Hypertrophy of muscle is apparently the result of work-induced enlargement of the remaining sound fibers in the face of adjacent fiber injury. However, examples of true hypertrophy of entire muscles prior to the first sign of weakness also occur and are difficult to explain. In these cases, large fibers may be present when at most there are only a few degenerating fibers. The more common feature of pseudohypertrophy is a result of lipocytic replacement of degenerated muscle fibers, but in its earlier stages, the presence of many enlarged fibers may contribute to the enlargement of muscle. Thus a true hypertrophy appears to give way to pseudohypertrophy. In the late stage of the dystrophic process, only a few scattered muscle fibers remain, almost lost in a sea of fat cells. It is notable that the late, or burned-out, stage of chronic polymyositis resembles muscular dystrophy in that the fiber population is depleted, the residual fibers are of variable size, and fat cells and endomysial fibrous tissue are increased; lacking only are the hypertrophied fibers of dystrophy. This resemblance confirms that many of the typical changes of muscular dystrophy are nonspecific, reflecting mainly the chronicity of the myopathic process.
Molecular Biology of Duchenne and Becker Dystrophies
The first important development in our understanding of the Duchenne and Becker muscular dystrophies was the discovery by Kunkel of the mutation on the X chromosome in what was later named DMD and of its gene product, dystrophin (Hoffman et al, 1987). The protein is expressed in skeletal, cardiac, and smooth muscle, as well as in brain. To date, the dystrophin gene is the largest one known in humans, spanning more than 2 Mb of DNA. This is in part the explanation for the observation that one-third of affected boys have a spontaneous mutation in the gene. Most mutations are deletions and combined with the less frequent duplications, account for over two-thirds of cases.
The biochemical assay of dystrophin and its histochemical demonstration near the sarcolemma have made possible the accurate diagnosis of the Duchenne and Becker phenotypes from biopsy material and have clarified the relationship between these two disorders. Whereas dystrophin is absent in patients with the Duchenne phenotype, it is present but structurally abnormal in the Becker type. Moreover, phenotypes that fall between the classic Duchenne and Becker forms exist and are characterized by a lower-than-normal amount of dystrophin. The
Duchenne and Becker dystrophies and their intermediate forms are spoken of as dystrophinopathies.
A slightly different form of dystrophin, originating in a different part of the gene, is found in neurons of the cerebrum and brainstem and in astrocytes, Purkinje cells, and Schwann cells at nodes of Ranvier (Harris and Cullen). A deficiency of cerebral dystrophin may in some yet unexplained way account for the mild cognitive developmental delay. It will be interesting to learn how such a deficiency might impair brain development and whether there is any connection to some cases of mental deficiency without muscular dystrophy.