bims-curels Biomed News
on Leigh syndrome
Issue of 2025–01–26
twelve papers selected by
Cure Mito Foundation
  1. Mitochondrial disease and epilepsy in children.
  2. Precise modelling of mitochondrial diseases using optimized mitoBEs.
  3. Sequencing and characterizing human mitochondrial genomes in the biobank-based genomic research paradigm.
  4. Family and genetic counseling in Leber hereditary optic neuropathy.
  5. Dear sceptics of patient engagement in research.
  6. Lateralised periodic discharges and photic sensitivity in adult onset MELAS syndrome in twin sisters.
  7. Mitochondrial DNA (mtDNA) as fluid biomarker in neurodegenerative disorders: A systematic review.
  8. Philanthropic drug development: understanding its importance, mechanisms, and future prospects.
  9. Mitochondrial transplantation: a promising strategy for the treatment of retinal degenerative diseases.
  10. Use of Quantum Dots as Nanotheranostic Agents: Emerging Applications in Rare Genetic Diseases.
  11. The use of Artificial Intelligence Algorithms in drug development and clinical trials: A scoping review.
  12. Mitochondrial DNA variants and their impact on epigenetic and biological aging in young adulthood.
  1. Front Neurol. 2024 ;15 1499876
    Mitochondrial disease and epilepsy in children.
    Xuan Zhang, Bo Zhang, Zhiming Tao, Jianmin Liang.
      Mitochondria is the cell's powerhouse. Mitochondrial disease refers to a group of clinically heterogeneous disorders caused by dysfunction in the mitochondrial respiratory chain, often due to mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that encodes mitochondrial proteins. This dysfunction can lead to a variety of clinical phenotypes, particularly affecting organs with high energy demands, such as the brain and muscles. Epilepsy is a prevalent neurological disorder in children and is also a frequent manifestation of mitochondrial disease. The exact mechanisms underlying epilepsy in mitochondrial disease remain unclear and are thought to involve multiple contributing factors. This review explores common mitochondrial diseases associated with epilepsy, focusing on their prevalence, seizure types, EEG features, therapeutic strategies, and outcomes. It also summarizes the relationship between the molecular genetics of mitochondrial respiratory chain components and the development of epilepsy.
    Keywords:  coenzyme Q; cytochrome C; epilepsy; genes; mitochondrial complex
    DOI:  https://doi.org/10.3389/fneur.2024.1499876
  2. Nature. 2025 Jan 22.
    Precise modelling of mitochondrial diseases using optimized mitoBEs.
    Xiaoxue Zhang, Xue Zhang, Jiwu Ren, Jiayi Li, Xiaoxu Wei, Ying Yu, Zongyi Yi, Wensheng Wei.
      The development of animal models is crucial for studying and treating mitochondrial diseases. Here we optimized adenine and cytosine deaminases to reduce off-target effects on the transcriptome and the mitochondrial genome, improving the accuracy and efficiency of our newly developed mitochondrial base editors (mitoBEs)1. Using these upgraded mitoBEs (version 2 (v2)), we targeted 70 mouse mitochondrial DNA mutations analogous to human pathogenic variants2, establishing a foundation for mitochondrial disease mouse models. Circular RNA-encoded mitoBEs v2 achieved up to 82% editing efficiency in mice without detectable off-target effects in the nuclear genome. The edited mitochondrial DNA persisted across various tissues and was maternally inherited, resulting in F1 generation mice with mutation loads as high as 100% and some mice exhibiting editing only at the target site. By optimizing the transcription activator-like effector (TALE) binding site, we developed a single-base-editing mouse model for the mt-Nd5 A12784G mutation. Phenotypic evaluations led to the creation of mouse models for the mt-Atp6 T8591C and mt-Nd5 A12784G mutations, exhibiting phenotypes corresponding to the reduced heart rate seen in Leigh syndrome and the vision loss characteristic of Leber's hereditary optic neuropathy, respectively. Moreover, the mt-Atp6 T8591C mutation proved to be more deleterious than mt-Nd5 A12784G, affecting embryonic development and rapidly diminishing through successive generations. These upgraded mitoBEs offer a highly efficient and precise strategy for constructing mitochondrial disease models, laying a foundation for further research in this field.
    DOI:  https://doi.org/10.1038/s41586-024-08469-8
  3. Sci China Life Sci. 2025 Jan 21.
    Sequencing and characterizing human mitochondrial genomes in the biobank-based genomic research paradigm.
    Lintao Luo, Mengge Wang, Yunhui Liu, Jianbo Li, Fengxiao Bu, Huijun Yuan, Renkuan Tang, Chao Liu, Guanglin He.
      Human mitochondrial DNA (mtDNA) harbors essential mutations linked to aging, neurodegenerative diseases, and complex muscle disorders. Due to its uniparental and haploid inheritance, mtDNA captures matrilineal evolutionary trajectories, playing a crucial role in population and medical genetics. However, critical questions about the genomic diversity patterns, inheritance models, and evolutionary and medical functions of mtDNA remain unresolved or underexplored, particularly in the transition from traditional genotyping to large-scale genomic analyses. This review summarizes recent advancements in data-driven genomic research and technological innovations that address these questions and clarify the biological impact of nuclear-mitochondrial segments (NUMTs) and mtDNA variants on human health, disease, and evolution. We propose a streamlined pipeline to comprehensively identify mtDNA and NUMT genomic diversity using advanced sequencing and computational technologies. Haplotype-resolved mtDNA sequencing and assembly can distinguish authentic mtDNA variants from NUMTs, reduce diagnostic inaccuracies, and provide clearer insights into heteroplasmy patterns and the authenticity of paternal inheritance. This review emphasizes the need for integrative multi-omics approaches and emerging long-read sequencing technologies to gain new insights into mutation mechanisms, the influence of heteroplasmy and paternal inheritance on mtDNA diversity and disease susceptibility, and the detailed functions of NUMTs.
    Keywords:  NUMT; evolutionary medicine; genomic database; heteroplasmy; mitochondrial DNA
    DOI:  https://doi.org/10.1007/s11427-024-2736-7
  4. Ophthalmic Genet. 2025 Jan 20. 1-9
    Family and genetic counseling in Leber hereditary optic neuropathy.
    David A Mackey, Sandra E Staffieri, M Isabel G Lopez Sanchez, Lisa S Kearns.
       AIM: Leber hereditary optic neuropathy (LHON) predominantly manifests during adolescence or young adulthood, resulting in sudden and profound vision loss in individuals who previously had normal vision. This abrupt change significantly impacts daily life, necessitating emotional support, counseling and low-vision rehabilitative services to help affected individuals cope with the shock and adapt to their residual vision. The psychosocial burden of dealing with vision loss extends beyond the individuals directly affected by LHON, affecting matrilineal relatives who face the dual challenges of grieving for their loved one's vision loss and managing their own uncertainty about potential vision loss and its familial implications.
    METHOD: We reviewed key information that needs to be obtained prior to genetic counseling for LHON. We reviewed key counseling issues within LHON-affected families and the issues pending several subgroups of family members with distinct and varying genetic counseling needs.
    RESULTS: Family subgroups requiring specific counseling issues include the individuals affected by LHON, their mother, siblings, father, partner, and children. Genetic counseling plays an integral part of clinical care in families affected by LHON, providing tailored support and information to each subgroup.
    CONCLUSION: To provide accurate information to families and guide them toward potential supports, treatments and preventive measures, health professionals need to be aware of the factors influencing visual recovery and individual risk of vision loss.
    Keywords:  Leber hereditary optic neuropathy; genetic counselling; mitochondrial mutations
    DOI:  https://doi.org/10.1080/13816810.2025.2451175
  5. BMJ. 2025 Jan 22. 388 r133
    Dear sceptics of patient engagement in research.
    Dawn P Richards.
      
    DOI:  https://doi.org/10.1136/bmj.r133
  6. Clin Neurol Neurosurg. 2025 Jan 14. pii: S0303-8467(25)00027-7. [Epub ahead of print]249 108744
    Lateralised periodic discharges and photic sensitivity in adult onset MELAS syndrome in twin sisters.
    Rümeysa Kahraman, Sena Ayşe Kaya, Serkan Demir, Şevki Şahin, Özdem Ertürk Çetin.
      Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most common mitochondrial disorders, typically presenting with symptoms before the age of 40. Epileptic seizures are a common manifestation, with both focal and generalized seizures being observed. EEG findings can be variable, with the most common patterns being slow background activity followed by epileptiform discharges.Here, we present monozygotic twin sisters with late-onset MELAS and specific EEG features, including lateralized periodic discharges and sensitivity to photic stimulation, which have been rarely reported in the literature. These cases emphasize the importance of considering MELAS in the differential diagnosis of late-onset symptoms. Furthermore, EEG findings such as sensitivity to photic stimulation may contribute to understanding MELAS pathophysiology, even during asymptomatic periods.
    Keywords:  Acidosis; Encephalopathy; MELAS; Mitochondrial; Seizure; Stroke
    DOI:  https://doi.org/10.1016/j.clineuro.2025.108744
  7. Eur J Neurol. 2025 Jan;32(1): e70014
    Mitochondrial DNA (mtDNA) as fluid biomarker in neurodegenerative disorders: A systematic review.
    Barbara Risi, Alberto Imarisio, Giada Cuconato, Alessandro Padovani, Enza Maria Valente, Massimiliano Filosto.
       BACKGROUND: Several studies evaluated peripheral and cerebrospinal fluid (CSF) mtDNA as a putative biomarker in neurodegenerative diseases, often yielding inconsistent findings. We systematically reviewed the current evidence assessing blood and CSF mtDNA levels and variant burden in Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Multiple sclerosis (MS) was also included as a paradigm of chronic neuroinflammation-driven neurodegeneration.
    METHODS: Medline, Embase, Scopus and Web of Science were searched for articles published from inception until October 2023. Studies focused on mtDNA haplogroups or hereditary pathogenic variants were excluded. Critical appraisal was performed using the Quality Assessment for Diagnostic Accuracy Studies criteria.
    RESULTS: Fifty-nine original studies met our a priori-defined inclusion criteria. The majority of CSF-focused studies showed (i) decreased mtDNA levels in PD and AD; (ii) increased levels in MS compared to controls. No studies evaluated CSF mtDNA in ALS. Results focused on blood cell-free and intracellular mtDNA were contradictory, even within studies evaluating the same disease. This poor reproducibility is likely due to the lack of consideration of the many factors known to affect mtDNA levels. mtDNA damage and methylation levels were increased and reduced in patients compared to controls, respectively. A few studies investigated the correlation between mtDNA and disease severity, with conflicting results.
    CONCLUSIONS: Additional well-designed studies are needed to evaluate CSF and blood mtDNA profiles as putative biomarkers in neurodegenerative diseases. The identification of "mitochondrial subtypes" of disease may enable novel precision medicine strategies to counteract neurodegeneration.
    Keywords:  Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; biomarker; blood; cerebrospinal fluid; mitochondrial DNA; neurodegeneration
    DOI:  https://doi.org/10.1111/ene.70014
  8. Drug Discov Today. 2025 Jan 21. pii: S1359-6446(25)00011-X. [Epub ahead of print] 104298
    Philanthropic drug development: understanding its importance, mechanisms, and future prospects.
    Marc Reichel, Eva M Murauer, Martin Steiner, Christoph Coch, Hubert Trübel.
      Philanthropic drug development (PDD) addresses gaps in traditional pharmaceutical innovation, particularly for rare and underserved diseases. Cost and timeline challenges discourage new investments, especially in niche therapeutic areas. Patient organizations (POs) are uniquely positioned to help to reduce development challenges by providing expertise, supporting early research, fostering collaborations, and driving patient-centered clinical trials. PDD relies on effective partnerships between POs, pharmaceutical companies, and other stakeholders, ensuring that patient perspectives inform the drug development process. PDD is poised to relieve the pressure on the traditional drug development process and thereby foster beneficial patient-focused innovations. In doing so, PDD allows pharmaceutical companies to expand their drug development activities into commercially unrewarding {AuQ: Edit OK?} areas, diversifying their portfolios beyond competitive fields.
    Keywords:  Drug development; Patient engagement; Patient organizations; Philanthropy; Rare diseases
    DOI:  https://doi.org/10.1016/j.drudis.2025.104298
  9. Neural Regen Res. 2024 Dec 07.
    Mitochondrial transplantation: a promising strategy for the treatment of retinal degenerative diseases.
    Jing Chi, Bin Fan, Yulin Li, Qing Jiao, Guang-Yu Li.
      The retina, a crucial neural tissue, is responsible for transforming light signals into visual information, a process that necessitates a significant amount of energy. Mitochondria, the primary powerhouses of the cell, play an integral role in retinal physiology by fulfilling the high-energy requirements of photoreceptors and secondary neurons through oxidative phosphorylation. In a healthy state, mitochondria ensure proper visual function by facilitating efficient conversion and transduction of visual signals. However, in retinal degenerative diseases, mitochondrial dysfunction significantly contributes to disease progression, involving a decline in membrane potential, the occurrence of DNA mutations, increased oxidative stress, and imbalances in quality-control mechanisms. These abnormalities lead to an inadequate energy supply, the exacerbation of oxidative damage, and the activation of cell death pathways, ultimately resulting in neuronal injury and dysfunction in the retina. Mitochondrial transplantation has emerged as a promising strategy for addressing these challenges. This procedure aims to restore metabolic activity and function in compromised cells through the introduction of healthy mitochondria, thereby enhancing the cellular energy production capacity and offering new strategies for the treatment of retinal degenerative diseases. Although mitochondrial transplantation presents operational and safety challenges that require further investigation, it has demonstrated potential for reviving the vitality of retinal neurons. This review offers a comprehensive examination of the principles and techniques underlying mitochondrial transplantation and its prospects for application in retinal degenerative diseases, while also delving into the associated technical and safety challenges, thereby providing references and insights for future research and treatment.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-00851
  10. Small. 2025 Jan 19. e2407353
    Use of Quantum Dots as Nanotheranostic Agents: Emerging Applications in Rare Genetic Diseases.
    Neethu K M, Shyamal Karmakar, Baishakhi Sahoo, Navniet Mishrra, Parikshit Moitra.
      Rare genetic diseases (RGDs) affect a small percentage of the global population but collectively have a substantial impact due to their diverse manifestations. Although the precise reasons behind these diseases remain unclear, roughly 80% of cases are genetically linked. Recent efforts focus on understanding pathology and developing new diagnostic and therapeutic approaches for RGDs. However, there persists a gap between fundamental research and clinical therapeutic approaches, where advancements in nanotechnology offer promising improvements. In this context, nanosized light-emitting quantum dots (QDs), ranging from 2-10 nm, are promising materials for diverse applications. Their size-tunable light emission, high quantum yield, and photostability allow for precise tracking of cargo. Additionally, QDs can be functionalized with therapeutic agents, antibodies, or peptides to target specific cellular pathways, enhancing treatment efficacy while minimizing side effects. By combining diagnostic and therapeutic capabilities in a single platform, QDs thus offer a versatile and powerful approach to tackle rare genetic disorders. Despite several reviews on various therapeutic applications of QDs, their utilization in the specific domain of RGDs is not well documented. This review highlight QDs' potential in diagnosing and treating certain RGDs and addresses the challenges limiting their application.
    Keywords:  bioimaging; diagnosis; quantum dot; rare genetic disease; therapy
    DOI:  https://doi.org/10.1002/smll.202407353
  11. Int J Med Inform. 2025 Jan 16. pii: S1386-5056(25)00015-2. [Epub ahead of print]195 105798
    The use of Artificial Intelligence Algorithms in drug development and clinical trials: A scoping review.
    Camila de Brito Pontes, Antonio Valerio Netto.
       BACKGROUND: Artificial Intelligence (AI) is transforming drug development and clinical trials, helping researchers find new treatments faster and personalize care for patients. By automating tasks like molecule screening and predicting treatment outcomes, AI addresses critical challenges in modern medicine.
    OBJECTIVES: This review explores how AI is being used in drug development and clinical trials, focusing on its benefits, limitations, and potential to improve healthcare outcomes.
    METHODS: A scoping review based on Arksey and O'Malley's, 2005 framework was conducted, analyzing 1,956 studies from PubMed, Web of Science, IEEE Xplore, and Scopus. Ten studies were selected for in-depth analysis.
    RESULTS: Common AI techniques include Support Vector Machines, Neural Networks, and Random Forests, applied in tasks such as identifying new drug uses, predicting antibiotic resistance, and streamlining clinical trials. While AI has shown great promise, challenges like inconsistent data quality and difficulties in clinical validation remain.
    CONCLUSIONS: AI offers exciting opportunities to improve healthcare by making drug development and clinical trials more efficient. However, overcoming barriers like data integration and methodological standardization is essential to ensure these tools benefit diverse populations, especially in settings like Brazil, where genetic diversity and health inequalities pose unique challenges.
    Keywords:  Algorithms; Artificial Intelligence; Pharmaceutical Preparations
    DOI:  https://doi.org/10.1016/j.ijmedinf.2025.105798
  12. Transl Psychiatry. 2025 Jan 22. 15(1): 16
    Mitochondrial DNA variants and their impact on epigenetic and biological aging in young adulthood.
    Klara Mareckova, Ana Paula Mendes-Silva, Martin Jáni, Anna Pacinkova, Pavel Piler, Vanessa F Gonçalves, Yuliya S Nikolova.
      The pace of biological aging varies between people independently of chronological age and mitochondria dysfunction is a key hallmark of biological aging. We hypothesized that higher functional impact (FI) score of mitochondrial DNA (mtDNA) variants might contribute to premature aging and tested the relationships between a novel FI score of mtDNA variants and epigenetic and biological aging in young adulthood. A total of 81 participants from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) prenatal birth cohort had good quality genetic data as well as blood-based markers to estimate biological aging in the late 20. A subset of these participants (n = 69) also had epigenetic data to estimate epigenetic aging in the early 20s using Horvath's epigenetic clock. The novel FI score was calculated based on 7 potentially pathogenic mtDNA variants. Greater FI score of mtDNA variants was associated with older epigenetic age in the early 20s and older biological age in the late 20s. These medium to large effects were independent of sex, current BMI, cigarette smoking, cannabis, and alcohol use. These findings suggest that elevated FI score of mtDNA variants might contribute to premature aging in young adulthood.
    DOI:  https://doi.org/10.1038/s41398-025-03235-4
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