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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.
Glossary
- BMD=
- Becker muscular dystrophy;
- CI=
- confidence interval;
- CS=
- corticosteroids;
- DMD=
- Duchenne muscular dystrophy;
- Dup2=
- duplication of exon 2;
- EF=
- ejection fraction;
- FVC%p=
- forced vital capacity percent predicted;
- HR=
- hazard ratio;
- IMD=
- intermediate muscular dystrophy;
- IMD=
- intermediate muscular dystrophy;
- IQR=
- interquartile range;
- IRES=
- internal ribosomal entry site;
- ITAF=
- IRES transactivation factor;
- LOA=
- loss of ambulation;
- LVEF=
- left ventricular ejection fraction;
- UDP=
- United Dystrophinopathy Project
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally as first authors.
↵† These authors contributed equally as last authors.
Italian DMD Network and the United Dystrophinopathy Project coinvestigators are listed at links.lww.com/WNL/B730.
- Received May 12, 2021.
- Accepted in final form December 13, 2021.
- © 2021 American Academy of Neurology
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