Clinical Phenotypes of DMD Exon 51 Skip Equivalent Deletions: A Systematic Review
| Autor: | Robert B. Weiss, Francesco Muntoni, Ann Martin, Alessandra Ferlini, Karin K Lucas, Megan A. Waldrop, Rabah Ben Yaou, Kevin M. Flanigan, Erin O'Rourke, Sylvie Tuffery-Giraud, Filnemus |
|---|---|
| Přispěvatelé: | Nationwide Children's Hospital, The Ohio State University Press, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sarepta Therapeutics, Parent Project Muscular Dystrophy [Hackensack, NJ, USA] (P2MD), Azienda Ospedaliero Universitaria di Ferrara [Cona, Italy], Great Ormond Street Institute of Child Health (UCL), University College of London [London] (UCL), Great Ormond Street Hospital for Children [London] (GOSH), Département Biologie du Médicament et Toxicologie [AP-HP - Hôpital Cochin Broca Hôtel Dieu] (HUPC), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Utah |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Standard of care [SDV]Life Sciences [q-bio] Eteplirsen Asymptomatic 03 medical and health sciences Exon 0302 clinical medicine BMD DMD Clinical information Humans Medicine eteplirsen Genetics business.industry Dilated cardiomyopathy medicine.disease Phenotype Exon skipping Muscular Dystrophy Duchenne 030104 developmental biology Neurology Neurology (clinical) medicine.symptom systematic review business 030217 neurology & neurosurgery exon skipping |
| Zdroj: | Journal of Neuromuscular Diseases Journal of Neuromuscular Diseases, 2020, 7 (3), pp.217-229. ⟨10.3233/JND-200483⟩ |
| ISSN: | 2214-3602 2214-3599 |
| DOI: | 10.3233/jnd-200483 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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