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 dystrophin-associated 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). |

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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[pic] 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.) |

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|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 |

|well-established 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. |

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|Table 27-4. Other Muscular Dystrophies |

|Disease and Inheritance |Gene and Locus |Clinical Findings |Pathologic Findings |

|Facioscapulohumeral muscular |Type 1A-deletion of |Variable age at onset |Dystrophic myopathy, but also |

|dystrophy; autosomal-dominant |variable number of |(most commonly 10-30 |often including inflammatory |

| |3.3-kB subunits of a |years); Weakness of |infiltrates of muscle. |

| |tandemly arranged |muscles of face, neck, | |

| |repeat (D4Z4) on 4q35 |and shoulder girdle | |

| |Type 1B | | |

| |(FSHMD1B)-locus | | |

| |unknown | | |

|Oculopharyngeal muscular dystrophy;|Poly(A)-binding |Onset in midadult life;|Dystrophic myopathy, but often |

|autosomal-dominant |protein-2 (PABP2) |ptosis and weakness of |including rimmed vacuoles in type|

| |gene; 14q11.2-q13 |extraocular muscles; |1 fibers |

| | |difficulty in | |

| | |swallowing | |

|Emery-Dreifuss muscular dystrophy; |Emerin (EMD1) gene; |Variable onset (most |Mild myopathic changes; absent |

|X-linked (mostly) |Xq28 |commonly 10-20 years); |emerin by immunohistochemistry |

| | |prominent contractures,| |

| | |especially of elbows | |

| | |and ankles | |

|Congenital muscular dystrophies; |Type 1A |Neonatal hypotonia, |Variable fiber size and extensive|

|autosomal-recessive (Also called |(merosin-deficient |respiratory |endomysial fibrosis |

|muscular dystrophy, congenital, |type)-laminin α2 |insufficiency, delayed | |

|subtypes MDC1A, MDC1B, MDC1C) |(merosin) gene; |motor milestones | |

| |6q22-q23 | | |

| |Type 1B-locus at 1q42;| | |

| |gene unknown | | |

| |Type 1C; | | |

| |fukutin-related | | |

| |protein gene; 19q13.3 | | |

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|Table 27-5. Limb Girdle Muscular Dystrophies |

|Type |Inheritance |Locus |Gene |Clinicopathologic Features |

|1A |Autosomal-dominant|5q31 |Myotilin |Onset in adult life with slow progression of |

| | | | |limb weakness, but sparing of facial muscles; |

| | | | |dysarthric speech |

|1B |Autosomal-dominant|1q21 |Lamin A/C |Onset before the age of 20 years in lower limbs,|

| | | | |progression during many years with cardiac |

| | | | |involvement |

|1C |Autosomal-dominant|3p25 |Caveolin-3 (M-caveolin) |Onset before the age of 20, clinically similar |

| | | | |to type 1B |

|1D |Autosomal-dominant|7p |Unknown |Limb girdle muscle weakness, adult onset |

|2A |Autosomal-recessiv|15q15.1-21.1 |Calpain 3 |Onset in late childhood to middle age; slow |

| |e | | |progression during 20-30 years |

|2B |Autosomal-recessiv|2p13.3-q13.1 |Dysferlin |Mild clinical course with onset in early |

| |e | | |adulthood |

|2C |Autosomal-recessiv|13q12 |γ-Sarcoglycan |Severe weakness during childhood, rapid |

| |e | | |progression; dystrophic myopathy on muscle |

| | | | |biopsy |

|2D |Autosomal-recessiv|17q21 |α-Sarcoglycan (adhalin) |Severe weakness during childhood, rapid |

| |e | | |progression; dystrophic myopathy on muscle |

| | | | |biopsy |

|2E |Autosomal-recessiv|4q12 |β-Sarcoglycan |Onset in early childhood, with Duchenne-like |

| |e | | |clinical course |

|2F |Autosomal-recessiv|5q33 |δ-Sarcoglycan |Early onset and severe myopathy; dystrophic |

| |e | | |myopathy on muscle biopsy |

|2G |Autosomal-recessiv|17q11-q12 |Telethonin |Distal weakness with limb-girdle weakness in |

| |e | | |late childhood to adulthood; rimmed vacuoles in |

| | | | |muscle cells |

|2H |Autosomal-recessiv|9q31-q34.1 |Tripartite |Limb-girdle and facial weakness with onset in |

| |e | |motif-containing protein |childhood, mild, slowly progressive course |

| | | |32 (TRIM32) | |

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|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 dinucleotide-tetrazolium 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. |

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|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[pic] 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. |

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|Table 27-6. Congenital Myopathies |

|Disease and Inheritance |Gene and Locus |Clinical Findings |Pathologic Findings |

|Central core disease; |Ryanodine receptor-1 |Early-onset hypotonia and |Cytoplasmic cores are lightly |

|autosomal-dominant |(RYR1) gene; 19q13.1 |nonprogressive weakness; |eosinophilic and distinct from |

| | |associated skeletal deformities; |surrounding sarcoplasm; Found |

| | |may develop malignant |only in type 1 fibers, which |

| | |hyperthermia |usually predominate, best seen |

| | | |on NADH stain |

|Nemaline myopathy; |Autosomal-dominant |Weakness, hypotonia, and delayed |Aggregates of subsarcolemmal |

|autosomal-dominant or |(NEM1)-Tropomyosin 3 |motor development in childhood; |spindle-shaped particles |

|autosomal-recessive |(TPM3) gene; |may also be seen in adults; |(nemaline rods); occur |

| |Autosomal-recessive |usually nonprogressive; involves |predominantly in type 1 fibers; |

| |(NEM2)-nebulin (NEB) |proximal limb muscles most |derived from Z-band material |

| |gene; 2q22 |severely; skeletal abnormalities |(α-actinin) and best seen on |

| |Autosomal-dominant or |may be present |modified Gomori stain |

| |recessive-skeletal | | |

| |muscle actin, α chain | | |

| |(ACTA1) gene; 1q42.1 | | |

|Myotubular |X-linked-myotubularin |X-linked form presents in infancy|Abundance of centrally located |

|(centronuclear) myopathy;|(MTM1) gene; Xq28 |with prominent hypotonia and poor|nuclei involving the majority of|

|X-linked (MTM1), |Autosomal-dominant- |prognosis; autosomal forms have |muscle fibers; central nuclei |

|autosomal-recessive, or |myogenic factor 6 |limb weakness and are slowly |are usually confined to type 1 |

|autosomal-dominant |(MYF6) gene; 12q21 |progressive; autosomal-recessive |fibers, which are small in |

| |Autosomal-recessive-loc|form is intermediate in severity |diameter, but can occur in both |

| |us and gene unknown |and prognosis |fiber types |

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|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 L-type 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. |

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|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) re-esterified 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. |

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|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. |

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|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.) |

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|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. 27-14B). 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. |

|[pic] |

|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 |

|[pic] |

|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[pic], 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[pic] 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. |

|[pic] |

|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[pic], plasmapheresis, and resection of |

|thymoma if it is present.81 |

|Lambert-Eaton Myasthenic Syndrome |

|page 1344 |

|[pic] |

|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. |

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