bims-curels Biomed News
on Leigh syndrome
Issue of 2025–06–08
seven papers selected by
Cure Mito Foundation
  1. Base editors model mitochondrial disease.
  2. Qualitative study of fatigue in adults with primary mitochondrial disease: Development of the PROMIS Fatigue Mitochondrial Disease Short Form.
  3. Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh Syndrome mice.
  4. Ndufs4-/- mice: a testing ground for longevity interventions.
  5. Understanding the impact of mitochondrial DNA mutations on aging and carcinogenesis (Review).
  6. Reflection on clinical and methodological issues in rare disease clinical trials.
  7. Prolonged Gastrointestinal Transit Times and Dysmotility in m.3243A>G Mitochondrial Disease.
  1. Nat Biotechnol. 2025 Jun 03.
    Base editors model mitochondrial disease.
    Patrick Buchholz, Jens Boch.
      
    DOI:  https://doi.org/10.1038/s41587-025-02706-9
  2. Mol Genet Metab. 2025 May 26. pii: S1096-7192(25)00144-1. [Epub ahead of print]145(4): 109153
    Qualitative study of fatigue in adults with primary mitochondrial disease: Development of the PROMIS Fatigue Mitochondrial Disease Short Form.
    Sarah Clifford, Renae J Stefanetti, Roxana Bahar, Magnus J Hansson, Gráinne S Gorman, Amel Karaa.
       BACKGROUND: Fatigue is a debilitating symptom in patients with primary mitochondrial disease nPMD). Developing new treatments that improve fatigue is a patient priority but is hampered by a lack of fit-for-purpose patient-reported outcome measures (PROMs). We aimed to understand the impact of fatigue on the lives of people with PMD and develop a brief PMD-specific PROM to evaluate fatigue in clinical trials.
    METHODS: Adults with genetically confirmed PMD and self-reported moderate-to-severe fatigue and myopathy/exercise intolerance participated in a concept elicitation interview to explore their experiences of fatigue. Interview transcripts were coded thematically using MAXQDA™. Characteristics and impacts that emerged from the interviews were mapped to items in the PROMIS® Fatigue item bank. Participants then engaged in a cognitive interview to assess relevance and understandability of PROMIS Fatigue items considered for the PROM.
    RESULTS: Twelve adults with PMD (n = 8 women, age 20-75 years) were interviewed. The most frequently reported characteristics of fatigue included tiredness, muscle weakness/fatigue, exhaustion, lack of energy, and mental fatigue. Fatigue affected patients' ability to perform daily life activities, including household chores, leisure activities, physical activity/exercise, and work/school, and negatively affected mood and relationships. Nine items were included in the final PROM based on level of endorsement of underlying concepts elicited by the concept elicitation interviews and relevance, clarity, and ease of answering, as assessed in the cognitive interviews.
    CONCLUSION: The nine-item PROMIS Fatigue Mitochondrial Disease Short Form is the first PROM designed specifically to assess fatigue in PMD. This study demonstrates the content validity of the short form, and future longitudinal studies will assess its psychometric properties.
    Keywords:  Fatigue; Mitochondrial disease; Patient-reported outcome; Questionnaire validation
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109153
  3. bioRxiv. 2025 May 16. pii: 2025.05.16.654318. [Epub ahead of print]
    Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh Syndrome mice.
    Sahitya Ranjan Biswas, Porter L Tomsick, Colin Kelly, Brooke A Lester, Julia P Milner, Sara N Henry, Yaris Soto, Samantha Brindley, Nicole DeFoor, Paul D Morton, Alicia M Pickrell.
      Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent clinical studies report behavioral phenotypes in human LS patients that are more reminiscent of neurodevelopmental delays. To determine if disruptions in epochs of rapid brain growth during infancy precede the hallmark brain lesions that arise during childhood, we evaluated neural and glial precursor cellular dynamics in a mouse model of LS. Single cell RNA sequencing along with histological and anatomical assessments were performed in NDUFS4 KO mice and compared with controls to determine the impact of Complex I deficiency on neural stem cells, their neuronal and oligodendroglial progeny, lineage progression, and overt differences in specific brain regions. Our findings show disruptions in all categories, specifically within the subventricular zone and corpus callosum. Given that LS is purely considered a neurodegenerative disease, we propose that mitochondrial dysfunction is a neurodevelopmental signature predating classic diagnosis in LS.
    DOI:  https://doi.org/10.1101/2025.05.16.654318
  4. Geroscience. 2025 Jun 05.
    Ndufs4-/- mice: a testing ground for longevity interventions.
    Jackson Nuss, Matt Kaeberlein, Alessandro Bitto, Anthony S Grillo.
      Mice missing the complex I subunit Ndufs4 of the electron transport chain are widely used as a leading animal model of Leigh syndrome, a pediatric neurodegenerative disorder that leads to premature death. More broadly, this animal model has enabled a better understanding of the pathophysiology of mitochondrial disease and mitochondrial dysfunction in sporadic disorders. Intriguingly, longevity interventions are very effective at treating symptoms of disease in this model. Herein, we introduce the model and its notable features that may help provide insights in longevity research. We performed a retrospective analysis of historical data from our laboratories over the past 10 years regarding the use of this animal model in aging studies, the manifestation and progression of mitochondrial disease, and factors that influence their premature death. We observed a correlation between weight and lifespan in female animals and a sex-independent correlation between the onset of clasping, a typical neurodegenerative symptom, and overall survival. We observed a sexual dimorphism in lifespan with female mice being more resilient despite a similar age of onset of disease symptoms. Lastly, we report increased lifespan and delayed onset of disease symptoms following treatment with 17-alpha-estradiol, a non-feminizing estrogen which can extend lifespan in genetically heterogeneous mice. This analysis serves as a useful guide for researchers utilizing this animal in the discovery of effective interventions for longevity and to prevent the onset of disease. It suggests there may be unprecedented underlying sex-specific differences in patients with Leigh syndrome and further strengthens the connection between normative aging and mitochondrial dysfunction.
    Keywords:  Interventions; Longevity; Mitochondrial dysfunction; Vertebrate models
    DOI:  https://doi.org/10.1007/s11357-025-01704-8
  5. Int J Mol Med. 2025 Aug;pii: 118. [Epub ahead of print]56(2):
    Understanding the impact of mitochondrial DNA mutations on aging and carcinogenesis (Review).
    Hiroshi Kobayashi, Shogo Imanaka.
      Mitochondria and mitochondrial DNA (mtDNA) are crucial for cellular energy metabolism and the adaptive response to environmental changes. mtDNA collaborates with the nuclear genome to regulate mitochondrial function. Dysfunctional mitochondria and mutations in mtDNA are implicated in a wide range of diseases, including mitochondrial disorders, neurodegenerative conditions, age‑associated pathologies and cancer. While the nuclear genome has been extensively studied for its role in driving the clonal expansion of oncogenes and other aging‑related genetic alterations, knowledge regarding mtDNA remains comparatively limited. However, advances in quantitative analysis have provided information regarding the complex patterns of mtDNA mutations. The present review offers a detailed examination of mtDNA mutations and their classifications in the contexts of aging and cancer, and elucidates the role of mtDNA mutations in these processes. Mutations in mtDNA can be detected as early as the neonatal stage, yet most transition mutations retain a normal cellular phenotype. In contrast to mutations in oncogenes and tumor suppressor genes within the nuclear genome, mtDNA exhibits conserved mutational signatures, irrespective of cancer tissue origin. To adapt to the aging process, mitochondria undergo clonal expansion of advantageous mtDNA mutations, maintaining a dynamic equilibrium among various mitochondrial clones. Over time, however, the loss of strand bias can disrupt this equilibrium, diminishing the pool of adaptive clones. This breakdown in mitochondrial homeostasis may contribute to tumorigenesis. In conclusion, the heterogeneity of mtDNA mutations and the collapse of its homeostasis are pivotal in the progression of age‑related diseases, including cancer, underscoring the importance of mtDNA mutations in health and disease.
    Keywords:  aging; carcinogenesis; clonal expansion; mitochondrial DNA; transition mutations
    DOI:  https://doi.org/10.3892/ijmm.2025.5559
  6. Orphanet J Rare Dis. 2025 Jun 05. 20(1): 277
    Reflection on clinical and methodological issues in rare disease clinical trials.
    Johan Verbeeck, Martin Geroldinger, Joakim Nyberg, Konstantin E Thiel, Andrew C Hooker, Arne C Bathke, Johann W Bauer, Geert Molenberghs, Martin Laimer, Georg Zimmermann.
      Rare diseases present critical challenges to healthcare systems, patients, and caregivers due to their low prevalence and unique characteristics. Designing clinical trials and developing statistical methodologies for evaluating interventions in rare diseases face several challenges. The "EBStatMax" project, part of the European Joint Programme on Rare Diseases' Demonstration Projects, aimed to address one of these challenges, namely: designing and analyzing longitudinal cross-over data in rare diseases, like Epidermolysis bullosa simplex (EBS). Although the main findings of the project have been published elsewhere, this manuscript reflects on additional hurdles encountered during the project, particularly regarding outcomes and methodological considerations. It explores issues surrounding outcome measurement, statistical methodology, and clinical considerations, emphasizing their broader relevance to methodological advancements in rare disease research beyond this specific case. This manuscript highlights the critical role of international collaboration in rare disease research to enhance evidence quality and aims to inspire further advancements in the field.
    Keywords:  Endpoints; Epidermolysis bullosa; Generalized estimating equations; Generalized pairwise comparisons; Model averaging; Non-parametric marginal model; Rare disease; Visual analogue scale
    DOI:  https://doi.org/10.1186/s13023-025-03805-1
  7. Neurogastroenterol Motil. 2025 Jun 04. e70092
    Prolonged Gastrointestinal Transit Times and Dysmotility in m.3243A>G Mitochondrial Disease.
    Simone Rask Nielsen, Malene Pontoppidan Stoico, Donghua Liao, Asbjørn Mohr Drewes, Inge Søkilde Pedersen, Anja Lisbeth Frederiksen, Christina Brock.
       BACKGROUND: Gastrointestinal (GI) symptoms are frequently reported from carriers of the pathogenic mitochondrial DNA variant m.3243A>G, causing decreased mitochondrial adenosine triphosphate (ATP) production. ATP deficiency may adversely affect both autonomic neurogenic and myogenic regulation of GI motility, contributing to the symptoms. This study examined if carriers of m.3243A>G exhibit GI dysmotility, characterized as prolonged segmental transit times and decreased motility indices.
    METHODS: Twenty-two Danish carriers of m.3243A>G and 22 healthy, sex- and age-matched controls with body mass index < 26 kg/m2 were included. Symptoms were assessed using the validated questionnaires Gastroparesis Cardinal Symptoms Index (GCSI) and Gastrointestinal Symptom Rating Scale (GSRS). GI segmental transit times and motility indices were measured using the ingestible SmartPill, which records pressure, temperature, and pH throughout the GI tract.
    KEY RESULTS: Median [interquartile range] GI symptoms were higher in carriers of m.3243A>G assessed with GCSI (1.3 [0.4-1.9] vs. 0.2 [0.0-0.4], p < 0.001) and GSRS (2.1 [1.4-3.3] vs. 1.1 [1.0-1.2], p < 0.001). m.3243A>G carriers further exhibited prolonged median [interquartile range] gastric emptying time (221 min [150-348] vs. 165 min [137-199], p = 0.02), colonic transit time (2283 min [1082-5153] vs. 1014 min [840-2451], p = 0.03) and decreased mean [confidence interval] colonic motility index (114.7 mmHg*s/min [86.2; 143.3] vs. 168.6 mmHg*s/min [129.9; 207.3], p = 0.03) compared to controls. However, these measures were not associated with the perceived GI symptoms.
    CONCLUSION & INFERENCES: Carriers of m.3243A>G demonstrated gastroenteropathy, evident as prolonged gastric and colonic transit time and decreased colonic motility index. It is plausible that the negative effect of impaired mitochondrial ATP production impacts the regulation of GI motility.
    Keywords:  enteric neuropathy; gastric emptying; gastroenteropathy; gastrointestinal motility; mitochondria; mitochondrial disease; visceral myopathy
    DOI:  https://doi.org/10.1111/nmo.70092
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