Associations between genetic mutations and loss of ambulation in males with childhood-onset dystrophinopathy


Real World Data - Disease registries, natural history, post marketing surveillance

Poster Number: 173


Natalie Street, Gregory Haber, PhD, Kristin Conway, PhD, Pangaja Paramsothy, PhD, MPH, Anindya Roy, PhD, Hobart Rogers, PharmD, PhD, Xiang Ling, PhD, Nicholas Kozauer, MD, Paul Romitti, MS, PhD, Deborah Fox, MPH, Han Phan, MD, Dennis Matthews, MD, Emma Ciafaloni, MD, Joyce Oleszek, MD, Katherine James, PhD, MSPH, MS, Maureen Galindo, MS, RN, Nedra Whitehead, MS, PhD, Nicholas Johnson, MD, Russell Butterfield, MD, PhD, Shree Pandya, DPT, Swamy Venkatesh, MD, Venkatesh Atul Bhattaram, PhD


1. Centers for Disease Control and Prevention, 9. University of Iowa, 12. Children's Hospital Colorado, 13. University of Rochester, 14. Children's Hospital Colorado, 18. Virginia Commonwealth University, 19. University of Utah, 20. University of Rochester

Background: Dystrophinopathies are X-linked muscle disorders caused by mutations in the DMD gene that result in a spectrum of severity and progression. With the development of genetic therapies, a better understanding of mutation-dependent differences in time to loss of ambulation (LoA) is important for clinical trial design.
Objective: To quantify associations between genetic mutations and time to LoA in a population-based cohort of males with dystrophinopathy.
Approach: Data were analyzed for 358 males born and diagnosed from 1982 through 2011 with a dystrophinopathy and ascertained by the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Time to LoA was defined as the age at which independent ambulation had ceased (e.g., full-time wheelchair use); the last known age ambulating was used for censored (ambulatory) cases. Time to LoA was compared by type of genetic mutation (deletion, duplication, point mutation) and by deletions amenable to exon-skipping therapy (8, 20, 44, 45, 46, 51, 52, 53, other deletions). Models were fit, controlling for corticosteroid use (Model I); corticosteroid use, race, and ethnicity (Model II); and corticosteroid use and age at onset of symptoms (Model III).
Results: There were no differences in time to LoA by mutation type. Among those with deletions amenable to exon-skipping therapy, reduced annual hazards of LoA were found for the exon 8 skippable (HR = 0.22; 95% CI = 0.08, 0.63 for Model I) and the exon 44 skippable (HR = 0.30; 95% CI = 0.12, 0.78 for Model I) subgroups compared to those with other exon deletions. Similar significant associations were seen for Models II and III.
Conclusion: The finding of prolonged time to LoA in males with mutations amenable to exon-skipping therapy of exons 8 or 44 is consistent with previous studies. These findings may be informative in the design of clinical trials to better characterize the patients to be enrolled.