The Accredited Duchenne Centers (ADC) Program is a global program initiated by the World Duchenne Organization (WDO). The aim of the ADC Program is to achieve global, uniform and up-to-date care for all people living with Duchenne Muscular Dystrophy (DMD) that are in line with the latest international care considerations and care guidelines. This will be realized by accrediting Duchenne care centers for children and/or adults that provide comprehensive care according to the latest care considerations, and supporting care centers that do not yet meet these criteria for accreditation, to improve care provided to DMD patients. The accreditation process consists of five stages ranging from application to maintenance of accreditation by continuous education. The accreditation criteria and procedures were developed in close collaboration with an international Advisory Board. This paper describes the development and content of the ADC Program. The ADC Program is the first global accreditation program for both children and adults with DMD. The results of the program may contribute to optimal implementation of the latest research insights and optimum care for all people living with DMD and their families.

BACKGROUND AND OBJECTIVE:To optimize care for patients with DMD, it is essential to know to what extent current care complies with the recommended monitoring frequencies suggested by the DMD care considerations. The objective of this study was to investigate the current care for patients with DMD in the Netherlands and to what extent the care complies with the international care considerations.METHODS:A cross-sectional questionnaire was carried out among the Dutch DMD patients and caregivers about the patients' functional and health status, visits to healthcare professionals, clinical tests and assessments, therapy, medication use and access to medical aids and devices. Compliance to guidelines was defined by comparing the frequency of visits to health care providers and clinical tests with the recommended frequencies derived from the care considerations of 2010.RESULTS:Eighty-four participants completed the questionnaire. The majority of participants met the recommended visit frequencies to a neuromuscular specialist and cardiologist. Compliance was suboptimal for respiratory assessments in the non-ambulatory phase, monitoring of side effects of corticosteroid use and neuromuscular assessments. Disease specific information supply was perceived as sufficient and participants were satisfied with the received care.CONCLUSIONS:This study identifies areas in which compliance is lacking. Countries, such as the Netherlands, working according to a shared care system require easy and low-threshold communication between health care centers and a clear division of roles and responsibilities to reach optimal compliance. In the Netherlands the Duchenne Center Netherlands has the coordinating role.

Background: In order to successfully implement the international clinical care guidelines for Duchenne muscular dystrophy (DMD) in the Netherlands, it is essential to know what barriers are experienced by healthcare practitioners regarding guideline adherence and organization of care. In the Netherlands, academic medical centers provide follow up visits and work together with peripheral hospitals, rehabilitation centers, centers for home ventilation and primary care centers for treatment. Objective: To investigate perceived barriers to international clinical DMD guideline adherence and identify potential areas of improvement for implementation in the Dutch ‘shared care’ organization. Methods: Semi-structured in-depth interviews with healthcare practitioners of academic medical hospitals and questionnaires for healthcare practitioners of rehabilitation centers, based on the framework of Cabana. Results: The analyses identified 4 barriers for non-adherence to the DMD guideline: (i) lack of familiarity/awareness, (ii) lack of agreement with specific guideline, (iii) lack of outcome expectancy, (iv) external barriers. Conclusions: A heterogeneous set of barriers is present. Therefore, a multifaceted intervention strategy is proposed to overcome these barriers, including a clear division of roles, allowing for local (Dutch) adaptations per specialism by local consensus groups, and the facilitation of easy communication with experts/opinion leaders as well as between care professionals.

Introduction/Aims: As 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. Methods A 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. Results Eighty-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). Discussion The 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.

Accelerometry of the upper extremity (UE) potentially provides information on the extent of activities in daily life in patients with Duchenne muscular dystrophy (DMD). The objective of this study is to evaluate the validity of home measurements of UE accelerometry.

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.

The field of translational research in Duchenne muscular dystrophy (DMD) has been transformed in the last decade by a number of therapeutic targets, mostly studied in ambulant patients. A paucity of studies focus on measures that capture the non-ambulant stage of the disease, and the transition between the ambulant and non-ambulant phase. In this prospective natural history study, we report the results of a comprehensive assessment of respiratory, upper limb function and upper limb muscle strength in a group of 89 DMD boys followed in 3 European countries, 81 receiving corticosteroids, spanning a wide age range (5-18 years) and functional abilities, from ambulant (n = 60) to non-ambulant (n = 29). Respiratory decline could be detected in the early ambulatory phase using Peak Expiratory Flow percentage predicted (PEF%), despite glucocorticoid use (mean annual decline: 4.08, 95% CI [-7.44,-0.72], p = 0.02 in ambulant; 4.81, 95% CI [-6.79,-2.82], p < 0.001 in non-ambulant). FVC% captured disease progression in non-ambulant DMD subjects, with an annual loss of 5.47% (95% CI [-6.48,-4.45], p < 0.001). Upper limb function measured with the Performance of Upper Limb (PUL 1.2) showed an annual loss of 4.13 points (95% CI [-4.79,3.47], p < 0.001) in the non-ambulant cohort. Measures of upper limb strength (MyoGrip and MyoPinch) showed a continuous decline independent of the ambulatory status, when reported as percentage predicted (grip force -5.51%, 95% CI [-6.54,-4.48], p < 0.001 in ambulant and a slower decline -2.86%; 95% CI -3.29,-2.43, p < 0.001, in non-ambulant; pinch force: -2.66%, 95% CI [-3.82,-1.51], p < 0.001 in ambulant and -2.23%, 95% CI [-2.92,-1.53], p < 0.001 in non-ambulant). Furthermore, we also explored the novel concept of a composite endpoint by combining respiratory, upper limb function and force domains: we were able to identify clear clinical progression in patients in whom an isolated measurement of only one of these domains failed to appreciate the yearly change. Our study contributes to the field of natural history of DMD, linking the ambulant and non-ambulant phases of the disease, and suggests that composite scores should be explored further.

BACKGROUND AND OBJECTIVES:Data on the natural history of facioscapulohumeral dystrophy (FSHD) in childhood are limited and critical for improved patient care and clinical trial readiness. Our objective was to describe the disease course of FSHD in children.METHODS:We performed a nationwide, single-center, prospective cohort study of FSHD in childhood assessing muscle functioning, imaging, and quality of life over 2 years of follow-up.RESULTS:We included 20 children with genetically confirmed FSHD who were 2 to 17 years of age. Overall, symptoms were slowly progressive, and the mean FSHD clinical score increased from 2.1 to 2.8 (p = 0.003). The rate of progression was highly variable. At baseline, 16 of 20 symptomatic children had facial weakness; after 2 years, facial weakness was observed in 19 of 20 children. Muscle strength did not change between baseline and follow-up. The most frequently and most severely affected muscles were the trapezius and deltoid. The functional exercise capacity, measured with the 6-minute walk test, improved. Systemic features were infrequent and nonprogressive. Weakness-associated complications such as lumbar hyperlordosis and dysarthria were common, and their prevalence increased during follow-up. Pain and fatigue were frequent complaints in children, and their prevalence also increased during follow-up. Muscle ultrasonography revealed a progressive increase in echogenicity.DISCUSSION:FSHD in childhood has a slowly progressive but variable course over 2 years of follow-up. The most promising outcome measures to detect progression were the FSHD clinical score and muscle ultrasonography. Despite this disease progression, an improvement on functional capacity may still occur as the child grows up. Pain, fatigue, and a decreased quality of life were common symptoms and need to be addressed in the management of childhood FSHD. Our data can be used to counsel patients and as baseline measures for treatment trials in childhood FSHD.

This study describes the amount of physical activity and perception of physical activity in boys with Duchenne muscular dystrophy (DMD) compared to healthy boys. A questionnaire described 6 domains of physical activity. Four Duchenne muscular dystrophy subgroups were made: early and late ambulatory, nonambulatory with relative good, or limited arm function. Eighty-four boys with Duchenne muscular dystrophy (15.0 ± 6.4 years) and 198 healthy boys (14.0 ± 4.3 years) participated. Daily activities were more passive for boys with Duchenne muscular dystrophy. Physical activity was less and low demanding compared to healthy boys. It decreased with disease severity ( P < .05), whereas screen time increased ( P < .05). Benefits of physical activity in boys with Duchenne muscular dystrophy were having fun and making friends. Barriers were lack of sport facilities and insufficient health. This study helps to quantify poor engagement in physical activity by boys with Duchenne muscular dystrophy, and demonstrates factors that contribute to it. Suggestions to stimulate physical activity are made.

Background The need for deeper understanding of Duchenne muscular dystrophy (DMD) natural history is supported by the rapid advances in translational research, the increase in clinical trials and outcome of recent studies. Aim Assess the natural history of DMD through a composite assessment tool encompassing ambulant and non-ambulant phases of the disease. Methods Multicentre study (5 centres: London, Newcastle, Paris, Leiden, Nijmegen) with a recruitment target of 80-DMD patients assessed 6-monthly according to a shared protocol. Assessments include 6 min walk distance (6 MWD), NorthStar Ambulatory Assessment (NSAA), Performance of Upper Limb (PUL), MyoSet, FVC and whole body DEXA scan (subgroup). Results We analysed longitudinal data for 79 patients, 39 with >24 months follow-up. Ambulant boys>7 years old declined 2.33 points/year in the NSAA (p<0.001). We observed strong correlations between NSAA and timed tests (6 MWD r=0.85,p<0.001; 10 metre run r=−0.87,p<0.001). Non-ambulant boys lost 3.70 PUL scores/year (p<0.001). PUL total had a strong correlation with myogrip (r=0.77,p<0.001), myopinch (r=0.75,p<0.001) and%FVC (r=0.69,p<0.001). All patients with >45% total lean body mass were ambulant. Conclusion This on-going study adds to current knowledge on DMD natural history including expected mean changes per year and the relationship between different outcome measures that will contribute to future trial design and interpretation.

Introduction: The 6-minute walk test (6MWT) is frequently used as an outcome measure for clinical trials in neuromuscular disease. Because this submaximal endurance test is not feasible for nonambulatory patients, the motor-assisted 6-minute cycling test (A6MCT) was developed. Methods: Nineteen children with neuromuscular disorders and children with OXPHOS-dysfunction performed the a6MCT and the 6MWT to explore feasibility and construct validity. Test-retest reproducibility was evaluated within 3 weeks. Results: The assisted 6-minute cycling test was feasible in 90% and 78% of the patients with a neuromuscular disorder and OXPHOS-dysfunction, respectively. The A6MCT for legs correlated with the 6MWT in both patient groups. The assisted 6-minute cycling showed good reproducibility for both legs and arms. Conclusions: This exploratory study indicates that the assisted 6-minute cycling test is a promising outcome measure for patients with a neuromuscular disorder and patients with OXPHOS-dysfunction.

Patients with Duchenne Muscular Dystrophy (DMD) develop progressive loss of arm function. Regular moderate-intensity activities are recommended to prevent disuse atrophy, but conventional resistance exercises are often too strenuous. We conducted a feasibility study to investigate the feasibility and safety of upper limb training with dynamic arm support. Eight boys with DMD who were unable to lift their arms against gravity (age 12-20 years) performed reaching movements with their non-dominant arm for 24 weeks. Participants played a virtual reality computer game and performed activities of daily living while using dynamic arm support. The dominant (untrained) arm of each participant served as a reference. Six of the eight participants completed the entire training program without any adverse events. The trained arm retained more motor function than the untrained arm in 4/6 participants. The findings indicate that boys with DMD can safely train their arms with dynamic arm support.

Novel emerging therapies for Duchenne muscular dystrophy (DMD), such as antisense oligomer (AO) mediated exon skipping, have generated the need of understanding the natural history study of the targeted genotype subgroups. Most natural history studies are focused on ambulant subjects; therefore very little data exists on non-ambulant DMD. Specifically targeting skippable deletions, we aim to assess the natural history of DMD through a composite assessment tool capable of capturing disease progression beyond loss of ambulation. With a recruitment target of 80 DMD patients with AO-skippable-mutations across 5 centres (i.e. London, Newcastle, Paris, Leiden, and Nijmegen), subjects are assessed every 6 months for 3 years according to an internationally agreed shared protocol, including the 6-minute walk test (6MWT), the North Star Ambulatory Assessment (NSAA), as well as the Performance of Upper Limb (PUL) and the MyoSet (i.e. MyoGrip MyoPinch and MoviPlate). Both ambulant and non-ambulant subjects undergo upper limb evaluation, respiratory function test and quality of life questionnaires. Serum biomarkers, including antidystrophin autoreactive T cells, are also evaluated. To date, 57 DMD subjects have been recruited (London, Newcastle and Paris), aged 5 to 18 years; 33 ambulant and 24 non-ambulant; 49 with 18 month follow-up data. The prevalence of autoreactive T cells is ~16%. Using multi-level modelling, nested within a random effect for centre/site, we describe the decline in motor functional parameters over time. We further investigate the relationship between these different variables, focussing on upper body measures, in relation to NSAA score and the 6MWT. We explore any relationship differences between boys with different skippable deletions. Our study offers a comprehensive up-to-date natural history data across all stages of ambulation for DMD subjects with skippable mutations amenable to AO therapies.

In this case study, a 9-year-old ambulatory girl with dystrophinopathy due to a mosaic translocation mutation participated in dynamic training. Because the role of exercise is unclear in both boys and girls with dystrophinopathy, a recently developed assisted bicycle training regimen was evaluated for its feasibility and effectiveness in this girl. The girl trained at home, first 15 minutes with her legs and then 15 minutes with her arms, 5 times a week, for 24 weeks. This case study showed that the training was feasible and safe. In addition, we found that no physical deterioration occurred during the training period: the Motor Function Measure and the Assisted 6-Minute Cycling Test results remained stable. Slight improvements in quantitative muscle ultrasound intensity were found, indicating less fatty infiltration in the muscles. These results suggest that physical training could be beneficial in females with dystrophinopathy who express low levels of dystrophin.

In this case study a 9-year old ambulatory symptomatic girl with Duchenne muscular dystrophy participated in a dynamic training. Since the role of exercise is far from clear in both boys and girls with DMD, a recently developed assisted bicycle training was evaluated for its feasibility and effectiveness in this girl. The girl trained at home, 15 min with her arms followed by her legs, 5 times a week, for 24 weeks. The primary outcomes were the Motor Function Measure, and the Assisted Six-Minute Cycling Test. Secondary outcomes were the Vignos and Brooke scale for lower and upper extremity functioning, timed tests (time to rise from a floor, to rise from a chair, to climb 3 stairs and to walk 10 m), the Medical Research Scale scale for muscle strength, and quantitative muscle ultrasound to determine the echo intensity of the biceps brachii muscle, the forearm flexors, the rectus femoris muscle and the tibialis anterior muscle. This case study showed that the assisted bicycle training was feasible and safe. Additionally, we found that no physical deterioration occurred during the training period: she remained stable on the Motor Function Measure and the Assisted Six-Minute Cycling Test. Slight improvements in quantitative muscle ultrasound intensity were found, indicating less fatty infiltration in the muscles. Since there are several indications from this case study that physical training could be beneficial in this population, we recommend further research on the effects of dynamic training in girls with DMD and its relation to the level of dystrophin.

AimA clinical trial is only as reliable as its outcomes, therefore the careful and systematic selection of outcome measures is extremely important. Currently, the selection of outcome measures for clinical trials designed to evaluate new drugs in patients with mitochondrial disorders is inefficient and has not been addressed systematically. Given that meaningful data can be obtained only from trials in which outcomes are assessed using valid instruments, one should first focus on the validation of a set of selected instruments in the target population. The aim of this review is to systematically select a ‘toolbox’ of robust outcome measures that are relevant to all patients.MethodUsing an extensive search of published literature, we systematically compiled a toolbox with outcome measures based on a primary search for possible instruments Subsequently, we reduced this toolbox using strict criteria that were adapted from the United States Food and Drug Administration.ResultsA toolbox with clinically relevant and psychometrically robust instruments for performing clinical research in children with mitochondrial disorders was compiled.InterpretationIn coming years, more experience using these outcome measures in children with various mitochondrial disease phenotypes must be obtained before reliable conclusions regarding the validity of these instruments can be drawn.

Apoptosis-resistance and metabolic imbalances are prominent features of cancer cells. We have recently reported on populations of human fibroblasts that exhibit resistance to mitochondrial-mediated apoptosis, acquired as a result of a single genotoxic exposure. The objective of the present study was to investigate the intrinsic bioenergetic profile of the death-resistant cells, as compared to the clonogenic control cells. Therefore, we analyzed the basic bioenergetic parameters including oxygen consumption and extracellular acidification rates, coupling efficiency, and spare respiratory capacity. Our data demonstrate a strong correlation between enhanced spare respiratory capacity and death-resistance, which we postulate to be indicative of the earliest stages of carcinogenesis.

BACKGROUND:Physical training might delay the functional deterioration caused by disuse in boys with Duchenne muscular dystrophy (DMD). The "No Use Is Disuse" study is the first explorative, randomized controlled trial in boys with DMD to examine whether assisted bicycle training is feasible, safe, and beneficial.METHODS:Ambulatory and recently wheelchair-dependent boys with DMD were allocated to the intervention or control group. The intervention group received assisted bicycle training of the legs and arms during 24 weeks. The control group received the same training after a waiting period of 24 weeks. The primary study outcomes were the Motor Function Measure (MFM) and the Assisted 6-Minute Cycling Test (A6MCT). Group differences were examined by an analysis of covariance.RESULTS:Thirty boys (mean age 10.5 ± 2.6 years, 18 ambulant and 12 wheelchair-dependent) were allocated to the intervention (n = 17) or the control (n = 13) group. All boys in the intervention group (except one) completed the training. After 24 weeks, the total MFM score remained stable in the intervention group, whereas it had significantly decreased in the control group (Δ = 4.9, 95% confidence interval = 2.2-7.6). No significant group differences were found for the A6MCT. No serious adverse events were observed.CONCLUSIONS:Our results suggest that assisted bicycle training of the legs and arms is feasible and safe for both ambulant and wheelchair-dependent children and may decline the deterioration due to disuse. Progressive deterioration, however, may compromise the design of trials for DMD.

Introduction: For late‐ or non‐ambulant children with a neuromuscular disorder no suitable endurance tests are currently available. We developed the assisted 6‐minute cycling test (A6MCT) for the legs and arms and investigated its psychometric properties in healthy boys and boys with Duchenne muscular dystrophy (DMD). Methods: Ninety‐nine healthy boys and 30 boys with DMD (12 wheelchair‐dependent) performed the A6MCT. Seventy healthy boys also performed the 6‐minute walk test (6MWT), and 23 boys performed the A6MCT twice within 2 weeks. Boys with DMD also performed the Motor Function Measure (MFM). Results: The A6MCT was feasible for >90% of all boys. Boys with DMD achieved fewer cycling revolutions than controls. The A6MCT was positively correlated with the 6MWT and was reproducible in healthy boys, and it correlated with disease severity in boys with DMD. Conclusions: The A6MCT is a promising outcome measure for the follow‐up of non‐ambulant children with a neuromuscular disorder. Muscle Nerve 46: 520–530, 2012

Samenvatting» Neuromusculaire aandoeningen (NMA) zijn aandoeningen van de zenuwen, de spier-zenuwovergangen en de spieren. Zij kennen verschillen in uitingsvorm, overerving, lokalisatie (neurogeen/musculair), zijn progressief of stationair en kunnen verschillen per leeftijdscategorie. Genezing is doorgaans niet mogelijk en daarom wordt vooral symptomatisch behandeld met onder andere fysiotherapie. De levensverwachting van kinderen met een neuromusculaire aandoening neemt toe en daarmee verschuift ook de nadruk van de fysiotherapeutische aanpak. Voor de kinderfysiotherapie ligt er nu meer nadruk op preventie of sturen van contractuurvorming, onderhoud van functionele mogelijkheden en verbeteren van de hart-longconditie. Ook is het van toenemend belang om meetinstrumenten te hanteren, om de effectiviteit van behandelingen in de loop van de tijd te evalueren.