Dataset Information

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 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 31 P 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.

SUBMITTER: Spitali P

PROVIDER: S-EPMC6104105 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies.

Spitali Pietro P Hettne Kristina K Tsonaka Roula R Charrout Mohammed M van den Bergen Janneke J Koeks Zaïda Z Kan Hermien E HE Hooijmans Melissa T MT Roos Andreas A Straub Volker V Muntoni Francesco F Al-Khalili-Szigyarto Cristina C Koel-Simmelink Marleen J A MJA Teunissen Charlotte E CE Lochmüller Hanns H Niks Erik H EH Aartsma-Rus Annemieke A

Journal of cachexia, sarcopenia and muscle 20180416 4

<h4>Background</h4>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 seru ...[more]

PMID: 29682908

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Project description:Heart impairment is classical in dystrophinopathies and its management relies on medical drugs. Mechanical ventilation is used to treat respiratory failure, but can affect cardiac function. We aimed to investigate the natural history of cardiac function in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies on home mechanical ventilation (HMV).We reviewed the chart of DMD and BMD patients, followed in our institution, to obtain ventilation setting at HMV initiation and echocardiographic data at baseline and end follow up, as well as onset cardiac events and thoracic mechanical complication. We analyzed cumulative incidence of cardiac events as well as echocardiographic parameters evolution and its association with ventilation settings.We included 111 patients (101 DMD and 10 BMD). Median age was 21 years [18-26], median pulmonary vital capacity (VC) 15% of predicted [10-24]. All patients were on HMV and 46% ventilated using tracheostomy. After a median follow up of 6.3 years, we found a slight decrease of the left ventricular ejection fraction (LVEF) (45% at end follow up vs 50% at baseline P?=?.019) and a stabilization of the LV end diastolic diameter indexed (LVEDD indexed 29.4?mm/m vs 30.7?mm/m at end follow up, P?=?.17). Tidal volume (VT) level was inversely associated with the annual rate of the LVEF decline (r?=?-0.29, P?=?.025). Left atrium (LA) diameter decreased with mechanical ventilation (24?mm vs 20?mm, P?=?.039) and we found a reduction of systolic pulmonary pressure (35?mm Hg vs 25?mm Hg, P?=?.011). The cumulative incidence of cardiac events was 12.6%. Pneumothorax occurred in 4% of patients. Hypoxic arrest secondary to the presence of tracheal plugin occurred in 4% of patients with invasive ventilation.HMV is not harmful, decreases pulmonary pressure and may protect heart in dystrophinopathies, in addition with cardioprotective drugs. In patients with DMD and BMD on HMV, cumulative incidence of cardiac events remains moderate and incidence of pneumothorax is rare.

Project description:IntroductionPrevious studies indicated variability in the prevalence of Duchenne and Becker muscular dystrophies (DBMD) by racial/ethnic groups. The Centers for Disease Control and Prevention's (CDC) Muscular Dystrophy Surveillance, Tracking, and Research network (MD STARnet) conducts muscular dystrophy surveillance in multiple geographic areas of the USA and continues to enroll new cases. This provides an opportunity to continue investigating differences in DBMD prevalence by race and ethnicity and to compare the impact of using varying approaches for estimating prevalence.ObjectiveTo estimate overall and race/ethnicity-specific prevalence of DBMD among males aged 5-9 years and compare the performance of three prevalence estimation methods.MethodsThe overall and race/ethnicity-specific 5-year period prevalence rates were estimated with MD STARnet data using three methods. Method 1 used the median of 5-year prevalence, and methods 2 and 3 calculated prevalence directly with different birth cohorts. To compare prevalence between racial/ethnic groups, Poisson modeling was used to estimate prevalence ratios (PRs) with non-Hispanic (NH) whites as the referent group. Comparison between methods was also conducted.ResultsIn the final population-based sample of 1,164 DBMD males, the overall 5-year prevalence for DBMD among 5-9 years of age ranged from 1.92 to 2.48 per 10,000 males, 0.74-1.26 for NH blacks, 1.78-2.26 for NH whites, 2.24-4.02 for Hispanics, and 0.61-1.83 for NH American Indian or Alaska Native and Asian or Native Hawaiian or Pacific Islander (AIAN/API). The PRs for NH blacks/NH whites, Hispanics/NH whites, and NH AIAN/API/NH whites were 0.46 (95% CI: 0.36-0.59), 1.37 (1.17-1.61), and 0.61 (0.40-0.93), respectively.ConclusionsIn males aged 5-9 years, compared to the prevalence of DBMD in NH whites, prevalence in NH blacks and NH AIAN/API was lower and higher in Hispanics. All methods produced similar prevalence estimates; however, method 1 produced narrower confidence intervals and method 2 produced fewer zero prevalence estimates than the other two methods.

Dataset Information

Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies.

Publications

Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies.

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