Clinical and genetic characterization of manifesting carriers of DMD mutations

Soltanzadeh, Payam; Friez, Michael J.; Dunn, Diane; von Niederhausern, Andrew; Gurvich, Olga L.; Swoboda, Kathryn J.; Sampson, Jacinda B.; Pestronk, Alan; Connolly, Anne M.; Florence, Julaine M.; Finkel, Richard S.; Bönnemann, Carsten G.; Medne, Livija; Mendell, Jerry R.; Mathews, Katherine D.; Wong, Brenda L.; Sussman, Michael D.; Zonana, Jonathan; Kovak, Karen; Gospe, Sidney M.; Gappmaier, Eduard; Taylor, Laura E.; Howard, Michael T.; Weiss, Robert B.; Flanigan, Kevin M.

doi:10.1016/j.nmd.2010.05.010

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Volume 20, Issue 8 , Pages 499-504, August 2010

Clinical and genetic characterization of manifesting carriers of DMD mutations

Payam Soltanzadeh
- Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
Michael J. Friez
- Molecular Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC, USA
Diane Dunn
- Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
Andrew von Niederhausern
- Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
Olga L. Gurvich
- Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
- Present address: Cork Cancer Research Centre, BioSciences Institute, University College Cork, Cork, Ireland.
Kathryn J. Swoboda
- Department of Neurology, University of Utah, Salt Lake City, UT, USA
- Department of Pediatrics, University of Utah, Salt Lake City, UT, USA
Jacinda B. Sampson
- Department of Neurology, University of Utah, Salt Lake City, UT, USA
Alan Pestronk
- Department of Neurology, Washington University, St. Louis, MO, USA
Anne M. Connolly
- Department of Neurology, Washington University, St. Louis, MO, USA
Julaine M. Florence
- Department of Neurology, Washington University, St. Louis, MO, USA
Richard S. Finkel
- Department of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Carsten G. Bönnemann
- Department of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Livija Medne
- Department of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Jerry R. Mendell
- Center for Gene Therapy, Nationwide Children’s Hospital, Department of Pediatrics, Ohio State University, Columbus, OH, USA
Katherine D. Mathews
- Department of Pediatrics, University of Iowa, Iowa City, IA, USA
Brenda L. Wong
- Departments of Neurology and Pediatrics, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Michael D. Sussman
- Department of Orthopedic Surgery, Shriners Hospital for Children, Portland, OR, USA
Jonathan Zonana
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
Karen Kovak
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
Sidney M. Gospe Jr.
- Departments of Neurology and Pediatrics, University of Washington, Division of Pediatric Neurology, Seattle Children’s Hospital, Seattle, WA, USA
Eduard Gappmaier
- Department of Physical Therapy, University of Utah, Salt Lake City, UT, USA
Laura E. Taylor
- Center for Gene Therapy, Nationwide Children’s Hospital, Department of Pediatrics, Ohio State University, Columbus, OH, USA
Michael T. Howard
- Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
Robert B. Weiss
- Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
Kevin M. Flanigan
- Center for Gene Therapy, Nationwide Children’s Hospital, Department of Pediatrics, Ohio State University, Columbus, OH, USA
- Corresponding author. Address: Center for Gene Therapy, Nationwide Children’s Hospital, 700 Children’s Drive, WA4023, Columbus, OH 43205, USA. Tel.: +1 614 355 2947; fax: +1 614 722 3273.

Received 15 August 2009; received in revised form 30 April 2010; accepted 18 May 2010.

Abstract

Manifesting carriers of DMD gene mutations may present diagnostic challenges, particularly in the absence of a family history of dystrophinopathy. We review the clinical and genetic features in 15 manifesting carriers identified among 860 subjects within the United Dystrophinopathy Project, a large clinical dystrophinopathy cohort whose members undergo comprehensive DMD mutation analysis. We defined manifesting carriers as females with significant weakness, excluding those with only myalgias/cramps. DNA extracted from peripheral blood was used to study X-chromosome inactivation patterns. Among these manifesting carriers, age at symptom onset ranged from 2 to 47years. Seven had no family history and eight had male relatives with Duchenne muscular dystrophy (DMD). Clinical severity among the manifesting carriers varied from a DMD-like progression to a very mild Becker muscular dystrophy-like phenotype. Eight had exonic deletions or duplications and six had point mutations. One patient had two mutations (an exonic deletion and a splice site mutation), consistent with a heterozygous compound state. The X-chromosome inactivation pattern was skewed toward non-random in four out of seven informative deletions or duplications but was random in all cases with nonsense mutations. We present the results of DMD mutation analysis in this manifesting carrier cohort, including the first example of a presumably compound heterozygous DMD mutation. Our results demonstrate that improved molecular diagnostic methods facilitate the identification of DMD mutations in manifesting carriers, and confirm the heterogeneity of mutational mechanisms as well as the wide spectrum of phenotypes.