bims-curels 2025-11-16 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–11–16
eleven papers selected by
Cure Mito Foundation

Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.
MT-ATP6 variant as a cause of adult-onset hereditary spastic paraparesis: A case report and literature review.
Testing the mother's curse hypothesis in human mitochondrial genome evolution.
Drug discovery research with the iPSC models of neurodegenerative diseases.
Uncommon yet impactful - case-based reflections on rare neurologic disorders.
RARE-X: A Patient-Driven Approach for Collecting Symptom and Patient-Reported Outcome Data in Rare Diseases.
Gene Therapy in Rare Genetic Disorders: Current Progress and Future Perspectives.
A qualitative study among guideline developers revealed challenges and strategies for rare disease guideline development.
Basket trials in rare diseases: a systematic review of current practices, methodological challenges, and future directions.
Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.
Exploring the role of patient activity in the clinical decision-making processes of health care practitioners working in hospital care: A qualitative study.

Int J Mol Sci. 2025 Oct 22. pii: 10275. [Epub ahead of print]26(21):

Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.

Shruti Somai, Chioma H Aloh, Dillon E King, William C Copeland.

  Mitochondria are vital for cellular energy production, as these organelles generate most of the cellular energy required for various metabolic processes. Mitochondria contain their own circular DNA, which is present in multiple copies and is exclusively maternally inherited. Cellular energy in the form of adenosine 5'-triphosphate is produced via oxidative phosphorylation and involves the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes. Mitochondrial DNA itself is replicated by a dedicated set of nuclear-encoded proteins composed of the DNA polymerase gamma, the Twinkle helicase, the mitochondrial single-stranded DNA binding protein, as well as several accessory factors. Mutations in these genes, as well as in the genes involved in nucleotide metabolism, are associated with a spectrum of mitochondrial disorders that can affect individuals from infancy to old age. Additionally, mitochondrial disease can arise as a result of point mutations, deletions, or depletion in the mitochondrial DNA or in genes involved in mitochondrial transcription, replication, maintenance, and repair. Although a cure for mitochondrial diseases is currently elusive, several treatment options have been explored. In this review, we explore the molecular insights of the core mitochondrial replisome proteins that have aided our understanding of mitochondrial diseases and influenced current therapies.

Keywords:  DNA polymerase γ; PolG; PolG2; Twinkle; mitochondria; mitochondrial diseases; mtDNA; mtDNA replication; mtSSB

DOI:  https://doi.org/10.3390/ijms262110275
J Neuromuscul Dis. 2025 Nov 12. 22143602251391068

MT-ATP6 variant as a cause of adult-onset hereditary spastic paraparesis: A case report and literature review.

Care4Rare Canada Consortium

  BackgroundHereditary spastic paraplegia (HSP) is a heterogenous group of rare genetic disorders characterized by progressive corticospinal and dorsal spinal cord axonal degeneration manifesting as muscle weakness and spasticity of the lower extremities. Over 98% of solved HSP cases are caused by pathogenic variants in the nuclear DNA.CaseWe report a family carrying the m.9035T > C [p.(Leu170Pro)] pathogenic variant in the mitochondrial MT-ATP6 gene in the setting of maternally inherited, late-onset HSP. The proband (age 67 years) presented with classical, late-onset, pure HSP. Her affected daughter (age 39 years) developed late-onset, complex HSP, with asymmetrical axonal sensorimotor polyneuropathy. Her second daughter (age 46 years) carried the same pathogenic variant with high heteroplasmy but was clinically unaffected at last assessment, suggesting age-dependent or incomplete penetrance.Summary of literatureThe substitution of a leucine for a proline affects a highly conserved transmembrane helix of the subunit "a" at a key functional domain in the mitochondrial ATP synthase complex. The m.9035T > C variant has been reported in several families presenting with common phenotypic presentations of ATP6-related disorders such as maternally inherited Leigh syndrome (MILS) and the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP). HSP is a rare presentation in ATP6-related disorders; mitochondrial ATP6-induced HSP has previously been published in only one family carrying a homoplasmic m.9176T > C [p.(Leu217Pro)] variant.ConclusionThis report highlights the role of MT-ATP6 pathogenic variants in complex and pure HSP and raises the relevance of genetic testing of MT-ATP6 in undiagnosed cases of sporadic or maternally inherited HSP.

Keywords:  gait ataxia; genome; heteroplasmy; maternal transmission; mitochondrial diseases; muscle spasticity; polyneuropathy

DOI:  https://doi.org/10.1177/22143602251391068
Genome Biol Evol. 2025 Nov 05. pii: evaf207. [Epub ahead of print]

Testing the mother's curse hypothesis in human mitochondrial genome evolution.

Ruiqi Yuan, Jianzhi Zhang.

  In species where mitochondrial DNA (mtDNA) is maternally inherited such as vertebrates, mtDNA mutations harming males only are not subject to purifying selection and thus can spread in a population, especially when these mutations benefit females. Therefore, the mother's curse hypothesis (MCH) posits a greater mtDNA mutation load in males than in females. MCH is potentially important for human health, disease, and evolution, but a systematic test that considers the vast human mtDNA variation is lacking. Analyzing the genotypic and phenotypic data of approximately 0.5 million British participants in the UK Biobank, we estimate the reproductive fitness of mtDNA variants in each sex. Contradicting MCH, a positive intersexual correlation in the number of offspring exists across mitochondrial haplogroups. While a significant variation in the number of opposite-sex sexual partners-a proxy for reproductive fitness in premodern societies-is present among mitochondrial haplogroups, no significant intersexual correlation in this quantity is detected. The frequencies of a few mtDNA variants differ significantly between males and females, suggesting that these variants differentially affect the survival in the two sexes, but the number of such variants with lower male frequencies is not significantly different from that with lower female frequencies. Analysis of disease associations also finds no enrichment of male disease-associated mtDNA variants despite the discovery of multiple sex-biased disease associations. Together, these findings provide no genomic support to MCH in humans and suggest no difference in mtDNA mutation load between the two sexes that is detectable in the UK Biobank.

Keywords:  GWAS; disease; fitness; mtDNA; mutation load; sex

DOI:  https://doi.org/10.1093/gbe/evaf207
Neurosci Res. 2025 Nov 08. pii: S0168-0102(25)00168-3. [Epub ahead of print] 104985

Drug discovery research with the iPSC models of neurodegenerative diseases.

Masahiro Adachi, Haruhiko Banno, Haruhisa Inoue.

  Induced pluripotent stem cells (iPSCs) are widely used in research because they can be used to create models of diseases with the same genomic background as in patients. Recently, it has become recognized that the use of iPSCs for screening can promote drug discovery research. Additionally, research is being conducted to develop high-quality models for drug discovery and to link translational research with clinical studies. The present work focuses on neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), and broadly introduces the latest research using iPSCs, from disease mechanism studies to drug discovery research. In addition, clinical trials based on research with iPSCs have been conducted: bosutinib, ropinirole and ezogabine for ALS, WVE-004 and BIIB078 for ALS with frontotemporal dementia (ALS/FTD), and bromocriptine for familial AD. Finally, we also wish to mention screening studies utilizing artificial intelligence (AI).

Keywords:  ALS with frontotemporal dementia (ALS/FTD); Alzheimer's disease (AD); amyotrophic lateral sclerosis (ALS); drug discovery research; induced pluripotent stem cells (iPSCs); neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.neures.2025.104985
Neurol Neurochir Pol. 2025 Nov 13.

Uncommon yet impactful - case-based reflections on rare neurologic disorders.

Tomasz Chmiela, Zbigniew K Wszolek.

  Rare diseases (RDs) are a heterogeneous group of disorders defined by their low prevalence - affecting fewer than 1 in 2,000 individuals in Europe and fewer than 200,000 people in the US. Although individually uncommon, rare diseases collectively impact an estimated 263 to 446 million people worldwide. Early recognition and diagnosis remain major challenges, particularly in neurology, where overlapping phenotypes and limited awareness often delay appropriate management. We present 3 illustrative case studies highlighting the diagnostic and therapeutic complexities associated with rare neurologic disorders. The first case describes a patient with CSF1R-related disorder; diagnosis was significantly delayed due to initial misattribution of symptoms to traumatic brain injury. This delay ultimately precluded timely intervention with disease-modifying therapies such as hematopoietic stem cell transplantation. The second case involves a patient with frontotemporal dementia and parkinsonism linked to chromosome 17 with a pathogenic c.837T>G, p.N279K variant in the MAPT gene, also known as pallidopontonigral degeneration. Although a strong family history facilitated early diagnosis, the case underscores the broader challenges of managing hereditary neurodegenerative diseases within affected families. The third case presents an exceptionally rare scenario of dual pathogenic mutations in ATXN3 and ATXN8OS, resulting in concurrent diagnoses of spinocerebellar ataxia types 3 and 8. This case exemplifies the clinical ambiguity and interpretive difficulty posed by co-occurring rare variants with overlapping symptomatology. Collectively, these 3 cases emphasize the importance of accurate, timely diagnosis to avoid unnecessary testing in rare neurologic diseases. Timely recognition enables access to emerging personalized therapies and support systems.

Keywords:  CSF1R-RD; MAPT; PPND; SCA; SCA3; SCA8; rare diseases

DOI:  https://doi.org/10.5603/pjnns.108495
Genet Med. 2025 Nov 12. pii: S1098-3600(25)00281-3. [Epub ahead of print] 101634

RARE-X: A Patient-Driven Approach for Collecting Symptom and Patient-Reported Outcome Data in Rare Diseases.

Vanessa Vogel-Farley, Karmen Trzupek, Jade Gosar, Katelyn Hobbs, Kelly Wentworth, Bridget Michaels, Geoffrey Beek, Tina Dang, Mackenzie Abramson, Megan O'Boyle, Nicole Boice, Charlene Son Rigby, Zohreh Talebizadeh.

   PURPOSE: Innovation in rare disease research is constrained by limited access to reliable and accessible patient data. Accurate characterization of many conditions requires infrastructure that captures population diversity. Existing efforts are often disease specific, investigators led, with limited data sharing. The RARE-X platform was developed to address these limitations by enabling patient-reported data collection and supporting broader data access.
METHODS: RARE-X is a disease-agnostic platform designed to capture symptoms and patient-reported outcomes using a shared survey structure. Participants across conditions complete a core set of surveys, enabling standardized data collection and cross-disease comparisons. The platform supports global participation, enables longitudinal data capture, and provides data access to researchers through an established request process.
RESULTS: Since its launch, and at the time of this report, RARE-X has enrolled 7,493 participants from 93 countries, including 3,857 patients and 3,636 caregivers or siblings, across 74 rare disease communities supported by over 120 Patient Advocacy Groups. Sixty-three percent are U.S.-based and 37% international. Data is used in research applications, community reporting, and computational analyses.
CONCLUSION: RARE-X addresses limitations of traditional registries by enabling standardized, cross-disease data collection, stakeholder input and data sharing, with potential to inform therapeutic development and advance rare disease research.

Keywords:  clinical outcome assessments; cross-disorder research; patient-driven; patient-reported outcomes; rare diseases

DOI:  https://doi.org/10.1016/j.gim.2025.101634
Curr Genomics. 2025 ;26(4): 278-289

Gene Therapy in Rare Genetic Disorders: Current Progress and Future Perspectives.

Sundus Khawaja, Raja Hussain Ali, Ishtiaq Ahmed, Muhammad Umair.

  Rare genetic disorders collectively affect millions of individuals worldwide, presenting a significant clinical and research challenge due to the diversity and complexity of the underlying mutations. Current treatment options are often limited, focusing on symptom management rather than addressing the root genetic causes. This review article aims to provide a perspective on the evolving field of gene therapy for rare genetic disorders, emphasizing recent advancements, current challenges, and future directions. A comprehensive review of recent advancements in gene therapy for rare genetic disorders was conducted, focusing on therapeutic strategies, delivery systems, and clinical outcomes. Key examples, such as the use of viral vectors and gene-editing technologies (e.g., CRISPR), were highlighted. The challenges, including immune responses and ethical concerns, were also examined. Gene therapy has achieved significant milestones, with the successful development of therapies like Zolgensma for spinal muscular atrophy and Luxturna for retinal dystrophy. However, several hurdles, including efficient gene delivery, immune reactions, and long-term safety, remain unresolved. Gene therapy holds transformative potential for the treatment of rare genetic disorders. While recent successes mark a new era in genetic medicine, ongoing research is required to refine delivery mechanisms, overcome immune-related barriers, and ensure ethical and safe therapeutic interventions.

Keywords:  Gene therapy; Zolgensma; ex vivo gene therapy; in vivo gene therapy; rare genetic disorders

DOI:  https://doi.org/10.2174/0113892029361490250310041259
J Clin Epidemiol. 2025 Nov 07. pii: S0895-4356(25)00378-6. [Epub ahead of print] 112045

A qualitative study among guideline developers revealed challenges and strategies for rare disease guideline development.

Mirthe J Klein Haneveld, Willemijn F E Irvine, Martina C Cornel, Federico Germini, Miranda W Langendam, Holger J Schünemann, Johanna H Van der Lee, Agnies M Van Eeghen, Charlotte M W Gaasterland.

   OBJECTIVE: Clinical practice guideline (CPG) development for rare diseases is challenging due to scarce evidence, small expert groups, limited resources, and heterogeneity and complexity of conditions. Critical appraisals of existing rare disease CPGs reveal variable methodological quality. We aimed to gather the experiences of rare disease guideline developers to identify methodological challenges and strategies and eventually inform methodological guidance for rare disease CPGs.
STUDY DESIGN AND SETTING: We conducted semi-structured interviews with 15 guideline developers from ten countries and diverse medical fields with hands-on experience in rare disease CPG development. Data were analysed through a combined deductive and inductive approach following the structure of the GIN-McMaster Guideline Development Checklist.
RESULTS: Small rare disease expert groups, while highly dedicated, faced significant risks related to conflicts of interest, limited methodological expertise, resource constraints, and challenges in achieving interest-holder representation. Guideline developers adopted pragmatic approaches to utilize scarce and very low-certainty direct evidence and supplement it with indirect and expert-based evidence, registry data, and mechanistic reasoning. The GRADE methodology was valued for providing transparency, structure, and consistency, but some considered it not feasible in rare disease contexts. Topics beyond the GIN-McMaster Guideline Development Checklist included deciding whether to develop a CPG or another type of quality document and supporting the broader knowledge cycle.
CONCLUSION: We gained insight into the most salient methodological issues and identified a need for further guidance and method development to improve guideline development processes for rare diseases.

Keywords:  GRADE; clinical practice guidelines; guideline development process; methodology; rare disease

DOI:  https://doi.org/10.1016/j.jclinepi.2025.112045
Orphanet J Rare Dis. 2025 Nov 12. 20(1): 578

Basket trials in rare diseases: a systematic review of current practices, methodological challenges, and future directions.

Wael Khazen, Solange Corriol-Rohou, Teresinha Evangelista, Arnauld Valent, Sarah Abbas, Xavier Nissan, Alexandre Mejat.

The development of therapies for rare diseases (RDs) continues to face persistent challenges, including small and geographically dispersed patient populations, pronounced clinical heterogeneity, and the absence of standardized outcome measures. Basket trials-master protocol studies evaluating a single therapeutic intervention across multiple diseases linked by shared molecular or clinical characteristics-offer a promising solution to these constraints. This systematic review identified 36 basket trials targeting RDs through comprehensive searches of clinical trial registries, academic databases, and grey literature. The majority (75%) focused on rare oncological indications, with only nine trials addressing non-oncological RDs. These non-oncological studies were highly heterogeneous, spread across 25 distinct conditions without overlap, and faced persistent challenges such as the lack of validated biomarkers and standardized endpoints. Most studies (81%) were Phase II trials, highlighting the exploratory role of basket designs in early-stage development. Trial designs were predominantly non-randomized and open-label (86%), reflecting the practical limitations of implementing rigorous methodologies in small, heterogeneous populations. The average trial duration was 6.5 years, and recruitment was logistically demanding, with trials involving a mean of 56 sites and, in some cases, over 1,000 centers. While basket trials show clear potential to accelerate therapeutic innovation in RDs, their application remains limited beyond oncology. Methodological constraints-such as inconsistent endpoints, limited randomization, and underpowered subgroup analyses-continue to restrict their broader use. Enhancing the utility of basket trials will require greater regulatory flexibility, wider adoption of adaptive and Bayesian designs, integration of real-world evidence, and stronger engagement with patients and advocacy groups. This review underscores both the opportunities and limitations of basket trials in RDs and provides a roadmap for realizing their potential, calling for concerted efforts from regulators, researchers, and patient advocates to expand their application and impact across the RDs spectrum.

DOI: https://doi.org/10.1186/s13023-025-04048-w
Int J Mol Sci. 2025 Oct 30. pii: 10581. [Epub ahead of print]26(21):

Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.

Margherita Zamberlan, Martina Semenzato.

  Tunneling nanotubes (TNTs) are dynamic, actin-based intercellular structures that facilitate the transfer of organelles, including mitochondria, between cells. Unlike other protrusive structures such as filopodia and cytonemes, TNTs exhibit structural heterogeneity and functional versatility, enabling both short- and long-range cargo transport. This review explores the mechanisms underlying mitochondrial transfer via TNTs, with a particular focus on cytoskeletal dynamics and the role of key regulatory proteins such as Miro1, GFAP, MICAL2PV, CD38, Connexin 43, M-Sec, thymosin β4, and Talin 2. Miro1 emerges as a central mediator of mitochondrial trafficking, linking organelle motility to cellular stress responses and tissue repair. We delve into the translational implications of TNTs-mediated mitochondrial exchange in regenerative medicine and oncology, highlighting its potential to restore bioenergetics, mitigate oxidative stress, and reprogram cellular states. Despite growing interest, critical gaps remain in understanding the molecular determinants of TNT formation, the quality and fate of transferred mitochondria, and the optimal sources for mitochondrial isolation. Addressing these questions will be essential for harnessing TNTs and mitochondrial transplantation as therapeutic tools.

Keywords:  Miro1; mitochondria; mitochondrial transplantation; tunneling nanotubes

DOI:  https://doi.org/10.3390/ijms262110581
Clin Rehabil. 2025 Nov 12. 2692155251393557

Exploring the role of patient activity in the clinical decision-making processes of health care practitioners working in hospital care: A qualitative study.

Carlos de Miguel Llorente, Miriam Van Der Velde, Ireen Scheffers, Cindy Veenhof, Karin Valkenet.

  ObjectiveThis study aims to explore the role of patient activity in the clinical decision-making processes of various health care practitioners working in hospital care.DesignQualitative research study.SettingThe study was conducted in the hospital care setting of UMC Utrecht, the Netherlands.ParticipantsHealth Care Practitioners working in the hospital setting were selected through purposive sampling. Doctors, nurses, and physiotherapists were included if their professional activity centered on inpatient care, they had worked in the hospital for over four weeks and were not students in the department.Main measuresData were collected through observations and interviews. Interview recordings were transcribed, and both the interview transcripts and observation fieldnotes were coded and analyzed using reflexive thematic analysis, following Braun and Clarke's approach. Themes were iteratively reviewed and refined, leading to the development of core themes, which were constructed by synthesizing subthemes and examining their interrelationships.ResultsThe study involved forty-two participants working at UMC Utrecht. Four core themes were identified: 1) Patient activity influences clinical decision-making, 2) clinical decision-making influences patient activity, 3) multidisciplinary dynamics influence how patient activity is valued in clinical decisions, and 4) limited use of objective measurements influences how patient activity informs clinical decisions.ConclusionThis study explores the complex interaction between clinical decision-making and patient activity and how patient activity is integrated from a multidisciplinary perspective in the hospital setting. The results highlight the importance of interdisciplinary communication, barriers and facilitators for improved decision-making and examines both implicit and explicit processes involved.

Keywords:  Patient activity; clinical decision-making; physical activity

DOI:  https://doi.org/10.1177/02692155251393557