bims-curels Biomed News
on Leigh syndrome
Issue of 2023‒12‒03
thirteen papers selected by
Cure Mito Foundation

  1. Zhonghua Er Ke Za Zhi. 2023 Dec 02. 61(12): 1077-1085
    Subspecialty Group of Neurology, the Society of Pediatrics, Chinese Medical Association
  2. Res Involv Engagem. 2023 Nov 28. 9(1): 106
    Pan-Canadian group of patient and public advisors
      BACKGROUND: The re-conceptualization of patients' and caregivers' roles in research from study participants to co-researchers ("patient partners") has led to growing pains within and outside the research community, such as how to effectively engage patients in research and as part of interdisciplinary teams. To support the growth of more successful research partnerships by developing a shared understanding of how patient partners conceptualize and contribute to their role, this study aimed to explore patient partners' motivations for engagement and understanding of their role.METHODS: We conducted semi-structured interviews with participants (n = 13) of an online survey of activities and impacts of patient engagement in Strategy for Patient-Oriented Research projects. Eligibility criteria included being a patient partner that indicated interest in interview participation upon survey completion, the ability to read/write in English and provide informed consent. Data were analyzed thematically using an inductive, codebook thematic analysis.
    RESULTS: Illuminating the lived/living patient and caregiver experience was central to how most patient partners conceptualized the role in terms of its definition, purpose, value, and responsibilities. Participants also identified four additional categories of motivations for becoming a patient partner and contributions that patient partners make to research that build upon and are in addition to sharing their lived/living experiences. Lastly, participants highlighted important connotations of the term patient partner, including temporal and context-specific considerations for the term "patient" and what "partner" may imply about the nature of the research relationship.
    CONCLUSIONS: At the onset of partnership, academic researchers and patient partners must create the space necessary to discuss and understand each other's underlying motivations for partnering and their perspectives on the purpose, value, and responsibilities of the patient partner role. These early conversations should help unearth what research partners hope to get out of and feel that they are able to contribute to engaging, and in such contribute to the development of reciprocal relationships that work towards shared and valued goals. Trial registration Not applicable.
    Keywords:  Patient and public involvement; Patient engagement; Patient engagement in research; Patient-oriented research; Qualitative interviews; Stakeholder engagement
  3. J Lasers Med Sci. 2023 ;14 e41
      Introduction: Despite a wide variety of clinical presentations in hereditary Mitochondrial Diseases, muscle fatigue is a common theme and impairs a patient's quality of life and ability to function. Current treatments are only supportive and include nutritional supplementation and physical therapy. Photobiomodulation therapy (PBMT) using low-intensity, narrow spectrum light in the red/near infrared (NIR) range, from a low-level laser or light-emitting diode sources, enhances mitochondrial function in preclinical and clinical studies on a range of conditions. However, little research has been done on the effectiveness of photobiomodulation in hereditary mitochondrial disorders. Methods: We performed a scoping review of the evidence of the beneficial effects of photobiomodulation for treating the muscle-related symptoms of hereditary mitochondrial disease. Results: No studies regarding photobiomodulation in hereditary mitochondrial disease were identified. However, in other clinical conditions featuring acquired mitochondrial impairment, we identified studies that suggested improved function, although sample sizes were small in number and statistical power. Conclusion: There is emerging evidence of efficacy for PBMT for diseases involving acquired mitochondrial insufficiency. We identified no published research on PBMT in hereditary mitochondrial disease, but this review confirms a theoretical rationale for a positive effect and suggests further research.
    Keywords:  Cytochrome oxidase; Fatigue; Mitochondrial disease; Muscle; Near-infrared; Photobiomodulation
  4. Nat Metab. 2023 Nov 30.
      Nuclease-mediated editing of heteroplasmic mitochondrial DNA (mtDNA) seeks to preferentially cleave and eliminate mutant mtDNA, leaving wild-type genomes to repopulate the cell and shift mtDNA heteroplasmy. Various technologies are available, but many suffer from limitations based on size and/or specificity. The use of ARCUS nucleases, derived from naturally occurring I-CreI, avoids these pitfalls due to their small size, single-component protein structure and high specificity resulting from a robust protein-engineering process. Here we describe the development of a mitochondrial-targeted ARCUS (mitoARCUS) nuclease designed to target one of the most common pathogenic mtDNA mutations, m.3243A>G. mitoARCUS robustly eliminated mutant mtDNA without cutting wild-type mtDNA, allowing for shifts in heteroplasmy and concomitant improvements in mitochondrial protein steady-state levels and respiration. In vivo efficacy was demonstrated using a m.3243A>G xenograft mouse model with mitoARCUS delivered systemically by adeno-associated virus. Together, these data support the development of mitoARCUS as an in vivo gene-editing therapeutic for m.3243A>G-associated diseases.
  5. Hum Genomics. 2023 Nov 27. 17(1): 108
      Recent advances in next-generation sequencing (NGS) technology have greatly accelerated the need for efficient annotation to accurately interpret clinically relevant genetic variants in human diseases. Therefore, it is crucial to develop appropriate analytical tools to improve the interpretation of disease variants. Given the unique genetic characteristics of mitochondria, including haplogroup, heteroplasmy, and maternal inheritance, we developed a suite of variant analysis toolkits specifically designed for primary mitochondrial diseases: the Mitochondrial Missense Variant Annotation Tool (MmisAT) and the Mitochondrial Missense Variant Pathogenicity Predictor (MmisP). MmisAT can handle protein-coding variants from both nuclear DNA and mtDNA and generate 349 annotation types across six categories. It processes 4.78 million variant data in 76 min, making it a valuable resource for clinical and research applications. Additionally, MmisP provides pathogenicity scores to predict the pathogenicity of genetic variations in mitochondrial disease. It has been validated using cross-validation and external datasets and demonstrated higher overall discriminant accuracy with a receiver operating characteristic (ROC) curve area under the curve (AUC) of 0.94, outperforming existing pathogenicity predictors. In conclusion, the MmisAT is an efficient tool that greatly facilitates the process of variant annotation, expanding the scope of variant annotation information. Furthermore, the development of MmisP provides valuable insights into the creation of disease-specific, phenotype-specific, and even gene-specific predictors of pathogenicity, further advancing our understanding of specific fields.
    Keywords:  Genetics; Machine learning; Pathogenicity predictor; Primary mitochondrial disease; Variant
  6. Rev Neurol (Paris). 2023 Nov 30. pii: S0035-3787(23)01115-3. [Epub ahead of print]
      The large number of technological developments suggests that patients with epilepsy can be better supported in the management of their seizures, especially when their condition is drug resistant. Patients and their caregivers, who are generally supportive of seizure detection and monitoring technologies, can provide relevant information to improve their effectiveness. We propose a comprehensive co-design approach to support more efficient development of seizure detection and monitoring technologies. Such an approach should follow the steps of the research and development process, take into account the temporal requirements characteristic of seizure management, focus on the themes of autonomy and self-management, and be guided by disease experts. If co-design practices are to continue to contribute to their development, they must also meet the scientific requirements of validity and reproducibility.
    Keywords:  Epilepsy; Patient input; Patient involvement; Technology
  7. Neuromuscul Disord. 2023 Nov 04. pii: S0960-8966(23)00774-5. [Epub ahead of print]
      A 16-year-old boy was evaluated for a history of exercise-induced fatigability associated with nausea even after minimal effort, lower limbs muscle hypotrophy, and swelling of the masseter muscles after chewing. Laboratory tests were remarkable for hyperlactatemia and metabolic acidosis after short physical activity. The muscle biopsy showed non-specific mitochondrial alterations and an increase in intrafibral lipids. Biochemical analysis showed reduced activity of the respiratory chain complexes. Mitochondrial DNA sequencing revealed the presence of a homoplasmic variant m.15992A>T in the MT-TP gene, coding for the mt-tRNAPro in the patient, in his mother and in his brother. Pathogenic or likely pathogenic variants in MT-TP gene are rare. They are responsible for different clinical presentation, almost ever involving the muscle tissue. We report the first family with exercise-induced muscle weakness and swelling of the chewing muscles due to m.15992A>T variant in absence of J1c10 haplogroup, confirming its pathogenicity.
    Keywords:  MT-TP; Masseter muscle swelling; Mitochondrial myopathy; Mitochondrial tRNA
  8. Medicine (Baltimore). 2023 Nov 24. 102(47): e36008
      RATIONALE: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a subset of rare mitochondrial diseases characterized by diverse clinical manifestations, which often complicates its diagnosis.PATIENT CONCERNS: This report chronicles the experiences of a 14-year-old female patient who underwent multiple misdiagnoses before the eventual identification of MELAS syndrome. Her journey began with symptoms that included growth retardation, hypertrophic cardiomyopathy, and epilepsy.
    DIAGNOSIS: The definitive diagnosis of MELAS syndrome was established through genetic confirmation, revealing a mutation in the MT-TL1 gene (m.3242A > G).
    INTERVENTIONS: Upon diagnosis, the patient received targeted symptomatic treatment, which led to pronounced improvements in her symptoms.
    OUTCOMES: The patient's condition stabilized with the administered treatments, and she exhibited significant symptom relief, emphasizing the importance of accurate diagnosis and timely intervention.
    LESSONS: This case underscores the imperative for heightened clinical vigilance and thorough differential diagnosis in the face of complex clinical presentations, such as those seen in MELAS syndrome, to ensure timely and appropriate interventions.
  9. Cell Mol Biol Lett. 2023 Nov 30. 28(1): 98
      Alzheimer's disease (AD) is a chronic illness marked by increasing cognitive decline and nervous system deterioration. At this time, there is no known medication that will stop the course of Alzheimer's disease; instead, most symptoms are treated. Clinical trial failure rates for new drugs remain high, highlighting the urgent need for improved AD modeling for improving understanding of the underlying pathophysiology of disease and improving drug development. The development of induced pluripotent stem cells (iPSCs) has made it possible to model neurological diseases like AD, giving access to an infinite number of patient-derived cells capable of differentiating neuronal fates. This advance will accelerate Alzheimer's disease research and provide an opportunity to create more accurate patient-specific models of Alzheimer's disease to support pathophysiological research, drug development, and the potential application of stem cell-based therapeutics. This review article provides a complete summary of research done to date on the potential use of iPSCs from AD patients for disease modeling, drug discovery, and cell-based therapeutics. Current technological developments in AD research including 3D modeling, genome editing, gene therapy for AD, and research on familial (FAD) and sporadic (SAD) forms of the disease are discussed. Finally, we outline the issues that need to be elucidated and future directions for iPSC modeling in AD.
    Keywords:  Alzheimer’s diseases; Cell-based therapies; Disease modeling; Drug development; Induced pluripotent stem cells; Mechanism of diseases; Regenerative medicine; iPSCs
  10. Arch Dis Child. 2023 Nov 23. pii: archdischild-2023-326318. [Epub ahead of print]
    Keywords:  Genetics; Infant Welfare; Paediatrics; Syndrome
  11. Methods Mol Biol. 2024 ;2739 239-247
      Maternally inherited symbiotic bacteria that interfere with the reproduction of their hosts can contribute to selective sweeps of mitochondrial haplotypes through hitch-hiking or coordinate inheritance of cytoplasmic bacteria and host mitochondria. The sweep will be manifested by genetic variations of mitochondrial genomic DNA of symbiont-infected hosts relative to their uninfected counterparts. In particular, at the population level, infected specimens will show a reduced mitochondrial DNA polymorphism compared to that in the nuclear DNA. This may challenge the use of mitochondrial DNA sequences as neutral genetic markers, as the mitochondrial patterns will reflect the evolutionary history of parasitism, rather than the sole evolutionary history of the host. Here, I describe a detailed step-by-step procedure to infer the occurrence and timing of symbiont-induced mitochondrial sweeps in host species.
    Keywords:  Cytoplasmic DNA; Hereditary symbiosis; Maternal transmission; Population genetics
  12. Health Expect. 2023 Nov 29.
      INTRODUCTION: Advancements in evaluating the impact of participatory health research (PHR) have been made through comprehensive models like the community-based participatory research (CBPR) conceptual model, which provides a useful framework for exploring how context and partnership processes can influence health research design and interventions. However, challenges in operationalising aspects of the model limit our understanding and evaluation of the PHR process. Trust is frequently identified as an important component of the CBPR model, which supports the development of key partnership outcomes, such as partnership synergy. However, trust continues to be limited to a binary view (as present or absent), which is problematic given its inherently dynamic and temporal nature.STUDY AIM: The aim of this qualitative study is to understand the evolution of trust in the national public and patient involvement (PPI) network in Ireland.
    SETTING AND PARTICIPANTS: Participants from the PPI network (n = 15/21) completed a semistructured interview discussing the evolution of trust by reviewing four social network maps derived from a previous longitudinal study.
    ANALYSIS: Following Braun and Clarke, we used reflexive thematic analysis, to iteratively develop, analyse and interpret our mediated reflection of the data.
    RESULTS: Participants described the evolution of trust as a function of three contextual factors: (1) the set-up and organisation of the network, (2) how people work together and (3) reflection on the process and outcomes. Their descriptions across these themes seemed to vary depending on partnership type with National Partners and Site Leads having more opportunities to demonstrate trust (e.g., via leadership roles or more resources), compared to Local. Thus, visibility and the opportunity to be visible, depending on the set-up and organisation of the network and how people work together, seemingly play an important role in the evolution of trust over time. Based on these findings, we provide important questions for reflection across themes that could be considered for future PHR partnerships.
    DISCUSSION: Given that the opportunity and visibility to build and maintain trust over time may not be equally available to all partners, it is important to find ways to invest in and commit to equitable relationships as the key to the success (i.e., longevity) of partnerships. We reflect on/offer important implications for those engaging in PHR partnerships and those who fund such research.
    PATIENT OR PUBLIC CONTRIBUTION: A Research Advisory Group comprising four research partners (representing academic, service and community organisations) from the PPI Ignite Network provided input and approval for the research objectives of this study as well as previously published work informing this study. Informal consultation occurred with members of this group to discuss findings from this study, assisting with the way findings are presented and described, to be accessible for diverse audiences. Two Research Advisory Group members were involved in the interpretation of the results, and one is a co-author of this manuscript (Zoe Hughes).
    Keywords:  community-based participatory research; participatory health research; qualitative; social networks; trust