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 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.

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
 contractures,
especially of
elbows and
ankles
Congenital muscular Type 1A Neonatal Variable fiber size and
dystrophies; autosomal- (merosin- hypotonia, extensive endomysial
recessive (Also called deficient type)- respiratory fibrosis
muscular dystrophy, laminin α2 insufficiency,
congenital, subtypes (merosin) gene; delayed motor
MDC1A, MDC1B, 6q22-q23 milestones
MDC1C) 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- 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 (M- Onset 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- 17q11- Telethonin Distal weakness with limb-girdle
recessive q12 weakness in late childhood to
 adulthood; rimmed vacuoles in
muscle cells
2H Autosomal- 9q31- Tripartite motif- Limb-girdle and facial weakness with
recessive q34.1 containing protein onset in childhood, mild, slowly
32 (TRIM32) 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 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.

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.
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Table 27-6. Congenital Myopathies

Disease and
Inheritance Gene and Locus Clinical Findings Pathologic Findings
Central core Ryanodine Early-onset hypotonia Cytoplasmic cores are
disease; receptor-1 and nonprogressive lightly eosinophilic and
autosomal- (RYR1) gene; weakness; associated distinct from surrounding
dominant 19q13.1 skeletal deformities; may sarcoplasm; Found only
develop malignant in type 1 fibers, which
hyperthermia usually predominate,
best seen on NADH
stain
Nemaline Autosomal- Weakness, hypotonia, Aggregates of
myopathy; dominant and delayed motor subsarcolemmal
autosomal- (NEM1)- development in spindle-shaped particles
dominant or Tropomyosin 3 childhood; may also be (nemaline rods); occur
autosomal- (TPM3) gene; seen in adults; usually predominantly in type 1
recessive Autosomal- nonprogressive; involves fibers; derived from Z-
recessive 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
Autosomal- present
dominant or
recessive-skeletal
muscle actin, α
chain (ACTA1)
gene; 1q42.1
Myotubular X-linked- X-linked form presents in Abundance of centrally
(centronuclear) myotubularin infancy with prominent located nuclei involving
myopathy; X- (MTM1) gene; hypotonia and poor the majority of muscle
linked (MTM1), Xq28 Autosomal- prognosis; autosomal fibers; central nuclei are
autosomal- dominant- forms have limb usually confined to type
recessive, or myogenic factor 6 weakness and are 1 fibers, which are small
autosomal- (MYF6) gene; slowly progressive; in diameter, but can
dominant 12q21 autosomal-recessive occur in both fiber types
Autosomal- form 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 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.

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.

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
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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

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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.