bims-curels Biomed News
on Leigh syndrome
Issue of 2025–02–09
fifteen papers selected by
Cure Mito Foundation
  1. iPSC models of mitochondrial diseases.
  2. Novel pathogenic mtDNA variants in Chinese children with neurological mitochondrial disorders.
  3. Novel intronic variant in NDUFS7 gene results in mitochondrial complex I assembly defect with early basal ganglia and midbrain involvement with progressive neuroimaging findings.
  4. Leber Hereditary Optic Neuropathy: Support, Genetic Prediction and Accurate Genetic Counselling Enhance Family Planning Choices.
  5. Ensuring patient access to gene therapies for rare diseases: Navigating reimbursement and coverage challenges.
  6. From Diabetes to Neuropathy: A Diagnostic Journey to Leigh Syndrome.
  7. The Frequencies of Different Inborn Errors of Metabolism in Adult Metabolic Centres: 10 Years Later, Another Report From the SSIEM Adult Metabolic Physicians Group.
  8. Revisiting the Role of Mitochondrial DNA Mutations in Aging: Bridging Theoretical Expectations with Empirical Observations.
  9. Endocrine dysfunction in primary mitochondrial diseases.
  10. MitoEdit: a pipeline for optimizing mtDNA base editing and predicting bystander effects.
  11. DNA repair pathways in the mitochondria.
  12. A new paradigm for neurodegenerative diseases classification: A clinical perspective.
  13. Whether to Offer Interventions at the End of Life: What Physicians Consider and How Clinical Ethicists Can Help.
  14. What's the role of kindness in the healthcare context? A scoping review.
  15. Estimating rare genetic disease prevalence: a challenging task.
  1. Neurobiol Dis. 2025 Jan 30. pii: S0969-9961(25)00038-5. [Epub ahead of print] 106822
    iPSC models of mitochondrial diseases.
    Sonja Heiduschka, Alessandro Prigione.
      Mitochondrial diseases are historically difficult to study. They cause multi-systemic defects with prevalent impairment of hard-to-access tissues such as the brain and the heart. Furthermore, they suffer from a paucity of conventional model systems, especially because of the challenges associated with mitochondrial DNA (mtDNA) engineering. Consequently, most mitochondrial diseases are currently untreatable. Human induced pluripotent stem cells (iPSCs) represent a promising approach for developing human model systems and assessing therapeutic avenues in a patient- and tissue-specific context. iPSCs are being increasingly used to investigate mitochondrial diseases, either for dissecting mutation-specific defects within two-dimensional (2D) or three-dimensional (3D) progenies or for unveiling the impact of potential treatment options. Here, we review how iPSC-derived 2D cells and 3D organoid models have been applied to the study of mitochondrial diseases caused by either nuclear or mtDNA defects. We anticipate that the field of iPSC-driven modeling of mitochondrial diseases will continue to grow, likely leading to the development of innovative platforms for treatment discovery and toxicity that could benefit the patient community suffering from these debilitating disorders with highly unmet medical needs.
    Keywords:  Brain organoids; Disease modeling; Drug discovery; Mitochondrial diseases; Pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.nbd.2025.106822
  2. Ann Clin Transl Neurol. 2025 Feb 06.
    Novel pathogenic mtDNA variants in Chinese children with neurological mitochondrial disorders.
    Zhimei Liu, Kexin Pan, Mingzhao Wang, Yijun Jin, Wenxin Yang, Keer Chen, Chaolong Xu, Xin Duan, Ying Zou, Changhong Ren, Lifang Dai, Suzhou Zhao, Ya Wang, Lijun Shen, Fang Fang, Hezhi Fang.
       OBJECTIVE: Pathogenic variations in the mitochondrial genome are tightly linked to neurological mitochondrial disorders in children. However, the mutation spectrum of mitochondrial DNA (mtDNA) in the Chinese population remains incomplete. Therefore, the primary objective of our study was to comprehensively characterize pathogenic mtDNA variants in Chinese children with mitochondrial disorders at clinical, molecular, and functional levels.
    METHODS: Between February 2019 and September 2023, we analyzed pathogenic mtDNA variants in a cohort of over 600 Chinese children suspected of having mitochondrial disorders. Whole-exome sequencing (WES) and whole-mtDNA sequencing were performed on the cohort.
    RESULTS: We identified 54 pathogenic or likely pathogenic mtDNA variants in 227 Chinese children with neurological mitochondrial disorders. Among the eight novel heteroplasmic variants detected in seven patients, in silico analyses suggested likely pathogenic features. Functional analyses using either primary fibroblasts or cybrid cells carrying different mutant loads of mtDNA variants showed impaired mitochondrial respiration, ATP generation, and mitochondrial membrane potential in five of the eight novel variants, including m.4275G>A, m.10407G>A, m.5828G>A, m.3457G>A, and m.13112T>C. The m.8427T>C variant was identified as a rare polymorphism because, despite being located at MT-ATP8, it does not affect both the assembly and activity of mitochondrial complex V in cells carrying homoplasmic m.8427T>C variation. Transcriptome profiling further confirmed the pathogenic contributions of these five variants by altering mitochondrial pathways.
    CONCLUSION: In summary, we revisited the mtDNA mutation spectrum in Chinese children with mitochondrial disorders, and identified five novel pathogenic mtDNA variants with functional verification that are related to neurological mitochondrial disorders in children.
    DOI:  https://doi.org/10.1002/acn3.52315
  3. Mitochondrion. 2025 Jan 31. pii: S1567-7249(25)00004-2. [Epub ahead of print] 102007
    Novel intronic variant in NDUFS7 gene results in mitochondrial complex I assembly defect with early basal ganglia and midbrain involvement with progressive neuroimaging findings.
    Jaakko Oikarainen, Reetta Hinttala, Naemeh Nayebzadeh, Salla M Kangas, Katariina Mankinen, Elisa Rahikkala, Hannaleena Kokkonen, Päivi Vieira, Maria Suo-Palosaari, Johanna Uusimaa.
      Leigh syndrome is the most common phenotype of mitochondrial disorders in children. This study demonstrates clinical, neuroradiological, and molecular genetic findings in siblings with Leigh syndrome and isolated complex I assembly defect associated with intronic c.16 + 5G > A variant in the NDUFS7 gene. Whole exome sequencing was carried out to identify the causative variant. The gene and protein expression of NDUFS7 were studied using patient-derived fibroblasts. Assembly of mitochondrial respiratory chain enzymes was analyzed using Blue Native PAGE. This study shows that the NDUFS7 c.16 + 5G > A variant (rs375282422) has a causative role in Leigh syndrome. Evolution of neuroimaging findings related to this gene variant are demonstrated.
    Keywords:  Intronic variant; Leigh syndrome; Mitochondrial; NDUFS7; Neuroimaging; Rare variant
    DOI:  https://doi.org/10.1016/j.mito.2025.102007
  4. Clin Exp Ophthalmol. 2025 Feb 02.
    Leber Hereditary Optic Neuropathy: Support, Genetic Prediction and Accurate Genetic Counselling Enhance Family Planning Choices.
    Lisa S Kearns, Sandra E Staffieri, David A Mackey.
      With the increased availability of genetic testing and the addition of mitochondrial genetic variants on disease panels, accurate genetic counselling for individuals and families affected by, or at risk of, Leber hereditary optic neuropathy (LHON) is becoming increasingly relevant. Challenges in providing genetic counselling for LHON include its mitochondrial inheritance pattern, different haplogroups, incomplete penetrance and that it predominantly affects males. Accurate genetic counselling aims to avoid incorrect disease-risk assessment and delays in either diagnosis or implementation of psychosocial support. Families are also empowered to make autonomous health decisions regarding potential trigger factors for LHON vision loss and informed reproductive choices. Using clinical vignettes, this review demonstrates that an increased awareness of LHON amongst eye care, general and genetic health professionals can address challenges and misconceptions.
    Keywords:  Leber hereditary optic neuropathy; counselling; genetics; mitochondrial disease
    DOI:  https://doi.org/10.1111/ceo.14493
  5. Mol Ther Methods Clin Dev. 2025 Mar 13. 33(1): 101403
    Ensuring patient access to gene therapies for rare diseases: Navigating reimbursement and coverage challenges.
    Diane Berry, Carolyn Hickey, Lisa Kahlman, James Long, Christina Markus, Caitlin K McCombs.
      The rapid transformation in rare disease treatment, driven by advances in genetic medicine and diagnostics, underscores the urgent need for access to these innovative therapies. With over 10,000 identified rare diseases globally, 80% of which are genetic, the current therapeutic landscape indicates that only 5% of these conditions have FDA-approved treatments. This article examines the critical logistical challenges in commercializing and paying for gene therapies for rare diseases. It highlights the importance of considering innovative payment models, addressing patient portability issues, and aligning payer coverage policies with FDA-approved indications. It emphasizes the need to account for the broader value of gene therapies, incorporate input from disease-specific clinical experts in payer coverage decisions, and reduce administrative barriers to coverage. By adopting a multifaceted approach, we can foster a more supportive environment for the sustainable delivery of gene therapies, significantly improving the lives of patients with rare genetic disorders while rewarding and driving continued innovation.
    DOI:  https://doi.org/10.1016/j.omtm.2024.101403
  6. Iran J Child Neurol. 2025 ;19(1): 113-119
    From Diabetes to Neuropathy: A Diagnostic Journey to Leigh Syndrome.
    Arya Behzadi, Pooya Poormehr, Hedyeh Saneifard, Marjan Shakiba.
      Diabetes is one of the most common chronic disorders in the world, characterized by chronic hyperglycemia. Among the rare causes of diabetes, Leigh syndrome is a rare genetic mitochondrial disorder with unusual manifestations like neurological deficits in addition to typical diabetes symptoms. This report enlightens others about the unusual presentation of diabetes in a pediatric population. The studied case is a 6-year-old girl with hypothyroidism and diabetes. Post-SARS-CoV-2 infection, she developed progressive lower limb weakness. Magnetic resonance imaging (MRI) and electromyography-nerve conduction velocity (EMG-NCV) revealed brain lesions and polyneuropathy. Genetic testing using whole exome and Sanger sequencing confirmed mitochondrial gene mutations in the MT-NDI location, diagnosing her with Leigh syndrome. Pediatric diabetic patients typically present with Type 1 diabetes mellitus (T1DM) or Type 2 diabetes mellitus (T2DM), but other causes must be considered. Leigh syndrome can manifest with neurological symptoms, requiring clinicians to recognize its diverse presentations for proper management. This case highlights the importance of considering rare etiologies for diabetes to improve the prognosis and quality of life.
    Keywords:  Diabetes; Leigh syndrome; Neurological disorders Mitochondrial disorders Genetic testing
    DOI:  https://doi.org/10.22037/ijcn.v19i1.46085
  7. J Inherit Metab Dis. 2025 Mar;48(2): e70005
    The Frequencies of Different Inborn Errors of Metabolism in Adult Metabolic Centres: 10 Years Later, Another Report From the SSIEM Adult Metabolic Physicians Group.
    Michel Tchan, Anna Lehman, Laura van Dussen, Janneke G Langendonk, Mirian C H Janssen, Mirjam Langeveld, Elaine Murphy, Bryony Ryder, Emma Glamuzina, Martin Merkel, Annalisa Sechi, Jean-Baptiste Arnoux, Fanny Mochel, Gonnie Alkemade, Francois Maillot, Elsa Kaphan, Karin Mazodier, Quentin Thomas, Vanessa Leguy-Seguin, Cecilia Marelli.
      There are still few centres, which specialise in the care of adults with inborn errors of metabolism (IEM). All physicians who participated in the SSIEM adult metabolic physicians group paper in 2014 were contacted to provide updated data on their IEM patients. Fifteen adult centres responded to our survey with information on their patients. Nine thousand, six hundred fifty-one patients were included in the final cohort, compared with 6 182 in the previous analysis. There were 394 separate diagnoses. The most common diseases were phenylketonuria (19.6%), mitochondrial disorders (12.3%) and lysosomal storage disorders such as Fabry disease (20.1% of LSD's), Pompe disease (3.1%), and Gaucher disease (2.8%). Among the disorders that can present with acute metabolic decompensation, the urea cycle disorders (4.0%), were most common (ornithine transcarbamylase deficiency 2.6%), followed by maple syrup urine disease (1.1%) and glycogen storage disease type I (0.7%). Patients were frequently diagnosed as adults, particularly those with mitochondrial disease and lysosomal storage disorders. Many patients are only diagnosed in adulthood (> 40%) and the cohort is increasing substantially with 9 651 patients included in the final analysis (34% increase compared to our original paper). Thus reinforcing the need for adult specialists to be trained in this area.
    Keywords:  adult; inborn error of metabolism; transition
    DOI:  https://doi.org/10.1002/jimd.70005
  8. Aging Dis. 2025 Feb 01.
    Revisiting the Role of Mitochondrial DNA Mutations in Aging: Bridging Theoretical Expectations with Empirical Observations.
    Runyu Liang, Qiang Tang, Jia Chen, Yongyin Huang, Luwen Zhu.
      Since the association between mitochondria and aging was first identified, significant efforts have been devoted to elucidating the role of mitochondrial DNA mutations in the aging process. Due to their age-dependent accumulation, intrinsically high mutation rates, and defective replication mechanisms, mtDNA mutations have often been regarded as pivotal drivers of aging. This has led to certain intuitive yet inherently limited conclusions. Aging, however, is a multifactorial process, and the role of mtDNA cannot be simply categorized in binary terms, as its influence emerges as a composite vector of numerous interconnected physiological processes. Adopting alternative perspectives may mitigate the discrepancies between theoretical expectations and empirical findings, offering new directions and insights for future research.
    DOI:  https://doi.org/10.14336/AD.2024.1469
  9. Endocr Rev. 2025 Feb 01. pii: bnaf002. [Epub ahead of print]
    Endocrine dysfunction in primary mitochondrial diseases.
    Rachel Varughese, Shamima Rahman.
      Primary mitochondrial disorders (PMD) are genetic disorders affecting the structure or function of the mitochondrion. Mitochondrial functions are diverse, including energy production, ion homeostasis, reactive oxygen species regulation, antioxidant defence, and biosynthetic responsibilities, notably including steroidogenesis. Mitochondria provide the energy to drive intracellular production and extracellular secretion of all hormones. The understanding of the endocrine consequences of PMD is key to timely identification of both endocrine complications in PMD patients, and PMD presenting primarily with endocrine disease. This is a narrative review on the endocrine manifestations of PMD, underlying disease mechanisms and current and emerging approaches to diagnosing and treating these complex disorders. Diabetes is the most frequent endocrine manifestation of PMD, but growth hormone deficiency, adrenal insufficiency, hypogonadism and parathyroid dysfunction may occur. Despite the intricate involvement of the thyroid gland in metabolic regulation, there is little evidence for a causal relationship between thyroid dysfunction and PMD. In conclusion, endocrine dysfunction is observed in PMD with varying incidence depending on the specific mitochondrial disorder and the endocrine organ in question. Diagnosis of PMD in a patient with endocrine presenting features requires a high level of clinical suspicion, particularly when apparently unrelated co-morbidities co-exist. Similarly, endocrine pathology may be subtle in patients with known PMD and thorough consideration must be given to ensure timely diagnosis and treatment. The scope for novel therapeutics for this group of devastating conditions is enormous, however, several challenges remain to be overcome before hopes of curative treatments can be brought into clinical practice.
    DOI:  https://doi.org/10.1210/endrev/bnaf002
  10. bioRxiv. 2025 Jan 25. pii: 2025.01.22.634390. [Epub ahead of print]
    MitoEdit: a pipeline for optimizing mtDNA base editing and predicting bystander effects.
    Devansh Shah, Kelly McCastlain, Ti-Cheng Chang, Gang Wu, Mondira Kundu.
       Motivation: Human mitochondrial DNA (mtDNA) mutations are causally implicated in maternally inherited mitochondrial respiratory disorders; however, the role of somatic mtDNA mutations in both late-onset chronic diseases and cancer remains less clear. Although recent advances in mtDNA base editing technology have the potential to model and characterize many of these mutations, current editing approaches are complicated by the potential for multiple unintentional edits (bystanders) that are only identifiable through empirical 'trial and error', thereby sacrificing valuable time and effort towards suboptimal construct development.
    Results: We developed MitoEdit, a novel tool that incorporates empirical base editor patterns to facilitate identification of optimal target windows and potential bystander edits. MitoEdit allows users to input DNA sequences in a text-based format, specifying the target base position and its desired modification. The program generates a list of candidate target windows with a predicted number of bystander edits and their functional impact, along with flanking nucleotide sequences designed to bind TALE (transcription activator-like effectors) array proteins. In silico evaluations indicate that MitoEdit can predict the majority of bystander edits, thereby reducing the number of constructs that need to be tested empirically. To the best of our knowledge, MitoEdit is the first tool to automate prediction of base edits.
    Availability and implementation: MitoEdit is freely available at Kundu Lab GitHub ( https://github.com/Kundu-Lab/mitoedit ).
    Contact: Corresponding email: Gang.Wu@stjude.org ; Mondira.Kundu@stjude.org.
    Supplementary information: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1101/2025.01.22.634390
  11. DNA Repair (Amst). 2025 Feb 01. pii: S1568-7864(25)00010-2. [Epub ahead of print]146 103814
    DNA repair pathways in the mitochondria.
    Dillon E King, William C Copeland.
      Mitochondria contain their own small, circular genome that is present in high copy number. The mitochondrial genome (mtDNA) encodes essential subunits of the electron transport chain. Mutations in the mitochondrial genome are associated with a wide range of mitochondrial diseases and the maintenance and replication of mtDNA is crucial to cellular health. Despite the importance of maintaining mtDNA genomic integrity, fewer DNA repair pathways exist in the mitochondria than in the nucleus. However, mitochondria have numerous pathways that allow for the removal and degradation of DNA damage that may prevent accumulation of mutations. Here, we briefly review the DNA repair pathways present in the mitochondria, sources of mtDNA mutations, and discuss the passive role that mtDNA mutagenesis may play in cancer progression.
    Keywords:  DNA repair; Mitochondria; MtDNA; Mutagenesis
    DOI:  https://doi.org/10.1016/j.dnarep.2025.103814
  12. J Clin Neurosci. 2025 Feb 03. pii: S0967-5868(25)00071-2. [Epub ahead of print]134 111099
    A new paradigm for neurodegenerative diseases classification: A clinical perspective.
    Alexandros Giannakis, Spiridon Konitsiotis.
      A vast progress has been made in the understanding of neurodegenerative diseases during the past few years. However, clinical diagnostic accuracy continues to be very low, despite the introduction of various diagnostic tools and repeated revisions of diagnostic criteria. For instance, patients with Alzheimer's disease (AD) may present with symptoms that overlap with other neurodegenerative conditions like dementia with Lewy bodies (DLB), making accurate diagnosis challenging. This diagnostic uncertainty can lead to delayed or incorrect treatment, significantly impacting patients' quality of life and prognosis. Thus, the definite diagnosis still relies on post-mortem pathological findings, placing a significant burden on both clinicians and researchers. As a growing body of evidence indicates, co-pathology seems to be the rule among neurodegenerative diseases. Additionally, a single pathological diagnosis, such as AD, can manifest in various clinical presentations, ranging from predominantly cognitive impairment to significant motor symptoms. Each of these presentations currently requires its own set of complicated diagnostic criteria. Perhaps, the time has come for a much-needed radical revision of existing clinical diagnostic criteria. Inclusion of patients do not neatly fit into existing diagnostic categories for neurodegenerative diseases, in future large-scale, longitudinal studies and/or clinical trials, and systematic assessment of their clinical features and disease progression using machine learning could generate valuable data on patients with mixed pathologies and improve our understanding of how to effectively treat these complex cases.
    Keywords:  Dementia; Diagnostic criteria; Neurodegenerative diseases; Synucleinopathies; Tauopathies
    DOI:  https://doi.org/10.1016/j.jocn.2025.111099
  13. AJOB Empir Bioeth. 2025 Feb 04. 1-9
    Whether to Offer Interventions at the End of Life: What Physicians Consider and How Clinical Ethicists Can Help.
    Joelle Robertson-Preidler, Mikaela Kim, Sophia Fantus, Janet Malek.
       BACKGROUND: Advances in life-prolonging technologies increasingly create dilemmas for physicians who must decide whether to offer various interventions to patients nearing the end of life. Clinical ethicists are often consulted to support physicians in making these complex decisions and can do so most effectively if they understand physicians' reasons for making recommendations in this context.
    METHODS: Semi-structured interviews were conducted with surgeons, nephrologists, intensivists, emergency physicians, and oncologists regarding the considerations they have used to make decisions about offering interventions for patients nearing the end of life. Interview transcripts were thematically analyzed.
    RESULTS: We identified six types of considerations physicians take into account: (1) patient characteristics at baseline; (2) likelihood to cause harm; (3) likelihood to achieve a goal or perceived benefit; (4) patient and family values and preferences; (5) institutional factors, and (6) professional and personal factors.
    CONCLUSIONS: While considerations converged into major themes, many participants evaluated and applied these themes differently, opening the door to potential disagreement and variation based on physicians' personal values. Clinical ethicists can help navigate uncertainty and resolve conflicts by helping physicians recognize, evaluate, and communicate their decisional factors to aid informed decision-making.
    Keywords:  Word; bioethics; clinical decision-making; clinical ethics; end of life; qualitative research
    DOI:  https://doi.org/10.1080/23294515.2025.2457705
  14. BMC Health Serv Res. 2025 Feb 05. 25(1): 207
    What's the role of kindness in the healthcare context? A scoping review.
    Angela Greco, Laura G González-Ortiz, Luca Gabutti, Daniel Lumera.
       INTRODUCTION: The role of kindness in healthcare is receiving increased attention. Indeed, international research shows that a culture of kindness has a positive impact on healthcare organizations, healthcare staff members, and patients. Benefits include better patient outcomes, as well as a humanized work environment, which helps to prevent stress and burnout among healthcare workers. Studies across different settings suggest that healthcare managers need to foster not only technical and organizational skills, but also social skills such as empathy and kindness. The purpose of this scoping review is to provide an overview of the current research landscape regarding initiatives based on acts of kindness in healthcare organizations. We will also explore whether this is a topic of interest to academics, which countries have conducted the most research on the subject, the practical implications for healthcare management, and potential directions for future research.
    METHODS: This scoping review was conducted using the Arksey and O'Malley framework. A search was performed in the electronic databases ScienceDirect, Pubmed and Web of Science, to identify studies published in English between 1994 and 2023 describing or evaluating kindness-based interventions in the healthcare context. Based on the predefined eligibility criteria, screening and studies selection were performed. Data were extracted and analyzed descriptively to summarize the evidence.
    RESULTS: 19 studies were analyzed and included in the review. The article assessment revealed four categories: 1) organizational culture; 2) burnout reduction and staff well-being; 3) staff education / training; and 4) communication and patient experience. Kindness in healthcare is a relatively new topic, but of great scientific interest. The countries most interested in the topic are English speaking (with a particular interest in category 2) and Western European, and the methodology most commonly used to investigate this topic is qualitative.
    CONCLUSIONS: The need for additional research on kindness in healthcare arises from a complex and dynamic healthcare environment, where the concept of kindness holds the potential to revolutionize the quality of care and the well-being of healthcare providers. The interest of the various countries in the 4 thematic categories proposed by the study and the performance results of healthcare organizations promoting kindness compared to others without this focus also bear further consideration.
    Keywords:  Compassion; Hospital; Humanization; Leadership; Performance
    DOI:  https://doi.org/10.1186/s12913-025-12328-1
  15. Blood Adv. 2025 Feb 04. pii: bloodadvances.2024015546. [Epub ahead of print]
    Estimating rare genetic disease prevalence: a challenging task.
    Koichi Kokame.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024015546
This page is being maintained by Thomas Krichel. It was last updated on 2025‒02‒09 at 1:11.