Gregory Haber1, Kristin M Conway2, Pangaja Paramsothy3, Anindya Roy4, Hobart Rogers5, Xiang Ling5, Nicholas Kozauer5, Natalie Street3, Paul A Romitti2, Deborah J Fox6, Han C Phan7, Dennis Matthews8, Emma Ciafaloni9, Joyce Oleszek8, Katherine A James10, Maureen Galindo11, Nedra Whitehead12, Nicholas Johnson13, Russell J Butterfield14, Shree Pandya9, Swamy Venkatesh15, Venkatesh Atul Bhattaram5. 1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA. 2. Department of Epidemiology, University of Iowa, Iowa City, Iowa, USA. 3. National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. 4. Department of Mathematics and Statistics, University of Maryland, Baltimore County, Baltimore, Maryland, USA. 5. Center for Drug Evaluation and Research, Food & Drug Administration, Silver Spring, Maryland, USA. 6. Bureau of Environmental and Occupational Epidemiology, New York State Department of Health, Albany, New York, USA. 7. Department of Pediatrics, Division of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA. 8. Department of Physical Medicine and Rehabilitation, Children's Hospital Colorado, Aurora, Colorado, USA. 9. Department of Neurology, University of Rochester, Rochester, New York, USA. 10. School of Public Health, University of Colorado, Boulder, Colorado, USA. 11. Department of Pediatrics, University of Arizona, Tucson, Arizona, USA. 12. Research Triangle Institute International, Research Triangle Park, North Carolina, USA. 13. Department of Neurology, Virginia Commonwealth University, Richmond, Virginia, USA. 14. Department of Pediatrics and Neurology, University of Utah, Salt Lake City, Utah, USA. 15. Department of Neurology, University of South Carolina, Columbia, South Carolina, USA.
Abstract
BACKGROUND: Quantifying associations between genetic mutations and loss of ambulation (LoA) among males diagnosed with childhood-onset dystrophinopathy is important for understanding variation in disease progression and may be useful in clinical trial design. METHODS: Genetic and clinical data from the Muscular Dystrophy Surveillance, Tracking, and Research Network for 358 males born and diagnosed from 1982 to 2011 were analyzed. LoA was defined as the age at which independent ambulation ceased. Genetic mutations were defined by overall type (deletion/duplication/point mutation) and among deletions, those amenable to exon-skipping therapy (exons 8, 20, 44-46, 51-53) and another group. Cox proportional hazards regression modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Mutation type did not predict time to LoA. Controlling for corticosteroids, Exons 8 (HR = 0.22; 95% CI = 0.08, 0.63) and 44 (HR = 0.30; 95% CI = 0.12, 0.78) were associated with delayed LoA compared to other exon deletions. CONCLUSIONS: Delayed LoA in males with mutations amenable to exon-skipping therapy is consistent with previous studies. These findings suggest that clinical trials including exon 8 and 44 skippable males should consider mutation information prior to randomization.
BACKGROUND: Quantifying associations between genetic mutations and loss of ambulation (LoA) among males diagnosed with childhood-onset dystrophinopathy is important for understanding variation in disease progression and may be useful in clinical trial design. METHODS: Genetic and clinical data from the Muscular Dystrophy Surveillance, Tracking, and Research Network for 358 males born and diagnosed from 1982 to 2011 were analyzed. LoA was defined as the age at which independent ambulation ceased. Genetic mutations were defined by overall type (deletion/duplication/point mutation) and among deletions, those amenable to exon-skipping therapy (exons 8, 20, 44-46, 51-53) and another group. Cox proportional hazards regression modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Mutation type did not predict time to LoA. Controlling for corticosteroids, Exons 8 (HR = 0.22; 95% CI = 0.08, 0.63) and 44 (HR = 0.30; 95% CI = 0.12, 0.78) were associated with delayed LoA compared to other exon deletions. CONCLUSIONS: Delayed LoA in males with mutations amenable to exon-skipping therapy is consistent with previous studies. These findings suggest that clinical trials including exon 8 and 44 skippable males should consider mutation information prior to randomization.
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