Summary Duchenne muscular dystrophy (DMD) is a severe, progressive disease that affects 1 in 3600–6000 live male births. Although guidelines are available for various aspects of DMD, comprehensive ...clinical care recommendations do not exist. The US Centers for Disease Control and Prevention selected 84 clinicians to develop care recommendations using the RAND Corporation–University of California Los Angeles Appropriateness Method. The DMD Care Considerations Working Group evaluated assessments and interventions used in the management of diagnostics, gastroenterology and nutrition, rehabilitation, and neuromuscular, psychosocial, cardiovascular, respiratory, orthopaedic, and surgical aspects of DMD. These recommendations, presented in two parts, are intended for the wide range of practitioners who care for individuals with DMD. They provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care. In part 1 of this Review, we describe the methods used to generate the recommendations, and the overall perspective on care, pharmacological treatment, and psychosocial management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with ...improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Objective To estimate the age when cardiomyopathy develops in boys with Duchenne muscular dystrophy (DMD) and to analyze the effect of corticosteroid treatment on the age of cardiomyopathy onset. ...Study design We identified a population-based sample of 462 boys with DMD, born between 1982 and 2005, in 5 surveillance sites in the US. Echocardiographic and corticosteroid treatment data were collected. Cardiomyopathy was defined by a reduced fractional shortening (<28%) or ejection fraction (<55%). The age of cardiomyopathy onset was determined. Survival analysis was performed to determine the effects of corticosteroid treatment on cardiomyopathy onset. Results The mean (SD) age of cardiomyopathy onset was 14.3 (4.2) years for the entire population and 15.2 (3.4) years in corticosteroid-treated vs 13.1 (4.8) in non-treated boys. Survival analysis described a significant delay of cardiomyopathy onset for boys treated with corticosteroids ( P < .02). By 14.3 years of age, 63% of non-treated boys had developed cardiomyopathy vs only 36% of those treated. Among boys treated with corticosteroids, there is a significant positive effect of duration of corticosteroid treatment on cardiomyopathy onset ( P < .0001). For every year of corticosteroid treatment, the probability of developing cardiomyopathy decreased by 4%. Conclusions Oral corticosteroid treatment was associated with delayed cardiomyopathy onset. The duration of corticosteroid treatment also correlated positively with delayed cardiomyopathy onset. Our analysis suggests that a boy with DMD treated for 5 years with corticosteroids might experience a 20% decrease in the likelihood of developing cardiomyopathy compared with untreated boys.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Optimum management of Duchenne muscular dystrophy (DMD) requires a multidisciplinary approach that focuses on anticipatory and preventive measures as well as active interventions to address ...the primary and secondary aspects of the disorder. Implementing comprehensive management strategies can favourably alter the natural history of the disease and improve function, quality of life, and longevity. Standardised care can also facilitate planning for multicentre trials and help with the identification of areas in which care can be improved. Here, we present a comprehensive set of DMD care recommendations for management of rehabilitation, orthopaedic, respiratory, cardiovascular, gastroenterology/nutrition, and pain issues, as well as general surgical and emergency-room precautions. Together with part 1 of this Review, which focuses on diagnosis, pharmacological treatment, and psychosocial care, these recommendations allow diagnosis and management to occur in a coordinated multidisciplinary fashion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
OBJECTIVE:To assess safety and efficacy of deflazacort (DFZ) and prednisone (PRED) vs placebo in Duchenne muscular dystrophy (DMD).
METHODS:This phase III, double-blind, randomized, ...placebo-controlled, multicenter study evaluated muscle strength among 196 boys aged 5–15 years with DMD during a 52-week period. In phase 1, participants were randomly assigned to receive treatment with DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, PRED 0.75 mg/kg/d, or placebo for 12 weeks. In phase 2, placebo participants were randomly assigned to 1 of the 3 active treatment groups. Participants originally assigned to an active treatment continued that treatment for an additional 40 weeks. The primary efficacy endpoint was average change in muscle strength from baseline to week 12 compared with placebo. The study was completed in 1995.
RESULTS:All treatment groups (DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, and PRED 0.75 mg/kg/d) demonstrated significant improvement in muscle strength compared with placebo at 12 weeks. Participants taking PRED had significantly more weight gain than placebo or both doses of DFZ at 12 weeks; at 52 weeks, participants taking PRED had significantly more weight gain than both DFZ doses. The most frequent adverse events in all 3 active treatment arms were Cushingoid appearance, erythema, hirsutism, increased weight, headache, and nasopharyngitis.
CONCLUSIONS:After 12 weeks of treatment, PRED and both doses of DFZ improved muscle strength compared with placebo. Deflazacort was associated with less weight gain than PRED.
CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that for boys with DMD, daily use of either DFZ and PRED is effective in preserving muscle strength over a 12-week period.
Objective
To develop RNA splicing biomarkers of disease severity and therapeutic response in myotonic dystrophy type 1 (DM1) and type 2 (DM2).
Methods
In a discovery cohort, we used microarrays to ...perform global analysis of alternative splicing in DM1 and DM2. The newly identified splicing changes were combined with previous data to create a panel of 50 putative splicing defects. In a validation cohort of 50 DM1 subjects, we measured the strength of ankle dorsiflexion (ADF) and then obtained a needle biopsy of tibialis anterior (TA) to analyze splice events in muscle RNA. The specificity of DM‐associated splicing defects was assessed in disease controls. The CTG expansion size in muscle tissue was determined by Southern blot. The reversibility of splicing defects was assessed in transgenic mice by using antisense oligonucleotides to reduce levels of toxic RNA.
Results
Forty‐two splicing defects were confirmed in TA muscle in the validation cohort. Among these, 20 events showed graded changes that correlated with ADF weakness. Five other splice events were strongly affected in DM1 subjects with normal ADF strength. Comparison to disease controls and mouse models indicated that splicing changes were DM‐specific, mainly attributable to MBNL1 sequestration, and reversible in mice by targeted knockdown of toxic RNA. Splicing defects and weakness were not correlated with CTG expansion size in muscle tissue.
Interpretation
Alternative splicing changes in skeletal muscle may serve as biomarkers of disease severity and therapeutic response in myotonic dystrophy. Ann Neurol 2013;74:862–872
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective To identify key factors for the delay in diagnosis of Duchenne muscular dystrophy (DMD) without known family history. Study design The cohort comes from the Muscular Dystrophy Surveillance, ...Tracking, and Research Network (MD STARnet), a multistate, multiple-source, population-based surveillance system that identifies and gathers information on all cases of Duchenne and Becker muscular dystrophy born since 1982. We analyzed medical records of 453 Duchenne and Becker muscular dystrophy boys to document the time course and steps taken to reach a definitive diagnosis. Results Among 156 boys without known family history of DMD prior to birth, first signs or symptoms were noted at a mean age of 2.5 years. Concerns resulted in primary care provider evaluation of the child at a mean age of 3.6 years. Mean age at time of initial creatine kinase was 4.7 years. Mean age at definitive diagnosis of DMD was 4.9 years. Conclusions There is a delay of about 2.5 years between onset of DMD symptoms and the time of definitive diagnosis, unchanged over the previous 2 decades. This delay results in lost opportunities for timely genetic counseling and initiation of corticosteroid treatment. We recommend checking creatine kinase early in the evaluation of boys with unexplained developmental delay.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
ABSTRACT
Introduction: In 2004, a Cochrane Review and AAN practice parameter concluded that prednisone 0.75 mg/kg/day is of short‐term efficacy in Duchenne muscular dystrophy (DMD). Subsequent ...efforts to standardize care for DMD indicated wide variation in corticosteroid use. Methods: We surveyed physicians who follow patients with DMD, including: (1) clinics in the TREAT‐NMD (Translational Research in Europe—Assessment and Treatment of Neuromuscular Diseases) network (predominantly Europe) and (2) U.S. MDA clinic directors. We also documented the co‐administered corticosteroids in a trial of a putative treatment (ataluren) for DMD. Results: Of 105 Treat‐NMD clinicians, corticosteroids were not used in 10 clinics, and 29 different regimens were used—the most frequent 0.75 mg/kg/day prednisone (61 centers); 10 days on/10 days off (36 centers); 0.9 mg/kg/day deflazacort (32 centers); and 5 mg/kg/day on weekends (10 centers). Similar diversity was identified in MDA clinics and in the ataluren trial. Conclusions: Variability in corticosteroid use suggests uncertainty about risks/benefits of corticosteroid regimens for DMD. Muscle Nerve, 2013
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objectives To evaluate growth patterns of ambulatory males with Duchenne muscular dystrophy (DMD) treated with corticosteroids compared with ambulatory, steroid-naïve males with DMD and age-matched ...unaffected general-population males and to test associations between growth and steroid treatment patterns among treated males. Study design Using data from the Muscular Dystrophy Surveillance, Tracking, and Research Network, we identified a total of 1768 height, 2246 weight, and 1755 body mass index (BMI) measurements between age 2 and 12 years for 324 ambulatory males who were treated with corticosteroids for at least 6 months. Growth curve comparisons and linear mixed-effects modeling, adjusted for race/ethnicity and birth year, were used to evaluate growth and steroid treatment patterns (age at initiation, dosing interval, duration, cumulative dose). Results Growth curves for ambulatory males treated with corticosteroids showed significantly shorter stature, heavier weight, and greater BMI compared with ambulatory, steroid-naïve males with DMD and general-population US males. Adjusted linear mixed-effects models for ambulatory males treated with corticosteroids showed that earlier initiation, daily dosing, longer duration, and greater dosages predicted shorter stature with prednisone. Longer duration and greater dosages predicted shorter stature for deflazacort. Daily prednisone dosing predicted lighter weight, but longer duration, and greater dosages predicted heavier weight. Early initiation, less than daily dosing, longer duration, and greater doses predicted greater BMIs. Deflazacort predicted shorter stature, but lighter weight, compared with prednisone. Conclusion Prolonged steroid use is significantly associated with short stature and heavier weight. Growth alterations associated with steroid treatment should be considered when making treatment decisions for males with DMD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
OBJECTIVE:To determine the short-term and long-term effects of dichlorphenamide (DCP) on attack frequency and quality of life in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis.
...METHODS:Two multicenter randomized, double-blind, placebo-controlled trials lasted 9 weeks (Class I evidence), followed by a 1-year extension phase in which all participants received DCP. Forty-four HOP and 21 HYP participants participated. The primary outcome variable was the average number of attacks per week over the final 8 weeks of the double-blind phase.
RESULTS:The median attack rate was lower in HOP participants on DCP than in participants on placebo (0.3 vs 2.4, p = 0.02). The 9-week mean change in the Physical Component Summary score of the Short Form–36 was also better in HOP participants receiving DCP (treatment effect = 7.29 points, 95% confidence interval 2.26 to 12.32, p = 0.006). The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant (p = 0.10). There were no significant effects of DCP on muscle strength or muscle mass in either trial. The most common adverse events in both trials were paresthesia (47% DCP vs 14% placebo, both trials combined) and confusion (19% DCP vs 7% placebo, both trials combined).
CONCLUSIONS:DCP is effective in reducing the attack frequency, is safe, and improves quality of life in HOP periodic paralysis.
CLASSIFICATION OF EVIDENCE:These studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP.
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