bims-curels 2025-06-01 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–06–01
eleven papers selected by
Cure Mito Foundation

Exploring the Phenotypic Heterogeneity and Bioenergetic Profile of the m.13513G>A mtDNA Substitution: A Heteroplasmy Perspective.
Delineating the mechanisms of cerebellar degeneration in paediatric and adult primary mitochondrial disease.
Assessment of the respiratory chain enzyme activity in peripheral blood monocytes for the noninvasive diagnostics of mitochondrial disease.
Tipping the balance: innate and adaptive immunity in mitochondrial disease.
The crossroads of Leber hereditary optic neuropathy and autosomal dominant optic Atrophy: Clinical profiles of patients with coexisting pathogenic genetic variants.
Refining the modified Brice questionnaire: Patient perspectives and clarity enhancement.
Deficiency in the conserved ECHS1 gene causes Leigh syndrome by impairing mitochondrial respiration efficiency and suppressing ADRB2-PKA signaling.
Seek and Ye Shall Not Find (Yet): Searching Clinical Trial Registries for Trials Designed With Patients-A Call to Action.
Rare genetic skeletal disorders: Evolving terminology, therapies, education and advocacy.
From roadmap to a sustainable end-to-end individualized therapy pathway.
Application of Real-World Evidence to Support FDA Regulatory Decision Making.

Int J Mol Sci. 2025 May 10. pii: 4565. [Epub ahead of print]26(10):

Exploring the Phenotypic Heterogeneity and Bioenergetic Profile of the m.13513G>A mtDNA Substitution: A Heteroplasmy Perspective.

Tatiana Krylova, Yulia Itkis, Polina Tsygankova, Denis Chistol, Konstantin Lyamzaev, Vyacheslav Tabakov, Svetlana Mikhaylova, Natalia Nikitina, Galina Rudenskaya, Aysylu Murtazina, Tatiana Markova, Natalia Semenova, Natalia Buchinskaya, Elena Saifullina, Hasyanya Aksyanova, Peter Sparber, Natalia Andreeva, Natalia Venediktova, Alina Ivanushkina, Daria Eliseeva, Yulia Murakhovskaya, Natalia Sheremet, Ekaterina Zakharova.

  The m.13513G>A (p.Asp393Asn) substitution in the MT-ND5 (Mitochondrially Encoded NADH/Ubiquinone Oxidoreductase Core Subunit 5) gene is a common pathogenic variant associated with primary mitochondrial disorders. It frequently causes Leigh syndrome and mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS). In this study, we present clinical data, heteroplasmy levels in various tissues (blood, urine, and skin fibroblasts), and bioenergetic characteristics from a cohort of 20 unrelated patients carrying the m.13513G>A mutation, classified according to the following phenotypes: Leigh syndrome (n = 12), MELAS (n = 2), and Leber's hereditary optic neuropathy (LHON, n = 6). We observed a significant correlation between high respiratory ratios and heteroplasmy levels in fibroblast cell lines of the patients. Furthermore, fibroblast cell lines with heteroplasmy levels exceeding 55% exhibited markedly reduced mitochondrial membrane potential. These findings contribute to a better understanding of the clinical and bioenergetic profiles of patients with m.13513G>A-variant-related phenotypes across different heteroplasmy levels, based on data from a single genetic center. Our data suggest that even a slight shift in heteroplasmy can improve cellular function and, consequently, the patients' phenotype, providing a solid foundation for the development of future gene therapies for mtDNA diseases.

Keywords:  LHON; Leigh; MELAS; heteroplasmy; mtDNA; respirometry

DOI:  https://doi.org/10.3390/ijms26104565
Acta Neuropathol. 2025 May 30. 149(1): 53

Delineating the mechanisms of cerebellar degeneration in paediatric and adult primary mitochondrial disease.

Laura A Smith, Elizaveta A Olkhova, Nichola Z Lax, Yi Shiau Ng, Robert W Taylor, Grainne S Gorman, Daniel Erskine, Robert McFarland.

  Cerebellar ataxia is a frequent, debilitating neurological manifestation of primary mitochondrial disease and is associated with extensive neurodegeneration of the cerebellar cortical circuitry. However, the precise neuropathological mechanisms resulting in cerebellar degeneration in paediatric and adult forms of mitochondrial disease remain unclear. We therefore sought to perform a comparative neuropathological study using post-mortem cerebellar tissues from 28 paediatric and adult patients with pathogenic bi-allelic POLG variants and pathogenic mitochondrial DNA variants (m.3243A > G, m.8344A > G, m.13094T > C, and m.14709T > C), in addition to 18 neurologically normal control cases. We also sought to assess the prevalence and progression of cerebellar ataxia in an adult mitochondrial disease patient clinical cohort (n = 310) harbouring the same pathogenic variants as the post-mortem cases. Analysis of the clinical patient cohort revealed that at least 23.5-39.7% of adult patients with primary mitochondrial disease had predominantly cerebellar ataxia, with disease progression evident in 38.8% of patients. In the mitochondrial disease post-mortem tissue cohort, there was clear evidence of selective loss of inhibitory Purkinje cells, with corresponding oxidative phosphorylation protein deficiencies, which were more severe in comparison to mainly excitatory neuronal populations of the granule cell layer and dentate nucleus. Remaining Purkinje cells also demonstrated an increased expression of mitophagy-related proteins, including LC3B and BNIP3. Focal necrotic cerebellar cortical lesions, identified in eight patients, were characterised by decreased parvalbumin immunoreactivity, and sporadic c-Fos immunoreactivity was observed throughout the cerebellar cortices of 14 patients, suggestive of cerebellar cortical hyperactivity. Overall, these neuropathological features were more severe in the early onset POLG-related disease group and patients who had epilepsy. Our findings provide an important insight to the pathological mechanisms contributing to the degeneration of the cerebellar cortex in paediatric and adult forms of primary mitochondrial disease, highlighting an increased burden of pathology in early onset POLG-related disease which may have important prognostic and therapeutic implications.

Keywords:  Alpers’ syndrome; DNA polymerase gamma (POLG); MELAS; MERRF; Stroke-like episodes; mtDNA

DOI:  https://doi.org/10.1007/s00401-025-02891-6
World J Pediatr. 2025 May 27.

Assessment of the respiratory chain enzyme activity in peripheral blood monocytes for the noninvasive diagnostics of mitochondrial disease.

Jing-Jing Liu, Si-Min Wang, Zi-Han Zhang, Xue-Qian Wang, Xiao-Hui Zhang, Hong-Ying Wang, Ting Chen.

   BACKGROUND: Mitochondrial diseases are among the most common metabolic disorders caused by mitochondrial dysfunction. Analyzing mitochondrial respiratory chain enzyme activity is essential for diagnosis. However, clinical laboratories often rely on mitochondria isolated from muscle biopsies or cultured skin fibroblasts, which may be unacceptable for some pediatric patients. This highlights the need for improved blood-based diagnostic methods.
METHODS: This paper describes spectrophotometric assays to evaluate mitochondrial respiratory chain enzyme activity in peripheral blood monocytes. Sample preparation methods and assays for respiratory complexes I-IV and the mitochondrial matrix enzyme citrate synthase are detailed. The assays were validated via samples from a panel of 28 healthy children and validated in patients with combined and isolated mitochondrial oxidative phosphorylation system (OXPHOS) deficiency.
RESULTS: The citrate synthase-normalized activities were 0.23 ± 0.08 for complex I, 0.22 ± 0.081 for complex II, 0.16 ± 0.07 for complex III, and 0.22 ± 0.07 for complex IV. All patients with mitochondrial disease exhibited the expected reductions in respiratory complex activity.
CONCLUSIONS: We established a method to analyze the respiratory complex activities via blood samples. The normal enzymatic activity ranges were established from healthy Chinese pediatric populations. We also validated the assay via samples from patients with mitochondrial disease. By establishing the first pediatric-specific reference ranges for mitochondrial respiratory chain complex activities in a Chinese population and validating this minimally invasive blood-based assay in patients with mitochondrial disease, our study enabled earlier detection, precise monitoring, and personalized management of mitochondrial disorders while avoiding the need for invasive tissue biopsies.

Keywords:  Mitochondrial disease; Mitochondrial respiratory chain; PBMC; Pediatrics; Spectrophotometric analysis

DOI:  https://doi.org/10.1007/s12519-025-00918-2
Curr Opin Immunol. 2025 May 26. pii: S0952-7915(25)00042-1. [Epub ahead of print]95 102566

Tipping the balance: innate and adaptive immunity in mitochondrial disease.

Andrew Phillip West, Peter J McGuire.

Mitochondrial diseases (MtD) provide a unique window into the complex interplay between metabolism and immune function. These rare disorders, caused by defects in oxidative phosphorylation, result in bioenergetic deficiencies that disrupt multiple organ systems. While traditionally studied for their metabolic impact, MtD also profoundly affect the immune system, altering both innate and adaptive responses. This review explores how mitochondrial dysfunction shapes immune dysregulation, influencing thymocyte maturation, regulatory T cells, and B cell function while also driving innate immune activation through mitochondrial DNA instability and type I interferon signaling. Additionally, MtD highlight an emerging overlap between inborn errors of metabolism and inborn errors of immunity, revealing shared pathways that connect mitochondrial dysfunction to immune deficiencies and inflammatory disease. Studying MtD not only advances our understanding of immunometabolism but also provides critical insights into more common inflammatory and autoimmune conditions, offering potential therapeutic targets that extend beyond rare mitochondrial disorders.

DOI: https://doi.org/10.1016/j.coi.2025.102566
Am J Ophthalmol Case Rep. 2025 Jun;38 102346

The crossroads of Leber hereditary optic neuropathy and autosomal dominant optic Atrophy: Clinical profiles of patients with coexisting pathogenic genetic variants.

Mohammed A Halawani, Nooran O Badeeb.

   Purpose: Leber Hereditary Optic Neuropathy (LHON) and Autosomal Dominant Optic Atrophy (ADOA) are hereditary optic neuropathies characterized by mitochondrial dysfunctions causing destruction to the retinal ganglion cells and their axons, painless bilateral vision loss and symmetrical temporal pallor of the optic nerve. We present six intrafamilial cases with different manifestations of LHON and/or ADOA and their genetic variant profiles.
Observations: Two brothers and their father had symptomatic bilateral vision loss, two sisters were asymptomatic, and the mother had left eye vision loss due to solar retinopathy; accompanied with headaches. Five of the patients had normal anterior and posterior segment exam aside from the affected optic nerves. The family pedigree showed an unaffected first generation and an affected male in the second generation. In the third generation, an affected male (the father in this family), diagnosed with optic atrophy due to OPA1 c.2383C > T variant, married a woman (the mother) carrying the LHON MT-ND4 m.11778G > A variant. Their offspring were one unaffected daughter, one affected daughter and two affected sons harboring both LHON and ADOA pathogenic variants inherited from their parents.
Conclusion and importance: Mitochondrial optic neuropathies, which result in loss of retinal ganglion cells, are a substantial cause of visual impairment. Herein, we report two cases of combined LHON- and ADOA-causing pathogenic variants in two brothers, in addition to the genetic and ophthalmologic profile of their parents and two sisters.

Keywords:  Autosomal dominant optic atrophy (ADOA); Leber hereditary optic neuropathy (LHON); Pathogenic variants; Vision loss

DOI:  https://doi.org/10.1016/j.ajoc.2025.102346
J Clin Anesth. 2025 May 27. pii: S0952-8180(25)00136-9. [Epub ahead of print]105 111876

Refining the modified Brice questionnaire: Patient perspectives and clarity enhancement.

Miguel A Valdez, Bethany R Tellor Pennington, Mary C Politi, Swisher Laura, Melissa M Wurst, Hugo de O Campos, Linda Zukowski, Michael S Avidan.

DOI: https://doi.org/10.1016/j.jclinane.2025.111876
Biochim Biophys Acta Mol Basis Dis. 2025 May 28. pii: S0925-4439(25)00278-9. [Epub ahead of print] 167930

Deficiency in the conserved ECHS1 gene causes Leigh syndrome by impairing mitochondrial respiration efficiency and suppressing ADRB2-PKA signaling.

Baojiang Wang, Yueyuan Qin, Yantao Bao, Shiguo Chen, Junge Zheng, Sheng Lin, Kaifeng Zheng, Shan Duan.

  Deficiency in the short-chain enoyl-CoA hydratase 1 (ECHS1) gene causes Leigh Syndrome (LS), a rare inherited metabolic disorder. Despite LS that arises as a result of inborn errors of energy metabolism, the specific contributions of ECHS1 deficiency to energy metabolism processes, developmental delay, and its mediated signaling mechanism remain unclear. Here, we identify a novel compound heterozygous variant [c.724G > A (p.Glu242Lys) and c.865G > A (Asp289Asn)] in the ECHS1 gene from a family of Han Chinese descent, with the affected individual displaying typical LS symptoms. The ECHS1 variants exhibit reduced 2-enoyl-CoA hydratase activity, resulting in a restricted ATP production rate, but the cellular ATP levels remains unchanged. ECHS1 deficiency also decreases cell viability and proliferation. Mechanistically, ECHS1 interacts with ADRB2, and its variants suppress the ADRB2/protein kinase A (PKA) signaling. Treatment with PKA signaling agonists or overexpression of PKA subunits in ECHS1-deficient cells can rescue the ATP production rate and restore cell viability. Additionally, the mitochondrial E3 ligase MUL1 mediates the ubiquitylation and degradation of ECHS1 protein variants. In conclusion, our study suggests that ECHS1 deficiency impairs mitochondrial respiratory efficiency, thereby lowering the ATP production rate, and reveals a promising therapeutic approach by targeting ADRB2/PKA signaling to combat ECHS1 deficiency-induced LS.

Keywords:  ADRB2; Developmental delay; ECHS1 deficiency; Leigh syndrome; Mitochondrial respiration; Neurodegenerative conditions

DOI:  https://doi.org/10.1016/j.bbadis.2025.167930
J Particip Med. 2025 May 30. 17 e72015

Seek and Ye Shall Not Find (Yet): Searching Clinical Trial Registries for Trials Designed With Patients-A Call to Action.

Karen Louise Woolley, J D Woolley, Mark James Woolley.

   Unlabelled: Clinical trial registries were designed to help patients search for potentially suitable clinical trials. When our family faced another serious cancer diagnosis, we searched multiple international clinical trial registries. Despite increasing evidence that trials designed with patients can be better for trial participants (eg, they can have more relevant outcome measures and fewer burdens), it is currently impossible to search registries for these specific types of trials. In this Patient Perspective article, we make the first "call to action" for clinical trial registries to include (1) a filter that allows for efficient searching for clinical trials designed with patients and (2) structured information, in plain language, on how patients were involved. We propose how these two innovations could help reduce barriers to clinical trial participation. We also highlight how new regulatory and ethical guidelines are encouraging patient involvement in trial design, and we identify the benefits to many of doing so. Given the pressing need to improve clinical trial participation, we respectfully call on the clinical trial community to respond to our call to action and consider our proposed action plan. Ideally, when patients want to search for clinical trials designed with patients for patients, we should be able to find them. A plain language summary for this publication is available in the supplementary material for this paper.

Keywords:  GRIPP2; caregiver author; clinical trial; clinical trial registry; diversity, equity, and inclusion; patient and public involvement; patient author; patient partner; plain language summary

DOI:  https://doi.org/10.2196/72015
J Pediatr Soc North Am. 2024 May;7 100057

Rare genetic skeletal disorders: Evolving terminology, therapies, education and advocacy.

Laura L Tosi.

  In the US, rare diseases are defined as disorders affecting fewer than 200,000 US residents or disorders for which there is no reasonable expectation that drug development costs will be recoverable by US sales. Almost 800 of the approximately 10,000 defined rare diseases are bone disorders. Until recently, their rarity and heterogeneity have unfortunately hindered their exploration at both clinical and scientific levels. However, wider availability of genetic testing, development of new surgical and pharmaceutical treatment options, and patient advocacy have motivated efforts to study, diagnose, and treat these disorders. Thus, care of the patient with a rare skeletal disorder is now evolving rapidly. This report presents a brief summary of important developments in skeletal disorders impacting bone quality and frequently co-managed by pediatric orthopaedic surgeons.
Key Concepts: (1)Although a "cure" is not yet available for most rare bone disease patients, new agents are frequently being advanced as new genes and their products are identified as molecules to target.(2)Medical therapies, often combined with surgical interventions and physical therapy, are reducing pain and increasing function in many pediatric orthopaedic patients with rare bone disorders.(3)New tools for physician education and patient management are increasingly available to assist the pediatric orthopaedic surgery community.

Keywords:  Clinical trials and therapeutic strategies; Patient advocacy; Physician education; Rare bone disease; Rare bone disease taxonomy

DOI:  https://doi.org/10.1016/j.jposna.2024.100057
Ther Adv Rare Dis. 2025 Jan-Dec;6:6 26330040251339204

From roadmap to a sustainable end-to-end individualized therapy pathway.

Anneliene H Jonker, Elena-Alexandra Tataru, David P Dimmock, Alison Bateman-House, Holm Graessner, Gareth Baynam, Erika F Augustine, Adam Jaffe, Anna M G Pasmooij, Oxana Iliach, Richard Horgan, James Davies, Shruti Mitkus, Larissa Lapteva, Matthis Synofzik, Timothy W Yu, Daniel O'Connor, Annemieke Aartsma-Rus.

  The field of individualized, or N-of-1, therapy development is growing and increasingly gaining attention as a novel option for people with serious diseases, caused by unique genetic variants for whom approved therapies are not available. The N-of-1 taskforce of the International Rare Disease Research Consortium previously outlined a roadmap of aspects involved in N-of-1 therapy development and implementation. Here, this follow-up paper looks forward and reflects on how to address existing gaps to advance the current state of individualized interventions toward an integrated and sustainable treatment development model. It discusses what needs to be established for N-of-1 therapies to be developed and utilized at a larger scale, which involves features like sustainability; safety; efficacy; regulatory aspects; dedicated registries and data sharing; tools; long-term treatment monitoring; partnering with patient advocates; and reimbursement models. It closes with recommendations to shape the future of individualized therapies, focusing on ethical implications, education, creation of tools, incentives for data sharing, and innovative payment models.

Keywords:  N-of-1 therapy; data sharing; education; individualized therapies; patient engagement; payment models

DOI:  https://doi.org/10.1177/26330040251339204
AAPS J. 2025 May 28. 27(4): 98

Application of Real-World Evidence to Support FDA Regulatory Decision Making.

Vipada Khaowroongrueng, Tae-Eun Kim, Sang-In Park, Kwang-Hee Shin.

  Real-world data (RWD) and real-world evidence (RWE) are valuable resources for drug development strategies. Historically, it has been used for safety evaluation during post-marketing surveillance. RWD and RWE have been utilized in the regulatory decision-making process for drug effectiveness, especially for rare diseases and cancers, where conducting randomized controlled trials is challenging. The Food and Drug Administration (FDA) is actively working on providing trustworthy information derived from RWD and RWE to supplement the data from clinical trials. This review discusses the potential use of RWE to make regulatory decisions on drug effectiveness for certain therapeutic areas as well as the challenges in drawing inferences on drug effectiveness from RWE. A review of FDA-approved new drug applications and biologics license applications suggests that several methodological considerations should be deliberated when designing a study using RWE to demonstrate product effectiveness. The acceptance of RWE, while promising, is dependent on the relevance and reliability of the data. The insight and engagement of all stakeholders contribute to the successful use of RWE for clinical evaluations.

Keywords:  FDA; real-world evidence; regulatory decision making

DOI:  https://doi.org/10.1208/s12248-025-01082-1