bims-curels 2025-01-05 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–01–05
nine papers selected by
Cure Mito Foundation

Exome Sequencing in the Diagnostic Pathway for Suspected Rare Genetic Diseases: Does the Order of Testing Affect its Cost-Effectiveness?
How to Teach Clinical Reasoning in the Context of Rare Diseases in Undergraduate Medical Education.
Evolving Concept of Value in Health Economics and Outcomes Research: Emerging Tools for Innovation and Access to Cell and Gene Therapies for Rare Diseases.
The role of mitochondrial DNA variants and dysfunction in the pathogenesis and progression of multiple sclerosis.
[Artificial intelligence for the comprehensive approach to orphan/rare diseases: A scoping review].
Targeting mitochondrial transfer: a new horizon in cardiovascular disease treatment.
Basic Science and Pathogenesis.
Mitochondrial dysfunction and Alzheimer's disease: pathogenesis of mitochondrial transfer.
Improving Social Media-Based Support Groups for the Rare Disease Community: Interview Study With Patients and Parents of Children with Rare and Undiagnosed Diseases.

Appl Health Econ Health Policy. 2024 Dec 30.

Exome Sequencing in the Diagnostic Pathway for Suspected Rare Genetic Diseases: Does the Order of Testing Affect its Cost-Effectiveness?

Care4Rare Canada

BACKGROUND: Patients with suspected rare diseases often experience lengthy and uncertain diagnostic pathways. This study aimed to estimate the cost-effectiveness of exome sequencing (ES) in different positions in the diagnostic pathway for patients suspected of having a rare genetic disease.
METHODS: Data collected retrospectively from 305 patients suspected of having a rare genetic disease (RGD), who received clinical-grade ES and participated in the Canadian multicentre Care4Rare-SOLVE study, informed a discrete event simulation of the diagnostic pathway. We distinguished between tests that can lead to the diagnosis of a specific RGD ('indicator tests') and more routine non-RGD diagnostic tests ('non-indicator tests'). Five strategies were considered: no-ES, and ES as 1st, 2nd, 3rd, or 4th test (Tier 1, Tier 2, Tier 3, and Tier 4, respectively), where ES was the final test in the diagnostic pathway if included. Outcomes included the diagnostic yield, time-to-diagnosis, time on the diagnostic pathway, and test costs for each strategy. The cost-effectiveness analysis from a Canadian healthcare system perspective was conducted with diagnostic yield as the primary outcome of interest. Probabilistic analyses and expert-defined scenario analyses quantified uncertainty.
RESULTS: Implementing ES increases the diagnostic yield by 16 percentage points from 20% with no-ES to 36%. Exome sequencing, as the first test (Tier 1), resulted in the shortest time to a diagnosis and the lowest testing cost. Mean testing costs per patient were CAD4347 (95% CI 3925, 4788) for no-ES, CAD2458 (95% CI 2406, 2512) for Tier 1, CAD3851 (95% CI 3684, 4021) for Tier 2, CAD5246 (95% CI 4956, 5551) for Tier 3 and CAD6422 (95% CI 5954, 6909) for Tier 4, with Tier 1 having the highest diagnostic yield at the lowest cost. The scenario analyses yielded results consistent with those of the base case.
CONCLUSIONS: Implementing ES to diagnose patients suspected of having a RGD can result in a higher diagnostic yield. Although a limitation of our study was that the yield for the non-ES indicator tests was estimated using expert opinion due to a lack of available data, the results underscore the value of ES as a first-line diagnostic test, offering reduced time to diagnosis and lower overall testing costs.

DOI: https://doi.org/10.1007/s40258-024-00936-7
Clin Teach. 2025 Feb;22(1): e70012

How to Teach Clinical Reasoning in the Context of Rare Diseases in Undergraduate Medical Education.

Eva Feigerlova.

  While rare diseases are individually rare, they are collectively common. Physicians are likely to see patients presenting with rare diseases during their medical practice. Despite the fact that rare diseases present diagnostic and therapeutic challenges, they are not sufficiently addressed by undergraduate medical curricula. The need to train medical students has been expressed by stakeholders in several countries. Moreover, among the objectives of the World Health Organization are to reduce a diagnostic time, decrease diagnostic errors and ensure the provision of multidisciplinary care. We have initiated an educational module aspiring to enhance understanding of rare diseases among undergraduate medical students. Based on our experience, on the literature data and related learning theories, this document presents some tips on how to foster training of undergraduate medical students in the context of rare diseases.

Keywords:  learning module; rare disease; undergraduate medical curriculum

DOI:  https://doi.org/10.1111/tct.70012
Value Health. 2024 Dec 30. pii: S1098-3015(24)06799-8. [Epub ahead of print]

Evolving Concept of Value in Health Economics and Outcomes Research: Emerging Tools for Innovation and Access to Cell and Gene Therapies for Rare Diseases.

Walter Toro, Min Yang, Anish Patel, Su Zhang, Omar Dabbous, Louis P Garrison.

   OBJECTIVE: Recent scientific breakthroughs have propelled the development of disease-modifying and potentially curative cell and gene therapies (CGTs) for rare diseases, including those diseases previously considered untreatable. However, the unique characteristics of CGTs pose challenges for the traditional methods of therapy value determination, reimbursement, and outcome evaluation used by regulatory and assessment agencies for product approval and market access. Notably, CGTs are one-time or short-course treatments, often first-in-class (precluding direct comparisons with effective alternatives), and have health benefits that are largely realized over time.
METHODS: We summarized emerging health economic and outcomes research (HEOR) solutions in five areas pertaining to CGTs for rare diseases using examples from literature and recently approved therapies. These solutions include the collection of real-world data (RWD) to generate real-world evidence (RWE), patient centricity and novel value assessment frameworks, evolution of economic evaluation methodologies, novel reimbursement models and management of affordability, and health equity and societal benefits.
RESULTS: Advances in HEOR methods have informed the design and collection of long-term RWD for CGT efficacy extrapolation, the use of novel (including surrogate) endpoints, the integration of the patient's voice and preferences, and application of sophisticated statistical methodology and AI/machine learning techniques.
CONCLUSIONS: The continued innovation of HEOR is expected to contribute to improved health outcomes, reduced costs, and enhanced access, ultimately enabling more efficient delivery of CGTs to patients living with rare diseases.

Keywords:  cell and gene therapies; health economic and outcomes research; onasemnogene abeparvovec; rare diseases; real-world evidence

DOI:  https://doi.org/10.1016/j.jval.2024.12.006
Mitochondrion. 2024 Dec 26. pii: S1567-7249(24)00160-0. [Epub ahead of print]81 102002

The role of mitochondrial DNA variants and dysfunction in the pathogenesis and progression of multiple sclerosis.

Ramyar Rahimi Darehbagh, Shaghayegh Khanmohammadi, Nima Rezaei.

  Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system (CNS). The etiology of MS remains elusive, with a complex interplay of genetic and environmental factors contributing to its pathogenesis. Recent studies showed mitochondrial DNA (mtDNA) as a potential player in the development and progression of MS. These studies encompassed mtDNA variants, copy number variations, and haplogroups. This narrative review aims to synthesize the current understanding of the role of mtDNA's in MS. The findings of this review suggest that mtDNA may indeed play a role in the development and progression of MS. Several studies have reported an association between mtDNA variants and increased susceptibility to MS, while others have found a link between mtDNA copy number variations and disease severity. Furthermore, specific mtDNA haplogroups have been demonstrated to confer protection against MS. MtDNA alterations may make neurons and oligodendrocytes more susceptible to inflammatory and oxidative stress, causing demyelination and axonal degeneration in MS patients. In conclusion, this review underscores the potential significance of mtDNA in the pathogenesis of MS and highlights the need for further research to fully elucidate its role. A deeper understanding of mtDNA's involvement in MS may pave the way for the development of novel therapeutic strategies to combat this debilitating disease.

Keywords:  Mitochondria; Multiple sclerosis; Neurodegeneration; Neuroinflammation; mitochondrial DNA

DOI:  https://doi.org/10.1016/j.mito.2024.102002
Semergen. 2024 Dec 28. pii: S1138-3593(24)00244-2. [Epub ahead of print]51(5): 102434

[Artificial intelligence for the comprehensive approach to orphan/rare diseases: A scoping review].

L M Acero Ruge, D A Vásquez Lesmes, E H Hernández Rincón, L P Avella Pérez.

   INTRODUCTION: Orphan diseases (OD) are rare but collectively common, presenting challenges such as late diagnoses, disease progression, and limited therapeutic options. Recently, artificial intelligence (AI) has gained interest in the research of these diseases.
OBJECTIVE: To synthesize the available evidence on the use of AI in the comprehensive approach to orphan diseases.
METHODS: An exploratory systematic review of the Scoping Review type was conducted in PubMed, Bireme, and Scopus from 2019 to 2024.
RESULTS: fifty-six articles were identified, with 21.4% being experimental studies; 28 documents did not specify an OD, 8 documents focused primarily on genetic diseases; 53.57% focused on diagnosis, and 36 different algorithms were identified.
CONCLUSIONS: The information found shows the development of AI algorithms in different clinical settings, confirming the potential benefits in diagnosis times, therapeutic options, and greater awareness among health professionals.

Keywords:  Aprendizaje automático; Aprendizaje profundo; Artificial intelligence; Computer assisted; Deep learning; Diagnosis; Diagnostic imaging; Diagnóstico por imagen; Diagnóstico por ordenador; Enfermedad huérfana; Enfermedad rara; Inteligencia artificial; Machine learning; Neuronal networks computer; Orphan diseases; Rare diseases; Redes neuronales de la computación

DOI:  https://doi.org/10.1016/j.semerg.2024.102434
J Transl Med. 2024 Dec 31. 22(1): 1160

Targeting mitochondrial transfer: a new horizon in cardiovascular disease treatment.

Baile Zuo, Xiaoyan Li, Dawei Xu, Liping Zhao, Yang Yang, Yi Luan, Bi Zhang.

  Cardiovascular diseases (CVDs) are the leading cause of mortality among individuals with noncommunicable diseases worldwide. Obesity is associated with an increased risk of developing cardiovascular disease (CVD). Mitochondria are integral to the cardiovascular system, and it has been reported that mitochondrial transfer is associated with the pathogenesis of multiple CVDs and obesity. This review offers a comprehensive examination of the relevance of mitochondrial transfer to cardiovascular health and disease, emphasizing the critical functions of mitochondria in energy metabolism and signal transduction within the cardiovascular system. This highlights how disruptions in mitochondrial transfer contribute to various CVDs, such as myocardial infarction, cardiomyopathies, and hypertension. Additionally, we provide an overview of the molecular mechanisms governing mitochondrial transfer and its potential implications for CVD treatment. This finding underscores the therapeutic potential of mitochondrial transfer and addresses the various mechanisms and challenges in its implementation. By delving into mitochondrial transfer and its targeted modulation, this review aims to advance our understanding of cardiovascular disease treatment, presenting new insights and potential therapeutic strategies in this evolving field.

Keywords:  Cardiomyopathies; Cardiovascular diseases; Mitochondrial transfer; Myocardial infarction; Therapeutic strategies

DOI:  https://doi.org/10.1186/s12967-024-05979-x
Alzheimers Dement. 2024 Dec;20 Suppl 1 e085457

Basic Science and Pathogenesis.

Weichen Zhou, Kalpita R Karan, Wenjin Gu, Hans-Ulrich Klein, Gabriel Sturm, Philip L De Jager, David A Bennett, Michio Hirano, Martin Picard, Ryan E Mills.

BACKGROUND: The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in non-human species and recently demonstrated to occur in rare instances from one human generation to the next.
METHOD: Here we investigated numtogenesis dynamics in humans in two ways. First, we quantified Numts in 1,187 post-mortem brain and blood samples from different individuals. Second, we tested the dynamic transfer of Numts using a repeated-measures whole genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging.
RESULT: In the ROSMAP dataset, compared to circulating immune cells (n = 389), post-mitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, more brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. In the lifespan model, the longitudinal experiments revealed a gradual accumulation of one Numt every ∼13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7-fold faster than healthy donors.
CONCLUSION: Combined, our data document spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human post-mitotic tissues produces functionally-relevant human Numts over timescales shorter than previously assumed.

DOI: https://doi.org/10.1002/alz.085457
Front Aging Neurosci. 2024 ;16 1517965

Mitochondrial dysfunction and Alzheimer's disease: pathogenesis of mitochondrial transfer.

Yun Wei, Xinlei Du, Hongling Guo, Jingjing Han, Meixia Liu.

  In recent years, mitochondrial transfer has emerged as a universal phenomenon intertwined with various systemic physiological and pathological processes. Alzheimer's disease (AD) is a multifactorial disease, with mitochondrial dysfunction at its core. Although numerous studies have found evidence of mitochondrial transfer in AD models, the precise mechanisms remain unclear. Recent studies have revealed the dynamic transfer of mitochondria in Alzheimer's disease, not only between nerve cells and glial cells, but also between nerve cells and glial cells. In this review, we explore the pathways and mechanisms of mitochondrial transfer in Alzheimer's disease and how these transfer activities contribute to disease progression.

Keywords:  AD treatment; Alzheimer’s disease; mitochondrial dysfunction; mitochondrial transfer; neuroprotection

DOI:  https://doi.org/10.3389/fnagi.2024.1517965
JMIR Hum Factors. 2024 Dec 30. 11 e57833

Improving Social Media-Based Support Groups for the Rare Disease Community: Interview Study With Patients and Parents of Children with Rare and Undiagnosed Diseases.

Tom A Doyle, Samantha L Vershaw, Erin Conboy, Colin M E Halverson.

   BACKGROUND: The rarity that is inherent in rare disease (RD) often means that patients and parents of children with RDs feel uniquely isolated and therefore are unprepared or unsupported in their care. To overcome this isolation, many within the RD community turn to the internet, and social media groups in particular, to gather useful information about their RDs. While previous research has shown that social media support groups are helpful for those affected by RDs, it is unclear what these groups are particularly useful or helpful for patients and parents of children with RDs.
OBJECTIVE: This study aimed to identify what specific features of disease-related support groups (DRSGs) the RD community finds particularly useful or supportive and provide a set of recommendations to improve social media-based RD support groups based on this information.
METHODS: Semistructured qualitative interviews were performed with patients and parents of patients with RDs. Interview participants had to be at least 18 years of age at the time of the interview, be seen by a genetics specialist at a partner health care institution and be proficient in the English language. Social media use was not a prerequisite for participation, so interview participants ranged from extensive users of social media to those who chose to remain off all social media. All interviews were conducted by phone, recorded, and then transcribed. Interview transcripts were then coded using the 6 steps outlined by Braun and Clarke. Three researchers (TAD, SLV, and CMEH) performed initial coding. After this, the study team conducted a review of themes and all members of the team agreed upon a final analysis and presentation of data.
RESULTS: We conducted 31 interviews (mean age 40, SD 10.04 years; n=27, 87% were women; n=30, 97% were non-Hispanic White). Thematic analysis revealed that social media DRSG users identified the informational usefulness of these groups as being related to the gathering and sharing of specific information about an RD, clarification about the importance and meaning of certain symptoms, and obtaining insight into an RD's progression and prognosis. Participants also identified that DRSGs were useful sources of practical information, such as tips and tricks about managing RD-related issues and concerns. In addition, participants found DRSGs to be a useful space for sharing their disease-related stories but also highlighted a feeling of exhaustion from overexposure and overuse of DRSGs.
CONCLUSIONS: This study identifies the usefulness of DRSGs for the RD community and provides a set of recommendations to improve future instances of DRSGs. These recommendations can be used to create DRSGs that are less prone to splintering into other DRSGs, thus minimizing the risk of having important RD-related information unhelpfully dispersed amongst a multitude of support groups.

Keywords:  Ehlers-Danlos syndrome; collagen disease; connective tissue disorders; cutis elastica; fibrillar collagen; genetic disorder; genetics; hyperelasticity; hypermobility of joints, inherited; pediatric; pediatric rare disease; rare disease; social media; support groups

DOI:  https://doi.org/10.2196/57833