bims-curels Biomed News
on Leigh syndrome
Issue of 2025–04–06
fifteen papers selected by
Cure Mito Foundation
  1. Diagnosis of Primary Mitochondrial Diseases.
  2. Perceived association of mood and symptom severity in adults with mitochondrial diseases.
  3. Investigating the safety and efficacy of deoxycytidine/deoxythymidine in mitochondrial DNA depletion disorders: phase 2 open-label trial.
  4. Profiling mitochondrial DNA variant segregation during human preimplantation development: a prerequisite to preimplantation genetic testing for mitochondrial DNA-related disorders.
  5. An engineered mitoCBE facilitates efficient mitochondrial DNA editing and modified mitochondrial transfer.
  6. Communicating Hope and Fact to Families With Leber Hereditary Optic Neuropathy.
  7. Synthetic data generation: a privacy-preserving approach to accelerate rare disease research.
  8. FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome: A rare cause of hyperammonemia.
  9. Strategies for Improving Case Reports Involving Patients With Rare Diseases.
  10. Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I.
  11. Successful birth after preimplantation genetic testing for rare mitochondrial DNA mutation m.10197G>A.
  12. Mitochondrial DNA copy number and Alzheimer's disease and Parkinson disease.
  13. Patient Engagement in Safety: Are We There Yet?
  14. Re-Analysis Yields Diagnosis in Over 500 Patients with Rare Diseases.
  15. Mitochondrial Genome Variants and Alzheimer's Disease.
  1. Muscle Nerve. 2025 Apr 03.
    Diagnosis of Primary Mitochondrial Diseases.
    Salman Bhai, Michio Hirano.
      Primary mitochondrial diseases are clinically heterogeneous and present diagnostic challenges due to the highly variable genotype-phenotype correlation. Clinical symptoms can range from non-specific fatigue, exercise intolerance, and weakness to syndromic phenotypes. Though multiple testing modalities exist to identify mitochondrial diseases, most of these tests are nonspecific, or results are associated with other diseases. Molecular testing can provide an efficient path toward diagnosis, as molecular detection techniques have improved and become less costly. A "genetics first" approach can reduce diagnostic delay and improve management, where the diagnostic pathway can be an invasive or noninvasive combination of targeted or comprehensive molecular testing. Prior to ordering these tests, clinicians must consider the ambiguities and nuances of various testing modalities during the work-up for mitochondrial diseases. Therefore, due to the diagnostic challenges associated with primary mitochondrial diseases, diagnosis should be made in the context of clinical and molecular data, potentially supplemented with histochemical and biochemical evidence. Confirmation of a diagnosis leads to improvements in the management of the disease, decreases unnecessary testing, informs reproductive planning, and improves research pipelines.
    Keywords:  genetic testing; mitochondria; mitochondrial disease; mitochondrial myopathy; primary mitochondrial disease
    DOI:  https://doi.org/10.1002/mus.28387
  2. Mitochondrion. 2025 Mar 29. pii: S1567-7249(25)00030-3. [Epub ahead of print] 102033
    Perceived association of mood and symptom severity in adults with mitochondrial diseases.
    Catherine Kelly, Marissa Cross, Alex Junker, Kris Englestad, Xiomara Rosales, Michio Hirano, Caroline Trumpff, Martin Picard.
      Individuals with genetic mitochondrial diseases suffer from multisystem symptoms that vary in severity and over time, but the factors influencing disease manifestations are poorly understood. Based upon i) patient and family reports that stressful life events trigger or exacerbate symptoms, ii) biologically plausible pathways whereby psychological states and stress hormones influence mitochondrial energy production capacity, and iii) epidemiological literature linking traumatic/stressful life events and multiple neurologic disorders, we hypothesized that mitochondrial disease symptom severity may in part vary with daily mood. To examine patients' perception around potential psycho-biological mechanisms known to operate in other chronic illnesses, we administered the Stress, Health and Emotion Survey (SHES) to 70 adults with self-reported mitochondrial diseases. Participants rated how severe each of their symptom(s) was over the past year, separately for either 'good' (happy, calm) or 'bad' (stress, sad) emotional days. On average, patients reported that most symptoms were better on "good" emotional days (p < 0.0001) and worse on "bad" emotional days (p < 0.0001). Of the 29 symptoms assessed, 27 were associated with daily mood (p < 0.01). Some but not all symptoms were reported to be less or more severe on good and bad days, respectively, including fatigue, exercise intolerance, brain fog, and fine motor coordination (ps < 0.0001). These associative results suggest that on average individuals living with mitochondrial diseases perceive a connection between their mood and symptoms severity. These preliminary findings constitute an initial step towards developing more comprehensive models of the psychobiological factors that influence the course of mitochondrial diseases.
    Keywords:  Clinical survey; Disease severity; Emotions; Mitochondrial disease; Patient care; Stress
    DOI:  https://doi.org/10.1016/j.mito.2025.102033
  3. J Neurol. 2025 Apr 02. 272(4): 307
    Investigating the safety and efficacy of deoxycytidine/deoxythymidine in mitochondrial DNA depletion disorders: phase 2 open-label trial.
    Saoussen Berrahmoune, Christelle Dassi, Heather Pekeles, Anthony C T Cheung, Tommy Gagnon, Paula J Waters, Daniela Buhas, Kenneth A Myers.
       OBJECTIVE: Mitochondrial DNA depletion disorders are rare genetic disorders involving mitochondrial dysfunction. These diseases are genetically and clinically heterogeneous but share the common feature of progressively degenerative courses. At present, there are no approved treatments for mitochondrial DNA depletion disorders, though recent reports have suggested that treatment with deoxycytidine/deoxythymidine could be effective for subtypes caused by pathogenic variants in two specific genes, POLG and TK2. We investigated the therapeutic potential of deoxycytidine/deoxythymidine for people with mitochondrial DNA depletion disorders due to pathogenic variants in genes other than POLG and TK2.
    METHODS: We analyzed interim data from an open-label clinical trial of deoxycytidine/deoxythymidine for treatment of mitochondrial DNA depletion disorders, specifically examining disorders due to pathogenic variants in genes other than POLG and TK2. Outcome measures included Newcastle Mitochondrial Disease Scale score and serum growth differentiation factor 15, a mitochondrial function biomarker.
    RESULTS: Data were available from eight individuals having pathogenic variants in FBXL4, SUCLG1, SUCLA2, or RRM2B. Newcastle Mitochondrial Disease Scale score improved in all individuals except for one who withdrew before the first follow-up visit; group level analysis was significant at 1-month and 6-month timepoints. Five patients had elevated growth differentiation factor 15 at baseline; of these, levels improved in four, including three whose values normalized.
    CONCLUSION: These data suggest deoxycytidine/deoxythymidine is a safe and therapeutically promising intervention for a broad range of mitochondrial DNA depletion disorders.
    Keywords:  Deoxycytidine; Deoxynucleoside; Deoxythymidine; FBXL4; Pyrimidine; SUCLG1
    DOI:  https://doi.org/10.1007/s00415-025-13060-w
  4. Hum Reprod. 2025 Apr 02. pii: deaf050. [Epub ahead of print]
    Profiling mitochondrial DNA variant segregation during human preimplantation development: a prerequisite to preimplantation genetic testing for mitochondrial DNA-related disorders.
    Paula Rubens, Anne Mayeur, Kalliopi Chatzovoulou, Nadine Gigarel, Sophie Monnot, Agnès Rötig, Arnold Munnich, Nelly Frydman, Julie Steffann.
       STUDY QUESTION: Is preimplantation genetic testing for mitochondrial DNA (mtDNA) disorders (PGT-mt) feasible at early compaction and blastocyst stages?
    SUMMARY ANSWER: Pathogenic mtDNA variants segregate evenly among cell types and various lineages of a given embryo during preimplantation development, supporting the relevance of genetic analyses performed on Day 4 blastomere and on Day 5 or 6 trophectoderm (TE) samples.
    WHAT IS KNOWN ALREADY: PGT-mt is validated at cleavage stage (Day 3 of development). However, its feasibility at later stages is questionable, as little is known regarding the segregation of pathogenic mtDNA variants during preimplantation development. Since mtDNA replication is silenced until the blastocyst stage (Day 5 or 6), uneven mtDNA segregation between preimplantation embryo cellular lineages known as a 'bottleneck' effect, cannot be excluded, posing a challenge for PGT-mt.
    STUDY DESIGN, SIZE, DURATION: We analyzed 112 'mito' embryos carrying pathogenic mtDNA variants and 28 control embryos with mtDNA polymorphism. Heteroplasmy levels were assessed in single cells of the TE, in different parts of blastocysts (inner cell mass and TE), and at three time points of development, namely cleavage (Day 3), early compaction (Day 4), and blastocyst stages (Day 5 or 6).
    PARTICIPANTS/MATERIALS, SETTING, METHODS: As part of clinical PGT, a blastomere biopsy was performed at cleavage or early compaction stages (Day 3 or 4) on 112 'mito' and 21/28 control embryos. Further analysis was carried out at Day 5 or 6 on 51 embryos deemed unsuitable for uterine transfer and donated to research. Heteroplasmy levels were determined by semi-quantitative PCR amplification of (i) the mtDNA pathogenic variants with additional enzymatic digestion or (ii) the mtDNA polymorphic hypervariable region 2.
    MAIN RESULTS AND THE ROLE OF CHANCE: Here, we first show that mtDNA variants segregate evenly among blastomeres during early compaction (Day 4), supporting the feasibility of PGT-mt at this stage. We also found that mtDNA ratios remain stable between cleavage and blastocyst stages. Yet, the substantial variation of heteroplasmy levels occurring among single TE cells in 1/8 embryos suggests that PGT is only feasible when at least 5-10 cells are collected by standard TE biopsy.
    LIMITATIONS, REASONS FOR CAUTION: This study sheds light on mtDNA segregation in human preimplantation embryo development. Its limitation lies in the scarcity of the material and the small number of embryos carrying a specific pathogenic mtDNA variant. Furthermore, the study of single cells from TE was performed on control embryos only.
    WIDER IMPLICATIONS OF THE FINDINGS: By supporting the relevance of blastocyst biopsy in the context of PGT for pathogenic mtDNA variants, this study contributes to the general trend of postponing the biopsy to later stages of embryonic development. However, particular attention should be paid to the number of TE cells tested. Due to the potential variation of mutant load during in utero development, a control amniocentesis for evolutive pregnancies following the transfer of heteroplasmic embryos is still recommended.
    STUDY FUNDING/COMPETING INTEREST(S): This work was funded by 'Association Française contre les Myopathies/AFM Téléthon' (22112, 24317, 28525); and EUR G.E.N.E. (No. ANR-17-EURE-0013). The authors have no competing interests to declare.
    TRIAL REGISTRATION NUMBER: N/A.
    Keywords:  heteroplasmy; human preimplantation embryo; mitochondria; mitochondrial DNA; morula biopsy; mtDNA segregation; pathogenic mtDNA variants; preimplantation genetic testing; trophectoderm biopsy
    DOI:  https://doi.org/10.1093/humrep/deaf050
  5. Mol Ther. 2025 Apr 03. pii: S1525-0016(25)00260-6. [Epub ahead of print]
    An engineered mitoCBE facilitates efficient mitochondrial DNA editing and modified mitochondrial transfer.
    Jie Liu, Jun Chen, Shisheng Huang, Junfan Guo, Xiangyang Li, Ying Yan, Ruijing Chen, Guanglei Li, Ming Liu, Jiao Wei, Xingxu Huang, Yunbo Qiao.
      Double-stranded DNA (dsDNA) cytosine deaminase DddA orthologs from multiple types of bacteria have been fused with TALE system for mitochondrial DNA (mtDNA) base editing, while the efficiencies remain limited and its nuclear off-targeting activity cannot be ignored yet. Here we identified a DddA ortholog from Burkholderia gladioli (BgDddA) and generated nuclear or mitochondrial DNA cytosine base editors (mitoCBEs), exhibiting higher C•G-to-T•A editing frequencies compared to canonical DdCBE, and fusion with transactivator Rta remarkably improved editing efficiencies by up to 6.4-fold at non-TC targets. Referring to DddA11, we further introduced six substitutions into BgDddA and generated mitoCBE3.2, which efficiently induced disease-associated mtDNA mutations in mouse and human cell lines at both TC and non-TC targets with efficiency reaching up to 99.2%. Using mitoCBE3.2, single clones containing homoplasmic mtDNA mutations or premature stop codons associated with human diseases were generated, and the functions of these mutations have been evaluated upon the treatment of ROS inducers. Importantly, mitochondria harboring these homoplasmic mutations were transplanted into wildtype cells, enabling precise base conversions, without risk of nuclear gene off-targets. Thus, we have engineered an efficient mitoCBE using BgDddA, facilitating mitochondrial disease modeling and potential mutation correction with the aid of mitochondrial transplantation.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.03.051
  6. Clin Exp Ophthalmol. 2025 Apr;53(3): 227-228
    Communicating Hope and Fact to Families With Leber Hereditary Optic Neuropathy.
    Clare L Fraser, Kate Ahmad.
      
    DOI:  https://doi.org/10.1111/ceo.14513
  7. Front Digit Health. 2025 ;7 1563991
    Synthetic data generation: a privacy-preserving approach to accelerate rare disease research.
    Jorge M Mendes, Aziz Barbar, Marwa Refaie.
      Rare disease research faces significant challenges due to limited patient data, strict privacy regulations, and the need for diverse datasets to develop accurate AI-driven diagnostics and treatments. Synthetic data-artificially generated datasets that mimic patient data while preserving privacy-offer a promising solution to these issues. This article explores how synthetic data can bridge data gaps, enabling the training of AI models, simulating clinical trials, and facilitating cross-border collaborations in rare disease research. We examine case studies where synthetic data successfully replicated patient characteristics, and supported predictive modelling and ensured compliance with regulations like GDPR and HIPAA. While acknowledging current limitations, we discuss synthetic data's potential to revolutionise rare disease research by enhancing data availability and privacy file enabling more efficient and effective research efforts in diagnosing, treating, and managing rare diseases globally.
    Keywords:  AI-driven diagnostics; European Health Data Space (EHDS); ethical frameworks; medical imaging; privacy preservation; rare disease research; regulatory compliance; synthetic data
    DOI:  https://doi.org/10.3389/fdgth.2025.1563991
  8. Mol Genet Metab Rep. 2025 Jun;43 101206
    FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome: A rare cause of hyperammonemia.
    Ayça Burcu Kahraman, Halil Çelik, Zafer Bagci, Abdullah Sezer, Mustafa Kılıç.
       Introduction: FBXL4- related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is caused by pathogenic variants in the FBXL4 gene, resulting in mitochondrial dysfunction and multisystem involvement. Hyperammonemia is reported in 45 % of cases but extremely elevated ammonia levels are rare.
    Case presentation: A male infant presented with dysmorphic features, hypotonia, failure to thrive, and lactic acidosis and severe hyperammonemia (ammonia: 1495 μmol/L). Genetic testing identified a homozygous FBXL4 pathogenic variant.
    Conclusion: To our knowledge, this report presents a neonatal case of FBXL4-related mtDNA depletion syndrome with the highest hyperammonemia level. This case emphasizes the importance of FBXL4 genetic testing in neonates with multisystem involvement, hyperammonemia, and dysmorphic features.
    Keywords:  Encephalopathy; FBXL4 gene; Hyperammonemia; Lactic acidosis; Mitochondrial DNA depletion syndromes
    DOI:  https://doi.org/10.1016/j.ymgmr.2025.101206
  9. Cureus. 2025 Feb;17(2): e79864
    Strategies for Improving Case Reports Involving Patients With Rare Diseases.
    Mikaela I Poling, Craig R Dufresne.
      For those treating patients with rare diseases, there may be a disproportionate clinical reliance on the literature, compared with those treating patients with common problems. Moreover, the rare disease literature consists of a preponderance of case reports. Together, these factors place a higher burden for accuracy on authors of case reports of patients with rare diseases. Our decades of experience with the rare congenital craniofacial myopathy, Freeman-Sheldon syndrome-now, Freeman-Burian syndrome, and other rare diseases suggests that accurate and current information may not efficiently proliferate in the rare disease literature-a potentially significant clinical and scholarly concern. Based on our experience of reading case reports of patients with Freeman-Burian syndrome, we suggest mutually supporting mitigation strategies. Our quality-improvement strategies for rare disease case reports emphasize a careful search of recent literature, not exclusively case reports, in-person clinical experience with the patient described, and involvement of a rare disease expert as bedrocks for improving case report accuracy. We propose that objectively demonstrating the patient's findings relative to an accepted diagnostic criteria, presenting the clinical course within a known disease mechanism, cautiously proposing a new one, and adhering to the relevant case report guidelines can help construct a stronger case report. We hope the wide dissemination of these quality improvement strategies among authors, editors, peer reviewers, and readers will improve the accuracy and completeness of case reports involving rare diseases to ensure the best chances for advancing clinical care and science for this often marginalized patient population.
    Keywords:  case report; clinical reasoning; clinical relevance; craniofacial dysostosis; freeman-burian syndrome; freeman-sheldon syndrome; medical writing; rare diseases; research methodology; whistling face syndrome
    DOI:  https://doi.org/10.7759/cureus.79864
  10. Sci Rep. 2025 Mar 29. 15(1): 10925
    Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I.
    Veronica Bazzani, Deepali L Kundnani, Mara Equisoain Redin, Francesca Agostini, Kirti Chhatlani, Angelo Corso Faini, Jakub Poziemski, Umberto Baccarani, Pawel Siedlecki, Silvia Deaglio, Francesca Storici, Carlo Vascotto.
      Hepatocellular carcinoma (HCC) is the most common form of liver cancer, which often arises from previous liver pathologies such as HBV, HCV, and alcohol abuse. It is typically associated with an enlarged cirrhotic organ. In this study, we analyzed tumor and distal tissues from a patient who underwent liver resection for HCC with no previous pathologies and whose liver showed normal function without signs of cirrhosis. Genetic analysis of mitochondrial DNA (mtDNA) revealed a novel variant of the gene encoding the NADH dehydrogenase subunit 6 (ND6) protein in the tumor tissue. The deletion of a thymidine generated an early stop codon, resulting in a truncated form of the protein (ΔND6) with 50% of the C-terminal primary sequence missing. ND6 is a subunit of the NADH dehydrogenase complex, also known as Complex I, the largest complex in the electron transport chain. Previous studies have linked mtDNA Complex I mutations to mitochondrial disorders and cancer. Through biochemical analyses, we characterized this new mutation and showed that the expression of ΔND6 negatively affects the stability and functionality of Complex I. Data were confirmed by molecular dynamics simulations suggesting conformational rearrangements, overall revealing a leading role of ND6 in the assembly of Complex I.
    Keywords:  Hepatocellular carcinoma; Mitochondria; Mitochondrial DNA; Molecular dynamics simulations.; ND6 gene mutation; Respiratory complex I assembly
    DOI:  https://doi.org/10.1038/s41598-025-91746-x
  11. Hum Genome Var. 2025 Apr 01. 12(1): 7
    Successful birth after preimplantation genetic testing for rare mitochondrial DNA mutation m.10197G>A.
    Yuki Mizuguchi, Kou Sueoka, Suguru Sato, Mamoru Tanaka.
      Here we report the first successful birth after preimplantation genetic testing for m.10197G>A mutation, a rare variant responsible for Leigh encephalopathy. Preimplantation genetic testing diagnosed the embryo with a mutant load of <5%, and transfer resulted in a live birth. The mutant load of embryos diagnosed in this case was skewed to the extremes. Skewed segregation patterns have been observed in common mutations, but this case suggests that the same phenomenon may be seen in this rare mutation.
    DOI:  https://doi.org/10.1038/s41439-025-00311-5
  12. Mitochondrion. 2025 Mar 27. pii: S1567-7249(25)00029-7. [Epub ahead of print]83 102032
    Mitochondrial DNA copy number and Alzheimer's disease and Parkinson disease.
    Pei Qin, Xiaojuan Chen, Panpan Ma, Xinying Li, Yunying Lin, Xiaoning Liu, Xiaoyan Liang, Tianhang Qin, Junyan Liang, Jipeng Ouyang.
       INTRODUCTION: A systematic review on the association of mitochondrial DNA copy number (mtDNA-CN) with Alzheimer's disease (AD) and Parkinson disease (PD) is lacking and the causal relationship remains unclear.
    OBJECTIVE: We aimed to conduct a systematic review of observational studies on the association of mtDNA-CN with AD and PD and perform a bidirectional 2-sample Mendelian randomization (MR) study to investigate their causal relationships.
    METHODS: PubMed, Embase, and Web of Science were searched for eligible studies before Jan 2025. The causal links were conducted with inverse-variance weighted (IVW) method as the main analysis.
    RESULTS: Fourteen case-control and 2 cohort studies investigated the association between mtDNA-CN and AD, with 13 reporting decreased mtDNA-CN associated with increased risk of AD and 3 showing no significant association. All the studies (9 case-control, 1 cross-sectional, 2 cohort studies) observed the relation between mtDNA-CN and PD except for 3 studies reporting no significant association. In MR analysis, genetically predicted mtDNA-CN was not associated with AD and PD, whereas genetically predicted AD (β -0.085, 95 % CI -0.156 to -0.013; P = 0.02) but not PD was associated with mtDNA-CN. Sensitivity and replication analyses showed a stable finding.
    DISCUSSION: The systematic review found limited observational studies on mtDNA-CN and AD and PD and majority were case-control study. Findings of the bidirectional MR study did not support a causal effect of mtDNA-CN in the development of AD and PD but found that AD can lead to decreased levels of mtDNA-CN, which suggest mtDNA-CN as a potential biomarker of AD.
    Keywords:  Alzheimer’s disease; Mendelian randomization; Mitochondrial DNA copy number; Observational study; Parkinson disease; Systematic review
    DOI:  https://doi.org/10.1016/j.mito.2025.102032
  13. Jt Comm J Qual Patient Saf. 2025 Mar 01. pii: S1553-7250(25)00089-3. [Epub ahead of print]
    Patient Engagement in Safety: Are We There Yet?
    Tejal Gandhi, Urmimala Sarkar.
      
    DOI:  https://doi.org/10.1016/j.jcjq.2025.02.006
  14. Am J Med Genet A. 2025 May;197(5): e63744
    Re-Analysis Yields Diagnosis in Over 500 Patients with Rare Diseases.
      
    DOI:  https://doi.org/10.1002/ajmg.a.63744
  15. Biochemistry (Mosc). 2025 Jan;90(Suppl 1): S146-S163
    Mitochondrial Genome Variants and Alzheimer's Disease.
    Maxim S Kozin, Olga G Kulakova, Ivan S Kiselev, Ekaterina V Semina, Viktor V Kakotkin, Mikhail A Agapov, Olga O Favorova.
      Alzheimer's disease (AD), a severe neurodegenerative disease of the central nervous system, is the most common cause of cognitive impairment in people over the age of 60. The etiology and pathogenesis of Alzheimer's disease are still unclear despite decades of active research. Numerous studies have shown that neurodegenerative processes in AD are associated with the mitochondrial dysfunction. In this review, we briefly discuss the results of these studies and present the reported evidence that mitochondrial dysfunction in AD is associated with mitochondrial DNA (mtDNA) variations. The results of association analysis of mtDNA haplogroups and individual polymorphic variants, including those whose combinations define haplogroups, with AD are described in detail. These data clearly indicate the role of variations in the mitochondrial genome in the susceptibility to AD, although the problem of significance of individual mtDNA variants is far from being resolved.
    Keywords:  Alzheimer’s disease; haplogroup; mitochondria; neurodegeneration; neurodegenerative diseases; single nucleotide polymorphism
    DOI:  https://doi.org/10.1134/S0006297924603174
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