We describe a young male adult presenting with cardiac failure followed by cardiac transplantation. Evaluation for neuromuscular disease (dystrophy, myositis), resulted in the discovery of mosaic immunostaining for dystrophin. Subsequent molecular analysis showed somatic mosaicism for a nonsense mutation in the dystrophin gene (Arg2905X). To our knowledge, this is the first report of DMD somatic mosaicism in a living patient.
The young man's presentation was most consistent with acutely decompensated heart failure secondary to muscular dystrophy associated dilated cardiomyopathy. A similar presentation could be expected with viral myocarditis, but the patient had no significant viral symptoms or fever and serum viral studies for coxsackie B, CMV, HIV, Influenza A and B, Hep B were all negative. PCR viral studies of the skeletal muscle biopsy were negative for enteroviruses and influenza B. The cardiac histological findings, approximately 2 weeks after presentation, do not meet the Dallas criteria for diagnosis of myocarditis [Aretz et al., 1987
]. The presentation is also less consistent with ischemic heart disease since there were no significant ST-T wave changes on his presenting electrocardiogram, no regional wall motion abnormalities on echocardiogram and the coronaries were normal on evaluation of the explanted heart.
The patient had a mixture of normal and mutant genes in peripheral blood and skeletal muscle, however the clinical presentation was in heart. In the patient's blood, we found the ratio of normal/mutant to be 50:50, functionally the same as most female carriers (due to random X inactivation) [Pegoraro et al., 1995
]. Cardiac muscle shows only two or so per cardiocyte, and thus the somatic mosaic male patient, like female carriers, would be expected to have populations of both dystrophin-positive and dystrophin-negative cardiocytes. Cardiocytes are less affected by dystrophin-deficiency than myofibers, however cardiocytes are generally incapable of regeneration leading to a late-stage cardiomyopathy. We suspect that the acute cardiac failure seen in the somatic mosaic patient presented here is a combination of the failure of cardiac muscle to regenerate, and a disproportionate number of dystrophin-negative cells comprising his heart. This interpretation is consistent with a reported high incidence of heart abnormalities in female carriers. In our previous study of 46 female manifesting carriers, 5 of 7 ECGs were reported as abnormal, and 2 patients presented with cardiac symptoms [Hoffman et al., 1992
]. Similar data have been found in additional reports [Kamakura et al., 1990
; Mirabella et al., 1993
; Kinoshita et al., 1995
; Politano et al., 1996
]. We cannot rule out that male sex and exercise did not exacerbate the cardiac symptoms as well.
Of note, we found that the patient's muscle tissue showed a much lower relative amount of mutant genes (20%) compared to peripheral blood (50%). There are two possible explanations for this discordance between muscle and blood. The first is that he may by chance have segregated more dystrophin-positive stem cells into the region of muscle biopsies. An alternative explanation is the somatic loss (necrosis) of dystrophin-negative muscle fibers with subsequent regeneration by dystrophin-positive stem cells. This process has been demonstrated in the majority of manifesting female carriers (functionally somatic mosaics, but due to X inactivation rather than somatic mutation) [Pegoraro et al., 1995
]. This previous study found that 11/14 of clinically manifesting carriers (80%) showed an average of threefold increase in muscle dystrophin-positive nuclei compared to blood nuclei, strongly arguing for replacement of dystrophin-negative myofibers with dystrophin positive skeletal muscle over time (genetic normalization). This process explains the reduction in serum creatine kinase in female carriers with advancing age, and the age-related improvement in clinical symptoms that can be seen with some manifesting carriers [Pegoraro et al., 1995
]. Heart tissue is unable to regenerate, and thus heart is incapable of showing genetic normalization (other than loss of dystrophin-negative regions to fibrosis). Nonsense-mediated decay is a common mechanism by which mRNA levels that contain premature stop mutations are reduced in tissue. This seems a likely explanation for the lower levels of mutant mRNA in skeletal muscle (10%) compared to the proportion in genomic DNA (20%).
Our data suggesting genetic normalization in skeletal muscle in this somatic mosaic patient may explain the paucity of male somatic mosaics for DMD, despite the expected high incidence of such cases based on mutation rates. The genetic normalization process, where dystrophin-negative muscle is gradually replaced by dystrophin-positive muscle as a function of age, would be expected to preclude the onset of skeletal muscular symptoms (weakness). This is in contrast to the heart, where the lack of regeneration in the heart prevents genetic normalization from occurring, and then leading to preferential expression of cardiac symptoms. This case suggests that male somatic mosaics for DMD may present with cardiomyopathy, not skeletal muscle symptoms, and that this diagnosis should be considered in idiopathic cardiomyopathy. Possible screening tests for identifying male somatic mosaics for DMD could include a persistence of the muscle (MM) isoforms of creatine kinase (reflective of a subclinical muscular dystrophy).