bims-curels Biomed News
on Leigh syndrome
Issue of 2024–01–28
fourteen papers selected by
Cure Mito Foundation
  1. [Migraine and mitochondrial diseases : Energy deficit in the brain].
  2. Conceptualizing and redefining successful patient engagement in patient advisory councils in learning health networks.
  3. Developing a community-led rare disease ELSI research agenda.
  4. Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.
  5. Patient engagement works: Patient and researcher experiences of patient partnership in primary healthcare research.
  6. A case of exacerbated encephalopathy with stroke-like episodes and lactic acidosis triggered by metformin in a patient with MELAS.
  7. Demonstrating the complexity of patient-partnered research in primary care: a snapshot of patient-partners.
  8. Establishing patient-partner priorities within the primary and integrated health care innovations network in Canada.
  9. Cross-border rare disease advocacy: Preethi Krishnaraj interviews Harsha Rajasimha.
  10. Challenges and opportunities to bridge translational to clinical research for personalized mitochondrial medicine.
  11. Applications of near-infrared spectroscopy in epilepsy, with a focus on mitochondrial disorders.
  12. The Research Progress of Mitochondrial Transplantation in the Treatment of Mitochondrial Defective Diseases.
  13. Mitochondrial genomes revisited: why do different lineages retain different genes?
  14. Friend turned foe: selfish behavior of a spontaneously arising mitochondrial deletion in an experimentally evolved C. elegans population.
  1. Nervenarzt. 2024 Jan 26.
    [Migraine and mitochondrial diseases : Energy deficit in the brain].
    Lucia Hämmerl, Torsten Kraya.
      Mitochondrial diseases are complex metabolic disorders caused by genetic mutations and lead to impaired energy production in the mitochondria of cells. The clinical spectrum ranges from severe multiorgan involvement in early childhood to mild monosymptomatic courses in adulthood. The brain, heart, and skeletal muscles are particularly affected due to their high energy demands. Headaches in general and migraine in particular, occur disproportionately more frequently in patients with mitochondrial diseases. In recent years similarities in the pathomechanism of mitochondrial diseases and migraine have been investigated in numerous biochemical, genetic, and therapeutic studies. The results suggest a dysfunctional energy metabolism with demonstrable mitochondrial damage as a central aspect in the pathogenesis of migraine. These findings are valuable for a better understanding of primary headache disorders and mitochondrial diseases as well as for the optimization of diagnostic and treatment procedures and should be applied in the clinical practice.
    Keywords:  Biomarkers; Energy metabolism; Headache; MELAS syndrome; Mitochondria
    DOI:  https://doi.org/10.1007/s00115-024-01622-8
  2. Learn Health Syst. 2024 Jan;8(1): e10377
    Conceptualizing and redefining successful patient engagement in patient advisory councils in learning health networks.
    ImproveCareNow Pediatric IBD Learning Health System
       Introduction: Patient engagement has historically referenced engagement in one's healthcare, with more recent definitions expanding patient engagement to encompass patient advocacy work in Learning Health Networks (LHNs). Efforts to conceptualize and define what patient engagement means-and what successful patient engagement means-are, however, lacking and a barrier to meaningful and sustainable patient engagement via patient advisory councils (PACs) across LHNs.
    Methods: Several co-authors (Madeleine Huwe, Becky Woolf, Jennie David) are former ImproveCareNow (ICN) PAC members, and we integrate a narrative review of the extant literature and a case study of our lived experiences as former ICN PAC members. We present nuanced themes of successful patient engagement from our lived experiences on ICN's PAC, with illustrative quotes from other PAC members, and then propose themes and metrics to consider in patient engagement across LHNs.
    Results: Successful patient engagement in our experiences with ICN's PAC reaches beyond the "levels of engagement" previously described in the literature. We posit that our successful patient/PAC engagement experiences with ICN represent key mechanisms that could be applied across LHNs, including (1) personal growth for PAC members, (2) PAC internal engagement/community, (3) PAC engagement and presence within the LHN, (4) local institutional engagement for those who participate in the LHN, and (5) tangible resources/products from PAC members.
    Conclusion: Patient engagement in LHNs, like ICN, holds significant power to meaningfully shape and co-produce healthcare systems, and engagement is undervalued and conceptualized dichotomously (eg, engaged or not engaged). Reconceptualizing successful patient/PAC engagement is critical in ongoing efforts to study, support, and understand mechanisms of sustainable and successful patient engagement. Having a modern, multidimensional definition for successful patient engagement in LHNs can support efforts to increase underrepresented voices in PACs, measure and track successful multidimensional patient engagement, and study how successful patient engagement may impact outcomes for patients and LHNs.
    Keywords:  learning health networks; patient advisory council; patient engagement
    DOI:  https://doi.org/10.1002/lrh2.10377
  3. Orphanet J Rare Dis. 2024 Jan 22. 19(1): 23
    Developing a community-led rare disease ELSI research agenda.
    Rare Voices Advisory Group
       BACKGROUND: Research priorities are best defined through engagement with communities who will be impacted by the research and have lived experience of the topics to be studied. We aimed to establish a pediatric rare disease community stakeholder group and empower them in (1) eliciting perspectives from affected families in the wider region and (2) synthesizing collective ideas into a research agenda focused on shared ethical, legal, and social implications (ELSI) across rare disease.
    METHODS: This two-year project utilized a community-centered approach to engage rare disease community members as equal partners in developing a research agenda for ELSI in rare disease. We established "Rare Voices" (RV), a 22-member stakeholder group of patients, parents, clinicians and researchers. Following capacity-building trainings, RV designed and conducted listening sessions with teen patients and parents of children with rare diseases to explore challenges, positive experiences, and ethical concerns. Listening session findings were synthesized and contextualized into research topics, which RV members further refined and prioritized. We used established measures to assess RV member engagement and satisfaction.
    RESULTS: From 14 listening sessions with parents (n = 52) and teen patients (n = 13), RV identified eight core research topics as most important for future rare disease research: coordinating care, communication, accessing resources and care, impact on family unit, community and support in society, mental health and identity, ethical aspects of care, and uncertainty. RV members were highly engaged throughout the two-year project and reported high levels of satisfaction with the experience and research agenda.
    CONCLUSIONS: Through capacity-building and authentic engagement, this project resulted in a community-led rare disease research agenda to guide future rare disease ELSI research that aligns with patients' and families' priorities. An environment of equal partnership and respect created a space for mutual learning where community members were empowered to shape the research agenda based on their collective experiences. The agenda recognizes the shared psychosocial and healthcare experiences of rare disease and offers practical areas of research to address patient and family needs.
    Keywords:  Community engagement; ELSI; Rare disease; Research agenda
    DOI:  https://doi.org/10.1186/s13023-023-02986-x
  4. Neurotherapeutics. 2024 Jan 19. pii: S1878-7479(24)00002-3. [Epub ahead of print]21(1): e00316
    Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.
    Daniel G Calame, Lisa T Emrick.
      Mitochondria are critical for brain development and homeostasis. Therefore, pathogenic variation in the mitochondrial or nuclear genome which disrupts mitochondrial function frequently results in developmental disorders and neurodegeneration at the organismal level. Large-scale application of genome-wide technologies to individuals with mitochondrial diseases has dramatically accelerated identification of mitochondrial disease-gene associations in humans. Multi-omic and high-throughput studies involving transcriptomics, proteomics, metabolomics, and saturation genome editing are providing deeper insights into the functional consequence of mitochondrial genomic variation. Integration of deep phenotypic and genomic data through allelic series continues to uncover novel mitochondrial functions and permit mitochondrial gene function dissection on an unprecedented scale. Finally, mitochondrial disease-gene associations illuminate disease mechanisms and thereby direct therapeutic strategies involving small molecules and RNA-DNA therapeutics. This review summarizes progress in functional genomics and small molecule therapeutics in mitochondrial neurodevelopmental disorders.
    Keywords:  Functional genomics; Mitochondrial disease; Neurodevelopmental disorders; Small molecules; Therapeutics
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00316
  5. Ann Fam Med. 2022 Apr 01. 20(Suppl 1):
    Patient engagement works: Patient and researcher experiences of patient partnership in primary healthcare research.
    Dana Howse, Alannah Delahunty-Pike, Olivier Dumont-Samson, Mathieu Bisson, Mireille Lambert, Shelley Doucet, Maud-Christine Chouinard, Catherine Hudon, Cathy Scott, Fred Burge, Linda Wilhelm, Michael Warren, Judy Porter, Charlotte Schwarz, Donna Rubenstein, Andre Gaudreau.
      Context: Health researchers are increasingly engaging patients and their families as partners in the research process, from inception to knowledge translation. The trend toward 'patient-oriented' research is encouraged by a growing view that studies which integrate the patient perspective will make better use of resources to produce more relevant evidence that can be more easily translated to clinical settings. While there is an emerging literature on best practices, challenges, and learnings related to patient engagement (PE), few studies consider the experiences of patient partners (PP) and researchers in the same project. This presentation will present PP and researcher experiences of PE, highlighting important similarities and differences and proposing recommendations. Objectives: To characterize PE experience from the perspective of researchers and PP working together on the same research program, PriCARE; to identify successes and challenges; to ascertain contributions of PE in health research. Study Design: Qualitative. Setting or Dataset: This study was conducted within the larger 5-province PriCARE study examining a nurse-led case management intervention for primary care patients with complex needs. Population studied: 22 members of the study team (7 PP, 8 coordinators, 2 co-investigators, 5 principal investigators). Methods: Data collection: In-depth interviews using guides co-created by researchers and PP covering topics such as PE-related training and knowledge, and reflections on PE processes and impact. Research assistants external to the PriCARE study conducted interviews, transcribed researcher interviews, and generated a summary of PP interviews. Analysis: Data were analyzed thematically using a coding framework that was co-developed with PP. Outcome Measures: Researcher and patient experiences of PE, PP contributions to health research. Results: All team members need PE training at the beginning of and throughout the research process. Evolving trust and flexibility helped team members to navigate different experiences and priorities. PP make integral contributions to study and instrument design, data analysis, and knowledge translation. Clear expectations about the degree and nature of PE and team members' roles are critical. Conclusions: Meaningful PE requires patient-researcher partnership and clear expectation setting at the outset and throughout the research process, and ongoing flexibility to adapt.
    DOI:  https://doi.org/10.1370/afm.20.s1.2908
  6. Neurol Sci. 2024 Jan 24.
    A case of exacerbated encephalopathy with stroke-like episodes and lactic acidosis triggered by metformin in a patient with MELAS.
    Hui Jin Shin, Ji-Hoon Na, Young-Mock Lee.
      Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited multisystemic disorder caused by mutations in mitochondrial DNA that result in cellular energy deficiency. MELAS affects the most metabolically active organs, including the brain, skeletal muscles, cochlea, retina, heart, kidneys, and pancreas. As a result, about 85% of carriers of m.3243A > G, the most common mutation in MELAS, develop diabetes by the age of 70. Although metformin is the most widely prescribed drug for diabetes, its usefulness in mitochondrial dysfunction remains controversial. Here, we present the case of a 32-year-old Korean patient diagnosed with MELAS who presented with exacerbated stroke-like episodes and lactic acidosis triggered by metformin.
    Keywords:  DNA, Mitochondrial; MELAS syndrome; Metformin; Point mutation; Seizures
    DOI:  https://doi.org/10.1007/s10072-024-07343-9
  7. Ann Fam Med. 2022 Apr 01. 20(Suppl 1):
    Demonstrating the complexity of patient-partnered research in primary care: a snapshot of patient-partners.
    Gilian Bartlett-Esquilante, Jamie DeMore, Roger Stoddard, Brenda Andreas, Ghislaine Rouly, Annick Beaudry, Alanna Baldwin, Mpho Begin, Karina Prevost, Lynne Mansell, Joan Cranston.
      Background: In Canada, we are still struggling to achieve the critical goal of enabling performant health care systems that moves research results to real-world impact particularly for primary care. To address this, we have created a primary care research network where patient partners are involved in all levels of decision making for governance, research, and innovation. For many researchers, however, it is unclear what primary care patient-partners 'brings to the table.' As the Pan-Canadian Patient Council of the Primary and Integrated Health Care Innovations Network, we wanted to provide insight into the richness of expertise and experience patient partners contribute. Objectives: To provide an example of the characteristics, history and lived experience that patient-partners in a primary care research network represent and demonstrate the resource this presents. Methods: As current council members, representing 10 provinces, we developed a survey of our demographics, personal history and experience in patient-oriented research using iterative, collaborative meetings. The answers to the questions provided "snapshots" for each of us. As a group, we worked with researchers to descriptively and thematically analyze the responses to provide insight and a description of primary care research patient partners. Results: With 2 men and 8 women, we represented an average of 42.5 years of experience with health conditions (range 10-84 years) including cancer, genetic conditions, and multiple chronic diseases. On average, we worked with 4.7 different organizations each (range 2-9) on research topics covering the spectrum of primary care. Many of us acted as mentors for researchers and trainees. All of us were innovators and influencers with demonstrated leadership skills. A need for more diversity in terms of age and underrepresented minorities was noted. Conclusion: Diversity of life experience, extensive exposure to the health care system and strong engagement with multiple organizations for primary care research characterized us as patient-partners. This lived expertise represents a significant asset for researchers. This work should encourage researchers to starting thinking about how to include primary care patient-partners as a crucial resource in health research.
    DOI:  https://doi.org/10.1370/afm.20.s1.2753
  8. Ann Fam Med. 2022 Apr 01. 20(Suppl 1):
    Establishing patient-partner priorities within the primary and integrated health care innovations network in Canada.
    Jamie DeMore, Roger Stoddard, Gilian Bartlett-Esquilant, Brenda Andreas, Kent Cadogan Loftsgard, Mpho Begin, Annick Beaudry, Karina Prevost, Ghislaine Rouly, Alanna Baldwin, Joan Cranston.
      Background: Many experienced primary care researchers have seen the benefits of meaningful engagement with patients and community members in their research, elevating them to a research partner status. The research questions and agendas, however, are often initiated and determined by the researchers. Increasingly, research teams, organizations and networks actively engage with patient-partners to better understand what their research priorities would look like, bringing patient-partners into the research process much earlier. Among many other initiatives within the Strategy for Patient Oriented Research program, a Primary and Integrated Health Care Innovations Network (PIHCIN) was established in Canada, which includes 11 geographically distributed research networks. As part of PIHCIN, a Pan-Canadian Patient Council (the Council) was established with representatives from each provincial site. To ensure their voices were being heard, the Council decided to establish their own research priorities for consideration by the PIHCI network. Objective: To establish patient-partner priorities in the Canadian primary health care context Methods: The main goal of the Council was to submit research priorities to identify what was important from a patient-partner perspective. Through consensus building and prioritization voting, the Council developed and presented a draft of their research priorities to the PIHCI Network Leadership Council. In a second step, the Council decided that the process was missing from the document. Subsequently, with the use of the SMART goal framework, the Council engaged in a process to establish how research priorities could be accomplished. Results: The initial research priorities comprised 11 items, including priorities concerning patient's access to data, integrated health teams, patient initiated collaborative research, virtual care, broader definition of health, etc. The initial priorities eventually evolved into a set of principles, strategic operating goals, and finalized research priorities. Conclusion: Through an iterative process, the Council was able to lead, initiate and differentiate strategic operating goals from the research priorities. This process and results can provide insight for developing critical input from patient-partners for primary health care research.
    DOI:  https://doi.org/10.1370/afm.20.s1.2765
  9. Dis Model Mech. 2024 Jun 01. pii: dmm050672. [Epub ahead of print]17(6):
    Cross-border rare disease advocacy: Preethi Krishnaraj interviews Harsha Rajasimha.
    Preethi Krishnaraj, Harsha K Rajasimha.
      
    DOI:  https://doi.org/10.1242/dmm.050672
  10. Neurotherapeutics. 2024 Jan 19. pii: S1878-7479(23)02027-5. [Epub ahead of print]21(1): e00311
    Challenges and opportunities to bridge translational to clinical research for personalized mitochondrial medicine.
    Andrea L Gropman, Martine N Uittenbogaard, Anne E Chiaramello.
      Mitochondrial disorders are a group of rare and heterogeneous genetic diseases characterized by dysfunctional mitochondria leading to deficient adenosine triphosphate synthesis and chronic energy deficit in patients. The majority of these patients exhibit a wide range of phenotypic manifestations targeting several organ systems, making their clinical diagnosis and management challenging. Bridging translational to clinical research is crucial for improving the early diagnosis and prognosis of these intractable mitochondrial disorders and for discovering novel therapeutic drug candidates and modalities. This review provides the current state of clinical testing in mitochondrial disorders, discusses the challenges and opportunities for converting basic discoveries into clinical settings, explores the most suited patient-centric approaches to harness the extraordinary heterogeneity among patients affected by the same primary mitochondrial disorder, and describes the current outlook of clinical trials.
    Keywords:  Clinical trial; Energy metabolism; Mitochondrial medicine; Next generation therapeutics; Patient-centric approach
    DOI:  https://doi.org/10.1016/j.neurot.2023.e00311
  11. Neurotherapeutics. 2024 Jan 19. pii: S1878-7479(24)00009-6. [Epub ahead of print]21(1): e00323
    Applications of near-infrared spectroscopy in epilepsy, with a focus on mitochondrial disorders.
    Kosar Khaksari, Wei-Liang Chen, Mongkol Chanvanichtrakool, Alexa Taylor, Rohan Kotla, Andrea L Gropman.
      Mitochondrial diseases are inherited disorders that impede the mitochondria's ability to produce sufficient energy for the cells. They can affect different parts of the body, notably the brain. Neurological symptoms and epilepsy are prevalent in patients with mitochondrial disorders. The epileptogenicity of mitochondrial disorder is a complex process involving the intricate interplay between abnormal energy metabolism and neuronal activity. Several modalities have been used to detect seizures in different disorders including mitochondrial disorders. EEG serve as the gold standard for diagnosis and localization, commonly complemented by additional imaging modalities to enhance source localization. In the current work, we propose the use of functional near-infrared spectroscopy (fNIRS) to identify the occurrence of epilepsy and seizure in patients with mitochondrial disorders. fNIRS proves an advantageous imaging technique due to its portability and insensitivity to motion especially for imaging infants and children. It has added a valuable factor to our understanding of energy metabolism and neuronal activity. Its real-time monitoring with high spatial resolution supplements traditional diagnostic tools such as EEG and provides a comprehensive understanding of seizure and epileptogenesis. The utility of fNIRS extends to its ability to detect changes in Cytochrome c oxidase (CcO) which is a crucial enzyme in cellular respiration. This facet enhances our insight into the metabolic dimension of epilepsy related to mitochondrial dysfunction. By providing valuable insights into both energy metabolism and neuronal activity, fNIRS emerges as a promising imaging technique for unveiling the complexities of mitochondrial disorders and their neurological manifestations.
    Keywords:  Brain biomarkers; Epilepsy; Mitochondrial disease; Near-infrared spectroscopy; Neuromonitoring; Seizure
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00323
  12. Int J Mol Sci. 2024 Jan 18. pii: 1175. [Epub ahead of print]25(2):
    The Research Progress of Mitochondrial Transplantation in the Treatment of Mitochondrial Defective Diseases.
    Cuilan Hu, Zheng Shi, Xiongxiong Liu, Chao Sun.
      Mitochondria are double-membrane organelles that are involved in energy production, apoptosis, and signaling in eukaryotic cells. Several studies conducted over the past decades have correlated mitochondrial dysfunction with various diseases, including cerebral ischemia, myocardial ischemia-reperfusion, and cancer. Mitochondrial transplantation entails importing intact mitochondria from healthy tissues into diseased tissues with damaged mitochondria to rescue the injured cells. In this review, the different mitochondrial transplantation techniques and their clinical applications have been discussed. In addition, the challenges and future directions pertaining to mitochondrial transplantation and its potential in the treatment of diseases with defective mitochondria have been summarized.
    Keywords:  cancer; cerebral ischemia; mitochondrial defective diseases; mitochondrial transplantation; myocardial ischemia-reperfusion
    DOI:  https://doi.org/10.3390/ijms25021175
  13. BMC Biol. 2024 Jan 25. 22(1): 15
    Mitochondrial genomes revisited: why do different lineages retain different genes?
    Anzhelika Butenko, Julius Lukeš, Dave Speijer, Jeremy G Wideman.
      The mitochondria contain their own genome derived from an alphaproteobacterial endosymbiont. From thousands of protein-coding genes originally encoded by their ancestor, only between 1 and about 70 are encoded on extant mitochondrial genomes (mitogenomes). Thanks to a dramatically increasing number of sequenced and annotated mitogenomes a coherent picture of why some genes were lost, or relocated to the nucleus, is emerging. In this review, we describe the characteristics of mitochondria-to-nucleus gene transfer and the resulting varied content of mitogenomes across eukaryotes. We introduce a 'burst-upon-drift' model to best explain nuclear-mitochondrial population genetics with flares of transfer due to genetic drift.
    Keywords:  CoRR hypothesis; Endosymbiont gene transfer; Evolutionary cell biology; Mitochondrial DNA; Mitochondrial evolution; Mitochondrial mutation rates
    DOI:  https://doi.org/10.1186/s12915-024-01824-1
  14. G3 (Bethesda). 2024 Jan 23. pii: jkae018. [Epub ahead of print]
    Friend turned foe: selfish behavior of a spontaneously arising mitochondrial deletion in an experimentally evolved C. elegans population.
    Abigail N Sequeira, Ian P O'Keefe, Vaishali Katju, Ulfar Bergthorsson.
      Selfish mitochondrial DNA (mtDNA) mutations are variants that can proliferate within cells and enjoy a replication or transmission bias without fitness benefits for the host. MtDNA deletions in Caenorhabditis elegans can reach high heteroplasmic frequencies despite significantly reducing fitness, illustrating how new mtDNA variants can give rise to genetic conflict between different levels of selection, and between the nuclear and mitochondrial genomes. During a mutation accumulation (MA) experiment in C. elegans, a 1,034 bp deletion originated spontaneously and reached an 81.7% frequency within an experimental evolution line. This heteroplasmic mtDNA deletion, designated as meuDf1, eliminated portions of two protein-coding genes (coxIII and nd4) and tRNA-thr in entirety. MtDNA copy-number in meuDf1 heteroplasmic individuals was 35% higher than in individuals with wildtype mitochondria. After backcrossing into a common genetic background, the meuDf1 mitotype was associated with reduction in several fitness traits and independent competition experiments found a 40% reduction in composite fitness. Experiments that relaxed individual selection by single individual bottlenecks demonstrated that the deletion-bearing mtDNA possessed a strong transmission bias, thereby qualifying it as a novel selfish mitotype.
    Keywords:   C. elegans ; fitness; genetic conflict; heteroplasmy; mtDNA; mutation; selfish mitochondria
    DOI:  https://doi.org/10.1093/g3journal/jkae018
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