bims-ripira Biomed News
on RRM2B MDMD in Adults
Issue of 2026–04–05
fourteen papers selected by
Martín Lopo
  1. Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders.
  2. Mitochondrial DNA as a driver of inflammation via the cGAS-STING pathway.
  3. MTALTCO1: a 259 amino-acid long mtDNA-encoded alternative protein that challenges conventional understandings of mitochondrial genomics.
  4. GDF15 - A potential novel biomarker of cognitive impairment in cervical dystonia.
  5. Metformin increases glycolysis and the stress-induced cytokine GDF15 but not FGF21 in humans.
  6. Inflammaging-associated mitochondrial degeneration occurs in hypoglossal motor neurons prior to tongue muscle.
  7. MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.
  8. Mitochondrial ROS dyshomeostasis: a key driver of accelerated supraspinatus atrophy after rotator cuff injury.
  9. Mitochondrial vulnerability underlies myocarditis from COVID-19 mRNA vaccine.
  10. Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise.
  11. Mitochondrial transfer as a therapeutic target for peripheral neuropathy.
  12. Molecular hydrogen as a treatment for ME/CFS: a mini-review of clinical evidence and mechanistic rationale.
  13. The inositol pyrophosphate 5-InsP7 regulates mitochondrial polyphosphate synthesis and bioenergetic function.
  14. Natural History of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP): A Retrospective Patient Cohort Study.
  1. FEBS Lett. 2026 Mar 30.
    Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders.
    Sahitya Ranjan Biswas, Porter L Tomsick, Alicia M Pickrell, Paul D Morton.
      Primary mitochondrial disorders (PMDs) are inherited metabolic diseases that most often present with neurological symptoms in infancy or adolescence, underscoring the central importance of mitochondrial function to brain health. Historically, the field has emphasized neurodegeneration-consistent with the high energetic demands of postmitotic neurons. However, neurodevelopmental manifestations are now recognized as common early phenotypes, frequently preceding clinical regression in many PMDs. Given the pivotal role of mitochondria in neural stem/progenitor cell maintenance and cell fate decisions, defects in the respiratory chain are poised to disrupt neurogenesis and gliogenesis. Evidence for such developmental vulnerabilities is reviewed here. Likewise, because mitochondrial metabolism and dynamics shift across the oligodendrocyte lineage-from oligodendrocyte precursor cell expansion to differentiation and the energetically intensive phase of myelin synthesis-callosal atrophy in mitochondrial leukoencephalopathies may, at least in part, reflect developmental shortcomings in oligodendrogenesis and myelination. This possibility warrants focused investigation in cellular and in vivo models.
    Keywords:  mitochondria; mitochondria disorders; neural stem cells; oligodendrocytes; white matter
    DOI:  https://doi.org/10.1002/1873-3468.70335
  2. Inflamm Res. 2026 Apr 01. pii: 77. [Epub ahead of print]75(1):
    Mitochondrial DNA as a driver of inflammation via the cGAS-STING pathway.
    Xingyue Wen, Fan Yang, Lan Zhang, Dingming Huang.
       BACKGROUND: Mitochondrial DNA (mtDNA), acting as a critical damage associated molecular pattern (DAMP), can translocate into the cytoplasm and directly activate the cGAS-STING signaling pathway. This activation induces the production of type I interferons and senescence associated secretory phenotype (SASP), positioning mtDNA as a key regulator of both inflammation and cellular senescence, namely mtDNA-cGAS-STING signaling axis.
    MAIN TEXT: Here, we summarize the molecular mechanisms by which cytoplasmic escape of mtDNA and activation of the cGAS-STING pathway trigger a series of downstream cascade reactions. In addition, we discuss the role of the mtDNA-cGAS-STING axis in various inflammation-related pathologies, including ocular diseases, neurodegenerative disorders, pulmonary inflammation, cardiovascular diseases, and oral diseases.
    CONCLUSIONS: Although interventions targeting the mtDNA-cGAS-STING signaling axis have shown promise in preclinical models, challenges regarding specificity, targeted delivery, and potential side effects remain and require further investigation before clinical translation. A deeper mechanistic understanding of the mtDNA-cGAS-STING axis may provide innovative therapeutic strategies for managing inflammation and aging-associated diseases.
    Keywords:  Aging; Chronic inflammation; Mitochondrial DNA; cGAS-STING signaling pathway
    DOI:  https://doi.org/10.1007/s00011-026-02231-8
  3. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250078. [Epub ahead of print]381(1947):
    MTALTCO1: a 259 amino-acid long mtDNA-encoded alternative protein that challenges conventional understandings of mitochondrial genomics.
    Francis Robitaille, Amy Campbell, Aziz Ben Hadj, Sarah Cornet, Ludovic Nadeau-Lachance, Thierry Niaison, Thierry Choquette, Liam Nyffeler, Xavier Roucou, Annie Angers, Sophie Breton.
      Mitochondrial alternative open reading frames (ORFs) substantially broaden the functional scope traditionally attributed to mitochondrial DNA, encoding peptides and proteins that participate in diverse cellular processes. These newly identified ORFs are embedded within annotated sequences, both coding and non-coding, and reveal layers of overlapping genetic information. We report the discovery of MTALTCO1, a 259 amino-acid protein, the longest mitochondrial alternative protein identified to date, encoded by an ORF located within the human cytochrome oxidase 1 gene, in the +3 reading frame. We confirm the expression and mitochondrial origin of MTALTCO1 through multiple independent lines of evidence, including a custom-designed antibody, mass spectrometry-derived peptides, sequence analysis and inhibitors of mitochondrial expression. Despite encoding AGR codons as arginine, contrary to the prevailing view that these function invariably as stop codons in the vertebrate mitochondrial genetic code, MTALTCO1 shows strong evidence of mitochondrial translation, challenging established models of mitochondrial codon usage and gene expression. Co-immunoprecipitations and pulldown assays delineate MTALTCO1's interaction landscape across major cellular pathways. Finally, we present the first in-depth analysis of conservation for a mitochondrial alternative ORF overlapping a reference protein-coding gene and discuss the results in light of MTALTCO1's suggested role in protein scaffolding. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  alternative proteins; conservation; intrinsically disordered proteins; mitochondria; mitochondrial-derived peptides; mitrochondrial translation; overlapping open reading frame; overprinting; protein function; scaffold proteins
    DOI:  https://doi.org/10.1098/rstb.2025.0078
  4. Front Neurosci. 2026 ;20 1771471
    GDF15 - A potential novel biomarker of cognitive impairment in cervical dystonia.
    Artur Drużdż, Małgorzata Dudzic, Joanna Poszwa, Anna Rajewska, Aleksandra Mikołajczak, Wojciech Kozubski, Jolanta Dorszewska.
       Introduction: Cervical dystonia (CD) is a chronic movement disorder characterized by motor symptoms and a spectrum of non-motor features, including cognitive difficulties, which may affect quality of life. To date, no biomarker exists to identify or monitor cognitive impairment in CD. Growth differentiation factor 15 (GDF15) has been associated with cognitive decline in several neurodegenerative diseases and movement disorders, providing a rationale for its investigation in CD. This study aimed to evaluate whether plasma GDF15 concentrations are associated with cognitive performance in individuals with CD and to assess examine the potential of GDF15 as a biomarker of cognitive decline in CD.
    Methods: Plasma GDF15 levels were measured in patients with CD before and after botulinum toxin (BoNT) treatment and compared with healthy controls. Correlations between GDF15 concentration, cognitive performance (MoCA total and domain scores), and clinical characteristics-including age, disease duration, and TWSTRS motor severity-were analyzed using Spearman's and Pearson's coefficients.
    Results: GDF15 concentrations were significantly higher in individuals with CD compared with healthy controls. However, GDF15 levels showed no association with age, disease duration, symptom severity, or treatment response, and remained stable following botulinum toxin administration. No correlations were found between GDF15 and global cognitive performance, with the exception of a correlation with the visuospatial MoCA sub score.
    Discussion: While GDF15 concentrations were elevated in CD, they did not demonstrate consistent relationships with clinical features or cognitive outcomes. These findings suggest that GDF15 cannot currently be considered a reliable biomarker of cognitive impairment in CD. Given the limited sample size, this study should be regarded as preliminary.
    Keywords:  GDF15; biomarker; botulinum toxin; cervical dystonia; cognitive decline
    DOI:  https://doi.org/10.3389/fnins.2026.1771471
  5. Front Endocrinol (Lausanne). 2026 ;17 1797525
    Metformin increases glycolysis and the stress-induced cytokine GDF15 but not FGF21 in humans.
    Kristoffer J Kolnes, Pauline M Møller, Rikke Kruse, Mette Marie H Christensen, Rasmus Kjøbsted, Martin Hey-Mogensen, Birgitte Andersen, Aase Handberg, Kurt Højlund.
       Background: Metformin lowers glucose by acting on the liver and the gastrointestinal tract and may reduce body weight by increasing circulating levels of the stress-induced cytokine GDF15. The tissue responsible for the release of GDF15 and whether this is paralleled by the induction of another, mainly liver derived, stress-responsive cytokine, FGF21, remains unclear.
    Objective: We examined the effect of metformin on GDF15 and FGF21 in humans and in intestinal cells in vitro.
    Methods: In a randomized, cross-over trial, 34 healthy individuals completed a 42-h fast twice, either with or without prior treatment with metformin for a week. Glucose metabolism was assessed using [3-3H]-glucose and indirect calorimetry and blood samples were drawn for the analysis of plasma metformin and serum GDF15 and FGF21. The effects of metformin on the expression and secretion of GDF15 and FGF21, and on mitochondrial respiration and glycolysis were examined in human intestinal epithelial cells (Caco-2).
    Results: Metformin increased glucose utilization (p=8.9x10-13) due to increased glycolysis (p=7.6x10-13) in vivo. This was accompanied by increased serum GDF15 (1004±61 vs 607±89 ng/ml; p<0.001), whereas serum FGF21 (146±30 vs 156±29 ng/ml; p=0.65) was unaltered. The change in serum GDF15 did not correlate with plasma metformin levels. In vitro, metformin markedly increased mRNA levels and secretion of GDF15, whereas FGF21 levels were not detectable in Caco-2 cells or media. Moreover, metformin dose-dependently inhibited mitochondrial respiration and increased glycolysis in vitro.
    Conclusions: The metformin-induced increase in serum GDF15, but not the liver-derived FGF21, in humans is consistent with the actions of metformin in human intestinal cells in vitro. These findings corroborate with recent studies demonstrating the gastrointestinal tract is an important site of metformin action.
    Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT01400191.
    Keywords:  FGF21; GDF15; glycolysis; intestine; metformin; mitochondrial respiration
    DOI:  https://doi.org/10.3389/fendo.2026.1797525
  6. Geroscience. 2026 Apr 01.
    Inflammaging-associated mitochondrial degeneration occurs in hypoglossal motor neurons prior to tongue muscle.
    Matthew J Fogarty, Debanjali Dasgupta, Trace A Christensen, Genesis A Hernandez-Vizcarrondo, Sanjana Mahadev Bhat, Kathryn D Rooker, Gary C Sieck.
      Mitochondrial degeneration and dysfunctions are increasingly linked with neurodegenerative diseases, with the greatest risk factor being increased age. Mitochondrial dysfunction is also implicated in sarcopenia, the age-associated weakness and atrophy of striated muscle. Untangling the pathophysiological effects of age-related mitochondrial degeneration and dysfunction is of huge interest in gerontology. In elderly humans and Fischer 344 (F344) rats, motor neuron (MN) death and denervation effects are becoming increasingly implicated in sarcopenia. We have previously demonstrated that MN loss and muscle weakness are prevalent in respiratory MNs and muscles; however, the chronology and mechanism of MN death and muscle weakness are relatively unexplored. We evaluated inflammaging (inflammatory cytokine release via ELISA), the endoplasmic reticulum (ER) stress response (via western blotting), mitochondrial degeneration (via serial block-face scanning electron microscopy), mitochondrial function (via SDHmax cellular assay), MN survival (via Nissl histopathology), and tongue muscle cross-sectional area (muscle H&E) and function (via ex vivo field stimulus) in young (6 months), late-middle-age (18 months) and old age (24 months) female and male F344 rats. Systemic, brainstem, and tongue muscle inflammatory cytokine TNFα was elevated from late-middle-age. The ER stress response (pIRE1αS724), transcriptional activation of downstream genes (CDK5), subsequent mitochondrial fission (pDRP1S616), and mitochondrial dysfunction (SDHmax) were elevated earlier at late-middle-age in brainstem and hypoglossal MNs compared to the tongue muscle. In the tongue muscle, resilience to inflammaging-triggered mitochondrial dysfunction was reflected by the maintenance of mitochondrial function and muscle morphology at late-middle-age. These findings are consistent with behavioral dysfunctions of swallow and airway defense in elderly humans and F344 rats. We propose that the vulnerability of MNs and their mitochondria to specific degenerative pathways may be a potent locus of therapeutic intervention.
    Keywords:  Aging; Brainstem; Hypoglossal; Mitochondria; Motor neuron; Sarcopenia; Tongue
    DOI:  https://doi.org/10.1007/s11357-026-02226-7
  7. Nat Struct Mol Biol. 2026 Apr 01.
    MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.
    Stephen P Burr, Kathryn Auckland, Angelos Glynos, Abhilesh Dhawanjewar, Cameron Ryall, Wei Wei, Antony Hynes-Allen, Malwina Prater, Matylda Sczaniecka-Clift, Julien Prudent, Patrick F Chinnery, Jelle van den Ameele.
      Mitochondria contain their own genome, mitochondrial DNA (mtDNA), which is under strict control by the cell nucleus. mtDNA occurs in many copies per cell and mutations often only affect a proportion of them, giving rise to heteroplasmy. mtDNA copy number and heteroplasmy level together shape the tissue-specific impact of mtDNA mutations, eventually giving rise to both rare mitochondrial and common neurodegenerative diseases. Here, we use MitoPerturb-Seq for CRISPR-Cas9-based, high-throughput single-cell interrogation of the nuclear genes and pathways that sense and control mtDNA copy number and heteroplasmy. We screened a panel of mtDNA maintenance genes in mouse cells with a heteroplasmic mtDNA mt-Ta mutation. This revealed both common and perturbation-specific aspects of the integrated stress response to mtDNA depletion caused by Tfam, Opa1 and Polg knockout. These responses are only partially mediated by ATF4 and cause cell-cycle stage-independent slowing of cell proliferation. MitoPerturb-Seq, thus, provides experimental insight into disease-relevant mitochondrial-nuclear interactions and may inform development of therapies targeting cell-type- and tissue-specific vulnerabilities to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41594-026-01779-7
  8. Front Physiol. 2026 ;17 1783596
    Mitochondrial ROS dyshomeostasis: a key driver of accelerated supraspinatus atrophy after rotator cuff injury.
    Erkai Pang, Yijin Zou, Kongye Lu, Jian Li, Xuxu Chen, Yu Zhu, Tao Wang, Linlin Shi, Hui Kang.
      Rotator cuff injuries are common musculoskeletal disorders and are frequently accompanied by progressive supraspinatus muscle atrophy, which severely compromises functional recovery and surgical outcomes. Accumulating evidence indicates that mitochondrial reactive oxygen species (mtROS) dyshomeostasis is a central pathological driver of post-injury muscle degeneration. This review synthesizes current knowledge on the anatomical and histopathological changes following rotator cuff tears and focuses on the mechanisms governing mitochondrial ROS production, clearance, and dysregulation in the supraspinatus muscle. We highlight how excessive mtROS contribute to oxidative damage, mitochondrial dysfunction, impaired energy metabolism, and activation of key atrophy-related signaling pathways, including FOXO, NF-κB, MAPK, the ubiquitin-proteasome system, and the autophagy-lysosome pathway. Particular emphasis is placed on the unique biomechanical unloading, ischemic stress, and metabolic vulnerability of the supraspinatus following rotator cuff injury, which predispose this muscle to ROS-driven degeneration. Finally, we critically evaluate emerging therapeutic strategies targeting mtROS, including mitochondria-targeted antioxidants and conventional redox-modulating interventions, and discuss their translational potential and current limitations.
    Keywords:  ROS; mitochondria-targeted antioxidants; mitochondrial dysfunction; muscle wasting pathways; oxidative stress; rotator cuff injury; supraspinatus atrophy
    DOI:  https://doi.org/10.3389/fphys.2026.1783596
  9. Nat Commun. 2026 Apr 01.
    Mitochondrial vulnerability underlies myocarditis from COVID-19 mRNA vaccine.
    Go Mori, Masayoshi Yamamoto, Kaori Ishikawa, Hiroaki Tamashiro, Hayate Suzuki, Seiya Mizuno, Kazuto Nakada, Atsushi Kawaguchi.
      mRNA vaccines against SARS-CoV-2 have been widely adopted to combat the COVID-19 pandemic. However, myocarditis has emerged as a rare but severe adverse effect, predominantly affecting young males. Here, we show that mitochondrial vulnerability is associated with mRNA vaccine-associated myocarditis. In our case-control study, patients with postvaccination myocarditis exhibited mitochondrial abnormalities. To examine the impact of mitochondrial damage, mRNA vaccines were administered to Polg+/D257A mice, which heterozygously express a proofreading-deficient mitochondrial DNA polymerase that sensitizes mitochondria to stress. mRNA vaccination in Polg+/D257A mice reduced left ventricular ejection fraction and induced cardiac immune cell infiltration. Bazedoxifene, a selective estrogen receptor modulator, prevented the reduction of cardiac function in Polg+/D257A mice, suggesting a protective role for estrogen signaling. Notably, mRNA vaccination induced mitochondrial reactive oxygen species, resulting in RIPK3 activation, a necroptosis-related kinase, in cardiomyocytes. Collectively, we propose that mitochondrial vulnerability is a potential risk factor for myocarditis following mRNA vaccination, possibly through reactive oxygen species-mediated necroptosis signaling.
    DOI:  https://doi.org/10.1038/s41467-026-71295-1
  10. Cell Metab. 2026 Mar 27. pii: S1550-4131(26)00104-X. [Epub ahead of print]
    Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise.
    Filip J Larsen.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.010
  11. Trends Mol Med. 2026 Apr 02. pii: S1471-4914(26)00061-4. [Epub ahead of print]
    Mitochondrial transfer as a therapeutic target for peripheral neuropathy.
    Junlin Wei, Fang Wang.
      Satellite glial cells transfer mitochondria to sensory neurons via myosin 10-dependent tunneling nanotubes. Ji et al. show that this transfer is impaired in diabetic neuropathy, causing energy failure. Restoring it via cell or mitochondrial transplantation alleviates pain and promotes nerve regeneration, revealing a new therapeutic strategy for peripheral neuropathy.
    Keywords:  diabetic peripheral neuropathy; mitochondrial transfer; neuroprotection; satellite glial cells; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.molmed.2026.03.004
  12. Front Med (Lausanne). 2026 ;13 1760210
    Molecular hydrogen as a treatment for ME/CFS: a mini-review of clinical evidence and mechanistic rationale.
    Fred Friedberg, Tyler W LeBaron.
      Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness characterized by profound fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction, yet it currently lacks FDA-approved treatments. Molecular hydrogen (H2), administered primarily as hydrogen-rich water (HRW), has emerged as a potential therapeutic candidate due to its selective antioxidant effects, anti-inflammatory activity, and support of mitochondrial and cellular homeostasis. These mechanisms align with several biological abnormalities implicated in ME/CFS, including oxidative stress, chronic inflammation, and impaired energy metabolism. This narrative mini-review summarizes mechanistic evidence relevant to ME/CFS and evaluates three developmental clinical studies of HRW in this population. Although early trials are small and methodologically limited, moderate-dose HRW consumed over extended durations has demonstrated feasibility and preliminary benefits in reducing fatigue and improving physical function, with generally mild side effects. Overlapping findings in Long COVID further suggest potential applicability across related post-viral fatigue conditions. Key limitations include small sample sizes, reliance on self-report outcomes, and the absence of objective biomarkers. Future research should prioritize larger, rigorously controlled trials incorporating remote biometric and biochemical assessments to clarify mechanisms of action and identify responsive subgroups. Overall, molecular hydrogen represents a promising, low-burden adjunctive therapy warranting further investigation in ME/CFS.
    Keywords:  ME/CFS; hydrogen-rich water; mitochondrial dysfunction; molecular hydrogen; oxidative stress
    DOI:  https://doi.org/10.3389/fmed.2026.1760210
  13. J Biol Chem. 2026 Mar 31. pii: S0021-9258(26)00283-8. [Epub ahead of print] 111413
    The inositol pyrophosphate 5-InsP7 regulates mitochondrial polyphosphate synthesis and bioenergetic function.
    Jayashree S Ladke, Azmi Khan, Anshit Singh, Henning J Jessen, Ullas Kolthur-Seetharam, Manish Jaiswal, Rashna Bhandari.
      Inorganic polyphosphate (polyP) is a linear polymer of phosphate residues linked by phosphoanhydride bonds. PolyP remains poorly understood in mammals due to its low abundance and lack of information on its metabolism. We developed a DAPI fluorescence-based assay to quantify the low levels of polyP present in mammalian cell lines and tissues, detecting an enrichment of polyP in the mitochondria compared with the nucleus and post-mitochondrial fraction. Mitochondrial polyP synthesis was found to depend on active FoF1 ATP synthase and an intact proton gradient across the inner mitochondrial membrane. Additionally, orthophosphate (Pi) is essential for mitochondrial polyP production, and ATP enhances Pi-driven polyP synthesis in isolated mitochondria. We discovered that the inositol pyrophosphate 5-InsP7, synthesized by IP6K1, regulates mitochondrial polyP levels. Mice and cells deficient in IP6K1 showed a significant reduction in mitochondrial polyP synthesis compared with wild type controls. Cells lacking IP6K1 also showed impaired mitochondrial respiration. The expression of active IP6K1, but not its catalytically inactive form, restored mitochondrial polyP synthesis in IP6K1 deficient cells, but mitochondrial respiration was rescued by expression of either active or inactive IP6K1. These data show that IP6K1 regulates mitochondrial function and polyP production both through the synthesis of 5-InsP7 and via a catalytic activity-independent mechanism. Our findings uncover a link between 5-InsP7, an energy sensor, and polyP, an energy store, in the regulation of mammalian mitochondrial homeostasis.
    Keywords:  ATP synthase; cell metabolism; inorganic polyphosphate; inositol phosphate; inositol pyrophosphates; mitochondria; mitochondrial membrane potential; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.jbc.2026.111413
  14. Neurol Ther. 2026 Mar 31.
    Natural History of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP): A Retrospective Patient Cohort Study.
    Stefanie N Hayer, Donald G McLaren, Robin M Nance, Holger Hengel, Benjamin Röben, Melanie Kellner, Eva Bürkle, Ludger Schöls, Benjamin Bender.
       INTRODUCTION: Colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) is a rare, progressive, fatal neurodegenerative disorder caused by pathogenic CSF1R gene variants, resulting in microglial dysfunction and neurodegeneration. In patients with CSF1R-ALSP, brain magnetic resonance imaging (MRI) shows early white matter lesions followed by brain atrophy accompanied by progressive cognitive, neuropsychiatric, and motor dysfunction. However, the natural history (NH) of this disease is not yet fully understood.
    METHODS: This study examined clinical features, brain MRI findings, and fluid biomarkers in a cohort of 16 symptomatic adults from Germany with genetically confirmed CSF1R-ALSP using a retrospective chart review to evaluate changes in symptoms and imaging during disease progression.
    RESULTS: In this cohort, median age of symptom onset was 45 years and disease duration varied widely (2‒15 years). The most common presenting clinical symptoms were cognitive impairment (81% of patients) and aphasia (63% of patients), which progressed rapidly over 24 months of observation. Scores for the Montreal Cognitive Assessment and the Barthel Index of independence in performing activities of daily living declined sharply during the observational period. MRI data showed white matter degeneration and brain atrophy accompanied by increased ventricular volume with significant annual progression. Significant correlations were observed between key volumetric MRI measures and clinical outcome assessments of cognition and functional independence.
    CONCLUSION: This retrospective study provides qualitative and quantitative data from the clinical setting for further characterization of the NH of CSF1R-ALSP, a rare neurological disorder with significant unmet medical need. Data will inform the design of and endpoint selection for future NH studies and interventional clinical trials, which will be central to the development of safe and efficacious therapies for CSF1R-ALSP. Further, it will guide clinicians less familiar with the disease in providing patients and caregivers with appropriate support and information about CSF1R-ALSP.
    Keywords:  Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; Aphasia; Brain atrophy; CSF1R-related leukoencephalopathy; Cognitive impairment; Dementia; Hereditary diffuse leukoencephalopathy with spheroids; Leukodystrophy; Magnetic resonance imaging; Primary microgliopathy
    DOI:  https://doi.org/10.1007/s40120-026-00916-0
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