bims-curels Biomed News
on Leigh syndrome
Issue of 2025–05–18
fourteen papers selected by
Cure Mito Foundation
  1. Reprogramming of two induced pluripotent stem cell clones from a patient with a novel MT-ATP6/8 mutation (m.8570 T > C).
  2. [Phenotypic Variability and Therapeutic Progress in Mitochondrial Disorders].
  3. A Patient with Organic Acidemia, Hyperammonemia, and a FBXL4 Variant Suggesting Mitochondrial DNA Depletion Syndrome.
  4. Health researchers' experience collaborating with patient partners: a qualitative study.
  5. What patients keep: A reflection on language and agency in clinical encounters.
  6. Neurodegenerative Diseases: Pathogenesis and Preclinical Models for Translational Drug Discovery.
  7. Safe use of sugammadex and 5% dextrose in 0.45% saline in Leigh syndrome.
  8. The cost of the diagnostic odyssey of patients with suspected rare diseases.
  9. Rare but not alone.
  10. Psychological Processes Related to Persistent Physical Symptoms in Patients With a Suspected Rare Disease: a Cross-sectional Interview Study.
  11. Investigating the dual role of mitochondrial and nuclear genome variants in pediatric cardiomyopathies.
  12. Uncharted territory: the role of mitochondrial DNA variation in macrophage-mediated host susceptibility to tuberculosis.
  13. Considerations and Approaches to Establishing Estimates of Meaningful Change for Digital Endpoints as Drug Development Tools.
  14. Frontier progress and translational challenges of pluripotent differentiation of stem cells.
  1. Stem Cell Res. 2025 May 08. pii: S1873-5061(25)00082-0. [Epub ahead of print]86 103732
    Reprogramming of two induced pluripotent stem cell clones from a patient with a novel MT-ATP6/8 mutation (m.8570 T > C).
    Anna Maria Haschke, Sebastian Diecke, Harald Stachelscheid, Markus Schuelke.
      iPSC-based models are valuable for studying the mechanisms and potential treatments of mitochondrial disorders. We generated two iPSC lines from fibroblasts of a patient with a novel MT-ATP6/8 mutation (m.8570 T > C). The infant was diagnosed with a mitochondrial disease featuring cardiac hypertrophy, brain atrophy, developmental delay, and metabolic crises with elevated lactate. Mutation heteroplasmy in blood leukocytes was 95 %. Leigh syndrome-like cranial MRI abnormalities were absent at 4 months of age. We introduced reprogramming factors by Sendai virus and assessed the pluripotency of the resulting iPSCs. As control iPSC-line, we characterized the CRMi004-A line from the RUCDR repository.
    DOI:  https://doi.org/10.1016/j.scr.2025.103732
  2. Brain Nerve. 2025 May;77(5): 513-525
    [Phenotypic Variability and Therapeutic Progress in Mitochondrial Disorders].
    Fumika Yamamoto, Hideaki Nishihara.
      Mitochondrial diseases are hereditary disorders caused by abnormalities in nuclear or mitochondrial genes. These diseases primarily lead to a wide range of symptoms due to impaired ATP production. Even with the same genetic mutation, phenotypic variability poses a significant diagnostic challenge. To date, 400 causative genes have been identified, and with ongoing progress in elucidating their pathophysiology, the development of novel therapeutic approaches, including gene therapy, is rapidly advancing.
    DOI:  https://doi.org/10.11477/mf.188160960770050513
  3. Mol Syndromol. 2025 Apr 01. 1-7
    A Patient with Organic Acidemia, Hyperammonemia, and a FBXL4 Variant Suggesting Mitochondrial DNA Depletion Syndrome.
    Merve Keser, Büşra Demirci, Habibe Koç Uçar, Özlem Akgün, İlknur Arslan, Berrak Bilginer Gürbüz.
       Introduction: Mitochondrial DNA depletion syndromes encompass rare genetic disorders stemming from various gene defects, including encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13), an autosomal recessive condition linked to FBXL4 gene variants. Although its prevalence is estimated at 1/100,000-400,000, the mechanism behind MTDPS13 remains incompletely understood. Recent studies suggest FBXL4 variants disrupt mitophagy, contributing to its pathogenesis.
    Case Presentation: A 3-year and 4-month-old male presented with respiratory distress, diarrhea, and unconsciousness. His medical history revealed developmental delay and dysmorphic features. Physical examination unveiled characteristic dysmorphisms, while neurological assessment indicated abnormalities. Laboratory findings exhibited metabolic disturbances consistent with MTDPS13, confirmed by genetic analysis revealing a homozygous c.1555C>T FBXL4 variant.
    Conclusion: FBXL4 defects, found in approximately 0.7% of suspected mitochondrial disease cases, lead to varied phenotypes with nonspecific facial dysmorphisms. The patient's presentation aligned with reported features, including growth delay, hypotonia, and developmental delay. Notably, the diagnosis occurred later than typical onset, highlighting the variability in disease manifestation. Treatment focused on symptom management, with dichloroacetic acid effectively addressing lactic acidosis. This case underscores the importance of considering mitochondrial diseases, particularly FBXL4-related MTDPS13, in patients presenting with metabolic disturbances and dysmorphic features. Early recognition facilitates appropriate management and genetic counseling for affected families.
    Keywords:  Growth retardation; Hyperammonemia; Lactic acidosis; Mitochondrial DNA depletion
    DOI:  https://doi.org/10.1159/000545585
  4. Res Involv Engagem. 2025 May 15. 11(1): 48
    Health researchers' experience collaborating with patient partners: a qualitative study.
    Magaly Brodeur, Catherine Wilhelmy, Denis Boutin, Amélie Deschamps, Olivia Fasan, Marie-Mychèle Pratte, Anne-Marie Auger, Marie-Eve Poitras, Marie-Claude Battista, Christine Loignon.
       BACKGROUND: Patient-oriented research (POR) and patient engagement (PE) have been increasingly adopted over recent decades, as they generate many positive academic and patient outcomes within various health research fields. While there has been research on the barriers and challenges experienced by patient partners (PPs), we know little about the experiences of the health researchers working with them. It is therefore important to gain a better understanding of the experiences of health researchers who work with PPs to improve their collaboration. This study, which was initiated by PPs themselves, aims to enhance the understanding of health researchers' experiences regarding the challenges of working with PPs.
    METHODS: This qualitative descriptive study involved 20 semi-structured interviews with researchers from various health science fields, such as primary care and general medicine, public health and health policy, specialized medical fields (i.e. cancerology, endocrinology, psychiatry, gerontology), biomedical engineering and medical technologies, and neuroscience. Participants, including researchers and research coordinators, were recruited through purposive sampling via email, newsletters, and social media, with their participation being voluntary and uncompensated. Thematic analysis was conducted over multiple steps, and the interview transcripts were coded to identify the main themes and subthemes relevant to the study's aims.
    RESULTS: The analysis resulted in six main themes: 1) PP individual and health-related challenges; 2) institutional barriers to PP involvement; 3) challenges in genuine PP involvement; 4) collaboration challenges in research projects; 5) time constraints in research projects; and 6) PP recruitment and representation issues.
    CONCLUSION: The findings of this study provide an in-depth view of the challenges experienced by health researchers who have involved PPs in their projects. However, it is important to highlight that this study goes beyond simply identifying challenges. These challenges are often interconnected and complex and influence one another in such a way that controlling for one element may cause further constraints in another. This article provides recommendations regarding current practices, ethics-related questioning, and time-related challenges, which will be useful for the continued meaningful involvement of PPs in research teams and for navigating the challenges.
    Keywords:  Challenges; Health research; Patient engagement; Patient involvement; Patient partner; Patient-oriented research; Qualitative; Recommendations; Thematic analysis
    DOI:  https://doi.org/10.1186/s40900-025-00730-2
  5. Patient Educ Couns. 2025 May 09. pii: S0738-3991(25)00183-1. [Epub ahead of print]137 108816
    What patients keep: A reflection on language and agency in clinical encounters.
    Melissa C Leeolou.
      
    Keywords:  Chronic disease management; Doctor patient communication; Empathy in Healthcare; Medical education; Patient experience; Patient-centered care; Reflective practice
    DOI:  https://doi.org/10.1016/j.pec.2025.108816
  6. Toxicol Pathol. 2025 May 15. 1926233251339105
    Neurodegenerative Diseases: Pathogenesis and Preclinical Models for Translational Drug Discovery.
    Laura Fusaro, Dinesh S Bangari, R Jeroen Pasterkamp, Javier Fernández-Ruiz, Sameh A Youssef, Alok K Sharma.
      The fourth session of the 2024 European Society of Toxicologic Pathology (ESTP) Congress brought together lectures focused on the use of in vitro and in vivo models to investigate neurodegenerative diseases. Four presentations highlighted various aspects of neurodegenerative diseases including dementia, immune-mediated conditions, and neuromuscular disorders. The session began with an overview of animal models of dementia underscoring their critical role in understanding disease pathogenesis and supporting the development of effective therapeutic drugs. Subsequent presentations investigated immunological self-tolerance in autoimmune neurodegenerative diseases, such as multiple sclerosis and Guillain-Barré syndrome, and the application of in vitro models to study neuromuscular diseases such as amyotrophic lateral sclerosis. The final presentation examined cannabinoid-based therapeutic options for treating neurodegenerative diseases, highlighting their potential in neuroprotection and neurorepair. This session provided valuable insights into the latest research and advancements in neurodegenerative disease modeling and therapy, offering promising directions for improved modeling and therapeutic strategies.
    Keywords:  animal models; autoimmune neurodegenerative diseases; cannabinoid-based therapeutics; dementia; human in vitro models; neurodegeneration; neuropathology; neurotoxicity
    DOI:  https://doi.org/10.1177/01926233251339105
  7. Indian J Anaesth. 2025 May;69(5): 518-519
    Safe use of sugammadex and 5% dextrose in 0.45% saline in Leigh syndrome.
    Chikeluba V Okafor, Dmitry Tumin, Sunny R Cai, Adrienne L Hutton.
      
    DOI:  https://doi.org/10.4103/ija.ija_1199_24
  8. Orphanet J Rare Dis. 2025 May 10. 20(1): 222
    The cost of the diagnostic odyssey of patients with suspected rare diseases.
    Rick Glaubitz, Luise Heinrich, Falko Tesch, Martin Seifert, Katrin Christiane Reber, Ursula Marschall, Jochen Schmitt, Gabriele Müller.
       PURPOSE: Patients with rare diseases often undergo a long diagnostic odyssey. However, there is little empirical evidence on the cost incurred during the diagnostic pathway for patients with suspected rare diseases. This study provides a comprehensive analysis of healthcare costs and utilization during the diagnostic pathway for a heterogeneous sample of patients with suspected rare diseases but unclear diagnosis.
    METHODS: Using claims data from five German statutory health insurance organizations for the years 2014-2019, we analyzed costs and healthcare utilization of 1,243 patients (aged 0 to 82 years) with suspected rare diseases referred to a rare disease center. A control cohort was assigned using 1:75 exact matching on age, sex and place of residence.
    RESULTS: In the years prior to referral to an expert center, healthcare utilization of patients with suspected rare diseases was, on average, substantially and significantly higher compared to a matched control cohort during the same observation period - e.g. in terms of the number of hospitalizations (3.1 (95%CI: 2.9-3.4) vs. 0.5 (95%CI: 0.5-0.5)), different diagnoses (50.0 (95%CI: 48.1-51.9) vs. 26.4 (95%CI: 26.2-26.5)), different active substances prescribed (12.7 (95%CI: 12.2-13.3) vs. 8.2 (95%CI: 8.2-8.3)) and the number of genetic tests (14.7 (95%CI: 12.6-16.7) vs. 0.3 (95%CI: 0.3-0.3)). We found evidence of heterogeneity in utilization by age and sex. On average, direct costs (inpatient, outpatient and prescription drug costs) of patients with suspected rare diseases during the diagnostic pathway were 7.6-fold higher than the costs of matched controls (€26,999 (95%CI: €23,751 - 30,247) vs. €3,561 (95% CI: € 3,455-3,667)). Inpatient costs were the main cost component, accounting for 62.5% of total costs.
    CONCLUSIONS: The diagnostic odyssey of patients with suspected rare diseases is associated with extensive healthcare utilization and high cost. Against this background, new ways to shorten the diagnostic journey have a high potential to decrease the financial burden related to rare diseases.
    Keywords:  Diagnostic costs; Diagnostic pathway; Rare diseases; Utilization
    DOI:  https://doi.org/10.1186/s13023-025-03751-y
  9. Fam Syst Health. 2025 Mar;43(1): 173
    Rare but not alone.
    Sara Moore.
      This short 55-word story highlights a clinical psychology doctoral student's work in therapy with individuals diagnosed with rare diseases. Upon diagnosis, clients may experience a range of emotions and feel isolated. Connection with a social network and support can increase hope and promote well-being. (PsycInfo Database Record (c) 2025 APA, all rights reserved).
    DOI:  https://doi.org/10.1037/fsh0000910
  10. Biopsychosoc Sci Med. 2025 May 13.
    Psychological Processes Related to Persistent Physical Symptoms in Patients With a Suspected Rare Disease: a Cross-sectional Interview Study.
    Julius Kowalski, Bernd Löwe, Christoph Schramm, Fabian Braun, Franziska Rillig, Natalie Uhlenbusch.
       OBJECTIVE: This cross-sectional interview study aimed to investigate subjective experiences and illness models of patients presenting at a rare disease center. Additionally, we strove to identify psychological factors that may be associated with patients' heterogeneous and often unspecific persistent physical symptoms (PPS).
    METHODS: We conducted semi-structured interviews with 27 adult patients (56% female; mean age: M(SD)=44(15.3) years) with a suspected rare disease presenting at the Martin Zeitz Center for Rare Diseases in Hamburg, Germany. Numeric rating scales and open-ended questions assessed disease burden, experiences with the healthcare system, and subjective thoughts and feelings related to PPS, along with psyche-soma interactions and the subjective illness theory. Data were analyzed with qualitative content analysis.
    RESULTS: All patients reported negative experiences with the healthcare system, including strained doctor-patient relationships (82%), for instance through stigmatization, and dissatisfaction with care (85%). Patients described several aspects that negatively influenced their PPS, including significant life events before symptom onset (41%), mental stress (44%) and the intense mental focus on symptoms (22%). Participants also described factors improving their PPS, such as psychotherapy (26%) and an optimistic attitude (26%). Some patients had an illness model that integrated psychosocial aspects (19%) while others had a biomedical explanation (26%).
    CONCLUSION: Patients with a suspected rare disease describe a variety of challenging experiences with their somatic symptoms and the diagnostic process. Our results support the assumption that psychological aspects may contribute to the heterogeneous and often unspecific somatic symptoms that patients at rare disease centers present with.
    Keywords:  ; = Martin Zeitz Center for Rare Diseases; = Numer of participants; NRS = Numeric rating scale; PPS = Persistent physical symptoms; STROBE = Strengthening the reporting of observational studies in epidemiology; UKE = University Medical Center Hamburg-Eppendorf.; persistent physical symptoms (PPS); persistent somatic symptoms (PSS); psychological aspects; psychosomatic; rare disease center (RDC); subjective illness theory
    DOI:  https://doi.org/10.1097/PSY.0000000000001403
  11. Sci Rep. 2025 May 14. 15(1): 16678
    Investigating the dual role of mitochondrial and nuclear genome variants in pediatric cardiomyopathies.
    M Arda Temena, Ebru Erzurumluoglu Gokalp, Ezgi Susam, Duygu Cinar, Hikmet Kiztanir, Pelin Kosger, Beyhan Durak Aras, Sevilhan Artan, Oguz Cilingir.
      Mitochondrial defects can lead to cardiomyopathies, which can be particularly severe in children. However, many cases of pediatric cardiomyopathy have no known etiology. To address this, we sought to explore if mitochondrial genome defects might be a contributor, as this could offer insights into disease mechanisms and guide targeted interventions. We first sequenced cardiomyopathy-related genes in twenty-seven pediatric patients diagnosed with primary non-syndromic cardiomyopathy and performed whole mtDNA sequencing in both patients and thirty-one healthy controls. The initial sequencing identified pathogenic variants in seven patients but subsequent mtDNA sequencing revealed additional insights. Specifically, a variant in FOXRED1, encoding FAD-dependent oxidoreductase domain-containing protein-1 which functions in mitochondrial complex I stability, and another variant in cytochrome c oxidase-I, MT-CO1, crucial for aerobic metabolism, were identified in two siblings with hypertrophic cardiomyopathy. In another case with hypertrophic cardiomyopathy, a variant in cytochrome b, MT-CYB, is likely a key factor in the abnormal contraction of cardiac muscle contraction. Furthermore, a novel 12 S rRNA variant was found in a patient with left ventricular non-compaction, and this offers a promising explanation for the pathogenesis, given the gene's high expression in the left ventricle. Taken together, mtDNA variants act synergistically with others, potentially disrupting myocardial bioenergetics.
    DOI:  https://doi.org/10.1038/s41598-025-01007-0
  12. Tuberculosis (Edinb). 2025 May 08. pii: S1472-9792(25)00045-9. [Epub ahead of print]153 102650
    Uncharted territory: the role of mitochondrial DNA variation in macrophage-mediated host susceptibility to tuberculosis.
    Dayna Croock, Yolandi Swart, Tomasz Janusz Sanko, Vuyo Mavumengwana, Marlo Möller, Caitlin Uren, Desiree C Petersen.
      Mitochondria form an integral, yet frequently underappreciated, part of the immune response to Mycobacterium tuberculosis (M.tb), particularly within macrophages. Despite growing recognition for their role in infection and immunity, studies investigating how mitochondrial DNA (mtDNA) variation influences host susceptibility to tuberculosis (TB) are limited. Notably, there are no studies in African-based populations, although Africans possess unparalleled human genetic diversity, including the earliest diverged mitochondrial haplogroups, and a high TB burden. This underrepresentation limits the discovery of novel ancestry-specific genetic loci associated with TB. In this review article, we describe the unique characteristics of mtDNA, highlight key mitochondrial functions relevant to macrophage responses during M.tb infection, and summarise published studies that investigate the role of host mtDNA variation in TB susceptibility. We further advocate for the inclusion of African populations in future studies to identify novel TB susceptibility genetic risk loci and expand the current knowledgebase on host TB susceptibility.
    Keywords:  Mitochondria; Mitochondrial DNA (mtDNA) variation; Mycobacterium tuberculosis (M.tb); Tuberculosis (TB) susceptibility
    DOI:  https://doi.org/10.1016/j.tube.2025.102650
  13. Ther Innov Regul Sci. 2025 May 13.
    Considerations and Approaches to Establishing Estimates of Meaningful Change for Digital Endpoints as Drug Development Tools.
    Marie Mc Carthy, Joseph C Cappelleri, Bill Byrom, Helen Doll, Junrui Di, Charmaine Demanuele, Joan Buenconsejo, Cheryl D Coon.
       OBJECTIVES: This paper seeks to identify some of the complexities associated with determining meaningful change for endpoints derived from digital health technologies (DHTs) and propose possible methodologies for this process. Ultimately, this is a call to action to consider appropriate methods and practices required to enable digital endpoints (DEs) to achieve their full potential as Drug Development Tools.
    METHODS: Using the Food and Drug Administration (FDA) Patient-Focused Drug Development (PFDD) guidance documents as a framework, we explore the nuances and challenges that exist when determining meaningful change for DEs compared with traditional clinical outcome assessments (COAs).
    RESULTS: There are unique characteristics associated with DEs that provide distinct challenges when determining meaningful change. This complexity spans the totality of meaningful change considerations, from ensuring that the DE itself is meaningful from the patient perspective to selecting appropriate anchors that enable determination of the magnitude of change that is meaningful for patients.
    CONCLUSIONS: With increased adoption of DHTs in clinical trials, their specific use is evolving, as evidenced by their being referred to as DHT-passive monitoring COAs in the FDA drug development tool (DDT) qualification program. However, the determination of meaningful change for these DEs can be more nuanced and challenging than for traditional COAs. Merely adapting existing approaches for traditional COAs does not readily support DEs derived from continuous datasets collected over long periods. New methods and approaches are required, and this can only be realised by working together, to ensure that the value and limitations of various methodologies as they relate to DEs can be refined.
    Keywords:  Clinical out assessments; Digital endpoint; Digital health technologies; Meaningful within patient change
    DOI:  https://doi.org/10.1007/s43441-025-00794-y
  14. Front Genet. 2025 ;16 1583391
    Frontier progress and translational challenges of pluripotent differentiation of stem cells.
    Zhengbing Su, Hui Dong, Xiang Fang, Wenli Zhang, Hong Duan.
      Stem cell research has significantly transformed regenerative medicine, with pluripotent stem cells (PSCs) serving as the cornerstone for disease modeling, drug screening, and therapeutic applications. Embryonic stem cells (ESCs) exhibit unparalleled self-renewal and tri-lineage differentiation, while induced pluripotent stem cells (iPSCs) bypass ethical constraints through somatic cell reprogramming. Clinical trials highlight the potential of mesenchymal stem cells (MSCs) in osteoarthritis and graft-versus-host disease, which leverage their immunomodulatory and paracrine effects. Despite advancements, challenges persist: iPSCs face epigenetic instability and tumorigenic risks, and adult stem cells struggle with inefficient differentiation. This paper systematically reviews stem cell source classification, differentiation regulatory mechanisms, cutting-edge technologies such as CRISPR/Cas9, and explores field-specific controversies (e.g., epigenetic stability of iPSCs) and future directions (e.g., integration of organoids and biomaterials). By analyzing current progress and challenges, it provides a multidimensional perspective for stem cell research.
    Keywords:  disease modeling; pluripotent stem cells; regenerative medicine; stem cell differentiation; stem cell therapy
    DOI:  https://doi.org/10.3389/fgene.2025.1583391
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