Phenotypic Spectrum of Dystrophinopathy Due to Duchenne Muscular Dystrophy Exon 2 Duplications

Abstract

Background and Objectives:To describe the phenotypic spectrum of dystrophinopathy in a large cohort of individuals with DMD exon 2 duplications (Dup2), whom may be particularly amenable to therapies directed at restoring expression of either full-length dystrophin, or nearly full-length dystrophin through utilization of the DMD exon 5 internal ribosome entry site (IRES).Methods: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 subjects into Duchenne (DMD), intermediate (IMD), or Becker (BMD) phenotypes. Log-rank tests for time-to event variables were used to compare age at loss of ambulation (LOA) in Dup2 subjects versus non-Dup2 controls in the UDP database, and for comparisons between steroid-treated vs. steroid-naive Dup2 subjects.Results:Among 66 Dup2 subjects (UDP=40, Italy=26), 61% percent were classified as DMD, 9% as IMD, and 30% as BMD. Median age at last observation was 15.4 years [IQR 8.79-26.0], and 75% had been on corticosteroids for at least 6 months. Age at LOA differed significantly between Dup2 DMD subjects and historical non-Dup2 DMD controls (p<0.001). Valid spirometry was limited but suggested a delay in the typical age-related decline in forced vital capacity, and 24 of 55 subjects with adequate cardiac data had cardiomyopathy.Discussion:Some Dup2 patients display a milder disease course than non-Dup2 DMD controls, 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.