Duchenne Muscular Dystrophy Population Research Articles

Duchenne Muscular Dystrophy-Associated Neurobehavioral Difficulties: Insights from Clinical Practice.

Emerging evidence underscores the high prevalence of neurobehavioral difficulties like ADHD, ASD and OCD, in patients with Duchenne muscular dystrophy (DMD). The substantial impact of these complex behavioral challenges in addition to motor function decline on the well-being of affected individuals and their families is increasingly evident. However, a uniform approach for effective screening, assessment and management of the neurobehavioral symptoms remains elusive. We explored strategies used by healthcare professionals with clinical expertise in DMD to address neurobehavioral symptoms, in order to uncover diverse practices and to identify potential directions for clinical approaches in managing DMD neurobehavioral symptoms. Twenty-eight respondents from 16 different countries completed an online survey. Only 35% of the centers systematically screened for neurobehavioral difficulties in their DMD population. Predominant screening methods included history taking and clinical observation. Common neurobehavioral difficulties encompassed learning challenges, dependency from adults, anxiety, concentration difficulties, and social deficits. The participating centers frequently employed parental counseling and liaison with psychosocial healthcare professionals for psychosocial intervention. This study underscores the complex behavioral landscape in DMD, highlighting the need for validated screening, assessment and management strategies and collaborative efforts in implementing these. We advocate for international consensus recommendations for screening, assessment and management of neurobehavioral difficulties in DMD to enhance patient care and communication across healthcare settings.

Discovery of Quinazoline and Quinoline-Based Small Molecules as Utrophin Upregulators via AhR Antagonism for the Treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease caused by the absence of a dystrophin protein. Elevating utrophin, a dystrophin paralogue, offers an alternative therapeutic strategy for treating DMD, irrespective of the mutation type. Herein, we report the design and synthesis of novel quinazoline and quinoline-based small molecules as potent utrophin modulators screened via high throughput In-Cell ELISA in C2C12 cells. Remarkably, lead molecule SG-02, identified from a library of 70 molecules, upregulates utrophin 2.7-fold at 800 nM in a dose-dependent manner, marking the highest upregulation within the nanomolar range. SG-02's efficacy was further validated through DMD patient-derived cells, demonstrating a significant 2.3-fold utrophin expression. Mechanistically, SG-02 functions as an AhR antagonist, with excellent binding affinity (Kd = 41.68 nM). SG-02 also enhances myogenesis, as indicated by an increased MyHC expression. ADME evaluation supports SG-02's oral bioavailability. Overall, SG-02 holds promise for addressing the global DMD population.

Patient- and caregiver-reported impact of symptoms in Duchenne muscular dystrophy.

To better understand the disease burden faced by individuals with Duchenne muscular dystrophy (DMD) of all ages and elucidate potential targets for therapeutics, this study determined the prevalence and relative importance of symptoms experienced by individuals with DMD and identified factors associated with a higher disease burden. We conducted qualitative interviews with individuals with DMD and caregivers of individuals with DMD to identify potential symptoms of importance to those living with DMD. We subsequently performed a cross-sectional study to assess which symptoms have the highest prevalence and importance in DMD and to determine which factors are associated with a higher disease burden. Thirty-nine individuals, aged 11 years and above, provided 3262 quotes regarding the symptomatic burden of DMD. Two hundred participants (87 individuals with DMD and 113 caregivers) participated in a subsequent cross-sectional study. Individuals with DMD identified limitations with mobility or walking (100%), inability to do activities (98.9%), trouble getting around (97.6%), and leg weakness (97.6%) as the most prevalent and life altering symptomatic themes in DMD. The symptomatic themes with the highest prevalence, as reported by caregivers on behalf of those with DMD for whom they care, were limitations with mobility or walking (90.3%), leg weakness (89.2%), and emotional issues (79.6%). Steroid/glucocorticoid use (e.g., prednisone or deflazacort) was associated with a lower level of disease burden in DMD. There are many symptomatic themes that contribute to disease burden in individuals with DMD. These symptoms are identified by both individuals with DMD and their caregivers and have a variable level of importance and prevalence in the DMD population.

Natural history of Duchenne muscular dystrophy in the United Kingdom: A descriptive study using the Clinical Practice Research Datalink.

Duchenne muscular dystrophy (DMD) is a rare, muscle-degenerative disease predominantly affecting males. Natural history models capture the full disease pathway under current care and combine with estimates of new interventions' effects to assess cost-effectiveness by health technology decision-makers. These models require mortality estimates throughout a patient's lifetime, but rare disease datasets typically contain relatively few patients with short follow-ups. Alternative (published) sources of mortality data may therefore be required. The Clinical Practice Research Datalink (CPRD) was evaluated as a source of mortality and natural history data for future economic evaluations of health technologies for DMD and rare diseases in general in the UK population. This retrospective longitudinal cohort study provides flexible parametric estimates of mortality rates and survival probabilities in the current UK DMD population through primary/secondary records in the CPRD since 1990. It also investigates clinically significant milestones such as corticosteroid use, spinal surgery, and cardiomyopathy in these patients. A total of 1121 male patients were included in the study, observed from 0.7 to 48.9 years. Median life expectancy was 25.64 years (95% confidence interval 24.73, 26.47), consistent with previous global estimates. This has improved to 26.47 (25.16, 27.89) years in patients born after 1990. The median ages at corticosteroid initiation, spinal surgery, ventilation, and cardiomyopathy diagnosis were 6.06 years (5.77, 6.29), 14.79 years (14.29, 15.09), 16.97 years (16.50, 18.31), and 15.26 years (14.22, 16.70), respectively. Estimates of mortality in UK-based DMD patients are age-specific in a uniquely large and nationally representative sample from the CPRD.

Left Atrial Phasic Function via Cardiac Magnetic Resonance Imaging in Patients with Duchenne Muscular Dystrophy.

Cardiac dysfunction is a leading cause of morbidity and mortality in Duchenne muscular dystrophy (DMD). Left atrial (LA) function is a poorly understood concept in this patient population, and research suggests underlying structural changes that could affect atrial function. Cardiac magnetic resonance (CMR) imaging may provide an important non-invasive approach to evaluating LA function. This study was a single center retrospective review of consecutive CMR studies over a 1year period comparing LA phasic function within a cohort of DMD patients, and to those with structurally and functionally normal hearts. LA strain measurements including global reservoir, conduit, boost-pump strain, and LA volumes were obtained retrospectively. Spearman correlation analyses were performed on atrial strain measurements. 107 DMD and 79 normal CMR studies were included. The DMD cohort had worse systolic function (p < 0.001), smaller indexed max LA and left ventricular (LV) volumes (p < 0.001), and greater LA emptying fraction (p < 0.001). In the DMD cohort, emptying fraction decreased with advanced patient age (p < 0.001) and diminishing systolic function (p < 0.001). DMD patients with moderate or severe LV dysfunction demonstrated lower LA emptying fraction (p = 0.002), more impaired 2-chamber LA reservoir (p = 0.003), and LA pump (p = 0.006) and conduit strain (p = 0.018). DMD patients with preserved function have lower indexed LA volumes with higher LA emptying fractions than controls. Progression of disease and age is associated with decreased LA emptying fraction with early manifestations in reservoir and conduit strain. These findings suggest that strain markers of LA compliance and early left ventricular relaxation are associated with worsening cardiomyopathy in the DMD population.

0068 Effect of Duchenne muscular dystrophy on sleep-dependent consolidation of episodic memory: Pilot

Abstract Introduction About 50% of patients with Duchenne muscular dystrophy (DMD) exhibit learning and memory deficits. Sleep issues are also common in DMD, and their potential relevance to cognitive deficits is unexplored. In this pilot study, we investigate the effect of DMD on sleep-dependent consolidation of episodic memory, with a focus on the role of sleep-brain dynamics. Methods We studied boys aged 6–15 years who were typically developing (TD) or had DMD. First, we compared memory performance in an episodic memory task during a day of wake versus a night of sleep within subjects (Phase 1, n = 13), including a one-week sleep diary, and parent-rated, memory, and cognitive assessments. In Phase 2, we measured memory improvement in the same task across a night with polysomnography (24 head electrodes). Sleep was scored with AASM criteria. Slow oscillations (SO) (0.5-1.5 Hz) and spindles (10-16Hz) were detected algorithmically, assessing density, amplitude, and coordination. Results In Phase 1, data confirmed sleep-specific gains in memory performance when task difficulty was adjusted to our extended age range (mean accuracy change: 7% sleep, 0% wake). The DMD participant in Phase 1 exhibited worse immediate recall compared to TD peers (independent samples t-test; t(9) = -4.38, p =.02) and worse parent-rated sleep habits (t(9) = 4.01, p = .03 on Children Sleep Health Questionnaire). Phase 2 showed a physiological range of SOs and spindles density, amplitude, and duration in both groups, with potential differences in overall sleep quality. Conclusion This pilot study established the feasibility of a sleep-memory experiment including polysomnography in controls and DMD patients in the context of a pediatric research hospital. Data suggests the need for adaptive recruitment approaches for the DMD population in expanding the study. Sleep EEG analysis suggests the potential for subtle differences in DMD sleep brain dynamics that need to be investigated in a larger sample size. Support (if any) Center for Clinical and Translational Science voucher support to MW and Neurodevelopmental Research Affinity Group Pilot Award to PM

Evaluation of Cardiac, Autonomic Functions in Ambulant Patients with Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder caused by dystrophin gene mutation resulting in muscle weakness, motor delays, difficulty in standing, and inability to walk by 12 years. As disease progresses, it leads to cardiac and respiratory failure. Evaluation of cardiac autonomic status and echocardiography in DMD patients at a young age can be a potential biomarker to assess disease progression. This study aimed to investigate the younger DMD population of 5-11years of age with mild to moderate cardiac involvement for early detection using non-invasive and cost-effective tools. Genetically confirmed male DMD patients, aged 5-11 years (n = 47), screened from the outpatient department of a tertiary neuroscience institution were subjected to heart rate variability and echocardiographic analysis, and values were correlated with their clinical variables. DMD patients showed a significantly higher difference in HR, interventricular septum, E m/s, and E-wave to A-wave (E/A) ratio than normal values (p < 0.001). Significantly higher HR indicates initial sinus tachycardia and decreased IVD (d), and increased E m/s and E/A ratio mark the onset of cardiac symptoms in DMD patients even though its chamber dimension remains normal and are associated with cardiac muscle fibrosis.

FP.25 Contracture management in ambulant boys with Duchenne muscular dystrophy (DMD)

Ankle contractures are a common feature in DMD, often developing in young boys as early as 4 or 5 years of age. This can contribute to premature loss of ambulation or at least some degree of impaired motor function. Preserving mobility by preserving ankle range of movement (ROM) can have positive effects on activity and participation as well as health related benefits related to respiratory function, scoliosis, and bone density. Traditional Physiotherapy techniques aim to reduce and prevent contractures occurring at the ankle by daily stretching regimes and night time splints (AFOs). In Newcastle, physiotherapy clinical experience has found issues with compliance with night time AFOs, limiting the benefit of these splints. The use of Contracture Control Devices (CCDs) has been explored as a novel alternative to these. To date there are no studies investigating the efficacy of CCDs or comparing these orthotic devices in contracture management in the DMD population. This pilot study aims to explore feasibility for a larger scale study comparing AFOs and CCDs in ambulant boys with DMD. It will explore intra-rater reliability of ROM and North Star Ambulatory Assessment (NSAA) evaluations and examine patient satisfaction and compliance. In an on-going pilot study, two ambulant boys were recruited to a single centre, single blinded Randomised Controlled Trial comparing standard night time AFO intervention (control arm) with the CCD group. Efficacy measures were ankle ROM and specific items from the NSAA. Intra-rater reliability was calculated using ICC. Patient adherence and satisfaction was measured using a self-completed diary and a validated satisfaction questionnaire, the OPUS. Currently N=2, with one boy randomised into each group. Intra-rater reliability was high for ankle ROM and NSAA items. Compliance was satisfactory for both individuals and the OPUS questionnaire informed patient satisfaction. Recruitment is ongoing, and updated results will be reported.

Respiratory Function and Sleep Disordered Breathing in Pediatric Duchenne Muscular Dystrophy.

The decline of respiratory function in Duchenne muscular dystrophy (DMD) is associated with sleep disordered breathing (SDB) and alteration of nocturnal gas exchange, first manifesting as nocturnal hypoventilation (NH). However, the correlation between the pulmonary function measured by spirometry (PFT) and the onset of SDB with or without NH is unclear. The aims of this study are to identify the prevalence and features of SDB and to investigate the relationship between lung function determined by forced vital capacity (FVC) and sleep abnormalities in a large pediatric DMD population. This was a retrospective, single-center cohort study. FVC% predicted (FVC%) was calculated using predicted equations from the Global Lung Function Initiative. NH was defined by transcutaneous (tc) CO2 &gt;50 mm Hg for &gt;25% of total sleep time (TST), borderline NH by a mean tcCO2 between 45 and 50 mm Hg or tcCO2&gt;50 mm Hg for ≤25% of TST, and clinically meaningful obstructive sleep apnea (OSA) by obstructive apnea-hypopnea index &gt;5. The sensitivity, specificity, and positive and negative predictive values of FVC &lt; 50% to indicate the presence of nocturnal hypoventilation were calculated. One hundred thirty-four patients underwent 284 sleep studies and 1222 PFT. The mean (SD) age at the first and the last sleep study was 12.9 (2.7) and 14.3 (2.6) years, respectively. Borderline NH (n = 31) was detected in both ambulant and early-nonambulant participants, while 100% of NH cases (n = 14) were nonambulant. NH was detected in 4 of the 14 patients despite an FVC &gt;50%. Seventeen of the 26 patients with OSA presented with concomitant NH or borderline NH. FVC &lt;50% was associated with NH indicating a sensitivity and specificity of 73% and 86%, respectively. Positive and negative predictive values were 32% and 97%, respectively. PFT showed a nonlinear, sudden FVC% decline in 18% of cases. FVC% &lt;50 was associated with NH in close to a third of patients. CO2 elevation can be associated with obstructive/pseudo-obstructive events and was also observed in early nonambulant cases or in the presence of FVC &gt;50%. These results are relevant for the clinical management of SDB.

Large scale population screening for Duchenne muscular dystrophy-Predictable and unpredictable challenges.

ObjectiveLarge deletions and duplications account for 65%–80% of pathogenic Duchenne muscular dystrophy (DMD) variants. A nationwide carrier screening for DMD was initiated in Israel in 2020. We assessed the carrier rate and spectrum of variants detected in a cohort of women screened for DMD carrier status and analyzed screening efficacy and challenges related to DMD population screening.MethodsA cohort of 12,362 women were tested at a single institute using multiplex ligation‐dependent probe amplification based copy number analysis of the 79 DMD exons. Consecutive sequencing of the primer region was performed when a single exon deletion was suspected.ResultsDeletions involving multiple exons were detected in seven cases and duplications involving multiple exons were found in four. Of these, nine were pathogenic based on previous reports and familial segregation testing, translating to a carrier rate of 1:1374. A family history was reported in three cases. Single exon deletions were suspected in 81 cases; further sequencing detected a single nucleotide variant affecting probe hybridization. These cases clustered according to ethnic origin.DiscussionPopulation screening for DMD has a significant yield. Most carriers did not report a family history of dystrophinopathies. Screening should be adjusted for methodological limitations. Some cases may require extensive genetic counseling and work‐up.

Longitudinal changes in cardiac function in Duchenne muscular dystrophy population as measured by magnetic resonance imaging

BackgroundThe lack of dystrophin in cardiomyocytes in Duchenne muscular dystrophy (DMD) is associated with progressive decline in cardiac function eventually leading to death by 20–40 years of age. The aim of this prospective study was to determine rate of progressive decline in left ventricular (LV) function in Duchenne muscular dystrophy (DMD) over 5 years.MethodsShort axis cine and grid tagged images of the LV were acquired in individuals with DMD (n = 59; age = 5.3–18.0 years) yearly, and healthy controls at baseline (n = 16, age = 6.0–18.3 years) on a 3 T MRI scanner. Grid-tagged images were analyzed for composite circumferential strain (ℇcc%) and ℇcc% in six mid LV segments. Cine images were analyzed for left ventricular ejection fraction (LVEF), LV mass (LVM), end-diastolic volume (EDV), end-systolic volume (ESV), LV atrioventricular plane displacement (LVAPD), and circumferential uniformity ratio estimate (CURE). LVM, EDV, and ESV were normalized to body surface area for a normalized index of LVM (LVMI), EDV (EDVI) and ESV (ESVI).ResultsAt baseline, LV ℇcc% was significantly worse in DMD compared to controls and five of the six mid LV segments demonstrated abnormal strain in DMD. Longitudinal measurements revealed that ℇcc% consistently declined in individuals with DMD with the inferior segments being more affected. LVEF progressively declined between 3 to 5 years post baseline visit. In a multivariate analysis, the use of cardioprotective drugs trended towards positively impacting cardiac measures while loss of ambulation and baseline age were associated with negative impact. Eight out of 17 cardiac parameters reached a minimal clinically important difference with a threshold of 1/3 standard deviation.ConclusionThe study shows a worsening of circumferential strain in dystrophic myocardium. The findings emphasize the significance of early and longitudinal assessment of cardiac function in DMD and identify early biomarkers of cardiac dysfunction to help design clinical trials to mitigate cardiac pathology. This study provides valuable non-invasive and non-contrast based natural history data of cardiac changes which can be used to design clinical trials or interpret the results of current trials aimed at mitigating the effects of decreased cardiac function in DMD.

Development of a novel startle response task in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD), an X-linked childhood-onset muscular dystrophy caused by loss of the protein dystrophin, can be associated with neurodevelopmental, emotional and behavioural problems. A DMD mouse model also displays a neuropsychiatric phenotype, including increased startle responses to threat which normalise when dystrophin is restored in the brain. We hypothesised that startle responses may also be increased in humans with DMD, which would have potential translational therapeutic implications. To investigate this, we first designed a novel discrimination fear-conditioning task and tested it in six healthy volunteers, followed by male DMD (n = 11) and Control (n = 9) participants aged 7-12 years. The aims of this methodological task development study were to: i) confirm the task efficacy; ii) optimise data processing procedures; iii) determine the most appropriate outcome measures. In the task, two neutral visual stimuli were presented: one 'safe' cue presented alone; one 'threat' cue paired with a threat stimulus (aversive noise) to enable conditioning of physiological startle responses (skin conductance response, SCR, and heart rate). Outcomes were the unconditioned physiological startle responses to the initial threat, and retention of conditioned responses in the absence of the threat stimulus. We present the protocol development and optimisation of data processing methods based on empirical data. We found that the task was effective in producing significantly higher physiological startle SCR in reinforced 'threat' trials compared to 'safe' trials (P < .001). Different data extraction methods were compared and optimised, and the optimal sampling window was derived empirically. SCR amplitude was the most effective physiological outcome measure when compared to SCR area and change in heart rate, with the best profile on data processing, the least variance, successful conditioned response retention (P = .01) and reliability assessment in test-retest analysis (rho = .86). The definition of this novel outcome will allow us to study this response in a DMD population.

Clinical and Genetic Characteristics in Young, Glucocorticoid-Naive Boys With Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a pediatric neuromuscular disorder caused by mutations in the dystrophin gene. Genotype-phenotype associations have been examined in glucocorticoid-treated boys, but there are few data on the young glucocorticoid-naive DMD population. A sample of young glucocorticoid-naive DMD boys is described, and genotype-phenotype associations are investigated. Screening and baseline data were collected for all the participants in the Finding the Optimum Corticosteroid Regime for Duchenne Muscular Dystrophy (FOR-DMD) study, an international, multicenter, randomized, double-blind, clinical trial comparing 3 glucocorticoid regimens in glucocorticoid-naive, genetically confirmed boys with DMD between 4 and <8 years of age. One hundred ninety-six boys were recruited. The mean ± SD age at randomization was 5.8 ± 1.0 years. The predominant mutation type was out-of-frame deletions (67.4%, 130 of 193), of which 68.5% (89 of 130) were amenable to exon skipping. The most frequent mutations were deletions amenable to exon 51 skipping (13.0%, 25 of 193). Stop codon mutations accounted for 10.4% (20 of 193). The mean age at first parental concerns was 29.8 ± 18.7 months; the mean age at genetic diagnosis was 53.9 ± 21.9 months; and the mean diagnostic delay was 25.9 ± 18.2 months. The mean diagnostic delay for boys diagnosed after an incidental finding of isolated hyperCKemia (n = 19) was 6.4 ± 7.4 months. The mean ages at independent walking and talking in sentences were 17.1 ± 4.2 and 29.0 ± 10.7 months, respectively. Median height percentiles were below the 25th percentile regardless of age group. No genotype-phenotype associations were identified expect for boys with exon 8 skippable deletions, who had better performance on time to walk/run 10 m (p = 0.02) compared to boys with deletions not amenable to skipping. This study describes clinical and genetic characteristics of a sample of young glucocorticoid-naive boys with DMD. A low threshold for creatine kinase testing can lead to an earlier diagnosis. Motor and speech delays were common presenting symptoms. The effects of low pretreatment height on growth and adult height require further study. These findings may promote earlier recognition of DMD and inform study design for future clinical trials. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01603407.

Abstract 13405: Prevalence of Cardiac Disease in Duchenne Muscular Dystrophy Patients by Age: A Cardiac Magnetic Resonance Natural History Study

Introduction: Duchenne muscular dystrophy (DMD) patients universally develop cardiomyopathy and considered a dilated cardiomyopathy. Cardiac magnetic resonance imaging (CMR) revealed LGE prior to ventricular dysfunction. Various novel trials including gene therapy are ongoing with growing interest on how it impacts the heart. There is paucity of CMR data at a given age. A major barrier is lack of age specific data. Hypothesis: We therefore, sought to determine the prevalence left ventricular (LV) dilation by endiastolic volume (LVEDV), ejection fraction (LVEF) and late gadolinium enhancement (LGE) status at a given age. Methods: Retrospective review of CMR studies in DMD. LV dilation is defined as LVEDVi z-score &gt; 2, abnormal LVEF (&lt;55%) and LGE (yes or no). Patients were group by age in one year interval (given smaller numbers patients &lt; 7 years were grouped together as were those ≥ 20 years). Results: 683 DMD patients were identified with average of 48.8±24 (range 19-94) patients per group divided into 14 age groups. Mean age was 12.3±4 (range 4-39 years). Table 1 summarizes the CMR data by age. LV dilation was uncommon even in older age patients (mean 1.9±2.6%, range 0-8.7%). LVEF is rarely abnormal before 10 years (&lt;5%) but increased with age (69.9% in the ≥ 20 year group). In all groups mean % LVEF &lt; 55% is 24.6±20.6% (range 2.5-69.9). LGE can be found as young as 6.5 years but uncommon before age 10 years (&lt;10%), increased to nearly 20% by age 10 years and incrementally increased to &gt;50% after 11 (4.3% &lt; 7 year group to &gt; 80% by 18 years). Conclusions: This is the first and largest CMR natural history study by individual age showing low prevalence of LV dilation in DMD population. LVEF abnormality and LGE is uncommon before 10 years but increased with age. Future longitudinal assessment is ongoing to determine rate of change at a given age, quantifying LGE and myocardial strain for earlier cardiac disease assessment and modeling for disease progression at different age.

REGISTRIES, CARE, QUALITY OF LIFE, MANAGEMENT OF NMD: P.342 Life expectancy and causes of death in patients with Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations in the dystrophin gene, which leads to an absence or deficiency of the protein dystrophin and continuous degeneration of muscle fibers. Without treatment, patients with DMD lost ambulation prior to 12 years of age and survived into their late teens. The most common cause of death has been cardiac or respiratory failure. Better disease management over the years has improved survival in DMD. The aim of this study was to estimate the prevalence, incidence and mortality rate in the total DMD population of Sweden between 1970-2019, as well as the age and causes of death. The study population included all male patients born in Sweden since 1970 with a confirmed DMD diagnosis. Patients were tracked after contact with the medical departments and pathology laboratories in Sweden and through patient registries; the home respirator registry Swedevox, the Neuromuscular Quality Register for Neuromuscular Diseases in Sweden (NMiS). Subsequently, extracts were requested from the National Board of Health's Cause of Death Register. The study has been approved by the Ethics Committee at the University of Gothenburg. We will present the prevalence and incidence of individuals with DMD in Sweden during the period 1970-2019. We will also present the life expectancy and causes of death for the entire DMD population, as well as compare life expectancy and mortality distribution across decades and regions in Sweden.

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.

Test-retest reliability of the Performance of Upper Limb (PUL) module for muscular dystrophy patients.

The Performance of the Upper Limb (PUL) module is an externally-assessed clinical scale, initially designed for the Duchenne muscular dystrophy population. It provides an upper extremity functional score suitable for both weaker ambulatory and non-ambulatory phases up to the severely impaired patients. It is capable of characterizing overall progression and severity of disease and of tracking the stereotypical proximal-to-distal progressive loss of upper limb function in muscular dystrophy. Since the PUL module has been validated only with Duchenne patients, its use also for Becker and Limb-Girdle muscular dystrophy patients has been here evaluated, to verify its reliability and extend its use. In particular, two different assessors performed this scale on 32 dystrophic subjects in two consecutive days. The results showed that the PUL module has high reliability, both absolute and relative, based on the calculation of Pearson's r (0.9942), Intraclass Correlation Coefficient (0.9943), Standard Error of Measurement (1.36), Minimum Detectable Change (3.77), and Coefficient of Variation (3%). The Minimum Detectable Change, in particular, can be used in clinical trials to perform a comprehensive longitudinal evaluation of the effects of interventions with the lapse of time. According to this analysis, an intervention is effective if the difference in the PUL score between subsequent evaluation points is equal or higher than 4 points; otherwise, the observed effect is not relevant. Inter-rater reliability with ten different assessors was evaluated, and it has been demonstrated that deviation from the mean is lower than calculated Minimum Detectable Change. The present work provides evidence that the PUL module is a reliable and valid instrument for measuring upper limb ability in people with different forms of muscular dystrophy. Therefore, the PUL module might be extended to other pathologies and reliably used in multicenter settings.

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.

EP.79The impact of ventilation on non-ambulatory patients with DMD

Duchenne muscular dystrophy (DMD) is a severe progressive muscular dystrophy caused by mutations in the DMD gene, leading to the absence of a functional dystrophin protein. During disease progression patients develop respiratory decline, which leads to the need for ventilation, either non-invasive or invasive, in their late teens or early twenties. Also the ability to cough becomes more compromised during the course of the disease. This has a huge impact on daily life and is a burden for both patients and families. To get an insight into the effects of respiratory decline, use of ventilation, the burden and the areas on which it has the most impact, a survey has been held among non-ambulatory DMD patients. The survey was completed by 114 patients from 21 countries (age range: 11 to 54). On average ventilation (any form) was started around 17 years of age (n=101) and continuous ventilation around 20 years (n=49). BiPAP is most commonly used (68%). Also cough assists are frequently used (54%). Respiratory complications sometimes resulted in missing school or work days by both patients and parents. For the majority (85%) the use of ventilation led to an improvement of the quality of life by improving sleeping (77%) and reducing anxiety (58% of those who felt anxious before). For most patients (87%) it facilitated their participation in social activities to some extent. Patients on average give their life a rating of 68 on the EQ-5D scale. This is around 20 points lower than the healthy population. While in the general population a decrease in EQ-5D score is seen with ageing, the contrary is seen for DMD. Thereby the differences between the general and the DMD population diminish with age. The main conclusion of the respiratory survey is that ventilation has a major positive impact on the quality of life, both physically and socially.

Risk Factors for Cerebral Infarction in Duchenne Muscular Dystrophy: Review With our 2 Cases

Background: Although the incidence of cerebral infarction is higher in Duchenne muscular dystrophy (.75 per 100) than in the general population (7.5-11.4 per 100 000), only 18 cases have been reported, and prevention and management guidelines for infarction in this disorder remain lacking. Patients and Methods: We encountered 2 cases of Duchenne muscular dystrophy with cerebral infarction. To clarify risk factors for such infarction in Duchenne muscular dystrophy, we reviewed 20 cases, including our 2 patients. Results: Age at onset of infarction ranged from 4 to 31 years (n = 19). Most patients were 16-21 years old (14 of 19; 73.7%). Eighteen patients (90%) had dilated cardiomyopathy (DCM), showing a higher frequency than in the age-matched general Duchenne muscular dystrophy population. Left ventricular ejection fraction (LVEF) ranged from 10.2% to 42% (median, 20%; n = 9). Detectable cardiac thrombus and atrial fibrillation were rare (2 of 17; 11.8%, and 1 of 17; 5.9%, respectively). Conclusions: Presence of DCM with low LVEF seems to be the strongest risk factor for cerebral infarction in Duchenne muscular dystrophy.