Females with X-Linked Muscle Disorders: an underestimated patient population

Carriers of genetic diseases including female carriers of X-linked disorders are traditionally believed to be asymptomatic due to the compensatory presence of the unmutated gene on the other allele. However, in recent decades numerous contributions have appeared in the literature showing how females carrying X-linked diseases can also present signs and symptoms linked to the specific gene defect. To explain the clinical manifestations observed in female carriers, several mechanisms leading to a reduced protein expression have been hypothesized, in particular the role of the X-chromosome inactivation (XCI). In this review, the focus will be on the relationship between skewed XCI and the development of muscle or cardiac symptoms in female carriers of the most frequent types of muscle disorders such as Duchenne and Becker muscular dystrophies, Emery-Dreifuss muscular dystrophy and Myotubular Myopathy. In all cases, there is a tendency for females with a more severe phenotype to have a skewed pattern of XCI, while females with an intermediate phenotype have a random pattern. Given the increasing recognition of important clinical presentations in females with X-linked muscle disorders and the recent availability of causal therapies for these diseases, specific guidelines are desirable and recommended that allow women to be properly recognized and have access to appropriate therapies.