Clinical and genetic characterization of manifesting carriers of DMD mutations.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Soltanzadeh, P; Friez, MJ; Dunn, D; von Niederhausern, A; Gurvich, OL; Swoboda, KJ; Sampson, JB; Pestronk, A; Connolly, AM; Florence, JM; Finkel, RS; Bönnemann, CG; Medne, L; Mendell, JR; Mathews, KD; Wong, BL; Sussman, MD; Zonana, J; Kovak, K; Gospe, SM; Gappmaier, E; Taylor, LE; Howard, MT; Weiss, RB; Flanigan, KM

Published Date

  • August 2010

Published In

Volume / Issue

  • 20 / 8

Start / End Page

  • 499 - 504

PubMed ID

  • 20630757

Pubmed Central ID

  • PMC2944769

Electronic International Standard Serial Number (EISSN)

  • 1873-2364

Digital Object Identifier (DOI)

  • 10.1016/j.nmd.2010.05.010


  • eng

Conference Location

  • England