Major Adverse Dystrophinopathy Event Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy

Abstract

<h3>Purpose</h3> Accurate assessments of heart failure (HF) severity in Duchenne Muscular Dystrophy (DMD) is challenging due to overlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy. We developed an ordinal scale of multiorgan clinical variables and events graded for severity that reflect cumulative disease burden-the <b>M</b>ajor <b>A</b>dverse <b>D</b>ystrophinopathy <b>E</b>vent <b>(MADE</b>) score. We hypothesized that a higher MADE score would be associated with increased mortality in DMD. We used the CINRG Duchenne Natural History Study (DNHS) dataset for MADE score validation. <h3>Methods</h3> DNHS variables were selected based on clinical relevance to prespecified MADE domains: Cardiac, Pulmonary, Myopathy, Nutrition. Severity points (0-4) were assigned and summed for study visits. MADE score for cohorts defined by age, ambulatory status, and survival were compared at enrollment and serially. Ability of baseline MADE score to predict mortality that occurred during the DNHS was examined. <h3>Results</h3> DNHS enrolled 440 males, 12.6 ± 6.1 years old, followed for 3,559 study visits over 4.6 ± 2.8 years, with 45 deaths. MADE score increased with age and was higher in the nonambulatory cohort. Effect of Cardiac and Pulmonary domains on total Score over time doubled and tripled respectively for nonambulatory vs ambulatory cohorts (p<.001). Mean MADE score per visit was 19 ± 10 for those who died vs. 9.8 ± 9.3 in survivors p=0.03. A baseline MADE score >12 predicted mortality independent of age (78% sensitivity, CPE.70). A rising MADE score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p<.001<b>.</b> Figure <h3>Conclusion</h3> A multiorgan severity score, MADE, was developed to track cumulative morbidities that impact HF in DMD. MADE score, independent of age, predicted DNHS mortality. MADE score can be used for serial HF assessment in nonambulatory DMD males and be optimized to serve as an endpoint for DMD clinical research.