Biomarkers of Muscular Dystrophy

Duchenne and Becker muscular dystrophy (DMD and BMD) share clinical symptoms like muscle weakness and wasting but differ in clinical presentation and severity. Immunohistochemistry using antibodies to dystrophin is the pathological basis for the diagnosis of DMD and BMD. While the sarcolemma of DMD muscle is negative, BMD muscle generally shows variable labeling because of the translation of a partially functional dystrophin that is localized to the sarcolemma. In some cases this differentiation is not possible. In such instances immunolabeling with antibodies to the neuronal form of nitric oxide synthase (nNOS) can be useful in suspecting a dystrophinopathy with a mutation in the ‘hot-spot’ rod domain and help to direct molecular analysis. nNOS localizes to the sarcolemma of mature muscle fibers via several components of the dystrophin-associated protein complex including dystrophin but sarcolemmal nNOS is lost when dystrophin levels are very low or absent because of deletions in critical regions of the rod domain.

Gene expression profiling of hind limb muscles of mouse models of muscular dystrophies have been shown to clearly discriminate between severely affected and mildly or nonaffected mouse models. Dystrophin-deficient and sarcoglycan- deficient profiles are remarkably similar, sharing inflammatory and structural remodeling processes. These processes are also ongoing in dysferlin-deficient animals, although at lower levels, in agreement with the later age of onset of this muscular dystrophy. The inflammatory proteins Spp1 and S100a9 were up-regulated in all animal models. Biomarker genes for which expression correlates with the severity of the disease have been identified. Comparative studies are an important step toward the development of an expression profiling-based diagnostic approach for muscular dystrophies in humans.

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