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), 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 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 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.

Results: 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 (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 participants with adequate cardiac data had cardiomyopathy.

Discussion: 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.

Figure 1. Age at Loss of Ambulation in the Entire Dup2 Cohort

Data were analyzed regardless of clinician-assigned clinical classification (e.g., Duchenne muscular dystrophy/intermediate muscular dystrophy/Becker muscular dystrophy). (A) Loss of ambulation (LOA) is similar between the United Dystrophinopathy Project (UDP) and Italian cohorts. Two participants from the UDP–duplication of exon 2 (Dup2) cohort are not included due to unknown ambulation status. Median age at estimated LOA was similar between groups: 13 years for the Italian cohort and 12.7 years for the UDP cohort (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.38–1.68; p = 0.54). (B) Loss of ambulation among entire Dup2 cohort suggests a significant corticosteroid treatment effect. Three participants are not included due to incomplete steroid information. Estimated LOA was significantly older for those who were exposed to >6 months of corticosteroids (CS-ever; median 16.5 years) vs those exposed to less than 6 months (CS-never; 11.0 years) (HR 0.45, 95% CI 0.21-0.94; p = 0.03).

Figure 2. Age at Loss of Ambulation in Patients Clinically Diagnosed With DMD Phenotypes

(A) All participants with duplication of exon 2 (Dup2) with Duchenne muscular dystrophy (DMD) phenotype. Estimated loss of ambulation (LOA) was not significantly older for those who were exposed to ≥6 months of corticosteroids (CS-ever; median of 12.0 years) vs those exposed to <6 months of corticosteroids (CS-never; 11.0 years) (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.21–1.19; p = 0.12). (B) All participants with Dup2 with DMD phenotype compared to a natural history comparator group. Comparison of participants with Dup2 clinically characterized with DMD, regardless of steroid treatment status, compared to participants without Dup2 DMD from the United Dystrophinopathy Project (UDP) database shows prolonged ambulation. The median age at LOA for the UDP cohort was 10.5 years vs 12.0 years for the combined Italian and UDP Dup2 cohorts (HR 0.29, 95% CI 0.17–0.51; p < 0.001). (C) CS-never participants with Dup2 with DMD phenotype compared to a natural history comparator group. Comparison of only corticosteroid-untreated participants with Dup2 clinically characterized with DMD to participants without Dup2 DMD from the UDP database also shows prolonged ambulation. Among CS-never participants, the median age at LOA for the UDP cohort was 10.0 years vs 11.0 years for the Dup2 CS-never participants (HR 0.65, 95% CI 0.52–0.82; p < 0.001).