bims-curels Biomed News
on Leigh syndrome
Issue of 2023–08–06
thirteen papers selected by
Cure Mito Foundation
  1. How to START? Four pillars to optimally begin your orphan drug development.
  2. Working together in health research: a mixed-methods patient engagement evaluation.
  3. [Research advances in pharmacotherapy for rare diseases in children].
  4. The IRDiRC Chrysalis Task Force: making rare disease research attractive to companies.
  5. 258th ENMC international workshop Leigh syndrome spectrum: genetic causes, natural history and preparing for clinical trials 25-27 March 2022, Hoofddorp, Amsterdam, The Netherlands.
  6. Planning anesthesia of a child with a rare disease: useful tools.
  7. The Parliamentary Inquiry into Mitochondrial Donation Law Reform (Maeve's Law) Bill 2021 in Australia: A Qualitative Analysis.
  8. [Expert recommendations on homogenization management of the diagnosis and treatment of rare diseases in children].
  9. Neuropathological hallmarks in autopsied cases with mitochondrial diseases caused by the mitochondrial 3243A>G mutation.
  10. Reporting involvement activities with children and young people in paediatric research: a framework analysis.
  11. The use of digital outcome measures in clinical trials in rare neurological diseases: a systematic literature review.
  12. Assessment of whole-exome sequencing results in neurogenetic diseases.
  13. Bringing researchers to the consumer table: The process and outcomes of a consumer roundtable on telehealth.
  1. Orphanet J Rare Dis. 2023 Aug 03. 18(1): 229
    How to START? Four pillars to optimally begin your orphan drug development.
    IRDiRC ODDG TF and IRDiRC TSC
      Drug development is a complex, resource intensive and long process in any disease area, and developing medicines to treat rare diseases presents even more challenges due to the small patient populations, often limited disease knowledge, heterogeneous clinical manifestations, and disease progression. However, common to all drug development programs is the need to gather as much information as possible on both the disease and the patients' needs ahead of the development path definition. Here, we propose a checklist named START, a tool that provides an overview of the key pillars to be considered when starting an orphan drug development: STakeholder mapping, Available information on the disease, Resources, and Target patient value profile. This tool helps to build solid foundations of a successful patient-centered medicines development program and guides different types of developers through a set of questions to ask for guidance through the starting phase of a rare disease therapeutic pathway.
    Keywords:  Data gathering; Drug development; Orphan drugs; Patients’ needs; Rare diseases; Stakeholder analysis and engagement
    DOI:  https://doi.org/10.1186/s13023-023-02845-9
  2. Res Involv Engagem. 2023 Aug 01. 9(1): 62
    Working together in health research: a mixed-methods patient engagement evaluation.
    Stella Babatunde, Sadia Ahmed, Maria Jose Santana, Ingrid Nielssen, Sandra Zelinsky, Anshula Ambasta.
       BACKGROUND: In patient-oriented research (POR), patients contribute their valuable knowledge and lived-experiences to work together as active research partners at all stages of the health research cycle. However, research looking to understand how patient research partners (PRPs) and researchers work together in meaningful and collaborative ways remains limited. This study aims to evaluate patient engagement with the RePORT Patient Advisory Council (PAC) and to identify barriers and facilitators to meaningful patient engagement encountered within research partnerships involving patient research partners and researchers.
    METHODS: The RePORT PAC members included nine PRPs and nine researchers (clinician-researchers, research staff, patient engagement experts) from both Alberta and British Columbia. All members were contacted and invited to complete an anonymous online survey (Public and Patient Engagement Evaluation (PPEET) tool) at two different project times points. The PAC was invited for a semi-structured interview to gain in-depth understanding of their experiences working together. Interviews were audio-recorded, transcribed, and the data was thematically analyzed with the support of a qualitative analysis software, NVivo.
    RESULTS: A total of nine PRPs (100%) and three researchers (33%) participated in the baseline survey in February 2022 while six PRPs (67%) responded and three researchers (33%) completed the follow up survey in May 2022. For the semi-structured interviews, nine PRPs (100%) and six researchers (67%) participated. According to the survey results, PAC members agreed that the supports (e. g. training, compensation) needed to contribute to the project were available throughout the project. The survey responses also showed that most members of the PAC felt their opinions and views were heard. Responses to the survey regarding diversity within the PAC were mixed. There were many suggestions for improving diversity and collaboration provided by PAC members during the semi-structured interviews. PAC members mentioned that PAC PRPs informed the co-development of research materials such as recruitment posters and interview guides for the RePORT study.
    CONCLUSIONS: Through fostering a collaborative environment, we can engage a diverse group of people to work together meaningfully in health research. We have identified what works well, and areas for improvement within our research partnership involving PRPs and researchers as well as recommendations for POR projects more broadly, going forward.
    Keywords:  Patient advisory council; Patient engagement; Patient research partners; Patient-oriented research
    DOI:  https://doi.org/10.1186/s40900-023-00475-w
  3. Zhongguo Dang Dai Er Ke Za Zhi. 2023 Jul 15. pii: 1008-8830(2023)07-0759-08. [Epub ahead of print]25(7): 759-766
    [Research advances in pharmacotherapy for rare diseases in children].
    Jia-Qi Li, Hui-Jun Wang.
      There are more than 7 000 rare diseases and approximately 475 million individuals with rare diseases globally, with children accounting for two-thirds of this population. Due to a relatively small patient population and limited financial resources allocated for drug research and development in pharmaceutical enterprises, there are still no drugs approved for the treatment of several thousands of these rare diseases. At present, there are no drugs for 95% of the patients with rare diseases, and consequently, the therapeutic drugs for rare diseases have been designated as orphan drugs. In order to guide pharmaceutical enterprises to strengthen the research and development of orphan drugs, various nations have enacted the acts for rare disease drugs, promoted and simplified the patent application process for orphan drugs, and provided scientific recommendations and guidance for the research and development of orphan drugs. Since there is a relatively high incidence rate of rare diseases in children, this article reviews the latest research on pharmacotherapy for children with rare diseases.
    Keywords:  Child; Enzyme replacement therapy; Gene therapy; Orphan drug production; Rare disease; Small-molecule drug
    DOI:  https://doi.org/10.7499/j.issn.1008-8830.2302048
  4. Ther Adv Rare Dis. 2023 Jan-Dec;4:4 26330040231188979
    The IRDiRC Chrysalis Task Force: making rare disease research attractive to companies.
    Katherine L Beaverson, Daria Julkowska, Mary Catherine V Letinturier, Annemieke Aartsma-Rus, Jennifer Austin, Juan Bueren, Simon Frost, Misako Hamamura, Jane Larkindale, Greg LaRosa, Rita Magenheim, Annamaria Merico, Anna Maria Gerdina Pasmooij, Vinciane Pirard, Nicholas Ekow Thomford, Michihiko Wada, Durhane Wong-Rieger, Adam L Hartman.
       Background: The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to use research to facilitate rapid diagnosis and treatment of rare diseases.
    Objective: IRDiRC launched the Chrysalis Task Force to identify key financial and nonfinancial factors that make rare disease research and development attractive to companies.
    Methods: The Chrysalis Task Force was comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders. The Task Force created a survey that was distributed to companies of different sizes with varied investment portfolios and interests in rare disease research. Based on the survey results, the Task Force then conducted targeted interviews.
    Results: The survey and interview respondents identified several factors that make rare disease research and development attractive (e.g. a good understanding of the underlying biology) as well as barriers (e.g. absence of an advocacy organization representing the affected community's needs). The concept of Return On Investment allowed the exploration of factors that were weighed differently by survey and interview respondents, depending on a number of intrinsic and extrinsic issues.
    Conclusions: The Chrysalis Task Force identified factors attributable to rare disease research and development that may be of interest to and actionable by funders, academic researchers, patients and their families, companies, regulators, and payers in the medium term to short term. By addressing the identified challenges, involved parties may seek solutions to significantly advance the research and development of treatments for rare diseases.
    Keywords:  IRDiRC; companies; drug development; rare disease research; rare diseases
    DOI:  https://doi.org/10.1177/26330040231188979
  5. Neuromuscul Disord. 2023 Jun 15. pii: S0960-8966(23)00150-5. [Epub ahead of print]
    258th ENMC international workshop Leigh syndrome spectrum: genetic causes, natural history and preparing for clinical trials 25-27 March 2022, Hoofddorp, Amsterdam, The Netherlands.
    Workshop participants
      
    Keywords:  Diagnosis; Leigh syndrome spectrum; Oxidative phosphorylation; Primary mitochondrial disease; Treatment
    DOI:  https://doi.org/10.1016/j.nmd.2023.06.002
  6. Anaesth Crit Care Pain Med. 2023 Jul 28. pii: S2352-5568(23)00092-9. [Epub ahead of print] 101284
    Planning anesthesia of a child with a rare disease: useful tools.
    Jean-Philippe Salaün, Jean-Louis Scholtes, Francis Veyckemans.
      Up to 8,000 rare diseases are currently described in the scientific literature. The presence of a rare disease constitutes an additional challenge for the practitioner given its implications on the management of anesthesia. Moreover, it is not possible for an anesthesiologist to know them all especially as the sources of information are scattered. This narrative review aims at proposing pre-anesthetic evaluation clear tools to summarize the individual aspects of a known or suspected rare disease in a patient and to define an adapted anesthetic strategy. It also describes a decision-making process, called « the rare disease reflex », to guide the practitioner to quickly initiate diagnostic investigations in the presence of unusual perioperative clinical signs suggestive of an undiagnosed rare disease.
    Keywords:  Anesthesia; preoperative evaluation; rare disease
    DOI:  https://doi.org/10.1016/j.accpm.2023.101284
  7. J Bioeth Inq. 2023 Aug 02.
    The Parliamentary Inquiry into Mitochondrial Donation Law Reform (Maeve's Law) Bill 2021 in Australia: A Qualitative Analysis.
    Jemima W Allen, Christopher Gyngell, Julian J Koplin, Danya F Vears.
      Recently, Australia became the second jurisdiction worldwide to legalize the use of mitochondrial donation technology. The Mitochondrial Donation Law Reform (Maeve's Law) Bill 2021 allows individuals with a family history of mitochondrial disease to access assisted reproductive techniques that prevent the inheritance of mitochondrial disease. Using inductive content analysis, we assessed submissions sent to the Senate Committee as part of a programme of scientific inquiry and public consultation that informed drafting of the Bill. These submissions discussed a range of bioethical and legal considerations of central importance to the political debate. Significantly, submissions from those with a first-hand experience of mitochondrial disease, including clinicians and those with a family history of mitochondrial disease, were in strong support of this legislation. Those in support of the Bill commended the two-staged approach and rigorous licencing requirements as part of the Bill's implementation strategy. Submissions which outlined arguments against the legislation either opposed the use of these techniques in general or opposed aspects of the implementation strategy in Australia. These findings offer a window into the ethical arguments and perspectives that matter most to those Australians who took part in the Senate inquiry into mitochondrial donation. The insights garnered from these submissions may be used to help refine policy and guidelines as the field progresses.
    Keywords:  Bioethics; Gene technology; Gene technology regulation; Medical technology legislation; Mitochondrial donation; Technological and regulatory advances
    DOI:  https://doi.org/10.1007/s11673-023-10257-4
  8. Zhongguo Dang Dai Er Ke Za Zhi. 2023 Jul 15. pii: 1008-8830(2023)07-0663-09. [Epub ahead of print]25(7): 663-671
    [Expert recommendations on homogenization management of the diagnosis and treatment of rare diseases in children].
    Expert Group on Homogeneous Management Model for Diagnosis and Treatment of Rare Diseases in Children
      Rare diseases in children are characterized by low prevalence, complex pathogenesis, variety, and difficulty in the diagnosis and treatment. With the development of medical services, progress has been made in the diagnosis and treatment of rare diseases. However, due to asymmetric allocation of medical resources at different levels, there are still many shortcomings in the establishment and promotion of the homogenized management system of rare disease diagnosis and treatment. In order to further standardize the homogenized management of rare diseases in children, achieve early and accurate diagnosis and treatment, and improve the quality of life of the children, the Rare Disease Diagnosis and Treatment Center of Tianjin Children's Hospital (Tianjin University Children's Hospital) invited relevant experts in the field to develop recommendations for the management model of homogenized diagnosis and treatment of rare diseases in children from the aspects of information construction, hierarchical diagnosis and treatment, personnel training, scientific popularization, and multi-participation. The recommendations provide reference for the regional homogenization of clinical diagnosis and treatment management system for children with rare diseases.
    Keywords:  Child; Diagnosis and treatment; Expert recommendation; Management; Rare disease
    DOI:  https://doi.org/10.7499/j.issn.1008-8830.2304036
  9. Brain Pathol. 2023 Aug 03. e13199
    Neuropathological hallmarks in autopsied cases with mitochondrial diseases caused by the mitochondrial 3243A>G mutation.
    Hiroaki Miyahara, Chisato Tamai, Masanori Inoue, Kazuhito Sekiguchi, Daisuke Tahara, Nao Tahara, Kazuhiro Takeda, Shusei Arafuka, Hideyuki Moriyoshi, Ryuichi Koizumi, Akio Akagi, Yuichi Riku, Jun Sone, Mari Yoshida, Kenji Ihara, Yasushi Iwasaki.
      The mitochondrial (m.) 3243A>G mutation is known to be associated with various mitochondrial diseases including mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Their clinical symptoms have been estimated to occur with an increased mitochondrial DNA (mtDNA) heteroplasmy and reduced activity of oxidative phosphorylation (OXPHOS) complexes, but their trends in the central nervous system remain unknown. Six autopsied mutant cases and three disease control cases without the mutation were enrolled in this study. The mutant cases had a disease duration of 1-27 years. Five of six mutant cases were compatible with MELAS. In the mutant cases, cortical lesions including a laminar necrosis were frequently observed in the parietal, lateral temporal, and occipital lobes; less frequently in the frontal lobe including precentral gyrus; and not at all in the medial temporal lobe. The mtDNA heteroplasmy in brain tissue samples of the mutant cases was strikingly high, ranging from 53.8% to 85.2%. The medial temporal lobe was preserved despite an inhospitable environment having high levels of mtDNA heteroplasmy and lactic acid. OXPHOS complex I was widely decreased in the mutant cases. The swelling of smooth muscle cells in the vessels on the leptomeninges, with immunoreactivity (IR) against mitochondria antibody, and a decreased nuclear/cytoplasmic ratio of choroidal epithelial cells were observed in all mutant cases but in none without the mutation. Common neuropathological findings such as cortical laminar necrosis and basal ganglia calcification were not always observed in the mutant cases. A high level of mtDNA heteroplasmy was observed throughout the brain in spite of heterogeneous cortical lesions. A lack of medial temporal lesion, mitochondrial vasculopathy in vessels on the leptomeninges, and an increased cytoplasmic size of epithelial cells in the choroid plexus could be neuropathological hallmarks helpful in the diagnosis of mitochondrial diseases.
    Keywords:  MELAS; choroidal epithelial cell swelling; mitochondrial 3243A>G mutation; mitochondrial vasculopathy; mtDNA heteroplasmy; stroke-like episodes
    DOI:  https://doi.org/10.1111/bpa.13199
  10. Res Involv Engagem. 2023 Jul 31. 9(1): 61
    Reporting involvement activities with children and young people in paediatric research: a framework analysis.
    Jennifer Preston, Giovanni Biglino, Victoria Harbottle, Emma Dalrymple, Helen Stalford, Michael W Beresford.
       BACKGROUND: The active involvement of patients and the public in the design and delivery of health research has been increasingly encouraged, if not enforced. Knowledge of how this is realised in practice, especially where children and young people (CYP) are concerned, is limited, partly due to the low level of reporting of patient and public involvement (PPI) in general. The aim of this work was to assess how researchers funded by the National Institute for Health and Care Research (NIHR) report the involvement of CYP in the design and conduct of child health research to better understand the opportunities offered to CYP, and the realities of involvement in practice.
    METHODS: A participation matrix, analysis framework and accompanying tools were adapted from existing frameworks, including a child-rights informed framework, the Guidance for Reporting Involvement of Patients and the Public Checklist Short Form (GRIPP2SF), and NIHR reporting expectations. Child-focused research reports were identified from the NIHR Journals Library, including any interventional or observational study involving CYP aged 0-< 24 years. In two co-design workshops with healthcare professionals and CYP, we tested and refined the participation matrix, analysis framework and accompanying tools.
    RESULTS: Only thirty-two NIHR reports out of 169 (19%) were identified as relevant and included reporting of PPI with CYP. We identified significant variability in the way PPI with CYP was reported. Only 4/32 (12%) reports fully met NIHR (and GRIPP2SF) reporting criteria. Only 3/32 (9%) reports formally evaluated or self-reflected on PPI activities with CYP, whilst 15/32 (47%) provided minimal information about CYP involvement. The most common approach to involving CYP (23/32, 72%) was through the medium of existing groups or networks.
    CONCLUSION: Despite the NIHR's commitment to increase the quality, transparency, and consistency of reporting PPI, the reporting of involvement with CYP remains sub-optimal. Neglecting to report key details of involvement methods and impacts deprives the research community of knowledge to advance the field of delivering 'meaningful' PPI with CYP. Practical guidance on how researchers can report the processes and outputs of CYP involvement more rigorously may help child health researchers to involve them more meaningfully. This research offers practical tools informed by CYP to aid the reporting process.
    DOI:  https://doi.org/10.1186/s40900-023-00477-8
  11. Orphanet J Rare Dis. 2023 Aug 02. 18(1): 224
    The use of digital outcome measures in clinical trials in rare neurological diseases: a systematic literature review.
    Margaux Poleur, Theodora Markati, Laurent Servais.
      Developing drugs for rare diseases is challenging, and the precision and objectivity of outcome measures is critical to this process. In recent years, a number of technologies have increasingly been used for remote monitoring of patient health. We report a systematic literature review that aims to summarize the current state of progress with regard to the use of digital outcome measures for real-life motor function assessment of patients with rare neurological diseases. Our search of published literature identified 3826 records, of which 139 were included across 27 different diseases. This review shows that use of digital outcome measures for motor function outside a clinical setting is feasible and employed in a broad range of diseases, although we found few outcome measures that have been robustly validated and adopted as endpoints in clinical trials. Future research should focus on validation of devices, variables, and algorithms to allow for regulatory qualification and widespread adoption.
    DOI:  https://doi.org/10.1186/s13023-023-02813-3
  12. J Hum Genet. 2023 Jul 31.
    Assessment of whole-exome sequencing results in neurogenetic diseases.
    Özgür Balasar, Müşerref Başdemirci.
      Neurogenetic diseases are rare genetic diseases in which neurological findings are prominent. Whole exome sequencing (WES) has led to great advances in the understanding of the causes of neurogenetic diseases. Etiological research ends with the WES method in many patients. This etiological research is called a "diagnostic odyssey" for many families. Here, we present the results of 168 patients who were previously undiagnosed and underwent WES with the suspicion of neurogenetic disease. A total of 168 cases, 94 males and 74 females, with suspected undiagnosed neurogenetic disease were included in the study. We presented the WES results of the patients. The mean age of patients at the time of WES request was 11 years (range 0.25-68 years). Seventy percent (n = 117) of the patients were born from consanguineous marriage. Most of the patients were children (n = 145). Patients were grouped according to age at the time of examination. Patients younger than 18 years of age at the time of examination were classified as children, otherwise adults. Seventy-eight patients had either a pathogenic variant or a likely pathogenic variant so the diagnostic rate for WES in our cohort was %46. Our experience showing the high diagnostic rate of WES, supports its use in undiagnosed neurogenetic diseases. It also affects medical treatment, prognosis and family planning by enabling early diagnosis in patients.
    DOI:  https://doi.org/10.1038/s10038-023-01185-7
  13. J Telemed Telecare. 2023 Jul 30. 1357633X231188536
    Bringing researchers to the consumer table: The process and outcomes of a consumer roundtable on telehealth.
    Bec Jenkinson, Jo Maxwell, Alison Bell, Adrienne Young, Anthony C Smith, Anja Christoffersen, Dale Trevor, Leonie Young, Trevor Russell.
       INTRODUCTION: Despite the significant expansion and rapid uptake of telehealth services as a COVID-19 response, the pandemic restricted opportunities to involve health consumers in telehealth research. Authentic consumer and community involvement in research begins with engagement in priority-setting. We report here on the process and outcomes of a consumer-led event intended to support involvement of consumers, from early in the research process.
    METHODS: In 2022, The University of Queensland's Consumer and Community Network hosted a Consumer Roundtable to 'bring researchers to the consumer table' and explore emerging issues and priorities for future research. The event used World Café Method, with three 20-min rounds of small group discussion centred on questions about telehealth experiences, followed by a facilitated harvest discussion about future research directions. Participants' notes from small group discussions were subjected to conventional inductive content analysis, and a visual record was created in real-time by a graphic artist.
    RESULTS: Twenty-eight consumers and 22 researchers took part. Content analysis identified three main foci from discussions: person-centred care, better access to better care, the (unrealised) potential of telehealth. Research questions prioritised by consumer vote focussed on marginalised groups and stigmatised conditions; differences between telehealth and face-to-face healthcare delivery; and the experience of conveying and receiving compassion via telehealth.
    DISCUSSION: The Consumer Roundtable created early engagement between health consumer representatives and telehealth researchers, which has yielded ongoing partnerships. World Café method proved particularly useful for seeding relationships between researchers and consumers. However, there was limited opportunity to generate consensus about research priorities.
    Keywords:  Telehealth; community participation; consumer involvement; public and patient involvement; research priorities
    DOI:  https://doi.org/10.1177/1357633X231188536
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