Figure 45-2 schematically represents the structural basis of the dystrophinopathies and certain of the limb-girdle and congenital dystrophies described further on. In normal skeletal and cardiac muscle, dystrophin is localized to the cytoplasmic surface of the sarcolemma, where it interacts with F-actin of the cytoskeleton (the filamentous reinforcing structure of the muscle cell). Dystrophin is also tightly bound to a complex of sarcolemmal proteins known as dystrophin-associated proteins (DAPs) and to dystrophin-associated glycoproteins (DAGs). Of special biologic importance in this complex are these proteins and a 156-kDa glycoprotein called dystroglycan. The latter actually lies just outside the muscle cell and links the sarcolemmal membrane to the extracellular matrix (the inner portion of the basement membrane) by binding with merosin, a subunit of laminin. The dystrophin–glycoprotein complex functions in this scheme as a transsarcolemmal structural link between the subsarcolemmal cytoskeleton and the extracellular matrix. Moreover, each of these membrane-binding proteins (adhalin, merosin, and laminin) is implicated in specific muscular dystrophies, as discussed later in this chapter.
The loss of dystrophin leads to a parallel loss of DAPs and to disruption of the dystroglycan–protein complex. This change renders the sarcolemma susceptible to breaks and tears during muscle contraction, a hypothesis proposed first by Mokri and Engel and entirely consistent with the ultrastructural abnormalities that characterize
Duchenne dystrophy. These authors demonstrated defects of the plasma membrane (sarcolemma) in a large proportion of nonnecrotic hyalinized muscle fibers, allowing ingress of extracellular fluid and calcium. The entrance of calcium is speculated to activate proteases and to increase protein degradation. The membrane defects and the associated alterations in the underlying region of the fiber represent the earliest and most basic pathologic change in Duchenne dystrophy and account for the leakage into the serum of CK and other enzymes of muscle.
Diagnosis of Duchenne and Becker dystrophies
Analysis of the dystrophin gene in DNA obtained from white blood cells or from 50 mg of skeletal muscle can demonstrate the gene mutations in Duchenne and Becker patients and discriminate between these diseases. Also, immunostaining of muscle for dystrophin makes possible the differentiation of Duchenne, Becker, the carrier state, and other muscle disorders. An alternative method, developed by Byers and colleagues, uses an ELISA to measure the dystrophin levels in muscle biopsy samples. This testing is a rapid and relatively inexpensive tool for establishing the diagnosis of Duchenne and Becker muscular dystrophies and distinguishing them from unrelated disorders.
Testing for the dystrophin protein has also brought to light several much rarer types of dystrophin abnormalities. One, described by Gospe and coworkers, takes the form of a familial X-linked myalgic-cramp-myoglobinuric syndrome, resulting from the deletion of the first third of the dystrophin gene. The muscle changes are mild and relatively nonprogressive. Another dystrophinopathy takes the form of an X-linked cardiomyopathy characterized by progressive heart failure in young persons without clinical evidence of skeletal muscle weakness; biopsy of skeletal muscle reveals reduced immunoreactivity to dystrophin (Jones and de la Monte). In yet another type, a glycerol-kinase deficiency is associated with varying degrees of adrenal hypoplasia, mental retardation, and myopathy.