Clinical and genetic characteristics of female dystrophinopathy carriers

Abstract

The present study aimed to determine the genetic status of manifesting carriers (MCs) of Duchenne muscular dystrophy (DMD)/Becker muscular dystrophy (BMD) and asymptomatic carriers with a family history of DMD/BMD, and identify potential simple and reliable methods for screening dystrophinopathy carriers. Clinical data from probable carriers and MCs were collected and analyzed. MCs underwent multiplex ligation-dependent probe amplification (MLPA) for dystrophin gene exons combined with muscle disease panel test based on a next-generation sequencing (NGS) platform. In addition, the status of probable carriers was determined by MLPA or Sanger sequencing, according to the mutations of probands. A total of 154 female were enrolled, among which 78 cases were found to be carriers, including 4 MCs and 74 asymptomatic female carriers. The 4 MCs exhibited duplication mutations. Among the 74 asymptomatic carriers, 41.89% harbored deletion mutations, including 2 cases with suspected germline mosaicism and no mutation in the dystrophin gene, while 44.59% harbored point mutations in exons and only 10 cases (13.51%) carried duplication mutations. The area under the receiver operating characteristic (ROC) curve of creatine kinase (CK) was 0.822, with a sensitivity of 65.38% and specificity of 92.1%. In addition, DMD was positively correlated with the CK, alanine transaminase and aspartate transaminase levels of the carriers. MLPA for exons of the dystrophin gene, along with NGS and Sanger sequencing, was effective for the diagnosis of MCs and for determining the status of probable carriers. The ROC curve analysis also demonstrated that CK level was an excellent predictor for distinguishing DMD/BMD carriers.

Mitochondrial Dysfunction Is an Early Consequence of Partial or Complete Dystrophin Loss in mdx Mice

“…Women who are carriers of the DMD gene are largely asymptomatic with regard to skeletal muscle symptoms, but are susceptible to cardiomyopathy (Childers and Klaiman, 2017;Viggiano et al, 2017;Florian et al, 2018;Ishizaki et al, 2018;Zhong et al, 2019). Given our observation of mitochondrial defects in presymptomatic mdx male muscle, we sought to query the impact upon mitochondria, muscle, and metabolism in adult 24-week-old, female mdx carrier (mdx carriers) mice.…”

Serum MyomiRs as Biomarkers for Female Carriers of Duchenne/Becker Muscular Dystrophy

“…Detection of female carriers is important to avoid the birth of affected children (4). CK is currently the most common used non-invasive biomarker in detecting carriers, but since CK is not always reliable and only 45.0-76.0% of female carriers have increased levels of CK, the search for new biomarkers in detecting DMD/BMD carriers is especially important (5)(6)(7)22). At present, there are also some studies on miRNAs as biomarkers of DMD, FIGURE 2 | ROC analysis of serum microRNAs levels in MD-carriers.…”

“…It is estimated that ∼2.5-40.0% of female carriers will have manifestations of muscular dystrophy (MD) such as muscle weakness or heart disease later on in their life, but these people rarely show symptoms during childhood (2)(3)(4). In addition, multiple studies have shown that ∼45-76% of female carriers have increased serum creatine kinase (CK) levels, while others are normal (5)(6)(7). For those asymptomatic carriers with normal CK levels, their affected male relatives are usually the first indication of their so-called "gene carrier" status (8).…”

Mitochondrial dysfunction is an early consequence of partial or complete dystrophin loss in mdx mice.

“…Women who are carriers of the DMD gene are largely asymptomatic with regard to skeletal muscle symptoms, but they are susceptible to cardiomyopathy (61)(62)(63)(64)(65). Recent Given that we observed mitochondrial defects in presymptomatic mdx muscle, we sought to query the impact upon mitochondria, muscle, and metabolism in 24-week-old female mdx carriers (mdx carriers) mice.…”