myofiber type depends on the innervating motor unit, reinnvervated fibers may change from type I to type II and vice versa. The presence of increasingly larger motor units alters the normal checkerboard type distribution of fibers by producing large clusters of the same type, fiber type grouping (
Fig. 22.4C6).
• Prolonged disuse of muscles from any cause (e.g., prolonged bed rest in the sick, casting of a broken bone) may cause focal or generalized muscle atrophy, which tends to affect type II fibers more than type I fibers.
• Glucocorticoid exposure, whether exogenous or endogenous (e.g., in Cushing syndrome), also may cause muscle atrophy. Proximal muscles and type II myofibers are affected preferentially in this setting.
Inherited mutations are responsible for a diverse collection of disorders marked by defects in skeletal muscle. In some of these disorders, skeletal muscle is the main site of disease, while in others multiple organs are involved. Of http://ebooksmedicine.net
Dystrophinopathies: Duchenne and the other organs involved, the heart is of particular impor- tance, because cardiac involvement is common and is often life-limiting. Included in this group of inherited muscular disorders are the following:
Muscular dystrophies are associated with progressive muscle injury in patients who have normal muscle function at birth.
Congenital muscular dystrophies, by contrast, are progressive, early-onset diseases. Some are also associated with malformations of the central nervous system.
Congenital myopathies typically present in infancy with muscle defects that tend to be static or to even improve with time. They are often associated with distinct structural abnormalities of the muscle.
The discussion of muscular dystrophies may at first glance appear confusing because of different classification systems and terminologies. This is reflective of our evolving understanding of these diseases, from a description based on phenotype and inheritance pattern, to one based on underlying genetic mutations. An additional layer of complexity stems from the fact that there is not a simple one-to-one correspondence between genotypes and phenotypes. Instead mutations in several different genes can, for example, present as autosomal recessive limb-girdle muscular dystrophy; conversely different mutations in a single gene (such as dystrophin) can lead to very different clinical phenotypes, as illustrated by Duchenne and Becker types of muscular dystrophy.
The most common muscular dystrophies are X-linked and are caused by mutations that disrupt the function of a large structural protein called dystrophin. As a result, these diseases are referred to as dystrophinopathies. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are the two most important diseases in this group. DMD has an incidence of about 1 per 3500 live male births and follows an invariably fatal course. It becomes clinically evident in early childhood; most patients are wheelchair-bound by the time they are teenagers and are dead of their disease by early adulthood. The Becker type of muscular dystrophy is less common and less severe.
MORPHOLOGYThehistologicalterationsinskeletalmusclesaffectedbyDMDandBMDaresimilar,exceptthatthechangesaremilderinBMD(
Fig.22.5 ).Thehallmarksoftheseaswellasothermusculardystrophiesareongoingmyofibernecrosisandregeneration.Progressivereplacementofmuscletissuebyfibrosisandfatistheresultofdegenerationoutpacingrepair.Asaresultofongoingrepair,musclestypicallyshowmarkedvariationinmyofibersizeandabnormalinternallyplacednuclei.BothDMDandBMDalsoaffectcardiacmuscles,whichshowvariabledegreesofmyocytehypertrophyandinterstitialfibrosis.