Stage Of Duchenne Muscular Dystrophy Research Articles

Mitohormesis during advanced stages of Duchenne muscular dystrophy reveals a redox-sensitive creatine pathway that can be enhanced by the mitochondrial-targeting peptide SBT-20

Mitochondrial creatine kinase (mtCK) regulates the “fast” export of phosphocreatine to support cytoplasmic phosphorylation of ADP to ATP which is more rapid than direct ATP export. Such “creatine-dependent” phosphate shuttling is attenuated in several muscles, including the heart, of the D2.mdx mouse model of Duchenne muscular dystrophy at only 4 weeks of age. However, the degree to which creatine-dependent and -independent systems of phosphate shuttling progressively worsen or potentially adapt in a hormetic manner throughout disease progression remains unknown. Here, we performed a series of proof-of-principle investigations designed to determine how phosphate shuttling pathways worsen or adapt in later disease stages in D2.mdx (12 months of age). We also determined whether changes in creatine-dependent phosphate shuttling are linked to alterations in mtCK thiol redox state. In permeabilized muscle fibres prepared from cardiac left ventricles, we found that 12-month-old male D2.mdx mice have reduced creatine-dependent pyruvate oxidation and elevated complex I-supported H2O2 emission (mH2O2). Surprisingly, creatine-independent ADP-stimulated respiration was increased and mH2O2 was lowered suggesting that impairments in the faster mtCK-mediated phosphocreatine export system resulted in compensation of the alternative slower pathway of ATP export. The apparent impairments in mtCK-dependent bioenergetics occurred independent of mtCK protein content but were related to greater thiol oxidation of mtCK and a more oxidized cellular environment (lower GSH:GSSG). Next, we performed a proof-of-principle study to determine whether creatine-dependent bioenergetics could be enhanced through chronic administration of the mitochondrial-targeting, ROS-lowering tetrapeptide, SBT-20. We found that 12 weeks of daily treatment with SBT-20 (from day 4–∼12 weeks of age) increased respiration and lowered mH2O2 only in the presence of creatine in D2.mdx mice without affecting calcium-induced mitochondrial permeability transition activity. In summary, creatine-dependent mitochondrial bioenergetics are attenuated in older D2.mdx mice in relation to mtCK thiol oxidation that seem to be countered by increased creatine-independent phosphate shuttling as a unique form of mitohormesis. Separate results demonstrate that creatine-dependent bioenergetics can also be enhanced with a ROS-lowering mitochondrial-targeting peptide. These results demonstrate a specific relationship between redox stress and mitochondrial hormetic reprogramming during dystrophin deficiency with proof-of-principle evidence that creatine-dependent bioenergetics could be modified with mitochondrial-targeting small peptide therapeutics.

A case report of early outpatient stage of Duchenne muscular dystrophy

A case report of early outpatient stage of Duchenne muscular dystrophy

Validity of the Functional Classification of the Upper Extremities for Duchenne Muscular Dystrophy.

Some upper-limb function assessments can evaluate treatments in the non-ambulatory stage of Duchenne muscular dystrophy (DMD). The Functional Classification of the Upper Extremities (FCUE) was developed for DMD in Japan. The FCUE is easier to use than the Performance of Upper Limb (PUL) and is more detailed than the Brooke Upper Extremity Scale. This study aimed to determine the concurrent validity of FCUE with other methods of assessment for DMD. This retrospective study reviewed the medical records of 39 boys with DMD from the National Center of Neurology and Psychiatry to evaluate the concurrent validity of the FCUE and PUL using non-parametric Spearman rank correlation (ρ). We also determined the concurrent validity of the Brooke Upper Extremity Scale and PUL for comparison. The ρ value between the FCUE and PUL was -0.914 (P<0.001). The FCUE showed robust concurrent validity with the PUL. That correlation between the FCUE and Brooke Upper Extremity Scale gave a ρ value of -0.854 (P<0.001). The FCUE had a higher concurrent validity with the PUL than with the Brooke Upper Extremity Scale. The FCUE is considered a valid assessment tool of upper-limb function in boys with DMD. Selecting the best assessment method depends on the severity of the patient's condition and a balance between assessment accuracy and evaluation time.

P138 Development and evaluation of a composite time-to-progression endpoint that spans ambulatory and non-ambulatory stages of Duchenne muscular dystrophy (DMD)

P138 Development and evaluation of a composite time-to-progression endpoint that spans ambulatory and non-ambulatory stages of Duchenne muscular dystrophy (DMD)

Alternative instrument for the evaluation of handgrip strength in Duchenne muscular dystrophy

BackgroundThe commonly used dynamometers can be ineffective in evaluating handgrip in patients with Duchenne muscular dystrophy (DMD), especially children with generalized muscle weakness. The aim of this study was to analyze whether the modified sphygmomanometer is an effective instrument for handgrip strength evaluation in patients with DMD, during different stages of the disease.MethodThe handgrip strength of 33 patients was evaluated by the Jamar dynamometer and the modified sphygmomanometer. Motor function was evaluated by the Motor Function Measurement (MFM) scale. Four evaluations, with a six-month interval between each, were performed: Evaluation 1 (N = 33), Evaluation 2 (N = 24), Evaluation 3 (N = 15), and Evaluation 4 (N = 8). A linear regression model with mixed effects was used for the longitudinal data and descriptive analysis of strength for all four evaluations.ResultThe first evaluation data presented very high correlations between the dynamometer and the modified sphygmomanometer (r = 0.977; p < 0.001). The longitudinal analysis showed a significant difference between Evaluation 1 and the other handgrip strength evaluations obtained using the dynamometer (p < 0.05) but not the modified sphygmomanometer (p > 0.05). Null values were obtained only when using the dynamometer device.ConclusionThe modified sphygmomanometer seems to be more suitable than the dynamometer for measuring handgrip strength in all stages of DMD.

Ultrasonographic assessment of lower limb muscle architecture in children with early-stage Duchenne muscular dystrophy.

Muscle imaging methods such as ultrasound and magnetic resonance imaging have been used for many years to determine the dystrophic process in muscular dystrophies. However, the knowledge regarding muscle architecture in children at early-stage Duchenne muscular dystrophy (DMD) with different functional levels is limited. To explore the effect of functional level on muscle architectural properties in children with early stage DMD and the difference between DMD and typically developing (TD) peers. Thirty children with DMD (15 Grade 1 and 15 Grade 2 according to the Vignos Scale) and 5 TD peers were included. Ultrasound imaging was used to measure muscle thickness (MT), fascicle length (FL), and pennation angle (PA) of vastus lateralis (VL) and medial gastrocnemius (MG) muscles bilaterally. The MT and FL values for VL, and MT, FL and PA values for MG muscles were higher in children with DMD compared with those of TD peers (p<0.05). The FL of VL, and MT and FL of GM muscles of children with DMD Grade 2 were higher than those of children with DMD Grade 1 (p<0.05). MT and FL are increased in children with DMD compared with TD peers. Additionally, muscle architecture seems to be affected even at the early stages of the disease.

Disease Progression Stages and Burden in Patients with Duchenne Muscular Dystrophy Using Administrative Claims Supplemented by Electronic Medical Records.

This study aims to identify stages of Duchenne muscular dystrophy (DMD) and assess the disease burden by progression stage using real-world administrative claims supplemented by relevant electronic medical record (EMR) data. Claims and EMR data from the Decision Resources Group's Real World Data Repository (2011-2020) were used to identify patients with DMD by diagnosis code and to stratify them into four disease stages by diagnosis and procedure markers reflective of DMD progression. Clinical and medical history data from the Cooperative International Neuromuscular Research Group (CINRG) were used to validate the developed claims-based staging algorithm. The distribution and drivers by disease stage, as well as disease burden, were examined. A total of 938 (94%) of patients with DMD identified in claims/EMR data had sufficient information for stage classification. Patients were classified by stage based on patient characteristics and the presence or absence of progression markers such as genetic testing, wheelchair usage, scoliosis treatment, or ventilation assistance. Average ages at stages1-4 are 7, 13, 18, and 23years, respectively. Using natural history data, the claims-based staging algorithm was validated with high sensitivity and specificity rates. Both healthcare resource utilization and medical charges increased by stage. For example, the average annualized total charges were $17,688 (stage1), $36,868 (stage2), $72,801 (stage3), and $167,285 (stage4). Large-scale claims data supplemented by EMR data can be used to characterize DMD progression and evaluate disease burden which may inform the design of future real-world studies about DMD.

Hepatic Steatosis Assessment as a New Strategy for the Metabolic and Nutritional Management of Duchenne Muscular Dystrophy.

Growing evidence suggests that patients with Duchenne muscular dystrophy (DMD) have an increased risk of obesity and metabolic syndrome (MetS). The aim of this study was to investigate the potential risk factors for MetS and hepatic steatosis in patients with different stages of DMD. A total of 48 patients with DMD were enrolled and classified into three stages according to ambulatory status. Body mass index (BMI), serum fasting glucose, insulin, and lipid profiles including triglycerides (TG) and high-density lipoprotein were measured, and the homeostatic model assessment for insulin resistance (HOMA-IR) index was evaluated. Ultrasound examinations of the liver were performed to assess hepatic steatosis using the Nakagami parameter index (NPI). The results showed that BMI, TG, HOMA-IR, and ultrasound NPI differed significantly among DMD stages (p < 0.05). In contrast to the low rates of conventional MetS indices, including disturbed glucose metabolism (0%), dyslipidemia (14.28%), and insulin resistance (4.76%), a high proportion (40.48%) of the patients had significant hepatic steatosis. The ultrasound NPI increased with DMD progression, and two thirds of the non-ambulatory patients had moderate to severe hepatic steatosis. Steroid treatment was a risk factor for hepatic steatosis in ambulatory patients (p < 0.05). We recommend that DMD patients should undergo ultrasound evaluations for hepatic steatosis for better metabolic and nutritional management.

Occurrence of symptoms in different stages of Duchenne muscular dystrophy and their impact on social participation.

Introduction/AimsAs life expectancy improves for patients with Duchenne muscular dystrophy (DMD), new symptoms are likely to arise. This aims of this study are: (1) to explore the prevalence of a broad variety of symptoms in the various stages of DMD (with and without steroid use); (2) to explore the prevalence of common secondary diagnoses; and (3) to evaluate the social participation level of patients with DMD older than 16 y of age; and to explore correlations between social participation and symptoms.MethodsA cross‐sectional self‐report questionnaire, including questions on functional level and health status, as well as a standardized participation scale was distributed among Dutch patients with DMD.ResultsEighty‐four male patients with a mean age of 22.0 (SD = 10.0) y were enrolled. The most prevalent and limiting symptoms were difficulty coughing (58%), coldness of hands (57%), contractures (51%), stiffness (49%), fatigue (40%), myalgia (38%), and low speech volume (33%). Prevalent secondary diagnoses included cardiac disease (14%), neurobehavioral diagnosis (13%), low blood pressure (13%), and arthrosis (5%). Social participation correlated negatively with coldness of hands (r = − .29; P < .03), decreased intelligibility (r = − .40; P < .003), and chewing problems (r = − .33; P < .02).DiscussionThe prevalence of a broad spectrum of symptoms and secondary diagnoses is high in patients with DMD, and some of these symptoms are correlated with social participation. Growing awareness of new symptoms and secondary diagnoses among patients, caregivers, and professionals can enhance their recognition, possibly facilitating prevention and early treatment.

Preserved thenar muscles in non-ambulant Duchenne muscular dystrophy patients.

BackgroundClinical trials in Duchenne muscular dystrophy (DMD) focus primarily on ambulant patients. Results cannot be extrapolated to later disease stages due to a decline in targeted muscle tissue. In non‐ambulant DMD patients, hand function is relatively preserved and crucial for daily‐life activities. We used quantitative MRI (qMRI) to establish whether the thenar muscles could be valuable to monitor treatment effects in non‐ambulant DMD patients.MethodsSeventeen non‐ambulant DMD patients (range 10.2–24.1 years) and 13 healthy controls (range 9.5–25.4 years) underwent qMRI of the right hand at 3 T at baseline. Thenar fat fraction (FF), total volume (TV), and contractile volume (CV) were determined using 4‐point Dixon, and T2water was determined using multiecho spin‐echo. Clinical assessments at baseline (n = 17) and 12 months (n = 13) included pinch strength (kg), performance of the upper limb (PUL) 2.0, DMD upper limb patient reported outcome measure (PROM), and playing a video game for 10 min using a game controller. Group differences and correlations were assessed with non‐parametric tests.ResultsTotal volume was lower in patients compared with healthy controls (6.9 cm3, 5.3–9.0 cm3 vs. 13.0 cm3, 7.6–15.8 cm3, P = 0.010). CV was also lower in patients (6.3 cm3, 4.6–8.3 cm3 vs. 11.9 cm3, 6.9–14.6 cm3, P = 0.010). FF was slightly elevated (9.7%, 7.3–11.4% vs. 7.7%, 6.6–8.4%, P = 0.043), while T2water was higher (31.5 ms, 30.0–32.6 ms vs. 28.1 ms, 27.8–29.4 ms, P < 0.001). Pinch strength and PUL decreased over 12 months (2.857 kg, 2.137–4.010 to 2.243 kg, 1.930–3.339 kg, and 29 points, 20–36 to 23 points, 17–30, both P < 0.001), while PROM did not (49 points, 36–57 to 44 points, 30–54, P = 0.041). All patients were able to play for 10 min at baseline or follow‐up, but some did not comply with the study procedures regarding this endpoint. Pinch strength correlated with TV and CV in patients (rho = 0.72 and rho = 0.68) and controls (both rho = 0.89). PUL correlated with TV, CV, and T2water (rho = 0.57, rho = 0.51, and rho = −0.59).ConclusionsLow thenar FF, increased T2water, correlation of muscle size with strength and function, and the decrease in strength and function over 1 year indicate that the thenar muscles are a valuable and quantifiable target for therapy in later stages of DMD. Further studies are needed to relate these data to the loss of a clinically meaningful milestone.

Ventricular Dysfunction and Calcium Handling Derangements in Isolated Hearts From Duchenne Muscular Dystrophy (DMD mdx‐4CV ) Mice Following Sustained Ventricular Preload

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and is caused by mutations in the dystrophin gene. Subclinical signs of cardiac disease present early and usually progress to dilated cardiomyopathy in late stage DMD patients. Dystrophin deficiency associates with stretch-induced myocyte calcium entry, adverse calcium overload, and cardiomyocyte damage. In this investigation we test the hypothesis that dystrophin deficiency leads to ventricular dysfunction and calcium handling abnormalities following sustained ventricular preload challenge. Hearts of 3-10 month male Control and Dmdmdx-4CV dystrophic mice were isolated, cannulated via both the aorta and left atrium, and perfused with physiological saline solution in working heart mode. Following elevation in preload to 20 mmHg, hearts of Control and Dmdmdx-4CV mice exhibited similar systolic maximum pressure development (PMax: 105±13 mmHg Control versus 102±7 mmHg Dmdmdx-4CV). However, while hearts of Control mice maintained systolic performance following the 30 minute pre-load challenge (PMax, 30 minutes - PMax, peak response: -6±3 mmHg, N=5), hearts of Dmdmdx-4CV mice exhibited a marked decline in systolic performance (PMax,30 minutes - PMax, peak response: -29±6 mmHg, N=7, P<0.01 vs. Control). The Dmdmdx-4CV hearts also had visible signs of damage following preload challenge. Using Control and Dmdmdx-4CV mice with transgenic, cardiac-specific expression of the GCaMP6f calcium indicator (MerCreMer-GCaMP6f), we examined incidence of calcium overload behavior following preload challenge. Isolated working hearts were subjected to 20 mmHg preload in working heart mode for 30 minutes, switched to Langendorff mode with physiological saline containing 40 uM blebbistatin, and imaged using laser-scanning confocal fluorescence microscopy. Calcium overload behavior was observed in 21% of cardiomyocytes of Dmdmdx-4CV hearts (n=30/140 cells equally sampled from N=4 hearts) compared to 1% of cardiomyocytes of Control hearts (n=2/140 cells from N=4 hearts). Taken together, these data indicate susceptibility to stretch-induced calcium overload, ventricular damage, and ventricular dysfunction in male Dmdmdx-4CV hearts.

Impaired myocardial strain in early stage of Duchenne muscular dystrophy: its relation with age and motor performance.

Duchenne muscular dystrophy (DMD) is complicated by an early and progressive left ventricular (LV) dysfunction. Despite the reduction of ejection fraction (EF) usually manifests in the second decade, subtle alterations in LV mechanics can be detected earlier. Longitudinal and circumferential LV deformation, evaluated by speckle tracking echocardiography (STE), are considered sensitive markers of early dysfunction. We retrospectively examined clinical and echocardiographic data of 32 DMD children with preserved LV function. According to the median age, patients were then divided into younger and older than 9 years, and compared to 24 age-matched healthy subjects. Six-minute-walk test (6MWT), North Star Ambulatory Assessment (NSAA), and a comprehensive cardiac evaluation were performed. Although EF was within the normal range, DMD patients had significantly lower values than healthy controls, and the same occurred for the remaining conventional systolic and diastolic indices. Global longitudinal strain (GLS) was reduced in all patients (older and younger, both p < 0.001). Global circumferential strain (GCS) was reduced only in older patients (< 0.001). Both GLS and GCS worsened with age in DMD patients (GLS p = 0.005; GCS p = 0.024). GLS was significantly worse in the apical segments and in the postero-lateral wall. GCS in the antero-septal, anterior and antero-lateral segments was significantly reduced in older patients, with a prevalent involvement of the sole septal wall in the younger boys. 6MWT appeared to be correlated inversely to GLS and directly to EF. A longitudinal evaluation should be scheduled in DMD boys to assess the global cardiac performance over time and to evaluate the impact of therapies.

LATE BREAKING NEWS E-POSTER PRESENTATION: LBP 5 HOPE-2 one-year results show clinically relevant improvements in upper limb &cardiac function in patients with later stage Duchenne Muscular Dystrophy

HOPE-2 (Halt cardiOmyopathy ProgrEssion in Duchenne 2, NCT03406780) is a randomized, double blind, placebo controlled trial designed to evaluate whether CAP-1002, a cell therapy, improves skeletal muscle function, measured by the performance of the upper limb (PUL), and cardiac function measured by MRI in patients with later stage Duchenne Muscular Dystrophy (DMD). Efficacy of the active treatment, CAP-1002, was evaluated in 20 subjects against placebo treatment through functional assessment of upper limb performance, cardiac measurements, pulmonary tests, quality of life indicators, and biomarkers of inflammation and muscle damage. In the ITT Population, both the full PUL 1.2 and full PUL 2.0 showed significant and meaningful differences between CAP-1002 and Placebo groups in favor of the treatment (PUL 1.2: D=4.1; p=0.03; PUL 2.0: D=2.4; p=0.05). CAP-1002 at 12 months resulted in statistically significant differences versus Placebo by cardiac MRI in mean left ventricular (LV) ejection fraction (mean change from baseline: -0.33% versus -1.89%; D=1.56%; p=0.004), greater reductions in indexed LV end-diastolic volume (D=7.35 mL/m2; p=0.070), LV end-systolic volume (D=6.31 mL; p=0.0045), and indexed LV end-systolic volume (4.80 mL/m2; p=0.0122). LV end-systolic volume is often used as a surrogate for LV remodeling in clinical trials evaluating cardiac outcomes. There was a marked decrease in the CK-MB isozyme biomarker in CAP-1002-treated compared to the Placebo arm indicative of reduced cardiac muscle damage over the course of the study. The HOPE-2 study demonstrated that CAP-1002 therapy is safe and effective in treating deterioration of upper limb and cardiac function in DMD patients.

Manual ability and upper limb performance in nonambulatory stage of Duchenne muscular dystrophy

PurposeThe functional use of the upper extremities in daily living activities has become important in the later ages with the increasing life expectancy of patients with Duchenne muscular dystrophy (DMD). This study aimed to assess manual ability and upper limb performance of nonambulatory children with DMD, and to determine their relationship with factors that might affect ability and performance. MethodsManual ability was determined via the ABILHAND-Kids questionnaire and upper limb performance was assessed with the Performance of Upper Limb (PUL) test. Possible related factors such as functional level, steroid usage, upper limb range of motion (ROM), thumb opposition, upper limb muscular strength, and grip strength were evaluated. Correlations of related factors with manual ability and upper limb performance were analyzed. ResultsThe mean age of 23 nonambulatory DMD children was 13.04±1.39 years. Moderate impairments were determined according to the ABILHAND-Kids and PUL, with scores of 26.30±10.74 and 46.22±15.02, respectively. The functional level, steroid usage, duration of wheelchair use, upper extremity ROM, and global upper limb muscle strength of children were weak-to-strongly correlated with at least one score of ABILHAND-Kids and PUL (P<0.05). ConclusionChildren with DMD may already have severe proximal and mid-level upper extremity involvement, even reflected in distal functions, at the time when they progress to the nonambulatory stage. Besides muscular strength, many related factors should be taken into account for therapists to assess and treat upper limb performance at later stages of DMD.

Transport of Ca2+ and Ca2+-dependent permeability transition in heart mitochondria in the early stages of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a progressive skeletal muscle disease that is associated with severe cardiac complications in the late stages. Significant mitochondrial dysfunction is reportedly responsible for the development of cardiomyopathy with age. At the same time, adaptive changes in mitochondrial metabolism in cardiomyocytes were identified in the early stages of DMD. In this work, we evaluate the functioning of calcium transport systems (MCU and NCLX), and MPT pore in the heart mitochondria of young dystrophin-deficient mice. As compared to wild-type animals, heart mitochondria of mdx mice have been found to be more efficient both in respect to Ca2+ uniport and Na+-dependent Ca2+ efflux. The data obtained indicate that the increased rate of Ca2+ uptake by heart mitochondria of mdx mice may be due to an increase in the ratio of MCU and MCUb subunits. In turn, an increase in the rate of Ca2+ efflux from organelles in DMD may be the result of a significant increase in the level of NCLX. Moreover, the heart mitochondria of mdx mice were more resistant to MPT pore opening, which may be due to an increase in the microviscosity of mitochondrial membranes of DMD mice. At the same time, the level of putative MPT pore proteins did not change. The paper discusses the effect of rearrangements of the mitochondrial proteome involved in the transport and accumulation of calcium on the adaptation of this organ to DMD.

Effects of Positioning on Cough Peak Flow and Muscular Electromyographic Activation in Duchenne Muscular Dystrophy.

Advanced stages of Duchenne muscular dystrophy (DMD) result in muscle weakness and the inability to generate an effective cough. Several factors influence the effectiveness of cough in patients with DMD. The aim of this study was to assess whether differences in positioning affect cough peak flow (CPF) and muscular electromyographic activation in subjects with DMD compared with paired healthy subjects. Optoelectronic plethysmography and surface electromyography were used to assess chest wall volumes, chest wall inspiratory capacity, CPF, breathing pattern, and electromyographic activity of sternocleidomastoid, scalene, rectus abdominis, and external oblique muscles during inspiratory and expiratory cough phases in the supine position, supine position with headrest raised at 45°, and sitting with back support at 80° in 12 subjects with DMD and 12 healthy subjects. Subjects with DMD had lower CPF (P < .01) in comparison to control subjects in all positions; the DMD group also exhibited lower CPF (P = .045) in the supine position versus 80°. Moreover, the relative volume contributions of the rib cage and abdominal compartments to tidal volume modified significantly with posture. The electromyographic activity during inspiratory and expiratory cough phases was lower in subjects with DMD compared to healthy subjects for all evaluated muscles (P < .05), but no significant differences were observed with posture change. In subjects with DMD, posture influenced CPF and the relative contribution of the rib cage and abdominal compartments to tidal volume. However, muscular electromyographic activation was not influenced by posture in subjects with DMD and healthy subjects.

Pulmonary and upper limbs function in children with early stage Duchenne muscular dystrophy compared to their healthy peers

BackgroundPulmonary and upper limbs function of children with Duchenne muscular dystrophy (DMD) are known to deteriorate throughout the disease process. However, there is a lack of information on the extent of impairments in the early stages of DMD when compared to healthy peers. ObjectiveTo investigate to what extent pulmonary and upper limbs function of children with early stage DMD are impaired. MethodsSixty-one children participated in the study: 31 with Grade 1 DMD (study group) according to the Brooke Upper and Lower Extremity Functional Classification Systems, and 30 age matched healthy peers (control group). Pulmonary function was determined with pulmonary function tests. The Performance of Upper Limb test was used to evaluate the upper limbs function. ResultsStudy and control groups were homogenous in terms of physical characteristics (p>0.05). Pulmonary and upper limbs function of children with DMD were about 85% and 93% of healthy peers, respectively. ConclusionThis study provides evidence for deterioration of pulmonary and upper limbs function in children with early stage DMD. Better knowledge of deterioration rate over time may help therapists to better plan and update their plan of care.

Normalized grip strength is a sensitive outcome measure through all stages of Duchenne muscular dystrophy.

The main aim was to explore the changes in hand-grip strength in patients with Duchenne muscular dystrophy (DMD) aged 5-29years. Secondary aims were to test the effect of mutation, ambulatory status and glucocorticoid use on grip strength and its changes over time and to compute the number of subjects needed for a clinical trial to stabilize grip strength. The analysis was performed on data collected during five international natural history studies on a cohort of DMD patients. Two hundred and two patients with genetically proven DMD were pooled from five different natural history studies. Excepting 13 patients with only one visit, the mean duration of follow-up was 2.2 ± 1.6years. A total of 977 measurement points were collected. Grip strength was measured on the dominant side with a high precision dynamometer. The analysis was performed using absolute values and normalized values expressed in percentage of predicted values for age. For absolute values, grip strength typically increased in ambulatory boys and decreased in non-ambulatory patients. However, when normalized, grip strength was already reduced at age 5years and thereafter continued to fall away from normal values. The weaker the patients, the less strength they are prone to lose over again. Grip strength constitutes a sensitive and continuous outcome measure that can be used across all stages of DMD. Its measurement is easy to standardized, can be used in ambulatory and non-ambulatory patients and does not present any floor or ceiling effect. It is thus attractive as an outcome measure in therapeutic trials.

Renal dysfunction can occur in advanced‐stage Duchenne muscular dystrophy

With improved treatments, patients with Duchenne muscular dystrophy (DMD) can survive far beyond adolescence. However, advanced-stage DMD patients are at risk of developing renal dysfunction. In this study, long-term renal function outcomes and associated risk factors in advanced stage DMD were analyzed. Fifty-one patients were classified into three different age groups (<20, 20-29, and ≥30 years of age), and cystatin C (CysC) levels were compared among groups. Median serum CysC levels were 0.74 mg/L, 0.63 mg/L, and 0.76 mg/L in the age groups of <20, 20-29, and ≥30 years, respectively (P = .003). Five of the nine patients in the ≥30 years age group showed elevated serum CysC and decreased cardiac function compared with the other four in the group (P = .014). Our results indicate an association between cardiac and renal dysfunction in patients with advanced-stage DMD.

EP.94Reliability and validity of trunk control measurement scale in Duchenne muscular dystrophy

Trunk control is essential for many daily activities such as sitting and walking. Impaired trunk control causes difficulties in performing daily activities especially at later stage of Duchenne muscular dystrophy (DMD). This study was planned to demonstrate the reliability and validity of trunk control measurement scale (TCMS) in DMD. Twenty boys with DMD were included in the study. Two physiotherapists evaluated all boys with TCMS for inter-rater reliability. TCMS was applied with two weeks interval by the same physiotherapist to examine inter-rater reliability. Criterion-related validity was determined with the correlation between TCMS and motor function measure (MFM), and functional independence measure (FIM). The mean age of children was 9.4±3.3 years. The ICC value of inter-rater reliability was 0.953-0.994 and intra-rater reliability was 0.978-0.997. A positive, strong correlation was found between TCMS and MFM (p<0.01, r=0.88) and TCMS and FIM (p<0.01, r=0.85). TCMS is found to be a reliable and valid assessment to measure trunk control in boys with DMD. The scale can help to clinicians and researchers to observe and determine the trunk control in clinical trials as well as clinical practice.