Pattern of X-chromosome inactivation as a key determinant of the clinicopathologic phenotype of Duchenne muscular dystrophy carriers

To the Editor: The recent article by Pegoraro et al. [1] addresses the importance of understanding the relationship between X-chromosome inactivation patterns and phenotypic expression of myopathy in females heterozygous for dystrophin gene mutations. The authors make two major observations reported in this and in a previous article [2] that deserve emphasis: (1) a highly skewed pattern of X-inactivation occurs in blood cells of female patients moderately to severely symptomatic with Duchenne muscular dystrophy (DMD) (although less skewing is apparent in the surviving muscle) and (2) skewing of X-inactivation may not be seen in asymptomatic or mildly affected DMD carriers. The authors argue indirectly from their data that a significant expansion of the nuclear domain of dystrophin (so-called ``biochemical normalization,'' occurring presumably by diffusion of protein away from myonuclei expressing the normal allele) is an important mechanism by which myofiber integrity can be preserved, despite overall reduction of dystrophin levels. We demonstrated the importance of such a mechanism directly in female mdx mice, which show a progressive decrease in numbers of dystrophin negative fiber segments between 10 and 60 days of age even after gamma-irradiation of muscle incapacitates satellite cells, …