bims-curels 2025-10-05 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–10–05
nine papers selected by
Cure Mito Foundation

Health-related quality of life in patients with mitochondrial disease and their carers.
Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases.
Exploring Patient and Caregiver Perceptions of the Facilitators and Barriers to Patient Engagement in Research: Participatory Qualitative Study.
Identification of novel NDUFA3 variants in a patient with mitochondrial disorders.
What Matters Ethically About How the UDN Has Changed Since Its Inception?
A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron-sulfur cluster and supercomplex formation.
Clinical data integration and processing challenges in healthcare caused by contemporary software design.
Engaging stakeholders along health technology assessment pathways: a scoping review of international practice.
Safety, Costs, and Ethical Issues in Drug Development and Gene Therapy for Rare Diseases.

J Med Genet. 2025 Sep 27. pii: jmg-2025-110896. [Epub ahead of print]

Health-related quality of life in patients with mitochondrial disease and their carers.

Deborah Schofield, Joshua Kraindler, Katherine Lim, Owen Tan, Sameen Haque, Karen Crawley, Sarah West, Adam Percival, Jayamala Parmar, Rupendra Shrestha, Carolyn Sue.

   BACKGROUND: Mitochondrial diseases are a group of rare, chronic disorders with a significant disease burden; however, there is limited knowledge about their effects on the health-related quality of life (HRQoL) of patients and their carers. This study estimates HRQoL among adult patients with mitochondrial diseases and their carers, using the Assessment of Quality-of-Life 8D (AQoL-8D), a validated instrument for measuring health utilities.
METHODS: Ninety-nine adult patients and 24 carers were recruited to the Economic and Psychosocial Impacts of Caring for Families Affected by Mitochondrial Disease (EPIC-MITO) Study, based in New South Wales, Australia.
RESULTS: Adult patients exhibited significantly lower utility values (0.52) compared with age-adjusted and gender-adjusted population norms (0.80; p<0.001). Regression analysis shows that mental health disorders, sleep disorders, financial stress and female gender were associated with reduced HRQoL. Carers also demonstrated AQoL-8D utility values (0.70) significantly below age-adjusted and gender-adjusted population norms (0.81; p=0.01) reflecting the broader burden of mitochondrial diseases on families.
CONCLUSION: With increasing use of genetic testing and genomic sequencing, as well as hope for gene therapies, health utility values will be necessary for economic evaluations of new interventions for mitochondrial disease. This paper shows the substantial impact on HRQoL of mitochondrial disease measured through utilities. The utility values from this paper can inform future economic evaluations for interventions for patients with mitochondrial disease. Further, the paper demonstrated that mitochondrial disease not only reduces the HRQoL of patients but also impacts the HRQoL of carers.

Keywords:  Economics; Neuromuscular Diseases

DOI:  https://doi.org/10.1136/jmg-2025-110896
Neural Regen Res. 2025 Sep 29.

Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases.

Tingting Fu, Xinyi Chen, Shuting Zhang, Ying Fu, Lin Huang, Wandi Xiong.

   ABSTRACT: The mitochondrial genomic homeostasis is essential for the function of the oxidative phosphorylation system and cellular homeostasis. Mitochondrial DNA is particularly susceptible to aging-related oxidative stress due to the lack of a histone coat. Disturbances in mitochondrial DNA may contribute to functional decline during the aging process and in neurodegenerative diseases, leading to further impairment of mitochondrial DNA and initiating a vicious cycle. To date, it remains unclear how disturbed mitochondrial DNA is involved in the etiology of pathological aging and neurodegenerative diseases. The purpose of this review is to clarify the crucial roles of mitochondrial DNA homeostasis in the pathogenesis of neurodegenerative diseases. Mitochondrial DNA is distributed within nucleoids and is then transcribed into polycistronic mitochondrial DNA molecules within the mitochondrial granule region. Within the ultrastructure of the mitochondrial nucleoid and granule, a group of essential mitochondrial proteins involved in DNA replication, DNA transcription, RNA translation, RNA surveillance, and RNA degradation plays a crucial role in maintaining mitochondrial structure, genome integrity, and mitochondrial DNA processing. The uniparentally inherited mitochondrial DNA undergoes heritable polyploid variations, which include homoplasmy and heteroplasmy. Accumulating mitochondrial DNA alterations, such as deletions, point mutations, and methylations, occur during the pathogenic processes of neurodegenerative diseases. The increased mitochondrial DNA alterations can be propagated by the rise of deleterious heteroplasmy in neurodegenerative diseases, ultimately resulting in impairment to the oxidative phosphorylation system, biogenesis defects, and cellular metabolic dysfunction. Therefore, developing appropriate gene editing tools to rectify aberrant alterations in mitochondrial DNA and targeting the key proteins involved in maintaining mitochondrial DNA homeostasis can be considered promising therapeutic strategies for neurodegenerative diseases. Although therapeutic strategies targeting mitochondrial DNA in diseases show great potential, challenges related to efficacy and safety require a better understanding of the mechanisms underlying mitochondrial DNA alterations in aging and neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Parkinson’s disease; aging; heteroplamy; mitochondrial DNA; mitochondrial DNA mutation; mitochondrial genome; mitochondrial haplogroup; mitochondrial homeostasis; neurodegenerative diseases

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00495
J Particip Med. 2025 09 30. 17 e79538

Exploring Patient and Caregiver Perceptions of the Facilitators and Barriers to Patient Engagement in Research: Participatory Qualitative Study.

Sasha Melanda Kullman, Louise Bird, Amy Clark, Amanda Doherty-Kirby, Diana Ermel, Nathalie Kinnard, Marion Knutson, Andrew Milroy, Lesley Singer, Anna Maria Chudyk.

   Background: Patient engagement in research is the meaningful and active involvement of patient and caregiver partners (ie, patients and their family or friends) in research priority-setting, conduct, and governance. With the proper support, patient and caregiver partners can inform every stage of the research cycle, but common barriers often prevent their full engagement.
Objective: This participatory qualitative study aimed to answer the question: What are the facilitators and barriers to patient engagement experienced by patient and caregiver partners in a Canadian research context?
Methods: Participants were N=13 patient and caregiver partners (median age 62 y, IQR 58-69 y; 11/13, 85% women; 13/13, 100% White) from 4 provinces who completed 60-90-minute semistructured videoconferencing interviews. The interviews were transcribed verbatim. A researcher and a patient partner reviewed the transcripts and curated a dataset of 90 participant quotations representing facilitators and barriers to patient engagement. This dataset was co-analyzed using participatory theme elicitation alongside 7 patient and caregiver partners with diverse identities who were not among the participants we interviewed and, therefore, contributed novel perspectives.
Results: We generated four themes depicting factors that facilitate meaningful patient engagement alongside barriers that arise when these factors are not in place: (1) Co-defining roles and expectations; (2) demonstrating the value and impact of engagement; (3) psychological safety; and (4) community outreach, training, and education. We then discuss how barriers to enacting these 4 factors can be mitigated and provide a practical checklist of considerations for both researchers and patient and caregiver partners for engaging together throughout the research cycle.
Conclusions: Research teams conducting patient and caregiver engagement activities should draw from our findings to mitigate barriers and facilitate meaningful engagement experiences.

Keywords:  co-analysis; participatory research; patient partnership; patient-oriented research; public and patient engagement

DOI:  https://doi.org/10.2196/79538
Pediatr Res. 2025 Oct 02.

Identification of novel NDUFA3 variants in a patient with mitochondrial disorders.

Yu Sun, Xiujuan Wei, Bing Xiao, Yongfeng Luo, Ya Wang, Ripeng Liu, Yongkun Zhan, Xiantao Ye, Xudong Cai, Shiyi Xu, Jianxin Lyu, Hezhi Fang, Yongguo Yu.

BACKGROUND: Mitochondrial respiratory chain (RC) dysfunction constitutes the biochemical defect underlining a group of heterogenous clinical presentations known as mitochondrial disorders. NDUFA3 is an accessory subunit of Complex I (CI) and has recently been associated with Leigh Syndrome. However, the genetic evidence is limited and no functional analysis is available on the molecular mechanism.
METHODS: We investigated the clinical features of the second family with biallelic NDUFA3 variants. The patient's cells and HEK293T cells with NDUFA3 knock down (KD) were assessed to study the RC dysfunction. A zebrafish model with the morpholino targeting on ndufa3 were generated to study the phenotypes caused by ndufa3 disruption.
RESULTS: The affected boy demonstrated global developmental delay, neurosensory hearing impairment, strabismus, muscle weakness, and hypertonia. He harbored a paternal exonic deletion NC_000019.9:g.54608143_54614387delinsCG and a maternally-inherited missense variant NM_004542.4:c.173G>A; p.(Arg58His). In patient's cells and HEK293T cells with NDUFA3 KD, reduced levels of NDUFA3 and CI and Complex IV (CIV) were observed, which further impaired endogenous respiration and ATP generation. Re-expression of the wild-type but not the mutant NDUFA3 restored the CI and CIV levels in NDUFA3 deficient cells. Zebrafish with ndufa3 disruption demonstrated ndufa3 KD affected locomotor development.
CONCLUSIONS: Our findings confirm the association between NDUFA3 molecular defects and Leigh syndrome spectrum.
IMPACT: NDUFA3 deficiency causes a mitochondrial respiration complex deficiency disorder. A family with biallelic NDUFA3 variants demonstrates phenotype resembling mitochondrial respiration complex defects. NDUFA3 defects reduce the amount of respiration complex I and IV; impair endogenous respiration and ATP generation. Zebrafish with ndufa3 knock down manifests delayed locomotor development. With this reported patient, the relationship between the gene and disease can be upgraded from "limited" to "moderate".

DOI: https://doi.org/10.1038/s41390-025-04403-4
AMA J Ethics. 2025 Oct 10. pii: amajethics.2025.756. [Epub ahead of print]27(10): E756-760

What Matters Ethically About How the UDN Has Changed Since Its Inception?

David A Pearce, Elena-Alexandra Tataru.

For persons living with an undiagnosed disease and their families, finding an accurate diagnosis can be a long and complex process. Having a rare condition that goes undiagnosed for a long period constitutes a significant part of these patients' disease burden. This article suggests the importance of international collaborative approaches to rare disease diagnostic practices and describes how the Undiagnosed Diseases Network can draw on best practices and clinical networks to motivate patient-participants' access to rare disease diagnoses.

DOI: https://doi.org/10.1001/amajethics.2025.756
Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2506761122

A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron-sulfur cluster and supercomplex formation.

Deborah G Murdock, Kevin A Janssen, Kierstin Keller, Katherine L Mitchell, Maina Beauplan, William T O'Brien, Lia D'Alessandro, Jeffrey A Haltom, Douglas C Wallace.

  MEPAN (Mitochondrial Enoyl CoA Reductase Protein-Associated Neurodegeneration) is an early-onset movement disorder characterized by ataxia, dysarthria, and optic atrophy. Here, we report the creation of a mouse model of MEPAN with patient-similar compound heterozygous mutations in the Mecr gene. The MEPAN mouse recapitulates the major hallmarks of MEPAN, including a movement disorder, optic neuropathy, defects in protein lipoylation, and reduced mitochondrial oxidative phosphorylation in the brain. MECR catalyzes the last step in mitochondrial fatty acid synthesis (mtFASII), and the mechanism by which loss of mtFASII leads to neurological disease is unknown. LC-MS/MS-based proteomic analysis of Mecr mutant cerebella identified loss of subunits of complex I of oxidative phosphorylation (OXPHOS) and subunits of the iron-sulfur cluster assembly (ISC) complex. Native gels revealed altered OXPHOS complex and supercomplex formation and changes in binding of the acyl carrier protein (ACP) to mitochondrial complexes. These results demonstrate that MECR plays a key role in the acylation of ACP which is necessary for ACP-LYRM-mediated supercomplex modulation and ISC biogenesis and suggest unique pathways for therapeutics.

Keywords:  genetics; iron; mitochondrial disease; mitochondrial fatty acid synthesis; mouse model

DOI:  https://doi.org/10.1073/pnas.2506761122
Digit Health. 2025 Jan-Dec;11:11 20552076251374233

Clinical data integration and processing challenges in healthcare caused by contemporary software design.

Valo Petri, Tran Antoine, Baranton Emma, Haas Hervé, Freyssinet Emma, Vrzáková Hana.

   Objective: The quantity of patient data in healthcare is exponentially increasing. While big data and artificial intelligence have emerged across the fields, in healthcare, such rapid development is hindered by numerous factors. Predominantly, health-care software developed decades ago cannot foresee the demands of modern data processing and analysis. We present the challenges, remedies, and steps of efficient patient data integration that have been co-developed with clinicians at Lenval Children's University Hospital in Nice, France.
Methods: In collaboration with pediatricians, we created an integration framework that integrated a patient's germane historical data (from the past 10 years) for research purposes. The clinical data presented in this study were collected between 2012 and 2021 in the Lenval Children's University Hospital Pediatric Emergency Department.
Results: We present the architecture of a clinical data warehouse (CDW) and demonstrate its use. CDW can also host doctoral notes, which is the key element for creating large language models that can help predict patient outcomes and provide critical information to health-care professionals. We also conducted several tests on the utilization of this new CDW, recorded multiple challenges on data integration, and gave three suggestions on software design. The CDW we created represents a solid foundation for future machine learning models of patient flow, hospital economics, and studies on rare diseases at CHU-Lenval.
Conclusion: Although the integration framework is grounded in pediatrics, the challenges discussed, and the proposed remedies are relevant for software development across medical specializations. Our recommendations for software design can help with future secondary usage of Electronic Health Record.

Keywords:  Secondary use of data; clinical data warehouse; data mining; data scrubbing; electronic health records; software design

DOI:  https://doi.org/10.1177/20552076251374233
Int J Technol Assess Health Care. 2025 Sep 30. 41(1): e69

Engaging stakeholders along health technology assessment pathways: a scoping review of international practice.

Drew Carter, Mah Laka, Yuan Gao, Olivia Choi, David Tamblyn, Tracy Merlin.

   OBJECTIVES: Health technology assessment (HTA) has been characterized as a complex adaptive system that centrally features stakeholder interactions. This article provides an overview of current practices in HTA stakeholder engagement concerning medicines.
METHODS: We conducted a scoping review of English-language sources published between 2018 and 2023, including 66 peer-reviewed articles and 264 gray literature sources describing stakeholder involvement in HTA processes relating to medicines.
RESULTS: Industry is commonly permitted to provide a submission for funding, though the modes and time points of industry engagement are many. Clinician and patient engagement are regarded as especially important with increased intervention complexity and innovation. Stakeholder engagement is perhaps mostly conducted to enhance the collation and interpretation of evidence, not necessarily to increase the legitimacy of the HTA process or give stakeholders influence over a decision that affects them. Patients are mostly engaged through broader public consultation. Sometimes they work directly with other stakeholders. Problems with patient engagement include challenges with recruitment, time, and resource constraints. Stakeholder groups can also differ in how they view and prioritize public and patient engagement. Public engagement is often limited to a matter of transparency and public accountability, but the reasons to undertake public engagement are numerous and varied. They include gaining input on affordability or prioritization issues.
CONCLUSIONS: HTA decision-making committees should commit to publicly communicating how they considered and made use of various stakeholder inputs. This could build trust and confidence in the committees and guide the public and patients on the information that committees find helpful.

Keywords:  biomedical; evidence-based medicine; patient participation; social responsibility; stakeholder participation; technology assessment

DOI:  https://doi.org/10.1017/S0266462325100494
Continuum (Minneap Minn). 2025 Oct;31(5): 1486-1500

Safety, Costs, and Ethical Issues in Drug Development and Gene Therapy for Rare Diseases.

Nicholas Johnson, A Gordon Smith.

Scientific advances have provided the ability to modify the course of genetic diseases through the use of genetic therapies. These therapies include RNA-based approaches that either reduce the translation of a toxic protein or skip exons to produce a more functional protein. Adeno-associated virus-based delivery of missing gene products has also been demonstrated to modify the overall course of diseases. The science has advanced beyond the ability of our health system infrastructure to keep pace. Challenges with drug pricing, manufacturing, regulatory pathways, and patient access remain. The ability to overcome these challenges will directly influence the ability to deliver these highly promising therapies to patients waiting for them.

DOI: https://doi.org/10.1212/cont.0000000000001619