Muscular Dystrophies

MUSCULAR DYSTROPHIES The muscular dystrophies are a heterogeneous group of inherited disorders, often beginning in childhood, that are characterized clinically by progressive muscle weakness and wasting. Histologically, the advanced cases are characterized by the replacement of muscle fibers by fibrofatty tissue. This feature distinguishes dystrophies from myopathies (described later), which also present with muscle weakness. X-Linked Muscular Dystrophy (Duchenne Muscular Dystrophy and Becker Muscular Dystrophy) The two most common forms of muscular dystrophy are X-linked: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). DMD is the most severe and the most common form of muscular dystrophy, with an incidence of about 1 per 3500 live male births.49 DMD becomes clinically manifest by the age of 5 years, with weakness leading to wheelchair dependence by 10 to 12 years of age, and progresses relentlessly until death by the early twenties. Although BMD involves the same genetic locus, it is less common and much less severe than DMD. Pathogenesis and Genetics. DMD and BMD are caused by abnormalities in a gene that is located in the Xp21 region and encodes a 427-kDa protein termed dystrophin. Deletions appear to represent a large proportion of the genetic abnormalities, with frameshift and point mutations accounting for the rest.11 Approximately two-thirds of the cases are familial, and the remainder represent new mutations. In the affected families, females are carriers; they are clinically asymptomatic but often have elevated serum creatine kinase and show minimal histologic abnormalities on muscle biopsy. Female carriers are at risk for developing dilated cardiomyopathy later in life. Dystrophin is a cytoplasmic protein located adjacent to the sarcolemmal membrane in myocytes (Fig. 27-10). The dystrophin molecule concentrates at the plasma membrane over Z-bands, where it forms a strong mechanical link to cytoplasmic actin. Thus, dystrophin and the dystrophinassociated protein complex form an interface between the intracellular contractile apparatus and the extracellular connective tissue matrix. The role of this complex of proteins in transferring the force of contraction to connective tissue has been proposed to be the basis for the myocyte degeneration that occurs in the absence of dystrophin50 or various other proteins that interact with dystrophin (see later). Muscle biopsy specimens from patients with DMD show minimal evidence of dystrophin by both staining and Western blot analysis.50 BMD patients, who also have mutations in the dystrophin gene, have diminished amounts of dystrophin, usually of an abnormal molecular weight, reflecting mutations that allow synthesis of the protein (Fig. 27-11B). page 1336 page 1337

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Morphology. Histopathologic abnormalities common to DMD and BMD include (1) variation in fiber size (diameter) due to the presence of both small and enlarged fibers, sometimes with fiber splitting; (2) increased numbers of internalized nuclei (beyond the normal range of 3% to 5%); (3) degeneration, necrosis, and phagocytosis of muscle fibers; (4) regeneration of muscle fibers; and (5) proliferation of endomysial connective tissue (Fig. 27-11A). DMD cases also often show enlarged, rounded, hyaline fibers that have lost their normal cross-striations, believed to

be hypercontracted fibers; this finding is rare in BMD. Both type 1 and type 2 fibers are involved, and no alterations in the proportion or distribution of fiber types are evident. Histo-chemical reactions sometimes fail to identify distinct fiber types in DMD. In later stages, the muscles eventually become almost totally replaced by fat and connective tissue. Cardiac involvement, when present, consists of interstitial fibrosis, more pro minent in the subendocardial layers. Despite the clinical evidence of CNS dysfunction in DMD, no consistent neuropathologic abnormalities have been described. Figure 27-10 Diagram showing the relationship between the cell membrane (sarcolemma) and the sarcolemmal associated proteins. Dystrophin, an intracellular protein, forms an interface between the cytoskeletal proteins and a group of transmembrane proteins, the dystroglycans and the sarcoglycans. These transmembrane proteins have interactions with the extracellular matrix, including the laminin proteins. Dystrophin also interacts with dystrobrevin and the syntrophins, which form a link with neuronal-type nitric oxide synthetase (nNOS) and caveolin. Mutations in dystrophin are associated with the X-linked muscular dystrophies, mutations in caveolin and the sarcoglycan proteins with the autosomal limb girdle muscular dystrophies, and mutations in the α2-laminin (merosin) with a form of congenital muscular dystrophy.

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Figure 27-11 A, Duchenne muscular dystrophy (DMD) showing variation in muscle fiber size, increased endomysial connective tissue, and regenerating fibers (blue hue). B, Western blot showing absence of dystrophin in DMD and altered dystrophin size in Becker muscular dystrophy (BMD) compared with control (Con). (Courtesy of Dr. L. Kunkel, Children's Hospital, Boston, MA.) page 1337 page 1338

Clinical Course. Boys with DMD are normal at birth, and early motor milestones are met on time. Walking, however, is often delayed, and the first indications of muscle weakness are clumsiness and inability to keep up with peers. Weakness begins in the pelvic girdle muscles and then extends to the shoulder girdle. Enlargement of the calf muscles associated with weakness, a phenomenon termed pseudohypertrophy, is an important clinical finding. The increased muscle bulk is caused initially by an increase in the size of the muscle fibers and then, as the muscle atrophies, by an increase in fat and connective tissue. Pathologic changes are also found in the heart, and patients may develop heart failure or arrhythmias. Although there are no wellestablished structural abnormalities of the central nervous system, cognitive impairment appears to be a component of the disease and is severe enough in some patients to be considered mental retardation.51 Serum creatine kinase is elevated during the first decade of life but returns to normal in the later stages of the disease, as muscle mass decreases. Death results from respiratory insufficiency, pulmonary infection, and cardiac decompensation. Gene therapy has received a great deal of attention in DMD, with some initial success in experimental animals with genetically similar disorders.50 The principal obstacle has been the introduction of a single large gene targeted into all muscle cells without initiation of an immune response to the new gene

product. Boys with BMD develop symptoms at a later age than those with DMD. The onset occurs in later childhood or in adolescence, and it is accompanied by a slower and more variable rate of progression, although there is considerable variation between pedigrees. Many patients have a nearly normal life span. Cardiac disease is frequently seen in these patients. Autosomal Muscular Dystrophies Other forms of muscular dystrophy share many features of DMD and BMD but have distinct clinical and pathologic characteristics. Some of these muscular dystrophics affect specific muscle groups, and the specific diagnosis is based largely on the pattern of clinical muscle weakness (Table 27-4). Several autosomal muscular dystrophies, however, affect the proximal musculature of the trunk and limbs, similar to the X-linked muscular dystrophies, and are termed limb girdle muscular dystrophies. Limb girdle muscular dystrophies are inherited in either an autosomal-dominant (type 1) or an autosomal-recessive (type 2) pattern (Table 27-5). Six subtypes of the dominant dys trophies (1A to 1F) and ten subtypes of the recessive limb girdle dystrophies (2A to 2J) have been identified. Mutations of the sarcoglycan complex of proteins have been identified in four of the limb girdle muscular dystrophies52 (2C, 2D, 2E, and 2F). These membrane proteins interact with dystrophin through another transmembrane protein, β-dystroglycan (Fig. 27-10). Myotonic Dystrophy Myotonia, the sustained involuntary contraction of a group of muscles, is the cardinal neuromuscular symptom in this disease.53 Patients often complain of "stiffness" and have difficulty in releasing their grip, for instance, after a handshake. Myotonia can often be elicited by percussion of the thenar eminence.

Table 27-4. Other Muscular Dystrophies Gene and Clinical Disease and Inheritance Locus Findings Pathologic Findings Facioscapulohumeral Type 1A-deletion Variable age at Dystrophic myopathy, but muscular dystrophy; of variable onset (most also often including autosomal-dominant number of 3.3-kB commonly 10-30 inflammatory infiltrates of subunits of a years); muscle. tandemly Weakness of arranged repeat muscles of face, (D4Z4) on 4q35 neck, and Type 1B shoulder girdle (FSHMD1B)locus unknown Oculopharyngeal Poly(A)-binding Onset in midadult Dystrophic myopathy, but muscular dystrophy; protein-2 life; ptosis and often including rimmed autosomal-dominant (PABP2) gene; weakness of vacuoles in type 1 fibers 14q11.2-q13 extraocular muscles; difficulty in swallowing Emery-Dreifuss muscular Emerin (EMD1) Variable onset Mild myopathic changes; dystrophy; X-linked gene; Xq28 (most commonly absent emerin by (mostly) 10-20 years); immunohistochemistry prominent

Congenital muscular dystrophies; autosomalrecessive (Also called muscular dystrophy, congenital, subtypes MDC1A, MDC1B, MDC1C)

contractures, especially of elbows and ankles Type 1A Neonatal (merosinhypotonia, deficient type)- respiratory laminin α2 insufficiency, (merosin) gene; delayed motor 6q22-q23 milestones Type 1B-locus at 1q42; gene unknown Type 1C; fukutinrelated protein gene; 19q13.3

Variable fiber size and extensive endomysial fibrosis

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Table 27-5. Limb Girdle Muscular Dystrophies Type Inheritance Locus Gene Clinicopathologic Features 1A Autosomal- 5q31 Myotilin Onset in adult life with slow dominant progression of limb weakness, but sparing of facial muscles; dysarthric speech 1B Autosomal- 1q21 Lamin A/C Onset before the age of 20 years in dominant lower limbs, progression during many years with cardiac involvement 1C Autosomal- 3p25 Caveolin-3 (MOnset before the age of 20, clinically dominant caveolin) similar to type 1B 1D Autosomal- 7p Unknown Limb girdle muscle weakness, adult dominant onset 2A Autosomal- 15q15.1- Calpain 3 Onset in late childhood to middle recessive 21.1 age; slow progression during 20-30 years 2B Autosomal- 2p13.3- Dysferlin Mild clinical course with onset in recessive q13.1 early adulthood 2C Autosomal- 13q12 γ-Sarcoglycan Severe weakness during childhood, recessive rapid progression; dystrophic myopathy on muscle biopsy 2D Autosomal- 17q21 α-Sarcoglycan Severe weakness during childhood, recessive (adhalin) rapid progression; dystrophic myopathy on muscle biopsy 2E Autosomal- 4q12 β-Sarcoglycan Onset in early childhood, with recessive Duchenne-like clinical course 2F Autosomal- 5q33 δ-Sarcoglycan Early onset and severe myopathy; recessive dystrophic myopathy on muscle biopsy 2G Autosomal- 17q11Telethonin Distal weakness with limb-girdle recessive q12 weakness in late childhood to

2H

Autosomalrecessive

9q31q34.1

Tripartite motifcontaining protein 32 (TRIM32)

adulthood; rimmed vacuoles in muscle cells Limb-girdle and facial weakness with onset in childhood, mild, slowly progressive course

Pathogenesis. Inherited as an autosomal-dominant trait, the disease tends to increase in severity and appear at a younger age in succeeding generations, a phenomenon termed anticipation. Myotonic dystrophy is associated with a trinucleotide CTG repeat expansion on chromosome 19q13.2-13.3. This expansion affects the mRNA for the dystrophila myotonia-protein kinase (DMPK).54 In normal subjects, fewer than 30 repeats are present; disease develops with expansion of this repeat, and in severely affected individuals, several thousand repeats may be present.54 The mutation is not stable within a pedigree; with each generation, more repeats accumulate, and this appears to correspond to the clinical feature of anticipation. Expansion of the trinucleotide repeat influences the eventual level of protein product. The pathologic features of the disease relate only in part to altered DMPK function. RNA that contains trinucleotide repeat expansions can directly affect splicing of other RNAs, including those for the ClC-1 chloride channel.55 A second form of myotonic dystrophy is associated with untranslated CCTG expansion in a gene called ZNF9 on chromosome 3.56 Morphology. Skeletal muscle may show variation in fiber size. In addition, there is a striking increase in the number of internal nuclei, which on longitudinal section may form conspicuous chains. Another well-recognized abnormality is the ring fiber, with a subsarcolemmal band of cytoplasm that appears distinct from the center of the fiber. The rim contains myofibrils that are oriented circumferentially around the longitudinally oriented fibrils in the rest of the fiber. The ring fiber may be associated with an irregular mass of sarcoplasm (sarcoplasmic mass) extending outward from the ring. These sarcoplasmic masses stain blue with hematoxylin and eosin, red with Gomori trichrome, and intensely blue with the nicotinamide adenine dinucleotidetetrazolium reductase (NADH-TR) histochemical reaction. Histochemical techniques have demonstrated a relative atrophy of type 1 fibers early in the course of the disease in some cases. Of all the dystrophies, only myotonic dystrophy shows pathologic changes in the intrafusal fibers of muscle spindles, with fiber splitting, necrosis, and regeneration. Clinical Course. The disease often presents in late childhood with abnormalities in gait secondary to weakness of foot dorsiflexors and subsequently progresses to weakness of the hand intrinsic muscles and wrist extensors. Atrophy of muscles of the face and ptosis ensue, leading to the typical facial appearance. Cataracts, which are present in virtually every patient, may be detected early in the course of the disease with slit-lamp examination. Other associated abnormalities include frontal balding, gonadal atrophy, cardiomyopathy, smooth muscle involvement, decreased plasma immunoglobulin G, and an abnormal glucose tolerance test response. Dementia has been reported in some cases. ION CHANNEL MYOPATHIES (CHANNELOPATHIES) The ion channel myopathies, or channelopathies, are a group of familial diseases characterized clinically by myotonia, relapsing episodes of hypotonic paralysis (induced by vigorous exercise, cold, or a high-carbohydrate meal), or both. Hypotonia variants associated with elevated, depressed, or normal serum potassium levels at the time of the attack are called hyperkalemic, hypokalemic, and normokalemic periodic paralysis, respectively. Pathogenesis. As their name indicates, at the molecular level these diseases are caused by mutations in genes that encode ion channels.57,58 Hyperkalemic periodic paralysis results from

mutations in the gene that encodes a skeletal muscle sodium channel protein (SCN4A), which regulates the entry of sodium into muscle during contraction. The gene for hypokalemic periodic paralysis encodes a voltage-gated calcium channel. page 1339 page 1340

Table 27-6. Congenital Myopathies Disease and Inheritance Central core disease; autosomaldominant

Nemaline myopathy; autosomaldominant or autosomalrecessive

Myotubular (centronuclear) myopathy; Xlinked (MTM1), autosomalrecessive, or autosomaldominant

Gene and Locus Clinical Findings Pathologic Findings Ryanodine Early-onset hypotonia Cytoplasmic cores are receptor-1 and nonprogressive lightly eosinophilic and (RYR1) gene; weakness; associated distinct from surrounding 19q13.1 skeletal deformities; may sarcoplasm; Found only develop malignant in type 1 fibers, which hyperthermia usually predominate, best seen on NADH stain AutosomalWeakness, hypotonia, Aggregates of dominant and delayed motor subsarcolemmal (NEM1)development in spindle-shaped particles Tropomyosin 3 childhood; may also be (nemaline rods); occur (TPM3) gene; seen in adults; usually predominantly in type 1 Autosomalnonprogressive; involves fibers; derived from Zrecessive proximal limb muscles band material (α-actinin) (NEM2)-nebulin most severely; skeletal and best seen on (NEB) gene; 2q22 abnormalities may be modified Gomori stain Autosomalpresent dominant or recessive-skeletal muscle actin, α chain (ACTA1) gene; 1q42.1 X-linkedX-linked form presents in Abundance of centrally myotubularin infancy with prominent located nuclei involving (MTM1) gene; hypotonia and poor the majority of muscle Xq28 Autosomal- prognosis; autosomal fibers; central nuclei are dominantforms have limb usually confined to type myogenic factor 6 weakness and are 1 fibers, which are small (MYF6) gene; slowly progressive; in diameter, but can 12q21 autosomal-recessive occur in both fiber types Autosomalform is intermediate in recessive-locus severity and prognosis and gene unknown

Malignant hyperpyrexia (malignant hyperthermia) is a rare clinical syndrome characterized by a dramatic hypermetabolic state (tachycardia, tachypnea, muscle spasms, and later hyperpyrexia) triggered by the induction of anesthesia, usually with halogenated inhalational agents and succinylcholine. The clinical syndrome may also occur in predisposed individuals with hereditary muscle diseases, including congenital myopathies, dystrophinopathies, and metabolic myopathies. The only reliable method of diagnosis is contraction of biopsied muscle on exposure to anesthetic. Mutations in different genes have been identified in families with susceptibility to

malignant hyperthermia, including genes encoding a voltage-gated calcium channel (lq32), an Ltype voltage-dependent calcium channel (7q21-q22), and a ryanodine receptor (19q13.1).59 CONGENITAL MYOPATHIES The congenital myopathies are a group of disorders defined largely on the basis of the pathologic findings within muscle.60 Most of these conditions share common clinical features, including onset in early life, nonprogressive or slowly progressive course, proximal or generalized muscle weakness, and hypotonia. Those affected at birth or in early infancy may present as "floppy babies" because of hypotonia or may have severe joint contractures (arthrogryposis); however, both hypotonia and arthrogryposis may also be caused by other neuromuscular dysfunction.

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Figure 27-12 A, Nemaline myopathy with numerous rod-shaped, intracytoplasmic inclusions (dark purple structures). B, Electron micrograph of subsarcolemmal nemaline bodies, showing material of Z-band density. page 1340 page 1341

The best-characterized congenital myopathies are listed in Table 27-6. Figure 27-12 shows the structural characteristics of nemaline ("rod body") myopathy, one of the most distinctive types. MYOPATHIES ASSOCIATED WITH INBORN ERRORS OF METABOLISM Many of the myopathies associated with metabolic disease are found in the setting of disorders of glycogen synthesis and degradation (Chapter 5). Combinations of clinical, pathologic, and molecular information are used to arrive at a specific diagnosis.61 Myopathies can also result from disorders of mitochondrial function. Lipid Myopathies Abnormalities of the carnitine transport system or deficiencies of the mitochondrial dehydrogenase enzyme systems can lead to the accumulation of lipid droplets within muscle (lipid myopathies).62 To undergo β-oxidation, cytoplasmic fatty acyl coenzyme A (acyl-CoA) esters are (1) transesterified with carnitine through the action of an outer membrane carnitine palmitoyltransferase (CPT I), (2) transported across the inner mitochondrial membrane, (3) reesterified to acyl-CoA esters by an inner membrane mitochondrial CPT (CPT II), and (4) catabolized to acetyl-CoA units by the acyl-CoA dehydrogenases. In different patients with lipid myopathy, the defect may involve carnitine, acyl-CoA dehydrogenase, or CPT enzymes.63,64 Morphology. In all of these lipid myopathies, the principal morphologic characteristic is accumulation of lipid within myocytes.62 The myofibrils are separated by vacuoles that stain with oil red O or Sudan black and have the typical appearance of lipid by electron microscopy. The vacuoles occur predominantly in type 1 fibers, and they are dispersed diffusely throughout the fiber. Mitochondrial Myopathies (Oxidative Phosphorylation Diseases) Approximately one-fifth of the proteins involved in mitochondrial oxidative phosphorylation are encoded by the mitochondrial genome (mtDNA); additionally, this circular genome encodes 22 mitochondrial-specific tRNAs and 2 rRNA species.66,67 The remainder of the mitochondrial enzyme complexes are encoded in the nuclear genome. Mutations in both nuclear and mitochondrial genes cause the so-called mitochondrial myopathies. Diseases that involve the

mtDNA show maternal inheritance, since only the oocyte contributes mitochondria to the embryo. There is a high mutation rate for mtDNA compared with nuclear DNA.68 The mitochondrial diseases may present in young adulthood and manifest with proximal muscle weakness, sometimes with severe involvement of the muscles that move the eyes (external ophthalmoplegia). The weakness may be accompanied by other neurologic symptoms, lactic acidosis, and cardiomyopathy, so this group of disorders is sometimes classified as mitochondrial encephalomyopathies (Chapter 28). Morphology. The most consistent pathologic finding in skeletal muscle is aggregates of abnormal mitochondria that are demonstrable only by special techniques.67,69,70 These occur under the subsarcolemma in early stages; but with severe involvement, they may extend throughout the fiber. The abnormal mitochondria impart a blotchy red appearance to the muscle fiber on the modified Gomori trichrome stain. Since they are also associated with distortion of the myofibrils, the muscle fiber contour becomes irregular on cross-section, and the descriptive term ragged red fibers has been applied to them (Fig. 27-13A).67 The electron microscopic appearance is often distinctive: There are increased numbers of, and abnormalities in, the shape and size of mitochondria, some of which contain paracrystalline parking lot inclusions or alterations in the structure of cristae67,69 (Fig. 27-13B). Cytochrome oxidase activity can be determined in muscle biopsy specimens using histochemistry, and cytochrome oxidase negative fibers may be present in a number of mitochondrial myopathies.

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Figure 27-13 A, Mitochondrial myopathy showing an irregular fiber with subsarcolemmal collections of mitochondria that stain red with the modified Gomori trichrome stain (ragged red fiber). B, Electron micrograph of mitochondria from biopsy specimen in A showing "parking lot" inclusions. page 1341 page 1342

Clinical Course and Genetics. The relationship between clinical course in the mitochondrial disorders and the genetic alterations is not entirely clear; however, three general categories have been defined.69 One set of mutations consists of point mutations in mtDNA. These disorders tend to show a maternal pattern of inheritance, and some examples include myoclonic epilepsy with ragged red fibers (MERRF), Leber hereditary optic neuropathy (LHON), and mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS). A second set of mutations involves genes encoded by nuclear DNA and shows autosomal-dominant or autosomal-recessive inheritance. Some cases of subacute necrotizing encephalopathy (Leigh syndrome), exertional myoglobinuria, and infantile X-linked cardioskeletal myopathy (Barth syndrome) are due to mutations in nuclear DNA. The final subset of mitochondrial myopathies is caused by deletions or duplications of mtDNA. Examples include chronic progressive external ophthalmoplegia, characterized by a myopathy with prominent weakness of external ocular

movements. Kearns-Sayre syndrome, another myopathy in this group, is also characterized by ophthalmoplegia but, in addition, includes pigmentary degeneration of the retina and complete heart block.67 INFLAMMATORY MYOPATHIES There are three subgroups of inflammatory muscle diseases: infectious, noninfectious inflammatory, and systemic inflammatory diseases that involve muscle along with other organs. Infectious myositis (Chapter 8) and systemic inflammatory diseases (Chapter 6) are discussed elsewhere. Noninfectious Inflammatory Myopathies Noninfectious inflammatory myopathies are a heterogeneous group of disorders that are probably immunologically mediated and are characterized by injury and inflammation of skeletal muscle. Three relatively distinct disorders, dermatomyositis, polymyositis, and inclusion body myositis, are included in this category.62,71 These may occur as an isolated myopathy or as one component of an immune-mediated systemic disease, particularly systemic sclerosis (Chapter 6). The clinical features of each disorder are presented first to facilitate discussion of pathogenesis and morphologic changes. Dermatomyositis. As the name implies, patients with dermatomyositis have an inflammatory disorder of the skin as well as skeletal muscle. It is characterized by a distinctive skin rash that may accompany or precede the onset of muscle disease. The classic rash takes the form of a lilac or heliotrope discoloration of the upper eyelids with periorbital edema (Fig. 27-14A). It is often accompanied by a scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees (Grotton lesions). Muscle weakness is slow in onset, is bilaterally symmetric, is often accompanied by myalgias, and typically affects the proximal muscles first. As a result, tasks such as getting up from a chair and climbing steps become increasingly difficult. Fine movements controlled by distal muscles are affected only late in the disease. Dysphagia resulting from involvement of oropharyngeal and esophageal muscles occurs in one-third of the patients. Extramuscular manifestations, including interstitial lung disease, vasculitis, and myocarditis, may be present in some cases. Compared to the normal population, patients with dermatomyositis have a higher risk of developing visceral cancers. According to several studies, nearly 40% of adult patients with dermatomyositis have cancer.72

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Figure 27-14 A, Dermatomyositis. Note the rash affecting the eyelids. B, Dermatomyositis. The histologic appearance of muscle shows perifascicular atrophy of muscle fibers and inflammation. C, Inclusion body myositis showing a vacuole within a myocyte. (Courtesy of Dr. Dennis Burns, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.) page 1342 page 1343

Juvenile dermatomyositis has a similar onset of rash and muscle weakness but more often is accompanied by abdominal pain and involvement of the gastrointestinal tract. Mucosal ulceration, hemorrhage, and perforation may occur as the result of the dermatomyositis-associated vasculopathy. Calcinosis, which is uncommon in adult dermatomyositis, occurs in one third of patients with juvenile dermatomyositis.71,73 Polymyositis. In this inflammatory myopathy, the pattern of symmetric proximal muscle involvement is similar to that seen in dermatomyositis. It differs from dermatomyositis by the lack of cutaneous involvement and its occurrence mainly in adults. Similar to dermatomyositis, there

may be inflammatory involvement of heart, lungs, and blood vessels. Inclusion Body Myositis. In contrast with the other two entities, inclusion body myositis begins with the in volvement of distal muscles, especially extensors of the knee (quadriceps) and flexors of the wrists and fingers. Furthermore, the weakness may be asymmetric. It is an insidiously developing disorder that typically affects indi viduals over the age of 50 years. Most cases are sporadic, but familial cases have been recognized as "inclusion body myopathy."74 Etiology and Pathogenesis. The cause of inflammatory myopathies is unknown, but the tissue injury seems to be mediated by immunologic mechanisms.62,71 In dermatomyositis, capillaries seem to be the principal targets. The microvasculature is attacked by antibodies and complement, resulting in foci of ischemic myocyte necrosis. The deposition of antibodies and complement in capillaries precedes inflammation and destruction of muscle fibers. B cells and CD4+ T cells are present within the muscle, but there is a paucity of lymphocytes within the areas of myofiber injury. The perifascicular distribution of myocyte injury also suggests a vascular pathogenesis. In contrast, polymyositis appears to be caused by cell-mediated injury of myocytes. CD8+ cytotoxic T cells and macrophages are seen near damaged muscle fibers, and the expression of HLA class I and class II molecules is increased on the sarcolemma of normal fibers. Similar to other immune-mediated diseases, ANAs are present in a variable number of cases, regardless of the clinical category (Chapter 6). The specificities of autoantibodies are quite varied, but those directed against tRNA synthetases seem to be more or less specific for inflammatory myopathies. The pathogenesis of inclusion body myositis is less clear. As in polymyositis, CD8+ cytotoxic T cells are found in the muscle, but in contrast to the other two forms of myositis, immunosuppressive therapy is not beneficial. Intracellular deposits of β-amyloid protein, amyloid β-pleated sheet fibrils, and hyperphosphorylated Tau protein are features in common with Alzheimer disease that have drawn attention to a possible relationship to aging. Abnormalities of protein folding have received some attention in inclusion body myopathy,74 as have similar deposits of amyloid fibrils in Alzheimer disease.75 The hereditary forms of inclusion body myopathy have a similar morphology but result from genetic mutations. The autosomal-recessive form is caused by mutations in the GNE gene (encoding UDP-N-acetylglucosamine-2 epimerase/N-acetylmannosamine kinase), and the autosomal-dominant form is caused by mutations in the gene encoding myosin heavy chain IIa.74 The role of these mutations in the pathogenesis of inclusion body myopathy is unclear. Morphology. The histologic features of the individual forms of myositis are quite distinctive and are described separately. Dermatomyositis. The inflammatory infiltrates in dermatomyositis are located predominantly around small blood vessels and in the perimysial connective tissue. Typically, groups of atrophic fibers are particularly prominent at the periphery of fascicles. This "perifascicular atrophy" is sufficient for diagnosis, even if the inflammation is mild or absent (Fig. 2714B). The perifascicular atrophy is most likely related to a relative state of hypoperfusion of the periphery of muscle fascicles. Quantitative analyses reveal a dramatic reduction in the intramuscular capillaries, believed to result from vascular endothelial injury and fibrosis. Necrotic muscle fibers and regeneration may also be seen throughout the fascicle, as in polymyositis. Polymyositis. In this condition, the inflammatory cells are found in the endomysium. CD8+ lymphocytes and other lymphoid cells surround and invade healthy muscle fibers. Both necrotic and regenerating muscle fibers are scattered throughout the fascicle, without the perifascicular atrophy seen in dermatomyositis. There is no evidence of vascular injury in polymyositis. Inclusion Body Myositis. The diagnostic finding in inclusion body myositis is

the presence of rimmed vacuoles (Fig. 27-14C). The vacuoles are present within myocytes, and they are highlighted by basophilic granules at their periphery. In addition, the vacuolated fibers may also contain amyloid deposits that reveal typical staining with Congo Red. Under the electron microscope, tubular and filamentous inclusions are seen in the cytoplasm and the nucleus, and they are composed of β-amyloid or hyperphosphorylated tau.76 The pattern of the inflammatory cell infiltrate is similar to that seen in polymyositis. The diagnosis of myositis is based on clinical symptoms, electromyography (EMG), elevated creatinine kinase in serum, and biopsy. EMG is particularly in formative in in flammatory myopathies, with mixed neurogenic and myopathic findings suggestive of inflammatory myopathy. As might be expected, muscle injury is associated with elevated serum levels of creatine kinase. Biopsy is required for definitive diagnosis. Immunosuppressive therapy is beneficial in adult and juvenile dermatomyositis and in polymyositis. TOXIC MYOPATHIES Thyrotoxic Myopathy page 1343 page 1344

Thyrotoxic myopathy presents most commonly as an acute or chronic proximal muscle weakness that may precede the onset of other signs of thyroid dysfunction. Exophthalmic ophthalmoplegia is characterized by swelling of the eyelids, edema of the conjunctiva, and diplopia. In hypothyroidism, there may be cramping or aching of muscles, and movements and reflexes are slowed. Findings include fiber atrophy, an increased number of internal nuclei, glycogen aggregates, and, occasionally, deposition of mucopolysaccharides in the connective tissue. In thyrotoxic myopathy, there is myofiber necrosis, regeneration, and interstitial lymphocytosis. In chronic thyrotoxic myopathy, there may be only slight variability of muscle fiber size, mitochondrial hypertrophy, and focal myofibril degeneration; fatty infiltration of muscle is seen in severe cases. Exophthalmic ophthalmoplegia is limited to the extraocular muscles, which may be edematous and enlarged. Another muscle disease associated with thyroid dysfunction is thyrotoxic periodic paralysis, which is characterized by episodic weakness that is often accompanied by hypokalemia. Males are affected four times more often than are females, with a high incidence in individuals of Japanese descent. Ethanol Myopathy Binge drinking of alcohol is known to produce an acute toxic syndrome of rhabdomyolysis with accompanying myoglobinuria, which may lead to renal failure. Clinically, the patient may acutely develop pain that is either generalized or confined to a single muscle group. Some patients have a complicated clinicopathologic syndrome consisting of proximal muscle weakness with electrophysiologic evidence of myopathy superimposed on alcoholic neuropathy. On histologic examination, there is swelling of myocytes, with fiber necrosis, myophagocytosis, and regeneration. There may also be evidence of denervation. Drug-Induced Myopathies Proximal muscle weakness and atrophy can occur as a result of the deleterious effects of steroids on muscle, whether in Cushing syndrome or during therapeutic administration of steroids, a condition known as steroid myopathy. The severity of clinical disability is variable and not directly related to the steroid level or the therapeutic regimen. It is characterized by muscle fiber atrophy, predominantly affecting type 2 fibers.76 When the myopathy is severe, there may be a bimodal distribution of fiber sizes, with type 1 fibers of nearly normal caliber and markedly atrophic type 2 fibers. Electron microscopy has shown dilation of the sarcoplasmic reticulum and thickening of the basal laminae.

Chloroquine , originally used in the treatment of malaria but subsequently used in other clinical settings, can produce a proximal myopathy in humans. The most prominent finding in chloroquine myopathy is the presence of vacuoles within myocytes. Two types of vacuoles have been described: autophagic membrane-bound vacuoles containing membranous debris and curvilinear bodies with short curved membranous structures with alternating light and dark zones. Vacuoles can be seen in as many as 50% of the myocytes, most commonly type 1 fibers, and with progression, myocyte necrosis may develop. A similar vacuolar myopathy occurs in some patients treated with hydrochloroquine.77 DISEASES OF THE NEUROMUSCULAR JUNCTION Myasthenia Gravis Now recognized as one of the best-defined forms of autoimmune disease, myasthenia gravis is a muscle disease caused by immune-mediated loss of acetylcholine receptors and having characteristic temporal and anatomic patterns as well as drug responses. The disease has a prevalence of about 3 in 100,000 persons.78 When arising before age 40 years, it is most commonly seen in women, but there is equal occurrence between the sexes in older patients. Thymic hyperplasia is found in 65% and thymoma in 15% of patients. Analysis of neuromuscular transmission in myasthenia gravis shows a decrease in the number of muscle acetylcholine receptors (AChRs), and circulating antibodies to the AChR are present in nearly all patients with myasthenia gravis.79,80 The disease can be passively transferred to animals with serum from affected patients. Morphology. By light microscopic examination, muscle biopsy specimens from patients with myasthenia are usually unrevealing. In severe cases, disuse changes with type 2 fiber atrophy may be found. The postsynaptic membrane is simplified, with loss of AChRs from the region of the synapse. Immune complexes as well as the membrane attack complex of the complement cascade (C5-Cq) can be found along the postsynaptic membrane as well. Pathogenesis. In most cases, the autoantibodies against the AChR lead to loss of functional AChRs at the neuromuscular junction by: (1) fixing complement and causing direct injury to the post-synaptic membrane, (2) increasing the internalization and degradation of the receptors, and (3) inhibiting binding and function of ACh. Electrophysiologic studies are notable for decrement in motor responses with repeated stimulation; nerve conduction study findings are normal. Sensory as well as autonomic functions are not affected. Despite the evidence that anti-AChR antibodies play a critical pathogenic role in the disease, there is not always a correlation between antibody levels and neurologic deficit. Interestingly, in light of the immune-mediated etiology of the disease, thymic abnormalities are common in these patients, but the precise link with autoimmunity to AChRs is uncertain. Regardless of the pattern of thymic pathology, most patients show improvement after thymectomy. Clinical Course. Typically, weakness begins with extraocular muscles; drooping eyelids (ptosis) and double vision (diplopia) cause the patient to seek medical attention. However, the initial symptoms may include generalized weakness. The weakness fluctuates, with alterations occurring during days, hours, or even minutes, and intercurrent medical conditions can lead to exacerbations of the weakness. Patients show improvement in strength in response to administration of anticholinesterase agents. This remains a most useful test on clinical examination.84 Respiratory compromise was a major cause of mortality in the past; 95% of patients now survive more than 5 years after diagnosis because of improved methods of treatment and better ventilatory support. Effective forms of treatment include anticholinesterase drugs, prednisone , plasmapheresis, and resection of thymoma if it is present.81 Lambert-Eaton Myasthenic Syndrome page 1344 page 1345

Lambert-Eaton myasthenic syndrome is a disease of the neuromuscular junction that is distinct from myasthenia gravis. It usually develops as a paraneoplastic process, most commonly with small cell carcinoma of the lung (60% of cases), although it can occur in the absence of underlying malignant disease. Patients develop proximal muscle weakness along with autonomic dysfunction. Unlike in myasthemia gravis, no clinical improvement is found upon administration of anticholinesterase agents, and electrophysiologic studies show evidence of enhanced neurotransmission with repetitive stimulation. These clinical features allow this disorder to be distinguished from myasthenia gravis. The content of anticholinesterase is normal in neuromuscular junction synaptic vesicles, and the postsynaptic membrane is normally responsive to anticholinesterase, but fewer vesicles are released in response to each presynaptic action potential. Some patients have antibodies that recognize pre synaptic PQ-type voltage-gated calcium channels, and a similar disease can be transferred to animals with these antibodies.82,83 This suggests that autoimmunity to the calcium channel causes the disease.