Cardiac Involvement in Dystrophin-Deficient Females: Current Understanding and Implications for the Treatment of Dystrophinopathies

Abstract

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive condition caused primarily by out-of-frame mutations in the dystrophin gene. In males, DMD presents with progressive body-wide muscle deterioration, culminating in death as a result of cardiac or respiratory failure. A milder form of DMD exists, called Becker muscular dystrophy (BMD), which is typically caused by in-frame dystrophin gene mutations. It should be emphasized that DMD and BMD are not exclusive to males, as some female dystrophin mutation carriers do present with similar symptoms, generally at reduced levels of severity. Cardiac involvement in particular is a pressing concern among manifesting females, as it may develop into serious heart failure or could predispose them to certain risks during pregnancy or daily life activities. It is known that about 8% of carriers present with dilated cardiomyopathy, though it may vary from 0% to 16.7%, depending on if the carrier is classified as having DMD or BMD. Understanding the genetic and molecular mechanisms underlying cardiac manifestations in dystrophin-deficient females is therefore of critical importance. In this article, we review available information from the literature on this subject, as well as discuss the implications of female carrier studies on the development of therapies aiming to increase dystrophin levels in the heart.

Keywords: Becker muscular dystrophy; Duchenne muscular dystrophy; cardiac involvement; female carrier models; female dystrophin mutation carriers; gene therapy; partial dystrophin deficiency.

Figure 1

Genetic mechanisms of dystrophinopathy manifestation in females. Chromosomes from different parents are represented by different shades of blue, with the DMD mutation represented by a red or yellow line. Females with dystrophin mutations may manifest symptoms as a result of: (A) skewed X chromosome inactivation (the inactive chromosome is hashed); (B) balanced translocations with an autosome, represented in yellow, involving regions within the DMD gene; (C) uniparental isodisomy; (D) inheritance of a single DMD mutation-containing X-chromosome (a subcategory of Turner syndrome); (E) Xq isochromosome formation in tandem with a DMD mutation on the other X chromosome; (F) compound heterozygosity, with the inheritance of two different DMD mutations on either chromosome; (G) homozygous DMD mutation inheritance due to consanguinity; and (H) androgen insensitivity in an X/Y female (due to an androgen receptor mutation, represented by a green line) in tandem with a DMD mutation.