bims-curels 2025-07-06 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–07–06
ten papers selected by
Cure Mito Foundation

Mitochondrial replacement techniques: The perspectives of mitochondrial disease specialists in Germany.
Mitochondrial DNA genotypes modify m.3243A>G-associated mitochondrial disease via the 15-HETE/Akt/FoxO1 pathway.
Rare presentation of dandy-walker variant syndrome associated with leigh syndrome: a promising therapeutic approach for prognosis in children related in a case report.
Genetic Underpinnings of Mitochondrial Cardiomyopathy: A Scoping 2010-2024 Update.
The mitochondrial disease biomarker GDF15 is dynamic, quantifiable in saliva, and correlates with disease severity.
Contributions and recognition of patient partners in pediatric health research: A rapid scoping review protocol.
Challenges and Progress of Orphan Drug Development for Rare Diseases.
Correction: The m.3290T > C variant might be a protective factor against the pathogenic m.3243 a > g variant: a case study.
"Don't Tell Them Anything": Should Surrogate Decision-Makers Be Allowed to Withhold Information from Other Family Members or Prevent Them from Visiting with a Patient?
The attitudes of individuals with or at risk of adult-onset genetic conditions on reproductive genetic testing: A systematic review.

Soc Sci Med. 2025 May 15. pii: S0277-9536(25)00507-6. [Epub ahead of print]382 118177

Mitochondrial replacement techniques: The perspectives of mitochondrial disease specialists in Germany.

Jacquelyne Luce.

  'Mitochondrial disease' is an umbrella category for neurogenetic and metabolic diseases which are associated with mitochondrial dysfunction caused by genetic variations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). This article draws on interviews with four mitochondrial disease specialists in Germany in order to explore their perspectives on mitochondrial replacement techniques (MRTs), emerging 'IVF-based technologies' which could potentially prevent the transmission of mitochondrial DNA disease. MRTs aim to exchange (or replace) the cytoplasm of an intended parent's egg cell, which contains disease-causing mtDNA, with the cytoplasm from an egg cell of another individual (aka the mitochondrial donor). MRTs are legal and regulated by assisted reproduction legislation in the UK (since 2015) and Australia (since 2022) for the explicit purpose of reducing the risk of transmitting an mtDNA variant associated with a high risk of severe mitochondrial disease. MRTs are not available in Germany. In other countries, MRTs are offered by fertility clinics for a variety of indications, ranging from the prevention of mitochondrial disease to broader experiences of fertility difficulties. Mitochondrial disease specialists in Germany emphasized the predictability of mitochondrial unpredictability and a mitochondrial disease severity spectrum. Closely engaging with the use of two concepts by the specialists I interviewed-'predictability/unpredictability' and 'severity'-which also appeared in formal and public representations and discussions in the UK, I show how the invocation of these notions may paradoxically both enable and curtail support for the clinical implementation of MRTs.

Keywords:  Assisted reproduction; Mitochondrial disease; Mitochondrial replacement techniques; Predictability; Rare disease; Severity spectrum; Unpredictability

DOI:  https://doi.org/10.1016/j.socscimed.2025.118177
Biochim Biophys Acta Mol Cell Res. 2025 Jun 30. pii: S0167-4889(25)00117-X. [Epub ahead of print]1872(7): 120012

Mitochondrial DNA genotypes modify m.3243A>G-associated mitochondrial disease via the 15-HETE/Akt/FoxO1 pathway.

Qian Wang, Chang You, Xiaoning Qu, YiQing Zhang, Yuxiao Bai, Xianlong Lin, Zhaoxia Wang, Hezhi Fang, Jianxin Lyu, Minghua Jiang, Ya Wang.

  Mitochondrial disease caused by mitochondrial DNA (mtDNA) 3243A>G mutation is characterized by high levels of clinical heterogeneity. Varied m.3243A>G mutation loads among patients are used to, but cannot fully explain, disease heterogeneity. Here, we found that mtDNA genotypes (haplogroups) modify m.3243A>G-associated natural selection and cell fate determination. mtDNA haplogroup M7 was less prevalent in a multi-center m.3243A>G disease cohort. Further functional studies using cybrids showed that M7 accelerated cell proliferation and shortened G0/G1 cell cycle when compared with cybrid carrying a non-M7 haplogroup (D5). However, mitochondrial function and cell viability were even worse in M7 cybrid than D5 cybrid when treated with mitochondrial oxidative phosphorylation (OXPHOS) inhibitors, indicating that M7 drives negative selection in patients with m.3243A>G during evolution. By adopting multi-omics strategies, we showed a lesser increase of 15-hydroxyeicosatetraenoic acid (15-HETE) levels in M7 cybrid owing to OXPHOS inhibition, leading to insufficient Akt/FoxO1 activation and increased apoptosis. Notably, 15-HETE administration activated Akt/FoxO1 phosphorylation and abolished apoptosis difference between M7 and D5 cybrids, suggesting that augmented 15-HETE was vital to protect cells from death. Collectively, our work identified a genetic modifier of m.3243A>G-associated mitochondrial disease and demonstrated that the mitochondrial retrograde 15-HETE/Akt/FOXO1 signaling cascade plays an important role in protecting cells from OXPHOS dysfunction-induced cell death.

Keywords:  15-HETE; Akt-FoxO1 signaling; Mitochondrial disease; m.3243A>G; mtDNA haplogroup

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120012
Oxf Med Case Reports. 2025 Jun;2025(6): omaf061

Rare presentation of dandy-walker variant syndrome associated with leigh syndrome: a promising therapeutic approach for prognosis in children related in a case report.

Bianca Frigo Pires, Graziele Ines Silva Lopo, Anaí Ramoa Siqueira, Luiza Resende Felisberto, Rafaella Simão Martini, Ana Beatriz Valim Alves, Amanda Carolina Rodrigues Silva, Flávia Xavier Lima Carvalho, Aline Pirola Aliseda, Mariane Martinhon Martins, Carla Kreuzberg Salgado, Salum Bueno da Silveira Junior, Camila Garcia Ferrari Jacob.

   INTRODUCTION: Dandy-Walker syndrome (D-WS) is a rare congenital brain anomaly that primarily impacts the fourth ventricle and cerebellum. Its variant is even rarer and includes cerebellar dysgenesis, with possible posterior fossa enlargement and variable cerebellar vermis hypoplasia.
CASE REPORT: We present the case of a patient diagnosed late with the Dandy-Walker Syndrome variant, associated with Leigh Syndrome, at a tertiary hospital. The patient received an optimized, multidisciplinary treatment approach to improve prognosis.
DISCUSSION: Early intervention in pediatric neurodegenerative diseases through a multidisciplinary team that includes medical, speech therapy, and physiotherapy support is crucial for a better prognosis in these cases.

Keywords:  dandy-walker variant; leigh syndrome; pediatric syndrome

DOI:  https://doi.org/10.1093/omcr/omaf061
DNA Cell Biol. 2025 Jul 02.

Genetic Underpinnings of Mitochondrial Cardiomyopathy: A Scoping 2010-2024 Update.

Insaf Moudian, Joaira Bakkach, Zeineb Zian, Naima Ghailani Nourouti, Amina Barakat, Mohcine Bennani Mechita.

  Mitochondrial cardiomyopathy is a rare specific myocardial condition characterized by abnormal myocardium structure and/or function due to mitochondrial respiratory chain deficiency. This cardiac disorder results from mutations in mitochondrial DNA or nuclear genes affecting mitochondrial function. These mutations disrupt oxidative phosphorylation and consequently lead to energy deficit in the myocardial tissue and systemic symptoms due to impaired mitochondrial metabolism. In the current review, we aimed to highlight genetic and molecular underpinnings of mitochondrial cardiomyopathy. The impact of mitochondrial DNA characteristics on mitochondrial cardiomyopathy, mutations in both mitochondrial and nuclear genomes, as well as diagnostic limitations and future therapies, will be presented in this work.

Keywords:  ETC genes; mitochondria; mitochondrial cardiomyopathy; mtDNA; mutations; tRNA

DOI:  https://doi.org/10.1089/dna.2025.0089
Mol Genet Metab. 2025 Jun 16. pii: S1096-7192(25)00170-2. [Epub ahead of print]145(4): 109179

The mitochondrial disease biomarker GDF15 is dynamic, quantifiable in saliva, and correlates with disease severity.

Qiuhan Huang, Caroline Trumpff, Anna S Monzel, Shannon Rausser, Jack Devine, Cynthia C Liu, Catherine Kelly, Mangesh Kurade, Shufang Li, Kris Engelstad, Kurenai Tanji, Vincenzo Lauriola, Tian Wang, Shuang Wang, Richard Sloan, Robert-Paul Juster, Michio Hirano, Martin Picard.

Circulating growth differentiation factor 15 (GDF15) is a biomarker of mitochondrial diseases and aging, but its natural dynamics and response to acute stress in blood and other biofluids have not been well defined. Using extensive samples from MiSBIE participants with rare mitochondrial diseases (MitoD), we examined GDF15 biology in 290 plasma and 860 saliva aliquots from 40 subjects with the m.3243 A > G mutation (n = 25) or with single, large-scale mtDNA deletions (n = 15). Compared to healthy controls, both MitoD groups exhibited significantly elevated blood and saliva GDF15 (p < 0.0001). To examine the origin of GDF15 protein in saliva, we profiled GDF15 expression in 48 tissues from the GTEx dataset and identified high GDF15 expression in salivary gland secretory cells. Despite being chronically elevated in MitoD, saliva GDF15 further increased in response to experimental laboratory mental stress alone (without physical exertion), whereas the stress-induced plasma GDF15 reactivity was blunted in MitoD compared to controls. Using a home-based saliva collection protocol, we show that similar to other stress-related metabolic hormones, saliva GDF15 is highest upon awakening and declines rapidly by 61.2 % within 45 min. Elevated saliva GDF15 levels persisted throughout the day in MitoD. Clinically, saliva GDF15 correlated with neurological symptoms, fatigue, and functional capacity. Importantly, stress-evoked changes in GDF15 did not amplify noisy disease severity associations, but rather consistently increased the effects sizes for GDF15-symptoms connections, pointing to converging psychobiology underlying the responses to mitochondrial OxPhos defects and acute mental stress. These results open the door to exploring saliva GDF15 as a non-invasive monitoring approach for mitochondrial diseases and call for further studies examining the psychobiological processes linking mitochondria, mental stress, and GDF15 dynamics.

DOI: https://doi.org/10.1016/j.ymgme.2025.109179
MethodsX. 2025 Dec;15 103447

Contributions and recognition of patient partners in pediatric health research: A rapid scoping review protocol.

Colleen Pawliuk, Elaha Niazi, Anne-Mette Hermansen, Candice Barrans, Danielle Pietramala, Gabriel Zamma, Harold Hal Siden.

  Patient-Oriented Research (POR) is an increasingly common approach that actively engages patients and families in the research process. Despite their significant contributions, patient-partners are rarely credited in academic publications through formal acknowledgment or authorship, and the lack of standardized documentation of their participation makes it difficult to locate patient-engaging studies. There is a limited understanding of how patient-partners are currently being engaged particularly within pediatric health research, and whether their involvement is adequately recognized. Clarifying these processes will strengthen POR in pediatrics to foster more meaningful collaboration and ultimately help improve health outcomes for children and their families. The objective of this rapid scoping review is to: 1) assess the prevalence of acknowledgement and authorship of patient partners in pediatric health research; 2) understand how patient partners contribute through the research process; and 3) assess how patient engagement is identified in publications. We will search MEDLINE (Ovid), Embase (Ovid) and CINAHL (EBSCOhost). In addition, we will search key sources of POR literature. Findings from this scoping review can be used to inform future patient-oriented research and guide the appropriate recognition of patient partner authors.•This rapid scoping review will map how patient partners are recognized for their contributions to pediatric research and how they are engaged throughout the research process•Aim is to provide an evidence base to guide appropriate recognition of patient partner authors.

Keywords:  Acknowledgement; Authorship; PPI; Patient and public input; Patient-oriented research; Rapid scoping review protocol; Scoping review

DOI:  https://doi.org/10.1016/j.mex.2025.103447
Curr Pharm Biotechnol. 2025 Jun 23.

Challenges and Progress of Orphan Drug Development for Rare Diseases.

Abhijit Debnath, Rupa Mazumder, Avijit Mazumder, Pankaj Kumar Tyagi, Rajesh Kumar Singh.

  Rare diseases, defined as conditions affecting fewer than 200,000 people in the United States or less than 1 in 2,000 people in Europe, pose significant challenges for healthcare systems and pharmaceutical research. This comprehensive review examines the evolving landscape of orphan drug development, analyzing scientific, economic, and regulatory challenges while highlighting recent technological breakthroughs and innovative approaches. We explore how artificial intelligence, next-generation sequencing, and personalized medicine are revolutionizing rare disease research and treatment development. The review details key advances in therapeutic approaches, including gene therapy, cell-based treatments, and drug repurposing strategies, which have led to breakthrough treatments for previously untreatable conditions. We analyze the impact of international collaborations, such as the International Rare Diseases Research Consortium, and discuss how regulatory frameworks worldwide have evolved to accelerate orphan drug development. The paper highlights the growing market for orphan drugs, projected to reach $242 billion by 2024 while examining the complex challenges of ensuring treatment accessibility and economic sustainability. We assess innovative clinical trial designs, patient registry development, and emerging strategies in personalized medicine that are transforming the field. Despite notable advancements, significant gaps remain in diagnosis, treatment accessibility, and sustainable funding for rare disease research. The review concludes by proposing specific actions for enhancing international collaboration, improving patient registries, and aligning incentives to address the unmet medical needs of rare disease patients, emphasizing the critical role of continued public-private partnerships and technological innovation in advancing orphan drug development.

Keywords:  Orphan Drug Act; Rare Diseases; orphan diseases; orphan drugs; pharmacoeconomics; public health policy; rare disease registries.; rare disorders

DOI:  https://doi.org/10.2174/0113892010371761250616112614
Orphanet J Rare Dis. 2025 Jul 01. 20(1): 320

Correction: The m.3290T > C variant might be a protective factor against the pathogenic m.3243 a > g variant: a case study.

Ning Zhang, Zhikang Zhang, Ying Zhang, Xun Su, Yuzhou Gao, Jing Yang, Weiwei Zou, Yunxia Cao, Dongmei Ji.

DOI: https://doi.org/10.1186/s13023-025-03872-4
HEC Forum. 2025 Jul 02.

"Don't Tell Them Anything": Should Surrogate Decision-Makers Be Allowed to Withhold Information from Other Family Members or Prevent Them from Visiting with a Patient?

Bryanna Moore, Shalom Schlagman, Laine E DiNoto, David C Kaufman, Nicholas Mercado, Michael J Nabozny, Marjorie Hodges Shaw.

  While patients have the right to control who has access to their health information and designate visitors, it is not always clear whether-when a patient lacks capacity-their surrogate also exercises such rights. States and federal laws are often vague about the limits of surrogate authority. Even where legal or institutional guidance on this issue is clear, requests by surrogates to withhold information or restrict visitation with a patient can be a source of ethical uncertainty and distress on the part of the clinical team. This paper explores the ethical issues raised by such requests. To date, there has been little exploration of this issue in the clinical ethics literature. First, we summarize the scant existing ethical and legal guidance on this issue. Second, we present two potential approaches to navigating requests from surrogates to withhold information or restrict visitation. Third, we discuss the merits and limitations of both approaches, and introduce some additional considerations that further complicate the picture. We argue for a flexible restrictive approach to information-sharing, and a constrained permissive approach to visitation. Finally, we propose several considerations that clinicians and clinical ethicists might think through in these situations to help guide their practice.

Keywords:  Clinical ethics; Clinical ethics consultation; Family disagreement; Privacy; Surrogate decision-making

DOI:  https://doi.org/10.1007/s10730-025-09554-9
J Genet Couns. 2025 Aug;34(4): e70079

The attitudes of individuals with or at risk of adult-onset genetic conditions on reproductive genetic testing: A systematic review.

Shanice Allen, Alisdair McNeill, Christopher McDermott, Felicity Boardman, Jade Howard.

  Individuals who carry a genetic variant for a genetic disease can access reproductive genetic testing in order to prevent the transmission of the gene variant to their children. This systematic review aimed to synthesize the findings from both qualitative and quantitative literature to understand these individuals' attitudes toward pre-implantation genetic testing (PGT) and prenatal testing (PNT) and how they make decisions around them. A systematic search was undertaken following PRISMA guidelines, with 37 articles meeting the inclusion criteria for evaluating experiences and attitudes of individuals with or at risk of adult-onset genetic conditions on reproductive genetic testing. Relevant findings from each study were included in a thematic synthesis. Five analytical themes were generated to elucidate the attitudes toward reproductive genetic testing and the factors that impact decision-making in individuals with or at risk of late-onset genetic diseases: (1) Preventing gene transmission; (2) finding the threshold: evaluating the necessity of reproductive genetic testing; (3) ethical/acceptability considerations; (4) external influences in decision-making; and (5) psychological and practical concerns of reproductive genetic testing. This review highlights several factors that influence attitudes toward reproductive genetic testing. Complex decision-making was a cross-cutting experience that characterizes and defines reproductive genetic testing for late-onset conditions. There was a general consensus of support for reproductive genetic testing and a belief that it should be available to all. The need for awareness and education on reproductive genetic testing is evident. Future work should look at how to address these knowledge deficits, while exploring individuals' preferences for when and by whom information is delivered. Acknowledging the complexity of decision-making can encourage meaningful discussions and address potential issues.

Keywords:  decision‐making; genetic diseases; late‐onset diseases; preimplantation genetic testing; prenatal testing; reproductive genetic testing; reproductive options

DOI:  https://doi.org/10.1002/jgc4.70079