Clinical and genetic characterization of manifesting carriers of DMD mutations

被引:126
作者
Soltanzadeh, Payam [2 ]
Friez, Michael J. [6 ]
Dunn, Diane [2 ]
von Niederhausern, Andrew [2 ]
Gurvich, Olga L. [2 ]
Swoboda, Kathryn J. [3 ,4 ]
Sampson, Jacinda B. [3 ]
Pestronk, Alan [7 ]
Connolly, Anne M. [7 ]
Florence, Julaine M. [7 ]
Finkel, Richard S. [8 ]
Boennemann, Carsten G. [8 ]
Medne, Livija [8 ]
Mendell, Jerry R. [1 ]
Mathews, Katherine D. [9 ]
Wong, Brenda L. [10 ]
Sussman, Michael D. [11 ]
Zonana, Jonathan [12 ]
Kovak, Karen [12 ]
Gospe, Sidney M., Jr. [13 ,14 ]
Gappmaier, Eduard [5 ]
Taylor, Laura E. [1 ]
Howard, Michael T. [2 ]
Weiss, Robert B. [2 ]
Flanigan, Kevin M. [1 ]
机构
[1] Ohio State Univ, Ctr Gene Therapy, Nationwide Childrens Hosp, Dept Pediat, Columbus, OH 43205 USA
[2] Univ Utah, Dept Human Genet, Salt Lake City, UT USA
[3] Univ Utah, Dept Neurol, Salt Lake City, UT USA
[4] Univ Utah, Dept Pediat, Salt Lake City, UT 84112 USA
[5] Univ Utah, Dept Phys Therapy, Salt Lake City, UT USA
[6] Greenwood Genet Ctr, Mol Diagnost Lab, Greenwood, SC 29646 USA
[7] Washington Univ, Dept Neurol, St Louis, MO USA
[8] Childrens Hosp Philadelphia, Dept Neurol, Philadelphia, PA 19104 USA
[9] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA
[10] Cincinnati Childrens Hosp, Dept Neurol & Pediat, Cincinnati, OH USA
[11] Shriners Hosp Children, Dept Orthoped Surg, Portland, OR 97201 USA
[12] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA
[13] Univ Washington, Dept Neurol, Seattle Childrens Hosp, Div Pediat Neurol, Seattle, WA 98195 USA
[14] Univ Washington, Dept Pediat, Seattle Childrens Hosp, Div Pediat Neurol, Seattle, WA 98195 USA
关键词
Manifesting carriers; Dystrophinopathy; DMD; Dystrophin; X-chromosome inactivation; Duchenne muscular dystrophy; Becker muscular dystrophy; DUCHENNE MUSCULAR-DYSTROPHY; X-CHROMOSOME-INACTIVATION; PATTERNS; FEMALES; EXPRESSION; DYSTROPHINOPATHIES; CARDIOMYOPATHY; ABNORMALITIES; METHYLATION; PATIENT;
D O I
10.1016/j.nmd.2010.05.010
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 47 years. 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. (C) 2010 Elsevier B.V. All rights reserved.
引用
收藏
页码:499 / 504
页数:6
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