Association of genetic mutations and loss of ambulation in childhood-onset dystrophinopathy.

BACKGROUND: Quantifying associations between genetic mutations and loss of ambulation (LoA) among males diagnosed with childhood-onset dystrophinopathy is important for understanding variation in disease progression and may be useful in clinical trial design. METHODS: Genetic and clinical data from the Muscular Dystrophy Surveillance, Tracking, and Research Network for 358 males born and diagnosed from 1982 to 2011 were analyzed. LoA was defined as the age at which independent ambulation ceased. Genetic mutations were defined by overall type (deletion/duplication/point mutation) and among deletions, those amenable to exon-skipping therapy (exons 8, 20, 44-46, 51-53) and another group. Cox proportional hazards regression modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Mutation type did not predict time to LoA. Controlling for corticosteroids, Exons 8 (HR = 0.22; 95% CI = 0.08, 0.63) and 44 (HR = 0.30; 95% CI = 0.12, 0.78) were associated with delayed LoA compared to other exon deletions. CONCLUSIONS: Delayed LoA in males with mutations amenable to exon-skipping therapy is consistent with previous studies. These findings suggest that clinical trials including exon 8 and 44 skippable males should consider mutation information prior to randomization.

Left ventricular dysfunction in Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy is associated with progressive cardiorespiratory failure, including left ventricular dysfunction. METHODS AND RESULTS: Males with probable or definite diagnosis of Duchenne muscular dystrophy, diagnosed between 1 January, 1982 and 31 December, 2011, were identified from the Muscular Dystrophy Surveillance Tracking and Research Network database. Two non-mutually exclusive groups were created: patients with ≥2 echocardiograms and non-invasive positive pressure ventilation-compliant patients with ≥1 recorded ejection fraction. Quantitative left ventricular dysfunction was defined as an ejection fraction <55%. Qualitative dysfunction was defined as mild, moderate, or severe. Progression of quantitative left ventricular dysfunction was modelled as a continuous time-varying outcome. Change in qualitative left ventricle function was assessed by the percentage of patients within each category at each age. Forty-one percent (n = 403) had ≥2 ejection fractions containing 998 qualitative assessments with a mean age at first echo of 10.8 ± 4.6 years, with an average first ejection fraction of 63.1 ± 12.6%. Mean age at first echo with an ejection fraction <55 was 15.2 ± 3.9 years. Thirty-five percent (140/403) were non-invasive positive pressure ventilation-compliant and had ejection fraction information. The estimated rate of decline in ejection fraction from first ejection fraction was 1.6% per year and initiation of non-invasive positive pressure ventilation did not change this rate. CONCLUSIONS: In our cohort, we observed that left ventricle function in patients with Duchenne muscular dystrophy declined over time, independent of non-invasive positive pressure ventilation use. Future studies are needed to examine the impact of respiratory support on cardiac function.

The effect of steroid treatment on weight in nonambulatory males with Duchenne muscular dystrophy.

To describe the long-term effect of steroid treatment on weight in nonambulatory males with Duchenne Muscular Dystrophy (DMD), we identified 392 males age 7-29 years with 4,512 weights collected after ambulation loss (176 steroid-naïve and 216 treated with steroids ≥6 months) from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Comparisons were made between the weight growth curves for steroid-naïve males with DMD, steroid-treated males with DMD, and the US pediatric male population. Using linear mixed-effects models adjusted for race/ethnicity and birth year, we evaluated the association between weight-for-age and steroid treatment characteristics (age at initiation, dosing interval, cumulative duration, cumulative dose, type). The weight growth curves for steroid-naïve and steroid-treated nonambulatory males with DMD were wider than the US pediatric male growth curves. Mean weight-for-age z scores were lower in both steroid-naïve (mean = -1.3) and steroid-treated (mean = -0.02) nonambulatory males with DMD, compared to the US pediatric male population. Longer treatment duration and greater cumulative dose were significantly associated with lower mean weight-for-age z scores. Providers should consider the effect of steroid treatment on weight when making postambulation treatment decisions for males with DMD.

Health profile of a cohort of adults with Duchenne muscular dystrophy.

INTRODUCTION: As the Duchenne muscular dystrophy (DMD) population ages, it is essential that we understand the late-stage health profile and provide the appropriate care for this emerging population. METHODS: We undertook a descriptive study to document the health profile of a cohort of adults with DMD using data from the Muscular Dystrophy Surveillance Tracking and Research network (MD STARnet). Data included information collected from Arizona, Colorado, Iowa, Georgia, and 12 counties in western New York on individuals born since January 1982 and followed through December 2012. RESULTS: In 208 adults with DMD, the number of individuals (N) and median ages (years) at which certain critical milestones were crossed and interventions initiated were as follows: development of cardiomyopathy, N = 145 (16.7); initiation of non-invasive ventilation, N = 99 (18.0); gastrostomy, N = 47 (19.0); and death, N = 59 (21.8). DISCUSSION: These population-based data provide critical information about late-stage health profiles among adults with DMD for developing appropriate models of care. Muscle Nerve 58: 219-223, 2018.

Corticosteroid Treatment and Growth Patterns in Ambulatory Males with Duchenne Muscular Dystrophy.

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.

Health services received by individuals with duchenne/becker muscular dystrophy.

INTRODUCTION: Anecdotal reports from families and care providers suggest a wide variation in services received by individuals with Duchenne/Becker muscular dystrophy (DBMD). METHODS: We documented the type and frequency of health services received by individuals with DBMD using the Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) interview data released in June 2012. Interviews with eligible caregivers from 5 sites (Arizona, Colorado, Georgia, Iowa, and western New York) were conducted from April 2007 to March 2012. RESULTS: Two hundred ninety-six caregivers (66% of those contactable) participated in the interview. There were significant differences among sites in the specialists seen and services received. Concurrence with cardiac recommendations was higher than that with respiratory recommendations. CONCLUSIONS: The results of this survey support and quantify the anecdotal reports from families and care providers regarding the disparities in services received by individuals with DBMD. It remains to be determined whether these differences affect outcomes.

Myotonic dystrophy health index: Correlations with clinical tests and patient function.

INTRODUCTION: The Myotonic Dystrophy Health Index (MDHI) is a disease-specific patient-reported outcome measure. Here, we examine the associations between the MDHI and other measures of disease burden in a cohort of individuals with myotonic dystrophy type-1 (DM1). METHODS: We conducted a cross-sectional study of 70 patients with DM1. We examined the associations between MDHI total and subscale scores and scores from other clinical tests. Participants completed assessments of strength, myotonia, motor and respiratory function, ambulation, and body composition. Participants also provided blood samples, underwent physician evaluations, and completed other patient-reported outcome measures. RESULTS: MDHI total and subscale scores were strongly associated with muscle strength, myotonia, motor function, and other clinical measures. CONCLUSIONS: Patient-reported health status, as measured by the MDHI, is associated with alternative measures of clinical health. These results support the use of the MDHI as a valid tool to measure disease burden in DM1 patients.

Rasch analysis of the Pediatric Evaluation of Disability Inventory-computer adaptive test (PEDI-CAT) item bank for children and young adults with spinal muscular atrophy.

INTRODUCTION: In this study we evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA). METHODS: PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types. RESULTS: Unidimensional content for each domain was confirmed. The PEDI-CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types. CONCLUSIONS: The PEDI-CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. Muscle Nerve 54: 1097-1107, 2016.

Spinal muscular atrophy functional composite score: A functional measure in spinal muscular atrophy.

INTRODUCTION: With clinical trials underway, our objective was to construct a composite score of global function that could discriminate among people with spinal muscular atrophy (SMA). METHODS: Data were collected from 126 participants with SMA types 2 and 3. Scores from the Hammersmith Functional Motor Scale-Expanded and Upper Limb Module were expressed as a percentage of the maximum score and 6-minute walk test as percent of predicted normal distance. A principal component analysis was performed on the correlation matrix for the 3 percentage scores. RESULTS: The first principal component yielded a composite score with approximately equal weighting of the 3 components and accounted for 82% of the total variability. The SMA functional composite score, an unweighted average of the 3 individual percentage scores, correlated almost perfectly with the first principal component. CONCLUSIONS: This combination of measures broadens the spectrum of ability that can be quantified in type 2 and 3 SMA patients.

Risk Factors for First Fractures Among Males With Duchenne or Becker Muscular Dystrophy.

BACKGROUND: Fractures are a significant concern for individuals with Duchenne/Becker muscular dystrophy with 21% to 44% of males experiencing a fracture. Factors that increase or decrease the risk for fracture have been suggested in past research, although statistical risk has not been determined. METHODS: In this retrospective cohort study, we used the Muscular Dystrophy Surveillance, Tracking and Research Network cohort, a large, population-based sample to identify risk factors associated with first fractures in patients with Duchenne or Becker muscular dystrophy. Our study cohort included males with Duchenne or Becker muscular dystrophy born between 1982 and 2006 who resided in Arizona, Colorado, Georgia, Iowa, and Western New York, retrospectively identified and followed through 2010. We utilized a multivariate Cox proportional hazard model to determine hazard ratios for relevant factors associated with first fracture risk including race/ethnicity, surveillance site, ambulation status, calcium/vitamin D use and duration, bisphosphonate use and duration, and corticosteroid use and duration. RESULTS: Of 747 cases, 249 had at least 1 fracture (33.3%). Full-time wheelchair use increased the risk of first fracture by 75% for every 3 months of use (hazard ratio=1.75, 95% confidence interval, 1.14, 2.68), but corticosteroid use, bisphosphonate use, and calcium/vitamin D use did not significantly affect risk in the final adjusted model. CONCLUSIONS: In this cohort, first fractures were common and full-time wheelchair use, but not corticosteroid use, was identified as a risk factor. The impact of prevention measures should be more thoroughly assessed. CLINICAL RELEVANCE: Fractures are a significant concern for individuals with dystrophinopathies, but the contribution of various risk factors has not been consistently demonstrated.

Splicing biomarkers of disease severity in myotonic dystrophy.

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.

Sibling concordance for clinical features of Duchenne and Becker muscular dystrophies.

INTRODUCTION: The correlation of markers of disease severity among brothers with Duchenne or Becker muscular dystrophy has implications for clinical guidance and clinical trials. METHODS: Sibling pairs with Duchenne or Becker muscular dystrophy (n = 60) were compared for ages when they reached clinical milestones of disease progression, including ceased ambulation, scoliosis of ≥ 20°, and development of cardiomyopathy. RESULTS: The median age at which younger brothers reached each milestone, compared with their older brothers ranged from 25 months younger for development of cardiomyopathy to 2 months older for ceased ambulation. For each additional month of ambulation by the older brother, the hazard of ceased ambulation by the younger brother decreased by 4%. CONCLUSIONS: The ages when siblings reach clinical milestones of disease vary widely between siblings. However, the time to ceased ambulation for older brothers predicts the time to ceased ambulation for their younger brothers.

Rasch analysis of clinical outcome measures in spinal muscular atrophy.

INTRODUCTION: Trial design for SMA depends on meaningful rating scales to assess outcomes. In this study Rasch methodology was applied to 9 motor scales in spinal muscular atrophy (SMA). METHODS: Data from all 3 SMA types were provided by research groups for 9 commonly used scales. Rasch methodology assessed the ordering of response option thresholds, tests of fit, spread of item locations, residual correlations, and person separation index. RESULTS: Each scale had good reliability. However, several issues impacting scale validity were identified, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum. CONCLUSIONS: The sensitivity and potential utility of each SMA scale as outcome measures for trials could be improved by establishing clear definitions of what is measured, reconsidering items that misfit and items whose response categories have reversed thresholds, and adding new items at the extremes of scale ranges.

Oral corticosteroids and onset of cardiomyopathy in Duchenne muscular dystrophy.

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.

Corticosteroids in Duchenne muscular dystrophy: major variations in practice.

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.

Role of disease severity, illness perceptions, and mood on quality of life in muscle disease.

INTRODUCTION: The aim of this study was to describe the effect of muscle disease upon QoL and to explore the influence of disease severity, mood, and illness perception on the QoL of these patients. METHODS: Validated questionnaires assessing QoL (Individualized Neuromuscular QoL and SF-36), disease severity (Health Assessment Questionnaire), mood (Hospital Anxiety and Depression Scale) and illness perception (Illness Perception Questionnaire) were sent to adults with muscle disease. RESULTS: We received 302 responses (return rate 75%). QoL was reduced, particularly for "physical" domains, but "psychological" domains were also affected. Disease severity was the main determinant for the "physical" domains of QoL, but mood and illness perception played a part. Conversely, mood and illness perception were the main determinants for the "psychological" domains of QoL. CONCLUSIONS: Because mood and illness perception explain significant variance in QoL in muscle disease, there is scope for devising psychosocial interventions that may improve QoL for those with muscle disease.

A quantitative measure of handgrip myotonia in non-dystrophic myotonia.

INTRODUCTION: Non-dystrophic myotonia (NDM) is characterized by myotonia without muscle wasting. A standardized quantitative myotonia assessment (QMA) is important for clinical trials. METHODS: Myotonia was assessed in 91 individuals enrolled in a natural history study using a commercially available computerized handgrip myometer and automated software. Average peak force and 90% to 5% relaxation times were compared with historical normal controls studied with identical methods. RESULTS: Thirty subjects had chloride channel mutations, 31 had sodium channel mutations, 6 had DM2 mutations, and 24 had no identified mutation. Chloride channel mutations were associated with prolonged first handgrip relaxation times and warm-up on subsequent handgrips. Sodium channel mutations were associated with prolonged first handgrip relaxation times and paradoxical myotonia or warm-up, depending on underlying mutations. DM2 subjects had normal relaxation times but decreased peak force. Sample size estimates are provided for clinical trial planning. CONCLUSION: QMA is an automated, non-invasive technique for evaluating myotonia in NDM.

Differentiation of Pediatric-Onset Duchenne and Becker Muscular Dystrophy Subphenotypes Using Data from the Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet).

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) phenotypes are used to describe disease progression in affected individuals. However, considerable heterogeneity has been observed across and within these two phenotypes, suggesting a spectrum of severity rather than distinct conditions. Characterizing the phenotypes and subphenotypes aids researchers in the design of clinical studies and clinicians in providing anticipatory guidance to affected individuals and their families. Using data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet), we used K-means cluster analysis to group phenotypically similar males with pediatric-onset dystrophinopathy. We identified four dystrophinopathy clusters: Classical BMD, Classical DMD, late ambulatory DMD, and severe DMD. The clusters that we identified align with both 'classical' and 'non-classical' dystrophinopathy described in the literature. Individuals with dystrophinopathies have heterogenous clinical presentations that cluster into phenotypically similar groups. Use of clinically-derived phenotyping may provide a clearer understanding of disease trajectories, reduce variability in study results, and prevent exclusion of certain cohorts from analysis. Findings from studying subphenotypes may ultimately improve our ability to predict disease progression.

Selected clinical and demographic factors and all-cause mortality among individuals with Duchenne muscular dystrophy in the Muscular Dystrophy Surveillance, Tracking, and Research Network.

Population-based estimates of survival among individuals with Duchenne muscular dystrophy (DMD) living in the United States are lacking. It is also unclear whether the association between glucocorticoid use and all-cause mortality persists in the context of other common treatments (cardiac medication, cough-assist, bilevel positive airway pressure, and scoliosis surgery) observed to delay mortality. Among 526 individuals identified by the Muscular Dystrophy Surveillance, Tracking, and Research Network, the estimated median survival time from birth was 23.7 years. Current glucocorticoid users had a lower hazard of mortality than non-users. Individuals who ever had scoliosis surgery had a lower hazard of mortality than individuals who did not have scoliosis surgery. Individuals who ever used cough assist had a lower hazard of mortality than individuals who never used cough assist. Non-Hispanic Black individuals had a higher hazard of mortality than non-Hispanic White individuals. No differences in hazards of mortality were observed between ever versus never use of cardiac medication and ever versus never use of bilevel positive airway pressure. The glucocorticoid observation is consistent with the 2018 Care Considerations statement that glucocorticoid use continues in the non-ambulatory phase. Our observations may inform the clinical care of individuals living with DMD.

Role Attainment in Emerging Adulthood: Subjective Evaluation by Male Adolescents and Adults with Duchenne and Becker Muscular Dystrophy.

BACKGROUND: Youth with Duchenne and Becker muscular dystrophy (DBMD) experience challenges in attaining adult roles, which may impact quality of life. New interventions and treatments may facilitate adult role attainment through improved function. Historical data on adult role attainment is important to assess the impact of new interventions on teens and young adults with DBMD. This study assesses medical knowledge, independence and employment, and relationships among adolescents and young adults with DBMD. METHODS: This study uses data from a 2013 Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) survey on adult transition. Males with DBMD aged 16-30 years were included. RESULTS: Sixty-five of 258 eligible males participated; we report results on 60 participants with an MD STARnet case definition of DMD or BMD. Individuals with BMD reported higher rates than those with DMD of frequently staying home without supervision (50% BMD; 14% DMD), independently performing daily physical needs (93% BMD; 7% DMD) and being employed full or part time (33% BMD; 4% DMD). Most participants understood medication and physical therapy goals; less than half indicated being often or always responsible for scheduling DMBD-related management and refilling medications. Most had not been in a romantic relationship but reported desiring such relationships. CONCLUSIONS: Our data reinforce the impact of DMD (and to a lesser extent, BMD) on transition to adult roles. These results provide an important historical comparator for teen and adult patients who are trying new interventions and therapies. Such data are important for assessing the quality-of-life impact of new treatments and to inform support and training programs for people with DBMD as they transition to new adult roles and responsibilities.