Function In Duchenne Muscular Dystrophy Research Articles

Effectiveness of Inspiratory muscle training using Ultrabreathe on Pulmonary function in Duchenne Muscular Dystrophy

Background: Individual with Duchenne Muscular Dystrophy are more prone for respiratory dysfunction. And thus the leading cause for death DMD. Objective: To find the effectiveness of inspiratory muscle training using ULTRABREATHE on pulmonary function in Duchenne Muscular Dystrophy. Methodology: The quasi experimental study was done in 5 Duchenne Muscular Dystrophy children as one group of age ranging from 9 to 16 years in wheelchair bound stage and they have been given for an ULTRABREATHE as an inspiratory muscle trainer for duration of six weeks. Outcome Measures: Pulmonary Function Test was analyzed using spirometry. Results: Statistical analysis shows, the mean and standard deviation value is 1.5380 and .84736 in pretest and the mean and standard deviation is 1.71 and .88752 with respect to tidal volume which shows significant improvement at p value> 0.038, whereas the other components like Duration of Inspiration, Total Lung Volume/Inspiration Time, Total Lung Volume, Inspiratory Capacity, Inspiration Time/Respiration Time, Forced Vital Capacity and Forced Expiratory Volume in One second (FEV1) not showed an significant improvement. Conclusion: The study concluded that the Effectiveness of inspiratory muscle training using ULTRABREATHE on pulmonary function in Duchenne Muscular Dystrophy children showed improvement only in Tidal Volume whereas all other components not showed a significant improvement.

Reducing sarcolipin expression improves muscle metabolism in mdx mice.

Duchenne muscular dystrophy (DMD) is an inherited muscle wasting disease. Metabolic impairments and oxidative stress are major secondary mechanisms that severely worsen muscle function in DMD. Here, we sought to determine whether germline reduction or ablation of sarcolipin (SLN), an inhibitor of sarco/endoplasmic reticulum (SR) Ca2+ ATPase (SERCA), improves muscle metabolism and ameliorates muscle pathology in the mdx mouse model of DMD. Glucose and insulin tolerance tests show that glucose clearance rate and insulin sensitivity were improved in the SLN haploinsufficient mdx (mdx:sln+/-) and SLN-deficient mdx (mdx:sln-/-) mice. The histopathological analysis shows that fibrosis and necrosis were significantly reduced in muscles of mdx:sln+/- and mdx:sln-/- mice. SR Ca2+ uptake, mitochondrial complex protein levels, complex activities, mitochondrial Ca2+ uptake and release, and mitochondrial metabolism were significantly improved, and lipid peroxidation and protein carbonylation were reduced in the muscles of mdx:sln+/- and mdx:sln-/- mice. These data demonstrate that reduction or ablation of SLN expression can improve muscle metabolism, reduce oxidative stress, decrease muscle pathology, and protects the mdx mice from glucose intolerance.

Investigating the Potential for Sulforaphane to Attenuate Gastrointestinal Dysfunction in mdx Dystrophic Mice.

Gastrointestinal (GI) dysfunction is an important, yet understudied condition associated with Duchenne muscular dystrophy (DMD), with patients reporting bloating, diarrhea, and general discomfort, contributing to a reduced quality of life. In the mdx mouse, the most commonly used mouse model of DMD, studies have confirmed GI dysfunction (reported as altered contractility and GI transit through the small and large intestine), associated with increased local and systemic inflammation. Sulforaphane (SFN) is a natural isothiocyanate with anti-inflammatory and anti-oxidative properties via its activation of Nrf2 signalling that has been shown to improve aspects of the skeletal muscle pathology in dystrophic mice. Whether SFN can similarly improve GI function in muscular dystrophy was unknown. Video imaging and spatiotemporal mapping to assess gastrointestinal contractions in isolated colon preparations from mdx and C57BL/10 mice revealed that SFN reduced contraction frequency when administered ex vivo, demonstrating its therapeutic potential to improve GI function in DMD. To confirm this in vivo, four-week-old male C57BL/10 and mdx mice received vehicle (2% DMSO/corn oil) or SFN (2 mg/kg in 2% DMSO/corn oil) via daily oral gavage five days/week for 4 weeks. SFN administration reduced fibrosis in the diaphragm of mdx mice but did not affect other pathological markers. Gene and protein analysis revealed no change in Nrf2 protein expression or activation of Nrf2 signalling after SFN administration and oral SFN supplementation did not improve GI function in mdx mice. Although ex vivo studies demonstrate SFN’s therapeutic potential for reducing colon contractions, in vivo studies should investigate higher doses and/or alternate routes of administration to confirm SFN’s potential to improve GI function in DMD.

Abstract 10639: Abbreviated Cardiac Magnetic Resonance Imaging versus Echocardiography for Interval Assessment of Systolic Function in Duchenne Muscular Dystrophy: Patient Satisfaction, Clinical Utility and Image Quality

Introduction: Interval assessment of systolic function in patients with Duchenne Muscular Dystrophy (DMD) is challenging by echocardiography (echo). Cardiac magnetic resonance imaging (CMR) has been limited due to study duration and patient experience. We developed an abbreviated CMR (aCMR) protocol which consisted only of cine acquisitions in the short axis, 4 chamber and vertical long axis planes, and compared it to echo in regard to: exam duration, patient satisfaction, clinical utility and image quality scores. Methods: DMD patients were recruited prospectively to undergo simultaneous echo and aCMR. Exclusion criteria included need for continuous positive pressure ventilation (PPV) and inability to lay supine ≥ 30 minutes. Subjects completed a patient satisfaction survey (PSS) comparing modalities. The clinical cardiologist completed a survey (CUS) assessing the clinical utility of each modality. A blinded expert reviewer completed an image quality survey (GQAS) for each modality. Results were compared using the Wilcoxon signed-rank test and Spearman correlation. Results: 19 DMD patients participated. PSS scores and exam duration were equivalent between modalities, while CUS and GQAS scores favored aCMR. ACMR scored particularly higher than echo in RV visualization and judgement of atrial size. Older age had a statistically significant negative correlation with echo GQAS and CUS scores, as well as aCMR PSS scores. Nighttime PPV requirement and non-ambulatory status were associated with worse echo CUS scores. Poor image quality precluding quantification existed in 4 (21%) echo and 0 aCMR studies. Conclusions: The aCMR protocol resulted in improved clinical utility and quality scores relative to echocardiography, without detriment in patient satisfaction or exam duration. For DMD patients known to have challenging echo acoustic windows, aCMR should be considered in lieu of echocardiography for interval assessment of systolic function.

Dystrophin deficiency affects human astrocyte properties and response to damage.

In addition to progressive muscular degeneration due to dystrophin mutations, 1/3 of Duchenne muscular dystrophy (DMD) patients present cognitive deficits. However, there is currently an incomplete understanding about the function of the multiple dystrophin isoforms in human brains. Here, we tested the hypothesis that dystrophin deficiency affects glial function in DMD and could therefore contribute to neural impairment. We investigated human dystrophin isoform expression with development and differentiation and response to damage in human astrocytes from control and induced pluripotent stem cells from DMD patients. In control cells, short dystrophin isoforms were up-regulated with development and their expression levels changed differently upon neuronal and astrocytic differentiation, as well as in 2-dimensional versus 3-dimensional astrocyte cultures. All DMD-astrocytes tested displayed altered morphology, proliferative activity and AQP4 expression. Furthermore, they did not show any morphological change in response to inflammatory stimuli and their number was significantly lower as compared to stimulated healthy astrocytes. Finally, DMD-astrocytes appeared to be more sensitive than controls to oxidative damage as shown by their increased cell death. Behavioral and metabolic defects in DMD-astrocytes were consistent with gene pathway dysregulation shared by lines with different mutations as demonstrated by bulk RNA-seq analysis. Together, our DMD model provides evidence for altered astrocyte function in DMD suggesting that defective astrocyte responses may contribute to neural impairment and might provide additional potential therapeutic targets.

The Efficacy of Naïve versus Modified Mesenchymal Stem Cells in Improving Muscle Function in Duchenne Muscular Dystrophy: A Systematic Review

As one of the most common genetic conditions, Duchenne muscular dystrophy (DMD) is a fatal disease caused by a recessive mutation resulting in muscle weakness in both voluntary and involuntary muscles and, eventually, in death because of cardiovascular failure. Currently, there is no pharmacologically curative treatment of DMD, but there is evidence supporting that mesenchymal stem cells (MSCs) are a novel solution for treating DMD. This systematic review focused on elucidating the therapeutic efficacy of MSCs on the DMD in vivo model. A key issue of previous studies was the material-choice, naïve MSCs or modified MSCs; modified MSCs are activated by culture methods or genetic modification. In summary, MSCs seem to improve pulmonary and cardiac functions and thereby improve survival regardless of them being naïve or modified. The improved function of distal skeletal muscles was observed only with primed MSCs treatment but not naïve MSCs. While MSCs can provide significant benefits to DMD mouse models, there is little to no data on the results in human patients. Due to the limited number of human studies, the differences in study design, and the insufficient understanding of mechanisms of action, more rigorous comparative trials are needed to elucidate which types of MSCs and modifications have optimal therapeutic potential.

Determinants of usage and nonadherence to noninvasive ventilation in children and adults with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to chronic respiratory insufficiency and failure. Use of home noninvasive ventilation (NIV) has been linked to improved outcomes including reduced mortality. Despite the importance of NIV, factors promoting optimal NIV usage and determinants of nonadherence have not been rigorously examined. Moreover, given that respiratory issues in DMD span between childhood and adulthood, examination across a broad age group is needed. The objectives of this study were to (1) evaluate NIV usage across a broad spectrum of patients with DMD, including both children and adults, and (2) identify biological and socioeconomic determinants of NIV usage and NIV nonadherence. We performed a retrospective review of all patients with DMD from February 2016 to February 2020 who underwent evaluation at associated pediatric and adult neuromuscular disease clinics. NIV use was determined objectively from device downloads. A priori, we defined nonadherence as < 4 hours use per night, quantified as the percentage of nights below this threshold across a 30-day period within 6 months of a clinic visit. We also assessed the average hours of NIV usage over this time period. Predictors examined included demographics, social determinants, and pulmonary function. 33 patients with DMD were identified, 29 (87%) of whom were using NIV (13 age < 21 years). Mean age was 22.9 ± 6.6 years (range 13-39 years), body mass index was 23.4 ± 10.4 kg/m2, and seated forced vital capacity was 23% ± 18% predicted. Mean nightly NIV usage was 7.4 ± 3.8 hours and mean percentage of nonadherent nights was 13% ± 30%. In univariable analysis, age did not predict use. Those with lower forced vital capacity had higher NIV usage hours (P = .01) and a trend toward less nonadherence (P = .06). Higher estimated household income demonstrated a trend toward increased usage hours and less nonadherence (both P = .08). Multivariable analysis found increased usage hours were predicted best by higher income, higher inspiratory positive airway pressure, and higher bicarbonate. Nonadherence was higher in those with lower income or higher forced vital capacity. In this cohort of adult and pediatric patients with DMD, most individuals were using NIV. While usage hours were higher with lower lung function, substantial variability remains unexplained by examined factors. Nonadherence was observed in some individuals, including those with advanced disease. Further investigations should focus on evaluating patient-oriented outcomes to define optimal NIV usage across the spectrum of disease and determine strategies to counteract issues with nonadherence. Hurvitz MS, Bhattacharjee R, Lesser DJ, Skalsky AJ, Orr JE. Determinants of usage and nonadherence to noninvasive ventilation in children and adults with Duchenne muscular dystrophy. J Clin Sleep Med. 2021;17(10):1973-1980.

Instruments to assess upper‐limb function in children and adolescents with neuromuscular diseases: a systematic review

To synthesize clinical and scientific evidence regarding the instruments available to assess upper-limb function in paediatric patients with neuromuscular disease (NMD). This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines (Prospective Registry of Systematic Reviews no. CRD42020140343). Two independent reviewers searched the PubMed/MEDLINE, LILACS, Embase, and Scopus databases. Inclusion criteria were cross-sectional or longitudinal studies or randomized controlled trials that used scales or questionnaires to assess upper-limb function in paediatric patients with NMDs. The COSMIN Risk of Bias checklist and criteria for good measurement properties were applied to assess the methodological quality of the instruments. In total, 34 articles and 12 instruments were included. The Brooke Upper Extremity (n=16) and Performance of Upper Limb (PUL) (n=12) instruments were the most used tools. The PUL and Duchenne muscular dystrophy (DMD) Upper Limb patient-reported outcome measures (PROMs) tested more measurement properties and provided higher methodological quality scores for patients with DMD. Likewise, the Revised Upper Limb Module (RULM) was the most suitable instrument for patients with spinal muscular atrophy. No instrument has been devised to assess upper-limb function in patients with Charcot-Marie-Tooth disease and no other disease-specific instruments were found. The PUL, DMD Upper Limb PROM, and RULM are the most suitable instruments to assess upper-limb function in the two most prevalent paediatric NMDs. The identified gaps and methodological flaws of the available instruments indicate a need to develop high-quality instruments to assess other types of paediatric NMDs. What this paper adds The most suitable observer-rater instrument to assess upper-limb function in Duchenne muscular dystrophy (DMD) is the Performance of Upper Limb. The most suitable observer-rater instrument to assess upper-limb function in spinal muscular atrophy is the Revised Upper Limb Module. The DMD Upper Limb patient-reported outcome measure is recommended to assess the upper-limb performance of patients with DMD. Literature gaps and methodological flaws indicate the need to develop high-quality instruments to assess other types of paediatric neuromuscular disease.

BODY-MASS INDEX AND BLOOD PRESSURE AS DISEASE MODIFIERS IN DYSTROPHINIC CARDIOMYOPATHY

Objective: Introduction: Duchenne muscular dystrophy (DMD) is one of many neuromuscular diseases, that commonly creates severe disability and early death. Cardiomyopathy associated with DMD is an increasingly acknowledged presentation of this neuromuscular disorder, significantly increasing morbidity and mortality, as well as the requirement for cardiological treatment. Design and method: Purpose: is to review literature data relatively the presence of elevated blood pressure values and body mass index in children with DMD and their impact on the development of heart disease. Results: Several studies have published cross-sectional data about the prevalence of hypertension and increased BMI in children with DMD. Wong et al., 2017 reported that 25.5% of patients on daily steroids aged 10–13 years had systolic hypertension. In patients aged 13–16 years, they reported systolic hypertension in 10.3% of patients. Corticosteroid treatment is thus an essential part of the standards of care in DMD and is recommended from the age of 4 to 5 years onward. Ricotti et al., 2013 observed hypertension in 5% of the patients aged 3–15 years on intermittent steroids while in a study by Braat et al., 2015, 45% of the patients had hypertension. In N.M. van de Velde et al., 2019, study increased BMI, but not systolic blood pressure, was related to early myocardial deformation defined by peak systolic GLS in young DMD patients &lt; 11 years of age. Prevalence of obesity has been described up to 73% in steroid-native DMD patients &lt; 13 years and higher BMI was associated with longer duration and higher cumulative dose in ambulant DMD patients using prednisone (Lamb et al., 2016). In Barber et al. study, 2013 use of corticosteroids has managed to prolongation of the ambulant stage in DMD by almost 3 years. It has also been correlated with a delayed onset of dystrophinic cardiomyopathy in Markham et al., 2008 and Davidson et al., 2014 studies. Conclusions: The results of this review suggest that factors influencing afterload, such as increased blood pressure and BMI, may play a role in the deterioration of cardiac function in DMD.

Abstract 14890: Diagnosing Duchenne Muscular Dystrophy-Associated Cardiomyopathy: Echocardiogram Shoots, Cardiac Magnetic Resonance Imaging Scores

Background: Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder characterized by progressive muscle degeneration. The leading cause of death is complications from the development of DMD-associated cardiomyopathy. The majority of DMD patients have skeletal abnormalities that limit the quality of echocardiograms (ECHO). Although cardiac magnetic resonance imaging (cMRI) is the gold standard cardiac imaging tool, the vast majority of DMD patients are evaluated by ECHO rather than cMRI. We hypothesized that when compared to ECHO, cMRI more accurately assesses cardiac function and provides more valuable data for the diagnosis of DMD-associated cardiomyopathy. Methods: We undertook a retrospective study of 20 DMD patients referred to the UT Southwestern Adult Neuromuscular Cardiomyopathy Clinic who had undergone both an ECHO and cMRI within 15 months of each other. We assessed the proportion of studies demonstrating reduced left ventricular (LV) function [cMRI LVEF&lt;62%, ECHO fractional shortening (FS)&lt;25%] and that were technically difficult by both techniques. In addition, we assessed the proportion of cMRIs with late gadolinium enhancement (LGE), a marker of myocardial fibrosis and associated with increased mortality. Results: Amongst these patients, 10% of cMRIs and 85% of ECHOs were technically difficult. By cMRI, 30% of the studies were normal (LVEF 64±2 %), while 70% showed reduced function (LVEF: 44±12%). By ECHO, 75% of the studies were normal (FS 32±5), while 25% showed reduced function (FS: 15±8). Of the patients with truly reduced function by cMRI, 64% were considered normal by ECHO. Finally, 61% of cMRI studies showed LGE (50% with normal LVEF and 67% with reduced LVEF). Conclusions: In summary, cMRI is superior to ECHO in assessing cardiac function in DMD. ECHO underestimates left ventricular dysfunction, likely due to the poor quality of studies obtained in this patient population. In addition, cMRI identifies LGE, a marker associated with increased mortality, irrespective of cardiac function. Earlier utilization of cMRI will expedite the diagnosis of DMD-associated cardiomyopathy and enable the cardiologist to initiate aggressive guideline-directed medical therapy at an earlier age.

The BDNF rs6265 Polymorphism is a Modifier of Cardiomyocyte Contractility and Dilated Cardiomyopathy.

Brain-derived neurotrophic factor (BDNF) is a neuronal growth and survival factor that harbors cardioprotective qualities that may attenuate dilated cardiomyopathy. In ~30% of the population, BDNF has a common, nonsynonymous single nucleotide polymorphism rs6265 (Val66Met), which might be correlated with increased risk of cardiovascular events. We previously showed that BDNF correlates with better cardiac function in Duchenne muscular dystrophy (DMD) patients. However, the effect of the Val66Met polymorphism on cardiac function has not been determined. The goal of the current study was to determine the effects of rs6265 on BDNF biomarker suitability and DMD cardiac functions more generally. We assessed cardiovascular and skeletal muscle function in human DMD patients segregated by polymorphic allele. We also compared echocardiographic, electrophysiologic, and cardiomyocyte contractility in C57/BL-6 wild-type mice with rs6265 polymorphism and in mdx/mTR (mDMD) mouse model of DMD. In human DMD patients, plasma BDNF levels had a positive correlation with left ventricular function, opposite to that seen in rs6265 carriers. There was also a substantial decrease in skeletal muscle function in carriers compared to the Val homozygotes. Surprisingly, the opposite was true when cardiac function of DMD carriers and non-carriers were compared. On the other hand, Val66Met wild-type mice had only subtle functional differences at baseline but significantly decreased cardiomyocyte contractility. Our results indicate that the Val66Met polymorphism alters myocyte contractility, conferring worse skeletal muscle function but better cardiac function in DMD patients. Moreover, these results suggest a mechanism for the relative preservation of cardiac tissues compared to skeletal muscle in DMD patients and underscores the complexity of BDNF signaling in response to mechanical workload.

MUSCLE IMAGING – MRI: P.167 Last but not least: preserved thenar muscles in non-ambulant Duchenne muscular dystrophy patients

Hand function in Duchenne muscular dystrophy (DMD) is preserved relatively long, and is crucial for daily-life activities of non-ambulant patients such as operating a wheelchair. As a potential target for therapy, it is important to know to what extent intrinsic hand muscles are affected. We used quantitative MRI (qMRI) to study the relation between thenar muscle fat fraction (FF), total volume (TV), contractile volume (CV), T2 of muscle (T2water) and pinch strength. Seventeen non-ambulant DMD patients (range 10.2-24.1 years) and 13 healthy controls (HC; range 9.5-25.4 years) underwent qMRI of the right hand at 3T while positioned on their right side.

PTEN Inhibition Ameliorates Muscle Degeneration and Improves Muscle Function in a Mouse Model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is caused by a mutation of the muscle membrane protein dystrophin and characterized by severe degeneration of myofibers, progressive muscle wasting, loss of mobility, and, ultimately, cardiorespiratory failure and premature death. Currently there is no cure for DMD. Herein, we report that skeletal muscle-specific knockout (KO) of the phosphatase and tensin homolog (Pten) gene in an animal model of DMD (mdx mice) alleviates myofiber degeneration and restores muscle function without increasing tumor incidence. Specifically, Pten KO normalizes myofiber size and prevents muscular atrophy, and it improves grip strength and exercise performance in mdx mice. Pten KO also reduces fibrosis and inflammation, and it ameliorates muscle pathology in mdx mice. Unbiased RNA sequencing reveals that Pten KO upregulates extracellular matrix and basement membrane components positively correlated with wound healing and suppresses negative regulators of wound healing and lipid biosynthesis, thus improving the integrity of muscle basement membrane at the ultrastructural level. Importantly, pharmacological inhibition of PTEN similarly ameliorates muscle pathology and improves muscle integrity and function in mdx mice. Our findings provide evidence that PTEN inhibition may represent a potential therapeutic strategy to restore muscle function in DMD.

Assessing the effect of non-invasive ventilation on cardiac function in Duchenne muscular dystrophy requires prospective studies.

Assessing the effect of non-invasive ventilation on cardiac function in Duchenne muscular dystrophy requires prospective studies.

Contribution of TRPC Channels to Intracellular Ca2 + Dyshomeostasis in Smooth Muscle From mdx Mice.

Duchenne muscular dystrophy (DMD) is an irreversible muscle disease characterized by a progressive loss of muscle function, decreased ambulation, and ultimately death as a result of cardiac or respiratory failure. DMD is caused by the lack of dystrophin, a protein that is important for membrane stability and signaling in excitable cells. Although vascular smooth muscle cells (VSMCs) dysfunction occurs in many pathological conditions, little is known about vascular smooth muscle function in DMD. We have previously shown that striated muscle cells, as well as neurons isolated from dystrophic (mdx) mice have higher intracellular Ca2+ ([Ca2+]i) and Na+ ([Na+]i) concentrations and decreased cell viability in comparison with wild type (Wt). Experiments were carried out in isolated VSMCs from mdx (a murine model of DMD) and congenic C57BL/10SnJ Wt mice. We found elevated [Ca2+]i and [Na+]i in VSMCs from mdx mice compared to Wt. Exposure to 1-oleoyl-2-acetyl-sn-glycerol (OAG), a TRPC3 and TRPC6 channel activator, induced a greater elevation of [Ca2+]i and [Na+]i in mdx than Wt VSMCs. The OAG induced increases in [Ca2+]i could be abolished by either removal of extracellular Ca2+ or by SAR7334, a blocker of TRPC3 and TRPC 6 channels in both genotypes. Mdx and Wt VSMCs were susceptible to muscle cell stretch-induced elevations of [Ca2+]i and [Na+]i which was completely inhibited by GsMTx-4, a mechanosensitive ion channel inhibitor. Western blots showed a significant upregulation of TRPC1 -3, -6 proteins in mdx VSMCs compare to age-matched Wt. The lack of dystrophin in mdx VSMCs produced a profound alteration of [Ca2+]i and [Na+]i homeostasis that appears to be mediated by TRPC channels. Moreover, we have been able to demonstrate pharmacologically that the enhanced stretch-induced elevation of intracellular [Ca2+] and concomitant cell damage in mdx VSMCs also appears to be mediated through TRPC1, -3 and -6 channel activation.

Risk Factors for Cardiac and Non-cardiac Causes of Death in Males with Duchenne Muscular Dystrophy.

As survival and neuromuscular function in Duchenne muscular dystrophy (DMD) have improved with glucocorticoid (GC) therapy and ventilatory support, cardiac deaths are increasing. Little is known about risk factors for cardiac and non-cardiac causes of death in DMD. A multi-center retrospective cohort study of 408 males with DMD, followed from January 1, 2005 to December 31, 2015, was conducted to identify risk factors for death. Those dying of cardiac causes were compared to those dying of non-cardiac causes and to those alive at study end. There were 29 (7.1%) deaths at a median age of 19.5 (IQR: 16.9-24.6) years; 8 (27.6%) cardiac, and 21 non-cardiac. Those living were younger [14.9 (IQR: 11.0-19.1) years] than those dying of cardiac [18 (IQR 15.5-24)years, p = 0.03] and non-cardiac [19 (IQR: 16.5-23)years, p = 0.002] causes. GC use was lower for those dying of cardiac causes compared to those living [2/8 (25%) vs. 304/378 (80.4%), p = 0.001]. Last ejection fraction prior to death/study end was lower for those dying of cardiac causes compared to those living (37.5% ± 12.8 vs. 54.5% ± 10.8, p = 0.01) but not compared to those dying of non-cardiac causes (37.5% ± 12.8 vs. 41.2% ± 19.3, p = 0.58). In a large DMD cohort, approximately 30% of deaths were cardiac. Lack of GC use was associated with cardiac causes of death, while systolic dysfunction was associated with death from any cause. Further work is needed to ensure guideline adherence and to define optimal management of systolic dysfunction in males with DMD with hopes of extending survival.

Use of a wearable device to assess sleep and motor function in Duchenne muscular dystrophy

Rest-activity disruption is an important feature of Duchenne muscular dystrophy (DMD). We sought to describe sleep impairment and its relationship to quality of life (QOL) and to evaluate associations between rest-activity, sleep quality, and 6-minute walk test (6MWT) in DMD. Sleep impairment and its relationship to QOL was assessed by questionnaire in 54 children (33 ambulatory, 21 nonambulatory) with DMD. Rest-activity characteristics were calculated for 23 of these children (14 ambulatory, nine nonambulatory) by actigraphy. Pathologic sleep was reported in 11 (20%) participants and correlated with lower QOL but not with ambulatory status. In ambulatory participants who completed actigraphy, rest-activity rhythm fragmentation was associated with subjective sleep impairment. Habitual daytime activity level was associated with 6MWT performance. Children with DMD experience substantial sleep impairment that is related to QOL. Wrist actigraphy may be a parsimonious tool for monitoring both sleep and motor impairment in ambulatory children with DMD.

Muscle Magnetic Resonance Imaging versus Clinical Function in Duchenne Muscular Dystrophy

Muscle Magnetic Resonance Imaging versus Clinical Function in Duchenne Muscular Dystrophy

EP.65Normal respiratory function in a young adult with Duchenne muscular dystrophy – the possible role of supplements

Idebenone has been shown to stabilize lung function in Duchenne muscular dystrophy (DMD) boys who are steroid naïve when given over 12 months. An ongoing clinical trial is currently running in DMD on steroids. We present a non-ambulant DMD, whose parents self-prescribed Idebenone and flavonoid-based supplement from the age of 13.5 and 14 respectively, since that time he has maintained normal lung function at 17 years, with no evidence of decline: Forced Vital Capacity (FVC) was 3.08 litres (98% corrected for height) and peak cough flow was 324l/min. Dystrophin analysis showed duplication exons 18-30. Intermittent prednisolone (0.7mg/kg) was started at 9 years then switched to daily deflazacort (0.46 mg/dl) at 11.5 years and maintained at a stable dose ever since. Loss of ambulation occurred at 13 years. At 13.5 years, the patient was diagnosed with pubertal delay and glucose intolerance and Metformin 250 mg twice/day and testosterone IM 25 mg monthly were started. At the same age, idebenone 400 mg daily was administered and six months later an oral flavonoid-based supplement was added. His lung function at that age was beyond expected with FVC 2.66 litres (108%) and a sleep study excluded sleep disordered breathing. Despite the progressive motor function deterioration and the reduction of steroids dose per weight, this patient has maintained, over time, normal respiratory function both in terms of lung volumes and in terms of good airway clearance and absence of respiratory infections. Moreover, his latest sleep study at the age of 17 showed a normal gas exchange and absence of any upper airway obstruction. This report highlights the need for careful review of all the medications DMD patients are taking, particularly supplements commonly available over the counter that can impact on some disease features. This will be relevant both during the regular follow up assessments and during the screening phase of clinical trials.

Abstract 184: Cardioprotective Effects of Brain-derived Neurotrophic Factor rs6265 Polymorphism in Duchenne Cardiomyopathy

We previously identified brain-derived neurotrophic factor (BDNF) as a putative cardiac-specific biomarker for preserved cardiac function in Duchenne Muscular Dystrophy (DMD). BDNF has cardioprotective qualities that may attenuate dilated cardiomyopathy, and a common, functional BDNF single nucleotide polymorphism rs6265 (Val66-Met) may be correlated with increased risk of cardiovascular events. We hypothesized that BDNF is protective in the setting of DMD and that BDNF’s beneficial effects are diminished in rs6265 allelic carriers. We compared circulating BDNF levels with cardiovascular and skeletal muscle functional parameters in DMD patients stratified by carrier status. Positive association of circulating BDNF with left ventricular ejection fraction in DMD patients was restricted to non-carriers of the rs6265 allele, whereas carriers exhibited worse cardiac function with increased BDNF, more fibrosis and worse skeletal muscle function. To more directly assess association of rs6265 with cardiac function, we used mice with knock-in of BDNF polymorphic Val66Met allele. RNASeq showed higher expression of extracellular matrix genes in Val66Met hearts, and there was a negative correlation of cardiac BDNF protein levels with fibrosis. Additionally, there were baseline echocardiographic and ECG differences, and isolated cardiomyocytes had decreased contractility. This overall cardiac phenotype was substantially enhanced when Val66Met mice were crossed with muscular dystrophy mice. Considered together, our results indicate that BDNF plays a protective role in the dystrophic heart and may represent a novel therapeutic candidate for DMD cardiomyopathy.