bims-curels Biomed News
on Leigh syndrome
Issue of 2025–02–16
thirteen papers selected by
Cure Mito Foundation
  1. Overview of neuroimaging in primary mitochondrial disorders.
  2. Evaluating the efficacy of vatiquinone in preclinical models of Leigh syndrome and GPX4 deficiency.
  3. Clinical spectrum, treatment and outcomes of the m.10197G>A mutation in MT-ND3: a case report, systematic review and meta-analysis.
  4. Mitochondrial DNA or Genomic DNA Variant(s): Utility of Exhaustive Sequencing in Leigh Syndrome.
  5. Use of Real-World Data and Real-World Evidence in Rare Disease Drug Development: A Statistical Perspective.
  6. [Focal Segmental Glomerulosclerosis Due to A3243G Point Mutation in the mtDNA Coding for tRNALeu(UUR)].
  7. Family misfortune caused by hereditary bias: a reflection on mitochondrial disease diagnosis in a family.
  8. An exploratory study to evaluate efficacy and safety of frequent Transcutaneous Electrical Stimulation for Leber Hereditary Optic Neuropathy.
  9. Adult Leigh Syndrome Associated with the m.15635T>C Mitochondrial DNA Variant Affecting the Cytochrome b (MT-CYB) Gene.
  10. The Role of mtDNA Mutations in Atherosclerosis: The Influence of Mitochondrial Dysfunction on Macrophage Polarization.
  11. Gene therapy for genetic diseases: challenges and future directions.
  12. Breaking the silence: challenges and opportunities in pediatric drug development.
  13. How can we enhance 'real-time' patient involvement in medical education? A qualitative study of patients and students.
  1. Pediatr Radiol. 2025 Feb 12.
    Overview of neuroimaging in primary mitochondrial disorders.
    Sedat Giray Kandemirli, Khalid Al-Dasuqi, Bulent Aslan, Amy Goldstein, Cesar Augusto P F Alves.
      Advancements in understanding the clinical, biochemical, and genetic aspects of primary mitochondrial disorders, along with the identification of a broad range of phenotypes frequently involving the central nervous system, have opened a new and crucial area in neuroimaging. This expanding knowledge presents significant challenges for radiologists in clinical settings, as the neuroimaging features and their associated metabolic abnormalities become more complex. This review offers a comprehensive overview of the key neuroimaging features associated with the common primary mitochondrial disorders. It highlights both the classical imaging findings and the emerging diagnostic insights related to several previously identified causative genes for these diseases. The review also provides an in-depth description of the clinicoradiologic presentations and potential underlying mitochondrial defects, aiming to enhance diagnostic abilities of radiologists in identifying primary mitochondrial diseases in their clinical practice.
    Keywords:  Kearns-Sayre syndrome; Leigh syndrome; Mitochondria; Mitochondrial diseases; Neuroimaging
    DOI:  https://doi.org/10.1007/s00247-025-06172-y
  2. Orphanet J Rare Dis. 2025 Feb 10. 20(1): 65
    Evaluating the efficacy of vatiquinone in preclinical models of Leigh syndrome and GPX4 deficiency.
    Ernst-Bernhard Kayser, Michael Mulholland, Elizaveta A Olkhova, Yihan Chen, Holly Coulson, Owen Cairns, Vivian Truong, Katerina James, Brittany M Johnson, Allison Hanaford, Simon C Johnson.
       BACKGROUND: Genetic mitochondrial diseases are a major challenge in modern medicine. These impact ~ 1:4,000 individuals and there are currently no effective therapies. Leigh syndrome is the most common pediatric presentation of mitochondrial disease. In humans, patients are often treated with antioxidants, vitamins, and strategies targeting energetics. The vitamin-E related compound vatiquinone (EPI-743, α-tocotrienol quinone) has been the subject of at least 19 clinical trials in the US since 2012, but the effects of vatiquinone on an animal model of mitochondrial disease have not yet been reported. Here, assessed the impact of vatiquinone in cellular assays and animal models of mitochondrial disease.
    METHODS: The efficacy of vatiquinone in vitro was assessed using human fibroblasts and HEK293 cells treated with the ferroptosis inducers RSL3 and BSO + Fe(III)Citrate, the mitochondrial oxidative stress inducer paraquat, and the electron transport chain complex I inhibitor rotenone. The therapeutic potential of vatiquinone in vivo was assessed using the tamoxifen-induced mouse model for GPX4 deficiency and the Ndufs4 knockout mouse model of Leigh syndrome.
    RESULTS: Vatiquinone robustly prevented death in cultured cells induced by RSL3 or BSO/iron, but had no effect on paraquat induced cell death. Vatiquinone had no impact on disease onset, progression, or survival in either the tamoxifen-inducible GPX4 deficient model or the Ndufs4(-/-) mouse model, though the drug may have reduced seizure risk.
    CONCLUSIONS: Vatiquinone prevents ferroptosis, but fails to attenuate cell death induced by paraquat or rotenone and provided no significant benefit to survival in two mouse models of disease. Vatiquinone may prevent seizures in the Ndufs4(-/-) model. Our findings are consistent with recent press statements regarding clinical trial results and have implications for drug trial design and reporting in patients with rare diseases.
    Keywords:  Antioxidant; EPI-743; GPX4; Leigh syndrome; Mitochondrial disease; ROS; Vatiquinone
    DOI:  https://doi.org/10.1186/s13023-025-03582-x
  3. Orphanet J Rare Dis. 2025 Feb 08. 20(1): 59
    Clinical spectrum, treatment and outcomes of the m.10197G>A mutation in MT-ND3: a case report, systematic review and meta-analysis.
    YuZhi Shi, Bin Chen, SongTao Niu, XinGao Wang, ZaiQiang Zhang.
       BACKGROUND: A correlation between various sites or types of mutations in mitochondrial DNA ND3 and the development of a specific mitochondrial disease or phenotype has yet to be fully established.
    METHODS: This study reports a rare case of adult-onset Leigh syndrome (LS) and Leber hereditary optic neuropathy and dystonia (LDYT) overlap syndrome caused by the m.10197G>A mutation in ND3. A review of the literature was conducted to investigate the clinical spectrum, treatment and outcome resulting from the m.10197G>A mutation. Phenotypes associated with the m.10197G>A mutation were classified into three categories: LS/LS+ (LS-involved overlap syndrome), Leber hereditary optic neuropathy (LHON)/LHON+ (LHON-involved overlap syndrome) and other mitochondrial encephalopathies or presentations.
    RESULTS: A total of 84 participants (78 patients and 6 asymptomatic carriers) with the m.10197G>A mutation retrieved from 33 articles and the patient whose case we reported were included in the review and meta-analysis. Among all the participants, 55.3% (47/85) and 28.2% (24/85) presented with LS/LS+ and LHON/LHON+, respectively. The median age at onset for LS/LS+ was significantly younger than that for LHON/LHON+ [median, (Q1-Q3), 3.0 (0.58-9.5) vs. 13.5 (5.75-41.75), P = 0.001]. A negative linear correlation was observed between mutation load and age of onset in patients who presented with LS/LS+ (R2 = 0.592, P < 0.001), with the age of onset ranging from infancy to adulthood. Patients with an older age at onset [OR (95% CI), 1.46 (1.12-1.91), P = 0.005] or higher mutation loads [OR (95% CI), 1.14 (1.03-1.26), P = 0.011] were more likely to present with LHON/LHON+ than with LS/LS+. A total of 17 patients were documented as having received a combination of mitochondrial cofactor treatments. Compared with patients with LHON/LHON+, patients with LS/LS+ exhibited an exceedingly high probability of a stable or worsen outcome (93.8% vs. 33.3%, P = 0.006).
    CONCLUSIONS: LS/LS+ and LHON/LHON+ are the predominant presentations of the m.10197G>A mutation. An older age at onset and greater mutation load increases the probability of an LHON/LHON+ presentation. Patients presenting with LS/LS+ have an exceedingly high possibility of an unfavorable outcome. The identification of factors and outcomes associated with phenotypes in patients with the m.10197G>A mutation facilitates the provision of improved prognostic counseling for patients and their family members who are carriers of this mutation.
    Keywords:   ND3 ; Dystonia; Leber hereditary optic neuropathy; Leigh syndrome; Mitochondrial disease
    DOI:  https://doi.org/10.1186/s13023-025-03588-5
  4. Am J Med Genet A. 2025 Feb 08. e64019
    Mitochondrial DNA or Genomic DNA Variant(s): Utility of Exhaustive Sequencing in Leigh Syndrome.
    Pauline Gaignard, Pierre-Hadrien Becker, Anne-Frederique Dessein, Elise Lebigot, Abdelhamid Slama, Karine Mention, Jamal Ghoumid.
      Pathogenic variants in the nuclear gene NDUFAF8 are a rare cause of mitochondrial complex I deficiency with only three cases described to date. We report here a new case of NDUFAF8 deficiency confirming the phenotype of NDUFAF8-induced complex I biochemical defect, Leigh syndrome and premature death. As a mitochondrial DNA variant in a gene encoding a complex I subunit was also identified in this patient, we discuss the molecular heterogeneity of Leigh syndrome and the need to explore the mitochondrial and nuclear genome to ensure a reliable diagnosis.
    Keywords:  Leigh syndrome; NDUFAF8; complex I; mitochondrial DNA
    DOI:  https://doi.org/10.1002/ajmg.a.64019
  5. Clin Pharmacol Ther. 2025 Feb 14.
    Use of Real-World Data and Real-World Evidence in Rare Disease Drug Development: A Statistical Perspective.
    Jie Chen, Susan Gruber, Hana Lee, Haitao Chu, Shiowjen Lee, Haijun Tian, Yan Wang, Weili He, Thomas Jemielita, Yang Song, Roy Tamura, Lu Tian, Yihua Zhao, Yong Chen, Mark van der Laan, Lei Nie.
      Real-world data (RWD) and real-world evidence (RWE) have been increasingly used in medical product development and regulatory decision-making, especially for rare diseases. After outlining the challenges and possible strategies to address the challenges in rare disease drug development (see the accompanying paper), the Real-World Evidence (RWE) Scientific Working Group of the American Statistical Association Biopharmaceutical Section reviews the roles of RWD and RWE in clinical trials for drugs treating rare diseases. This paper summarizes relevant guidance documents and frameworks by selected regulatory agencies and the current practice on the use of RWD and RWE in natural history studies and the design, conduct, and analysis of rare disease clinical trials. A targeted learning roadmap for rare disease trials is described, followed by case studies on the use of RWD and RWE to support a natural history study and marketing applications in various settings.
    DOI:  https://doi.org/10.1002/cpt.3576
  6. G Ital Nefrol. 2024 Dec 23. pii: 2024-vol6. [Epub ahead of print]41(6):
    [Focal Segmental Glomerulosclerosis Due to A3243G Point Mutation in the mtDNA Coding for tRNALeu(UUR)].
    Michele Marchini, Valentina Bianco, Matteo Trezzi, Sonila Mocka, Lucio Manenti.
      Mithocondropathies are inherited disorders that can result from abnormalities in the mitochondrial or nuclear DNA. Genetic abnormalities impacting the mitochondrial DNA (mtDNA) are consequently passed down through the maternal line. Renal manifestations of mtDNA disorders are often poorly recognized or misdiagnosed for the widely diverse phenotypic expression of this condition. Here we describe the case of a 34-year-old man with a history of chronic kidney disease, proteinuria, diabetes mellitus and sensorineural hearing loss, with worsening renal function and proteinuria with positive family history. Kidney biopsy showed focal segmental glomerulosclerosis (FSGS) and whole exome sequencing revealed a mtDNA point mutation (A→G) at position 3243 which code for a transfer RNA (tRNALeu(UUR)). Different point mutations in mitochondrial DNA have now been associated with focal segmental glomerulosclerosis but genetic screening for mtDNA mutations is often neglected and this condition overlooked. Consideration of an underlying mitochondrial disease should be made in patients presenting with deafness, diabetes, renal failure and a positive family history of kidney disease.
    Keywords:  Focal segmental glomerulosclerosis; Genetics of Kidney Disease; Mitochondrial disease; Nephrotic Syndrome
    DOI:  https://doi.org/10.69097/41-06-2024-07
  7. J Assist Reprod Genet. 2025 Feb 12.
    Family misfortune caused by hereditary bias: a reflection on mitochondrial disease diagnosis in a family.
    Yan Meng, Lin Wan, Xi-Ying Yang, Fang Han, Meng-Na Zhang, Wen He, Xiu-Yu Shi, Guang Yang, Li-Ping Zou, Lin-Yan Hu.
       AIM: Assisted reproductive technology (ART) is an invaluable strategy for preventing the inheritance of genetic disorders and promoting the birth of healthy children. Nevertheless, the general public's limited understanding of genetics and low awareness of available services obstruct effective utilization of genetic counseling. Our analysis of a family affected by mitochondrial genetic disease aims to improve public understanding of genetic knowledge and the importance of genetic counseling.
    METHODS: We gathered comprehensive data on a family with mitochondrial disease and scrutinized the genetic sequencing and diagnostic procedures used to identify mitochondrial disease within the family.
    RESULTS: In a case involving a family with two daughters, both began to exhibit symptoms such as abnormal gait, myodystonia, and excessive fatigue at the age of 4. These symptoms were incorrectly assumed to be paternally inherited, as the mother believed the father had a mild intellectual disability. As a result, the family opted for ART, specifically in vitro fertilization (IVF) with donor sperm, without thorough genetic counseling or a conclusive diagnosis for the children. Despite these precautions, the son born from IVF presented with symptoms mirroring his sisters' at the age of 6, including typical MRI abnormal signals in the bilateral basal ganglia. Furthermore, the eldest daughter's naturally conceived child also started to show identical symptoms by the age of 3. Subsequent genetic testing revealed a homoplasmic pathogenic mutation in the MT-ND6 gene (m.14459G>A), confirming that the dystonia was maternally inherited, with the mother exhibiting an 89.2% heteroplasmic variation in the same gene.
    CONCLUSIONS: This case study demonstrates the significant consequences of a lack of genetic knowledge and prevailing misconceptions when applying ART. It underscores the urgent need to bolster genetic literacy and emphasizes the vital importance of informed decision-making within genetic healthcare services.
    Keywords:  Assisted reproductive technology; Genetic counseling; Genetic literacy; Mitochondrial disease
    DOI:  https://doi.org/10.1007/s10815-025-03399-4
  8. Sci Rep. 2025 Feb 09. 15(1): 4829
    An exploratory study to evaluate efficacy and safety of frequent Transcutaneous Electrical Stimulation for Leber Hereditary Optic Neuropathy.
    Fumio Takano, Kaori Ueda, Takuji Kurimoto, Mina Arai, Takayuki Nagai, Yuko Yamada-Nakanishi, Makoto Nakamura.
      Electrical stimulation (ES) may be effective for intractable retinal or optic nerve diseases. We studied frequent transcutaneous ES in a single-center, single-arm prospective study in patients with Leber hereditary optic neuropathy (LHON) who carry the mitochondrial (mt) 11778 G > A mutation. A 30-min ES was applied to either eye every other day for 12 weeks. The primary outcome was the difference in the logarithm of the minimum angle of resolution (LogMAR) at baseline and 1 week after completion of ES treatment. The secondary outcomes included changes in visual field; LogMAR; critical flicker frequency; and inner retinal thickness. Safety endpoints included the corneal endothelial cell density and complications during ES. Fourteen patients participated in the study; four dropped out. The median (interquartile range) LogMAR values before stimulation and 1, 4, and 8 weeks after ES were 1.60 (1.45-1.80), 1.70 (1.35-1.80), 1.60 (1.43-1.73), and 1.50 (1.43-1.73), respectively, indicating no significant improvement (primary outcome: Wilcoxon's signed rank test, p = 1.000, secondary outcome: Friedman test, p = 0.229). There were no improvements in any secondary efficacy endpoints and no complications. In conclusion, frequent transcutaneous ES did not improve visual acuity in patients with LHON carrying the mt11778 G > A mutation.
    Keywords:  Electrical stimulation; Leber Hereditary Optic Neuropathy; Mitochondrial disease; Prospective study; Visual field
    DOI:  https://doi.org/10.1038/s41598-025-89076-z
  9. Int J Mol Sci. 2025 Jan 27. pii: 1116. [Epub ahead of print]26(3):
    Adult Leigh Syndrome Associated with the m.15635T>C Mitochondrial DNA Variant Affecting the Cytochrome b (MT-CYB) Gene.
    Concetta Valentina Tropeano, Chiara La Morgia, Alessandro Achilli, Luisa Iommarini, Gaia Tioli, Leonardo Caporali, Anna Olivieri, Maria Lucia Valentino, Rocco Liguori, Piero Barboni, Andrea Martinuzzi, Caterina Tonon, Raffaele Lodi, Antonio Torroni, Valerio Carelli, Anna Maria Ghelli.
      We report on a sporadic patient suffering Leigh syndrome characterized by bilateral lesions in the lenticular nuclei and spastic dystonia, intellectual disability, sensorineural deafness, hypertrophic cardiomyopathy, exercise intolerance, and retinitis pigmentosa. Complete sequencing of mitochondrial DNA revealed the heteroplasmic nucleotide change m.15635T>C affecting a highly conserved amino acid position (p.Ser297Pro) in the cytochrome b (MT-CYB) gene on a haplogroup K1c1a background, which includes a set of four non-synonymous polymorphisms also present in the same gene. Biochemical studies documented respiratory chain impairment due to complex III defect. This variant fulfils the criteria for being pathogenic and was previously reported in a sporadic case of fatal neonatal polyvisceral failure.
    Keywords:  Leigh syndrome; MT-CYB; Respiratory complex III; mtDNA
    DOI:  https://doi.org/10.3390/ijms26031116
  10. Int J Mol Sci. 2025 Jan 25. pii: 1019. [Epub ahead of print]26(3):
    The Role of mtDNA Mutations in Atherosclerosis: The Influence of Mitochondrial Dysfunction on Macrophage Polarization.
    Evgeniya I Fedotova, Alexey V Berezhnov, Daniil Y Popov, Elena Y Shitikova, Andrey Y Vinokurov.
      Atherosclerosis is a complex inflammatory process associated with high-mortality cardiovascular diseases. Today, there is a growing body of evidence linking atherosclerosis to mutations of mitochondrial DNA (mtDNA). But the mechanism of this link is insufficiently studied. Atherosclerosis progression involves different cell types and macrophages are one of the most important. Due to their high plasticity, macrophages can demonstrate pro-inflammatory and pro-atherogenic (macrophage type M1) or anti-inflammatory and anti-atherogenic (macrophage type M2) effects. These two cell types, formed as a result of external stimuli, differ significantly in their metabolic profile, which suggests the central role of mitochondria in the implementation of the macrophage polarization route. According to this, we assume that mtDNA mutations causing mitochondrial disturbances can play the role of an internal trigger, leading to the formation of macrophage M1 or M2. This review provides a comparative analysis of the characteristics of mitochondrial function in different types of macrophages and their possible associations with mtDNA mutations linked with inflammation-based pathologies including atherosclerosis.
    Keywords:  atherosclerosis; inflammation; macrophages; mtDNA; mutations; polarization
    DOI:  https://doi.org/10.3390/ijms26031019
  11. MedComm (2020). 2025 Feb;6(2): e70091
    Gene therapy for genetic diseases: challenges and future directions.
    Beibei Qie, Jianghua Tuo, Feilong Chen, Haili Ding, Lei Lyu.
      Genetic diseases constitute the majority of rare human diseases, resulting from abnormalities in an individual's genetic composition. Traditional treatments offer limited relief for these challenging conditions. In contrast, the rapid advancement of gene therapy presents significant advantages by directly addressing the underlying causes of genetic diseases, thereby providing the potential for precision treatment and the possibility of curing these disorders. This review aims to delineate the mechanisms and outcomes of current gene therapy approaches in clinical applications across various genetic diseases affecting different body systems. Additionally, genetic muscular disorders will be examined as a case study to investigate innovative strategies of novel therapeutic approaches, including gene replacement, gene suppression, gene supplementation, and gene editing, along with their associated advantages and limitations at both clinical and preclinical levels. Finally, this review emphasizes the existing challenges of gene therapy, such as vector packaging limitations, immunotoxicity, therapy specificity, and the subcellular localization and immunogenicity of therapeutic cargos, while discussing potential optimization directions for future research. Achieving delivery specificity, as well as long-term effectiveness and safety, will be crucial for the future development of gene therapies targeting genetic diseases.
    Keywords:  gene editing; gene replacement; gene therapy; muscular disorders; rare genetic diseases
    DOI:  https://doi.org/10.1002/mco2.70091
  12. Pediatr Res. 2025 Feb 08.
    Breaking the silence: challenges and opportunities in pediatric drug development.
    Kanwaljit Singh, Tim Franson, Susan McCune, Daniel Jorgensen, Kenneth Getz, Cynthia Bearer, Jonathan M Davis.
      Pediatric drug development faces significant challenges, including underfunding, ethical concerns, and complex regulatory frameworks. Despite significant advances in adult drug development, children remain underserved due to their unique physiological needs and difficulties conducting clinical trials. Current pediatric therapeutic options are limited, off-label, and lack evidence from well-controlled trials. Incorporating global regulatory frameworks can provide valuable insights when addressing these challenges. The disparity in investment is evident as several pharmaceutical companies have recently closed their pediatric drug centers with plans to focus on more profitable adult markets, leaving pediatric research underprioritized. This article discusses the root causes of this imbalance and potential solutions including: 1) the use of emerging technologies - artificial intelligence, modeling, and simulation; 2) leveraging innovative trial designs, 3) the use of real-world data, 4) the need for public-private partnerships to drive progress in pediatric drug development; and 5) advocacy groups to shape policies and investments. By focusing on enhancing regulatory incentives, encouraging long-term industry commitment, and engaging patient advocacy groups, a more sustainable pipeline can be established. This call to action underscores the moral imperative of prioritizing pediatric health and fostering innovation to improve outcomes for vulnerable pediatric populations and shape a healthier future for all children. IMPACT: Pediatric drug development faces significant challenges, including underfunding, ethical concerns, and complex regulatory frameworks. The most important causes include the absence of robust advocacy, regulatory hurdles, and economic disincentives. Potential solutions involve leveraging innovative trial designs, the use of real-world data, and public-private partnerships.
    DOI:  https://doi.org/10.1038/s41390-025-03923-3
  13. BMC Med Educ. 2025 Feb 10. 25(1): 216
    How can we enhance 'real-time' patient involvement in medical education? A qualitative study of patients and students.
    Adedoyin Alao, Bryan Burford, Hugh Alberti, Gillian Vance.
       BACKGROUND: Patient contact is integral to undergraduate medical training. While political strategies emphasise the 'patient's voice' in medical education, the literature on how to enhance the active involvement of real-time patients is sparse. Increased demands for real-time patient interactions in primary care poses a challenge for educators to provide adequate opportunities for students to learn. Evidence on how students may benefit from patients' active involvement may inform the design and construction of teaching/learning encounters to optimise the educational value while maintaining positive patient experiences. This study aimed to identify how the involvement of real-time patients in medical education might be enhanced. It examined two research questions: •How does enhanced patient involvement support student learning in different areas of practice? • What can be done to enhance patients' active involvement in medical students' training to support those learning benefits?
    METHODS: We conducted focus groups with patients, workshops and interviews with medical students and analysed the data using codebook thematic analysis.
    RESULTS: Patient contact helped students develop their knowledge, clinical and interpersonal skills, professional values, confidence and sense of identity. Students learn by practising the role of a doctor, observing clinicians and reflecting on their experiences. Real-time patients provided experience of diversity, real-life stories and contextual variations that promoted learning. Patients would like to perform active roles, such as shaping encounters and providing explanations, feedback and emotional support to students. While such active involvement may provide learning opportunities for students, many patients were unable to perform active roles during their previous interactions with students. Patients' active involvement may be facilitated by ensuring adequate introductions, good relationships and an explicit invitation.
    CONCLUSION: The resulting model may form the basis for future research and interventions that encourage and support patients to actively participate in teaching consultations. [293 words].
    Keywords:  Active involvement; Active patient involvement; Bedside teaching; General practice; Medical education; Medical students; Patient involvement; Primary care; Teaching consultations; Undergraduate training
    DOI:  https://doi.org/10.1186/s12909-025-06767-x
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