Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies
Abstract Background Analysis of muscle biopsies allowed to characterize the pathophysiological changes of Duchenne and Becker muscular dystrophies (D/BMD) leading to the clinical phenotype. Muscle tissue is often investigated during interventional dose finding studies to show in situ proof of concep...
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Wiley
2018-08-01
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Series: | Journal of Cachexia, Sarcopenia and Muscle |
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Online Access: | https://doi.org/10.1002/jcsm.12304 |
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doaj-0eb35a80d432451f8651ce90e2352016 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Pietro Spitali Kristina Hettne Roula Tsonaka Mohammed Charrout Janneke van denBergen Zaïda Koeks Hermien E. Kan Melissa T. Hooijmans Andreas Roos Volker Straub Francesco Muntoni Cristina Al‐Khalili‐Szigyarto Marleen J.A. Koel‐Simmelink Charlotte E. Teunissen Hanns Lochmüller Erik H. Niks Annemieke Aartsma‐Rus |
spellingShingle |
Pietro Spitali Kristina Hettne Roula Tsonaka Mohammed Charrout Janneke van denBergen Zaïda Koeks Hermien E. Kan Melissa T. Hooijmans Andreas Roos Volker Straub Francesco Muntoni Cristina Al‐Khalili‐Szigyarto Marleen J.A. Koel‐Simmelink Charlotte E. Teunissen Hanns Lochmüller Erik H. Niks Annemieke Aartsma‐Rus Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies Journal of Cachexia, Sarcopenia and Muscle Biomarker Duchenne muscular dystrophy Becker muscular dystrophy Longitudinal analysis Proteomics Sarcopenia |
author_facet |
Pietro Spitali Kristina Hettne Roula Tsonaka Mohammed Charrout Janneke van denBergen Zaïda Koeks Hermien E. Kan Melissa T. Hooijmans Andreas Roos Volker Straub Francesco Muntoni Cristina Al‐Khalili‐Szigyarto Marleen J.A. Koel‐Simmelink Charlotte E. Teunissen Hanns Lochmüller Erik H. Niks Annemieke Aartsma‐Rus |
author_sort |
Pietro Spitali |
title |
Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies |
title_short |
Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies |
title_full |
Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies |
title_fullStr |
Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies |
title_full_unstemmed |
Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies |
title_sort |
tracking disease progression non‐invasively in duchenne and becker muscular dystrophies |
publisher |
Wiley |
series |
Journal of Cachexia, Sarcopenia and Muscle |
issn |
2190-5991 2190-6009 |
publishDate |
2018-08-01 |
description |
Abstract Background Analysis of muscle biopsies allowed to characterize the pathophysiological changes of Duchenne and Becker muscular dystrophies (D/BMD) leading to the clinical phenotype. Muscle tissue is often investigated during interventional dose finding studies to show in situ proof of concept and pharmacodynamics effect of the tested drug. Less invasive readouts are needed to objectively monitor patients' health status, muscle quality, and response to treatment. The identification of serum biomarkers correlating with clinical function and able to anticipate functional scales is particularly needed for personalized patient management and to support drug development programs. Methods A large‐scale proteomic approach was used to identify serum biomarkers describing pathophysiological changes (e.g. loss of muscle mass), association with clinical function, prediction of disease milestones, association with in vivo 31P magnetic resonance spectroscopy data and dystrophin levels in muscles. Cross‐sectional comparisons were performed to compare DMD patients, BMD patients, and healthy controls. A group of DMD patients was followed up for a median of 4.4 years to allow monitoring of individual disease trajectories based on yearly visits. Results Cross‐sectional comparison enabled to identify 10 proteins discriminating between healthy controls, DMD and BMD patients. Several proteins (285) were able to separate DMD from healthy, while 121 proteins differentiated between BMD and DMD; only 13 proteins separated BMD and healthy individuals. The concentration of specific proteins in serum was significantly associated with patients' performance (e.g. BMP6 serum levels and elbow flexion) or dystrophin levels (e.g. TIMP2) in BMD patients. Analysis of longitudinal trajectories allowed to identify 427 proteins affected over time indicating loss of muscle mass, replacement of muscle by adipose tissue, and cardiac involvement. Over‐representation analysis of longitudinal data allowed to highlight proteins that could be used as pharmacodynamic biomarkers for drugs currently in clinical development. Conclusions Serum proteomic analysis allowed to not only discriminate among DMD, BMD, and healthy subjects, but it enabled to detect significant associations with clinical function, dystrophin levels, and disease progression. |
topic |
Biomarker Duchenne muscular dystrophy Becker muscular dystrophy Longitudinal analysis Proteomics Sarcopenia |
url |
https://doi.org/10.1002/jcsm.12304 |
work_keys_str_mv |
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doaj-0eb35a80d432451f8651ce90e23520162020-11-25T02:23:38ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092018-08-019471572610.1002/jcsm.12304Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophiesPietro Spitali0Kristina Hettne1Roula Tsonaka2Mohammed Charrout3Janneke van denBergen4Zaïda Koeks5Hermien E. Kan6Melissa T. Hooijmans7Andreas Roos8Volker Straub9Francesco Muntoni10Cristina Al‐Khalili‐Szigyarto11Marleen J.A. Koel‐Simmelink12Charlotte E. Teunissen13Hanns Lochmüller14Erik H. Niks15Annemieke Aartsma‐Rus16Department of Human Genetics Leiden University Medical Center Leiden The NetherlandsDepartment of Human Genetics Leiden University Medical Center Leiden The NetherlandsDepartment of Medical Statistics and Bioinformatics Leiden University Medical Center Leiden The NetherlandsDepartment of Human Genetics Leiden University Medical Center Leiden The NetherlandsDepartment of Neurology Leiden University Medical Center Leiden The NetherlandsDepartment of Neurology Leiden University Medical Center Leiden The NetherlandsC.J. Gorter Center for High Field MRI, Department of Radiology Leiden University Medical Center Leiden The NetherlandsC.J. Gorter Center for High Field MRI, Department of Radiology Leiden University Medical Center Leiden The NetherlandsJohn Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine University of Newcastle Newcastle upon Tyne UKJohn Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine University of Newcastle Newcastle upon Tyne UKDubowitz Neuromuscular Centre University College London Great Ormond Street Institute of Child Health London UKDivision of Proteomics, School of Biotechnology KTH—Royal Institute of Technology Stockholm SwedenNeurochemistry Lab and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience VU University Medical Center Amsterdam The NetherlandsNeurochemistry Lab and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience VU University Medical Center Amsterdam The NetherlandsJohn Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine University of Newcastle Newcastle upon Tyne UKDepartment of Neurology Leiden University Medical Center Leiden The NetherlandsDepartment of Human Genetics Leiden University Medical Center Leiden The NetherlandsAbstract Background Analysis of muscle biopsies allowed to characterize the pathophysiological changes of Duchenne and Becker muscular dystrophies (D/BMD) leading to the clinical phenotype. Muscle tissue is often investigated during interventional dose finding studies to show in situ proof of concept and pharmacodynamics effect of the tested drug. Less invasive readouts are needed to objectively monitor patients' health status, muscle quality, and response to treatment. The identification of serum biomarkers correlating with clinical function and able to anticipate functional scales is particularly needed for personalized patient management and to support drug development programs. Methods A large‐scale proteomic approach was used to identify serum biomarkers describing pathophysiological changes (e.g. loss of muscle mass), association with clinical function, prediction of disease milestones, association with in vivo 31P magnetic resonance spectroscopy data and dystrophin levels in muscles. Cross‐sectional comparisons were performed to compare DMD patients, BMD patients, and healthy controls. A group of DMD patients was followed up for a median of 4.4 years to allow monitoring of individual disease trajectories based on yearly visits. Results Cross‐sectional comparison enabled to identify 10 proteins discriminating between healthy controls, DMD and BMD patients. Several proteins (285) were able to separate DMD from healthy, while 121 proteins differentiated between BMD and DMD; only 13 proteins separated BMD and healthy individuals. The concentration of specific proteins in serum was significantly associated with patients' performance (e.g. BMP6 serum levels and elbow flexion) or dystrophin levels (e.g. TIMP2) in BMD patients. Analysis of longitudinal trajectories allowed to identify 427 proteins affected over time indicating loss of muscle mass, replacement of muscle by adipose tissue, and cardiac involvement. Over‐representation analysis of longitudinal data allowed to highlight proteins that could be used as pharmacodynamic biomarkers for drugs currently in clinical development. Conclusions Serum proteomic analysis allowed to not only discriminate among DMD, BMD, and healthy subjects, but it enabled to detect significant associations with clinical function, dystrophin levels, and disease progression.https://doi.org/10.1002/jcsm.12304BiomarkerDuchenne muscular dystrophyBecker muscular dystrophyLongitudinal analysisProteomicsSarcopenia |