We present the case of a male patient who was ultimately diagnosed with Becker muscular dystrophy (BMD; MIM# 300376) after the onset of muscle weakness in his teens progressively led to... Show moreWe present the case of a male patient who was ultimately diagnosed with Becker muscular dystrophy (BMD; MIM# 300376) after the onset of muscle weakness in his teens progressively led to significant walking difficulties in his twenties. A genetic diagnosis was pursued but initial investigation revealed no aberrations in the dystrophin gene (DMD), although immunohistochemistry and Western blot analysis suggested the diagnosis of dystrophinopathy. Eventually, after more than 10 years, an RNA analysis captured abnormal splicing where 154 nucleotides from intron 43 were inserted between exon 43 and 44 resulting in a frameshift and a premature stop codon. Normal splicing of the DMD gene was also observed. Additionally, a novel variant c.6291–13537A>G in DMD was confirmed in the genomic DNA of the patient. The predicted function of the variant aligns with the mRNA results. To conclude, we here demonstrate that mRNA analysis can guide the diagnosis of non-coding genetic variants in DMD. Show less
BackgroundBecker muscular dystrophy (BMD) is an X-linked disorder characterized by slow, progressive muscle damage and muscle weakness. Hallmarks include fibre-size variation and replacement of... Show moreBackgroundBecker muscular dystrophy (BMD) is an X-linked disorder characterized by slow, progressive muscle damage and muscle weakness. Hallmarks include fibre-size variation and replacement of skeletal muscle with fibrous and adipose tissues, after repeated cycles of regeneration. Muscle histology can detect these features, but the required biopsies are invasive, are difficult to repeat and capture only small muscle volumes. Diffusion-tensor magnetic resonance imaging (DT-MRI) is a potential non-invasive alternative that can calculate muscle fibre diameters when applied with the novel random permeable barrier model (RPBM). In this study, we assessed muscle fibre diameters using DT-MRI in BMD patients and healthy controls and compared these with histology. MethodsWe included 13 BMD patients and 9 age-matched controls, who underwent water-fat MRI and DT-MRI at multiple diffusion times, allowing RPBM parameter estimation in the lower leg muscles. Tibialis anterior muscle biopsies were taken from the contralateral leg in 6 BMD patients who underwent DT-MRI and from an additional 32 BMD patients and 15 healthy controls. Laminin and Sirius-red stainings were performed to evaluate muscle fibre morphology and fibrosis. Twelve ambulant patients from the MRI cohort underwent the North Star ambulatory assessment, and 6-min walk, rise-from-floor and 10-m run/walk functional tests. ResultsRPBM fibre diameter was significantly larger in BMD patients (P = 0.015): mean (SD) = 68.0 (25.3) mu m versus 59.4 (19.2) mu m in controls. Inter-muscle differences were also observed (P <= 0.002). Both inter- and intra-individual RPBM fibre diameter variability were similar between groups. Laminin staining agreed with the RPBM, showing larger median fibre diameters in patients than in controls: 72.5 (7.9) versus 63.2 (6.9) mu m, P = 0.006. However, despite showing similar inter-individual variation, patients showed more intra-individual fibre diameter variability than controls-mean variance (SD) = 34.2 (7.9) versus 21.4 (6.9) mu m, P < 0.001-and larger fibrosis areas: median (interquartile range) = 21.7 (5.6)% versus 14.9 (3.4)%, P < 0.001. Despite good overall agreement of RPBM and laminin fibre diameters, they were not associated in patients who underwent DT-MRI and muscle biopsy, perhaps due to lack of colocalization of DT-MRI with biopsy samples. ConclusionsDT-MRI RPBM metrics agree with histology and can quantify changes in muscle fibre size that are associated with regeneration without the need for biopsies. They therefore show promise as imaging biomarkers for muscular dystrophies. Show less
Objective: No treatments are approved for Becker muscular dystrophy (BMD). This study investigated the efficacy and safety of givinostat, a histone deacetylase pan-inhibitor, in adults with BMD.... Show moreObjective: No treatments are approved for Becker muscular dystrophy (BMD). This study investigated the efficacy and safety of givinostat, a histone deacetylase pan-inhibitor, in adults with BMD. Methods: Males aged 18-65 years with a diagnosis of BMD confirmed by genetic testing were randomized 2:1 to 12 months treatment with givinostat or placebo. The primary objective was to demonstrate statistical superiority of givinostat over placebo for mean change from baseline in total fibrosis after 12 months. Secondary efficacy endpoints included other histological parameters, magnetic resonance imaging and spectroscopy (MRI and MRS) measures, and functional evaluations. Results: Of 51 patients enrolled, 44 completed treatment. At baseline, there was greater disease involvement in the placebo group than givinostat, based on total fibrosis (mean 30.8 vs. 22.8%) and functional endpoints. Mean total fibrosis did not change from baseline in either group, and the two groups did not differ at Month 12 (least squares mean [LSM] difference 1.04%; p = 0.8282). Secondary histology parameters, MRS, and functional evaluations were consistent with the primary. MRI fat fraction in whole thigh and quadriceps did not change from baseline in the givinostat group, but values increased with placebo, with LSM givinostat-placebo differences at Month 12 of -1.35% (p = 0.0149) and -1.96% (p = 0.0022), respectively. Adverse events, most mild or moderate, were reported by 88.2% and 52.9% patients receiving givinostat and placebo. Conclusion: The study failed to achieve the primary endpoint. However, there was a potential signal from the MRI assessments suggesting givinostat could prevent (or slow down) BMD disease progression. Show less
Introduction/Aims Becker muscular dystrophy (BMD) is characterized by variable disease severity and progression, prompting the identification of biomarkers for clinical trials. We used data from an... Show moreIntroduction/Aims Becker muscular dystrophy (BMD) is characterized by variable disease severity and progression, prompting the identification of biomarkers for clinical trials. We used data from an ongoing phase II study to provide a comprehensive characterization of a cohort of patients with BMD, and to assess correlations between histological and magnetic resonance imaging (MRI) markers with muscle function and strength. Methods Eligible patients were ambulatory males with BMD, aged 18 to 65 years (200 to 450 meters on 6-minute walk test). The following data were obtained: function test results, strength, fat-fraction quantification using chemical shift-encoded MRI (whole thigh and quadriceps), and fibrosis and muscle fiber area (MFA) of the brachial biceps. Results Of 70 patients screened, 51 entered the study. There was substantial heterogeneity between patients in muscle morphology (histology and MRI), with high fat replacement. Total fibrosis correlated significantly and mostly moderately with all functional endpoints, including both upper arm strength assessments (left and right elbow flexion rho -.574 and -.588, respectively [both P < .0001]), as did MRI fat fraction (whole thigh and quadriceps), for example, with four-stair-climb velocity -.554 and -.550, respectively (both P < .0001). Total fibrosis correlated significantly and moderately with both MRI fat fraction assessments (.500 [P = .0003] and .423 [.0024], respectively). Discussion In this BMD cohort, micro- and macroscopic morphological muscle parameters correlated moderately with each other and with functional parameters, potentially supporting the use of MRI fat fraction and histology as surrogate outcome measures in patients with BMD, although additional research is required to validate this. Show less
Lin, N. van; Paliouras, G.; Vroom, E.; Hoen, P.A.C. 't; Roos, M. 2021
Background: For patients with rare diseases such as Duchenne and Becker muscular dystrophy (DMD/BMD), access to their health data is key to being able to advocate for themselves and be in control... Show moreBackground: For patients with rare diseases such as Duchenne and Becker muscular dystrophy (DMD/BMD), access to their health data is key to being able to advocate for themselves and be in control of their care. Since 2018, the DMD/BMD patient community has been committed to making DMD/BMD-related data FAIR, i.e., Findable, Accessible, Interoperable, and Reusable. On March 3, 2021, the second international meeting on FAIR data sharing for DMD/BMD was held virtually.Objective: The aim of this meeting report is to summarize the presentations and discussions of the meeting.Methods: During this meeting, the progress of FAIRification efforts since the first international meeting in 2019, new developments, stakeholder perspectives, and experiences from implementing FAIR data principles in practice were presented and discussed.Results: Over 120 attendees representing various stakeholder groups (ie, patient organizations, clinicians, clinical and academic researchers, pharmaceutical companies, regulators, and EU organizations) from 22 countries participated in the meeting. This meeting report summarizes the presentations and discussions from the meeting, provides an overview of the key lessons learned since the first meeting, and outlines the next steps.Conclusions: Patient organizations are key drivers of the FAIRification process in practice and dialogue with stakeholders is critical to success. Show less
Quantitative MRI and MRS of muscle are increasingly being used to measure individual pathophysiological processes in Becker muscular dystrophy (BMD). In particular, muscle fat fraction was shown to... Show moreQuantitative MRI and MRS of muscle are increasingly being used to measure individual pathophysiological processes in Becker muscular dystrophy (BMD). In particular, muscle fat fraction was shown to be highly associated with functional tests in BMD. However, the muscle strength per unit of contractile cross-sectional area is lower in patients with BMD compared with healthy controls. This suggests that the quality of the non-fat-replaced (NFR) muscle tissue is lower than in healthy controls. Consequently, a measure that reflects changes in muscle tissue itself is needed. Here, we explore the potential of waterT(2)relaxation times, diffusion parameters and phosphorus metabolic indices as early disease markers in patients with BMD. For this purpose, we examined these measures in fat-replaced (FR) and NFR lower leg muscles in patients with BMD and compared these values with those in healthy controls. Quantitative proton MRI (three-point Dixon, multi-spin-echo and diffusion-weighted spin-echo echo planar imaging) and 2D chemical shift imaging(31)P MRS data were acquired in 24 patients with BMD (age 18.8-66.2 years) and 13 healthy controls (age 21.3-63.6 years). Muscle fat fractions, phosphorus metabolic indices, and averages and standard deviations (SDs) of the waterT(2)relaxation times and diffusion tensor imaging (DTI) parameters were assessed in six individual leg muscles. Phosphodiester levels were increased in the NFR and FR tibialis anterior, FR peroneus and FR gastrocnemius lateralis muscles. No clear pattern was visible for the other metabolic indices. IncreasedT(2)SD was found in the majority of FR muscles compared with NFR and healthy control muscles. No differences in average waterT(2)relaxation times or DTI indices were found between groups. Overall, our results indicate that primarily muscles that are further along in the disease process showed increases inT(2)heterogeneity and changes in some metabolic indices. No clear differences were found for the DTI indices between groups. Show less
Variations in the DMD gene that affect dystrophin production underlie both the severe Duchenne and the milder Becker muscular dystrophies (DMD and BMD, respectively). Depending on their location,... Show moreVariations in the DMD gene that affect dystrophin production underlie both the severe Duchenne and the milder Becker muscular dystrophies (DMD and BMD, respectively). Depending on their location, deletions and duplications involving one or more exons of a gene can have a range of consequences. This overview, summarizing the important points to consider, was drafted in response to frequent questions we receive about deletions/duplications involving the dystrophin encoding DMD gene. Although directed at DMD, the observations made can be applied to many other genes. The overview is meant primarily for healthcare professionals involved with interpreting the results of genetic analyses in clinical practice. Show less
In African neurological practice, muscle disorders are either underdiagnosed or underrepresented. This may in part be due to the large burden of other more common neurological disorders. In this... Show moreIn African neurological practice, muscle disorders are either underdiagnosed or underrepresented. This may in part be due to the large burden of other more common neurological disorders. In this report we describe the first Tanzanian patient with genetically confirmed Becker muscular dystrophy. His phenotype and genotype were compatible with elsewhere in the world. Remarkably, this patient reported his progressive weakness of the legs with difficulty in walking only after a fall. We demonstrate that muscular dystrophies occur in sub-Saharan Africa. Neurologists must however be aware that patients are likely to delay seeking medical care for muscle disorders. (C) 2019 Elsevier B.V. All rights reserved. Show less
Spitali, P.; Hettne, K.; Tsonaka, R.; Charrout, M.; Bergen, J. van den; Koeks, Z.; ... ; Aartsma-Rus, A. 2018
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... Show moreBackground 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 4.4years 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. Show less
Spitali, P.; Hettne, K.; Tsonaka, R.; Charrout, M.; Bergen, J. van den; Koeks, Z.; ... ; Aartsma-Rus, A. 2018
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... Show moreBackground 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 4.4years 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. Show less
Duchenne spierdystrofie (Duchenne MD) en Becker spierdystrofie (Becker MD) zijn progressieve spierziekten die beide veroorzaakt worden door een genetische afwijking op het X-chromosoom. Omdat het... Show moreDuchenne spierdystrofie (Duchenne MD) en Becker spierdystrofie (Becker MD) zijn progressieve spierziekten die beide veroorzaakt worden door een genetische afwijking op het X-chromosoom. Omdat het eiwit dystrofine ontbreekt in de spieren hebben jongens met Duchenne MD vanaf de kleuterleeftijd progressief spierzwakte en worden zij rolstoelafhankelijk. Pati_nten met Becker MD hebben een milder beloop omdat zij in de spieren wel een afwijkend, partieel functionerend, eiwit kunnen maken waardoor het klinisch beloop milder is en de debuutleeftijd later. Het proefschrift focust op heterogene klinische kenmerken. Het IQ en de leerprestaties kunnen sterk verschillen tussen jongens met Duchenne MD. Met MRI onderzoek van de hersenen hebben wij gevonden dat het volume van de hersenen en van de grijze stof bij jongens met Duchenne MD kleiner is ten opzichte van controles. Dit komt het duidelijkst naar voren in een subgroep van pati_nten met een bepaalde lokalisatie van de genetische mutatie. Bij pati_nten met Becker MD kan juist het klachtenpatroon vari_ren tussen pati_nten van zeer mild tot ernstige spierzwakte. Deze heterogeniteit kan het diagnosticeren van de ziekte bemoeilijken. Bij complexe pati_nten met (een verdenking op) een erfelijke spierdystrofie is het essentieel dat de clinicus overlegt met de moleculair geneticus over de mogelijke diagnostische testen Show less
Westrum, S.S. van; Dekker, L.; Haan, R. de; Endert, E.; Ginjaar, I.; Visser, M. de; Kooi, A. van der 2013
