bims-curels Biomed News
on Leigh syndrome
Issue of 2024–06–16
eleven papers selected by
Cure Mito Foundation
  1. Evidence for sodium valproate toxicity in mitochondrial diseases: a systematic analysis.
  2. Nanobiopsy investigation of the subcellular mtDNA heteroplasmy in human tissues.
  3. What guidance exists to support patient partner compensation practices? A scoping review of available policies and guidelines.
  4. Clinical drivers of hospitalisation in patients with mitochondrial diseases.
  5. Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease.
  6. Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism.
  7. Hematologic Manifestations in Primary Mitochondrial Diseases.
  8. Epigenetic reprogramming of mtDNA and its etiology in mitochondrial diseases.
  9. Exploring genetic counselors' practice of discussing clinical trials with patients.
  10. Exploring potential drivers of patient engagement with their health data through digital platforms: A scoping review.
  11. The rate and nature of mitochondrial DNA mutations in human pedigrees.
  1. BMJ Neurol Open. 2024 ;6(1): e000650
    Evidence for sodium valproate toxicity in mitochondrial diseases: a systematic analysis.
    Thiloka E Ratnaike, Nour Elkhateeb, Angela Lochmüller, Christopher Gilmartin, Katherine Schon, Rita Horváth, Patrick F Chinnery.
       Background: We aimed to determine whether sodium valproate (VPA) should be contraindicated in all mitochondrial diseases, due to known VPA-induced severe hepatotoxicity in some mitochondrial diseases.
    Methods: We systematically reviewed the published literature for mitochondrial DNA (mtDNA) and common nuclear genotypes of mitochondrial diseases using PubMed, Ovid Embase, Ovid Medline and MitoPhen databases. We extracted patient-level data from peer-reviewed articles, published until July 2022, using the Human Phenotype Ontology to manually code clinical presentations for 156 patients with genetic diagnoses from 90 publications.
    Results: There were no fatal adverse drug reactions (ADRs) in the mtDNA disease group (35 patients), and only 1 out of 54 patients with a non-POLG mitochondrial disease developed acute liver failure. There were fatal outcomes in 53/102 (52%) POLG VPA-exposed patients who all harboured recessive mutations.
    Conclusions: Our findings confirm the high risk of severe ADRs in any patient with recessive POLG variants irrespective of the phenotype, and therefore recommend that VPA is contraindicated in this group. However, there was limited evidence of toxicity to support a similar recommendation in other genotypes of mitochondrial diseases.
    Keywords:  EPILEPSY; GENETICS; MITOCHONDRIAL DISORDERS; NEUROGENETICS; NEUROPHARMACOLOGY
    DOI:  https://doi.org/10.1136/bmjno-2024-000650
  2. Sci Rep. 2024 Jun 14. 14(1): 13789
    Nanobiopsy investigation of the subcellular mtDNA heteroplasmy in human tissues.
    Alexander Bury, Angela Pyle, Amy E Vincent, Paolo Actis, Gavin Hudson.
      Mitochondrial function is critical to continued cellular vitality and is an important contributor to a growing number of human diseases. Mitochondrial dysfunction is typically heterogeneous, mediated through the clonal expansion of mitochondrial DNA (mtDNA) variants in a subset of cells in a given tissue. To date, our understanding of the dynamics of clonal expansion of mtDNA variants has been technically limited to the single cell-level. Here, we report the use of nanobiopsy for subcellular sampling from human tissues, combined with next-generation sequencing to assess subcellular mtDNA mutation load in human tissue from mitochondrial disease patients. The ability to map mitochondrial mutation loads within individual cells of diseased tissue samples will further our understanding of mitochondrial genetic diseases.
    DOI:  https://doi.org/10.1038/s41598-024-64455-0
  3. Health Expect. 2024 Feb;27(1): e13970
    What guidance exists to support patient partner compensation practices? A scoping review of available policies and guidelines.
    Grace Fox, Dean A Fergusson, Ahmed Sadeknury, Stuart G Nicholls, Maureen Smith, Dawn Stacey, Manoj M Lalu.
       BACKGROUND: An integral aspect of patient engagement in research, also known as patient and public involvement, is appropriately recognising patient partners for their contributions through compensation (e.g., coauthorship, honoraria). Despite known benefits to compensating patient partners, our previous work suggested compensation is rarely reported and researchers perceive a lack of guidance on this issue. To address this gap, we identified and summarised available guidance and policy documents for patient partner compensation.
    METHODS: We conducted this scoping review in accordance with methods suggested by the JBI. We searched the grey literature (Google, Google Scholar) in March 2022 and Overton (an international database of policy documents) in April 2022. We included articles, guidance or policy documents regarding the compensation of patient partners for their research contributions. Two reviewers independently extracted and synthesised document characteristics and recommendations.
    RESULTS: We identified 65 guidance or policy documents. Most documents were published in Canada (57%, n = 37) or the United Kingdom (26%, n = 17). The most common recommended methods of nonfinancial compensation were offering training opportunities to patient partners (40%, n = 26) and facilitating patient partner attendance at conferences (38%, n = 25). The majority of guidance documents (95%) suggested financially compensating (i.e., offering something of monetary value) patient partners for their research contributions. Across guidance documents, the recommended monetary value of financial compensation was relatively consistent and associated with the role played by patient partners and/or specific engagement activities. For instance, the median monetary value for obtaining patient partner feedback (i.e., consultation) was $19/h (USD) (range of $12-$50/h). We identified several documents that guide the compensation of specific populations, including youth and Indigenous peoples.
    CONCLUSION: Multiple publicly available resources exist to guide researchers, patient partners and institutions in developing tailored patient partner compensation strategies. Our findings challenge the perception that a lack of guidance hinders patient partner financial compensation. Future efforts should prioritise the effective implementation of these compensation strategies to ensure that patient partners are appropriately recognised.
    PATIENT OR PUBLIC CONTRIBUTIONS: The patient partner coauthor informed protocol development, identified data items, and interpreted findings.
    Keywords:  compensation; financial compensation; guidance; patient engagement; patient partner
    DOI:  https://doi.org/10.1111/hex.13970
  4. BMJ Neurol Open. 2024 ;6(1): e000717
    Clinical drivers of hospitalisation in patients with mitochondrial diseases.
    Sameen Haque, Karen Crawley, Ryan Davis, Deborah Schofield, Rupendra Shrestha, Carolyn M Sue.
       Background: Mitochondrial diseases in adults are generally chronic conditions with a wide spectrum of severity contributing to disease burden and healthcare resource utilisation. Data on healthcare resource utilisation in mitochondrial diseases are limited.
    Objectives: We performed a retrospective longitudinal study to investigate the clinical drivers of hospitalisation in adult patients with mitochondrial diseases to better understand healthcare resource utilisation.
    Methods: We recruited participants from our specialised Mitochondrial Disease Clinic in Sydney, Australia between September 2018 and December 2021. We performed a retrospective chart review for the period 2013-2022 considering emergency department (ED) and/or hospital admission notes, as well as discharge summaries. We used multiple linear regression models to examine the association between the type of presenting symptom(s) and duration of hospital stay and frequency of admissions, while adjusting for relevant covariates.
    Results: Of the 99 patients considered, the duration of hospitalisation ranged from 0 to 116 days per participant and the number of admissions ranged from 0 to 21 per participant. Participants with one or more mitochondrial disease-associated admissions constituted 52% of the study cohort. 13% of the participants presented to the ED without requiring an admission and 35% never attended the ED or required a hospital admission during this period. Neurological (p<0.0001), gastroenterological (p=0.01) and symptoms categorised as 'other' (p<0.0001) were the main presentations driving the total number of days admitted to hospital. A statistically significant association was evident for the number of admissions and all types of presenting symptoms (p<0.0001).
    Conclusion: There are variable reasons for hospitalisation in adults with mitochondrial diseases, with neurological and gastroenterological presentations being associated with prolonged and complex hospitalisation. A better understanding of clinical drivers such as these allows for better informed and well-coordinated management aimed at optimising healthcare resource utilisation.
    Keywords:  HEALTH ECONOMICS; MITOCHONDRIAL DISORDERS; NEUROEPIDEMIOLOGY; NEUROGENETICS; NEUROMUSCULAR
    DOI:  https://doi.org/10.1136/bmjno-2024-000717
  5. Cell Death Dis. 2024 Jun 10. 15(6): 405
    Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease.
    Patricia Morcillo, Khushbu Kabra, Kevin Velasco, Hector Cordero, Sarah Jennings, Taekyung D Yun, Delfina Larrea, H Orhan Akman, Eric A Schon.
      Genetic mutations causing primary mitochondrial disease (i.e those compromising oxidative phosphorylation [OxPhos]) resulting in reduced bioenergetic output display great variability in their clinical features, but the reason for this is unknown. We hypothesized that disruption of the communication between endoplasmic reticulum (ER) and mitochondria at mitochondria-associated ER membranes (MAM) might play a role in this variability. To test this, we assayed MAM function and ER-mitochondrial communication in OxPhos-deficient cells, including cybrids from patients with selected pathogenic mtDNA mutations. Our results show that each of the various mutations studied indeed altered MAM functions, but notably, each disorder presented with a different MAM "signature". We also found that mitochondrial membrane potential is a key driver of ER-mitochondrial connectivity. Moreover, our findings demonstrate that disruption in ER-mitochondrial communication has consequences for cell survivability that go well beyond that of reduced ATP output. The findings of a "MAM-OxPhos" axis, the role of mitochondrial membrane potential in controlling this process, and the contribution of MAM dysfunction to cell death, reveal a new relationship between mitochondria and the rest of the cell, as well as providing new insights into the diagnosis and treatment of these devastating disorders.
    DOI:  https://doi.org/10.1038/s41419-024-06781-9
  6. J Clin Invest. 2024 Jun 13. pii: e170994. [Epub ahead of print]
    Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism.
    Eiki Kanemaru, Kakeru Shimoda, Eizo Marutani, Masanobu Morita, Maria Miranda, Yusuke Miyazaki, Claire Sinow, Rohit Sharma, Fangcong Dong, Donald B Bloch, Takaaki Akaike, Fumito Ichinose.
      Leigh syndrome is the most common inherited mitochondrial disease in children and is often fatal within the first few years of life. In 2020, mutations in the gene encoding sulfide:quinone oxidoreductase (SQOR), a mitochondrial protein, were identified as a cause of Leigh syndrome. Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome. SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogens sulfide (H2S) levels. Because H2S is produced by both gut microbiota and host tissue, we tested whether metronidazole (a broad-spectrum antibiotic) or a sulfur-restricted diet rescues SqorΔN/ΔN mice from developing Leigh syndrome. Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice. Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome. Taken together, these observations suggest that mitochondrial SQOR is essential to prevent systemic accumulation of H2S. Administration of metronidazole or a sulfur-restricted diet may be therapeutic approaches to treatment of patients with Leigh syndrome caused by mutations in SQOR.
    Keywords:  Metabolism; Mitochondria; Mouse models; Neurological disorders; Therapeutics
    DOI:  https://doi.org/10.1172/JCI170994
  7. J Pediatr Hematol Oncol. 2024 Jun 10.
    Hematologic Manifestations in Primary Mitochondrial Diseases.
    Arthavan Selvanathan, Juliana Teo, Bindu Parayil Sankaran.
      Primary mitochondrial disorders (PMDs) are known for their pleiotropic manifestations in humans, affecting almost any organ or system at any time. Hematologic manifestations, such as cytopenias and sideroblastic anemia, occur in 10% to 30% of patients with confirmed PMDs. These can be the initial presenting features or complications that develop over time. Surveillance for these manifestations allows for prompt identification and treatment. This article provides an overview of the pathophysiology underpinning the hematologic effects of mitochondrial dysfunction, discussing the 3 key roles of the mitochondria in hematopoiesis: providing energy for cell differentiation and function, synthesizing heme, and generating iron-sulfur clusters. Subsequently, the diagnosis and management of mitochondrial disorders are discussed, focusing on hematologic manifestations and the specific conditions commonly associated with them. Through this, we aimed to provide a concise point of reference for those considering a mitochondrial cause for a patient's hematologic abnormality, or for those considering a hematologic manifestation in a patient with known or suspected mitochondrial disease.
    DOI:  https://doi.org/10.1097/MPH.0000000000002890
  8. J Physiol Biochem. 2024 Jun 12.
    Epigenetic reprogramming of mtDNA and its etiology in mitochondrial diseases.
    Anil Kumar, Anita Choudhary, Anjana Munshi.
      Mitochondrial functionality and its regulation are tightly controlled through a balanced crosstalk between the nuclear and mitochondrial DNA interactions. Epigenetic signatures like methylation, hydroxymethylation and miRNAs have been reported in mitochondria. In addition, epigenetic signatures encoded by nuclear DNA are also imported to mitochondria and regulate the gene expression dynamics of the mitochondrial genome. Alteration in the interplay of these epigenetic modifications results in the pathogenesis of various disorders like neurodegenerative, cardiovascular, metabolic disorders, cancer, aging and senescence. These modifications result in higher ROS production, increased mitochondrial copy number and disruption in the replication process. In addition, various miRNAs are associated with regulating and expressing important mitochondrial gene families like COX, OXPHOS, ND and DNMT. Epigenetic changes are reversible and therefore therapeutic interventions like changing the target modifications can be utilized to repair or prevent mitochondrial insufficiency by reversing the changed gene expression. Identifying these mitochondrial-specific epigenetic signatures has the potential for early diagnosis and treatment responses for many diseases caused by mitochondrial dysfunction. In the present review, different mitoepigenetic modifications have been discussed in association with the development of various diseases by focusing on alteration in gene expression and dysregulation of specific signaling pathways. However, this area is still in its infancy and future research is warranted to draw better conclusions.
    Keywords:  Epigenetics; Hydroxymethylation; Methylation; miRNAs; mito-miRNAs; mt-DNA
    DOI:  https://doi.org/10.1007/s13105-024-01032-z
  9. J Genet Couns. 2024 Jun 09.
    Exploring genetic counselors' practice of discussing clinical trials with patients.
    Thea Bloom, Katherine E Bonini, Melissa Gutierrez-Kapheim, Lisa M Kinsley, Maureen E Smith, Debra Duquette.
      Despite concerted and accelerated efforts to increase the knowledge of medicine and disease via clinical studies, clinical trials continue to face low enrollment for all patient groups. The dissemination of the availability of clinical trials to individuals with or at risk for hereditary disorders is critical. This study acts as a foundation in determining an unexplored role of clinical trial discussion in genetic counseling practice. Board-certified, patient-facing genetic counselors in the United States were invited to participate in an anonymous survey via the National Society of Genetic Counselors. Between February and April 2022, 157 participants (N = 157) completed the survey on clinical trial discussion with patients, barriers, and facilitators to discussing clinical trials with patients, research experience, and demographics. Survey results identified that most respondents have discussed the availability of clinical trials with a patient (85%). Almost one-third have previous research experience working for a clinical trial (30%). Most agreed that discussions of clinical trials are within the scope of genetic counseling (82%); however, one-third were not comfortable discussing them with patients (34%). Respondents who know how to find specific clinical trials (p < 0.001) were reportedly more likely to be comfortable discussing clinical trials with their patients. In addition to clinical research exposure, this study suggests that further education and training is necessary for genetic counselors to learn how to find and identify specific clinical trials for their patients. In turn, we hope for this to increase genetic counselors' comfort of clinical trial discussion.
    Keywords:  attitudes; clinical trials; counseling techniques; genetic counseling; public health; referral practices
    DOI:  https://doi.org/10.1002/jgc4.1934
  10. Int J Med Inform. 2024 Jun 05. pii: S1386-5056(24)00176-X. [Epub ahead of print]189 105513
    Exploring potential drivers of patient engagement with their health data through digital platforms: A scoping review.
    Robin van Kessel, Sruthi Ranganathan, Michael Anderson, Brian McMillan, Elias Mossialos.
       BACKGROUND: Patient engagement when providing patient access to health data results from an interaction between the available tools and individual capabilities. The recent digital advancements of the healthcare field have altered the manifestation and importance of patient engagement. However, a comprehensive assessment of what factors contribute to patient engagement remain absent. In this review article, we synthesised the most frequently discussed factors that can foster patient engagement with their health data.
    METHODS: A scoping review was conducted in MEDLINE, Embase, and Google Scholar. Relevant data were synthesized within 7 layers using a thematic analysis: (1) social and demographic factors, (2) patient ability factors, (3) patient motivation factors, (4) factors related to healthcare professionals' attitudes and skills, (5) health system factors, (6) technological factors, and (7) policy factors.
    RESULTS: We identified 5801 academic and 200 Gy literature records, and included 292 (4.83%) in this review. Overall, 44 factors that can affect patient engagement with their health data were extracted. We extracted 6 social and demographic factors, 6 patient ability factors, 12 patient motivation factors, 7 factors related to healthcare professionals' attitudes and skills, 4 health system factors, 6 technological factors, and 3 policy factors.
    CONCLUSIONS: Improving patient engagement with their health data enables the development of patient-centered healthcare, though it can also exacerbate existing inequities. While expanding patient access to health data is an important step towards fostering shared decision-making in healthcare and subsequently empowering patients, it is important to ensure that these developments reach all sectors of the community.
    DOI:  https://doi.org/10.1016/j.ijmedinf.2024.105513
  11. Cell. 2024 Jun 03. pii: S0092-8674(24)00531-2. [Epub ahead of print]
    The rate and nature of mitochondrial DNA mutations in human pedigrees.
    Erla R Árnadóttir, Kristján H S Moore, Valdís B Guðmundsdóttir, S Sunna Ebenesersdóttir, Kamran Guity, Hákon Jónsson, Kári Stefánsson, Agnar Helgason.
      We examined the rate and nature of mitochondrial DNA (mtDNA) mutations in humans using sequence data from 64,806 contemporary Icelanders from 2,548 matrilines. Based on 116,663 mother-child transmissions, 8,199 mutations were detected, providing robust rate estimates by nucleotide type, functional impact, position, and different alleles at the same position. We thoroughly document the true extent of hypermutability in mtDNA, mainly affecting the control region but also some coding-region variants. The results reveal the impact of negative selection on viable deleterious mutations, including rapidly mutating disease-associated 3243A>G and 1555A>G and pre-natal selection that most likely occurs during the development of oocytes. Finally, we show that the fate of new mutations is determined by a drastic germline bottleneck, amounting to an average of 3 mtDNA units effectively transmitted from mother to child.
    Keywords:  germline bottleneck; germline selection; hypermutability; mitochondria; mitochondrial bottleneck; mtDNA; mutation rate; negative selection; pathogenic mutations; pedigrees
    DOI:  https://doi.org/10.1016/j.cell.2024.05.022
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