bims-curels Biomed News
on Leigh syndrome
Issue of 2025–04–13
eleven papers selected by
Cure Mito Foundation
  1. Adult-Onset Bilateral Optic Neuropathy in a Patient with Non-Familial Childhood-Onset Generalized Dystonia Associated with Mitochondrial DNA 14459G>A Mutation: A Case Report and Review of Literature.
  2. Preliminary investigation on the economic cost of mitochondrial disease in Chinese children.
  3. Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.
  4. Mitochondrial complex I deficiency in a 4-year-old boy due to compound heterozygous NDUFV1 mutation: a case report of a new pathogenic variant.
  5. A decisive technical leap forward for personalized medicine to treat mitochondrial diseases.
  6. Pharmacogenomics and rare diseases: optimizing drug development and personalized therapeutics.
  7. Aminolevulinate/iron exposure elicited Nrf-2-mediated cytoprotection in DARS2 deficient fibroblasts with impaired energy and antioxidant metabolisms.
  8. Challenges in the clinical management of rare diseases and center-based multidisciplinary approach to creating solutions.
  9. The Volume of Mitochondria Inherited Impacts mtDNA Homeostasis in Budding Yeast.
  10. Patient Engagement and Patient Experience Data in Regulatory Review and Health Technology Assessment: Where Are We Today?
  11. Recruitment through empathy and education: The role of the clinical experience on workforce development.
  1. Neuroophthalmology. 2025 ;49(3): 206-211
    Adult-Onset Bilateral Optic Neuropathy in a Patient with Non-Familial Childhood-Onset Generalized Dystonia Associated with Mitochondrial DNA 14459G>A Mutation: A Case Report and Review of Literature.
    M Thaller, A P Samra, U J Chaudhary, M Roque, H Pall, S P Mollan, V Srinivasan.
      The occurrence of Leber Hereditary Optic Neuropathy in association with dystonia is exceedingly rare. There have been only a few previously reported cases describing this clinical phenotype with the mitochondrial DNA 14459 G>A/ND6 mutation. This mutation has been described to also manifest as isolated Leber Hereditary Optic Neuropathy or Leigh Syndrome/Leigh-like Syndrome in a very small number of patients. We report the case of a 27-year-old female who presented with bilateral sequential optic neuropathy on a background of non-familial generalized dystonia. Magnetic resonance imaging performed during childhood had shown bilateral high signal changes in the basal ganglia. Extensive testing for a possible autoimmune etiology was unrevealing. Her vision did not improve with aggressive steroid and plasma exchange treatment. Targeted genetic testing revealed a mitochondrial DNA 14459 G>A/ND6 mutation. Genetic analysis for the mitochondrial DNA 14459 G>A/ND6 mutation should be tested in a patient presenting with bilateral sequential optic neuropathy with co-morbid dystonia.
    Keywords:  Lebers hereditary optic neuropathy; idiopathic dystonia; mitochondria; optical coherence tomography; vision
    DOI:  https://doi.org/10.1080/01658107.2024.2405697
  2. Orphanet J Rare Dis. 2025 Apr 10. 20(1): 172
    Preliminary investigation on the economic cost of mitochondrial disease in Chinese children.
    Chaolong Xu, Dan Zhao, Xin Duan, Zhimei Liu, Tongyue Li, Yunxi Zhang, Zixuan Zhang, Tianyu Song, Ying Zou, Huafang Jiang, Fang Fang.
       BACKGROUND: The prevalence of mitochondrial diseases is increasing, leading to a significant economic burden on families and society. However, nationwide cost data on their effects on China's economy remain limited. This study aimed to investigate the economic cost of mitochondrial diseases in Chinese children, analyse the relevant influencing factors, and provide a foundation for strategies to reduce the healthcare burden.
    METHODS: In this single-centre, cross-sectional study, an online questionnaire was randomly administered to paediatric patients diagnosed with mitochondrial diseases between January 2012 and January 2022. The questionnaire included questions regarding demographic data, clinical information, and expenditure-related costs. Multivariate analysis of economic cost was performed using a generalised linear gamma conjugate model (A1).
    RESULTS: The responses to 102 questionnaires were analysed. The median direct economic cost incurred for the diagnosis of mitochondrial disease was $8,520.19, with direct medical and non-medical costs of $6,769.06 and $2,092.98, respectively, and an indirect cost of $3,162.93. Healthcare insurance covers 27.29% of direct medical expenses. Multivariate analysis showed that the economic cost of diagnosing mitochondrial diseases was significantly correlated with the year of disease onset (P < 0.001). The median annual economic cost for treatment and symptom management after diagnosis was $12,292.79, with direct medical and non-medical costs of $10,887.53 and $1,360.44, respectively, and an indirect cost of $5,442.21. Healthcare insurance covered only 15.16% of direct medical expenses. No significant differences were observed between the subgroups after diagnosis and the annual economic costs of treatment or symptom management.
    CONCLUSION: The study findings indicated that the economic burden of both the diagnosis and treatment of patients with mitochondrial diseases was substantial. Increased emphasis should be placed on primary and secondary prevention strategies to further reduce the overall economic burden of rare genetic diseases, such as mitochondrial diseases.
    Keywords:  Children; China; Economic costs; Mitochondrial disease
    DOI:  https://doi.org/10.1186/s13023-025-03708-1
  3. Hum Mol Genet. 2025 Apr 11. pii: ddaf047. [Epub ahead of print]
    Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.
    Benjamin Munro, Declan Hines, Juliane S Mueller, Rita Horvath.
      Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are rare, clinically heterogeneous mitochondrial disorders resulting from nuclear variants in genes of the mitochondrial DNA replication or maintenance machinery. Supplementation with pyrimidine deoxynucleosides have been beneficial in patients and mice with TK2-related MDDS, however, it has not been systematically explored in other forms of MDDS. To investigate the effect of deoxynucleoside supplementation in mitigating the disease in mitochondrial DNA depletion due to pathogenic RRM2B variants, we generated a novel zebrafish knock-out model of this disease and studied the effect of different combinations of deoxynucleosides. Zebrafish larvae carrying a homozygous nonsense mutation in rrm2b present with impaired movement, reduced mtDNA copy number and elevated lactate. Supplementation with different combination of deoxynucleosides was performed, resulting in increased mtDNA copy numbers when supplemented with the two purine deoxynucleosides (dGuo and dAdo), while other combinations had no effect or even further compromised mtDNA copy number in zebrafish. In parallel with increased mtDNA copy number, we detected improved movement and reduction of lactate in the rrm2b-/- fish, confirming the beneficial effect of deoxynucleosides on the whole organism. This treatment did not result in any deleterious effect in wild type and heterozygous fish. Our data suggest that supplementation with deoxynucleosides may be beneficial and should be further investigated in RRM2B-related disease, adding to the growing evidence that it is a valid therapeutic approach which can be trialled for treating a wider range of genetic forms of MDDS.
    Keywords:  Deoxynucleoside supplementation; MDDS; Mitochondrial DNA depletion syndromes; RRM2B; zebrafish
    DOI:  https://doi.org/10.1093/hmg/ddaf047
  4. Oxf Med Case Reports. 2025 Apr;2025(4): omae166
    Mitochondrial complex I deficiency in a 4-year-old boy due to compound heterozygous NDUFV1 mutation: a case report of a new pathogenic variant.
    Salim Haddad, Elie Salloum, Abdullah Silan, Gazel Kalecioğlu, Maria Abdulnour, Sultaneh Haddad, Diana Alasmar, Mahmoud Alayash, Ahmed Noman Ghaleb.
      Mutations in the NDUFV1 gene are associated with mitochondrial complex I deficiency and have been linked to various clinical conditions such as Leigh syndrome, severe infantile lactic acidosis, newborn cardiomyopathy, progressive leukoencephalopathy, and other encephalomyopathies. Genetic alterations revealed mitochondrial complex 1 deficiency, nuclear type 4 |AR: two compound heterozygous missense mutations in the NDUFV1 gene, c.640G < A (p.E214K) chr11:67377981 (Exon 1) and c.248C < T (p.S83L) chr11:67376115 (Exon 3) gene. Our case identifies a previously unknown pathogenic effect of the variant 'c.248C > T' in the NDUFV1 gene, observed in a 4-year-old boy with left-sided facial paralysis and balance impairment. While this discovery is significant, further exploration of NDUFV1 gene variants is essential for a comprehensive understanding and effective treatment strategies.
    Keywords:  NDUFV1 mutation; mitochondrial complex I deficiency; mitochondrial diseases; white matter
    DOI:  https://doi.org/10.1093/omcr/omae166
  5. EMBO Mol Med. 2025 Apr 09.
    A decisive technical leap forward for personalized medicine to treat mitochondrial diseases.
    Abi S Ghifari, Martin Ott.
      
    DOI:  https://doi.org/10.1038/s44321-025-00232-4
  6. Pharmacogenomics. 2025 Apr 07. 1-8
    Pharmacogenomics and rare diseases: optimizing drug development and personalized therapeutics.
    Youssef M Roman.
      Pharmacogenomics (PGx) is an evolving field that integrates genetic information into clinical decision-making to optimize drug therapy and minimize adverse drug reactions (ADRs). Its application in rare disease (RD) drug development is promising, given the genetic basis of many RDs and the need for precision medicine approaches. Despite significant advancements, challenges persist in developing effective therapies for RDs due to small patient populations, genetic heterogeneity, and limited surrogate biomarkers. The Orphan Drug Act in the U.S. has incentivized RD drug development. However, the traditional drug approval process is constrained by logistical and economic challenges, necessitating innovative PGx-driven strategies. Identifying genetic biomarkers in the early drug development stages can optimize dose selection, enhance therapeutic efficacy, and reduce ADRs. Case studies such as eliglustat for Gaucher disease and ivacaftor for cystic fibrosis demonstrate the efficacy of PGx-guided treatment strategies. Integrating PGx into global drug development requires the harmonization of regulatory policies and increased diversity in genetic research. Artificial intelligence (AI) tools further enhance genetic analysis, disease prediction, and clinical decision-making. Modernizing drug labeling with PGx information is critical to ensuring safe and effective druguse. Collectively, PGx offers transformative potential in RD therapeutics by facilitating personalized medicine approaches and addressing unmet medical needs.
    Keywords:  Pharmacogenomics; dose optimization; drug development; genetic biomarkers; personalized medicine; precision medicine; rare diseases
    DOI:  https://doi.org/10.1080/14622416.2025.2490465
  7. Biochim Biophys Acta Mol Basis Dis. 2025 Apr 02. pii: S0925-4439(25)00169-3. [Epub ahead of print]1871(5): 167824
    Aminolevulinate/iron exposure elicited Nrf-2-mediated cytoprotection in DARS2 deficient fibroblasts with impaired energy and antioxidant metabolisms.
    Wei-Lin Huang, Tuany Eichwald, Alexander Stover, Milad Gazanfari, Philip H Schwartz, Alexandra Latini, Jose E Abdenur.
      Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a disorder caused by mutations in the mitochondrial aspartyl-tRNA synthetase gene DARS2, which compromises mitochondrial protein translation. The typical presentation is juvenile in onset with gradually progressive spasticity and ataxia. Only palliative treatment is available for LBSL individuals. Here we showed that the use of the Food and Drug Administration-approved heme precursors, aminolevulinate plus ferrous iron (ALA/Fe), can result in a novel pharmacological treatment that increases energy status in DARS2 deficient cells. The marked mitochondrial and antioxidant deficiencies observed in fibroblasts from two LBSL-affected brothers, harboring intron-2 (c.228-17C > G) and intron-5 (c.492 + 2 T > C) DARS2 mutations, were rescued by ALA/Fe exposure, and the use of dexamethasone, a known Nrf-2 inhibitor, blocked the positive effects of ALA/Fe. Altogether, this study showed that fibroblasts can be used as a biological system to identify potential new treatments for LBSL that can reduce morbidity and mortality, and that the activation of Nrf-2-mediated cytoprotection can be targeted for the treatment of LBSL and other mitochondrial diseases.
    Keywords:  Antioxidant enzymes; Free radicals; Mitochondrial biogenesis; Mitochondrial capacity; Mitochondrial disorders; Respiratory chain complexes
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167824
  8. Eur J Pediatr. 2025 Apr 05. 184(5): 281
    Challenges in the clinical management of rare diseases and center-based multidisciplinary approach to creating solutions.
    D Gunes, M Karaca, A Durmus, B Ak, N Aktay Ayaz, Z U Altınel, A D Aslanger, F Atalar, M C Balci, L Bilgin, F Darendeliler, D Demirkol, O Durmaz, A Gedikbasi, E Inan Balci, E Z Ince, S G Karadag, G Keskindemirci, K Nisli, M Ozcetin, A Somer, A Unuvar, M Uysalol, E Yildiz, Z N Yuruk Yildirim, M Demirkol, G F Gokcay.
      The diagnosis and treatment of rare diseases present significant global challenges. This study aimed to identify the difficulties faced by specialists in the diagnosis and management of rare diseases, as well as to gather their recommendations for potential solutions. An expert committee specializing in inborn metabolic disease and genetics developed a comprehensive survey, which was then distributed online to professionals working with rare diseases. A total of 21 specialists actively engaged in the management of rare diseases participated in the survey. All participants acknowledged the substanstial significant diagnostic challenges associated with rare diseases, with 86% indicating that these diagnostic challenges negatively affect their clinical practice. The primary obstacles encountered in the diagnosis and follow-up of rare diseases were low awareness, a lack of a multidisciplinary approach, insufficient numbers of specialists and inadequate infrastructure, limited newborn screening programs, challenges in accessing treatment, and insufficient psychosocial support. All participants emphasized the need for a multidisciplinary approach in the management of rare diseases. Proposed solutions included enhanced training for healthcare professionals, the establishment of multidisciplinary teams and diagnostic algorithms, the regular convening of councils and meetings, and the establishment of robust registries. While all participants rated their own clinical experience as proficient in diagnosing and treating rare diseases, the establishment of multidisciplinary teams was the most frequently suggested area for improvement.
    CONCLUSION: Addressing the challenges in the diagnosis, treatment, and monitoring of rare diseases requires a multifaceted approach, including raising awareness, enhancing patient services, developing robust research and improving the infrastructure, establishing multidisciplinary care frameworks, and implementing preventive medicine and social policies.
    WHAT IS KNOWN: • It is estimated that over 300 million people globally are living with one or more rare diseases. The process of diagnosis, treatment, and follow-up of rare diseases involves significant global challenges.
    WHAT IS NEW: • In our study, the difficulties encountered by specialists in the diagnosis and treatment of rare diseases in Türkiye and solution suggestions are presented. This is the first study on this subject in Türkiye.
    Keywords:  Multidisciplinary approach; Rare diseases; Solution proposals; Specialist education; Türkiye
    DOI:  https://doi.org/10.1007/s00431-025-06101-z
  9. bioRxiv. 2025 Mar 26. pii: 2025.03.25.645216. [Epub ahead of print]
    The Volume of Mitochondria Inherited Impacts mtDNA Homeostasis in Budding Yeast.
    Michael W Ray, WeiTing Chen, Chengzhe Duan, Guadalupe Bravo, Kyle Krueger, Erica M Rosario, Alexis A Jacob, Laura L Lackner.
      Most eukaryotic cells maintain mitochondria in well-distributed, reticular networks. The size of the mitochondrial network and copy number of its genome scale with cell size. However, while the size scaling features of mitochondria and their genome are interrelated, the fitness consequences of this interdependence are not well understood. We exploit the asymmetric cell division of budding yeast to test the hypothesis that mitochondrial scaling with cell size impacts mitochondrial DNA (mtDNA) function. We find that the volume of mitochondria inherited by daughter cells affects the ability of cells to maintain functional mtDNA; daughter cells that inherit a significantly reduced volume of mitochondria have an increased frequency of losing respiratory competence. In cells with such mitochondrial inheritance defects, mtDNA integrity can be maintained by upregulating mtDNA copy number. Collectively, these data support a bet-hedging model whereby the faithful inheritance of an adequate volume of mitochondria ensures enough mtDNA copies are transmitted to daughter cells to counteract pre-existing and/or inevitable mtDNA mutations.
    Summary: Ray et al. demonstrate that the volume of mitochondria inherited impacts mtDNA homeostasis in the model system budding yeast. They propose a model by which inheritance of an adequate mitochondrial volume results in the transmission of sufficient mtDNA copies to counteract existing and/or inevitable mutations.
    DOI:  https://doi.org/10.1101/2025.03.25.645216
  10. Ther Innov Regul Sci. 2025 Apr 10.
    Patient Engagement and Patient Experience Data in Regulatory Review and Health Technology Assessment: Where Are We Today?
    Neil Bertelsen, Elisabeth Oehrlein, Bronwyn Lewis, Tiffany Westrich-Robertson, Jim Elliott, Tom Willgoss, Nidhi Swarup, Ify Sargeant, Oishika Panda, Maria M Marano, Hayley Chapman, Nicholas Brooke.
       BACKGROUND: As healthcare stakeholders aim to support patient-centered care, patients play an increasingly important role in pharmaceutical and medical technology development and healthcare decision-making. Patient engagement (PE), patient experience data (PED), and meaningful integration of PE to enrich PED have been evolving rapidly. This landscape review focuses on emerging PE/PED practices and guidelines in 2023.
    METHODS: References published between January-December 2023 on the use of PE and PED from health technology assessment (HTA) and regulatory bodies in different countries, three peer-reviewed journals, and referred resources from collaborators were analyzed. These references were compared with those in our previous publication (August 2021-January 2023, 17-month period).
    RESULTS: Overall, 28 references from HTA/regulatory bodies, 26 from peer-reviewed articles, and 17 referred resources were identified. Eight references on PE and PED integration (PE + PED) were identified in 2023 from HTA/regulatory bodies, compared with none in the previous 17-month analysis. Emerging trends on the role of PE, PED, and real-world evidence in HTA/regulatory deliberations, transparency and geographic variations in the use of such evidence and practices, and gaps thereof have been highlighted.
    CONCLUSIONS: The increase in PE, PED, and PE + PED references worldwide in 2023 versus the prior 17-month analysis suggests accelerated adoption of PE + PED practices. However, a need remains for comprehensive, actionable guidance on best practices for use of PE and PED for harmonization and incorporation into HTA/regulatory processes. Patient input-essential for evidence-based decision-making-provides valuable insights that enhance care quality, treatment relevance and effectiveness, and builds trust and sustainability.
    Keywords:  Health technology assessment; Patient engagement; Patient experience data; Real-world evidence; Regulatory assessment
    DOI:  https://doi.org/10.1007/s43441-025-00770-6
  11. Mol Genet Metab. 2025 Mar 28. pii: S1096-7192(25)00092-7. [Epub ahead of print]145(1): 109101
    Recruitment through empathy and education: The role of the clinical experience on workforce development.
    Rishisree Achanta, Ashley Cannon, Shayla R Goldberg, Ryan Ha, Andriae LaCour, Christine Maccia, Deepika Burkardt, Jennifer Micham, Debra S Regier.
      
    Keywords:  Medical students; Metabolism; Rare disease; Workforce
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109101
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