Muscle-specific discordant skewing of X-chromosome inactivation leads to different clinical phenotypes of Duchenne muscular dystrophy in two monozygotic female twins

Background: Mutations within the DMD gene leading to the absence or vast reduction of dystrophin cause Duchenne muscular dystrophy (DMD). The majority of female heterozygous carriers of X-linked recessive DMD mutations are asymptomatic or mildly affected due to the balanced X-inactivation. However, in rare cases of female DMD carriers skewed X-inactivation leads to clinical symptoms.

Case Reports: Here, we report on a pair of 2-year old female monozygotic twins who presented with marked but discordant hyperCKemia soon after birth (A. 10 – 40,000 U/L, K. 1 – 5,000 U/L. Clinically, only A. presented with progressive muscle hypotonia and delay in achieving motor milestones. Both twins were subjected to a muscle biopsy which displayed marked dystrophic changes in the case of A.'s specimen, whereas K.'s biopsy revealed only mild abnormalities, compatible with a nondystrophic myopathy. Immunostaining revealed almost complete lack of dystrophin-expression in A.'s biopsy, whereas K.'s biopsy displayed an equal mosaic for dystrophin positive- versus negative-fibers. Consequently, we found an out-of-frame deletion spanning exons 51 to 59 of DMD gene, corroborating the diagnosis of a somatic carrier-status for DMD. Because of the marked discordance for the expression of the DMD-mutation in these monozygotic twins we analyzed the X-inactivation status. In the peripheral blood leukocytes, both girls displayed the same pronounced skewed X-inactivation pattern, where approximately 90% of the paternal (healthy) X-chromosome was preferentially silenced. However, when we tested the X-inactivation pattern in muscle biopsies we found a completely different pattern: approximately 95% of the paternal X-chromosomes were silenced in the severely affected biopsy, whereas in K.'s muscle biopsy we found an almost random X-inactivation pattern.

Conclusions: Although the discordant clinical courses of X-linked diseases in female monozygotic twins has been frequently recognized, our report is the first to show discordant disease manifestation in female DMD carriers because of tissue-specific differential X-chromosome inactivation.