bims-curels Biomed News
on Leigh syndrome
Issue of 2023‒08‒13
fourteen papers selected by
Cure Mito Foundation

  1. Handb Clin Neurol. 2023 ;pii: B978-0-323-98818-6.00025-X. [Epub ahead of print]195 563-585
      Mitochondrial dysfunction, especially perturbation of oxidative phosphorylation and adenosine triphosphate (ATP) generation, disrupts cellular homeostasis and is a surprisingly frequent cause of central and peripheral nervous system pathology. Mitochondrial disease is an umbrella term that encompasses a host of clinical syndromes and features caused by in excess of 300 different genetic defects affecting the mitochondrial and nuclear genomes. Patients with mitochondrial disease can present at any age, ranging from neonatal onset to late adult life, with variable organ involvement and neurological manifestations including neurodevelopmental delay, seizures, stroke-like episodes, movement disorders, optic neuropathy, myopathy, and neuropathy. Until relatively recently, analysis of skeletal muscle biopsy was the focus of diagnostic algorithms, but step-changes in the scope and availability of next-generation sequencing technology and multiomics analysis have revolutionized mitochondrial disease diagnosis. Currently, there is no specific therapy for most types of mitochondrial disease, although clinical trials research in the field is gathering momentum. In that context, active management of epilepsy, stroke-like episodes, dystonia, brainstem dysfunction, and Parkinsonism are all the more important in improving patient quality of life and reducing mortality.
    Keywords:  Ataxia; CPEO; Leigh syndrome; MELAS; Mitochondrial DNA; Movement disorders; Myopathy; Neuropathy
  2. Pract Neurol. 2023 Aug 11. pii: pn-2023-003862. [Epub ahead of print]
      A previously healthy 27-year-old man was admitted to the acute neurology ward with events involving his face, throat and upper limb, which video telemetry later confirmed were refractory focal seizures. He also had progressive pyramidal features, dysarthria and ataxia. MR scans of the brain identified progressive bilateral basal ganglia abnormalities, consistent with Leigh syndrome. However, extensive laboratory and genetic panels did not give a unifying diagnosis. A skeletal muscle biopsy showed no histopathological abnormalities on routine stains. Sequencing of the entire mitochondrial genome in skeletal muscle identified a well-characterised pathogenic variant (m.10191T>C in MT-ND3; NC_012920.1) at 85% heteroplasmy in skeletal muscle. We discuss the clinical and molecular diagnosis of an adult presenting with Leigh syndrome, which is more commonly a paediatric presentation of mitochondrial disease, and how early recognition of a mitochondrial cause is important to support patient care.
  3. Surgery. 2023 Aug 08. pii: S0039-6060(23)00432-4. [Epub ahead of print]
      Who better to serve as "Dr. Google" than an actual doctor? Patients often present with a list of symptoms and turn to their favorite search engine to understand their constellation of symptoms. In this editorial, we attempt to address the following key elements in surgeons' use of social media (#SoMe4Surgery) as a tool for patient engagement: marketing, demystifying and differentiating the surgical specialty, a fast track to the latest specialty-specific guidelines and recommendations, and combatting medical misinformation. The increased social media presence in the medical space can be used to improve health literacy and simplify the navigational process of one's healthcare journey. These platforms can humanize physicians, make them more accessible, and bridge the gap that sometimes exists, preventing patients from moving to their next step in care due to fear. The extent of social media use in healthcare far surpasses this brief discussion, and it is up to the individual user to exercise the appropriate uses and responsibilities regarding patient communication.
  4. Brain Pathol. 2023 Aug 08. e13192
      Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high-dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(-/-) mouse model of LS. While the dose-response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony-stimulating Factor 1 receptor (CSF1R) macrophage super-enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1rΔFIRE allele ablates microglia in both control and Ndufs4(-/-) animals, but onset of CNS lesions and sequalae in the Ndufs4(-/-), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the Ndufs4(-/-) model.
    Keywords:  CNS lesions; Leigh syndrome; microglia; mitochondrial disease; pediatric disease; subacute necrotizing encephalomyelopathy
  5. Genet Med. 2023 Aug 04. pii: S1098-3600(23)00961-9. [Epub ahead of print] 100948
      PURPOSE: Exome and genome sequencing have rapidly transitioned from research methods to widely used clinical tests for diagnosing rare genetic diseases. We sought to synthesize the topics covered and appraise the development processes of clinical guidance documents generated by genetics professional organizations.METHODS: We conducted a scoping review of guidance documents published since 2010, systematically identified in peer-reviewed and grey literature, using established methods and reporting guidelines. We coded verbatim recommendations by topic using content analysis and critically appraised documents using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool.
    RESULTS: We identified 30 guidance documents produced by eight organizations (2012-2022), yielding 611 recommendations covering 21 topics. The most common topic related to findings beyond the primary testing indication. Mean AGREE II scores were low across all six quality domains; scores for items related to rigour of development were among the lowest. More recently published documents generally received higher scores.
    CONCLUSION: Guidance documents included a broad range of recommendations, but were of low quality, particularly in their rigour of development. Developers should consider using tools such as AGREE II and basing recommendations on living knowledge syntheses to improve guidance development in this evolving space.
    Keywords:  AGREE II; Clinical guidance documents; Exome sequencing; Genome sequencing; Rare disease; Scoping review
  6. Orphanet J Rare Dis. 2023 08 09. 18(1): 236
      BACKGROUND: Rare diseases have become a major public health concern worldwide. However, detailed epidemiological data are lacking. With the development of the Internet, search queries have played an important role in disease surveillance. In this study, we explored a new method for the epidemiological research on rare diseases, using large-scale online search queries and reported case data. We distilled search logs related to rare diseases nationwide from 2016 to 2019. The case data were obtained from China's national database of rare diseases during the same period.RESULTS: A total of 120 rare diseases were included in this study. From 2016 to 2019, the number of patients with rare diseases estimated using search data and those obtained from the case database showed an increasing trend. Rare diseases can be ranked by the number of search estimated patients and reported patients, and the rankings of each disease in both search and reported case data were generally stable. Furthermore, the disease rankings in the search data were relatively consistent with the reported case data in each year, with more than 50% of rare diseases having a ranking difference of -20 to 20 between the two systems. In addition, the relationship between the disease rankings in the two systems was generally stable over time. Based on the relationship between the disease rankings in the search and reported case data, rare diseases can be classified into two categories.
    CONCLUSION: Online search queries may provide an important new resource for detecting rare diseases. Rare diseases can be classified into two categories to guide different epidemiological research strategies.
    Keywords:  Epidemiological research; Rare disease; Reported case data; Search query
  7. Orphanet J Rare Dis. 2023 Aug 10. 18(1): 240
      BACKGROUND: Genetic testing can facilitate the diagnosis and subsequent therapeutic management of rare diseases. However, there is a lack of data on the use of genetic testing for rare diseases. This study aims to describe the utilization rate and troubles encountered by clinicians in treating rare diseases with genetic testing.METHODS: A cross-sectional electronic questionnaire survey was conducted between June and October 2022 among the medical staff from the hospitals covering all provinces, municipalities, and autonomous regions of China. The survey on genetic testing focused on whether genetic testing was used in the diagnosis and treatment of rare diseases, the specific methods of genetic testing, and the problems encountered when using genetic testing.
    RESULTS: A total of 20,132 physicians who had treated rare diseases were included, of whom 35.5% were from the central region, 36.7% were from the eastern region, and 27.8% were from the western region. The total utilization rate of genetic testing for rare diseases was 76.0% (95%CI: 75.4-76.6). The use of genetic testing was highest in the Eastern region (79.2% [95% CI: 78.3-80.1]), followed by the Central (75.9% [95% CI: 74.9-76.9]) and Western regions (71.9% [95% CI: 70.7-73.1]). More than 90% (94.1% [95%CI: 93.4-94.8]) of pediatricians had used genetic testing to treat rare diseases, with surgeons having the lowest use of genetic testing (58.3% [95% CI: 56.6-60.0]). Physicians' departments and education levels affect the use of genetic testing. Most physicians have used a variety of genetic tests in the management of rare diseases, the most popular methods were "Whole-exome sequencing (Proband)" and "Whole-exome sequencing (families of three or more)". Doctors have encountered many problems with the use of genetic testing in the diagnosis and treatment of rare diseases, among which the high price was the main concern of medical workers.
    CONCLUSION: Three-quarters of physicians used genetic testing in rare disease practice, and there were regional differences in the use of genetic testing. Recognition of the utilization of genetic testing can help identify patterns of resource utilization in different regions and provide a more comprehensive picture of the epidemiology of rare diseases in jurisdictions.
    Keywords:  Accessibility; Genetic testing; Rare diseases; Utilization
  8. Orphanet J Rare Dis. 2023 Aug 11. 18(1): 242
      BACKGROUND: A rare disease (RD) diagnosis and therapy can affect the family's quality of life and mental health. A lack of information and missing care options lead to helplessness and psychological stress within families. This work aims to identify patients' and parents' experiences in daily life and with the health care system as well as their needs and current pathways to psychosocial care to develop implementation strategies adapted to the families' needs.METHODS: The present analysis is part of the national multicenter study "Children Affected by Rare Disease and Their Families-Network (CARE-FAM-NET)." We conducted semi-structured telephone interviews with children, adolescents, and young adults with RD (aged 12 to 21 years) and parents of children with RD (aged 0 to 17 years). We analyzed the transcribed and anonymized interviews using the method of focused interview analyses to identify previous experiences with medical and psychosocial care and possible needs for improvement and support.
    RESULTS: Seventy-four parents of children with RD and 15 children, adolescents, and young adults with RD participated. Five main themes emerged. Daily life with an RD: RD affects the everyday and social life of the respondents, negatively impacting mental well-being. Experiences with the health care system: The long diagnostic path is stressful for families. Professionals' lack of information/education leads to inadequate care for those affected. Psychosocial support: Families do not know about psychosocial care services. In some cases, the families take advantage of psychosocial support services (such as support groups or advocacy groups), which are predominantly very helpful. Difficulties and barriers: Time, socio-legal and organizational problems burden families and lead to advantages in using psychosocial services. Improvements for patient-oriented support: Those affected wished for timely, preventive support (especially in administrative and socio-legal matters) and education regarding psychosocial care services.
    CONCLUSION: RD represent a great challenge for all family members - patients, parents, and siblings. The patients' and parents' previous experiences in daily life, medical and psychosocial care show a need for target-group specific support, including training of health care professionals and low-threshold access care services and practical help for all family members.
    Keywords:  Parents; Pathway to care; Pediatric patients; Psychosocial care; Qualitative study; Rare chronic health conditions; Rare diseases
  9. BMC Health Serv Res. 2023 Aug 10. 23(1): 846
      BACKGROUND: Patient engagement is seen as a necessary component in achieving the triple aim of improved population health, improved experience of care, and lower per capita health care costs. While there has been a substantial increase in the number of tools and patient-centered initiatives designed to help patients participate in health decisions, there remains a limited understanding of engagement from the perspective of patients and a lack of measures designed to capture the multi-faceted nature of the concept.METHODS: Development of a concept map of patient engagement followed a five-step modified Group Concept Mapping (GCM) methodology of preparation, generation, structuring, analysis and interpretation. We engaged a Project Advisory Committee at each step, along with three rounds of survey collection from clinicians and patients for element generation (272 clinicians, 61 patients), statement sorting (30 clinicians, 15 patients), and ranking and rating of statements (159 clinicians, 67 patients). The survey of three separate samples, as opposed to focus groups of 'experts,' was an intentional decision to gain a broad perspective about the concept of patient engagement. We conducted the structure and analysis steps within the groupwisdom concept mapping software.
    RESULTS: The final concept map comprised 47 elements organized into 5 clusters: Relationship with Provider, Patient Attitudes and Behaviors, Access, Internal Resources and External Resources. There was considerable agreement in the way elements in each cluster were rated by patients and clinicians. An analysis of the importance of the constitutive elements of patient engagement relative to their addressability highlighted actionable items in the domain of Relationship with Provider, aimed at building trust and enabling patients to ask questions. At the same time, the analysis also identified elements traditionally considered barriers to engagement, like personal access to the internet and the patient's level of digital literacy, as difficult to address by the healthcare system, but also relatively less important for patients.
    CONCLUSIONS: Through our GCM approach, incorporating perspectives of both patients and clinicians, we identified items that can be used to assess patient engagement efforts by healthcare systems. As a result, our study offers specific insight into areas that can be targeted for intervention by healthcare systems to improve patient engagement.
    Keywords:  Group concept mapping.; Patient engagement; Patient-centered care
  10. Health Expect. 2023 Aug 10.
      BACKGROUND: Most health systems are insufficiently prepared to promote the participation of chronically ill patients in their care. Strong primary health care (PHC) strengthens patients' resources and thus promotes their participation. The tasks of providing continuous care to people with chronic diseases and promoting self-management are the responsibility of PHC nurses. Recent research assessing enablers of or barriers to nurses' efforts to support patients' participation has mostly not considered the special situation of patients with chronic diseases or focused on the PHC setting.OBJECTIVE: To investigate enablers of and barriers to PHC nurses' efforts to promote the participation of chronically ill patients in their care.
    METHODS: We interviewed 34 practicing PHC nurses and 23 key informants with advanced knowledge of PHC nursing practice in Brazil, Germany and Spain. The data was analyzed using thematic coding.
    RESULTS: We identified four categories of barriers and enablers. (1) Establishing bonds with patients: Interviewees emphasized that understanding patients' views and behaviours is important for PHC nurses. (2) Cooperation with relatives and families: Good relationships with families are fundamental, however conflicts within families could challenge PHC nurses efforts to strengthen participation. (3) Communication and cooperation within PHC teams: PHC nurses see Cooperative team structures as a potential enabler, while the dominance of a 'biomedical' approach to patient care is seen as a barrier. (4) Work environment: Interviewees agreed that increased workload is a barrier to patient participation.
    DISCUSSION AND CONCLUSIONS: Supporting patient participation should be acknowledged as an important responsibility for nurses by general practitioners and PHC planners. PHC nurses should be trained in communicative competence when discussing participation with chronically ill patients. Interprofessional education could strengthen other professionals' understanding of patient participation as a nursing task.
    PATIENT OR PUBLIC CONTRIBUTION: This study is part of a research project associated with the research network 'forges: User-oriented care: Promotion of health in the context of chronic diseases and care dependency'. The study's focus and provisional results were discussed continuously with partners in health and social care practice and presented to and discussed with the public at two conferences in which patient representatives, professionals and researchers participated.
    Keywords:  chronic disease; family caregiver; patient education as topic; patient participation; person-centred care; primary health care; qualitative research
  11. J Am Acad Orthop Surg. 2023 Aug 09.
      Patient-reported outcome (PRO) measures offer a unique opportunity to systematically incorporate patient perspectives of their health and wellbeing into treatment, view progress over time, and develop opportunities related to clinical decision support, shared decision making, and outcomes-driven payment and practice transformation. As healthcare institutions increasingly look toward adopting PRO measures in their practices, more information is needed regarding the practicalities of implementing a successful PRO program outside of the research setting. This article offers a stepwise approach to implementing a PRO program while overcoming barriers and leveraging facilitators that commonly exist in the realms of human contribution or team building, technological infrastructure, and process design. To routinely adopt and implement these instruments, we need a multifaceted approach to operationalizing patient-reported outcome measure (PROMs) for high-value outcomes-driven, patient-centered musculoskeletal care.
  12. Cancer Discov. 2023 Aug 11. OF1
      The FDA is ramping up Project FrontRunner, which urges drugmakers to seek accelerated approval of experimental drugs as first-line treatments for patients with advanced or metastatic disease, rather than focusing on patients who have tried multiple therapies and/or exhausted available options. Experts say the program has the potential to expand access while improving the risk-benefit assessment of new drugs by initiating randomized controlled trials earlier in the drug development process.