Major Adverse Dystrophinopathy Events (MADE) score as marker of cumulative morbidity and risk for mortality in boys with Duchenne muscular dystrophy

Abstract

BackgroundOverlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy confound assessment of heart failure in Duchenne Muscular Dystrophy. We developed an ordinal scale of multiorgan clinical variables that reflect cumulative disease burden—the Major Adverse Dystrophinopathy Event (MADE) Score. We hypothesized that a higher MADE Score would be associated with increased mortality in boys with Duchenne Muscular Dystrophy. The Cooperative International Neuromuscular Research Group Duchenne Natural History Study dataset was utilized for validation. MethodsDuchenne Natural History Study variables were selected based on clinical relevance to prespecified domains: Cardiac, Pulmonary, Myopathy, and Nutrition. Severity points (0–4) were assigned and summed for study visits. MADE Score for cohorts defined by age, ambulatory status, and survival was compared at enrollment and longitudinally.Associations between MADE Score and mortality were examined. ResultsDuchenne Natural History Study enrolled 440 males, 12.6 ± 6.1 years old, with 3559 visits over 4.6 ± 2.8 years, 45 deaths. MADE Score increased with age and nonambulatory status. Mean MADE Score per visit was 19 ± 10 for those who died vs. 9.8 ± 9.3 in survivors p = 0.03. Baseline MADE Score >12 predicted mortality independent of age (78 % sensitivity, CPE.70). Rising MADE Score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p < 0.001. ConclusionA multiorgan severity score, MADE, was developed to track cumulative morbidities that impact heart failure in Duchenne muscular dystrophy. MADE Score predicted Duchenne Natural History Study mortality. MADE Score can be used for serial heart failure assessment in males with Duchenne muscular dystrophy and may serve as an endpoint for related clinical research.