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

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.

Download Full-text

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

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18126179 ◽

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.

Download Full-text

Magnetic resonance imaging in a large cohort of facioscapulohumeral muscular dystrophy patients: Pattern refinement and implications for clinical trials

Annals of Neurology ◽

10.1002/ana.24640 ◽

2016 ◽

Vol 79 (5) ◽

pp. 854-864 ◽

Cited By ~ 43

Author(s):

Giorgio Tasca ◽

Mauro Monforte ◽

Pierfrancesco Ottaviani ◽

Marco Pelliccioni ◽

Roberto Frusciante ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Clinical Trials ◽

Magnetic Resonance ◽

Muscular Dystrophy ◽

Facioscapulohumeral Muscular Dystrophy ◽

Large Cohort ◽

Resonance Imaging

Download Full-text

The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy

Life ◽

10.3390/life11070648 ◽

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.

Download Full-text

Duchenne Muscular Dystrophy - Family in a Crisis

Journal of Medicine ◽

10.3329/jom.v10i3.2015 ◽

1970 ◽

pp. 36-39

Author(s):

M Robed Amin ◽

Chowdhury Chironjib Borua ◽

Kaji Shafiqul Alam ◽

Fazle Rabbi Chowdhury ◽

Rabiul Jahan Sarkar ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Case Series ◽

Dystrophin Gene ◽

Muscle Disease ◽

Motor Neuron Diseases ◽

Muscle Diseases ◽

Progressive Muscle Weakness ◽

Recessive Disorders ◽

Dystrophin Protein

Progressive muscular weakness with deformity leading to crippled states develop due to musculoskeletal and neurological disorders. Sometimes it is difficult to differentiate between primary muscle disease and neurological disease. But there is some classical presentation of muscle diseases which have its own entity and thus can be clinically differentiated from neurological disorder especially spinal cord and motor neuron diseases. Muscular dystrophy is one of those disorder with distinct clinical features. Muscular dystrophy refers to a group of genetic, hereditary muscle diseases that cause progressive muscle weakness. Most types of MD are multi-system disorders with manifestations in body systems including skeletal system, the heart, gastrointestinal and nervous systems, endocrine glands, skin, eyes and other organs. Duchenne muscular dystrophy (DMD), is inherited in an X-linked recessive pattern, meaning that the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes, and is thus considered sex-linked. Males are therefore affected by X-linked recessive disorders much more often than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. Duchenne muscular dystrophy and Backers muscular dystrophy are caused by mutations of the gene for the dystrophin protein and lead to an overabundance of the enzyme creatine kinase. The dystrophin gene is the largest gene in humans. In this case series a family with three brothers suffering from Duchenne muscular dystrophy is described and review with literature was done. Â doi:10.3329/jom.v10i3.2015 J Medicine 2009; 10 (Supplement 1): 36-39

Download Full-text

128th ENMC International Workshop on ‘Preclinical optimization and Phase I/II Clinical Trials Using Antisense Oligonucleotides in Duchenne Muscular Dystrophy’ 22–24 October 2004, Naarden, The Netherlands

Neuromuscular Disorders ◽

10.1016/j.nmd.2005.02.007 ◽

2005 ◽

Vol 15 (6) ◽

pp. 450-457 ◽

Cited By ~ 24

Author(s):

Francesco Muntoni ◽

Kate Bushby ◽

Gertjan van Ommen

Keyword(s):

Clinical Trials ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

The Netherlands ◽

Phase I ◽

Antisense Oligonucleotides ◽

International Workshop

Download Full-text

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

Circulation ◽

10.1161/circ.130.suppl_2.19370 ◽

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.

Download Full-text

Laminin-111 protein therapy enhances muscle regeneration and repair in the GRMD dog model of Duchenne muscular dystrophy

Human Molecular Genetics ◽

10.1093/hmg/ddz086 ◽

2019 ◽

Vol 28 (16) ◽

pp. 2686-2695 ◽

Cited By ~ 6

Author(s):

Pamela Barraza-Flores ◽

Tatiana M Fontelonga ◽

Ryan D Wuebbles ◽

Hailey J Hermann ◽

Andreia M Nunes ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Strength ◽

Premature Death ◽

Muscle Disease ◽

Muscle Pathology ◽

Mdx Mouse ◽

Protein Therapy ◽

Muscle Fibrosis ◽

Dog Model

Abstract Duchenne muscular dystrophy (DMD) is a devastating X-linked disease affecting ~1 in 5000 males. DMD patients exhibit progressive muscle degeneration and weakness, leading to loss of ambulation and premature death from cardiopulmonary failure. We previously reported that mouse Laminin-111 (msLam-111) protein could reduce muscle pathology and improve muscle function in the mdx mouse model for DMD. In this study, we examined the ability of msLam-111 to prevent muscle disease progression in the golden retriever muscular dystrophy (GRMD) dog model of DMD. The msLam-111 protein was injected into the cranial tibial muscle compartment of GRMD dogs and muscle strength and pathology were assessed. The results showed that msLam-111 treatment increased muscle fiber regeneration and repair with improved muscle strength and reduced muscle fibrosis in the GRMD model. Together, these findings support the idea that Laminin-111 could serve as a novel protein therapy for the treatment of DMD.

Download Full-text

MRI vastus lateralis fat fraction predicts loss of ambulation in Duchenne muscular dystrophy

Neurology ◽

10.1212/wnl.0000000000008939 ◽

2020 ◽

Vol 94 (13) ◽

pp. e1386-e1394 ◽

Cited By ~ 6

Author(s):

Karin J. Naarding ◽

Harmen Reyngoudt ◽

Erik W. van Zwet ◽

Melissa T. Hooijmans ◽

Cuixia Tian ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Predictive Value ◽

Mixed Model ◽

Cox Model ◽

Medical Center ◽

Vastus Lateralis ◽

Hazard Ratio ◽

Quantitative Mri ◽

Fat Fraction

ObjectiveWe studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchenne muscular dystrophy by assessing the additive predictive value of vastus lateralis (VL) fat fraction (FF) to age on loss of ambulation (LoA).MethodsVL FFs were determined on longitudinal Dixon MRI scans from 2 natural history studies in Leiden University Medical Center (LUMC) and Cincinnati Children's Hospital Medical Center (CCHMC). CCHMC included ambulant patients, while LUMC included a mixed ambulant and nonambulant population. We fitted longitudinal VL FF values to a sigmoidal curve using a mixed model with random slope to predict individual trajectories. The additive value of VL FF over age to predict LoA was calculated from a Cox model, yielding a hazard ratio.ResultsEighty-nine MRIs of 19 LUMC and 15 CCHMC patients were included. At similar age, 6-minute walking test distances were smaller and VL FFs were correspondingly higher in LUMC compared to CCHMC patients. Hazard ratio of a percent-point increase in VL FF for the time to LoA was 1.15 for LUMC (95% confidence interval [CI] 1.05–1.26; p = 0.003) and 0.96 for CCHMC (95% CI 0.84–1.10; p = 0.569).ConclusionsThe hazard ratio of 1.15 corresponds to a 4.11-fold increase of the instantaneous risk of LoA in patients with a 10% higher VL FF at any age. Although results should be confirmed in a larger cohort with prospective determination of the clinical endpoint, this added predictive value of VL FF to age on LoA supports the use of qMRI FF as an endpoint or stratification tool in clinical trials.

Download Full-text