bims-curels Biomed News
on Leigh syndrome
Issue of 2023–07–23
eleven papers selected by
Cure Mito Foundation
  1. Nanopore long-read next-generation sequencing for detection of mitochondrial DNA large-scale deletions.
  2. Droplet digital polymerase chain reaction to measure heteroplasmic m.3243A>G mitochondrial mutations.
  3. Mitochondrial DNA 13513G>A Mutation Causing Leber Hereditary Optic Neuropathy Associated With Adult-Onset Renal Failure.
  4. Correction to: The evolution of the mitochondrial disease diagnostic odyssey.
  5. Preserving mitochondria to treat hypertrophic cardiomyopathy: From rare mitochondrial DNA mutation to heart failure therapy?
  6. A systematic review of models of patient engagement in the development and life cycle management of medicines.
  7. [Advanced Practice Nursing Experience of a Female Adolescent With Leigh Syndrome and Her Family: A Family Strengths-Oriented Therapeutic Conversations Approach].
  8. "We're back in control of the story and we're not letting anyone take that away from us": patient teacher programs as means for patient emancipation.
  9. Reconsidering patient-centred care: Authority, expertise and abandonment.
  10. Introduction to special issue on rare disease drug discovery.
  11. MTFMT-Related Leigh Syndrome Phenotypically Manifesting with Mobile Dystonia and Hypoacusis.
  1. Front Genet. 2023 ;14 1089956
    Nanopore long-read next-generation sequencing for detection of mitochondrial DNA large-scale deletions.
    Chiara Frascarelli, Nadia Zanetti, Alessia Nasca, Rossella Izzo, Costanza Lamperti, Eleonora Lamantea, Andrea Legati, Daniele Ghezzi.
      Primary mitochondrial diseases are progressive genetic disorders affecting multiple organs and characterized by mitochondrial dysfunction. These disorders can be caused by mutations in nuclear genes coding proteins with mitochondrial localization or by genetic defects in the mitochondrial genome (mtDNA). The latter include point pathogenic variants and large-scale deletions/rearrangements. MtDNA molecules with the wild type or a variant sequence can exist together in a single cell, a condition known as mtDNA heteroplasmy. MtDNA single point mutations are typically detected by means of Next-Generation Sequencing (NGS) based on short reads which, however, are limited for the identification of structural mtDNA alterations. Recently, new NGS technologies based on long reads have been released, allowing to obtain sequences of several kilobases in length; this approach is suitable for detection of structural alterations affecting the mitochondrial genome. In the present work we illustrate the optimization of two sequencing protocols based on long-read Oxford Nanopore Technology to detect mtDNA structural alterations. This approach presents strong advantages in the analysis of mtDNA compared to both short-read NGS and traditional techniques, potentially becoming the method of choice for genetic studies on mtDNA.
    Keywords:  MinION; complex-rearrangements; long reads; macrodeletion; mtDNA; multiple deletions; oxford nanopore; structural variants
    DOI:  https://doi.org/10.3389/fgene.2023.1089956
  2. Lab Med. 2023 Jul 21. pii: lmad063. [Epub ahead of print]
    Droplet digital polymerase chain reaction to measure heteroplasmic m.3243A>G mitochondrial mutations.
    Shinya Matsumoto, Takeshi Uchiumi, Nozomi Noda, Yasushi Ueyanagi, Taeko Hotta, Dongchon Kang.
       OBJECTIVE: Different mitochondrial DNA genotypes can coexist in a cell population as well as in a single cell, a condition known as heteroplasmy. Here, we accurately determined the heteroplasmy levels of the m.3243A>G mutation, which is the most frequently identified mutation in patients with mitochondrial diseases, using droplet digital polymerase chain reaction (ddPCR).
    METHODS: The m.3243A>G heteroplasmy levels in artificial heteroplasmy controls mixed with various proportions of wild-type and mutant plasmids were measured using ddPCR, PCR-restriction fragment length polymorphism, and Sanger sequencing. The m.3243A>G heteroplasmy levels in DNA, extracted from the peripheral blood of patients with suspected mitochondrial disease and healthy subjects, were determined using ddPCR.
    RESULTS: The accuracy of the ddPCR method was high. The lower limit of detection was 0.1%, which indicated its higher sensitivity compared with other methods. The m.3243A>G heteroplasmy levels in peripheral blood, measured using ddPCR, correlated inversely with age at the time of analysis. The m.3243A>G mutation may be overlooked in the peripheral blood-derived DNA of elderly people, as patients >60 years of age have heteroplasmy levels <10%, which is difficult to detect using methods other than the highly sensitive ddPCR.
    CONCLUSION: ddPCR may be considered an accurate and sensitive method for measuring m.3243 A>G heteroplasmy levels of mitochondrial DNA.
    Keywords:  droplet digital PCR; heteroplasmy; m.3243A>G; mitochondrial DNA; mitochondrial disease; peripheral blood
    DOI:  https://doi.org/10.1093/labmed/lmad063
  3. J Neuroophthalmol. 2023 Jul 21.
    Mitochondrial DNA 13513G>A Mutation Causing Leber Hereditary Optic Neuropathy Associated With Adult-Onset Renal Failure.
    Grace Swart, Clare L Fraser, Meena Shingde, Elizabeth O Thompson, Amali Mallawaarachchi, Mitchell Lawlor, Kate Ahmad, Gabor M Halmagyi.
       BACKGROUND: Leber hereditary optic neuropathy (LHON) is one of the more common mitochondrial diseases and is rarely associated with mitochondrial renal disease. We report 3 unrelated patients with a background of adult-onset renal failure who presented to us with LHON and were shown to have a heteroplasmic mitochondrial DNA mutation (m.13513G>A).
    METHODS: Retrospective chart review.
    RESULTS: All 3 patients had a background of chronic renal failure and presented to us with bilateral optic neuropathy (sequential in 2) and were found to have heteroplasmic m.13513G>A mutations in the MT-ND5 gene. Two of the patients were females (aged 30 and 45 years) with chronic kidney disease from their 20s, attributed to pre-eclampsia, one of whom also had diabetes and sudden bilateral hearing loss. One patient was a male (aged 54 years) with chronic kidney disease from his 20s attributed to IgA nephropathy. His mother had diabetes and apparently sudden bilateral blindness in her 70s. Renal biopsy findings were variable and included interstitial fibrosis, acute tubular necrosis, focal segmental glomerulosclerosis, and IgA/C3 tubular casts on immunofluorescence. Mild improvements in vision followed treatment with either idebenone or a combination supplement including coenzyme Q10, alpha-lipoic acid, and B vitamins.
    CONCLUSIONS: Our cases expand the clinical syndromes associated with m.13513G>A to include bilateral optic neuropathy and adult-onset renal disease. This highlights that in patients with bilateral, especially sequential, optic neuropathy a broad approach to mitochondrial testing is more useful than a limited LHON panel. Mitochondrial diseases present a diagnostic challenge because of their clinical and genetic variability.
    DOI:  https://doi.org/10.1097/WNO.0000000000001946
  4. Orphanet J Rare Dis. 2023 Jul 20. 18(1): 194
    Correction to: The evolution of the mitochondrial disease diagnostic odyssey.
    John L P Thompson, Amel Karaa, Hung Pham, Philip Yeske, Jeffrey Krischer, Yi Xiao, Yuelin Long, Amanda Kramer, David Dimmock, Amy Holbert, Cliff Gorski, Kristin M Engelstad, Richard Buchsbaum, Xiomara Q Rosales, Michio Hirano.
      
    DOI:  https://doi.org/10.1186/s13023-023-02832-0
  5. J Clin Invest. 2023 07 17. pii: e171965. [Epub ahead of print]133(14):
    Preserving mitochondria to treat hypertrophic cardiomyopathy: From rare mitochondrial DNA mutation to heart failure therapy?
    Abhinav Diwan.
      Hypertrophic cardiomyopathy and pathological cardiac hypertrophy are characterized by mitochondrial structural and functional abnormalities. In this issue of the JCI, Zhuang et al. discovered 1-deoxynojirimycin (DNJ) through a screen of mitochondrially targeted compounds. The authors described the effects of DNJ in restoring mitochondria and preventing cardiac myocyte hypertrophy in cellular models carrying a mutant mitochondrial gene, MT-RNR2, which is causally implicated in familial hypertrophic cardiomyopathy. DNJ worked via stabilization of the mitochondrial inner-membrane GTPase OPA1 and other, hitherto unknown, mechanisms to preserve mitochondrial crista and respiratory chain components. The discovery is likely to spur development of a class of therapeutics that restore mitochondrial health to prevent cardiomyopathy and heart failure.
    DOI:  https://doi.org/10.1172/JCI171965
  6. Drug Discov Today. 2023 Jul 13. pii: S1359-6446(23)00218-0. [Epub ahead of print] 103702
    A systematic review of models of patient engagement in the development and life cycle management of medicines.
    F I Auwal, C Copeland, E J Clark, C Naraynassamy, G R McClelland.
      There is currently no universally agreed code of practice for patient engagement (PE), and existing guidelines do not fully cover the scope across medicine development and subsequent life cycle management. This review conceptualises the meaning and summarises the current models of PE. A systematic literature review was conducted and analysed by thematic synthesis. Eight themes were identified as components of how to achieve meaningful PE, and five were identified for where to engage with patients in drug development. This review provides summative guidance for stakeholders intending to introduce PE and establishes a starting point for the development of a universal code of practice.
    Keywords:  guidance; medicines development; models; patient engagement; research and development; roadmap
    DOI:  https://doi.org/10.1016/j.drudis.2023.103702
  7. Hu Li Za Zhi. 2023 Aug;pii: JN.202308_70(4).13. [Epub ahead of print]70(4): 103-111
    [Advanced Practice Nursing Experience of a Female Adolescent With Leigh Syndrome and Her Family: A Family Strengths-Oriented Therapeutic Conversations Approach].
    Ching-Wen Cheng, Bih-Shya Gau.
      This article applied a family strengths-oriented therapeutic conversations approach to explore the advanced practice nursing experience of a female adolescent with Leigh Syndrome and her family. During the nursing care period from September 20 to November 19, 2022, the author collected data through direct care, observation, interview, telecare, home visits, and medical record reviews and confirmed the nursing problems to be the inadequate coping capability of the family. The author leveraged her advanced nurse practitioner role and used family strength-oriented therapeutic conversations to enable the parents of the patient to reflect on their experiences with this disease and to improve their quality of life and satisfaction with healthcare services. Three modes of care, including accessibility, coordination, and comprehensiveness, were offered to the female adolescent patient and her family to achieve the goal of family-centered, community-based, and medical-system-centered care. It is suggested that before making healthcare decisions, patients and their families should be given the opportunity to participate in the healthcare process and reach consensus on healthcare decisions based on existing evidence and their values and preferences. The medical decisions made by patients and their families after carefully considering their current situation and needs should be supported and assisted.
    Keywords:  Leigh syndrome; advanced practice nurse; family strengths oriented therapeutic conversations
    DOI:  https://doi.org/10.6224/JN.202308_70(4).13
  8. Adv Health Sci Educ Theory Pract. 2023 Jul 16.
    "We're back in control of the story and we're not letting anyone take that away from us": patient teacher programs as means for patient emancipation.
    E Kangasjarvi, J Forsey, J S Simpson, S L Ng.
      While patient engagement in healthcare professions education (HPE) has significantly increased in the past decades, a theoretical gap remains. What are the varied reasons as to why patients get involved with HPE programs? With a focus on understanding what drives patient involvement with HPE programs, this study examined how a patient as teacher (PAT) program was experienced by medical students, patient teachers, and faculty within a medical school. Through a phenomenographic approach, this study captures and describes the different ways our study participants experienced a PAT program (the 'phenomenon'). 24 semi-structured interviews were conducted in total, comprised of interviews with patient teachers (N = 10), medical students (N = 10) and program facilitators (N = 4) who participated in a PAT program. Our focus was on participants' description of the program and was grounded in their experiences of as well as their beliefs about it. Our findings captured 4 layers representing the qualitatively different (yet interrelated) ways in which participants experienced/perceived and conceptualized the various aspects of their experience with the PAT program: (1) A productive disruption of the learning space (2) A re-humanization within healthcare (3) A means of empowerment and agency (4) A catalyst for change and emancipation. Our outcome space results can be visually illustrated by a nesting "Matryoshka" doll, representing the four layers and depicting the process of uncovering the less conscious layers of sense-making within this phenomenon. HPE programs that are co-produced with patients and actively involve patients as teachers have the potential, but not guarantee, to be emancipatory. To engage in PAT programs that exhibit an emancipatory potential, we need to consider transformative paradigms of education, which are aligned with social change, and disrupt the traditional teacher-learner hierarchy.
    Keywords:  Health professions education; Medical education; Patient educators; Patient emancipation; Patient engagement; Patient-centredness; Patients as teachers; Transformative education
    DOI:  https://doi.org/10.1007/s10459-023-10255-6
  9. Health Expect. 2023 Jul 20.
    Reconsidering patient-centred care: Authority, expertise and abandonment.
    Alison Pilnick.
      Patient-centred care is commonly framed as a means to guard against the problem of medical paternalism, exemplified in historical attitudes of 'doctor knows best'. In this sense, patient-centred care (PCC) is often regarded as a moral imperative. Reviews of its adoption in healthcare settings do not find any consistent improvement in health outcomes; however, these results are generally interpreted as pointing to the need for more or 'better' training for staff, rather than raising more fundamental questions. Patient autonomy is generally foregrounded in conceptualizations of PCC, to be actualized through the exercising of choice and control. But examining healthcare interaction in practice shows that when professionals attempt to enact these underpinnings, it often results in the sidelining of medical expertise that patients want or need. The outcome is that patients can feel abandoned to make decisions they feel unqualified to make, or even that care standards may not be met. This helps to explain why PCC has not produced the hoped-for improvement in health outcomes. It also suggests that, rather than focusing on scoring individual consultations, we need to consider how medical expertise can be rehabilitated for a 21st century public, and how patient expertise can be better incorporated into co-design and co-production of services and resources rather than being seen as something to be expressed through a binary notion of control. PATIENT AND PUBLIC CONTRIBUTION: This viewpoint draws on research conducted by the author across a range of settings in health and social care, all of which incorporated patient and public involvement when it was conducted.
    Keywords:  abandonment; authority; choice; control; expertise; patient-centred care
    DOI:  https://doi.org/10.1111/hex.13815
  10. Bioorg Med Chem. 2023 Jun 08. pii: S0968-0896(23)00223-7. [Epub ahead of print] 117375
    Introduction to special issue on rare disease drug discovery.
    Darby Schmidt.
      
    DOI:  https://doi.org/10.1016/j.bmc.2023.117375
  11. Mov Disord Clin Pract. 2023 Jul;10(7): 1162-1163
    MTFMT-Related Leigh Syndrome Phenotypically Manifesting with Mobile Dystonia and Hypoacusis.
    Josef Finsterer, Fulvio Alexandre Scorza, Carla Alexandra Scorza, Antoni-Carlos G de Almeida.
      
    Keywords:  Leigh syndrome; MTFMT; dystonia; mitochondrial disorder; respiratory chain
    DOI:  https://doi.org/10.1002/mdc3.13761
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