Adult Duchenne Muscular Dystrophy Research Articles

359VP Social difficulties and care burden of adult Duchenne muscular dystrophy in Japan: A questionnaire survey based on the Japanese Registry of muscular dystrophy (Remudy)

359VP Social difficulties and care burden of adult Duchenne muscular dystrophy in Japan: A questionnaire survey based on the Japanese Registry of muscular dystrophy (Remudy)

356P A retrospective review of adult Duchenne muscular dystrophy patients in a UK centre of excellence and report the results of adherence to the standards of care guidelines for cardiac management

356P A retrospective review of adult Duchenne muscular dystrophy patients in a UK centre of excellence and report the results of adherence to the standards of care guidelines for cardiac management

Social difficulties and care burden of adult Duchenne muscular dystrophy in Japan: a questionnaire survey based on the Japanese Registry of Muscular Dystrophy (Remudy).

Little is known about the social difficulties and health care needs of adult Duchenne muscular dystrophy (DMD) patients in Japan, as well as the financial and physical stress experienced by their caregivers. This study aimed to clarify the social circumstances surrounding adult DMD patients and assess the degree of involvement of family members in their care and the associated economic burden of the disorder in Japan. Adult DMD patients were identified through the Registry of Muscular Dystrophy (Remudy) in Japan and invited to complete a questionnaire together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate the costs associated with DMD from social and caregiver household perspectives. In total, 234 (63.7%) of 367 adult DMD patients (mean age, 27.4 ± 6.0; range, 20-48years) completed the questionnaire. Of these, 38 (21%) had developmental disorders (mental retardation, autism, and learning disorders), 57 (33%) experienced bullying in school, and 44 (77%) indicated the reason for bullying to be their physical handicap. Employment histories were noted by 72 (31%), although 23 (10%) lost their jobs mainly due to physical difficulties. Of the 234 patients, 164 (74%) lived with their relatives, and 78% of care time was supplied by family members, in particular, their mothers. The mean rate of care work provided by family members was 81%. Household income of families with an adult DMD patient was lower, whereas the rate of living with parent(s) and grandparent(s) was higher, in comparison with the general Japanese population. Adult DMD patients in Japan experience many social difficulties from childhood up to adulthood. As adults, many DMD patients experience bullying and workplace difficulties. Families were found to provide most of the care and financial support for DMD patients. Our results suggest the need to improve public patient care systems, including financial support, to address the physical and economic burdens of care for adult DMD patients in Japan.

Age Related Burden of Swallowing in Adult Patients Affected by Duchenne Muscular Dystrophy.

In Duchenne muscular dystrophy (DMD), dysphagia is a common but often overlooked symptom, which may affect quality of life (QoL). Its possible causes are progressive deterioration of muscle groups involved in swallowing function (oropharyngeal, inspiratory muscles) or impairment of autonomic function. In adult patients with DMD, we aimed to identify predictors of swallowing-related QoL and to compare swallowing-related QoL at different ages. Forty-eight patients aged 30.0±6.6 years were enrolled. Questionnaires were administered: the Swallowing Quality of Life questionnaire (SWAL-QOL) for swallowing-related QoL assessment, and the Compass 31 for autonomic symptoms assessment. The Brooke Upper Extremity Scale was used for upper limbs muscular function assessment. Respiratory and muscle function tests were performed, including spirometry, arterial blood gases, polysomnography, maximal inspiratory pressure (MIP), maximal expiratory pressure and sniff nasal inspiratory pressure. An abnormal composite SWAL-QOL score (≤86) was found in 33 patients. Autonomic symptoms were mild, while a severe impairment was shown by the Brooke Upper Extremity Scale. Spirometry and muscle strength tests demonstrated severe alterations, while diurnal and nocturnal blood gases were normal, due to effective use of noninvasive ventilation. Independent predictors of the composite SWAL-QOL score were age, MIP and Compass 31. A MIP < 22 had an accuracy of 92% in predicting altered swallowing-related QoL. The composite SWAL-QOL score was worse in subjects > 30 years old than in younger patients (64.5±19.2 vs 76.6±16.3, p < 0.02), due to worse scores in items pertinent to mental and social functioning; scores in domains pertinent to the physical function were similar in both groups. In adult DMD, swallowing-related QoL, which is altered in most patients, can be predicted by age, inspiratory muscles strength and autonomic dysfunction symptoms. While swallowing function is already altered in young patients, swallowing-related QoL can progressively worsen with advancing age due to psychological and social factors.

Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from Duchenne Muscular Dystrophy Patients.

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene and dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality in DMD patients. We tested the hypothesis that DCM is caused by metabolic impairments by employing induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from four DMD patients; an adult male, an adult female, a 7-year-old (7y) male and a 13-year-old (13y) male, all compared to two healthy volunteers. To test the hypothesis, we measured the bioenergetics, metabolomics, electrophysiology, mitochondrial morphology and mitochondrial activity of CMs, using respirometry, LC–MS, patch clamp, electron microscopy (EM) and confocal microscopy methods. We found that: (1) adult DMD CMs exhibited impaired energy metabolism and abnormal mitochondrial structure and function. (2) The 7y CMs demonstrated arrhythmia-free spontaneous firing along with “healthy-like” metabolic status, normal mitochondrial morphology and activity. In contrast, the 13y CMs were mildly arrhythmogenic and showed adult DMD-like bioenergetics deficiencies. (3) In DMD adult CMs, mitochondrial activities were attenuated by 45–48%, whereas the 7y CM activity was similar to that of healthy CMs. (4) In DMD CMs, but not in 7y CMs, there was a 75% decrease in the mitochondrial ATP production rate compared to healthy iPSC-CMs. In summary, DMD iPSC-CMs exhibit bioenergetic and metabolic impairments that are associated with rhythm disturbances corresponding to the patient’s phenotype, thereby constituting novel targets for alleviating cardiomyopathy in DMD patients.

Frontal lobe-dominant cerebral blood flow reduction and atrophy can be progressive in Duchenne muscular dystrophy

This study aimed to clarify the characteristics and progressive changes of brain image abnormalities in Duchenne muscular dystrophy (DMD). Brain images of 39 adult patients (median age, 24 years) were retrospectively reviewed, along with intellectual and/or neurodevelopmental test results. On magnetic resonance imaging (n = 13), atrophy of the frontal lobe, pars opercularis (without other frontal atrophy), and cerebellum was observed in 6, 1, and 1 patients, respectively. On computed tomography (n = 32), atrophy of the frontal lobe, pars opercularis, temporal lobe, and occipital lobe was observed in 20, 1, 1, and 1 patients, respectively. Re-imaging of 12 patients revealed progression of cerebral atrophy in 6. All 18 patients who underwent single photon emission computed tomography had reduced total and/or focal blood flow. Reduced total cerebral blood flow was observed significantly more frequently in patients with deleterious Dp140 mutations compared to those without. Re-examination 4 years later revealed worsening of reduced blood flow in the frontotemporal lobe in 1 patient. Abnormalities were detected by at least one imaging modality in 32 of 39 patients. No significant relationship was observed between imaging abnormalities and developmental disorders or intelligence quotient. In conclusion, DMD patients frequently exhibit frontal lobe-dominant cerebral blood flow reduction and atrophy, and may be at risk of progressive cerebral atrophy and reduced cerebral blood flow. MRI, CT, and/or brain single photon emission CT are useful for detecting brain abnormalities in adult DMD patients.

Image Viability of Echocardiography in Adult Patients with Duchenne Muscular Dystrophy

Increasingly, patients with Duchenne Muscular Dystrophy (DMD) are surviving to adulthood, requiring monitoring for DMD-related cardiomyopathy. Transthoracic echo (TTE) parameters, including LV ejection fraction, fractional shortening and LV end-diastolic diameter have been recommended to detect DMD-related cardiomyopathy. We examined the viability of obtaining these parameters, and the proportion of adult DMD patients on medications for cardiomyopathy. From 2000–2021 at a tertiary Australian hospital, 53 patients with DMD were identified. The number of patients who had a TTE, technical difficulty, echocardiographic parameters and medication data were obtained. Of the 53 patients, only 29 patients had TTE studies (54.7%). In 84% of these, the TTE was described as technically difficult due to the patient being wheelchair-bound, having severe scoliosis or respiratory failure. Other than LVEDD, no parameter was successfully obtained at a high frequency. The mean fractional shortening was 27.4+/-10.1% and the mean LVEDD was 4.4+/-1.9 cm. None of the 53 patients had a cardiac MRI scan performed as an alternate imaging modality. ACE inhibitors & ARBs (87%) were the most commonly prescribed medications at time of TTE, followed by beta blockers (31%). Although TTE is recommended for DMD patients, images are often difficult to reliably obtain. Failure to identify heart failure may reduce prescription of essential medications in this high-risk population.Tabled 1TTE parameterRecordedDifficult study61 (84%)Fractional shortening35 (48%)Ejection fraction (Simpson’s bi-plane)18 (25%)LV end-diastolic diameter60 (82%)LA diameter44 (60%)E/A ratio42 (58%)Global longitudinal strain0 (0%) Open table in a new tab

Psychosocial adjustment in adults with Duchenne muscular dystrophy: A pilot study on a shortened parent-report questionnaire

The primary aim of this study was to describe the psychometric properties of an adult revision of the 28 item Personal Adjustment and Role Skills Scale (PARS-III). This scale was originally developed to assess psychosocial adjustment in children 4–18 years of age and has been applied in boys with Duchenne muscular dystrophy (DMD) and was found to be reliable and valid. Within the context of a longer lifespan in dystrophinopathies there is a growing need to assess psychosocial adjustment in an adult population. The original 28 items questionnaire was administered to parents of 90 adult men with DMD. The items of the PARS-III were rated by three experts, one parent, and one adult with DMD to indicate appropriateness of the items. For 22 items, there was consensus among the raters. Results of the Confirmatory Factor Analysis show an acceptable fit and closely resembles the original factor structure of the PARS-III, thereby justifying the use of the previously identified six subscales of psychosocial adjustment. In conclusion, the current 22 item PARS-Adult is a valuable, reliable, and valid screening of psychosocial adjustment in adult DMD patients. With this tool, continuity of assessment and follow up can be guaranteed in this clinical population.

Leadless intracardiac transcatheter pacing system: 20 months follow up in adult Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked muscular dystrophy in relation with dystrophin deficient. Heart and respiratory function are classically involved and affect long-term prognosis. Significant atrio-ventricular block may occur in some patients. Implantation of traditional pacemaker may be challenging in patients with tracheotomy and on permanent home mechanical ventilation. We report the first case of a successful leadless intra-cardiac trans-catheter pacing system implantation in an adult DMD on wheelchair and on permanent home mechanical ventilation.

Nutritional status, swallowing disorders, and respiratory prognosis in adult Duchenne muscular dystrophy patients.

Malnutrition and swallowing disorders are common in Duchenne muscular dystrophy (DMD) patients. We assessed, in adult DMD with home mechanical ventilation (HMV) and cough assist device, its prevalence and the relationships with respiratory muscle strength and long-term respiratory prognosis. We reviewed the patients (n = 117, age 18-39 years [median 24]), followed in a reference center, from 2006 to 2015, to obtain clinical baseline, nutritional status, vital capacity (VC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP). The median body mass index (BMI) was low (15.6 kg/m²). Included patients had severe restrictive respiratory function with a median VC of 10.5% [7-17] of the predicted value. All patients were on HMV. Prevalence of malnutrition, swallowing disorders, and gastrostomy were respectively 62%, 34%, and 11%. BMI and serum albumin level were significantly associated with MIP, MEP, and VC. The 1-year/5-years cumulative incidences of respiratory events (pulmonary sepsis and acute respiratory distress) were, respectively, 20.7%/44.5%. Using univariate analysis, predictive factors for respiratory events were swallowing disorders (p = .001), transthyretinemia (p = .034), MIP (p = .039), and MEP (p = .03) but not BMI or albuminemia. Using multivariate analysis, only swallowing disorders remained significantly associated with respiratory events (OR = 4.2, IC 95% 1.31-12.2, p = .01). In conclusion, this study highlights the interrelationships between nutritional intake, swallowing function, airway clearance, and respiratory function in adult DMD. A multidisciplinary approach focusing on these previous factors is essential to optimize DMD patient health.

Expert recommendation: treatment of nonambulatory patients with Duchenne muscular dystrophy

HintergrundDie Muskeldystrophie Duchenne (DMD) ist die häufigste genetische neuromuskuläre Krankheit im Kindesalter, bei der es meist im Alter von 9 bis 11 Jahren zum Verlust der Gehfähigkeit kommt.Ziel der Arbeit und Material und MethodenAuf der Grundlage aktueller Leitlinien und Studien erarbeiteten neuropädiatrische und neurologische Experten im Rahmen eines von der Firma PTC Therapeutics GmbH (Frankfurt am Main, Deutschland), die die Substanz Ataluren vertreibt, gesponserten Advisory Boards Empfehlungen zur Behandlung nichtgehfähiger Patienten mit DMD mit Schwerpunkt medikamentöse Therapien von Erwachsenen.Ergebnisse und DiskussionDer Verlust der Gehfähigkeit wird in Studien sehr unterschiedlich definiert und bezieht sich u. a. auf die Rollstuhlpflicht, das selbständige Gehen ohne Hilfsmittel oder die maximale Gehstrecke. Grundlage der Therapie von Patienten mit DMD in jedem Krankheitsstadium sind supportive und symptomatische Maßnahmen, die in der Regel auch nach dem Verlust der Gehfähigkeit intensiv weitergeführt werden sollten. Zusätzlich stehen den Patienten medikamentöse Therapien mit dem Ziel der Modifikation des Krankheitsverlaufes zur Verfügung. Glukokortikoide bilden den Stützpfeiler der medikamentösen Therapie auch über den Verlust der Gehfähigkeit hinaus, dann meist in reduzierter Dosis. Für Patienten mit DMD aufgrund einer Nonsense-Mutation (nmDMD), ca. 13 % aller DMD-Patienten, steht Ataluren als potenziell dystrophinwiederherstellende, krankheitsmodifizierende Therapie zur Verfügung; klinische Daten aus dem STRIDE-Register zeigen eine verzögerte Krankheitsprogression auch nach Verlust der Gehfähigkeit. Zum Exon-Skipping liegen für erwachsene Patienten derzeit noch keine belastbaren Daten vor. Das Antioxidans Idebenon kommt bei nichtgehfähigen, jugendlichen Patienten ohne therapeutische Alternative, die nicht mit Glukokortikoiden behandelt werden können, infrage. Ataluren eignet sich zur kombinierten Behandlung mit Glukokortikoiden, eine Kombination von Idebenon und Glukokortikoiden wird derzeit in einer klinischen Studie überprüft. Eine Add-on-Therapie mit Idebenon zusätzlich zu Ataluren ist bei nichtgehfähigen nmDMD-Patienten zu erwägen. Bedingt durch die Tatsache, dass sich einige der diskutierten Therapieoptionen noch in der Phase der klinischen Prüfung befinden oder noch keine oder nur begrenzte Daten für ältere Patienten mit DMD vorliegen, handelt es sich um Expertenempfehlungen entsprechend der Evidenzklasse IV.

DMD & BMD – CLINICAL: P.48 Facilitators and barriers to wearing hand orthoses by adults with Duchenne muscular dystrophy. A mixed method study design

Many patients with Duchenne muscular dystrophy (DMD) do not wear the prescribed hand orthoses regularly. To slow down shortening of finger flexors hand orthoses are prescribed in patients with DMD; however many do not wear the orthoses. Thus we need to get insight in the factors influencing compliance. In this study we aimed to evaluate the compliance regarding hand orthoses in an adult DMD population, and to explore experiences and perceptions regarding wearing orthoses of DMD patients and their caregivers.

Facilitators and Barriers to Wearing Hand Orthoses by Adults with Duchenne Muscular Dystrophy: A Mixed Methods Study Design.

Background:To retard shortening of finger flexors in patients with Duchenne muscular dystrophy (DMD), hand orthoses are prescribed. However, many patients do not wear the orthoses regularly. To optimize orthotic interventions, we need insight into the factors influencing compliance.Objective:To evaluate the compliance regarding hand orthoses in an adult DMD population and to explore experiences and perceptions of DMD patients wearing orthoses, and of their caregivers.Methods:Mixed methods observational study, combining quantitative and qualitative data from medical charts combined with qualitative semi-structured interviews using a constant comparative method and a short validated questionnaire (D-QUEST).Results:65 medical charts were analyzed. 48 patients were assessed as needing hand orthoses, of whom 37.5 % were compliant. Qualitative data analyses revealed (1) motivation: preservation of hand function; (2) barriers: discomfort and impediments; (3) facilitators: good fit and personalized wearing schedule; (4) fitting process: satisfactory, but patients do not readily seek help when barriers appear.Conclusions:Patients are motivated to wear hand orthoses, but often discontinue use because of orthosis-and disease-specific barriers. The identification of these barriers leads to practical and feasible recommendations concerning the orthoses and the fitting process, such as less rigid material, preservation of some function while wearing the orthoses, and fixed evaluation points. The findings were confirmed by the D-QUEST.

Subjective sleep quality in adult patients affected by Duchenne muscular dystrophy. Beyond nocturnal hypoventilation

ObjectiveIn stable neuromuscular patients under long-term non-invasive ventilation (NIV), subjective sleep quality may be predicted by chronic hypoventilation, as assessed by base excess (BE), and %N3 sleep stage duration. In this study, we explored how other variables, closely associated with self-reported health complaints, contributed to subjective sleep quality in adult patients with Duchenne muscular dystrophy (DMD). MethodsThis is a secondary analysis of a quality of life study in 48 adult DMD patients under NIV therapy, with little evidence of residual hypoventilation. Subjective sleep quality was evaluated by the Pittsburgh Sleep Quality Index (PSQI). A PSQI score >5 was considered indicative of poor sleep quality. Several other symptoms were evaluated: sleepiness, by the Epworth Sleepiness Scale (ESS); depression and anxiety, by the anxiety and depression subscales of the Hospital Anxiety and Depression Scale (HADS-A and HADS-D); autonomic symptoms, by the Composite Autonomic Symptom Score 31; pain, by the Numeric Pain Rating Scale (NPRS); and fatigue, by the Fatigue Severity Scale (FSS). ResultsMean PSQI was 6.1 ± 2.9. Abnormal scores were found for NPRS in 40, for HADS-A in 10 and for FSS in 24 subjects. The NPRS, HADS-A and FSS scores and the N3 sleep stage, independently predicted PSQI (R2 = 0.47, p < 0.0001). ConclusionsIn adult DMD patients, pain, fatigue and anxiety may have a prominent influence on subjective sleep quality. Improvement of sleep quality may be of utmost importance in DMD, as it may ameliorate quality of life and extend its benefits to cardiovascular morbidity and life expectancy.

P.309Mechanistic insights into Duchenne muscular dystrophy-associated cardiomyopathy

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder that is associated with progressive muscle wasting and cardiomyopathy. Utilizing cardiac MRI, we have demonstrated that adult DMD patients have small hearts with very low LV mass as compared to patients with non-ischemic cardiomyopathy or healthy patients. Thus, we hypothesize that DMD-associated cardiomyopathy develops secondary to dysregulation of cardiac signaling pathways that modulate cardiac growth, namely cardiomyocyte proliferation. Utilizing the mdx mouse, a model of DMD, decreased heart/body weight ratios were noted from birth (P1: Hrt/BW 5.6 ± 0.16 vs. 4.8 ± 0.18 NTg vs mdx p<0.005 n=32). NTg and mdx hearts have similar cardiomyocyte cell size (WGA staining: 0.08 ± 0.001 vs 0.08 ± 0.002 NTg vs mdx p<0.05; n=3). FACS analysis indicated mdx hearts have fewer cardiomyocytes (35% reduction; 51.7e ± 4.9e vs. 33.8e ± 3.5e NTg vs mdx p<0.05 n=6). Transcriptome profiling demonstrated that molecular pathways governing cardiac proliferation were significantly reduced in mdx hearts (Ki67: 4.8 ± 0.3 vs 2.0 ± 0.1 NTg vs mdx p<0.005 n=3), with a corresponding increase in cardiac atrophy gene expression at later time points (Foxo3 1.4 ± 0.2 vs 2.8 ± 0.3 NTg vs mdx p<0.005 n=3). Likewise, immunohistochemical (IHC) analyses showed significantly reduced proliferation in mdx hearts (Ki67: 13.7 ± 1.2 vs. 6.0 ± 1.0 NTg vs mdx p<0.005, n=3; pH3: 118 ± 5.3 vs 59 ± 4.5 p<0.005 n=3). RNA-Seq data revealed a disruption of the Yap signaling pathway, an important co-transcriptional mediator of cardiomyocyte proliferation, in mdx P4 hearts. By quantitative RT-PCR, cell cycle targets of Yap were reduced in mdx hearts. Finally, western blot and IHC revealed less nuclear localization of Yap in mdx cardiomyocytes. Collectively, this data suggests a novel mode of cardiac remodeling that contributes to the development of DMD-associated cardiomyopathy.

IP3 receptor blockade restores autophagy and mitochondrial function in skeletal muscle fibers of dystrophic mice

Duchenne muscular dystrophy (DMD) is characterized by a severe and progressive destruction of muscle fibers associated with altered Ca2+ homeostasis. We have previously shown that the IP3 receptor (IP3R) plays a role in elevating basal cytoplasmic Ca2+ and that pharmacological blockade of IP3R restores muscle function. Moreover, we have shown that the IP3R pathway negatively regulates autophagy by controlling mitochondrial Ca2+ levels. Nevertheless, it remains unclear whether IP3R is involved in abnormal mitochondrial Ca2+ levels, mitochondrial dynamics, or autophagy and mitophagy observed in adult DMD skeletal muscle. Here, we show that the elevated basal autophagy and autophagic flux levels were normalized when IP3R was downregulated in mdx fibers. Pharmacological blockade of IP3R in mdx fibers restored both increased mitochondrial Ca2+ levels and mitochondrial membrane potential under resting conditions. Interestingly, mdx mitochondria changed from a fission to an elongated state after IP3R knockdown, and the elevated mitophagy levels in mdx fibers were normalized. To our knowledge, this is the first study associating IP3R1 activity with changes in autophagy, mitochondrial Ca2+ levels, mitochondrial membrane potential, mitochondrial dynamics, and mitophagy in adult mouse skeletal muscle. Moreover, these results suggest that increased IP3R activity in mdx fibers plays an important role in the pathophysiology of DMD. Overall, these results lead us to propose the use of specific IP3R blockers as a new pharmacological treatment for DMD, given their ability to restore both autophagy/mitophagy and mitochondrial function.

Abstract 310: Mechanistic Insights into Duchenne Muscular Dystrophy-Associated Cardiomyopathy

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder resulting from a mutation in the dystrophin gene. Loss of dystrophin function leads to progressive muscle wasting and cardiomyopathy. In 2018, advanced cardiomyopathy is the primary mode of death, despite the application of standard of care CHF therapies. Our group has recently undertaken a cardiac MRI study demonstrating that adult DMD patients have small hearts with very low LV mass as compared to patients with non-ischemic cardiomyopathy or healthy patients. The central hypothesis is DMD-associated cardiomyopathy develops secondary to dysregulation of various cardiac signaling pathways that modulate cardiac growth, namely cardiomyocyte proliferation. Utilizing the mdx mouse, a model of DMD, decreased heart/body weight ratios were noted from birth (P1: Hrt/BW 5.6 ± 0.16 vs. 4.8 ± 0.18 NTg vs mdx p&lt;0.005 n=32). NTg and m dx hearts have similar cardiomyocyte cell size (WGA staining: 0.08 ± 0.001 vs 0.08 ± 0.002 NTg vs mdx p&lt;0.05 n=3), suggesting there are fewer cells in mdx hearts. FACS analysis indicated mdx hearts have fewer cardiomyocytes than NTg hearts (35% reduction; 51.7e 4 ± 4.9e 4 vs. 33.8e 4 ± 3.5e 4 NTg vs mdx p&lt;0.05 n=6). Transcriptome profiling demonstrated that molecular pathways governing cardiac proliferation were significantly reduced in mdx hearts (Ki67: 4.8 ± 0.3 vs 2.0 ± 0.1 NTg vs mdx p&lt;0.005 n=3), with a corresponding increase in cardiac atrophy gene expression at later time points (Foxo3 1.4 ± 0.2 vs 2.8 ± 0.3 NTg vs mdx p&lt;0.005 n=3). Furthermore, immunohistochemical analyses showed significantly reduced proliferation in mdx hearts (Ki67: 13.7 ± 1.2 vs. 6.0 ± 1.0 NTg vs mdx p&lt;0.005, n=3; pH3: 118 ± 5.3 vs 59 ± 4.5 p&lt;0.005 n=3). Finally, RNA-Seq data revealed a disruption of the YAP signaling pathway, an important mediator of cardiomyocyte proliferation, in mdx P4 hearts. Cell cycle targets of YAP were reduced in P4 mdx hearts (20/27 genes, n=3) suggesting a disruption of the Hippo-Yap pathways in mdx hearts. Collectively, the current study provides a unique insight into the mechanism leading to the development DMD cardiomyopathy and directs investigation into potential therapeutic targets for the amelioration of DMD-associated cardiomyopathy.

Long-term follow-up of dysphagia in adult patients with Duchenne muscular dystrophy

Abstract Background Dysphagia is a well-known dysfunction in patients with Duchenne muscular dystrophy (DMD), but long-term follow-up of this symptom has not been reported. The aims of this study were to investigate swallowing status, prospectively study the prognosis of swallowing function in adult patients with DMD over the course of 6 years, and to identify clinical factors related to prognosis. Methods Participants were 81 patients with DMD. Swallowing status was assessed using the Neuromuscular Disease Swallowing Status Scale (NdSSS) every 2 years for 6 years. Results NdSSS was related to age, functional ability assessed using the Swinyard staging and the status of ventilator dependence. Median NdSSS changed from 6 to 4, 4 and 3 over the 4 time points. Number of patients with tube feeding increased by 5–10% every 2 years. Initial NdSSS was a predictor of future swallowing status. Conclusion Swallowing status declined over time in patients with adult DMD, with initial NdSSS as a predictor.

D40 - Analysis of premature mortality in a cohort of adult Duchenne muscular dystrophy

D40 - Analysis of premature mortality in a cohort of adult Duchenne muscular dystrophy

Left bundle branch block in Duchenne muscular dystrophy: Prevalence, genetic relationship and prognosis.

BackgroundDuchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. We designed this study to determine the prevalence of left bundle branch block (LBBB), whether there is a relationship between LBBB and genetic pattern, and to assess predictive factors for acute cardiac events and mortality in adult DMD patients.MethodsWe reviewed the charts of DMD followed at the Home Mechanical Ventilation Unit of the Raymond Poincare University Hospital.ResultsA total of 121 patients, aged from 18 to 41 years have been included in our study. Median vital capacity (VC) was 12% [7; 19.5] of predicted. Almost all patients were on home mechanical ventilation (95%). LBBB was present in 15 patients (13%); among them, 10 disclosed exonic deletions. After a median follow up of 6 years, 21 patients (17%) experienced acute heart failure (AHF), 7 patients (6%) supraventricular arrhythmia, 3 patients (2.4%) ventricular tachycardia, 4 patients (3%) significant electrical disturbances. LBBB was significantly associated with cardiac events (OR = 12.7; 95%CI [3.78–42.7]; p <0.0001) and mortality (OR = 4.4; 95%CI [1.44–13.7]; p 0.009). Presence of residual dystrophin protein was not associated with significant less cardiac events. Age and LVEF were also predictive factors for cardiac events and mortality.ConclusionLBBB is relatively frequent in DMD and is a major predictive factor for cardiac events and mortality. Presence of residual dystrophin protein was not associated with a lower incidence of cardiac events.