bims-curels Biomed News
on Leigh syndrome
Issue of 2025–11–30
twelve papers selected by
Cure Mito Foundation



  1. Pediatr Nephrol. 2025 Nov 27.
       BACKGROUND: Primary mitochondrial diseases are a group of rare, heterogeneous, multisystem disorders. While renal involvement is increasingly recognised, especially in paediatric patients, data on kidney transplantation outcomes in this population remain limited.
    OBJECTIVES: To evaluate kidney transplantation outcomes in genetically confirmed primary mitochondrial diseases with multi-organ involvement and provide clinical insights from systematic literature review.
    DATA SOURCES: We systematically searched PubMed, MEDLINE, EMBASE and Google Scholar from inception to 10 June 2025 using keywords and MeSH terms related to "mitochondrial disease", "transplantation" and "outcome".
    STUDY ELIGIBILITY CRITERIA: We included studies that reported post-transplant clinical outcomes in patients with genetically confirmed primary mitochondrial diseases. Studies without genetic confirmation or transplant follow-up were excluded. Patients with Co-enzyme Q 10 deficiency were excluded as they mainly manifest as isolated steroid resistant nephrotic syndrome with subtypes that respond well to co-enzyme replacement.
    PARTICIPANTS AND INTERVENTIONS: Participants included paediatric or adult patients diagnosed with genetically confirmed primary mitochondrial diseases who received isolated kidney transplant from living or deceased donor.
    STUDY APPRAISAL AND SYNTHESIS METHODS: Data were extracted on demographics, genotypes, renal and extra-renal features, transplant characteristics, complications and outcomes. Risk of bias was assessed qualitatively by two independent reviewers. Discrepancies were resolved through consensus or discussion with third reviewer. Due to clinical and methodological heterogeneity, a narrative synthesis was performed.
    RESULTS: Forty-six patients (15 paediatric, 31 adult) were included from 18 eligible studies. Ten patients had RMND1-related disease. All harboured either homozygous or compound heterozygous c.713A > G variants in RMND1. Thirty patients carried the m.3243A > G mtDNA point mutation variant in MT-TL1. The remaining six patients harboured an m.3271 T > C variant in MT-TL1, single mtDNA deletions, m.8618dup in MT-ATP6, m.12418delA in MT-ATP6 and m.13513G > A in MT-ND5 respectively. At nephrology referral, chronic kidney disease and kidney failure each was present in 26.1% of patients. Median time from renal presentation to kidney failure was 6 years. Graft and patient survival exceeded 90% across different genetic mutations and age groups. Post-transplant deterioration of neurological or metabolic features was reported predominantly in patients with an m.3243A > G variant.
    LIMITATIONS: The review is limited by small sample size, selection and reporting bias, heterogeneous follow-up durations and outcome measures. Data were derived mainly from case reports and small case series.
    CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Kidney transplantation is a viable option of kidney replacement therapy for patients with mitochondrial diseases. Patients with primary mitochondrial diseases should be considered for kidney transplantation. Further prospective studies are needed to define optimal transplant timing, immunosuppression strategies and long-term systemic outcomes.
    SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD420251086889.
    Keywords:  Kidney failure kidney transplantation; Patient survival; Primary mitochondrial diseases
    DOI:  https://doi.org/10.1007/s00467-025-07034-3
  2. Nat Commun. 2025 Nov 23.
      Leber hereditary optic neuropathy (LHON), a maternally inherited mitochondrial disorder, results from point mutations in mitochondrial DNA (mtDNA), primarily affecting the MT-ND4 gene. To date, no animal model harboring authentic LHON mutations has been available, limiting therapeutic development. However, when we attempted to generate such models using mitochondrial base editors, we found that activity-enhanced DddA11-based cytosine base editors (DdCBEs) induce off-target mtDNA mutations and developmental arrest in embryos. Using a high-fidelity DdCBE (Hifi-DdCBE), we successfully generate mice carrying the pathogenic MT-ND4 G11778A mutation, the most common LHON variant. These mice exhibit hallmark phenotypes, including retinal ganglion cell loss and impaired visual function. Intravitreal delivery of adeno-associated virus encoding TALE-linked deaminases (TALEDs) restores both phenotype and genotype in these mice. Furthermore, optimized TALEDs corrects the ND4 mutation with minimal off-target effects in LHON patient-derived cells, highlighting the potential of mitochondrial base editing as a therapeutic strategy for mtDNA-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-025-66600-3
  3. Children (Basel). 2025 Nov 10. pii: 1522. [Epub ahead of print]12(11):
      Leigh syndrome is a rare, progressive mitochondrial disorder of childhood. Early diagnosis is often challenging due to nonspecific clinical manifestations. We report a 1-month-old male infant initially referred for suspected congenital muscular torticollis who ultimately received a diagnosis of Leigh syndrome. Despite unremarkable perinatal history, he subsequently developed persistent feeding difficulties, recurrent vomiting, failure to thrive, and global developmental delay. Early neurological assessment revealed poor repertoire patterns on General Movement Assessment. The Neonatal Oral-Motor Assessment Scale (NOMAS) demonstrated dysfunctional oral-motor control, whereas the video fluoroscopic swallowing study (VFSS) revealed aspiration during swallowing. Brain MRI revealed symmetric basal ganglia lesions. Expanded whole-exome sequencing identified a pathogenic MT-ATP6 m.8993T>G variant with high heteroplasmy level (>90% in blood), confirming the diagnosis of Leigh syndrome. The variant was maternally inherited, although neither the mother nor the older sibling exhibited clinical features of mitochondrial disease. Leigh syndrome can initially manifest with subtle systemic features rather than overt neurological features. Persistent feeding difficulties and growth delay in infancy warrant thorough evaluation, including neuroimaging and comprehensive genomic testing, to enable timely diagnosis and optimize clinical management.
    Keywords:  Leigh syndrome; MT-ATP6; feeding difficulties; global developmental delay; mitochondria; torticollis
    DOI:  https://doi.org/10.3390/children12111522
  4. Genes (Basel). 2025 Nov 01. pii: 1298. [Epub ahead of print]16(11):
       BACKGROUND: Point mutations in mitochondrial DNA (mtDNA) cause a range of neurometabolic disorders that currently have no curative treatments. The m.8993T>G mutation in the Homo sapiens MT-ATP6 gene leads to neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) when heteroplasmy exceeds approximately 70%.
    METHODS: We engineered a split DddA-derived cytosine base editor (DdCBE), each half fused to programmable TALE DNA-binding domains and a mitochondrial targeting sequence, to correct the m.8993T>G mutation in patient-derived induced pluripotent stem cells (iPSCs). Seven days after plasmid delivery, deep amplicon sequencing showed 35 ± 3% on-target C•G→T•A conversion at position 8993, reducing mutant heteroplasmy from 80 ± 2% to 45 ± 3% with less than 0.5% editing at ten predicted off-target loci.
    RESULTS: Edited cells exhibited a 25% increase in basal oxygen consumption rate, a 50% improvement in ATP-linked respiration, and a 2.3-fold restoration of ATP synthase activity. Directed neural differentiation yielded 85 ± 2% Nestin-positive progenitors compared to 60 ± 2% in unedited controls.
    CONCLUSIONS: Edits remained stable over 30 days in culture. These results establish mitochondrial base editing as a precise and durable strategy to ameliorate biochemical and cellular defects in NARP patient cells.
    Keywords:  DdCBE; MT-ATP6; NARP; base editing; heteroplasmy; iPSCs; m.8993T>G; mitochondrial DNA
    DOI:  https://doi.org/10.3390/genes16111298
  5. J Med Internet Res. 2025 Nov 28. 27 e77087
       BACKGROUND: Caring for children with rare genetic disorders is challenging due to complex medical needs and limited information. Often, information is scarce due to geographical dispersion and lack of access to expertise. Social media groups are increasingly used in parenting and in healthcare as tools for data sharing and acquisition, and online peer support. Online groups relating to specific rare diseases are increasingly used by parents navigating the difficulties of understanding their child's diagnosis and providing them with support. Parents expect professionals to interact with them about information reported from online groups, but little is known regarding the content within these groups and the impact on families.
    OBJECTIVE: We aimed to synthesize current knowledge of social media use among parents and caregivers of children with a rare genetic syndrome to inform how these data might be used in parent-doctor interactions and in the research setting.
    METHODS: We completed a comprehensive literature review across Web of Science, PubMed, and PsycINFO using a search strategy with themes of caregivers, rare genetic disease, and social media. Studies published in English from 2005 onwards, with parents and caregivers as a cohort and a focus on rare genetic diseases, were included. In total, 159 articles were identified, which underwent a title sift followed by an abstract sift based on inclusion and exclusion criteria. Reference lists of included articles were also reviewed. A total of 12 studies were included, and a critical synthesis methodology was used to extract relevant points.
    RESULTS: Most parents and caregivers use social media platforms, especially Facebook (Meta Platforms, Inc), particularly the group function. They are using social media groups as a tool for finding information related to their child's rare genetic disease. A majority also engaged in online groups by sharing information and contributions of their own. This review highlights that caregivers are seeking three main types of support from social media: (1) medical information around diagnosis and treatments, (2) practical tips on care needs and equipment, and (3) social support, involving connection with other families who shared similar experiences. The use of social media improved accessibility to information regardless of time or geography and reduced feelings of isolation. Caregivers felt empowered in decision-making, and their interactions with health care professionals improved. Challenges include misinformation, concerns around privacy, emotional impacts of comparison, and a lack of online spaces for the rarest conditions.
    CONCLUSIONS: Social media is a key tool for caregivers of children with rare genetic diseases. Addressing the associated challenges and harnessing the potential of these platforms can positively impact these families. Health care providers should consider discussing social media engagement in conversations with caregivers, and future research should focus on larger, longitudinal studies to explore the impacts of social media engagement.
    Keywords:  genetic disease; online support group; parent; rare disease; social media
    DOI:  https://doi.org/10.2196/77087
  6. Prog Brain Res. 2025 ;pii: S0079-6123(25)00123-2. [Epub ahead of print]297 1-52
      The chapter outlines how precision medicine is reshaping the way neurodegenerative diseases (NDs) which includes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are understood, diagnosed, and treated. It discusses the limitations of current therapies, which mainly address symptoms without altering disease progression. Genetic and molecular factors that influence disease development are described, including distinctions between familial and sporadic forms. The chapter also covers the roles of epigenetic changes, gene expression, protein dysfunction, mitochondrial DNA, and non-coding RNAs in NDs. Biomarkers in blood and cerebrospinal fluid, along with imaging techniques and digital tools, are presented as key elements in early diagnosis and disease monitoring. Patient stratification based on clinical features, molecular profiles, and biomarkers helps guide treatment decisions and improve outcomes. The chapter reviews ongoing developments in genotype-based drug design, gene therapy, pharmacogenomics, and personalized lifestyle strategies. Clinical case studies show how these approaches are being used in practice. The chapter also discusses challenges in applying precision medicine, such as trial design, data integration, unequal access, and regulatory hurdles. Finally, it highlights the future tools like single-cell transcriptomics, digital twins, and global research collaborations that aim to bring precision approaches into everyday care.
    Keywords:  Artificial intelligence; Biomarker discovery; Digital health technologies; Epigenetics; Genetic profiling; Multi-omics integration; Neurodegenerative diseases; Patient stratification; Personalized therapeutics; Precision medicine; Transcriptomics
    DOI:  https://doi.org/10.1016/bs.pbr.2025.08.006
  7. J Genet Couns. 2025 Dec;34(6): e70149
      The aim of this qualitative interview study was to explore the lived experiences of parents, experiencing high anxiety and poorer quality-of-life/family functioning, caring for a child with a rare and undiagnosed condition. Data analysis led to the generation of a substantial corpus of insights focusing on how parents cope with grief amidst the uncertainty surrounding their child's condition. Whereas much is known about grief related to death in pediatric cancer patients, research focusing on grief in the area of rare and undiagnosed conditions is sparse. We conducted semi-structured interviews with 24 parents of children affected by a rare and undiagnosed condition undergoing whole genome sequencing (WGS) through the Genomic Medicine Service (GMS) in England and Wales. Participants were purposively sampled based on scores to validated psychological measures. We used reflexive thematic analysis, situated within an interpretivist and post-positivist research paradigm, to explore the data. The central organizing concept was named "Navigating Grief In The Context Of Uncertainty." This overarching theme describes how these parents grieve the loss of the envisioned future they held while navigating an unpredictable reality shaped by their child's undiagnosed condition. Our findings also highlight the "potential ongoingness" of grief, although it may change over time. Parents adapt through constructive reframing, seeking meaning and acceptance, and fostering resilience all of which we found to aid in coping. Understanding the grieving process, particularly the role of uncertainty, is essential for improving the clinical support provided to families affected by rare and undiagnosed conditions and for designing future psychological intervention strategies that address parents who grieve the loss of their anticipated family life.
    Keywords:  ambiguous loss; chronic sorrow; coping with grief; family grief; genomic sequencing; grief; mental health; parent caregivers; psychosocial support; rare diseases; uncertainty; undiagnosed conditions
    DOI:  https://doi.org/10.1002/jgc4.70149
  8. Medicines (Basel). 2025 Nov 13. pii: 28. [Epub ahead of print]12(4):
      Drug repurposing is the process of discovering new therapeutic indications for already existing drugs. By using already approved molecules with known safety profiles, this approach reduces the time, costs, and failure rates associated with traditional drug development, accelerating the availability of new treatments to patients. Artificial Intelligence (AI) plays a crucial role in drug repurposing by exploiting various computational techniques to analyze and process big datasets of biological and medical information, predict similarities between biomolecules, and identify disease mechanisms. The purpose of this review is to explore the role of AI tools in drug repurposing and underline their applications across various medical domains, mainly in oncology, neurodegenerative disorders, and rare diseases. However, several challenges remain to be addressed. These include the need for a deeper understanding of molecular mechanisms, ethical concerns, regulatory requirements, and issues related to data quality and interpretability. Overall, AI-driven drug repurposing is an innovative and promising field that can transform medical research and drug development, covering unmet medical needs efficiently and cost-effectively.
    Keywords:  artificial intelligence; drug development; drug repurposing; machine learning
    DOI:  https://doi.org/10.3390/medicines12040028
  9. JMIR Form Res. 2025 Nov 24. 9 e79286
       Background: Reducing patient harm and improving patient safety is a central objective in global health care. Effective communication and meaningful patient engagement are considered essential strategies to achieve this goal. However, implementation of structured and strategic patient engagement at the organizational level remains limited, particularly in the context of patient safety. Patient and family advisory councils (PFACs) offer a promising model to enhance organizational-level patient engagement, yet guidance on implementation and targeted training for PFAC members is scarce.
    Objective: This study aimed to codevelop an evidence-informed, blended educational program designed to strengthen PFAC members' competencies in patient safety and communication, and to foster strategic collaboration between PFACs and health care organizations.
    Methods: The intervention was systematically developed using a logic model framework that structures the development process from available and required resources to the ultimate objectives and impacts. The primary target group included PFAC members, such as patients, relatives, and advocates, as well as health care representatives in leadership, quality management, or coordination roles. The program's content and structure were informed by a nationwide needs and requirements analysis among PFAC members, conducted using a mixed methods Delphi approach, and by a rapid scoping review on existing educational resources and evidence on PFAC engagement in patient safety.
    Results: Our Partners for Patient Safety blended educational program consisted of 2 modular components: a self-paced e-learning module and a subsequent on-site workshop module. Content addressed three core topics: (1) fundamentals of patient safety, (2) engagement of PFACs, and (3) communication and collaborative goal setting. The e-learning module provided theoretical knowledge using diverse didactic formats, such as interactive tasks, videos, and downloadable materials, and included applied examples using established decision-making and goal-setting frameworks. The workshop module built on the e-learning module and facilitated local implementation through collaborative exercises focused on stakeholder perspectives, communication barriers, and joint goal development. Both modules were aligned with defined learning objectives and combined passive and active learning strategies to promote engagement and practical application.
    Conclusions: The Partners for Patient Safety program seeks to develop PFAC members' competencies, promote collaboration in patient safety, and foster a culture of safety and partnership within health care organizations. By combining theoretical knowledge with practical, collaborative learning, the program addresses key barriers to effective PFAC engagement at the organizational level. Its modular design allows flexible implementation and has the potential to strengthen cooperation between PFACs and health care representatives, ultimately improving patient safety outcomes. Further evaluation of the program's implementation and effectiveness is needed.
    Keywords:  collaboration; communication; educational program; patient engagement; patient safety
    DOI:  https://doi.org/10.2196/79286
  10. NPJ Digit Med. 2025 Nov 28. 8(1): 732
      Synthetic tabular data generation (SDG) is increasingly important in healthcare research and innovation while preserving patients' privacy. However, ethical concerns remain, primarily over residual privacy vulnerability and insufficient oversight. This review analyzes the only published SDG regulatory guidelines to date, from United Kingdom, Singapore, and South Korea. All emphasize privacy, acknowledging synthetic data is not inherently free from disclosure risks. Thresholds for sufficiently low risk are yet to be determined.
    DOI:  https://doi.org/10.1038/s41746-025-02112-0
  11. Ther Innov Regul Sci. 2025 Nov 24.
      In the context of clinical research, computational models have received increasing attention over the past decades. In this systematic review, we aimed to provide an overview of the role of so-called in silico clinical trials (ISCTs) in medical applications. Exemplary for the broad field of clinical medicine, we focused on in silico (IS) methods applied in drug development, sometimes also referred to as model informed drug development (MIDD). We searched PubMed and ClinicalTrials.gov for published articles and registered clinical trials related to ISCTs. We identified 202 articles and 48 trials, and of these, 76 articles and 19 trials were directly linked to drug development. We extracted information from all 202 articles and 48 clinical trials and conducted a more detailed review of the methods used in the 76 articles that are connected to drug development. Regarding application, most articles and trials focused on cancer and imaging-related research while rare and pediatric diseases were only addressed in 14 articles and 5 trials, respectively. While some models were informed combining mechanistic knowledge with clinical or preclinical (in-vivo or in-vitro) data, the majority of models were fully data-driven, illustrating that clinical data is a crucial part in the process of generating synthetic data in ISCTs. Regarding reproducibility, a more detailed analysis revealed that only 24% (18 out of 76) of the articles provided an open-source implementation of the applied models, and in only 20% of the articles the generated synthetic data were publicly available. Despite the widely raised interest, we also found that it is still uncommon for ISCTs to be part of a registered clinical trial and their application is restricted to specific diseases leaving potential benefits of ISCTs not fully exploited.
    Keywords:  Clinical trial; In silico; Model-informed drug development; Pediatric disease; Rare disease; Systematic review
    DOI:  https://doi.org/10.1007/s43441-025-00893-w