Large-scale proteomics profiling of peripheral blood of DM1 patients identifies biomarkers for disease severity and functional capacity.

Journal: Journal of neuromuscular diseases
Published Date: Jan 16, 2026

Abstract

BackgroundMyotonic Dystrophy Type 1 (DM1), the most common genetic neuromuscular disorder in adults, poses significant challenges for drug development due to its multisystem nature and high clinical variability in symptoms and disease progression. With a growing number of therapies entering clinical trials, this study addresses the urgent need for biomarkers that can serve as surrogate endpoints.MethodsWe profiled 437 serum samples from adult DM1 patients collected at two timepoints of the OPTIMISTIC trial using bottom-up mass spectrometry with data-independent acquisition. Associations between protein expression, the disease-causing CTG-repeat and 25 clinical outcome measures were studied using linear mixed-effect models. All key study findings were validated in an independent cohort of 69 DM1 patients and 10 healthy controls.ResultsOf the 259 identified proteins, 161 showed significant associations with the CTG-repeat length (FDR < 5%). Hypogammaglobulinemia was confirmed and shown to be worse in severely affected patients. A strong proteomic signature was associated with clinical measures of functional capacity, with the 6-Minute Walk Test showing the strongest signal (70 associations, FDR < 5%). These novel associations reveal a compelling link between chronic inflammation and reduced functional capacity. A machine learning algorithm identified a minimal set of 13 proteins robustly reflecting both the underlying genetic defect and functional capacity.ConclusionsDM1 induces a broad disease fingerprint in the serum proteome, predominantly affecting proteins of the immune system. A carefully selected panel of proteins showed the greatest potential to meet the statistical criteria required for surrogate endpoints in clinical trials.

Authors

  • Daniël van As
    Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Tine Claeys
    VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium.
  • Renee Salz
    Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Delphi Van Haver
    VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium.
  • Sara Dufour
    VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium.
  • Amber van Deelen
    Translational Metabolic Laboratory, Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Jolein Gloerich
    Translational Metabolic Laboratory, Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Ralf Gabriels
    VIB-UGent Center for Medical Biotechnology, VIB, Albert Baertsoenkaai 3, B-9000, Ghent, Belgium.
  • Pieter Jan Volders
    Limburg Clinical Research Center (LCRC), UHasselt, Diepenbeek, Belgium.
  • Vera Dobelmann
    Department of Neurology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • Andrea Gangfuss
    Department of Pediatric Neurology, Centre for Neuromuscular Disorders, University Duisburg-Essen, Essen, Germany.
  • Tobias Ruck
    Department of Neurology, Ruhr University Bochum, BG University Hospital Bergmannsheil, Bochum, Germany.
  • Genevieve Gourdon
    Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, Paris, France.
  • Elise Duchesne
    Interdisciplinary Research Group on Neuromuscular Diseases (GRIMN), Integrated University Health and Social Services Centre of Saguenay-Lac-Saint-Jean, Saguenay, QC, Canada.
  • Cynthia Gagnon
    Interdisciplinary Research Group on Neuromuscular Diseases (GRIMN), Integrated University Health and Social Services Centre of Saguenay-Lac-Saint-Jean, Saguenay, QC, Canada.
  • Andreas Roos
    Department of Neurology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • Alain van Gool
    Translational Metabolic Laboratory, Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Francis Impens
    VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium.
  • Lennart Martens
    VIB-UGent Center for Medical Biotechnology, VIB , Ghent , Belgium.
  • Hanns Lochmüller
    John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, University of Newcastle, Newcastle upon Tyne, UK.
  • Benedikt Schoser
    Friedrich-Baur-Institute at the Department of Neurology, LMU University Hospital, LMU Munich, Ziemssenstr.1 80336 Munich, Germany.
  • Guillaume Bassez
    Neuromuscular Reference Centre, Pitiè-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
  • Baziel Gm van Engelen
    Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Peter Ac 't Hoen
    Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands.

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