Phenotypic Spectrum of Dystrophinopathy Due to Duchenne Muscular Dystrophy Exon 2 Duplications
Alberto A. Zambon, Megan A. Waldrop, Roxane Alles, Robert B. Weiss, Sara Conroy, Melissa Moore-Clingenpeel, Stefano Previtali, Kevin M. Flanigan, on behalf of the Italian DMD Network and the United Dystrophinopathy Project
Abstract
<h3>Background and Objectives</h3> To describe the phenotypic spectrum of dystrophinopathy in a large cohort of individuals with <i>DMD</i> exon 2 duplications (Dup2), who may be particularly amenable to therapies directed at restoring expression of either full-length dystrophin or nearly full-length dystrophin through utilization of the <i>DMD</i> exon 5 internal ribosome entry site (IRES). <h3>Methods</h3> In this retrospective observational study, we analyzed data from large genotype–phenotype databases (the United Dystrophinopathy Project [UDP] and the Italian DMD network) and classified participants into Duchenne muscular dystrophy (DMD), intermediate muscular dystrophy (IMD), or Becker muscular dystrophy (BMD) phenotypes. Log-rank tests for time-to-event variables were used to compare age at loss of ambulation (LOA) in participants with Dup2 vs controls without Dup2 in the UDP database and for comparisons between steroid-treated vs steroid-naive participants with Dup2. <h3>Results</h3> Among 66 participants with Dup2 (UDP = 40, Italy = 26), 61% were classified as DMD, 9% as IMD, and 30% as BMD. Median age at last observation was 15.4 years (interquartile range 8.79–26.0) and 75% had been on corticosteroids for at least 6 months. Age at LOA differed significantly between participants with Dup2 DMD and historical controls without Dup2 DMD (<i>p</i> < 0.001). Valid spirometry was limited but suggested a delay in the typical age-related decline in forced vital capacity and 24 of 55 participants with adequate cardiac data had cardiomyopathy. <h3>Discussion</h3> Some patients with Dup2 display a milder disease course than controls without Dup2 DMD, and prolonged ambulation with corticosteroids suggests the potential of IRES activation as a molecular mechanism. As Dup2-targeted therapies reach clinical applications, this information is critical to aid in the interpretation of the efficacy of new treatments.