bims-curels 2025-12-28 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–12–28
ten papers selected by
Cure Mito Foundation

Profiles of paediatric patients experiencing stroke-like episodes associated with mitochondrial disease.
Sequential development of three syndromes in a patient with m.3243A>G mutation: a case report.
Advances in gene therapy for mitochondrial genetic disorders: current status and clinical implementation challenges.
Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice.
[Unsolicited findings in genomic testing: what do we tell the patient?]
A Zebra in Horse's Clothing: Rethinking the Diagnosis of Rare Diseases.
From Severe Neonatal Encephalopathy to Slowly Neurologic Progressive Disease: Pyruvate Dehydrogenase Deficiency Related to PDHA1 Variants.
I've Never Heard of This! An Approach to Child and Family-Centred Care for Children and Young People With Rare Diseases.
Synthetic data generation methods for longitudinal and time series health data: a systematic review.
Emerging nano-delivery systems for targeting mitochondria.

Front Neurol. 2025 ;16 1657852

Profiles of paediatric patients experiencing stroke-like episodes associated with mitochondrial disease.

Gülhan Karakaya Molla, Özlem Ünal Uzun, Hanım Babazade Agakisili, Emine Genç, Zümrüt Arslan Gülten, Tarık Yıldırım, Aydan Sezgin Ersoy, Belkıs Ak, Aliye Gülbahçe, Sevil Yıldız, Nafiye Emel Çakar, Meryem Karaca, Tanyel Zübarioğlu, Burcu Öztürk Hişmi, Şahin Erdöl, Hasan Önal, Bülent Kara, Gülden Fatma Gökçay.

   Introduction: Stroke-like episodes (SLE) are defined as events characterized by the sudden onset of neurological symptoms with clinical manifestations similar to those of a stroke. However, they are distinguished by the presence of radiological lesions that do not conform to single vascular territory. MELAS syndrome, which is characterized by metabolic encephalopathy, lactic acidosis, and SLE, has been identified as the first genetically defined and most widely known mitochondrial cause of SLE. It has been demonstrated that SLE may occur in the course of a variety of mitochondrial diseases, including those that are the result of nuclear DNA mutations.
Objective: In this retrospective, multicenter, observational cohort study, we sought to determine the clinical, radiological, EEG, and genetic characteristics of patients with mitochondrial gene mutations presenting with SLE and the frequency and treatment of SLE.
Methods: Thirty-four patients with a genetically diagnosed mitochondrial disease from 9 paediatric metabolic disease centres in the Marmara Region of Turkey were included in the study, of whom 13 pateints had SLEs. Demographic characteristics, symptoms, clinical features, cranial MRI, EEG findings, and genetic characteristics were evaluated.
Conclusion: In this study, stroke-like episodes in genetically defined mitochondrial disorders were most frequently observed in MELAS and POLG mutations, and rarely in CoQ10 deficiency, Leigh syndrome cases. Cranial MRI findings are often frontotemporal in location and inconsistent with vascular distribution, and focal epileptiform activity on EEG are diagnostically significant. In MELAS, clinical improvement was observed in patients when L-arginine was initiated in the acute period. The findings emphasise that SLE should be evaluated in the differential diagnosis of sudden onset neurological symptoms in mitochondrial diseases.

Keywords:  CoQ10 deficiency; MELAS; POLG mutations; mitochondrial diseases; stroke-like episodes

DOI:  https://doi.org/10.3389/fneur.2025.1657852
Front Med. 2025 Dec 26.

Sequential development of three syndromes in a patient with m.3243A>G mutation: a case report.

Guoling Zeng, Rongpei Liu, Xiaotian Li, Zhaoqi Lv, Lei Cui, Xiong Zhang, Jianyong Wang.

  Mitochondrial disorders are highly heterogeneous and can manifest as a spectrum of clinically heterogeneous disorders that affect multiple organ systems. Herein, we report a Chinese female patient carrying mitochondrial DNA m.3243A>G mutation who sequentially experienced myoclonic epilepsy with ragged red fibers, mitochondrial neurogastrointestinal encephalomyopathy, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. This report expands the current understanding of phenotypic heterogeneity in mitochondrial disorders.

Keywords:  m.3243A>G; mitochondrial disorders; mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); myoclonic epilepsy with ragged red fibers (MERRF)

DOI:  https://doi.org/10.1007/s11684-025-1186-7
J Transl Med. 2025 Dec 23. 23(1): 1415

Advances in gene therapy for mitochondrial genetic disorders: current status and clinical implementation challenges.

Lei Lyu, Beibei Qie, Yanjie He, Feilong Chen, Bao Liu.

  Mitochondria function as the primary energy hubs of cells and possess semi-autonomous genetic characteristic. Mutations in mitochondrial DNA (mtDNA) frequently lead to severe illness and even premature death. The rapid advancement of gene therapy offers promising potential for correcting such disorders. This review first aims to delineate the mechanisms of gene therapy strategies applicable to mitochondrial diseases, including the allotopic expression of mtDNA in the nucleus, mitochondrial-targeted nuclease cleavage, and mtDNA-targeted base editing. It also discusses in detail the clinical efficacy of mtDNA allotopic expression and the preclinical progress of other strategies. Furthermore, the unique physiological features of mitochondria, such as heteroplasmy and independent molecular transport mechanisms, pose distinct challenges for the clinical implementation of mitochondrial gene therapy strategies. Accordingly, this review elaborates on the current limitations of each approach. Finally, it highlights potential optimization directions to address these challenges, emphasizing that understanding heteroplasmy dynamics and their corresponding phenotypes, ensuring the safe delivery and tissue-specific expression of therapeutic elements, and maintaining long-term therapeutic specificity and efficiency are essential for the clinical translation of mitochondrial gene therapy.

Keywords:  Allotopic expression; Base editing; Mitochondrial DNA; Mitochondrial disorders; Nuclease

DOI:  https://doi.org/10.1186/s12967-025-07420-3
EMBO Mol Med. 2025 Dec 22.

Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice.

Sahitya Ranjan Biswas, Porter L Tomsick, Colin Kelly, Brooke A Lester, Julia P Milner, Sara N Henry, Yairis Soto, Samantha Brindley, Nicole DeFoor, Paul D Morton, Alicia M Pickrell.

  Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent clinical studies report behavioral phenotypes in human LS patients that are more reminiscent of neurodevelopmental delays. To determine if disruptions in epochs of rapid brain growth during infancy precede the hallmark brain lesions that arise during childhood, we evaluated neural and glial precursor cellular dynamics in a mouse model of LS. Loss of Complex I significantly impacted neural stem cell proliferation, neuronal and oligodendroglial progeny, lineage progression, and displayed overt differences in specific brain regions across postnatal development. Our findings show that these disruptions in all categories occur specifically within the subventricular zone and corpus callosum prior to the age when these mice experience neurodegeneration. Given that LS is considered a neurodegenerative disease, we propose that there are neurodevelopmental signatures predating classic diagnosis in LS.

Keywords:  Corpus Callosum; Leigh Syndrome; Neural Stem Cells; Postnatal Neurogenesis; Subventricular Zone

DOI:  https://doi.org/10.1038/s44321-025-00367-4
Ned Tijdschr Geneeskd. 2025 Dec 29. pii: D8589. [Epub ahead of print]168

[Unsolicited findings in genomic testing: what do we tell the patient?]

Vyne van der Schoot, Helger Yntema, Martine van Koolwijk, Ilse Feenstra, Anke Oerlemans.

The increasing use of comprehensive genomic testing raises the likelihood of encountering unsolicited findings. These are (likely) pathogenic variants that predispose to a disease unrelated to the clinical question, but might be of relevantceto the patient and/or their family members. Any healthcare professional requesting genomic testing may encounter unsolicited findings. It is generally recommended to report unsolicited findings only if it is considered medically actionable, unless the patient has explicitly opted out of receiving such information. Ultimately, the healthcare professional requesting the genetic test, is responsible for deciding whether to communicate the finding to the patient. In this paper, we present two fictional case studies to illustrate the dilemmas that may arise in the context of unsolicited findings. This will help doctors when choosing genomic testing and weighing the expected benefits against potential harms. It also enables them to better inform patients about the possibility and implications of unsolicited findings.
Mol Genet Genomic Med. 2025 Dec;13(12): e70172

A Zebra in Horse's Clothing: Rethinking the Diagnosis of Rare Diseases.

Rajeev Dutta, Cathy Duong, Virginia Kimonis, Changrui Xiao.

   INTRODUCTION: Rare diseases sometimes present with deceptively common symptoms, complicating diagnosis and decisions about genetic testing. While testing for rare disease offers important benefits, it also carries risks that warrant careful consideration.
METHODS: We review illustrative cases of rare diseases, along with current screening and diagnostic practices, to reexamine guiding principles for genetic testing. The analysis focuses on balancing clinical utility, patient-centered care, and broader policy implications.
RESULTS: We propose a number of recommendations to guide testing, including ruling out common causes before proceeding, ensuring the presentation is atypical for other common conditions, confirming consistency with a specific, treatable rare disease entity or group, assessing patient or family capacity for informed decision-making, and matching test invasiveness to expected diagnostic utility. Comparison with newborn screening and diagnostic testing highlights discrepancies between these principles and common practices, highlighting the difficulty of achieving consistency.
CONCLUSIONS: Establishing uniform guidelines for genetic testing remains challenging, particularly given the limited knowledge surrounding rare disorders. Coordinated efforts are needed to protect patient interests, assess the utility of diagnoses across varied contexts, and ensure that both clinical practice and policy development maximize benefits while minimizing harms.

Keywords:  diagnosis; genetic testing; rare and undiagnosed diseases; zebra

DOI:  https://doi.org/10.1002/mgg3.70172
J Child Neurol. 2025 Dec 23. 8830738251404115

From Severe Neonatal Encephalopathy to Slowly Neurologic Progressive Disease: Pyruvate Dehydrogenase Deficiency Related to PDHA1 Variants.

Sofia Corbaz, Daniela Alejandra Pibernus, Mariana Amina Loos, María Mercedes Pérez, María Celeste Buompadre, Francisco Martín García, María Paula Rodriguez, Carlos Rugilo, Marisa Armeno, Go Hun Seo, Rin Khang, Cristina Noemi Alonso, Hilda Verónica Aráoz.

  Pyruvate dehydrogenase complex (PDC) deficiency is a rare mitochondrial disorder characterized by impaired oxidative metabolism, predominantly due to pathogenic variants in the PDHA1 gene. We present the clinical, biochemical, radiologic, and molecular characterization of 4 Argentine pediatric patients with PDHA1-related PDC deficiency, including a novel missense variant, c.260T>C p.(Ile87Thr). Clinical presentations ranged from severe neonatal encephalopathy with central apneas to a more slowly progressive neurodegenerative course in childhood. All patients exhibited lactic acidosis and structural brain abnormalities, with 3 fulfilling criteria for Leigh syndrome. Molecular studies identified 4 missense variants located in conserved regions of the E1α subunit. In silico analysis of the novel p.(Ile87Thr) variant suggested impaired thiamine pyrophosphate binding. All patients received thiamine and a ketogenic diet, with favorable outcomes in seizure control, neurodevelopment, and metabolic stability. Our findings expand the clinical and molecular spectrum of PDHA1-related PDC deficiency and underscore the importance of early diagnosis and targeted metabolic therapy. Furthermore, we report a previously undescribed radiologic pattern in one patient and propose potential structural implications of the novel variant based on protein modeling.

Keywords:  Ketogenic diet; Leigh syndrome; PDHA1; mitochondrial disease; pyruvate dehydrogenase deficiency

DOI:  https://doi.org/10.1177/08830738251404115
J Paediatr Child Health. 2025 Dec 22.

I've Never Heard of This! An Approach to Child and Family-Centred Care for Children and Young People With Rare Diseases.

Lisa J Ewans, Kris Pierce, Eleanor Farley, Rachel Bowden, Carolyn Shalhoub, Elizabeth Emma Palmer.

  Paediatricians strive to deliver best practice care for their patients. However, when they encounter a child with one of the over 8000 rare diseases, a majority (> 70%) of which have a genetic cause, it is challenging to find clinical guidelines and point-of-care resources to support their practice. This article provides a framework for a collaborative management approach for rare diseases. It draws on the team's experience in delivering multidisciplinary clinics for ultra-rare conditions, running a rare disease registry and undiagnosed disease programme, and in founding a rare disease patient advocacy group for SCN2A-related conditions. This article signposts useful resources to facilitate paediatricians in delivering 'wraparound' rare disease care that is comprehensive, holistic and child and family-centred. These include Australia's first National Recommendations for Rare Disease Health Care and the RARE (Rare Awareness Rare Education) portal led by the national peak body for people living with a rare disease, Rare Voices Australia. Six key approaches are suggested that paediatricians can incorporate into their clinical practice to deliver high quality care for each child and young person with a rare disease. This includes strategies to support a timely diagnosis, including accessing undiagnosed disease programmes and linking children, young people and their caregivers with peers, patient advocacy groups and rare disease registries to reduce isolation and uncertainty. As less than 5% of rare diseases are currently amenable to a targeted therapy, it also suggests resources and approaches to facilitate access to and shared decision-making about research and novel advanced therapeutics.

Keywords:  coordinated care; patient advocacy groups; rare disease

DOI:  https://doi.org/10.1111/jpc.70267
BMC Med Inform Decis Mak. 2025 Dec 24.

Synthetic data generation methods for longitudinal and time series health data: a systematic review.

Marko Miletic, Murat Sariyar.

   BACKGROUND: Synthetic data generation (SDG) has emerged as a critical enabler for data-driven healthcare research, offering privacy-preserving alternatives to real patient data. Temporal health data - ranging from physiological signals to electronic health records (EHRs) - pose unique challenges for SDG due to their complexity, irregularity, and clinical sensitivity.
OBJECTIVE: This review systematically examines SDG methods for longitudinal and time-series health data. Its aims are to (1) propose a lightweight taxonomy to support orientation across the SDG landscape along five structural dimensions, (2) characterize the major synthesis techniques and their alignment with temporal structures and data modalities, and (3) synthesize the utility and privacy evaluation strategies used in practice.
METHODS: A systematic literature review was conducted following PRISMA guidelines across four major databases (ACM, arXiv, IEEE Xplore, Europe PMC) for publications from 2017 to 2025. Eligible studies proposed or applied SDG techniques to healthcare-relevant temporal data with sufficient methodological transparency. Structured data extraction and thematic analysis were used to identify modeling trends, evaluation metrics, and domain-specific requirements, complemented by a comparative synthesis of SDG methods.
RESULTS: A total of 115 studies were included. Deep generative models - especially Generative Adversarial Networks (GANs), Autoencoders (AEs), and diffusion-based methods - dominate the field, with increasing adoption of autoregressive and hybrid simulation approaches. Event-based EHR data are most commonly targeted, while continuous and irregular time series remain underexplored. Utility evaluations vary widely, with strong emphasis on descriptive statistics and predictive performance, but limited attention to inferential validity and clinical realism. Privacy assessments are sparse and inconsistently reported: only 30% of studies included any metric, and just around 6% implemented differential privacy (DP), often without parameter disclosure. This limited adoption may reflect technical challenges, limited expertise, and the absence of regulatory incentives.
CONCLUSIONS: Synthetic temporal data play an increasingly vital role across clinical prediction, public health modeling, and Artificial Intelligence (AI) development. However, SDG research remains fragmented in terminology, evaluation practices, and privacy safeguards. Responsible-AI considerations - such as fairness, transparency, and trust - along with evidence on clinical adoption remain underexplored but are critical for future integration. This review provides a unified conceptual and methodological framework to guide future research, standardization efforts, and interdisciplinary collaboration for responsible, effective use of synthetic health data.

Keywords:  Data sharing; Longitudinal patient data; Privacy-preserving data publishing; Synthetic data generation; Systematic review; Temporal health data

DOI:  https://doi.org/10.1186/s12911-025-03326-8
Nanoscale. 2025 Dec 22.

Emerging nano-delivery systems for targeting mitochondria.

Agata N Burska, Kristina E Raish, Dinmukhamet Bayandy, Vesselin N Paunov.

This review aims to provide a comprehensive analysis of the potential of mitochondria-targeting nanosystems as a novel therapeutic approach for treating a wide range of diseases. It explores the underlying mechanisms of mitochondrial dysfunction in disease progression and shows how nanotechnology offers an innovative platform for delivering targeted therapies directly to mitochondria. We also highlight the role of mitochondria in cellular function and disease pathology particularly in cancer, followed by a consideration of the therapeutic potential of targeting these organelles. We explore the recent development and design principles of mitochondria-targeting nanosystems, assessing their applications and challenges and finally outline future research directions, emphasizing the importance of overcoming current limitations to expand the use of these nanosystems in medicine. This is intended to provide valuable insights into the promising connection of mitochondrial biology and nanotechnology, with the goal of advancing innovative treatments for various diseases.

DOI: https://doi.org/10.1039/d5nr03935e