bims-curels 2025-08-17 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–08–17
eight papers selected by
Cure Mito Foundation

Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.
Severe clinical manifestation of mitochondrial disease due to the m.3243A>T variant: a case report of early-onset, multi-organ involvement and premature death.
Zagociguat prevented stressor-induced neuromuscular dysfunction, improved mitochondrial physiology, and increased exercise capacity in diverse mitochondrial respiratory chain disease zebrafish models.
Corrigendum to 'Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations' [Molecular Genetics and Metabolism Volume 146, Issues 1-2 (2025) Pages 109197].
RePOWER: An International, Prospective, Non-Interventional Registry of Patients With Primary Mitochondrial Myopathy.
The PKU Patient Registry: Development of a patient-driven registry and initial outcomes.
Patient research partners in core outcome set development: a systematic review.
ndufs2 -/- zebrafish have impaired survival, neuromuscular activity, morphology, and one-carbon metabolism treatable with folic acid.

EMBO Mol Med. 2025 Aug 11.

Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.

María J Pérez, Rocío B Colombo, Sebastián M Real, María T Branham, Sergio R Laurito, Carlos T Moraes, Lía Mayorga.

  Mitochondrial diseases, caused by mutations in nuclear or mitochondrial DNA (mtDNA), have limited treatment options. For mtDNA mutations, reducing the mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising strategy, though it currently faces challenges. Previous research showed that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, through changes in DNA methylation, absent or less important for subtle mitochondrial impairment. Therefore, we hypothesized that targeting nuclear DNA methylation could impair cells with high-mutant mtDNA load while sparing those with lower levels, reducing overall heteroplasmy. Using cybrid models harboring two disease-causing mtDNA mutations-m.13513 G > A and m.8344 A > G-at varying heteroplasmies, we discovered that both the mutation type and load distinctly shape the nuclear DNA methylome. We found this methylation pattern critical for the survival of high-heteroplasmy cells but not for low-heteroplasmy ones. Treatment with FDA-approved DNA methylation inhibitors selectively impacted high-heteroplasmy cybrids and reduced heteroplasmy. These findings were validated in cultured cells and xenografts. Our findings highlight nuclear DNA methylation as a key regulator of heteroplasmic cell survival and a potential therapeutic target for mitochondrial diseases.

Keywords:  DNA Methylation; Epigenetics; Heteroplasmy; Mitochondrial DNA; Mitochondrial Diseases

DOI:  https://doi.org/10.1038/s44321-025-00285-5
J Rare Dis (Berlin). 2025 ;4(1): 47

Severe clinical manifestation of mitochondrial disease due to the m.3243A>T variant: a case report of early-onset, multi-organ involvement and premature death.

Hannah Gillespie, Yi Shiau Ng, Katrina M Wood, Sila Hopton, Charlotte L Alston, Emma L Blakely, Nick Thompson, Robert W Taylor, Andrew C Browning, Robert McFarland, John A Sayer.

  The spectrum of disease associated with pathogenic mitochondrial DNA (mtDNA) variants is wide. Most often, heteroplasmic mitochondrial DNA disease is the result of an adenine to guanine transition at position 3243 of mtDNA (m.3243A > G) in the MT-TL1 gene encoding tRNALeu(UUR). Here, we present a case of a patient with a rarer m.3243A > T variant whose phenotype was severe and included delayed growth, developmental delay, myoclonic jerks and tonic-clonic seizures, progressive myopathy, cerebellar ataxia, severe malnutrition due to intestinal dysmotility despite naso-jejunal feeding requiring total parenteral nutrition, bilateral sensorineural hearing loss, and visual impairment, including bilateral cataracts requiring treatment and pigmentary retinopathy. At age 18 years, he developed severe nephrotic syndrome secondary to a membranoproliferative pattern of glomerular injury, which was resistant to treatment and led to premature death.

Keywords:  MELAS; Membranoproliferative glomerulonephritis; Mitochondrial disorders; Nephrotic syndrome; mtDNA

DOI:  https://doi.org/10.1007/s44162-025-00110-0
Front Pharmacol. 2025 ;16 1588426

Zagociguat prevented stressor-induced neuromuscular dysfunction, improved mitochondrial physiology, and increased exercise capacity in diverse mitochondrial respiratory chain disease zebrafish models.

Leonard Burg, Heeyong Yoon, Min Peng, Peter Germano, Emily Reesey Gretzmacher, Rui Xiao, Vernon E Anderson, Eiko Nakamaru-Ogiso, Marni J Falk.

   Background: Zagociguat (zag) is a CNS-penetrant, soluble guanylate cyclase (sGC) stimulator that has been evaluated in phase 2a, with phase 2b ongoing, clinical studies of primary mitochondrial disease (PMD) subjects with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS). To explore its utility in a broader array of PMDs and secondary mitochondrial disorders, we performed prfeclinical modeling of zag across larval and adult zebrafish models with biochemical deficiencies in diverse respiratory chain (RC) complexes or dihydrolipoamide dehydrogenase (Dldh).
Methods: Zag was evaluated for tissue uptake, gross toxicity, protection from RC toxin-induced brain death, neuromuscular dysfunction, heartbeat loss, and biochemical dysfunction in transgenic or toxin-exposed zebrafish with mitochondrial enzyme deficiencies in complex I (ndufs2 -/- or rotenone-exposed wild type (WT)), complex IV (surf1 -/- or azide-exposed WT), multiple RC complexes (fbxl4 -/- ), or pyruvate dehydrogenase complex (dldh -/- ). Zag effects were also studied on the whole-body oxygen consumption capacity (MO2) and swimming activity of WT and complex IV disease adult zebrafish.
Results: Similar zag levels were observed in adult brains and tail muscle. No morphological or functional toxic effects of zag were observed on larvae viability. Zag provided neuromuscular protection in complex I deficient genetic and pharmacologic inhibitor models. In complex IV deficient models, prevention from brain death occurred at 100 nM zag in high-dose azide-exposed WT larvae; however, no rescue of swimming or neuromuscular phenotypes in low-dose azide-exposed surf1 -/- larvae was observed. A total of 100 nM zag rescued MO2 and maximum swimming speed in adult surf1 -/- zebrafish. Larval swimming activity was also preserved with 10 nM zag treatment in azide-stressed fbxl4 -/- larvae but not at 10 nM, 100 nM, or 1 µM zag in dldh -/- larvae. Zag (10 nM) enhanced complex I enzyme activity that is suggestive of mitochondrial biogenesis and key aspects of mitochondrial physiology in azide-exposed surf1 -/- and fbxl4 -/- larvae.
Conclusion: Preclinical evaluation of zag demonstrated its safety, significant protection of neuromuscular dysfunction and/or acute RC stressor-induced decompensation, and improved mitochondrial physiology across multiple different genetic and/or pharmacologic models of RC-deficient PMD. Thus, zag may yield therapeutic potential for an array of diseases with mitochondrial dysfunction beyond MELAS, potentially including Leigh syndrome spectrum disorder and primary mitochondrial myopathies.

Keywords:  mitochondrial disease; mitochondrial physiology; preclinical modeling; soluble guanylate cyclase; therapy

DOI:  https://doi.org/10.3389/fphar.2025.1588426
Mol Genet Metab. 2025 Aug 09. pii: S1096-7192(25)00210-0. [Epub ahead of print]146(1-2): 109219

Corrigendum to 'Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations' [Molecular Genetics and Metabolism Volume 146, Issues 1-2 (2025) Pages 109197].

G Preston, N Jacob, I Elsharkawi, E Morava, T Kozicz.

DOI: https://doi.org/10.1016/j.ymgme.2025.109219
Clin Genet. 2025 Aug 11.

RePOWER: An International, Prospective, Non-Interventional Registry of Patients With Primary Mitochondrial Myopathy.

RePOWER, MMPOWER‐3, and MOTOR investigators

  Primary mitochondrial myopathies (PMMs), a group of genetic mitochondrial oxidative phosphorylation disorders, primarily affect skeletal muscle function. No approved treatments for PMM exist, and patient information is limited. The international RePOWER registry (NCT03048617) assessed genotypic and phenotypic relationships in PMM and identified patients for MMPOWER-3 (elamipretide Phase 3 study). RePOWER enrolled screened and ambulatory patients aged 16-80 years. With signs and/or symptoms of PMM (N = 376; 60.4% female; mean [SD] age 42.6 [14.4] years; ~75% with an mtDNA variant and ~25% with an nDNA variant). Baseline information, current symptoms, qualityoflife, and functional assessments (6-Minute Walk Test [6MWT], Triple-Timed Up-and-Go [3TUG] Test, and 5-Times Sit-to-Stand Test [5XSST]) were captured. Accredited laboratory and genetic testing methods were available to most patients. The majority of enrolled PMM patients presented with progressive external ophthalmoplegia and fatigue. US patients were observed to use more medical interventions. Compared to non-US patients, US patients did not perform as well on the 6MWT (mean 364.6 vs. 375.2 m) and 5XSST (mean 21.6 vs. 18.6 s); US patients performed better on the 3TUG test (mean 40.2 vs. 45.0 s). The RePOWER registry provided data on patients with genetically confirmed PMM, thereby improving our understanding of PMM diagnosis and treatment and the differences in global mitochondrial clinical practice.

Keywords:   MMPOWER ; PMM ; RePOWER ; elamipretide; primary mitochondrial myopathy

DOI:  https://doi.org/10.1111/cge.70026
Mol Genet Metab. 2025 Jul 22. pii: S1096-7192(25)00190-8. [Epub ahead of print]146(1-2): 109199

The PKU Patient Registry: Development of a patient-driven registry and initial outcomes.

Lauren Youngborg, Christine S Brown, Eileen M Blakely, Olaf Bodamer, Rhonda Connolly, Kathryn D Moseley, Elaina Jurecki, Kelsey McQueen, Susan A Berry.

  A patient registry facilitates collection of data on a group of patients with similar conditions. While some registries collect clinician-input data, patient-entered registries prioritize the perspective of patients and families. To better support research for phenylketonuria (PKU), National PKU Alliance (NPKUA) launched the PKU Patient Registry in 2017 to collect patient-entered lived experience and natural history data. It gathers medical information and queries the lived experience of PKU through the completion of surveys, developed by a group of key stakeholders, individuals with PKU, and healthcare providers which includes validated tools and patient surveys. The data collected provide insights about the needs of the community and assist in recruitment for external research studies. This Registry uses the National Organization for Rare Disorders' IAMRARE® platform, as it is a secure, user-friendly system compliant with federal and state information privacy laws. The Registry and participant data are owned by NPKUA on behalf of the PKU community and are governed by NPKUA and the Registry Advisory Committee. As of November 2024, there are 1125 consented participants representing 46 states plus the District of Columbia and 36 different countries with the completion of 123,044 surveys over the past seven years. Since the Registry's inception, it has supported recruitment for over 35 external research studies and shared anonymized data through industrial and federal collaborations. The PKU Patient Registry collects longitudinal patient-entered data and allows for collaboration with other PKU datasets, permitting an improved understanding of the natural history of this condition.

Keywords:  Inborn error of metabolism; Natural history; PKU; Patient registry; Patient-reported outcomes; Phenylalanine; Phenylketonuria; Rare disease registry

DOI:  https://doi.org/10.1016/j.ymgme.2025.109199
J Clin Epidemiol. 2025 Aug 07. pii: S0895-4356(25)00259-8. [Epub ahead of print] 111926

Patient research partners in core outcome set development: a systematic review.

Nan-Su Huang, Ian J Saldanha, Ann-Margret Ervin.

   BACKGROUND: A core outcome set (COS) is a minimal set of outcomes that clinical trials in a specific health or healthcare area should report. Patient research partners (PRPs) should engage in all stages of COS development (co-leading and co-developing the COS). PRPs contribute the lived experience of a condition, and this perspective can improve the quality and uptake of COSs. However, there is variability in PRP responsibilities, which can impede meaningful involvement in COS development.
OBJECTIVES: To systematically review the roles of PRPs in COS development studies and compare their involvement strategies with available guidance.
METHODS: We included ongoing and completed COS development studies published in English that involved PRPs. We searched Medline, Embase, and Web of Science on September 15, 2023. We applied COS-Standards for Development (COS-STAD) to assess the quality of the COS. We extracted, tabulated, and described details of the COS development studies.
RESULTS: Our searches identified 2,261 unique records, of which we included 94 articles describing 64 COS development studies. The earliest publication was in 2014. Forty-one (64%) studies cited the Core Outcome Measures in Effectiveness Trials (COMET) Handbook when designing patient engagement for COS development. Among research team members, the proportion who was PRPs was similar in studies that cited the COMET Handbook (17%) and in those that did not (17%). Sixty-nine percent of studies included PRPs but did not specifically include this nomenclature, and 31% also involved PRPs in other activities, such as Delphi studies and interviews. The studies described various PRP tasks, the most frequent of which were guiding the process (70%) and designing questionnaires (64%).
CONCLUSION: This systematic review identified variations in PRP terminology, roles, and engagement across existing COS studies. We recommend that researchers refer to established guidelines, such as the COMET Handbook, for consistent PRP terminology and definitions. Such guidance can also help identify appropriate avenues for engaging patients as partners throughout the COS development process. These findings lay the foundation for future PRP involvement, aiming to balance meaningful engagement with feasibility in COS development.

Keywords:  Core outcome set (COS); Patient and public involvement (PPI); Patient research partner (PRP); outcomes

DOI:  https://doi.org/10.1016/j.jclinepi.2025.111926
bioRxiv. 2025 Jul 18. pii: 2025.07.16.664929. [Epub ahead of print]

ndufs2 -/- zebrafish have impaired survival, neuromuscular activity, morphology, and one-carbon metabolism treatable with folic acid.

Dana V Mitchell, Donna M Iadarola, Neal D Mathew, Kelsey Keith, Christoph Seiler, Sanghyeon Yu, Man S Kim, Niki Woodard, Vernon E Anderson, Eiko Nakamaru-Ogiso, Deanne M Taylor, Marni J Falk.

Mitochondrial complex I (CI) deficiency represents a common biochemical pathophysiology underlying Leigh syndrome spectrum (LSS), manifesting with progressive multi-system dysfunction, lactic acidemia, and early mortality. To facilitate mechanistic studies and rigorous screening of therapeutic candidates for CI deficient LSS, we used CRISPR/Cas9 to generate an ndufs2 -/- 16 bp deletion zebrafish strain . ndufs2 -/- larvae exhibit markedly reduced survival, severe neuromuscular dysfunction including impaired swimming capacity, multiple morphologic malformations, reduced growth, hepatomegaly, uninflated swim bladder, yolk retention, small intestines, and small eyes and pupils with abnormal retinal ganglion cell layer. Transcriptome profiling of ndufs2 -/- larvae revealed dysregulation of the electron transport chain, TCA cycle, fatty acid beta-oxidation, and one-carbon metabolism. Similar transcriptomic profiles were observed in ndufs2 -/- missense mutant C. elegans ( gas-1(fc21) ) and two human CI-disease fibroblast cell lines stressed in galactose media. ndufs2 -/- zebrafish had 80% reduced CI enzyme activity. Unbiased metabolomic profiling showed increased lactate, TCA cycle intermediates, and acyl-carnitine species. One-carbon metabolism associated pathway alterations appear to contribute to CI disease pathophysiology, as folic acid treatment rescued the growth defect and hepatomegaly in ndufs2 -/- larvae. Overall, ndufs2 -/- zebrafish recapitulate severe CI deficiency, complex metabolic pathophysiology, and relevant LSS neuromuscular and survival phenotypes, enabling future translational studies of therapeutic candidates.

DOI: https://doi.org/10.1101/2025.07.16.664929