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

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.

Monitoring daily physical activity of upper extremity in young and adolescent boys with Duchenne muscular dystrophy: A pilot study.

INTRODUCTION: 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. METHODS: This was a cross-sectional study in 16 patients with DMD (aged 7-17 years). Patients were monitored for 1 to 3 days with two accelerometers on the UE and one accelerometer on the wheelchair. RESULTS: The mean intensity of activity and the mean frequency of transfers of arm elevation from low to middle were approximately twofold higher in patients with a Brooke scale score of 1 or 2 than in patients with a Brooke scale score of 3 or 4. Correlations with the Performance of Upper Limb scale score were high for intensity and for the total frequency of arm elevations per hour. DISCUSSION: Intensity, percentage of time in middle orientation, and frequency of transfers of the upper arm correlated well with functional measurements.

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study.

OBJECTIVE: Facioscapulohumeral dystrophy (FSHD) is one of the most frequent heritable muscular dystrophies, with a large variety in age at onset and disease severity. The natural history and molecular characteristics of FSHD in childhood are incompletely understood. Our objective is to clinically and genetically characterize FSHD in childhood. METHODS: We performed a nationwide, single-investigator, natural history study on FSHD in childhood. RESULTS: Multiple-source recruitment resulted in 32 patients with FSHD (0-17 years), leading to an estimated prevalence of 1 in 100,000 children in The Netherlands. This series of 32 children with FSHD revealed a heterogeneous phenotype and genotype in childhood. The phenotypic hallmarks of FSHD in childhood are: facial weakness with normal or only mildly affected motor performance, decreased functional exercise capacity (6-minute walk test), lumbar hyperlordosis, and increased echo intensity on muscle ultrasonography. In addition, pain and fatigue were frequent and patients experienced a lower quality of life compared to healthy peers. In contrast to the literature on early-onset FSHD, systemic features such as hearing loss and retinal and cardiac abnormalities were infrequent and subclinical, and epilepsy and intellectual disability were absent. Genotypically, patients had a mean D4Z4 repeat array of 5 units (range, 2-9), and 14% of the mutations were de novo. INTERPRETATION: FSHD in childhood is more prevalent than previously known and the genotype resembles classic FSHD. Importantly, FSHD mainly affects functional exercise capacity and quality of life in children. As such, these results are paramount for counseling, clinical management, and stratification in clinical research. Ann Neurol 2018;84:635-645.

Explaining long-term inter-individual growth variation in plant populations: persistence of abiotic factors matters.

An unanswered question in ecology is whether the environmental factors driving short-term performance also determine the often observed long-term performance differences among individuals. Here, we analyze the extent to which temporal persistence of spatial heterogeneity in environmental factors can contribute to long-term inter-individual variation in stem length growth. For a natural population of a long-lived understorey palm, we first quantified the effect of several environmental factors on stem length growth and survival. We then performed individual-based simulations of growth trajectories, in which we varied, for two environmental factors: (1) the strength of the effect on stem length growth and (2) the temporal persistence. Short-term variation in stem length growth was strongly driven by light availability. Auto-correlation in light availability and soil pH increased simulated variation in stem length growth among 20-year-old palms to levels similar to the observed variation. Analyses in which we varied both the strength of the effect on stem length growth and the temporal persistence of the environmental factors revealed that a large fraction of observed long-term growth differences can be explained, as long as one of these effects is strong. This implies that environmental factors that are relatively unimportant for short-term performance can still drive long-term performance differences when the environmental variation is sufficiently persistent over time.

Assisted 6-minute cycling test: An exploratory study in children.

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. Muscle Nerve, 2015. Muscle Nerve 54: 232-238, 2016.

Quantitative muscle ultrasound and muscle force in healthy children: a 4-year follow-up study.

INTRODUCTION: No longitudinal data on the normal development of muscle thickness (MT), quantitative muscle ultrasound echo intensity (EI), and muscle force (MF) in healthy children are yet available. METHODS: Reference values of MT, EI, and MF of 4 muscles from infancy to age 16 years were established during a 4-year follow-up period and correlated with age and growth. RESULTS: For most muscles, MT and MF correlated with growth and aging, with almost equal influences of weight and height. EI increased only slightly (1% per year) with height, weight, and age. CONCLUSIONS: To use these reference values for repeated measurements, MF and MT can be corrected for either weight or height. It does not seem necessary to correct EI for these factors during follow-up of a few years. These results provide a basis for more precise detection of changes in muscle structure or force in neuromuscular disorders.

Towards the harmonization of outcome measures in children with mitochondrial disorders.

AIM: A 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. METHOD: Using 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. RESULTS: A toolbox with clinically relevant and psychometrically robust instruments for performing clinical research in children with mitochondrial disorders was compiled. INTERPRETATION: In 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.

The assisted 6-minute cycling test to assess endurance in children with a neuromuscular disorder.

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.

Clinical Management of Duchenne Muscular Dystrophy in the Netherlands: Barriers to and Proposals for the Implementation of the International Clinical Practice Guidelines.

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.

Compliance to DMD Care Considerations in the Netherlands.

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.

Habitat Quality Differentiation and Consequences for Ecosystem Service Provision of an Amazonian Hyperdominant Tree Species.

Ecosystem services of Amazonian forests are disproportionally produced by a limited set of hyperdominant tree species. Yet the spatial variation in the delivery of ecosystem services by individual hyperdominant species across their distribution ranges and corresponding environmental gradients is poorly understood. Here, we use the concept of habitat quality to unravel the effect of environmental gradients on seed production and aboveground biomass (AGB) of the Brazil nut, one of Amazonia's largest and most long-lived hyperdominants. We find that a range of climate and soil gradients create trade-offs between density and fitness of Brazil nut trees. Density responses to environmental gradients were in line with predictions under the Janzen-Connell and Herms-Mattson hypotheses, whereas tree fitness responses were in line with resource requirements of trees over their life cycle. These trade-offs resulted in divergent responses in area-based seed production and AGB. While seed production and AGB of individual trees (i.e., fitness) responded similarly to most environmental gradients, they showed opposite tendencies to tree density for almost half of the gradients. However, for gradients creating opposite fitness-density responses, area-based seed production was invariable, while trends in area-based AGB tended to mirror the response of tree density. We conclude that while the relation between environmental gradients and tree density is generally indicative of the response of AGB accumulation in a given area of forest, this is not necessarily the case for fruit production.

Physical training in boys with Duchenne Muscular Dystrophy: the protocol of the No Use is Disuse study.

BACKGROUND: "Use it or lose it" is a well known saying which is applicable to boys with Duchenne Muscular Dystrophy (DMD). Besides the direct effects of the muscular dystrophy, the increasing effort to perform activities, the fear of falling and the use of personal aids indirectly impair leg and arm functions as a result of disuse. Physical training could oppose this secondary physical deterioration. The No Use is Disuse (NUD) study is the first study in human subjects with DMD that will examine whether a low-intensity physical training is beneficial in terms of preservation of muscle endurance and functional abilities. The study consists of two training intervention studies: study 1 "Dynamic leg and arm training for ambulant and recently wheelchair-dependent boys with DMD and, study 2 "Functional training with arm support for boys with DMD who have been confined to a wheelchair for several years". This paper describes the hypotheses and methods of the NUD study. METHODS: Study 1 is an explorative randomized controlled trial with multiple baseline measurements. Thirty boys with a DNA-established diagnosis of DMD will be included. The intervention consists of a six-months physical training during which boys train their legs and arms with active and/or assisted cycling training equipment. The primary study outcomes are muscle endurance and functional abilities, assessed with a Six-Minute Bicycle Test and the Motor Function Measure. Study 2 has a within-group repeated measurements design and will include ten boys with DMD who have already been confined to a wheelchair for several years. The six-months physical training program consists of 1) a computer-assisted training and 2) a functional training with an arm support. The primary study outcome is functional abilities of the upper extremity, assessed with the Action Research Arm Test. DISCUSSION: The NUD study will fill part of the gap in the current knowledge about the possible effects of training in boys with DMD and will increase insight into what type of exercise should be recommended to boys with DMD. The study will finish at the end of 2010 and results are expected in 2011. TRIAL REGISTRATION: The Netherlands National Trial Register1631.

Heritability of growth and leaf loss compensation in a long-lived tropical understorey palm.

INTRODUCTION: Defoliation and light competition are ubiquitous stressors that can strongly limit plant performance. Tolerance to defoliation is often associated with compensatory growth, which could be positively or negatively related to plant growth. Genetic variation in growth, tolerance and compensation, in turn, plays an important role in the evolutionary adaptation of plants to changing disturbance regimes but this issue has been poorly investigated for long-lived woody species. We quantified genetic variation in plant growth and growth parameters, tolerance to defoliation and compensation for a population of the understorey palm Chamaedorea elegans. In addition, we evaluated genetic correlations between growth and tolerance/compensation. METHODS: We performed a greenhouse experiment with 711 seedlings from 43 families with twelve or more individuals of C. elegans. Seeds were collected in southeast Mexico within a 0.7 ha natural forest area. A two-third defoliation treatment (repeated every two months) was applied to half of the individuals to simulate leaf loss. Compensatory responses in specific leaf area, biomass allocation to leaves and growth per unit leaf area were quantified using iterative growth models. RESULTS: We found that growth rate was highly heritable and that plants compensated strongly for leaf loss. However, genetic variation in tolerance, compensation, and the individual compensatory responses was low. We found strong correlations between family mean growth rates in control and defoliation treatments. We did not find indications for growth-tolerance/compensation trade-offs: genetic correlation between tolerance/compensation and growth rate were not significant. IMPLICATIONS: The high genetic variation in growth rate, but low genetic variation in tolerance and compensation observed here suggest high ability to adapt to changes in environment that require different growth rates, but a low potential for evolutionary adaptation to changes in damage or herbivory. The strong correlations between family mean growth rates in control and defoliation treatments suggest that performance differences among families are also maintained under stress of disturbance.

Virtual Reality Computer Gaming with Dynamic Arm Support in Boys with Duchenne Muscular Dystrophy.

BACKGROUND: In boys with Duchenne muscular dystrophy (DMD), loss of upper limb function becomes more evident after the onset of wheelchair-dependency, because of the inability to lift the arms against gravity. With an increasing population of older wheelchair-dependent boys with DMD it is worthwhile to know whether training can delay the loss of upper limb functions. Dynamic arm supports may enable boys with impaired arm function to train their muscles without becoming exhausted by providing external mechanical compensation for muscle weakness. OBJECTIVE: This study investigated the effect of gravity-compensated 3D-training for the arms on the functional abilities in boys with DMD. METHODS: An explorative RCT was conducted among boys with DMD with impaired arm function (n = 16). Boys in the intervention group (n = 7) trained their arms by playing virtual reality games while using dynamic arm support during 20 weeks. The primary endpoint was the difference in change in Performance of the Upper Limb (PUL) score between the intervention and control group (n = 9) after 20 weeks. Secondary outcome measures were at the different ICF-CY levels. RESULTS: No significant group differences were found for the PUL. Elbow range of motion (p = 0.018) and extension strength (p = 0.038) improved in the intervention group and worsened in the control group. CONCLUSIONS: Although this study did not show a significant effect of training on the primary outcome measure, there are indications that training may decline the loss of range of motion and strength. This may prolong the functional abilities on long-term. TRIAL REGISTRATION: Netherlands Trial Register 3857.

Physical Activity in Boys With Duchenne Muscular Dystrophy Is Lower and Less Demanding Compared to Healthy Boys.

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.

What can we learn from assisted bicycle training in a girl with dystrophinopathy? A case study.

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.

Assisted bicycle training delays functional deterioration in boys with Duchenne muscular dystrophy: the randomized controlled trial "no use is disuse".

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.

Quantitative muscle ultrasound is a promising longitudinal follow-up tool in Duchenne muscular dystrophy.

Responsive outcome measures are needed to follow the disease status of Duchenne muscular dystrophy (DMD) patients, as new therapeutic approaches become available for affected boys. Quantitative muscle ultrasound (QMUS) is potentially an attractive follow up tool for DMD because it reflects the severity of the dystrophic process without the need for invasive procedures, by quantifying echo intensity (i.e., mean grey level of muscle images) and muscle thickness. We performed a longitudinal follow-up of lower and upper extremity QMUS in 18 DMD patients and compared this with physical functioning in 11 of these patients. QMUS could be performed in every patient, and no patient was subjected to more than a total of 20min of ultrasound scanning time for this study. As expected we found a significant increase of echo intensity with age, reflecting increasing dystrophic muscle changes. This increase was related to ambulatory status, functional grading, muscle strength and motor ability. Our study establishes QMUS as a practical and child-friendly tool for the longitudinal follow up of DMD patients.