bims-curels 2025-11-09 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–11–09
eight papers selected by
Cure Mito Foundation

Gut instinct: microbiome as a modifiable target in the management of neurologic symptoms in myoclonic epilepsy with ragged-red fibers (MERRF).
Mitochondrial Leigh syndrome: the state of the art.
Mitochondrial Activation and Therapeutics: Innovations in Cell- and Organelle-Specific Medicine.
Model systems informing mechanisms and drug discovery: a review of POLG-related disease models.
AI-powered neuroimaging markers: a new era in paediatric Leigh syndrome diagnosis.
Imaging patterns of paediatric CNS mitochondrial disorders.
Genetic testing: real patient autonomy needs medical supervision.
Cracking the code: a head-to-head comparison of expert clinicians and artificial intelligence in diagnosing rare diseases.

Ann Med Surg (Lond). 2025 Oct;87(10): 6904-6905

Gut instinct: microbiome as a modifiable target in the management of neurologic symptoms in myoclonic epilepsy with ragged-red fibers (MERRF).

Amna Rahman, Muneeb Faiz, Maliha Khalid, Muhammad Talha, Aminath Waafira.

  Myoclonic epilepsy with ragged-red fibers (MERRF) is a rare mitochondrial disorder primarily driven by mutations in mitochondrial DNA, particularly the m.8344A>G variant in MT-TK, and is characterized by epilepsy, myoclonus, ataxia, and other multisystemic features. With no curative therapy, recent attention has turned to the gut microbiome as a modifiable factor influencing neurologic symptoms in mitochondrial diseases. Dysbiosis-induced by antibiotics, diet, or preservatives-has been linked to altered microbial metabolites such as short-chain fatty acids and indoxyl sulfate, which may exacerbate neurological dysfunction. Preliminary clinical trials and preclinical studies suggest that probiotics and dietary interventions can modestly improve disease burden and symptoms such as constipation. However, significant challenges remain, including lack of standardization in analytical protocols, heterogeneous host-microbiota responses, and inadequate patient stratification. To fully realize the therapeutic potential of microbiome-based approaches in MERRF, coordinated multicenter trials, clear regulatory guidelines, and machine learning-enhanced stratification will be essential.

Keywords:  MERRF syndrome; gut microbiome; mitochondrial disease; neurologic symptoms

DOI:  https://doi.org/10.1097/MS9.0000000000003777
Arch Pediatr. 2025 Nov 05. pii: S0929-693X(25)00182-4. [Epub ahead of print]

Mitochondrial Leigh syndrome: the state of the art.

Gauthier Toutain, Célia Hoebeke, Marguerite Gastaldi, Mathieu Milh, Brigitte Chabrol.

   BACKGROUND: Leigh syndrome or subacute necrotizing encephalomyelopathy was first recognized as a neuropathological entity in 1951. It is a progressive neurological disease characterized by neuroradiological lesions, particularly in the brainstem and basal ganglia. Leigh's syndrome is a pan-ethnic disorder with onset usually in infancy or early childhood. Over the last six decades, this complex neurodegenerative disorder has been shown to comprise >100 separate monogenic disorders associated with enormous clinical and biochemical heterogeneity. This article reviews clinical, radiological, biochemical and genetic aspects of the disorder.
OBJECTIVES: this overview provides a better understanding of this rare mitochondrial disease by identifying its clinical, radiological and genetic manifestations in order to improve early diagnosis, patient follow-up and genetic counseling.
METHODOLOGY: systematic literature review RESULTS: Leigh syndromes present with childhood developmental regression, a loss of previously achieved developmental milestones. Numerous non-neurological manifestations of Leigh syndrome have been reported, many of which are related to the underlying genetic defects. These include cardiomyopathy, renal tubulopathy, gastrointestinal and endocrine dysfunction, and liver disease. Known genetic causes, including defects in 16 mitochondrial DNA (mtDNA) genes and nearly 100 nuclear genes, are categorized into disorders of subunits and assembly factors of the five oxidative phosphorylation enzymes, disorders of pyruvate metabolism and vitamin and cofactor transport and metabolism, disorders of mtDNA maintenance, and defects in mitochondrial gene expression, protein quality control, lipid remodeling, dynamics and toxicity. An approach to diagnosis is presented, together with known treatable causes and an overview of current supportive management options and emerging therapies on the horizon CONCLUSION: Management of mitochondrial diseases must be multidisciplinary, and in collaboration with a center of reference (CRMR) or a center of competence (CCMR) with expertise in mitochondrial diseases.

Keywords:  Central nervous system; Genetic; Itochondrial DNA; Leigh syndrome; Metabolic disease; Mitochondrial disease; Neurodegeneration; Neuroimaging; Nuclear DNA; OXPHOS; Treatment

DOI:  https://doi.org/10.1016/j.arcped.2025.04.007
Biol Pharm Bull. 2025 ;48(11): 1652-1666

Mitochondrial Activation and Therapeutics: Innovations in Cell- and Organelle-Specific Medicine.

Itsumi Sato, Masahiro Shiraishi, Kaede Norota, Kaoru Shiraki, Yuma Yamada.

  Mitochondria are essential for cellular functions, including ATP production, calcium homeostasis, oxidative stress regulation, and apoptosis. Mitochondrial dysfunction is associated with a variety of diseases, including neurodegenerative disorders, skeletal muscle diseases, and mitochondrial diseases. This review explores the latest mitochondrial-targeted therapeutic approaches across the following key perspectives: (1) technological innovations in mitochondrial transplantation, focusing on tunnel nanotubes and extracellular vesicles; (2) the role of mitochondria in skeletal muscle diseases and therapeutic activation strategies; (3) advances in mitochondrial enhancement techniques within cell therapy, particularly in pediatric applications; and (4) the latest treatment modalities for mitochondrial diseases, such as gene and cell therapies. Taken together, these strategies demonstrate the transformative potential of mitochondrial targeting in cell- and organelle-specific medicine. Additionally, the MITO-Porter system is highlighted as an innovative drug delivery platform contributing to these advances.

Keywords:  cell therapy; drug delivery system; mitochondria; mitochondrial disease; organelle medicine; skeletal muscle disease

DOI:  https://doi.org/10.1248/bpb.b25-00218
Wellcome Open Res. 2023 ;8 33

Model systems informing mechanisms and drug discovery: a review of POLG-related disease models.

Jonathan Meyrick, Renae J Stefanetti, Linda Errington, Robert McFarland, Gráinne S Gorman, Nichola Z Lax.

   Introduction: Pathogenic variants in the gene encoding the catalytic subunit of DNA polymerase gamma ( POLG), comprise an important single-gene cause of inherited mitochondrial disorders. Clinical manifestations are now recognised as an array of overlapping clinical features rather than discrete syndromes as originally conceptualised. Animal and cellular models have been used to address numerous scientific questions, from basic science to the development and assessment of novel therapies. Here, we sought to employ systematic approaches, wherever possible, to investigate the cellular and animal models used in POLG-related research and assess how well they help us understand disease mechanisms in patients.
Methods: Four databases were searched from inception to May 31 st, 2022: MEDLINE, Scopus, Web of Science, and Cochrane Review. Original articles available in English, reporting the use of a model system designed to recapitulate POLG-related disease, or related pathogenicity, were eligible for inclusion. Risk of bias and the methodological quality of articles were assessed by an adapted version of the Cochrane Risk of Bias Tool, with the quality of evidence synthesized across each model.
Results: A total of 55 articles, including seven model organisms (Human, yeast [ Saccharomyces cerevisiae and Schizosaccharomyces pombe], Drosophila, Mouse, Caenorhabditis elegans, and Zebrafish) with 258 distinct variants were included. Of these, 69% (N=38/55) of articles recapitulated mitochondrial DNA (mtDNA) depletion, 33% (N=18/55) utilised tissue-specific models of POLG-related dysfunction, while 13% (N=7/55) investigated the effect of potential therapeutics in POLG-related mitochondrial disorders.
Discussion: While some evidence is available to support the ability of POLG-related disease models to recapitulate molecular mechanisms and phenotypes, much is of limited quality, with inconsistencies evident across the literature. Further success in examining and translating novel therapies into effective treatments will be enhanced by the availability of more robust models that better recapitulate the entire spectrum of POLG-related disease.
PROSPERO registration: CRD42021234883.

Keywords:  POLG; epilepsy; mitochondria; mtDNA; neurological manifestations; preclinical

DOI:  https://doi.org/10.12688/wellcomeopenres.18637.2
Ann Med Surg (Lond). 2025 Nov;87(11): 7798-7799

AI-powered neuroimaging markers: a new era in paediatric Leigh syndrome diagnosis.

Raiha Yasser, Faiza Imran, Maliha Khalid, Muhammad Talha, Aminath Waafira.

  Leigh syndrome is a severe pediatric mitochondrial disorder characterized by progressive neurological decline and epilepsy as a frequent manifestation. Traditional diagnostic approaches, including EEG and MRI, are often limited in their sensitivity and specificity, leading to diagnostic delays. Artificial intelligence (AI)-powered neuroimaging markers have emerged as promising tools that integrate multimodal patient data - including clinical history, imaging, and genetic sequencing - to enhance diagnostic precision and facilitate early intervention. Recent studies have demonstrated AI's ability to classify epilepsy subtypes, automate EEG interpretation, and detect early neurodegenerative changes, underscoring its clinical potential. However, challenges such as algorithm transparency, dataset bias, and ethical concerns remain. Integrating AI-driven neurotechnology with existing modalities may significantly improve the early diagnosis and prognosis of Leigh syndrome, offering a pathway toward precision neurodiagnostics in pediatric care.

Keywords:  Leigh syndrome; artificial intelligence; neuroimaging; pediatric neurology

DOI:  https://doi.org/10.1097/MS9.0000000000003999
Neuroradiology. 2025 Nov 05.

Imaging patterns of paediatric CNS mitochondrial disorders.

Pritika Gaur, Cesar Alves, Harun Yildiz, Kshitij Mankad, Sniya Sudhakar, Shamima Rahman, Asthik Biswas.

  This review seeks to provide neuroradiologists and clinicians with an imaging-based pattern recognition framework for primary mitochondrial disorders affecting the central nervous system (CNS). By utilising a comprehensive imaging phenotype approach to CNS mitochondrial disorders, it highlights the wide spectrum of neuroimaging patterns and the complexities they present in clinical settings. Using illustrative case examples, the review demonstrates how imaging acts as a vital bridge between clinical phenotypes and genotypes.

Keywords:  Brain; Mitochondrial disorders; Paediatric; Spine

DOI:  https://doi.org/10.1007/s00234-025-03805-9
Recenti Prog Med. 2025 Nov;116(11): 652-660

Genetic testing: real patient autonomy needs medical supervision.

Federico Pennestrì, Giuseppe Banfi, Virginia Sanchini.

Adults who think to be at greater risk for developing some disease in the future make different choices about whether to get tested. Incidental findings resulting from patients tested for other clinical purposes, population screenings and research programs increase proportionally with genetic testing methodologies available in the market. Consumers can buy home kits online and receive test results without any doctor involved in the process. Increasing options for prenatal care put on women more testing choice and responsibility, which need qualified and punctual support to result more beneficial than detrimental. In our opinion, many issues related to genetic testing (incidental findings, direct-to-consumer use, prenatal care value) are due to lacking medical interpretation or supervision, because the one thing is the patient taking care in autonomy, the other thing is leaving patients alone to figure out whether a certain result is relevant to their health and choices. In particular, a doctor-patient relationship is crucial to avoid genetic reductionism, that is, underestimating the impact of clinical strategies, individual behavior, social network and living environment on health. Taking tests under appropriate medical supervision increases the opportunity to generate value and minimize risk, based on the informed preferences of the individual patient.

DOI: https://doi.org/10.1701/4588.45980
Orphanet J Rare Dis. 2025 Nov 05. 20(1): 564

Cracking the code: a head-to-head comparison of expert clinicians and artificial intelligence in diagnosing rare diseases.

Georg Wolfgang Sendtner, Martin Muecke, Lorenz Grigull, Tim Bender, Charlotte Behning, Valentin Sebastian Schäfer.

   BACKGROUND: Patients with rare diseases often face prolonged diagnostic journeys due to the low prevalence and diverse clinical presentations of these conditions. In Germany, specialized centers for rare diseases, established at university hospitals, offer targeted diagnostic and therapeutic care to reduce diagnostic delays. Tools like "Isabel Healthcare" can support clinicians by streamlining the differential diagnosis process and aiding in the accurate identification of rare conditions.
RESULTS: The study included 100 patients with a mean age of 44 years. "Isabel Healthcare DDx companion" and the interdisciplinary case conferences generated a total of 727 diagnosis suggestions. Among the top ten diagnoses suggested by "Isabel Healthcare DDx companion", 28% matched at least one diagnosis identified during the interdisciplinary case conferences. The diagnoses suggested as "more likely" by "Isabel Healthcare DDx companion" showed a higher correlation with the differential diagnoses and procedures identified during the interdisciplinary case conferences, suggesting a potential alignment in clinical decision-making processes.
CONCLUSION: This study has demonstrated the potential of the differential diagnostic tool "Isabel Healthcare DDx companion" to assist in patient diagnosis. However, discrepancies between the tool's findings and expert decisions suggest that, although it can support clinicians in decision-making, its independent effectiveness may be limited by accurately filtering and interpreting the essential medical history required for a precise diagnosis.

Keywords:  Artificial intelligence; Diagnostic tool; Rare disease

DOI:  https://doi.org/10.1186/s13023-025-04112-5