Abstract
Eteplirsen, the first FDA-approved therapy for DMD, is applicable to ~13% of the DMD population where skipping exon 51 would restore an open reading frame in the DMD mRNA. Because multiple deletions of one or more exons are amenable to exon 51 skipping, the therapeutic isoforms resulting from these various exon 51-skipped transcripts may vary significantly in stability and function, and hence in their associated phenotype. In order to provide a better estimation of anticipated outcomes of eteplirsen therapy, we conducted a detailed review of both published literature and unpublished database records and compiled reported phenotypes of patients with exon 51 skip-equivalent mutations. Combinatorically, there are 48 potential different in-frame transcripts that may result from exon 51 skipping. We found sufficient clinical information to reliably described phenotypic severity for 137 patients representing 11 of these mutations. All 11 mutations (91 patients) were found in database records and 6 mutations (46 patients) were also reported in the literature. The majority (108/137 patients, or 79%) had a range of mild phenotypes, including isolated dilated cardiomyopathy (n=2) and BMD (n= 94). Of particular interest are patients described as asymptomatic (n=8) or with hyperCKemia alone (n=4), reported among the patients with deletions of exons 45-51, 48-51, and 49-51. Among the remainder, 17 (12%) had a more severe phenotype described as intermediate (IMD, n=2) or DMD (n=15), and 12 reports had no definitive phenotype described. In addition to evaluating clinical phenotypes of reported exon 51 skip-equivalent patients, we are undertaking computer modeling to evaluate the predicted protein structure of all potential exon 51 skipped dystrophin isoforms. We anticipate providing a detailed resource for neuromuscular clinicians that will provide insight into the potential range of outcomes following eteplirsen treatment for patients amenable to exon 51 skipping.