bims-curels 2026-04-19 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2026–04–19
fifteen papers selected by
Cure Mito Foundation

Clinical and genetic analysis of Chinese patients with Leigh syndrome caused by biallelic loss-of-function variants of the NDUFAF6 gene.
Diagnostic Criteria and Management of MELAS and Stroke-Like Episodes: Consensus-Based Statements.
Bayesian quantitative decision-making framework in cell and gene therapy development for rare diseases.
Loss of TMEM65 in mice causes mitochondrial disease mediated by mitochondrial Ca2.
Beyond the genome: clinical challenges in diagnosing LONP1-related mitochondrial disorders.
Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease.
Mitochondrial DNA (MtDNA) 3243 A>G mutation associated with recurrent cholangitis post-Kasai procedure in biliary atresia.
New Treatments, Novel Conversations: A Need to Study the Science of Communication about Treatment Options for Inborn Errors of Metabolism.
Applying natural language processing and large language models to clinical notes for phenotyping and diagnosing rare diseases: a systematic review.
Shared decision-making in medical education - a systematic review.
The Patient, the Provider, and the TikTok Creator: Qualitative Analysis of the Content and Quality of Videos on Prenatal Genetic Screening.
Multi-omics applications in health and diseases.
Navigating Patient-Initiated Non-Standard Care (PINSC) Requests: Applying an Ethically Coherent Framework for Shared Decision-Making.
Pathogenic role of mitochondrial DNA mutations in heart failure: clinical features, mechanisms, and therapeutic prospects.
Navigating uncertainty during non-invasive prenatal testing: Genetic counselors' experiences of supporting autonomous reproductive decision-making.

Front Neurol. 2026 ;17 1778719

Clinical and genetic analysis of Chinese patients with Leigh syndrome caused by biallelic loss-of-function variants of the NDUFAF6 gene.

Qi Yang, Qiang Zhang, Xunzhao Zhou, Zailong Qin, Xuanjing Liang, Sheng Yi, Shujie Zhang, Weiliang Lu, Shang Yi, Jingsi Luo.

  Leigh syndrome (LS) is the most common pediatric mitochondrial disorder, typically presenting in infancy with developmental regression, neurological dysfunction, and characteristic brain MRI lesions. It is linked to over 110 genes affecting cellular energy production, making it highly genetically heterogeneous, with complex I deficiency being the most frequent cause. Biallelic mutations in NDUFAF6-a key assembly factor of complex I-cause autosomal recessive Leigh syndrome, specifically NDUFAF6-related Leigh syndrome, also designated as mitochondrial complex I deficiency, nuclear type 17 (MC1DN17; OMIM 618239). Herein, we describe two patients with biallelic loss-of-function variants in NDUFAF6. Patient 1 was homozygous for an in-frame duplication (c.362_364dupTGG; p. Val121dup), whereas patient 2 carried this duplication in trans with a novel frameshift variant (c.169_190dup; p. Leu64fs*2). Both patients manifested motor deterioration, dystonia, dysphagia, and elevated blood lactate levels during infancy, along with symmetrical basal ganglia necrosis on brain MRI. A retrospective analysis of all 24 MC1DN17 cases confirmed infantile/childhood onset, psychomotor regression, dystonia, bilateral striatal necrosis with additional features, and hyperlactataemia as universal characteristics. Mortality was low (1/24; 4%), with motor function maintained for longer than in some other LS-associated genetic subtypes. No clear genotype-phenotype correlation was identified, and disease progression remains difficult to predict. There are currently no disease-modifying treatments available; only supportive care can be provided. Our study expands the NDUFAF6 mutational spectrum and consolidates its distinct clinical profile, highlighting the need for long-term data to define natural history and guide therapy.

Keywords:  Leigh syndrome; NDUFAF6 gene; complex I deficiency; novel variant; whole-exome sequencing

DOI:  https://doi.org/10.3389/fneur.2026.1778719
Eur J Neurol. 2026 Apr;33(4): e70588

Diagnostic Criteria and Management of MELAS and Stroke-Like Episodes: Consensus-Based Statements.

Michelangelo Mancuso, Marcello Bellusci, Valerio Carelli, Irenaeus de Coo, Daria Diodato, Felix Distelmaier, Omar Hikmat, Michio Hirano, Rita Horvath, Amel Karaa, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Chiara La Morgia, Piervito Lopriore, Mika Henrik Martikainen, Robert McFarland, Olimpia Musumeci, Robert D S Pitceathly, Guido Primiano, Shamima Rahman, Fernando Scaglia, Andrew Schaefer, Manuel Schiff, Luisa Semmler, Costanza Lamperti, Serenella Servidei.

   BACKGROUND AND PURPOSE: Mitochondrial Encephalomyopathy, Lactic acidosis and Stroke-like episodes (MELAS) is a rare multisystem mitochondrial disorder with clinical heterogeneity. Diagnostic criteria and management strategies for MELAS and mitochondrial stroke-like episodes (SLE) remain inconsistent. This work provides international consensus recommendations on the definition, diagnosis, and management of MELAS and SLE in pediatric and adult populations.
METHODS: An international Delphi consensus process was conducted within the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD), in collaboration with the US Mitochondrial Medicine Society, the ERN for Hereditary Metabolic Disorders (MetabERN), and patient representatives. Following a systematic literature review, 54 statements addressing diagnostic definitions and management of MELAS were evaluated. Statements not reaching consensus were revised and re-evaluated during a face-to-face meeting.
RESULTS: Consensus supported defining MELAS as a clinical syndrome characterized by one or more SLE in the context of mitochondrial dysfunction caused by a pathogenic mitochondrial DNA variant, particularly m.3243A>G in MT-TL1. The use of terms such as "MELAS-like" or "MELAS spectrum" was discouraged. The panel agreed that the efficacy of L-arginine, L-taurine, L-citrulline, coenzyme Q10, vitamins, and other supplements remains unproven and requires validation in clinical trials. Antiseizure medications should be initiated promptly when seizures are suspected during SLE, and intravenous corticosteroids may be beneficial acutely. Multidisciplinary management of neurological, neuropsychiatric, and systemic complications was endorsed.
CONCLUSIONS: This international consensus provides updated definitions and practical guidance for the diagnosis and management of MELAS and SLE, aiming to harmonize clinical practice and inform future evidence-based research.

Keywords:  MELAS; consensus; diagnostic criteria; management; primary mitochondrial diseases; recommendations

DOI:  https://doi.org/10.1111/ene.70588
J Biopharm Stat. 2026 Apr 14. 1-24

Bayesian quantitative decision-making framework in cell and gene therapy development for rare diseases.

Rui Kang, Yusuke Yamaguchi, Cong Han.

  Developing drugs including cell and gene therapies for rare diseases presents unique challenges, primarily due to small patient populations and limited clinical data. In such settings, traditional quantitative decision-making (QDM) frameworks, which play a crucial role in guiding go/no-go decisions in proof-of-concept (PoC) studies, often lead to inconclusive decisions due to limited information. This paper is the first study presenting a Bayesian QDM framework specifically tailored to cell and gene therapy candidates in the rare disease space, with an emphasis on borrowing information from external data sources to improve the robustness of QDM. While technical components of Bayesian QDM framework have been established in the literature, our contribution lies in (1) a unified framework accommodating both controlled and uncontrolled PoC studies with hypothetical controls, (2) the systematic integration of power priors with flexible control of information borrowing, and (3) practical implementation guidance through an open-source R Shiny application. The proposed framework offers potential advantages, such as more informed decision-making based on reduced trial durations and improved resource allocation, which are critical for accelerating drug development in rare diseases. Simulation studies and a case study are conducted to illustrate the practical application of Bayesian QDM, demonstrating its benefits in early-stage clinical trials.

Keywords:  Bayesian statistics; Quantitative decision-making; cell and gene therapy; proof-of-concept study

DOI:  https://doi.org/10.1080/10543406.2026.2655410
Nat Commun. 2026 Apr 14.

Loss of TMEM65 in mice causes mitochondrial disease mediated by mitochondrial Ca2.

Yingfan Zhang, Hailey A Parry, Laura Reyes, Alex Shamoun, Junhui Sun, Chengyu Liu, Danielle Springer, Audrey Noguchi, Sachiko Nakamori, Angel M Aponte, Jeeva Munasinghe, Raul Covian, Elizabeth Murphy, Brian Glancy.

Transmembrane protein 65 (TMEM65) depletion in a patient caused severe mitochondrial encephalomyopathy, highlighting its clinical importance. Recent studies show TMEM65 acts as a mitochondrial Na+/Ca2+ exchanger in vitro. Here, we generated conditional Tmem65 knockout mice to define its role in neuromuscular tissues in vivo. Both whole-body and nervous system-specific Tmem65 knockouts exhibited severe growth retardation and seizure-associated sudden death at ~3 weeks, establishing TMEM65 as indispensable for neuronal function. Additionally, skeletal muscle-specific knockout produced adult-onset myopathy preceded by elevated mitochondrial Ca2+. Consistently, TMEM65 ablation caused loss of Na+-dependent mitochondrial Ca2+ export. Notably, blocking mitochondrial Ca2+ entry by mitochondrial calcium uniporter (MCU) knockout rescued the early lethality of whole-body Tmem65 ablation, extending lifespan from ~3 weeks to >1 year. These data reveal an essential physiological role for TMEM65 and suggest that modulating mitochondrial Ca2+ may offer therapeutic value for TMEM65 misexpression and other mitochondrial diseases associated with Ca2+ overload.

DOI: https://doi.org/10.1038/s41467-026-71761-w
Front Cell Dev Biol. 2026 ;14 1779332

Beyond the genome: clinical challenges in diagnosing LONP1-related mitochondrial disorders.

Qianni Jiang, Jing Duan, Chao Liu, Yuanyuan Zhu, Qi Zeng, Yuhui Hu, Zhiqiang Luo, Dezhi Cao, Jianxiang Liao, Li Chen.

   Background: LONP1 encodes an ATP-dependent protease essential for maintaining mitochondrial homeostasis. LONP1 variants have been associated with cerebral-ocular-dental-auricular-skeletal anomalies syndrome, pediatric cataract, congenital diaphragmatic hernia, and neurodevelopmental disorders; moreover, these variants can be inherited in both autosomal recessive and autosomal dominant modes.
Methods: We conducted a retrospective analysis of the clinical data and genetic test results of a Chinese boy diagnosed as having mitochondrial encephalopathy. Subsequently, we evaluated the pathogenicity of candidate variants and conducted a literature review encompassing 47 cases of LONP1 variants.
Result: The proband was a 4.5-year-old boy who had experienced focal epilepsy seizures since birth. He presented with recurrent seizures and did not respond to anti-seizure medications. He showed global developmental delay, microcephaly, pachygyria, and hyperlactatemia. Initial genetic testing through single and trio whole-exome sequencing before 6 months of age yielded no conclusive results. Recurrent seizures and elevated lactic acid levels at 18 months of age prompted reanalysis with trio whole-exome sequencing, leading to the identification of a likely pathogenic variant in LONP1: c.901C>T (p.Arg301Trp). By 10 months of age, the patient had already developed primary adrenal insufficiency and experienced multiple adrenal crises triggered by respiratory infections, necessitating admission to the intensive care unit. The crises were effectively managed with hydrocortisone. However, despite intensive medical interventions, the patient succumbed to a metabolic crisis triggered by a severe respiratory infection at the age of 4.5 years.
Conclusion: In this study, we discuss the clinical manifestations and genetic features of a pediatric patient with mitochondrial encephalopathy resulting from a rare LONP1 variant, emphasizing the diagnostic and therapeutic challenges of mitochondrial disorders. Furthermore, our findings enhance the understanding of LONP1-related diseases and offer additional evidence supporting the autosomal dominant inheritance pattern of LONP1.

Keywords:  CODAS syndrome; LONP1; adrenal crises; autosomal dominant; mitochondrial encephalopathy

DOI:  https://doi.org/10.3389/fcell.2026.1779332
HGG Adv. 2026 Apr 13. pii: S2666-2477(26)00055-2. [Epub ahead of print] 100615

Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease.

Matthieu Mantecon, Cerina Chhuon, Kevin Roger, Ida Chiara Guerrera, Christine Bole, Patrick Nitschke, Claire-Marie Dufeu-Bérat, Margaret Ashcroft, Robert W Taylor, Nathalie Boddaert, Agnès Rötig.

Mitochondrial disorders show remarkable clinical and genetic heterogeneity, and result from variants in either mitochondrial- or nuclear-encoded genes. CHCHD4 is a component of the mitochondrial import and assembly pathway that imports small cysteine-containing substrates. We report a pediatric patient with biallelic CHCHD4 variants who presented with severe neurological regression and early death. Western blot analysis showed decreased levels of CHCHD4 and diminished assembly of complexes I and IV in his fibroblasts. To demonstrate that CHCHD4 variants were responsible for the observed biochemical phenotype, we overexpressed wild-type CHCHD4 in control and subject fibroblasts, restoring levels of complex I and IV proteins and the associated assembly defects Proteomic studies pointed to electron transport and complex I biogenesis as the main dysregulated pathways and showed a severe loss of several complex I and IV proteins and/or assembly factors rescued by overexpression of wild-type CHCHD4. CHCHD4 has numerous targets and interacting factors and is involved in the export of iron-sulfur clusters synthesized inside mitochondria. Surprisingly, few of these interacting factors or non-mitochondrial functions were impacted by the observed CHCHD4 defect. In conclusion, our work establishes CHCHD4 deficiency as a cause of dysregulated mitochondrial protein import resulting in a severe neurological condition.

DOI: https://doi.org/10.1016/j.xhgg.2026.100615
Transl Pediatr. 2026 Mar 23. 15(3): 94

Mitochondrial DNA (MtDNA) 3243 A>G mutation associated with recurrent cholangitis post-Kasai procedure in biliary atresia.

Jie Sun, Yanan Zhang, Dayan Sun, Jinshi Huang.



Keywords:  Kasai procedure; biliary atresia (BA); cholangitis; liver transplantation; m.3243A>G

DOI:  https://doi.org/10.21037/tp-2026-1-0137
Genet Med. 2026 Apr 13. pii: S1098-3600(26)00899-3. [Epub ahead of print] 102581

New Treatments, Novel Conversations: A Need to Study the Science of Communication about Treatment Options for Inborn Errors of Metabolism.

Emily Shelkowitz, Samantha A Schrier Vergano, Monica Penon-Portmann, Gailon Wixson, Erika Beckman, Teresa Campbell, Maria R Mills, Aaina Kochhar, Benjamin S Wilfond, Amy Trowbridge, Curtis R Coughlin, Aaron Wightman.

  Over the past thirty years, therapeutic options for rare diseases, and particularly, inborn errors of metabolism (IEMs), have expanded tremendously, markedly improving the lives of patients and families, and invigorating clinicians, researchers, and the rare disease community. Concurrently, the increasing availability of treatments has introduced new intricacies to clinical communication and created a growing need for the field to advance its understanding of how to communicate nuanced and complex information to patients and families and support them through the shared decision-making process. In this article, we argue that therapeutic options for IEMs must be considered within a shared decision-making framework and explain why high-quality communication is a requisite for this process. We delineate notable communication and decision-making challenges in the field of genetics and metabolism and recommend that discipline-specific empirical work be conducted. We draw on established scholarship in other fields and review the existing literature related to IEMs. Finally, we advocate for the development of evidence-based tools, standards, and best practices to guide clinicians in supporting families through complex treatment-related decision-making. We propose that research focused on the treatment decision-related communication needs of patients and families be prioritized in the field of genetics and metabolism.

Keywords:  Communication; Decision-Making; Inborn Errors of Metabolism; Therapeutics; Treatment

DOI:  https://doi.org/10.1016/j.gim.2026.102581
J Am Med Inform Assoc. 2026 Apr 16. pii: ocag045. [Epub ahead of print]

Applying natural language processing and large language models to clinical notes for phenotyping and diagnosing rare diseases: a systematic review.

Seungjun Kim, Yiliang Zhou, Yawen Guo, Changrui Xiao, Kai Zheng.

   OBJECTIVES: Patients with rare diseases often face long delays before receiving a diagnosis. Using electronic health records for automated phenotyping and diagnosis of rare diseases is a promising approach but can be challenging because critical information is often recorded in unstructured notes rather than structured fields. This systematic review synthesizes the current literature applying natural language processing (NLP) and large language models (LLMs) for rare disease phenotyping and diagnosis from clinical text.
MATERIALS AND METHODS: A systematic search was conducted in PubMed, ACM Digital Library, and IEEE Xplore. Two reviewers independently screened papers and extracted data. Methodological rigor and quality of the studies were evaluated using the MI-CLAIM framework.
RESULTS: The search resulted in 135 studies; 27 of them met the inclusion criteria. Methods used spanned rule-based systems, classical ML/DL models, transformer architectures, and LLMs. Transformer- and LLM-based approaches outperformed earlier methods in entity recognition, phenotype extraction, and diagnostic ranking. Several studies demonstrated clinical impact, such as increased genetic testing and identification of undiagnosed cases. However, most studies relied on retrospective and single-center datasets. Reporting of preprocessing, evaluation, and reproducibility was largely inconsistent, and interpretability, fairness, and privacy were rarely addressed.
DISCUSSION: Natural language processing and LLMs show strong potential to accelerate rare disease diagnosis. However, heterogeneity in methods and metrics hinders cross-study comparability. Data scarcity, lack of generalization, and limited transparency remain significant challenges.
CONCLUSIONS: Natural language processing/LLM methods can support timely diagnosis of rare diseases using unstructured clinical text. Future research should prioritize multicenter studies, standardized evaluation frameworks, transparency, and fairness safeguards to enable reliable, equitable deployment.

Keywords:  electronic health records; language models; natural language processing; phenotype; rare diseases/diagnosis; statistical

DOI:  https://doi.org/10.1093/jamia/ocag045
Dan Med J. 2026 Mar 19. pii: A04250257. [Epub ahead of print]73(4):

Shared decision-making in medical education - a systematic review.

Anna Sofie Kiel Ørom, Peter Musaeus.

INTRODUCTION: This systematic review examined teaching strategies used to enhance medical students' skills in shared decision-making (SDM) and their impact on students' learning and educational outcomes.
METHODS: Twenty-three studies published between 2014 and 2025 were identified through systematic searches of PubMed, Scopus and Embase. Eligible studies evaluated SDM-focused educational interventions for medical students and reported SDM-related outcomes.
RESULTS: Teaching approaches varied widely, most often involving role-play with SPs or peers, case-based discussions and blended or online modules. Despite heterogeneous outcome measures, experiential methods consistently enhanced students' confidence, communication and attitudes towards SDM. Most studies relied on self-reported data rather than validated, performance-based tools, and few studies included follow-up.
CONCLUSIONS: Although heterogeneity limits firm conclusions, active, experiential approaches appear most promising in developing SDM competencies among medical students. This review synthesises current approaches to SDM training and highlights key research gaps, including the need for validated, performance-based, longitudinal studies to determine which teaching strategies most effectively support long-term competence in SDM.

DOI: https://doi.org/10.61409/A04250257
J Midwifery Womens Health. 2026 Apr 13.

The Patient, the Provider, and the TikTok Creator: Qualitative Analysis of the Content and Quality of Videos on Prenatal Genetic Screening.

Erin P Johnson, Naomi O Riches, Stephanie Arceneaux, Emma Murdock, Caitlin Quade, Susanna R Cohen, Robin E Jensen.

   INTRODUCTION: Although providers may view the use of the noninvasive prenatal testing (NIPT) screen as an opportunity for patients to learn more about potential chromosomal variants of a fetus, research suggests that patients may view the genetic screening test primarily as an opportunity to learn about their fetus's sex chromosomes and may not understand the implications of a screening test, as compared with a diagnostic test. This study critically evaluates the informational quality of TikTok content related to NIPT, with a specific focus on the use and conflation of sex and gender terminology.
METHODS: A total of 83 TikTok videos met our inclusion criteria. Two team members systematically coded the videos using a modified DISCERN instrument and content-specific codes to assess reliability and informational quality across 3 content creator categories: patients/nonexperts, health care professionals, and organizations. Many codes focused specifically on the use of gendered language in the videos.
RESULTS: Patient-generated content exhibited the highest engagement metrics but frequently misrepresented NIPT as a confirmatory test and conflated sex with gender. Health care provider and organizational videos demonstrated higher informational reliability but were not immune to deterministic language around sex and gender and promotional framing.
DISCUSSION: The findings underscore the influence of social media as a health information source and reveal significant gaps in public understanding of NIPT, particularly regarding its screening nature and limitations. Additionally, these results highlight the need for clinical protocols that address patient misconceptions and suggest that health care professionals should actively engage with digital platforms to familiarize themselves with what patients are seeing and hearing online. Recommendations include avoiding gendered mirroring, asking questions about patient knowledge, and leveraging social media for public health education.

Keywords:  health education; noninvasive prenatal testing; social media

DOI:  https://doi.org/10.1111/jmwh.70121
Prog Mol Biol Transl Sci. 2026 ;pii: S1877-1173(26)00012-8. [Epub ahead of print]221 43-70

Multi-omics applications in health and diseases.

Samitha Amarapathy, Sonika Tyagi.

  Multi-omics research has transformed our ability to study biological systems by capturing information across multiple molecular layers, including genomics, transcriptomics, epigenomics, proteomics, metabolomics, and microbiomics. Each omics dimension provides a unique perspective on cellular and organismal function, yet single-omics approaches often fail to capture the full complexity of health and disease. Integrating diverse omics datasets offers a systems-level view that is essential for advancing precision medicine, addressing disease heterogeneity, and uncovering mechanisms of pathogenesis. The increasing availability of high-dimensional, heterogeneous data demands robust computational and AI-driven approaches. Methods ranging from traditional statistical techniques to advanced deep learning and network-based models enable the integration, analysis, and interpretation of multi-omics data. These approaches have already demonstrated significant impact in cancer, cardiovascular and metabolic disorders, neurodegenerative diseases, infectious diseases, and rare genetic conditions. Translational applications include biomarker discovery, patient stratification, therapy optimization, drug repurposing, and clinical decision support. Despite these advances, challenges remain in data standardization, scalability, interpretability, and ethical use of genomic information. Future directions emphasize explainable AI, regulatory frameworks, and integration with digital health records to bridge research insights with clinical practice. Overall, AI-powered multi-omics integration will shape the future of biomedical research and precision healthcare.

Keywords:  Artificial intelligence; Disease modelling; Multiomics

DOI:  https://doi.org/10.1016/bs.pmbts.2026.01.012
Health Care Anal. 2026 Apr 16.

Navigating Patient-Initiated Non-Standard Care (PINSC) Requests: Applying an Ethically Coherent Framework for Shared Decision-Making.

Joshua T Landry.

  In current medical decision-making, prioritizing patient autonomy and shared decision-making has reshaped the ethical landscape. Medical decisions are no longer solely driven by a strong physician paternalism, where doctors are assumed to know best, but are increasingly characterized by a sharing of information, collaboration on decisions, and incorporation of patient values and preferences. While this shift promotes shared decision-making and patient-centered care, it has also given rise to additional ethically-complex challenges, including what will be referred to here as Patient-Initiated Non-Standard Care (PINSC) requests. PINSC requests emerge when patients or their surrogate decision-maker(s) seek interventions which fall outside accepted medical guidelines or evidence-based standards of care. This paper recounts various PINSC requests received at several hospitals in Ontario, Canada. Fundamental distinctions between PINSC requests and other cases of informed refusal are then established to highlight their novel ethical complexity, and I argue that this complexity gives rise to significant ethical and professional concerns that warrant increased attention. I then explore the reasons why clinicians often feel obligated to accede to PINSC requests, review the limitations of existing response strategies to addressing them, and propose that a model of shared decision-making called the Professionally-Driven Zone of Patient or Surrogate Discretion, or Professionally-Driven ZPSD, can be used as an ethically-defensible framework for navigating these cases. The Professionally-Driven ZPSD supports clinicians to develop a range of treatment options ("the zone") for decision makers to choose from that are ethically permissible, as they would fall between those treatments which cause unjustifiable harm, and those (or that) which would be in the patient's best interests to have if this can be defined.

Keywords:  Autonomy; Clinical decision-making; Healthcare ethics; Medical benefit; Non-standard care; Shared decision-making

DOI:  https://doi.org/10.1007/s10728-026-00567-0
Front Cardiovasc Med. 2026 ;13 1781927

Pathogenic role of mitochondrial DNA mutations in heart failure: clinical features, mechanisms, and therapeutic prospects.

Mingyang Ni, Aijia Zheng, Hang Zheng, Wenqing Jia, Yuansheng Wang, Yuqing Peng, Chenguang Yao, Yanhong Wei, Xueli Wang, Sini Kang.

  Heart failure (Heart failure, HF) is a complex clinical syndrome caused by any abnormality in the structure or function of the heart, resulting in impaired ventricular filling or ejection capacity, with mitochondrial dysfunction recognized as one of the key pathological foundations. In recent years, numerous studies have demonstrated that mitochondrial DNA (mtDNA) mutations play a significant role in cardiomyopathy and HF; however, systematic understanding of their modes of action in disease progression remains limited. Most studies have attributed the pathogenic effects of mtDNA mutations to impaired energy metabolism, emphasizing the consequences of defective oxidative phosphorylation and insufficient ATP production on myocardial function. Emerging evidence, however, indicates that mtDNA mutations also contribute to the development and progression of HF by inducing reactive oxygen species accumulation, disrupting mitochondrial structural and dynamic homeostasis, and activating innate immune inflammatory signaling pathways. Furthermore, variations in mtDNA mutation load and heteroplasmy levels constitute an important molecular basis for the diverse clinical phenotypes of HF, although the underlying mechanisms have yet to be systematically integrated. This review comprehensively summarizes the pathogenic mechanisms of cardiac mtDNA mutations and their heteroplasmy in HF, with particular emphasis on the intrinsic links among mitochondrial metabolic reprogramming, oxidative stress, immune activation, and myocardial remodeling, and outlines potential diagnostic and therapeutic strategies based on mitochondrial dysfunction and mtDNA stability.

Keywords:  cardiomyopathy; energy metabolism; heart failure; immune activation; mitochondrial DNA mutations; mitochondrial dysfunction; oxidative stress; therapeutic strategies

DOI:  https://doi.org/10.3389/fcvm.2026.1781927
J Genet Couns. 2026 Apr;35(2): e70202

Navigating uncertainty during non-invasive prenatal testing: Genetic counselors' experiences of supporting autonomous reproductive decision-making.

Chanelle Warton, Danya F Vears.

  There is limited understanding of how healthcare professionals understand and apply the concept of reproductive autonomy in their clinical practice with non-invasive prenatal testing (NIPT). Existing research indicates potential misalignment between theoretical understandings of reproductive autonomy and its operationalization by healthcare professionals in clinical practice. Despite genetic counselors (GCs) having unique expertise and experience in prenatal genetic counseling, there is a dearth of research regarding their understanding and practices relating to reproductive autonomy. To address this gap, we explored GCs' NIPT clinical practice, particularly focusing on their conceptualization and facilitation of autonomous reproductive decision-making. Semi-structured interviews were undertaken with 23 GCs experienced in providing NIPT in Australia. Data were analyzed using inductive content analysis. GCs viewed their role as facilitating reproductive genetics decision-making and supporting patients to navigate the uncertainty inherent to prenatal screening, including phenotypic uncertainty. Uncertainty was viewed by GCs as an inherent feature of prenatal genetic testing, but not one that was incompatible with reproductive autonomy. Diverse views were expressed regarding the scope of conditions available via NIPT. Cost was viewed as a source of inequity, with all GCs supporting some level of public funding for NIPT.

Keywords:  decision‐making; ethics; genetic counselling; non‐invasive prenatal testing; qualitative; reproductive autonomy

DOI:  https://doi.org/10.1002/jgc4.70202