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

Gregory Haber; Kristin M Conway; Pangaja Paramsothy; Anindya Roy; Hobart Rogers; Xiang Ling; Nicholas Kozauer; Natalie Street; Paul A Romitti; Deborah J Fox; Han C Phan; Dennis Matthews; Emma Ciafaloni; Joyce Oleszek; Katherine A James; Maureen Galindo; Nedra Whitehead; Nicholas Johnson; Russell J Butterfield; Shree Pandya; Swamy Venkatesh; Venkatesh Atul Bhattaram

doi:10.1002/mus.27113

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

Journal article

Peer reviewed

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

Gregory Haber, Kristin M Conway, Pangaja Paramsothy, Anindya Roy, Hobart Rogers, Xiang Ling, Nicholas Kozauer, Natalie Street, Paul A Romitti, Deborah J Fox, …

Muscle & nerve, Vol.63(2), pp.181-191

02/2021

DOI: 10.1002/mus.27113

PMCID: PMC8094042

PMID: 33150975

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https://www.ncbi.nlm.nih.gov/pmc/articles/8094042View

Open Access

Abstract

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. 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). 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. 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.

Adolescent

Adrenal Cortex Hormones - therapeutic use

Child

Dependent Ambulation

Disease Progression

Dystrophin - genetics

Exons

Gene Duplication

Humans

Male

Mobility Limitation

Muscular Dystrophy, Duchenne - drug therapy

Muscular Dystrophy, Duchenne - genetics

Muscular Dystrophy, Duchenne - physiopathology

Point Mutation

Proportional Hazards Models

Sequence Deletion

Wheelchairs

Details

Title: Subtitle: Association of genetic mutations and loss of ambulation in childhood-onset dystrophinopathy
Creators: Gregory Haber - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
Kristin M Conway - Department of Epidemiology, University of Iowa, Iowa City, Iowa, USA
Pangaja Paramsothy - National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
Anindya Roy - Department of Mathematics and Statistics, University of Maryland, Baltimore County, Baltimore, Maryland, USA
Hobart Rogers - Center for Drug Evaluation and Research, Food & Drug Administration, Silver Spring, Maryland, USA
Xiang Ling - Center for Drug Evaluation and Research, Food & Drug Administration, Silver Spring, Maryland, USA
Nicholas Kozauer - Center for Drug Evaluation and Research, Food & Drug Administration, Silver Spring, Maryland, USA
Natalie Street - National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
Paul A Romitti - Department of Epidemiology, University of Iowa, Iowa City, Iowa, USA
Deborah J Fox - Bureau of Environmental and Occupational Epidemiology, New York State Department of Health, Albany, New York, USA
Han C Phan - Department of Pediatrics, Division of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA
Dennis Matthews - Department of Physical Medicine and Rehabilitation, Children's Hospital Colorado, Aurora, Colorado, USA
Emma Ciafaloni - Department of Neurology, University of Rochester, Rochester, New York, USA
Joyce Oleszek - Department of Physical Medicine and Rehabilitation, Children's Hospital Colorado, Aurora, Colorado, USA
Katherine A James - School of Public Health, University of Colorado, Boulder, Colorado, USA
Maureen Galindo - Department of Pediatrics, University of Arizona, Tucson, Arizona, USA
Nedra Whitehead - Research Triangle Institute International, Research Triangle Park, North Carolina, USA
Nicholas Johnson - Department of Neurology, Virginia Commonwealth University, Richmond, Virginia, USA
Russell J Butterfield - Department of Pediatrics and Neurology, University of Utah, Salt Lake City, Utah, USA
Shree Pandya - Department of Neurology, University of Rochester, Rochester, New York, USA
Swamy Venkatesh - Department of Neurology, University of South Carolina, Columbia, South Carolina, USA
Venkatesh Atul Bhattaram - Center for Drug Evaluation and Research, Food & Drug Administration, Silver Spring, Maryland, USA
Resource Type: Journal article
Publication Details: Muscle & nerve, Vol.63(2), pp.181-191
DOI: 10.1002/mus.27113
PMID: 33150975
PMCID: PMC8094042
NLM abbreviation: Muscle Nerve
ISSN: 0148-639X
eISSN: 1097-4598
Grant note: U01 DD001108 / NCBDD CDC HHS U01DD001123 / ACL HHS U01 DD001116 / NCBDD CDC HHS CC999999 / Intramural CDC HHS K08 NS097631 / NINDS NIH HHS U01DD001108 / ACL HHS U01 DD001119 / NCBDD CDC HHS K23 NS091511 / NINDS NIH HHS U01DD001117 / ACL HHS U01DD001126 / ACL HHS U01 DD001126 / NCBDD CDC HHS U01 DD000392 / NCBDD CDC HHS U01DD001116 / ACL HHS U01 DD000187 / NCBDD CDC HHS U01 DD001123 / NCBDD CDC HHS U01 DD000190 / NCBDD CDC HHS U01 DD001248 / NCBDD CDC HHS U01DD001119 / ACL HHS R01 FD006071 / FDA HHS U01 DD000189 / NCBDD CDC HHS R01 NS104010 / NINDS NIH HHS U01 DD001247 / NCBDD CDC HHS U01 DD000191 / NCBDD CDC HHS U01 DD001117 / NCBDD CDC HHS U01 DD001255 / NCBDD CDC HHS
Language: English
Date published: 02/2021
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9984214663402771

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