Association of genetic mutations and loss of ambulation in childhood-onset dystrophinopathy

Details

• Alternative Title:
  Muscle Nerve
• Personal Author:
  Haber, Gregory ; Conway, Kristin M. ; Paramsothy, Pangaja ; Roy, Anindya ; Rogers, Hobart ; Ling, Xiang ; Kozauer, Nicholas ; Street, Natalie ; Romitti, Paul A. ; Fox, Deborah J. ; Phan, Han C. ; Matthews, Dennis ; Ciafaloni, Emma ; Oleszek, Joyce ; James, Katherine A. ; Galindo, Maureen ; Whitehead, Nedra ; Johnson, Nicholas ; Butterfield, Russell J. ; Pandya, Shree ; Venkatesh, Swamy ; Bhattaram, Venkatesh Atul
• Description:
  Introduction
  
  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 1982–2011 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 hazards ratios (HR) and 95% confidence intervals (CI).
  
  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.
  
  Discussion
  
  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.
  
  
• Subjects:
  Adolescent Adrenal Cortex Hormones Article Child Dependent Ambulation Disease Progression Duchenne Muscular Dystrophy Dystrophin Exons Exon Skipping Gene Duplication Humans Loss Of Ambulation Male MD STARnet Mobility Limitation Muscular Dystrophy, Duchenne Natural History Study Point Mutation Proportional Hazards Models Sequence Deletion Wheelchairs

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• Source:
  Muscle Nerve. 63(2):181-191
• Pubmed ID:
  33150975
• Pubmed Central ID:
  PMC8094042
• Document Type:
  Journal Article
• Funding:
  K08 NS097631/NS/NINDS NIH HHSUnited States/ ; U01 DD000187/DD/NCBDD CDC HHSUnited States/ ; U01 DD001247/DD/NCBDD CDC HHSUnited States/ ; U01DD001119/ACL/ACL HHSUnited States/ ; U01DD001108/ACL/ACL HHSUnited States/ ; CC999999/ImCDC/Intramural CDC HHSUnited States/ ; R01 FD006071/FD/FDA HHSUnited States/ ; U01 DD000191/DD/NCBDD CDC HHSUnited States/ ; U01 DD001248/DD/NCBDD CDC HHSUnited States/ ; U01DD001117/ACL/ACL HHSUnited States/ ; U01 DD001117/DD/NCBDD CDC HHSUnited States/ ; U01 DD000392/DD/NCBDD CDC HHSUnited States/ ; U01 DD001126/DD/NCBDD CDC HHSUnited States/ ; U01 DD001123/DD/NCBDD CDC HHSUnited States/ ; R01 NS104010/NS/NINDS NIH HHSUnited States/ ; U01DD001116/ACL/ACL HHSUnited States/ ; U01DD001123/ACL/ACL HHSUnited States/ ; U01 DD000189/DD/NCBDD CDC HHSUnited States/ ; U01 DD001116/DD/NCBDD CDC HHSUnited States/ ; U01DD001126/ACL/ACL HHSUnited States/ ; K23 NS091511/NS/NINDS NIH HHSUnited States/ ; U01 DD001119/DD/NCBDD CDC HHSUnited States/ ; U01 DD001108/DD/NCBDD CDC HHSUnited States/ ; U01 DD001255/DD/NCBDD CDC HHSUnited States/ ; U01 DD000190/DD/NCBDD CDC HHSUnited States/
• Volume:
  63
• Issue:
  2
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:69bed67d98722c3c9ea7486f04a34f7276f30b47d905a51a764b81974ace1e30
• Download URL:
  https://stacks.cdc.gov/view/cdc/105954/cdc_105954_DS1.pdf
• File Type:
  [PDF - 994.69 KB ]