Characteristics of Disease Progression and Genetic Correlation in Ambulatory Iranian Boys With Duchenne Muscular Dystrophy

2021 ◽  
Author(s):  
Gholamreza Zamani ◽  
Sareh Hosseinpour ◽  
Mahmoud Reza Ashrafi ◽  
Mahmoud Mohammadi ◽  
Reza Shervin Badv ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Motor Function ◽  
Pediatric Population ◽  
Disease Onset ◽  
Clinical History ◽  
Disease Diagnosis ◽  
The Mean ◽  
Mutation Type

Abstract Introduction: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in the pediatric population. The manifestations are progressive muscle weakness, impairment in walking and motor function leading to loss of ambulation by age of 13 years. Molecular studies are standard tests for diagnosis. This article describes the status of disease progression and genetic pattern in the Iranian affected boys and furthermore, concerns to find a correlation between the genotype and motor function phenotype of them. Methods This study was performed on 152 DMD patients. Clinical history including disease phenotype, steroid therapy data and the NorthStar Ambulatory Assessment (NSAA) score were all collected. Molecular diagnoses were confirmed by multiplex ligation dependent probe amplification and Next Generation Sequencing tests. Results We studied a total of 152 Iranian DMD patients. The mean age at disease onset was 4.04 ± 2.00 year and the mean age at diagnosis was 5.05 ± 2.08 year. The mean age of loss of ambulatory was 10.9 year. Contracture was seen in 38.9 %. The overall mean of NSAA total score versus age of the patients peaked at 4 year with mean NSAA score of 24. We assessed the yearly changes in the NSAA linear score for all cases based on mutation type and exon site. We found deletion mutation in 79.1%, duplication in 6.8%, nonsense in 12.8%, and splice site in 1.4%. The most common single exon was deletion exon 44 in our patients (5.3%) and the most common multiexon deletion was 45–50 and 45–52 exon equally with 4.6%. This study did not show any correlation between age at disease onset, loss of ambulation age and wheelchair dependency with mutation type but a correlation between contracture with mutation type was found. A significant deference in NSAA score were seen between deletion and nonsense groups at the age of 3 year (P = 0.036) and 3.5 years (p = 0.04). We couldn’t find any correlation among phenotype and Exon site. 91.1% had a history of corticosteroid taking and 54.1% of patient had compliance with rehabilitation. Conclusion This study has demonstrated the phenotype and mutational features of DMD boys and provide information of the disease natural motor history, disease progression and disease diagnosis with the management status of DMD in Iran. Achieved data will encourage the development of clinical trials and advance future molecular therapies in Iran.

scholarly journals Tamoxifen in Duchenne muscular dystrophy (TAMDMD): study protocol for a multicenter, randomized, placebo-controlled, double-blind phase 3 trial

Trials ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Sara Nagy ◽  
Patricia Hafner ◽  
Simone Schmidt ◽  
Daniela Rubino-Nacht ◽  
Sabine Schädelin ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Motor Function ◽  
Primary Endpoint ◽  
Extension Phase ◽  
Open Label ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Open Label Extension

Abstract Background Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder of childhood with a devastating disease course. Several targeted gene therapies and molecular approaches have been or are currently being tested in clinical trials; however, a causative therapy is still not available and best supportive care is limited to oral glucocorticoids with numerous long-term side effects. Tamoxifen is a selective estrogen receptor regulator, and shows antioxidant actions and regulatory roles in the calcium homeostasis besides its antitumor activity. In a mouse model of DMD, oral tamoxifen significantly improved muscle strength and reduced muscle fatigue. This multicenter, randomized, double-blind, placebo-controlled phase III trial aims to demonstrate safety and efficacy of tamoxifen over placebo in pediatric patients with DMD. After completion of the double-blind phase, an open-label extension of the study will be offered to all participants. Methods/design At least 71 ambulant and up to 20 nonambulant patients with DMD are planned to be enrolled at multiple European sites. Patients will be randomly assigned to receive either tamoxifen 20 mg or placebo daily over 48 weeks. In the open-label extension phase, all patients will be offered tamoxifen for a further 48 weeks. The primary endpoint of the double-blind phase is defined as the change of the D1 domain of the motor function measure in ambulant patients or a change of the D2 domain in nonambulant patients under tamoxifen compared to placebo. Secondary outcome measures include change in timed function tests, quantitative muscle testing, and quantitative magnetic resonance imaging of thigh muscles. Laboratory analyses including biomarkers of tamoxifen metabolism and muscle dystrophy will also be assessed. Discussion The aim of the study is to investigate whether tamoxifen can reduce disease progression in ambulant and nonambulant patients with DMD over 48 weeks. Motor function measures comprise the primary endpoint, whereas further clinical and radiological assessments and laboratory biomarkers are performed to provide more data on safety and efficacy. An adjacent open-label extension phase is planned to test if earlier initiation of the treatment with tamoxifen (verum arm of double-blind phase) compared to a delayed start can reduce disease progression more efficiently. Trial registration ClinicalTrials.gov, NCT03354039. Registered on 27 November 2017.

scholarly journals Quantitative muscle ultrasound detects disease progression in Duchenne muscular dystrophy

2017 ◽  
Vol 81 (5) ◽  
pp. 633-640 ◽  
Author(s):  
Craig M. Zaidman ◽  
Jim S. Wu ◽  
Kush Kapur ◽  
Amy Pasternak ◽  
Lavanya Madabusi ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Muscle Ultrasound

scholarly journals Genotype characterization and delayed loss of ambulation by glucocorticoids in a large cohort of patients with Duchenne muscular dystrophy

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Shu Zhang ◽  
◽  
Dongdong Qin ◽  
Liwen Wu ◽  
Man Li ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Hazard Ratio ◽  
Large Cohort ◽  
Muscle Disease ◽  
Clinical Progression ◽  
Large Deletions ◽  
The Mean ◽  
Lower Hazard

Abstract Background Duchenne muscular dystrophy (DMD) is the most common genetic muscle disease in human. We aimed to describe the genotype distribution in a large cohort of Chinese DMD patients and their delayed loss of ambulation by glucocorticoid (GC) treatments. This is to facilitate protocol designs and outcome measures for the emerging DMD clinical trials. Results A total of 1163 patients with DMD were recruited and genotyped. Genotype variations were categorized as large deletions, large duplications, and small mutations. Large deletions were further analyzed for those amenable to exon-skipping therapies. Participants aged 5 years or older were grouped into GC-treated and GC-naïve groups. Clinical progression among different genotypes and their responses to GC treatments were measured by age at loss of ambulation (LOA). Among the mutation genotypes, large deletions, large duplications, and small mutations accounted for 68.79%, 7.14%, and 24.07%, respectively. The mean age at diagnosis was 4.59 years; the median ages at LOA for the GC-naïve, prednisone/prednisolone-treated, and deflazacort-treated groups were 10.23, 12.02, and 13.95 years, respectively. The “deletion amenable to skipping exon 44” subgroup and the nonsense-mutation subgroup had older ages at LOA than the “other deletions” subgroup. Subgroups were further analyzed by both genotypes and GC status. All genotypes showed significant beneficial responses to GC treatment. Deletions amenable to skipping exon 44 showed a lower hazard ratio (0.155). The mean age at death was 18.57 years in this DMD group. Conclusion Genotype variation influences clinical progression in certain DMD groups. Beneficial responses to GC treatment were observed among all DMD genotypes. Compared with other genotypes, deletions amenable to skipping exon 44 had a lower hazard ratio, which may indicate a stronger protective effect of GC treatments on this subgroup. These data are valuable for designing future clinical trials, as clinical outcomes may be influenced by the genotypes.

scholarly journals Respiratory Telerehabilitation of Boys and Young Men with Duchenne Muscular Dystrophy in the COVID-19 Pandemic

2021 ◽  
Vol 18 (12) ◽  
pp. 6179
Author(s):  
Agnieszka Sobierajska-Rek ◽  
Łukasz Mański ◽  
Joanna Jabłońska-Brudło ◽  
Karolina Śledzińska ◽  
Eliza Wasilewska ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Physical Therapy ◽  
Muscular Dystrophy ◽  
Healthcare System ◽  
Online Survey ◽  
Young Men ◽  
The Mean ◽  
Respiratory Exercises

Background: The COVID-19 pandemic forced reorganization of the multidisciplinary healthcare system for Duchenne muscular dystrophy. Digital solutions seem to be optimal for providing rehabilitation at this time. The aim of this study was to investigate whether it is possible to conduct respiratory physical therapy with the use of telerehabilitation in Duchenne muscular dystrophy. Methods: The study was conducted during an online conference for families with DMD. During the physical therapy panel we showed the video with the instructions of respiratory exercises. All participants (n = 152) were asked to fill in the online survey evaluating the quality, acceptance, and understanding of the instructions. Results: The survey was filled in by 45 (29.6%) participants. The mean rating of satisfaction was 4.70/5, and for intelligibility was 4.78/5. Thirty-seven (82.2%) patients declared that they had performed the exercises, all caregivers declared that it was possible to perform the proposed exercises a few times a week or daily, and only two respondents replied to invitations to individual online sessions. Conclusions: Findings from the study show that respiratory telerehabilitation may be implemented for DMD patients; however, the interest in digital rehabilitation among caregivers of DMD boys in Poland is low. The reasons for this situation require further research.

scholarly journals Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

2019 ◽  
Vol 8 ◽  
pp. 204800401987958
Author(s):  
HR Spaulding ◽  
C Ballmann ◽  
JC Quindry ◽  
MB Hudson ◽  
JT Selsby
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Mdx Mice ◽  
Dystrophin Deficiency ◽  
Muscle Wasting Disease ◽  
Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

scholarly journals The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 648
Author(s):  
Andrea L. Reid ◽  
Matthew S. Alexander
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mitochondrial Dysfunction ◽  
Disease Onset ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Muscle Disease ◽  
Mitochondrial Morphology ◽  
Gene Therapies ◽  
Dystrophin Protein

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack of dystrophin in the muscle results in myofiber death, fibrotic infiltration, and mitochondrial dysfunction. There is no cure for DMD, although dystrophin-replacement gene therapies and exon-skipping approaches are being pursued in clinical trials. Mitochondrial dysfunction is one of the first cellular changes seen in DMD myofibers, occurring prior to muscle disease onset and progresses with disease severity. This is seen by reduced mitochondrial function, abnormal mitochondrial morphology and impaired mitophagy (degradation of damaged mitochondria). Dysfunctional mitochondria release high levels of reactive oxygen species (ROS), which can activate pro-inflammatory pathways such as IL-1β and IL-6. Impaired mitophagy in DMD results in increased inflammation and further aggravates disease pathology, evidenced by increased muscle damage and increased fibrosis. This review will focus on the critical interplay between mitophagy and inflammation in Duchenne muscular dystrophy as a pathological mechanism, as well as describe both candidate and established therapeutic targets that regulate these pathways.

scholarly journals Monitoring disease activity noninvasively in the mdx model of Duchenne muscular dystrophy

2018 ◽  
Vol 115 (30) ◽  
pp. 7741-7746 ◽  
Author(s):  
Antonio Filareto ◽  
Katie Maguire-Nguyen ◽  
Qiang Gan ◽  
Garazi Aldanondo ◽  
Léo Machado ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Premature Death ◽  
Response To Therapy ◽  
Luciferase Reporter ◽  
Luciferase Expression ◽  
Muscle Degeneration ◽  
Reporter Strain ◽  
Novel Treatments

Duchenne muscular dystrophy (DMD) is a rare, muscle degenerative disease resulting from the absence of the dystrophin protein. DMD is characterized by progressive loss of muscle fibers, muscle weakness, and eventually loss of ambulation and premature death. Currently, there is no cure for DMD and improved methods of disease monitoring are crucial for the development of novel treatments. In this study, we describe a new method of assessing disease progression noninvasively in the mdx model of DMD. The reporter mice, which we term the dystrophic Degeneration Reporter strains, contain an inducible CRE-responsive luciferase reporter active in mature myofibers. In these mice, muscle degeneration is reflected in changes in the level of luciferase expression, which can be monitored using noninvasive, bioluminescence imaging. We monitored the natural history and disease progression in these dystrophic report mice and found that decreases in luciferase signals directly correlated with muscle degeneration. We further demonstrated that this reporter strain, as well as a previously reported Regeneration Reporter strain, successfully reveals the effectiveness of a gene therapy treatment following systemic administration of a recombinant adeno-associated virus-6 (rAAV-6) encoding a microdystrophin construct. Our data demonstrate the value of these noninvasive imaging modalities for monitoring disease progression and response to therapy in mouse models of muscular dystrophy.

Abstract 19370: Myocardial Extracellular Volume is Elevated in Human Duchenne Muscular Dystrophy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jonathan H Soslow ◽  
Stephen M Damon ◽  
Bruce M Damon ◽  
David A Parra ◽  
W B Burnette ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Age Of Onset ◽  
Extracellular Volume ◽  
Lv Function ◽  
Therapeutic Approaches ◽  
Matrix Expansion ◽  
The Mean ◽  
Normal Lvef ◽  
Extracellular Matrix Expansion

Introduction: Duchenne muscular dystrophy (DMD) leads to cardiomyopathy (CM) with variable severity and age of onset. Predicting early CM would alter therapeutic approaches and improve morbidity and mortality. Extracellular volume (ECV) calculated with cardiac MRI (CMR) quantifies extracellular matrix expansion, including myocardial fibrosis, and has never been reported in human DMD. We hypothesized that subjects with DMD would have abnormal ECV and that these values would correlate with other markers of LV function. Methods: 27 DMD subjects were prospectively studied. CMR included LVEF, late gadolinium enhancement (LGE), circumferential strain (ε cc ), and modified Look-Locker (MOLLI) sequences to calculate ECV maps (in-house software using Matlab). ECV calculated for each segment in the short axis at mid-ventricle and compared with LVEF and ε cc using linear regression. Normal values taken from unmatched cohort of healthy male adults with mean ECV of 0.25 ± 0.015 (range 0.23-0.28). Results: Imaging was adequate to calculate ECV maps in 20 DMD subjects. Mean age in years was 14. Mean LVEF was 52% and mean global ε cc was -14.6%; 11 subjects had LVEF < 55% and 6 had negative LGE. Mean ECV was 0.33 ± 0.05 (0.25-0.45); there was significant intersubject and intersegment variability (Figure 1). When compared with highest mean control ECV (0.28), only one subject had a normal ECV in every segment. In subjects with LVEF ≥ 55%, the mean ECV was 0.32 ± 0.07 (0.25-0.45). In subjects with negative LGE, the mean ECV was 0.28 ± 0.04 (0.25-0.36). The ECV of the inferolateral and anterolateral segments correlated with LVEF (p=0.025 and p<0.001) and the inferolateral ECV correlated with mean ε cc (p=0.025). Conclusions: In this cohort, 19/20 DMD subjects have elevated segmental ECV, even with normal LVEF and negative LGE. Segmental ECV correlates with both LVEF and mean ε cc . ECV may be a more subtle biomarker of early myocardial disease than standard measures such as LVEF and LGE in human DMD.

Abstract 16916: Asymptomatic Patients With Duchenne Muscular Dystrophy Have Elevated Troponin

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Aryaz Sheybani ◽  
Kim CRUM ◽  
Frank J Raucci ◽  
Larry W Markham ◽  
Jonathan H Soslow
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Troponin I ◽  
Statistical Significance ◽  
Myocardial Inflammation ◽  
Gadolinium Enhancement ◽  
Normal Ranges ◽  
Asymptomatic Patients ◽  
Future Drug

Introduction: Cardiomyopathy is the leading cause of death in Duchenne Muscular Dystrophy (DMD), but traditional heart failure biomarkers have limited utility. Cardiac Troponin I (cTnI) has been used in DMD research studies as a marker of toxicity, but little is known about cTnI levels in asymptomatic patients. The goal of this study was to longitudinally evaluate cTnI, NTproBNP, and BNP in an asymptomatic DMD cohort. We hypothesized the biomarkers would not correlate with cardiac function, but some asymptomatic patients would exhibit a cTnI leak, reflecting ongoing myocardial inflammation related to disease progression. Methods: Asymptomatic DMD patients (N=69) and controls with normal cardiac evaluations (N=18) were enrolled. In DMD subjects, biomarker levels were obtained at time of cardiac magnetic resonance imaging (CMR), which included assessment of atrial and ventricular volumes, function, and late gadolinium enhancement (LGE). Normal ranges for biomarkers were created based on control values. Spearman correlation was used for analysis. Results: There was no consistent correlation between biomarkers and disease progression by CMR (Table 1). Several DMD subjects had transiently elevated cTnI (Fig 1). Those with elevated cTnI trended towards being more likely to have LGE on baseline CMR, though this did not reach statistical significance (p= 0.08). Conclusions: CTnI, BNP, and NTproBNP do not correlate with CMR assessment of cardiomyopathy progression. There is a subset of the DMD cohort with asymptomatic cTnI leak. While this cTnI leak is of uncertain clinical significance, it is important to recognize if cTnI is used to assess for cardiac toxicity in future drug trials.

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