bims-curels 2026-04-05 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2026–04–05
eleven papers selected by
Cure Mito Foundation

Neurological manifestations and genotype-phenotype correlations in NDUFAF6-associated mitochondrial disease.
Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.
Real-world data and evidence in the development of cell and gene therapies.
Supporting researchers to involve patient partners in health service research: developing and assessing the feasibility and acceptability of a co-produced training programme for researchers.
Journeys Through Genomics: Co-Producing Visual Resources to Communicate Patient Experiences.
MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.
The Potential of Digital Twins for Pediatric Rare Diseases.
Bioinformatics and AI/ML approaches using multi-omics data to accelerate diagnosis and delivery of precision care for patients with rare diseases.
"No Words Needed": Results of a Survey on How Parents of Children With Neurodevelopmental Disorders Perceive (In)formal Peer Support.
Blueprint for Drug Repurposing Success: Foundational Concepts and Practical Framework.
Rethinking mitochondrial heteroplasmy: selection, conflict and adaptation.

Brain Commun. 2026 ;8(2): fcag095

Neurological manifestations and genotype-phenotype correlations in NDUFAF6-associated mitochondrial disease.

Alessandra Torraco, Charlotte L Alston, Giulia Barcia, Daniela Verrigni, Teresa Rizza, Michela Di Nottia, Anastasia Altobelli, Diego Martinelli, Daria Diodato, Stephanie Efthymiou, Melis Kose, Yamna Kriouile, Albert Z Lim, Silvia Morlino, Barbara Siri, Nebal Waill Saadi, Antonio Novelli, Henry Houlden, Carlo Dionisi-Vici, Robert McFarland, Agnès Rötig, Enrico Bertini, Robert W Taylor, Rosalba Carrozzo.

  NDUFAF6 encodes a mitochondrial complex I assembly factor essential for the proper biogenesis and stability of the nicotinamide adenine dinucleotide (NAD) + hydrogen (H) (NADH)-ubiquinone oxidoreductase complex. Pathogenic variants in NDUFAF6 have been increasingly recognized as a cause of mitochondrial disease, particularly Leigh syndrome, a severe neurodegenerative disorder characterized by bilateral symmetrical lesions in the central nervous system. To date, fewer than 50 patients with NDUFAF6-related mitochondrial disease have been reported, displaying a broad phenotypic spectrum ranging from early-onset neurodevelopmental regression to milder, more chronic presentations. The molecular mechanisms underlying these phenotypes are linked to impaired complex I assembly and reduced enzymatic activity, highlighting the critical role of NDUFAF6 in mitochondrial function. Here we present a cohort of 27 patients (14 males and 13 females) from 18 families harbouring biallelic variants in the NDUFAF6 gene. The patient's mean age was 9.15 ± 8.30 years (range: 4 weeks to 25 years); 12 patients (37%) had died by the time the data were collected for this article. The clinical presentation showed wide phenotypic variability, from mild to severe psychomotor regression (74%) most commonly before the age of 5 years, hypotonia (22%), movement disorders (30%), and hypertonia (15%). Bilateral striatal necrosis lesions were the most characteristic features on cranial MRI (67%) although white matter abnormalities were also noted (15%), occasionally accompanied by cystic formations, suggestive of early neurodevelopmental anomalies. Genomic sequencing was applied, leading to the identification of 19 distinct variants in the NDUFAF6 gene, including nine novel variants not previously reported and either absent or extremely rare in public population databases. Functional studies confirmed the pathogenicity of these variants, demonstrating a deleterious effect on NDUFAF6 protein expression and a consequent impairment in complex I assembly and stability. To date, this represents the largest reported cohort of patients with NDUFAF6-associated mitochondrial disease. Our findings provide a comprehensive overview of clinical characteristics-including age of symptom onset, phenotypic variability, and patient outcomes-aiming to improve prognostic information and facilitate genetic counselling in clinical practice.

Keywords:  Assembly factors; Leigh syndrome; Mitochondrial disease; NADH–ubiquinone oxidoreductase; Respiratory chain complexes

DOI:  https://doi.org/10.1093/braincomms/fcag095
Am J Hum Genet. 2026 Mar 30. pii: S0002-9297(26)00113-8. [Epub ahead of print]

Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.

Natalie B Tan, Matthias Gautschi, Michael Raum, Daniella H Hock, Robert Kopajtich, Jia Wang, Xiao Qian, Tanavi Sharma, Timothy E Green, Jean-Marc Nuoffer, Katrina M Bell, Katarzyna Pospieszny, Tegan Stait, Chloe Pike, Michelle Cao, Susan M White, David R Thorburn, Theresa Brunet, Matias Wagner, Wolfgang Müller-Felber, Leopold Zeng, Thomas Klopstock, André Schaller, Jing Liu, David A Stroud, Holger Prokisch.

  NDUFA5 encodes a structural subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) located in the peripheral arm of the enzyme complex. Complex I is the largest enzyme of the mitochondrial respiratory chain and is essential for oxidative phosphorylation. There are many well-characterized conditions associated with nuclear-encoded mitochondrial complex I dysfunction, including Leigh syndrome, leukoencephalopathy, lethal infantile mitochondrial disease, hypertrophic cardiomyopathy, and exercise intolerance. The vast majority of these nuclear-encoded mitochondrial complex I deficiencies are autosomal-recessive conditions. To date, variants in NDUFA5 have not been associated with mitochondriopathy in humans. We identified a cohort of four individuals from three unrelated families with bi-allelic variants in NDUFA5. All individuals present with variable multisystem disease in the setting of a mitochondrial complex I deficiency, biochemically proven via an array of respiratory chain enzymology, blue native PAGE, and mass-spectrometry-based proteomics in peripheral blood mononuclear cells, lymphoblastoid cell lines, fibroblasts, and skeletal muscle. Transcriptomics and RT-PCR demonstrated aberrant mRNA expression in all affected individuals. Finally, we generated zebrafish ndufa5 F0 mutants that exhibited defects of morphological development, locomotor deficits, and abnormal brain activity. Our data demonstrate that bi-allelic variants in NDUFA5 cause a mitochondrial complex I deficiency, characterized by a variable multisystem phenotype that encompasses severe congenital heart defects, hematological abnormalities, and neurological involvement consistent with Leigh syndrome.

Keywords:  CI deficiency; NDUFA5; complex I deficiency; mitochondrial disease; mitochondriopathy

DOI:  https://doi.org/10.1016/j.ajhg.2026.03.003
J Biopharm Stat. 2026 Mar 29. 1-16

Real-world data and evidence in the development of cell and gene therapies.

Yeonhee Kim, Shihua Wen, Khadija Rerhou Rantell, Zhenzhen Xu, Patricia Anderson.

  Cell and gene therapies (CGTs) are rapidly growing fields in regenerative medicine with the potential to tackle the most difficult-to-treat diseases. Despite their transformative potential, the development of CGTs is inherently complex, resource-intensive, and associated with high costs, posing substantial barriers in development and commercialization. As a feasible approach to address these challenges, real-world data (RWD) and real-world evidence (RWE) are gaining increasing recognition as powerful tools to potentially support and accelerate CGT development. This manuscript aims to identify the potential role of RWE and RWD in CGT development, with a focus on its application in regulatory licensure to date. Furthermore, we discuss current challenges, limitations, and evolving regulatory landscape pertaining to the use of RWE in regulatory decision-making.

Keywords:  Real-world data; cell and gene therapy; external control; historical control; hybrid trial; real-world evidence

DOI:  https://doi.org/10.1080/10543406.2026.2648311
Res Involv Engagem. 2026 Mar 28.

Supporting researchers to involve patient partners in health service research: developing and assessing the feasibility and acceptability of a co-produced training programme for researchers.

S C Tscherning, T W Vedelø, F O Jensen, A L Jensen, H L Bekker, L Ø Rodkjaer.

   BACKGROUND: Involving people and next of kin as patient partners in research can enhance research quality. Training researchers seems to be an effective way to support meaningful involvement of patient partners. Although guidance is increasingly available, Danish researchers lack support for implementing patient partner involvement. Providing a dedicated training programme for researchers could help them establish meaningful partnerships with patient partners.
METHODS: This study aimed to develop and evaluate the feasibility and acceptability of a training programme designed to assist researchers in involving patient partners. The training programme was co-produced by researchers and patient partners, who are referred to as patient partner teachers. The development and feasibility phases were guided by the Medical Research Council's framework for developing complex interventions and structured according to the six parameters of the didactic relationship model: 'prerequisites for learning', 'learning goals', 'settings and conditions', 'learning process', 'educational content', and 'evaluation of learning'. Feasibility and acceptability were assessed through questionnaires completed by participants before, during, and after the training programme.
RESULTS: The didactic relationship model provided a strong pedagogical basis for developing a training programme. The co-production process was effectively managed, with patient partner teachers reporting feeling involved throughout the project, especially in communication and partnership within the development team. A total of 32 participants, including researchers with various job titles, attended the training. Most participants indicated they had extensive research experience but limited knowledge of and confidence in involving patient partners. The training programme - which was customised to meet the needs of diverse participants and delivered in small groups - proved beneficial, boosting their confidence. Overall, the participants expressed satisfaction with the programme and enthusiasm for the patient partner teachers, and 85% would recommend the training to a colleague.
CONCLUSIONS: This training programme was feasible and addressed participants' needs. The co-production process was essential for both developing and delivering the training. Future research should examine additional factors that encourage meaningful involvement of patient partners in the research process.

Keywords:  Co-production; Complex intervention design; Patient and public involvement; Patient engagement; Public involvement; Research personnel; Training programme

DOI:  https://doi.org/10.1186/s40900-026-00874-9
Sociol Res Online. 2025 Mar;30(1): 278-285

Journeys Through Genomics: Co-Producing Visual Resources to Communicate Patient Experiences.

Kate Lyle, Susie Weller, Anneke Lucassen.

  Journeys through Genomics is a series of illustrations co-produced with patients and families to communicate their experiences of seeking genomic explanations for a health condition and the wider impact on their lives. The resources are embedded within qualitative longitudinal research exploring patient's experiences of genomic medicine. This research takes place as genomic medicine becomes an integral part of mainstream care within the UK healthcare system. The depiction of genomic medicine often focuses on its technological components and the speed by which genetic code can be analysed, but here, we present a dynamic and situated understanding of the challenges genomic testing presents for patients and families. We describe the process of working with research participants and an artist to co-produce visual resources that illustrate the complexity of participant's journeys, situating genomic testing within the broader context of their lives. These resources are designed to help future patients, families, and healthcare professionals understand the process, opportunities, and challenges they may face.

Keywords:  co-production; genomics; illustration; patient experience

DOI:  https://doi.org/10.1177/13607804241252528
Nat Struct Mol Biol. 2026 Apr 01.

MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.

Stephen P Burr, Kathryn Auckland, Angelos Glynos, Abhilesh Dhawanjewar, Cameron Ryall, Wei Wei, Antony Hynes-Allen, Malwina Prater, Matylda Sczaniecka-Clift, Julien Prudent, Patrick F Chinnery, Jelle van den Ameele.

Mitochondria contain their own genome, mitochondrial DNA (mtDNA), which is under strict control by the cell nucleus. mtDNA occurs in many copies per cell and mutations often only affect a proportion of them, giving rise to heteroplasmy. mtDNA copy number and heteroplasmy level together shape the tissue-specific impact of mtDNA mutations, eventually giving rise to both rare mitochondrial and common neurodegenerative diseases. Here, we use MitoPerturb-Seq for CRISPR-Cas9-based, high-throughput single-cell interrogation of the nuclear genes and pathways that sense and control mtDNA copy number and heteroplasmy. We screened a panel of mtDNA maintenance genes in mouse cells with a heteroplasmic mtDNA mt-Ta mutation. This revealed both common and perturbation-specific aspects of the integrated stress response to mtDNA depletion caused by Tfam, Opa1 and Polg knockout. These responses are only partially mediated by ATF4 and cause cell-cycle stage-independent slowing of cell proliferation. MitoPerturb-Seq, thus, provides experimental insight into disease-relevant mitochondrial-nuclear interactions and may inform development of therapies targeting cell-type- and tissue-specific vulnerabilities to mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41594-026-01779-7
CPT Pharmacometrics Syst Pharmacol. 2026 Apr;15(4): e70234

The Potential of Digital Twins for Pediatric Rare Diseases.

Rahuman S Malik-Sheriff, Anurag Limdi, Evangelia Petsalaki, Henning Hermjakob, Ellen M McDonagh.

Rare diseases affect over 300 million people globally, with approximately 75% manifesting in childhood. Their diagnosis is often delayed and approved treatments are lacking for most of the conditions. Pediatric rare diseases research is further complicated by ethical constraints and developmental diversity across childhood. Digital Twins, virtual representations of patients built from mechanistic and AI/ML models, offer a promising solution by enabling hypothesis testing, precision diagnostics, personalized therapies, and in silico trials for pediatric rare diseases. This article discusses the potential of DT applications in advancing precision medicine for pediatric rare diseases, alongside associated regulatory perspectives, modeling strategies, uncertainty analysis, as well as data, ethical and legal challenges.

DOI: https://doi.org/10.1002/psp4.70234
Methods Cell Biol. 2026 ;pii: S0091-679X(25)00099-8. [Epub ahead of print]204 109-139

Bioinformatics and AI/ML approaches using multi-omics data to accelerate diagnosis and delivery of precision care for patients with rare diseases.

Kritika Singh, Sarah Usman, Saman Zeeshan, Naveena Yanamala, Mark Nichols, Vikram Bhise, Sabahat Bokhari, Partho P Sengupta, Zeeshan Ahmed.

  Rare diseases, characterized by their low prevalence, cumulatively affect millions of people around the world and place significant burden on the healthcare system. With limited clinical expertise and infrastructure in this field, patients encounter barriers in obtaining an accurate diagnosis and accessing treatment. Rare diseases are commonly attributable to genetic alterations; thus, we can optimize modern genetic technologies to pinpoint pertinent genes and molecular pathways involved in disease phenotypes. In this article, we discuss rare diseases in context of multi-omics, an integrative approach combining data from various sources, including genomics, transcriptomics, and epigenomics. Advancements in multi-omics have facilitated the collection of more high-dimensional data, particularly useful for rare diseases comprising limited sample sizes. Artificial intelligence (AI) and machine learning (ML) are powerful tools for extracting disease-relevant patterns from complex datasets and unraveling causative markers underlying disease. Together, these tools are invaluable for incorporating precision medicine in rare diseases through guiding therapeutic strategies aimed at modifying the structure and functionality of specific genes to address the root cause of disease. Specifically, we curate a list of twenty-three rare diseases, prioritized by the medical community based on unmet medical needs and prevalence. To illustrate the current landscape of precision medicine for these diseases, we summarize advancements in genomic sequencing and computational methods for their diagnosis, and utilization of gene-editing technologies for personalized treatment. Overall, the various bioinformatic strategies discussed in this paper help formulate an end-to-end workflow of the integration of gene testing, multi-omics, and AI/ML to guide effective rare disease management.

Keywords:  Artificial intelligence; Bioinformatics; Machine learning; Precision medicine; Rare diseases

DOI:  https://doi.org/10.1016/bs.mcb.2025.03.018
Child Care Health Dev. 2026 May;52(3): e70264

"No Words Needed": Results of a Survey on How Parents of Children With Neurodevelopmental Disorders Perceive (In)formal Peer Support.

Monica Verkooijen, Marjolijn Ketelaar, Leonie Te Grefte, Indira Tendolkar, Wouter Staal, Janneke Zinkstok.

   BACKGROUND: Parents caring for children with neurodevelopmental disorders (NDD) face unique and ongoing challenges that impact family well-being. Peer support from individuals with shared lived experiences can offer recognition, shared understanding and empowerment. Despite its promise, peer support for parents of children with NDD remains largely informal, under-researched and poorly integrated within standard healthcare, limiting its potential accessibility and impact. Little is known about what parents seek in peer support, how they experience it, and which factors facilitate meaningful engagement. This study therefore aimed to explore parents' perceptions of peer support, focusing on uptake, impact and conditions influencing its effectiveness.
METHODS: A survey co-created with parent-carers collected quantitative and qualitative data on perceptions, needs, concerns and barriers related to peer support. The online survey was distributed via parent organisations. Descriptive statistics summarised participant characteristics and peer support uptake, while thematic analysis identified key experiential themes from open-ended responses.
RESULTS: Among the 225 participating parents (89% mothers), 77.3% expressed a need for peer support, mostly because friends and family did not fully understand their situation. Of these parents, 65.6% reported finding peer support, mostly informal initiatives. Thematic analysis of participants' comments revealed four key categories describing the experience with and need for peer support: (1) support, (2) mutual learning, (3) connection by recognition and (4) experiencing no judgement. Also included in the results are concerns reported by parents and factors facilitating or hindering successful peer support.
CONCLUSION: Parents of children with NDD valued peer support for emotional connection, practical advice and shared understanding. Preferences are highly individual, emphasising the need for tailored peer support. These findings may guide the design and implementation of peer support initiatives aligned with parents' needs and preferences. Future research should focus on how the full potential of peer support for these parents can be unlocked.

Keywords:  family‐oriented care; neurodvelopmental disorders; parents; peer support

DOI:  https://doi.org/10.1111/cch.70264
Drug Dev Res. 2026 Apr;87(2): e70270

Blueprint for Drug Repurposing Success: Foundational Concepts and Practical Framework.

Aayusree Ray, Shreya Dey, Debjeet Sur.

  Drug repurposing involves identifying new therapeutic applications for existing clinically evaluated compounds. In contrast to conventional drug development, which typically spans over a decade and demands substantial financial investment, repurposed drugs can achieve regulatory approval in approximately half the time and cost by capitalizing on their established pharmacokinetic, safety, and clinical profiles. This review provides a comprehensive analysis of the traditional and computational strategies employed in drug repurposing. Experimental methodologies include binding affinity assays, clinical data mining and phenotype-based screening. Computational approaches are categorized into structure-based, signature-based, pathway-based, knowledge-based, and target-based strategies. The recent integration of artificial intelligence (AI) and machine learning (ML) within repurposing pipelines is also examined, emphasizing their ability to efficiently process large-scale datasets, improve the predictive accuracy of drug-target interactions, and support the advancement of repurposing efforts. Furthermore, this review systematically compares prominent computational platforms, virtual screening tools, and bioinformatics resources, highlighting their respective strengths and limitations. Emerging AI-driven models, such as deep learning architectures, graph neural networks, knowledge graphs, and network pharmacology frameworks, have transformative roles in broadening the scope of drug repurposing. This comprehensive review is intended to assist medicinal chemists, computational biologists, and drug discovery scientists in expediting research efforts by effectively utilizing existing resources for repurposing-driven innovations.

Keywords:  artificial intelligence; computational drug discovery; drug discovery; drug repurposing; translational research

DOI:  https://doi.org/10.1002/ddr.70270
Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250079. [Epub ahead of print]381(1947):

Rethinking mitochondrial heteroplasmy: selection, conflict and adaptation.

Jade R Kannangara, Hansong Ma, Damian K Dowling.

  Mitochondrial DNA (mtDNA) variation is increasingly recognized for its role in shaping evolutionary changes at the species and population levels. Yet, its evolutionary relevance within individuals remains less explored. Eukaryotic cells typically carry multiple copies of mtDNA. When these copies differ in sequence, heteroplasmy arises-a form of intra-organismal genetic diversity with potentially profound biological implications. To elucidate the evolutionary significance of heteroplasmy in animals, we first review how natural selection shapes adaptive mtDNA dynamics at broader biological levels, via cases of mito-nuclear coadaptation, environmental-mediated and sex-specific selection and balancing selection. We then explore whether analogous selective pressures may operate at the intra-individual level. Heteroplasmy introduces the potential for multi-level selection-from the genome to the organism-potentially yielding synergistic or antagonistic evolutionary outcomes. This framework encompasses both the selfish transmission of certain mtDNA variants and emerging evidence for adaptive shifts in heteroplasmy levels under environmental stress. These findings are supported by theoretical models suggesting that paternal mtDNA transmission-historically viewed as a stochastic anomaly-may confer adaptive benefits under specific ecological and evolutionary contexts by introducing intra-individual mtDNA diversity. Collectively, these insights suggest that heteroplasmy may act as an underappreciated reservoir of adaptive potential, enhancing the evolutionary capacity of organisms in a changing world. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.

Keywords:  adaptation; adaptive; environmental change; evolution; heteroplasmy; mito-nuclear; mitochondria; mtDNA; selfish; selfish drive

DOI:  https://doi.org/10.1098/rstb.2025.0079