bims-curels 2023-10-01 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2023–10–01
twelve papers selected by
Cure Mito Foundation

Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome.
Patient perceptions of in-hospital laboratory blood testing: A patient-oriented and patient co-designed qualitative study.
Optimized Nutrition in Mitochondrial Diseases Correlates with Improved Muscle Fatigue, Strength, and Quality of Life: You Are What You Eat, or Are You?
The fountain of youth of mitochondrial research: Research is targeting mitochondrial dysfunction to tackle aging and much more, but hype is an increasing concern.
Patient Engagement and Patient Experience Data in Regulatory Review and Health Technology Assessment: A Global Landscape Review.
Generation of an induced pluripotent stem cell line (BCHNCi003-A) from a patient with mitochondrial pyruvate carrier deficiency caused by biallelic MPC1 mutations.
Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5.
Engaging the public in digital health.
Mitochondrial proteome research: the road ahead.
Hearing Impairment and Neuroimaging Results in Mitochondrial Diseases.
Pain catastrophizing: A patient-centered approach.
The right not to know: Non-disclosure of primary genetic test results and genetic counselors' response.

Br J Anaesth. 2023 Sep 26. pii: S0007-0912(23)00442-7. [Epub ahead of print]

Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome.

Kira A Spencer, Michael Mulholland, John Snell, Miranda Howe, Katerina James, Allison R Hanaford, Philip G Morgan, Margaret Sedensky, Simon C Johnson.

   BACKGROUND: Volatile anaesthetics are widely used in human medicine. Although generally safe, hypersensitivity and toxicity can occur in rare cases, such as in certain genetic disorders. Anaesthesia hypersensitivity is well-documented in a subset of mitochondrial diseases, but whether volatile anaesthetics are toxic in this setting has not been explored.
METHODS: We exposed Ndufs4(-/-) mice, a model of Leigh syndrome, to isoflurane (0.2-0.6%), oxygen 100%, or air. Cardiorespiratory function, weight, blood metabolites, and survival were assessed. We exposed post-symptom onset and pre-symptom onset animals and animals treated with the macrophage depleting drug PLX3397/pexidartinib to define the role of overt neuroinflammation in volatile anaesthetic toxicities.
RESULTS: Isoflurane induced hyperlactataemia, weight loss, and mortality in a concentration- and duration-dependent manner from 0.2% to 0.6% compared with carrier gas (O2 100%) or mock (air) exposures (lifespan after 30-min exposures ∗P<0.05 for isoflurane 0.4% vs air or vs O2, ∗∗P<0.005 for isoflurane 0.6% vs air or O2; 60-min exposures ∗∗P<0.005 for isoflurane 0.2% vs air, ∗P<0.05 for isoflurane 0.2% vs O2). Isoflurane toxicity was significantly reduced in Ndufs4(-/-) exposed before CNS disease onset, and the macrophage depleting drug pexidartinib attenuated sequelae of isoflurane toxicity (survival ∗∗∗P=0.0008 isoflurane 0.4% vs pexidartinib plus isoflurane 0.4%). Finally, the laboratory animal standard of care of 100% O2 as a carrier gas contributed significantly to weight loss and reduced survival, but not to metabolic changes, and increased acute mortality.
CONCLUSIONS: Isoflurane is toxic in the Ndufs4(-/-) model of Leigh syndrome. Toxic effects are dependent on the status of underlying neurologic disease, largely prevented by the CSF1R inhibitor pexidartinib, and influenced by oxygen concentration in the carrier gas.

Keywords:  electron transport chain complex I; mitochondrial disease; neurodegenerative disease; paediatric disease; toxicity

DOI:  https://doi.org/10.1016/j.bja.2023.08.009
Health Expect. 2023 Sep 26.

Patient perceptions of in-hospital laboratory blood testing: A patient-oriented and patient co-designed qualitative study.

Surakshya Pokharel, Zoha Khawaja, Jonathan Williams, Adnan Adil Mithwani, Kimberly Strain, Prachi Khanna, Anna Rychtera, Veronika Kiryanova, Karen Tang, Pamela Mathura, Chris Hylton, Anshula Ambasta.

   BACKGROUND: Indiscriminate use of laboratory blood testing in hospitals contributes to patient discomfort and healthcare waste. Patient engagement in low-value healthcare can help reduce overuse. Understanding patient experience is necessary to identify opportunities to improve patient engagement with in-hospital laboratory testing.
OBJECTIVES: To understand patient experience with the process of in-hospital laboratory blood testing.
METHODS: We used a qualitative study design via semistructured interviews conducted online or over the phone. Participants were adult patients or family members/caregivers (≥18 years of age) with a recent (within 12 months of interview) experience of hospitalization in Alberta or British Columbia, Canada. We identified participants through convenience sampling and conducted interviews between May 2021 and June 2022. We analysed transcripts using thematic content analysis. Recruitment was continued until code saturation was reached.
RESULTS: We interviewed 16 participants (13 patients, 1 family member and 2 caregivers). We identified four themes from patients' experiences of in-hospital laboratory blood testing: (i) patients need information from healthcare teams about expected blood testing processes, (ii) blood draw processes should consider patient comfort and preferences, (iii) patients want information from their healthcare teams about the rationale and frequency of blood testing and (iv) patients need information on how their testing results affect their medical care.
CONCLUSION: Current laboratory testing processes in hospitals do not facilitate shared decision-making and patient engagement. Patient engagement with laboratory testing in hospitals requires an empathetic healthcare team that provides clear communication regarding testing procedures, rationale and results, while considering patient preferences and offering opportunities for involvement.
PATIENT OR PUBLIC CONTRIBUTION: We interviewed 16 patients and/or family members/caregivers regarding their in-hospital laboratory blood testing experiences. Our findings show correlations between patient needs and patient recommendations to make testing processes more patient-centred. To bring a lived-experience lens to this study, we formed a Patient Advisory Council with 9-11 patient research partners. Our patient research partners informed the research design, co-developed participant recruitment strategies, co-conducted data collection and informed the data analysis. Some of our patient research partners are co-authors of this manuscript.

Keywords:  blood testing in hospitals; laboratory testing in hospitals; patient experience; patient-oriented research

DOI:  https://doi.org/10.1111/hex.13880
Neurotherapeutics. 2023 Sep 28.

Optimized Nutrition in Mitochondrial Diseases Correlates with Improved Muscle Fatigue, Strength, and Quality of Life: You Are What You Eat, or Are You?

Russell P Saneto, Amel Karaa.



Keywords:  Mitochondrial activity factor; Muscle fatigue; Myopathy; Nutrition; Primary mitochondrial disease

DOI:  https://doi.org/10.1007/s13311-023-01445-6
EMBO Rep. 2023 Sep 28. e58118

The fountain of youth of mitochondrial research: Research is targeting mitochondrial dysfunction to tackle aging and much more, but hype is an increasing concern.

Andrea Rinaldi.

A new wave of studies is untangling the connection between primary genetic mitochondrial diseases and the role of mitochondria in aging: what are the implications for longevity?

DOI: https://doi.org/10.15252/embr.202358118
Ther Innov Regul Sci. 2023 Sep 24.

Patient Engagement and Patient Experience Data in Regulatory Review and Health Technology Assessment: A Global Landscape Review.

Neil Bertelsen, Lode Dewulf, Silvia Ferrè, Rebecca Vermeulen, Karlin Schroeder, Laureline Gatellier, Ify Sargeant, Daniela Luzuriaga, Hayley Chapman, Nicholas Brooke.

   BACKGROUND: Working with patients through meaningful patient engagement (PE) and incorporating patient experience data (PXD) is increasingly important in medicines and medical device development. However, PE in the planning, organization, generation, and interpretation of PXD within regulatory and health technology assessment (HTA) decision-making processes remains challenging. We conducted a global review of the PE and PXD landscape to identify evolving resources by geography to support and highlight the potential of integration of PE and PXD in regulatory assessment and HTA.
METHODS: A review of literature/public information was conducted (August 2021-January 2023), led by a multistakeholder group comprising those with lived or professional experience of PE and PXD, to identify relevant regulatory and HTA initiatives and resources reviewed and categorized by geography and focus area.
RESULTS: Overall, 53 relevant initiatives/resources were identified (global, 14; North America, 11; Europe, 11; Asia, nine; UK, six; Latin America, one; Africa, one). Most focused either on PE (49%) or PXD (28%); few (11%) mentioned both PE and PXD (as largely separate activities) or demonstrated an integration of PE and PXD (11%).
CONCLUSIONS: Our analysis demonstrates increasing interest in PE, PXD, and guidance on their use individually in decision-making. However, more work is needed to offer guidance on maximizing the value of patient input into decisions by combining both PE and PXD into regulatory and HTA processes; the necessity of integrating PE in the design and interpretation of PXD programs should be highlighted. A co-created framework to achieve this integration is part of a future project.

Keywords:  Health technology assessment; Patient engagement; Patient experience data; Real-world evidence; Regulatory assessment

DOI:  https://doi.org/10.1007/s43441-023-00573-7
Stem Cell Res. 2023 Sep 21. pii: S1873-5061(23)00192-7. [Epub ahead of print]72 103206

Generation of an induced pluripotent stem cell line (BCHNCi003-A) from a patient with mitochondrial pyruvate carrier deficiency caused by biallelic MPC1 mutations.

Huafang Jiang, Chaolong Xu, Wenyan Li, Ling Zhou, Fang Fang.

Mitochondrial pyruvate carrier deficiency (MPYCD) is a rare mitochondrial disease characterized by developmental delay, microcephaly, growth failure, increased serum lactate with a normal lactate/pyruvate ratio. Mutations in the MPC1 gene have been identified to cause MPYCD. Herein, we generated an induced pluripotent stem cell (iPSC) line from the skin fibroblasts of a patient with MPYCD, carrying biallelic mutations, c.208G>A (p.Ala70Thr) and c.290G>A (p.Arg97Gln) in MPC1. These iPSCs showed the expression of pluripotency markers, the ability to differentiate into three germ layers, and MPC1 mutations with normal karyotype.

DOI: https://doi.org/10.1016/j.scr.2023.103206
Mov Disord. 2023 Sep 27.

Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5.

Pin-Shiuan Chen, Ni-Chung Lee, Chieh-Ju Sung, Ya-Wen Liu, Wen-Chin Weng, Pi-Chuan Fan, Wang-Tso Lee, Yin-Hsiu Chien, Chao-Szu Wu, Yueh-Feng Sung, Ming-Chen Tsai, Yi-Chung Lee, Hsueh-Wen Hsueh, Sabrina Mai-Yi Fan, Meng-Chen Wu, Hsun Li, Huan-Yun Chen, Han-I Lin, Chih-Hsin Ou-Yang, Wuh-Liang Hwuh, Chin-Hsien Lin.

   BACKGROUND: Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome.
OBJECTIVE: We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations.
METHODS: Patients with biallelic NDUFAF5 mutations were recruited from multi-centers in Taiwan. Clinical, laboratory, radiological, and follow-up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts.
RESULTS: Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early-onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late-onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late-onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early-onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early-versus late-onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early-onset case than a late-onset patient.
CONCLUSIONS: The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  Leigh syndrome; NDUFAF5; dystonia; mitochondria; mitochondrial complex I deficiency; striatal necrosis

DOI:  https://doi.org/10.1002/mds.29604
BMJ. 2023 09 25. 382 2155

Engaging the public in digital health.

Richard Fitton.

DOI: https://doi.org/10.1136/bmj.p2155
Nat Rev Mol Cell Biol. 2023 Sep 29.

Mitochondrial proteome research: the road ahead.

Zakery N Baker, Patrick Forny, David J Pagliarini.

Mitochondria are multifaceted organelles with key roles in anabolic and catabolic metabolism, bioenergetics, cellular signalling and nutrient sensing, and programmed cell death processes. Their diverse functions are enabled by a sophisticated set of protein components encoded by the nuclear and mitochondrial genomes. The extent and complexity of the mitochondrial proteome remained unclear for decades. This began to change 20 years ago when, driven by the emergence of mass spectrometry-based proteomics, the first draft mitochondrial proteomes were established. In the ensuing decades, further technological and computational advances helped to refine these 'maps', with current estimates of the core mammalian mitochondrial proteome ranging from 1,000 to 1,500 proteins. The creation of these compendia provided a systemic view of an organelle previously studied primarily in a reductionist fashion and has accelerated both basic scientific discovery and the diagnosis and treatment of human disease. Yet numerous challenges remain in understanding mitochondrial biology and translating this knowledge into the medical context. In this Roadmap, we propose a path forward for refining the mitochondrial protein map to enhance its discovery and therapeutic potential. We discuss how emerging technologies can assist the detection of new mitochondrial proteins, reveal their patterns of expression across diverse tissues and cell types, and provide key information on proteoforms. We highlight the power of an enhanced map for systematically defining the functions of its members. Finally, we examine the utility of an expanded, functionally annotated mitochondrial proteome in a translational setting for aiding both diagnosis of mitochondrial disease and targeting of mitochondria for treatment.

DOI: https://doi.org/10.1038/s41580-023-00650-7
J Pers Med. 2023 Aug 29. pii: 1329. [Epub ahead of print]13(9):

Hearing Impairment and Neuroimaging Results in Mitochondrial Diseases.

Gabriella Cadoni, Guido Primiano, Pasqualina M Picciotti, Rosalinda Calandrelli, Jacopo Galli, Serenella Servidei, Guido Conti.

  Mitochondrial diseases (MDs) are heterogeneous genetic disorders characterized by mitochondrial DNA (mtDNA) defects, involving tissues highly dependent on oxidative metabolism: the inner ear, brain, eye, skeletal muscle, and heart. We describe adult patients with genetically defined MDs, characterizing hearing function and neuroimaging results. We enrolled 34 patients (mean age: 50.02 ± 15 years, range: 18-75 years; 20 females and 14 males) classified in four groups: MELAS, MIDD, PEO, and Encephalopathy/Polyneuropathy. Audiological evaluations included psychoacoustical tests (pure-tone and speech audiometry), electrophysiological tests (Auditory Brainstem Responses, ABRs), and Impedenzometry. Neuroimaging evaluations considered global MRI abnormalities or structural brain changes. In total, 19/34 patients carried the m.3243A > G mutation (6 affected by MELAS, 12 affected by MIDD, and 1 affected by PEO); 11 had an mtDNA deletion (all affected by PEO); 3 had nuclear genes associated with MDs (POLG1 and OPA1); and 1 patient had an mtDNA deletion without an identified nuclear gene defect (affected by PEO). Sensory neural, bilateral, and symmetrical hearing loss was present in 25 patients (73.5%) to different degrees: 9 mild, 9 moderate, 5 severe, and 2 profound. The severe/profound and mild hearing losses were associated with pantonal and high-frequency audiograms, respectively. Instead, moderate hearing losses were associated with both high-frequency (five cases) and pantonal (five cases) audiogram shapes. In addition, 21/25 patients showed a cochlear site of lesion (84%), and 4/25 (16%) showed a retrocochlear site. We found global MRI abnormalities or structural brain changes in 26/30 subjects (86.6%): 21 had white matter abnormalities, 15 had cortical atrophy, 10 had subcortical atrophy, 8 had basal nuclei involvement or cerebellar atrophy, 4 had stroke-like lesions or laminar necrosis, and 1 had cysts or vacuolated lesions. We concluded that genetic alterations are associated with different clinical presentations for both auditory function and neuroradiological findings. There is no fixed relationship between genotype and phenotype for the clinical conditions analyzed.

Keywords:  MRI; brain changes; cochlear; deafness; mitochondrial diseases; mtDNA; retrocochlear

DOI:  https://doi.org/10.3390/jpm13091329
Nursing. 2022 Apr 01. 52(4): 30-31

Pain catastrophizing: A patient-centered approach.

DOI: https://doi.org/10.1097/01.NURSE.0000828996.86520.83
J Genet Couns. 2023 Sep 26.

The right not to know: Non-disclosure of primary genetic test results and genetic counselors' response.

Claire Murphy, Sarah Sturm, Meghan Juliana McKenna, Kelly E Ormond.

  As part of clinical genetic counseling practice, patients may request that their primary genetic test results be disclosed to someone else, such as a relative or referring provider, or request that results be disclosed to no one (non-disclosure). In making these requests, patients employ the ethical principle of the "right not to know," which argues that autonomous individuals can choose not to know relevant health information. Although the right not to know has been well-studied in medicine in general, and in the return of genomic secondary findings, we are not aware of other studies that have explored the return of primary genetic test results when patients request non-disclosure or disclosure to another individual. This study aimed to describe common clinical scenarios in which these requests occur, how genetic counselors respond, and what ethical considerations they employ in their decision-making process. We recruited participants from the National Society of Genetic Counselors' (NSGC) "Student Research Surveys and Reminders" listserv and conducted semi-structured interviews with 11 genetic counselors in the United States who described genetic counseling cases where this occurred. Interviews were transcribed and coded inductively, and themes were identified. Case details varied, but in our study data the requests for non-disclosure were most commonly made by patients with poor, often oncologic, prognoses who requested their test results be disclosed to a family member instead of themselves. Genetic counselors considered similar factors in deciding how to respond to these requests: patient autonomy, medical actionability of results for the patient and family, the relationship between the patient and the person to whom results might be disclosed, and legal or practical concerns. Genetic counselors often made decisions on a case-by-case basis, depending on how relevant each of these factors were. This study adds to the growing body of literature regarding patients' "right not to know" and will hopefully provide guidance for genetic counselors who experience this situation in clinical practice.

Keywords:  disclosure; ethics; genetic counseling; genetic counselor; genetic testing; non-disclosure; return of results; right not to know

DOI:  https://doi.org/10.1002/jgc4.1797