Porth's Essentials of Pathophysiology, 4e

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Disorders of Neuromuscular Function

C h a p t e r 3 6

Skeletal Muscle Disorders Muscle Atrophy

specimens from individuals with DMD show little or no dystrophin. In comparison, those with BMD, who also have mutations in the dystrophin gene, show diminished amounts of dystrophin, usually of an abnormal molecu- lar weight, reflecting mutations that allow synthesis of an abnormal protein of smaller size. 8 Clinical Course. Boys with DMD are usually asymptom- atic at birth and during infancy. 8–11 Early gross movements such as rolling, sitting, and standing are usually achieved at the proper age. The postural muscles of the hips and shoul- ders are usually the first to be affected. Pseudohypertrophy of the calf muscle eventually develops (Fig. 36-5). Signs of muscle weakness usually become evident beginning at 2 to 3 years of age, when the child begins to fall fre- quently. Imbalances between agonist and antagonist mus- cles lead to abnormal postures and the development of contractures and joint immobility. Scoliosis (curvature of the spine) is common. Wheelchairs usually are needed at approximately 7 to 12 years of age. 10 Function of the dis- tal muscles usually is preserved well enough that the child can continue to use eating utensils and a computer key- board. The function of the extraocular muscles also is well preserved, as is the function of the muscles controlling uri- nation and defecation. Incontinence is an uncommon and late event. Respiratory muscle involvement results in weak and ineffective cough, frequent respiratory infections, and decreasing respiratory reserve. Cardiomyopathy is a common feature of the disease. The severity of cardiac involvement, however, does not necessarily correlate with skeletal muscle weakness. Some persons die early as the result of severe cardio- myopathy, whereas others maintain adequate cardiac function until the terminal stages of the disease. Death from respiratory and cardiac muscle involvement usu- ally occurs in young adulthood. Diagnosis and Treatment. Observation of the child’s voluntary movement and a complete family history pro- vide important diagnostic data for the disease. Serum levels of the enzyme creatine kinase (CK), which leaks out of damaged muscle fibers, suggests the presence of

Maintenance of muscle strength requires relatively fre- quent movements against resistance. Reduced use results in muscle atrophy, which is characterized by a reduction in the diameter of the muscle fibers because of a loss of protein filaments. 8 When a normally innervated muscle is not used for long periods, the muscle cells shrink in diameter, and although the muscle cells do not die, they lose much of their contractile proteins and become weak- ened. This is called disuse atrophy, and it occurs with conditions such as immobilization and chronic illness. The most extreme examples of muscle atrophy are found in persons with disorders that deprive muscles of their LMN innervation. This is called denervation atrophy. Muscular Dystrophy Muscular dystrophy is a term applied to a number of genetic disorders that produce progressive degenera- tion and necrosis of skeletal muscle fibers and eventual replacement with fat and connective tissue. 9–11 They are primary diseases of muscle tissue and probably do not involve the nervous system. As the muscle undergoes necrosis, fat and connective tissue replace the muscle fibers, which increases muscle size and results in muscle weakness. The increase in muscle size resulting from connective tissue infiltration is called pseudohypertro- phy. Muscle weakness is insidious in onset but continu- ally progressive, varying with the type of disorder. The two most common forms of muscular dystrophy are Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), both of which are inher- ited as an X-linked recessive trait. Duchenne muscular dystrophy is the most common and severe form, with an incidence of 1 in every 3600 to 6000 live male births. 11 Despite the X-linked inheritance in DMD, about 30% of cases are due to new mutations and the mother is not a carrier. 10 Female carriers are usually asymptomatic. Affected girls are occasionally encountered, but usually have much milder symptoms than boys. Becker muscular dystrophy, which shares the same genetic locus as DMD, manifests later in childhood or adolescence and has a slower and less severe course of progression. Both DMD and BMD are caused by mutations in the dystrophin gene, located on the short arm of the X chromosome. Dystrophin is a large protein that is expressed in a variety of tissues, including all types of muscle cells. 8–11 It attaches portions of the muscle sarco- mere to the cell membrane, maintaining the structural integrity of skeletal and cardiac muscle cells. The role of dystrophin in transferring the force of contraction to the extracellular connective tissue matrix has been proposed as the basis for muscle cell degeneration that occurs with dystrophin defects or changes in other pro- teins that interact with dystrophin. The dystrophin gene is one of the largest in the human genome, spanning 2.3 million base pairs, a factor that is thought to make it particularly vulnerable to mutations. Muscle biopsy

FIGURE 36-5. Pseudohypertrophy of the calves exercise for a child with proximal muscle weakness caused by Duchenne muscular dystrophy.