Breathing exercises for children with pseudohypertrophic muscular dystrophy.

What Can We Learn From Clinical Trials of Exon Skipping for DMD?

Research Article| January 01 2010 Delayed Diagnosis of Duchenne Muscular Dystrophy AAP Grand Rounds (2010) 23 (1): 3. https://doi.org/10.1542/gr.23-1-3 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Delayed Diagnosis of Duchenne Muscular Dystrophy. AAP Grand Rounds January 2010; 23 (1): 3. https://doi.org/10.1542/gr.23-1-3 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search nav search search input Search input auto suggest search filter All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: delayed diagnosis, duchenne's muscular dystrophy Source: Ciafaloni E, Fox DJ, Mathews KD, et al. Delayed diagnosis in Duchenne muscular dystrophy: data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). J Pediatr. 2009; 155(3): 380– 385; doi: https://doi.org/10.1016/j.jpeds.2009.02.007Google Scholar Investigators from New York, Iowa, Arizona, and Colorado collaborated in a study to assess delay in diagnosis of Duchenne muscular dystrophy (DMD) in patients without a known family history. Study patients were identified using a four-state registry system established by the Muscular Dystrophy Surveillance, Tracking and Research Network. Initially, records of 453 children diagnosed with either Duchenne or Becker muscular dystrophy, born since 1982, were reviewed. Patients classified as having definite or probable DMD, without a known family history prior to birth, were included in the analysis. Abstracted information from patient records included place of birth; residential history; growth data; symptoms; diagnostic tests; disease effects on pulmonary, cardiac and musculoskeletal systems; clinical treatment; and changes in mobility and function over time. The final data set included a cohort of 156 boys with definite or probable DMD. The initial signs and symptoms (SS) of possible DMD in study patients were noted by parents or caregivers at a mean age of 2.5 years. In 28% of these boys the first SS were noted before 1.5 years of age; 58% had SS prior to the age of 3 years. The most frequent SS were motor delay and muscle weakness. There was an average delay of over one year before boys with SS were taken to a health care professional for evaluation. The mean age at which concerns about the initial SS led to a clinical evaluation of the child was 3.6 years. The initial evaluation of the SS by a health care provider included a serum creatine kinase (CK) test in only 35% of cases. For the entire cohort of nonfamilial patients with DMD, the mean age for obtaining the first serum CK was 4.7 years. Between 1982 and 2000, the age at which care providers obtained the first CK in boys with nonfamilial DMD remained unchanged. Overall, there was a delay of about 2.5 years between the onset of DMD symptoms and the time of diagnosis. The authors conclude that there is a significant time lag between onset of SS and diagnosis of DMD and recommend that a CK test be a standard tool in the assessment of developmental delay in boys. DMD, the most common muscular dystrophy in children, is an X-linked recessive disorder occurring in 1 of every 3,500 male newborns,1 resulting from an absence of an essential transmembrane muscle protein. Thirty percent of cases arise from spontaneous mutation in the dystrophin gene. The diagnosis should be suspected in boys with motor difficulties. Global developmental delay does not exclude the diagnosis of DMD as cognitive, behavioral, and language abnormalities are found in one third of cases.2 An elevated serum CK level is a sensitive marker for early detection of DMD.... You do not currently have access to this content.

Based on the available evidence from RCTs, early treatment with ACE inhibitors or ARBs may be comparably beneficial for people with a dystrophinopathy; however, the certainty of evidence is very low. Very low-certainty evidence indicates that adding eplerenone might give additional benefit when early cardiomyopathy is detected. No clinically meaningful effect was seen for growth hormone or idebenone, although the certainty of the evidence is also very low.

Missed Opportunities for Duchenne Muscular Dystrophy

Characterization of the Ocular Phenotype of Duchenne and Becker Muscular Dystrophy

Duchenne muscular dystrophy (DMD) causes progressive respiratory muscle weakness and decline in function, which can go undetected without monitoring. DMD respiratory care guidelines recommend scheduled respiratory assessments and use of respiratory assist devices. To determine the extent of adherence to these guidelines, we evaluated respiratory assessments and interventions among males with DMD in the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) from 2000 to 2011. MD STARnet is a population-based surveillance system that identifies all individuals born during or after 1982 residing in Arizona, Colorado, Georgia, Hawaii, Iowa, and western New York with Duchenne or Becker muscular dystrophy. We analyzed MD STARnet respiratory care data for non-ambulatory adolescent males (12-17 y old) and men (≥18 y old) with DMD, assessing whether: (1) pulmonary function was measured twice yearly; (2) awake and asleep hypoventilation testing was performed at least yearly; (3) home mechanical insufflation-exsufflation, noninvasive ventilation, and tracheostomy/ventilators were prescribed; and (4) pulmonologists provided evaluations. During 2000-2010, no more than 50% of both adolescents and men had their pulmonary function monitored twice yearly in any of the years; 67% or fewer were assessed for awake and sleep hypoventilation yearly. Although the use of mechanical insufflation-exsufflation and noninvasive ventilation is probably increasing, prior use of these devices did not prevent all tracheostomies, and at least 18 of 29 tracheostomies were performed due to acute respiratory illnesses. Fewer than 32% of adolescents and men had pulmonologist evaluations in 2010-2011. Since the 2004 publication of American Thoracic Society guidelines, there have been few changes in pulmonary clinical practice. Frequencies of respiratory assessments and assist device use among males with DMD were lower than recommended in clinical guidelines. Collaboration of respiratory therapists and pulmonologists with clinicians caring for individuals with DMD should be encouraged to ensure access to the full spectrum of in-patient and out-patient pulmonary interventions.

Studies on the carrier state in X-linked recessive (Duchenne) muscular dystrophy

Enhanced myocardial ERK activation in animal models of Duchenne and Limb Girdle 2F Muscular Dystrophy

Muscular dystrophy is a neuromuscular disorder that begins with muscle weakness and impaired motor function. Duchenne muscular dystrophy (DMD) is more severe and destructive than Becker muscular dystrophy (BMD), and both are progressive in nature. These 2 types of muscular dystrophy are caused by mutations in related to X-chromosome genes.1 The mutations that occur in DMD are nonsense mutations. Deletion is present in 60% of DMD cases, while duplication occurs in 10% of DMD cases, resulting in loss of dystrophin protein. Mutations in BMD are missense mutations, so dystrophin is still formed, but in decreased amounts and quality.2,3
 The prevalence of DMD was reported to be three times greater than that of BMD, with a prevalence of 1.02 per 10,000 male births vs. 0.36 per 10,000 male infants, respectiveley.4 Anatomical pathology examination revealed loss of dystrophin in the examination of muscle biopsy without the presence of evidence leading to other neuromuscular diseases. Clinical DMD symptoms begin to appear at the age of 2-4 years. The child is observed to fall often and has difficulty climbing stairs. Muscle weakness worsens, especially in the upper limbs, continuing with heart and respiratory problems. The main causes of death in DMD are respiratory failure and heart failure.5 The BMD has varied clinical symptoms, beginning with the appearance of myalgia, muscle cramps, and arm weakness progressing towards myopathy. Some patients are asymptomatic until the age of 15, but 50% of patients show symptoms at age 10, and almost all by age 20.6

Introduction: DMD is the most common muscular dystrophy and is characterized by the absence of dystrophin. Cardiomyopathy and associated arrhythmias have emerged as a leading cause of death in DMD. Hypothesis: We hypothesized that the pathophysiology of DMD cardiomyopathy can be modeled using DMD hiPSC-derived cardiomyocytes (CM), which can be interrogated at the cellular and molecular level. Methods: Dermal fibroblasts were obtained from patients with genetically confirmed DMD and healthy controls and reprogrammed to hiPSC using human reprogramming transcription factors. DMD and control hiPSC lines were differentiated to CMs using a directed differentiation protocol. Functional analysis including wheat-germ agglutinin co-immunoprecipitation and calcium handling was performed at d60. Results: DMD hiPSCs demonstrated DYSTROPHIN exon mutations consistent with patient mutations. DMD and control hiPSCs differentiated to beating, electrically coupled CM sheets. Quantitative western blot analysis for dystroglycan complex (DGC) components and novel cardiac DGC proteins Cryab and Cypher demonstrated expression of the majority of DGC and novel cardiac DGC proteins at d60 of differentiation in control hiPSC-derived CM. Dystrophin and DGC proteins including novel cardiac DGC proteins are associated with the DGC in all control hiPSC CM at d60. DMD hiPSC-derived CM have absence of dystrophin and a disrupted DGC. We identified that cypher is absent in DMD hiPSC CM and validated this in human DMD left ventricular tissue. Calcium imaging demonstrated significantly abnormal calcium transients in DMD hiPSC-derived CM correlating to arrhythmias. Conclusion: Our results suggest that the control hiPSC-derived CMs have a largely nucleated DGC at d60 including novel cardiac DGC associated proteins. DMD hiPSCs have the hallmark absence of dystrophin and a disrupted DGC. The phenotype of increased arrhythmias in DMD patients is also reflected in DMD hiPSC CM. DMD hiPSC-derived CMs can be used as a model for investigation of DMD cardiomyopathy and further evaluation of the molecular and physiologic phenotype of DMD hiPSC cardiomyocytes will serve as a platform for testing current therapies and developing novel therapies for patients with DMD cardiomyopathy.

Long-term Engraftment of Multipotent Mesenchymal Stromal Cells That Differentiate to Form Myogenic Cells in Dogs With Duchenne Muscular Dystrophy

Towards harmonisation of outcome measures for DMD and SMA within TREAT-NMD; Report of three expert workshops: TREAT-NMD/ENMC Workshop on outcome measures, 12th–13th May 2007, Naarden, The Netherlands; TREAT-NMD Workshop on outcome measures in experimental trials for DMD, 30th June–1st July 2007, Naarden, The Netherlands; Conjoint Institute of Myology TREAT-NMD Meeting on physical activity monitoring in neuromuscular disorders, 11th July 2007,

In Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), interventions reducing the progression of myocardial disease could affect survival. To assess the effect of early angiotensin-converting enzyme (ACE) inhibitor therapy in patients with normal left ventricular function on the progression of myocardial fibrosis (MF) identified on cardiovascular magnetic resonance (CMR). A randomized clinical trial conducted in 2 centers included 76 male patients with DMD or BMD undergoing 2 CMR studies with a 2-year interval for ventricular function and MF assessment. In a non-intent-to-treat trial, 42 patients with MF and normal left ventricular ejection fraction (LVEF) were randomized (1:1) to receive or not receive ACE inhibitor therapy. The study was conducted from June 26, 2009, to June 30, 2012. Data analysis was performed from June 30, 2013, to October 3, 2016. Randomization (1:1) to receive or not receive ACE inhibitor therapy. Primary outcome was MF progression from baseline to the 2-year CMR study. Of the 76 male patients included in the study, 70 had DMD (92%) and 6 had BMD (8%); mean (SD) age at baseline was 13.1 (4.4) years. Myocardial fibrosis was present in 55 patients (72%) and LV systolic dysfunction was identified in 13 patients (24%). Myocardial fibrosis at baseline was an independent indicator of lower LVEF at follow-up (coefficient [SE], -0.16 [0.07]; P = .03). Among patients with MF and preserved LVEF (42 [55%]), those randomized (21 patients in each arm) to receive ACE inhibitors demonstrated slower MF progression compared with the untreated group (mean [SD] increase of 3.1% [7.4%] vs 10.0% [6.2%] as a percentage of LV mass; P = .001). In multivariate analysis, ACE inhibitor therapy was an independent indicator of decreased MF progression (coefficient [SE], -4.51 [2.11]; P = .04). Patients with MF noted on CMR had a higher probability of cardiovascular events (event rate, 10 of 55 [18.2%] vs 0 of 21 [0%]; log-rank P = .04). In this 2-year, follow-up, randomized clinical trial of patients with Duchenne or Becker muscular dystrophy whose LVEF was preserved and MF was present as determined on CMR, ACE inhibitor therapy was associated with significantly slower progression of MF. The presence of MF was associated with worse patient prognosis. clinicaltrials.org Identifier: NCT02432885.

In order to offer carrier detection, genetic counseling, and prenatal diagnosis to families with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) in our country, segregation analysis of highly polymorphic short tandem repeats (STR) (dC-dA)n: (dG-dT)n loci was utilized. The risks to females of 15 DMD BMD families (9 familial and 6 sporadic) were evaluated on STR, pedigree and serum creatine kinase (SCK) data. From the 36 females at risk of being carriers (not including 8 obligate carriers), results of STR analysis were compatible with carrier status in 7 and not compatible in 20. In 9 females, no information regarding carriership was derived from the STR analysis. Prenatal diagnosis is now possible on the carrier females. Previously identified deletions in the central part of the gene were confirmed by STR analysis in 3 families. Five new alleles were identified in Argentine individuals; allele frequencies differed from those of North American people. Results derived from this study are useful for carrier detection and genetic counseling in DMD/BMD. One case of probable mosaicism in an unaffected father was detected on a pedigree basis in a family with DMD patients.

Background Patients with Duchenne muscular dystrophy (DMD) develop cardiomyopathy (CM) at an earlier age compared to Becker muscular dystrophy (BMD), but the age of onset within each diagnosis is variable. A method to predict CM onset associated with dystrophinopathy could alter therapeutic approaches and improve outcomes. Shortened post-contrast T1 relaxation times are an early marker of myocardial fibrosis and are abnormal in patients with DMD as described in our previous work. To our knowledge, T1 mapping has not been evaluated in BMD patients. We hypothesized that patients with BMD would also have abnormal T1 times and that these abnormalities would precede LV dysfunction. Methods Twenty-six CMR scans from these 2 dystrophinopathy populations (N=5 BMD and N=21 DMD) were compared with 10 CMR scans from control patients without cardiovascular disease. T1 maps were created from the Look-Locker sequence, obtained 10 minutes after gadolinium injection, using MRMap. Using MatLab, T1 times were obtained for every voxel in 6 standard myocardial segments in the short axis at the level of the papillary muscles. Mean T1 times were compared between BMD, DMD and controls using a Kruskal Wallis test. A subset of patients with normal LVEF and dystrophinopathy (BMD or DMD) was compared to controls using a Mann-Whitney U test. Results The mean age of patients was 25.4 ± 8.1 years in the BMD group, 15.7 ± 4.3 years in the DMD group, and 16.9 ± 1.3 years in controls. One patient with BMD and 13 patients with DMD had LVEF < 55%. Two patients from both BMD and DMD had LV dilatation. BMD and DMD patients had significantly shorter mean postcontrast T1 compared with controls (BMD: 355 ms, 95% CI (314, 395), DMD:357 ms, 95% CI (323, 390), control: 420 ms, 95% CI (389, 451), p=0.035) (Figure 1). The subset of BMD and DMD patients and normal LVEF also had a significant decrease in post-contrast T1 when compared to controls (-52.4 ms, 95% CI (-7.2, -97.5), p=0.018) (Figure 2). Conclusions Myocardial post-contrast T1 relaxation times in BMD and DMD are significantly shorter than in controls. They remain significantly decreased in the subset of patients with normal LVEF, suggesting that CMR may have prognostic utility in detecting subclinical myocardial damage associated with loss of dystrophin prior to a decline in LVEF. Further longitudinal study is necessary to evaluate whether T1 times can predict future onset of CM in BMD and DMD. Funding none.