Deep characterization of females with heterozygous Duchenne muscular dystrophy mutations

Duchenne muscular dystrophy (DMD) is an X-linked muscular dystrophy due to null mutations in the DMD gene that predominantly affects males, while heterozygous females are usually asymptomatic carriers. In approximately 10-20% of cases, they may present with muscle weakness and/or cardiomyopathy. We aimed to describe clinical and molecular characteristics of DMD heterozygous females.

A monocentric, observational, and cross-sectional study was designed. Clinical and molecular data were collected along with, when available, muscle biopsies. The pattern of X inactivation was determined in peripheral blood and the genotypes at SPP1, LTBP4 and CD40 modifier genes were established.

We recruited 47 participants: 27 (57%) were asymptomatic and 20 (43%) manifested symptoms. Proximal muscles were prominently involved, as in male dystrophinopathies. Twenty % of carriers showed cardiac involvement. Creatine kinase (CK) values were in the normal range in ~ 20% of symptomatic and ~ 46% asymptomatic patients. In all muscle biopsies, a mosaic of dystrophin positive and negative fibers was observed that only marginally correlated to dystrophin amount. No correlation was found between X chromosome inactivation pattern and the severity of muscular involvement, nor any association with cardiomyopathy. No genotype-phenotype correlations were identified.

Genotype/phenotype correlations in females heterozygous for DMD mutations are influenced by multiple mechanisms, of which better understanding will be crucial for future dystrophin gene replacement therapies. An earlier molecular identification is essential to lead to greater awareness of the potential cardiac complications, and hence the reinforcement of  appropriate cardiac follow-up.