Affiliations: [a] The Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, USA
| [b] Departments of Neurology and Pediatrics, The Ohio State University, Columbus, OH, USA
| [c] Center of Research in Myology, Sorbonne Université - Inserm UMRS 974; Databases unit; APHP, Nord/Est/Ile-de-France Neuromuscular reference center, Institut de Myologie, Hôpital Pitié-Salpêtrière, Paris, France
| [d] Sarepta Therapeutics, Inc., Cambridge, MA, USA
| [e] Parent Project Muscular Dystrophy, Hackensack, NJ, USA
| [f] French health network for neuromuscular diseases, Hôpital La Timone, Marseille, France, http://www.filnemus.fr/
| [g] U.O. Genetica Medica, Azienda Ospedaliero-Universitaria di Ferrara | [h] Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neuroscience Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom
| [j] APHP, Laboratoire de Génétique et Biologie Moléculaires, HUPC Hôpital Cochin, Paris, France; Center of Research in Myology, Sorbonne Université - Inserm UMRS 974 | [k] Université de Montpellier, Laboratoire de Génétique de Maladies Rares, Montpellier, France
| [l] Department of Human Genetics, The University of Utah, Salt Lake City, UT, USA
Correspondence to: Megan A. Waldrop, MD, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Research Building II, Room 3013, 700 Children’s Drive, Columbus, OH 43230, USA. E-mail: [email protected].
Note: [‡] Contributors from the Filnemus network and the United Dystrophinopathy project are listed at the end of the manuscript.
Abstract: Background:Eteplirsen, the first FDA-approved RNA-modifying therapy for DMD, is applicable to ∼13% of patients with DMD. Because multiple exonic deletions are amenable to exon 51 skipping, the isoforms resulting from the various exon 51-skipped transcripts may vary in stability, function, and phenotype. Objective/Methods:We conducted a detailed review of dystrophinopathy published literature and unpublished databases to compile phenotypic features of patients with exon 51 “skip-equivalent” deletions. Results:Theoretically, 48 different in-frame transcripts may result from exon 51 skipping. We found sufficient clinical information on 135 patients carrying mutations that would result in production of 11 (23%) of these transcripts, suggesting the remainder have not been identified in vivo. The majority had mild phenotypes: BMD (n = 81) or isolated dilated cardiomyopathy (n = 3). Particularly interesting are the asymptomatic (n = 10) or isolated hyperCKemia (n = 20) patients with deletions of exons 45– 51, 48– 51, 49– 51 and 50– 51. Finally, 16 (12%) had more severe phenotypes described as intermediate (n = 2) or DMD (n = 14), and 6 reports had no definitive phenotype. Conclusions:This review shows that the majority of exon 51 “skip-equivalent” deletions result in milder (BMD) phenotypes and supports that exon 51 skipping therapy could provide clinical benefit, although we acknowledge that other factors, such as age at treatment initiation or ongoing standard of care, may influence the degree of benefit.