G.P.81 Duchenne clinically discordant brothers: A “Ringo-like” phenotype in humans?

Abstract

Here we report two half-brothers who called our attention due to their strikingly different phenotypes. The youngest one, currently aged 9, is showing a severe course, enlarged calves and can only walk short distances. His older brother, aged 13 is very mildly affected. Their mother only noticed he was affected when the youngest one was diagnosed. He has some difficulties only for running and climbing stairs but he can walk freely and has discrete calves’ hypertrophy. Serum CK was 3260U/l in the younger and 3620U/l in the older brother. DNA analysis revealed that both carry an “out of frame” duplication of exon 2 in the dystrophin gene, which was not present in the mother DNA lymphocytes, indicating a gonadal mosaicism. Surprisingly, muscle biopsies analyzed in blind test revealed a very similar pattern in both, despite the clinical differences. Histopathology showed fiber size variation, internally located nuclei, degenerated and hyaline fibers, scattered regenerated fibers and discrete connective tissue replacement in both of them. Dystrophin immunostaining with antibodies against the N-terminal and rod domains showed a weak patchy pattern but was negative with the C-terminal domain antibody. Some clusters of 6–8 positive fibers (revertant fibers) were seen in both of them with all antibodies. Western-blot analysis showed a faint band of about 5% of normal, in both of them but a total deficiency with the C-terminal antibody. Muscle dystrophin deficiency has been associated to a severe course in both humans and golden-retriever muscular dystrophy (GRMD) dogs. However, a rare DMD patient and an exceptional GRMD dog, Ringo, showing a mild course despite the absence of muscle dystrophin have been previously reported. Further investigation of these exceptional cases, which is currently underway, may help to identify new genes or “protective” mechanisms which might hopefully open new avenues of treatment.