due to the relationship between mitochondrial dysfunction, IDH-mutant gliomas, and toxic sensitivity to chemoradiotherapy. This case highlights the need for caution in formulating treatment plans for similar patient cases in the future.
    DOI:  https://doi.org/10.12659/AJCR.949191
  2. Health Res Policy Syst. 2025 Oct 23. 23(1): 139
    Introducing PROSPECT: a novel process for prospectively tracking research engagement.
    Melinda Craike, Bojana Klepac, Amy Mowle.
      Health researchers are increasingly encouraged to engage with nonacademic stakeholders and provide evidence of their engagement. However, evidencing research engagement and advancing the evidence base is challenging, partly because of the lack of available tools to prospectively track research engagement activities. To fill this gap, this Commentary introduces PROcess for Systematic Prospective Engagement Capture and Tracking (PROSPECT), a novel process based on event logging that offers a systematic way to track and measure research engagement activities. The development of PROSPECT was informed by a literature search, a series of reflective practice sessions and application to one of our research programs. PROSPECT includes five phases: (1) determine the purpose, (2) define research engagement and categories of research engagement, (3) determine the information to be recorded for each research engagement activity, (4) determine the data collection system and (5) analyse, present and report. We provide examples of how we are applying each phase. We have used the data collected through PROSPECT in funder reports to describe our engagement activities and to gain insights into patterns of engagement throughout our research program. Whilst PROSPECT offers a promising approach to capturing research engagement data, we have encountered a range of practical, conceptual and technical challenges in applying this process. We suggest some next steps in its development to address these challenges. Once the challenges of applying the process are addressed, PROSPECT will be a valuable tool for researchers, leaders of research institutions and funders.
    Keywords:  Collaboration; Engagement; Measurement; Partnership; Prospective; Tool; Tracking
    DOI:  https://doi.org/10.1186/s12961-025-01414-9
  3. J Inherit Metab Dis. 2025 Nov;48(6): e70102
    Trial Readiness: Understanding the Natural History of Rare Diseases.
    Thomas Opladen, Ulrike Mütze, Florian Gleich, Sven F Garbade, Oya Kuseyri Hübschmann, Matthias Zielonka, Stefan Kölker.
      Inherited metabolic diseases (IMD) represent the largest and still growing group of treatable genetic disorders and are increasingly amenable to targeted interventions that achieve varying degrees of prognostic improvement. Innovative therapies are on the horizon and offer promising opportunities for disease-changing treatment for a variety of IMDs. For the development of clinical trials specifically for IMDs and in the context of trial readiness, a thorough understanding of the natural history of the IMDs is indispensable for an objective evaluation of meaningful improvement of novel treatment options. Patient registries are key instruments in this regard, since they are recognized as powerful instruments for the collection of longitudinal real-world data, elucidating the phenotypic diversity of disease courses, understanding the impact of diagnosis and treatment on clinical outcomes, and investigating prognostic factors. At the same time, they enable the collection of patient-specific outcome parameters (PROMs) that improve the understanding of the natural phenotype in rare diseases by identifying clinically relevant endpoints, disease burden over time, unmet medical needs, and the impact of diseases and prescribed diets and medication on the quality of life of patients and caregivers. Meta-analysis and quantitative retrospective natural history modeling allow the evaluation of the disease course with the help of published aggregate data, where patient registries are not available. Finally, the various data sources provide the theoretical basis for practical applications such as the creation of consensus-based guidelines, pass studies, and mathematical modeling. This review describes the various options for evaluating and understanding the natural history of rare IMDs in detail, with the ultimate aim of achieving adequate trial readiness.
    DOI:  https://doi.org/10.1002/jimd.70102
  4. Invest Ophthalmol Vis Sci. 2025 Oct 01. 66(13): 34
    Development of Two In Vitro ND1-LHON Models for Evaluating Gene Therapy Efficacy.
    Xin Li, Jun Yuan, Zhang Chen, Yue Zhang, Yuefeng Liu, Yong Zhang.
       Purpose: The purpose of this study was to address the lack of effective treatments for NADH-ubiquinone oxidoreductase chain 1 (ND1)-related Leber hereditary optic neuropathy (LHON), this study aimed to (1) establish in vitro models mimicking mitochondrial dysfunction in LHON and (2) evaluate the therapeutic potential of recombinant adeno-associated virus (AAV)-mediated ND1 gene therapy (rAAV-ND1).
    Methods: Two in vitro models were developed: (1) transmitochondrial cybrid cells carrying the m.3460G>A mutation in the ND1 gene; and (2) patient-derived induced pluripotent stem cells (iPSC)-differentiated retinal ganglion cells (RGCs). Mitochondrial function was assessed via measurements of oxygen consumption and adenosine triphosphate (ATP) production. The efficacy of rAAV-ND1 was tested by infecting both models to rescue mitochondrial deficiency.
    Results: Our two LHON models - ND1-mutant cybrid cells and patient-derived iPSC-RGCs - successfully recapitulated characteristic mitochondrial dysfunction, demonstrating impaired oxidative phosphorylation and reduced ATP production. Through qPCR and subcellular fractionation analyses, we confirmed dose-dependent ND1 transgene expression and proper mitochondrial localization. Notably, rAAV2-ND1 treatment effectively restored mitochondrial function in both models: in ND1-cybrids, it recovered spare respiratory capacity to 85% of the control levels, enhanced complex I activity from 65.5% to 90.5%, and increased ATP production from 47.6% to 69.5%; whereas in ND1-RGCs, it also ameliorated bioenergetic deficits, partially reversing SRC reduction, and improving ATP-linked respiration.
    Conclusions: The study demonstrates the utility of transmitochondrial cybrids and iPSC-derived RGCs as reliable in vitro models for studying ND1-related LHON. The rAAV-ND1 gene therapy effectively restored mitochondrial function, highlighting its potential as a treatment for LHON caused by ND1 mutations. These findings underscore the value of in vitro systems for evaluating therapies when robust animal models are unavailable.
    DOI:  https://doi.org/10.1167/iovs.66.13.34
  5. Proc ACM Hum Comput Interact. 2025 Nov;9(7):
    Bridging Ontologies of Neurological Conditions: Towards Patient-centered Data Practices in Digital Phenotyping Research and Design.
    Jianna So, Faye X Yang, Krzysztof Z Gajos, Naveena Karusala, Anoopum S Gupta.
      Amidst the increasing datafication of healthcare, deep digital phenotyping is being explored in clinical research to gather comprehensive data that can improve understanding of neurological conditions. However, participants currently do not have access to this data due to researchers' apprehension around whether such data is interpretable or useful. This study focuses on patient perspectives on the potential of deep digital phenotyping data to benefit people with neurodegenerative diseases, such as ataxias, Parkinson's disease, and multiple system atrophy. We present an interview study (n=12) to understand how people with these conditions currently track their symptoms and how they envision interacting with their deep digital phenotyping data. We describe how participants envision the utility of this deep digital phenotyping data in relation to multiple stages of disease and stakeholders, especially its potential to bridge different and sometimes conflicting understandings of their condition. Looking towards a future in which patients have increased agency over their data and can use it to inform their care, we contribute implications for shaping patient-driven clinical research practices and deep digital phenotyping tools that serve a multiplicity of patient needs.
    Keywords:  Ataxia; Digital phenotyping; Parkinson’s disease; ethics; mobility impairment; neurology
    DOI:  https://doi.org/10.1145/3757562
  6. IEEE Trans Haptics. 2025 Oct 20. PP
    The Ethics of Digital Touch.
    Nicholas A Barrow, Orestis Georgiou, Patrick N Haggard.
      Digital touch refers to haptic technologies that deliver somatic sensations primarily via cutaneous mechanoreceptors, with additional involvement of deeper receptors (e.g., muscles and joints). Like all emerging technologies, its benefits must be balanced against potential risks. We explore ethical concerns for future digital touch technologies by analysing the distinctive physiology and function of the human somatosensory system. Much current research on digital touch focuses on active touch. However, we argue that most pressing ethical concerns emerge with passive touch, where touch stimuli are controlled by external agents. First, somatosensation is "always on". Haptic technologies such as alerting systems often make use of this sensory availability, although doing so potentially undermines our sensory autonomy-the right to control our own sensations. Second, users need transparency about who/what is touching them and why, necessitating clear consent mechanisms. Third, as touch directly connects us with our environment, haptics that alter this interaction pose significant epistemic challenges, potentially distorting a user's perception of reality. Our analysis raises critical questions about cultural norms, privacy of bodily sensation, bodily self-awareness, control, transparency, and epistemic procedures. We propose an ethical design framework for digital touch, comprising four simple questions to guide future development of digital touch systems.
    DOI:  https://doi.org/10.1109/TOH.2025.3623531
  7. Stat Biopharm Res. 2025 Oct 08.
    On the Two-Step Hybrid Design for Augmenting Randomized Trials Using Real-World Data.
    Jiapeng Xu, Ruben P A van Eijk, Alicia Ellis, Tianyu Pan, Lorene M Nelson, Kit C B Roes, Marc van Dijk, Maria Sarno, Leonard H van den Berg, Lu Tian, Ying Lu.
      Hybrid clinical trials, which borrow real-world data (RWD) from patient registries, claims databases, or electronic health records (EHRs) to augment randomized clinical trials, are of increasing interest. Hybrid clinical trials are especially relevant for rare diseases, where the recruitment of large sample sizes may be challenging. While these trials may better use available information, they assume that the RWD and randomized control arm are exchangeable. Violating this assumption can induce bias, inflate Type I error, or adversely affect statistical power. A two-step hybrid design first tests the exchangeability between randomized control arm and external data sources before incorporating RWD as a comparator for statistical inferences (Yuan et al. 2019). This approach reduces the chance of inappropriate borrowing but may simultaneously inflate the Type I error rate. We propose four different methods to control the Type I error rate under the exchangeability assumption. Approach 1 estimates the variance of the overall test statistic and rejects the null hypothesis based on a Z-test. Approach 2 uses a numerical method to determine the exact critical value for Type I error control. Approach 3 splits the Type I error rates according to the equivalence test outcome. Approach 4 adjusts the critical value only when equivalence is established. We illustrate these methods using a hypothetical scenario in the context of amyotrophic lateral sclerosis (ALS). We evaluate the Type I error and power under various clinical trial conditions in comparison with the Bayesian power prior approach (Ibrahim et al. 2015). We demonstrate that our proposed methods and Bayesian power prior control Type I error and increase power under the exchangeability assumption, whereas the method proposed by Yuan et al. (2019) results in an increased Type I error. In the scenario where the exchangeability assumption does not hold, all methods fail to control the Type I error. Our proposed methods, however, limit a maximum Type I error inflation ranging from 6% to 8%, which compares favorably to 10% for Yuan et al. (2019) and 16% for the Bayesian power prior. All methods increase statistical power under the exchangeability condition but may lead to a loss of statistical power when the exchangeability assumption is violated.
    Keywords:  Amyotrophic lateral sclerosis; Conditional borrowing; Hybrid clinical trials; Real-world data (RWD) randomized controlled clinical trials; Test-then-pool; Type I error
    DOI:  https://doi.org/10.1080/19466315.2025.2547855
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