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Faculdade de Medicina de São José do Rio Preto Departamento de Ciências Neurológicas

Laboratório de Investigação Neuromuscular

MUSCLE DISEASES Richard J. Barohn

Prof. Dr. João Aris Kouyoumdjian jaris@famerp.br

Texto baseado no livro-texto Cecil (Medicina, 2007)

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APPROACH TO MUSCLE DISEASES Definition Diseases of skeletal muscle, termed myopathies, are disorders in which there is a primary structural or functional impairment of muscle. Myopathies therefore do not include diseases of the central nervous system (CNS), lower motor neurons (motor neuron disease), peripheral nerves, or neuromuscular junction that secondarily produce muscle weakness. Myopathies can be differentiated from other disorders of the motor unit by characteristic clinical and laboratory findings (Table 1). In addition, the disorders of muscles can be categorized and subdivided so that it is generally possible to recognize a particular myopathy on the basis of its distinctive features (Table 2).

Table 1 - Clinical findings differentiating muscle from nerve disease

Finding Myopathy Anterior Horn Cell Disease

Peripheral Neuropathy

Neuromuscular Junction Disease

Distribution Usually proximal, symmetrical

Distal, asymmetrical, and bulbar

Distal, symmetrical

Extraocular, bulbar, proximal limb

Atrophy Slight early, marked late

Marked early Moderate Absent

Fasciculations Absent Frequent Sometimes present

Absent

Reflexes Lost late Variable, can be hyperreflexic

Lost early Normal

Pain Diffuse in myositis

Absent Variable, distal when present

Absent

Cramps Rare Frequent Occasional Absent

Sensory loss Absent Absent Usually present Absent

Serum creatine kinase

Usually elevated

Occasionally slightly elevated

Normal Normal

Table 2 - Classification of myopathies

HEREDITARY

Muscular dystrophies Congenital myopathies Myotonias and channelopathies Metabolic myopathies Mitochondrial myopathies

ACQUIRED

Inflammatory myopathies Endocrine myopathies Myopathies associated with systemic illness Drug-induced/toxic myopathies

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Pathobiology A single motor unit consists of four components: (1) a motor neuron, (2) its peripheral axon and terminal branches, (3) the neuromuscular junctions at each terminal nerve ending, and (4) all of the skeletal muscle fibers innervated by the axon. The number of muscle fibers innervated by a single motor unit varies from muscle to muscle. Muscles subserving finely coordinated movements, such as the ocular muscles, can have fewer than 10 muscle fibers in a motor unit. Powerful proximal limb muscles have large motor units with 1000 or 2000 fibers innervated by a single motor neuron. Individual fibers from different motor units intermingle randomly in the muscle. The muscle also contains connective tissue and blood vessels. Each of these tissues can be affected in myopathic disorders.

The muscle fibers consist of thick and thin filaments (myofibrils) arranged in repeating units, or sarcomeres, that are limited by Z discs. The thin filaments (actin, troponin, and tropomyosin) are anchored to the Z discs and interdigitate between the thick filaments (myosin) in the central region (A band) of the sarcomere. The myofibrils are associated with transverse (T) tubules, sarcoplasmic reticulum (SR), glycogen, and mitochondria. The head of each myosin molecule acts as a cross-bridge between myosin and actin. T tubules are inward projections of the muscle fiber surface membrane and serve to propagate the action potential into the muscle fiber. The SR contains calcium and partially surrounds the T tubules. Depolarization of T tubules triggers the opening of calcium channels and release of calcium from the SR into the myofilament space. Calcium then binds to troponin on the thin filaments, which acts on tropomyosin to allow repeated binding of the myosin cross-bridges to actin. The conformational change in the myosin-actin cross-bridge moves the thin filaments toward the center of the sarcomere, and the Z discs are pulled closer together to produce muscle fiber contraction. This contraction is an energy-dependent process that requires adenosine triphosphate (ATP), which is split by an ATPase on the cross-bridge.

The myofibrils and associated constituents are surrounded by the sarcolemmal membrane and basal lamina (Fig.1). Many muscular dystrophies are caused by genetic defects in this region. The sarcolemmal components are known as the dystrophin-glycoprotein complex, a trans-sarcolemmal complex of proteins and glycoproteins that link the subsarcolemmal cytoskeleton to the extracellular matrix. The role of the dystrophin-glycoprotein complex is to provide structural support to the sarcolemma during muscle contraction and stretch. In addition, the dystrophin-glycoprotein complex may have a role in the regulation of intracellular calcium and in signal transduction.

Dystrophin is a rod-shaped molecule on the cytoplasmic side of the skeletal and cardiac sarcolemma. It consists of an amino-terminal domain that binds to the cytoskeletal thin actin filaments. The mid-rod domain and the carboxy-terminal domain are important in linking dystrophin to the other glycoproteins of the dystrophin-glycoprotein complex. These dystrophin-glycoprotein complex components are the dystroglycan complex (�, �), the sarcoglycan complex (�, �, �, �), and the syntrophin complex (�, �1, �2).

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Figure 1. The dystrophin-glycoprotein complex and related proteins.

Closely adherent to the extracellular portion of the sarcolemma is the basal lamina, which is composed of collagen types I and IV, heparin sulfate proteoglycan, entactin, fibronectin, and laminin. Laminin is a heterotrimer composed of �, �, and � chains held together by disulfide bonds. Merosin is the collective name for laminins that share a common �2 chain. �-Dystroglycan binds to laminin and anchors the basal lamina to the sarcolemma. Another group of transmembrane proteins that are distinct from the dystrophin-glycoprotein complex are the integrins, which link the extracellular matrix to the sarcolemma. Integrins also bind merosin to skeletal muscle, and this interaction appears to be as important as the �-dystroglycan linkage in providing structural stability. In addition, integrins are important in transducing signals from the extracellular matrix to the cell.

Clinical Manifestations Symptoms of muscle disease can be divided into “negative” and “positive” complaints.

Negative Symptoms The most common symptom of a patient with muscle disease is weakness. An inability to perform activities because of proximal muscle weakness is the most common symptom in a myopathic disorder. However, occasional patients with myopathies can complain of poor handgrip (difficulty opening jar tops and turning door knobs) or tripping because of ankle weakness secondary to distal muscle weakness. Some myopathies involve “proximal” cranial muscles. Other crucial points in the history concern the age at onset of symptoms. Was the weakness (or other symptoms) first apparent at birth or was the onset in the first, second, third, or later decade? It is important to determine the tempo of the disease.

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Patients should be asked whether the weakness is present all the time or intermittently. Myopathies can be manifested as either fixed weakness (muscular dystrophies, inflammatory myopathies) or episodic periods of weakness with normal strength interictally (periodic paralysis secondary to channelopathies, metabolic myopathies secondary to certain disorders in the glycolytic pathway). Disorders of muscles can have acute (<4 weeks), subacute (4 to 8 weeks), or chronic (>8 weeks) periods over which the weakness evolves. The disorders with episodic weakness have acute weakness that can return to normal strength within hours or days. The tempo of the disorders with persistent weakness can vary from (1) acute or subacute in some inflammatory myopathies (dermatomyositis and polymyositis) to (2) chronic slow progression over a period of years (most muscular dystrophies) or to (3) fixed weakness with little change over decades (congenital myopathies). Finally, both constant and episodic myopathic disorders can cause symptoms that may be monophasic or polyphasic (relapsing).

Objective weakness is the most reliable symptom of a patient with a myopathy. Many patients who complain of generalized global “weakness” or fatigue are not weak and do not have a disorder of muscle, particularly if the findings on neurologic examination are normal. On the other hand, abnormal fatigability after exercise can result from certain metabolic and mitochondrial myopathies, and it is important to define the duration and intensity of exercise that provoke it.

Positive Symptoms Myalgia

Muscle pain (myalgia) is a nonspecific complaint that accompanies some myopathies. Myalgias may be episodic (e.g., metabolic myopathies) or nearly constant (e.g., inflammatory muscle disorders). However, muscle pain is surprisingly uncommon in most muscle diseases, and limb pain is more likely to be due to bone or joint disorders. It is rare for a muscle disease to be responsible for diffuse aching pain and discomfort in muscle if the results of neurologic examination and laboratory studies are normal.

Muscle Cramps

A specific category of muscle pain is the involuntary muscle cramp. Cramps are usually localized to a particular muscle region and last from seconds to minutes. They are generally benign, occur in normal individuals, do not reflect an underlying disease process, and are seldom a feature of a primary myopathy. Cramps can occur with dehydration, hyponatremia, azotemia, and myxedema and in disorders of the motor neuron (especially amyotrophic lateral sclerosis) or nerve.

Muscle Contractures

Muscle contractures are uncommon but can superficially resemble cramps. They usually last longer than cramps and are provoked by exercise in patients with glycolytic enzyme defects. They can be distinguished from cramps with needle electromyography (EMG). Contractures are electrically silent, whereas cramps are associated with rapidly firing motor unit discharges. Muscle contractures should not be confused with fixed tendon contractures.

Myotonias

Myotonia is impaired relaxation of muscle after forceful voluntary contraction. Patients may complain of muscle stiffness or persistent contraction in almost any muscle group, particularly those involving the hands and eyelids. They will note difficulty releasing their handgrip after a handshake, unscrewing a bottle top, or turning a doorknob. If they shut their eyes forcefully, they have difficulty opening their eyelids. With repeated exercise, the

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myotonia improves: the so-called warm-up phenomenon. Paramyotonia is the paradoxical phenomenon in which exercise makes the myotonia worse. Myotonia is due to repetitive depolarization of the muscle membrane. Exposure to cold worsens myotonia and paramyotonia.

Rhabdomyolysis

Patients who complain of exercise-induced weakness and myalgias should be asked whether their urine has ever turned dark or red during or after these episodes, which is indicative of myoglobinuria. Myoglobinuria follows excessive release of myoglobin from muscle during periods of rapid muscle destruction.

Diagnosis The most important aspect of evaluating a patient with a myopathy is the information obtained from the history. After taking the history, the physician should formulate a reasonable preliminary diagnosis that places the patient into one of the categories in Table 2 . The findings on physical examination, in particular the pattern of weakness, help further define the diagnosis.

History

A detailed family history should be obtained to look for autosomal dominant, recessive X-linked, and vertical maternal (mitochondrial) patterns of transmission. Identifying a particular hereditary pattern is of help in diagnosis and genetic counseling.

Potential precipitating factors should be explored. Is the patient taking legal or illegal drugs or exposed to myotoxins? Does exercise provoke weakness, pain, or dark urine? Are episodes of weakness associated with or preceded by a fever, a feature of carnitine palmitoyltransferase (CPT) deficiency? Does the ingestion of a high-carbohydrate meal precede the weakness, suggestive of a periodic paralysis? Does cold exposure precipitate muscle stiffness, suggestive of myotonia?

Neurologic Examination

It is important to grade muscle power at the bedside. All muscle groups should be tested bilaterally. Knee extension and hip flexion should be tested in the seated position, knee flexion should be tested prone, and knee abduction should be tested in the lateral decubitus position. Assessment of muscle strength is usually based on the Medical Research Council of Great Britain (MRC) grading scale:

5—Normal power

4—Active movement against gravity and resistance

3—Active movement against gravity

2—Active movement only with gravity eliminated

1—Trace contraction

0—No contraction

It is important to watch the patient perform functional activities: walking (to look for a wide-based waddling gait with hyperlordosis, which is a sign of pelvic muscle weakness); rising from a chair, from a squat, or from a seated position on the floor (Gowers' sign); or climbing stairs (noting whether the patient needs to use the arms, another sign of proximal weakness in the lower extremities). An inability to walk on the heels or toes can indicate weakness in the distal leg muscles. Observe the patient talk and smile to determine whether

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facial weakness is present. Does the patient have the so-called horizontal smile, indicative of lower facial muscle weakness? Is the patient unable to close the eyes completely when asked to do so, indicative of upper facial muscle weakness? Are the upper eyelids lowered so that they touch the pupil, indicative of ptosis? Is the patient's speech nasal, indicative of palatal muscle involvement?

Finally, if the patient complains of muscle stiffness, myotonia should be sought by asking the patient to squeeze the examiner's finger and then observing whether the patient has an inability to relax the handgrip. Additionally, the muscles can be directly percussed with a reflex hammer. Observe for a slow persistent contraction and delayed relaxation. The muscles that can be most easily percussed to look for myotonia are the thenar and wrist/finger extensor muscle groups. Facial myotonia can also be observed after forceful voluntary eye closure. The patient will be unable to open the eyes easily after this maneuver.

The sensory examination should be normal in patients with muscle disease. Reflexes are usually present early in the disease process. Once the myopathy is advanced and the muscles are extremely weak, reflexes can become hypoactive or unobtainable. Evidence of damage to upper motor neurons (spasticity, extensor plantar responses, clonus) is present in myopathies only if there is coincidental CNS disease.

Pattern of Weakness

Once the muscles have been inspected and tested for power and functional activity has been observed, an attempt should be made to place the patient in one of the patterns of muscle weakness that can occur in myopathic disorders. The various patterns of muscle weakness can be divided into six broad groups:

1. The pattern (most common) of weakness that is exclusively or predominantly found in the proximal muscles of the legs and arms—the so-called limb-girdle distribution. The neck flexor and extensor muscles can also be affected. This pattern of weakness can be seen in many hereditary and acquired myopathies and is therefore the least specific in arriving at a particular diagnosis. It is not known why most myopathic disorders selectively involve the proximal muscles.

2. The pattern of distal weakness in the upper extremities (extensor muscle group) or lower extremities (anterior or posterior compartment muscle groups). Selective weakness and atrophy in distal extremity muscles are more often features of neuropathies and are uncommonly due to a primary muscle disease. When this pattern of weakness is determined to be due to a myopathic rather than a neuropathic disorder, a diagnosis of distal myopathy is appropriate. Examples include myotonic dystrophy, distal dystrophies (see later), titinopathy, zaspopathy, and inclusion body myositis.

3. The pattern of proximal upper extremity weakness of the periscapular muscles and distal lower extremity weakness of the anterior compartment—the scapuloperoneal pattern. The scapular muscle weakness is usually accompanied by scapular winging. When this pattern is associated with facial weakness, it is highly suggestive of facioscapulohumeral dystrophy. Other hereditary myopathies can be associated with a scapuloperoneal syndrome, for example, scapuloperoneal dystrophy, Emery-Dreifuss dystrophy, acid maltase deficiency, and some congenital myopathies.

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4. The pattern of distal upper extremity weakness in the distal forearm muscles (wrist and finger flexors) and proximal lower extremity weakness involving the knee extensors (quadriceps). This pattern is essentially pathognomonic of inclusion body myositis. In addition, the weakness is often asymmetrical between the two sides, a pattern that is uncommon in most myopathies.

5. Predominant involvement of the ocular or pharyngeal muscles. The combination of ptosis, ophthalmoplegia without diplopia, and pharyngeal weakness should suggest the diagnosis of oculopharyngeal dystrophy, especially if the onset is in middle age or later. Ptosis and ophthalmoplegia without prominent pharyngeal involvement are hallmarks of many of the mitochondrial myopathies. Ptosis and facial weakness without ophthalmoplegia or pharyngeal weakness are common features of myotonic dystrophy. Therefore, the presence of ocular or pharyngeal muscle involvement can suggest a particular muscle disorder. Patients with ocular or pharyngeal involvement can also have the typical pattern of limb-girdle weakness.

6. Prominent neck extensor weakness. Some myopathic conditions have such a dramatic degree of weakness of the neck extensor muscles that the term dropped head syndrome is used. The neck flexors may or may not be weak. Neck extensor weakness can also occur with myopathies such as those with a limb-girdle pattern of weakness. Prominent neck extensor weakness is common in two other neuromuscular diseases: amyotrophic lateral sclerosis and myasthenia gravis. These six patterns of myopathy have limitations but are useful in narrowing the differential diagnosis. Patients with neuromuscular diseases other than myopathies can also have one of these weakness patterns.

Laboratory Studies

The results of the laboratory studies (blood tests, EMG, muscle biopsy, molecular studies) serve to confirm the preliminary diagnosis arrived at from the history and physical examination.

Serum Enzymes of Muscle Origin

Creatine kinase (CK) occurs in high concentration in the sarcoplasm of skeletal and cardiac muscle. The MM isoenzyme of CK predominates in skeletal muscle, MB occurs primarily in cardiac muscle, and BB is found mainly in brain. When skeletal muscle is injured, CK can leak into blood. Therefore, an elevated serum CK level is present in many muscle diseases. However, the absence of an elevated serum CK level does not exclude a myopathy, particularly in patients with severe muscle atrophy. In addition, elevation of the serum CK level does not necessarily imply that the muscle is the primary site of abnormality. The CK level is often elevated in normal individuals for days after strenuous voluntary exercise. Involuntary prolonged muscle contraction from a generalized motor seizure or tetany can elevate the CK level. The serum CK level is above the normal range in some African individuals, in individuals with large muscles, and after minor muscle trauma (e.g., EMG). Finally, other neuromuscular disorders such as motor neuron disease can produce up to a five-fold increase in the CK level. The serum CK level is normal in peripheral neuropathies and neuromuscular junction disorders.

The serum CK level is the most sensitive for muscle disease, and it is rarely necessary to measure other enzymes that can be released from injured skeletal muscle, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), or lactate dehydrogenase (LDH), all three of which are also elevated in hepatic disease. Because AST, ALT, and

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LDH are often measured in large screening chemical panels, their elevation should prompt measurement of CK to determine whether the source is muscle or liver. If a patient with an inflammatory myopathy is treated with a drug that may have hepatotoxicity as a side effect, it is not sufficient to measure ALT and AST levels; the liver-specific enzyme �-glutamyltransferase should be monitored.

In general, CK isoenzymes are not helpful in the evaluation of myopathy. Elevated CK-MM levels are typical of muscle disease, but the CK-MB level is also elevated in myopathies and does not indicate that cardiac disease is present.

Electromyography and Muscle Biopsy

EMG is the electrophysiologic assessment of the neuromuscular system. It consists of a nerve conduction study and needle EMG. A muscle specimen can be obtained through either an open or a closed (needle or punch) biopsy procedure. The biopsy should sample a muscle that is moderately weak. Biopsy specimens should generally not be taken from severely weak (MRC grade 2 or less) muscles. Muscles that have recently been studied by needle EMG often have artifacts from the procedure.

The muscle biopsy findings can establish whether there is evidence of either a neuropathic or a myopathic disorder. A neuropathy can produce denervation atrophy with small angular fibers, groups of atrophic fibers, and as a result of reinnervation, groups of fibers of the same histochemical type and target fibers. These features should not be present in a myopathy. Typical myopathic abnormalities include central nuclei, both small and large hypertrophic round fibers, split fibers, and degenerating and regenerating fibers. Inflammatory myopathies are characterized by mononuclear inflammatory cells in the endomysial and perimysial connective tissue between fibers and occasionally around blood vessels. Atrophy of fibers located on the periphery of a muscle fascicle, or perifascicular atrophy, is a common finding in a particular inflammatory myopathy, dermatomyositis. Any long-standing chronic myopathy can produce an increase in connective tissue and fat. Mitochondrial disorders are suggested by the identification of ragged red fibers on Gomori stain and various abnormal staining patterns on oxidative stains.

Electron microscopy (EM) evaluates the ultrastructural components of muscle fibers. In most myopathic disorders, EM is not usually required to make a pathologic diagnosis. However, EM is important in the study of certain disease states with abnormal light microscopic findings: congenital myopathies (e.g., nemaline rod, central core) and mitochondrial disorders.

Molecular Genetic Studies

The specific molecular genetic defect is known for an increasing number of myopathies. Molecular genetic testing is important for both diagnosis and carrier detection.

Other Tests

Electrolyte, endocrine, and immunologic tests are indicated to establish specific medical diagnoses. A decrease in the serum creatinine level is a useful indicator of decreased muscle mass.

Forearm exercise testing in patients with a suspected metabolic myopathy is often performed to determine whether there is a defect in the glycolytic enzyme pathway. After vigorous exercise, serum lactate and ammonia levels are measured. In disorders such as phosphorylase deficiency (McArdle's disease), the characteristic elevation in the serum lactate level after exercise is absent.

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Urinalysis can detect the presence of myoglobinuria, which should be suspected if the urine is positive for blood but no red blood cells are seen.

Imaging studies include computed tomography, magnetic resonance imaging (MRI), and ultrasound. MRI can show specific regional myopathies and help with muscle biopsy when it is unclear from the neurologic examination and EMG which muscle should be selected for biopsy.

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MUSCULAR DYSTROPHIES

Muscular dystrophies are inherited myopathies characterized by progressive muscle weakness and degeneration and by subsequent replacement with fibrous and fatty connective tissue. Historically, muscular dystrophies were categorized by their distribution of weakness, age at onset, and inheritance pattern. Advances in molecular understanding of the muscular dystrophies have defined the genetic mutation and abnormal gene product for many of these disorders (Table 3).

Table 3 - Muscular dystrophies

Disease Mode of Inheritance

Gene Mutation Location Gene Defect/Protein

X-LINKED MD

Duchenne's/Becker's XR Xp21 Dystrophin

Emery-Dreifuss XR Xq28 Emerin

LIMB-GIRDLE MD

LGMD 1A AD 5q22-34 Myotilin

LGMD 1B AD 1q11-21 Lamin A/C

LGMD 1C AD 3p25 Caveolin-3

LGMD 2A AR 15q15 Calpain-3

LGMD 2B[*] AR 2p12 Dysferlin

LGMD 2C AR 13q12 �-Sarcoglycan

LGMD 2D AR 17q12 �-Sarcoglycan

LGMD 2E AR 4q12 �-Sarcoglycan

LGMD 2F AR 5q33 �-Sarcoglycan

LGMD 2G AR 17q11 Telethonin

LGMD 2H AR 9q31 E3 ubiquitin ligase

LGMD 2I AR 19q13.3 Fukutin-related protein 1

LGMD 2J AR 2q31 Titin

CONGENITAL MD

WITH CNS INVOLVEMENT

Fukuyama's CMD AR 9q31-33 Fukutin

Walker-Warburg CMD AR 9q31-33 ?Fukutin

Muscle-eye-brain CMD AR 1p Glycosyltransferase

WITHOUT CNS INVOLVEMENT

Merosin-deficient, classic type AR 6q2 Laminin-2 (merosin)

Merosin-positive, classic type AR ? Not known

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Disease Mode of Inheritance

Gene Mutation Location Gene Defect/Protein

Integrin-deficient CMD AR 12q13 Integrin �7

Rigid-spine syndrome AR 1p3 Selenoprotein NI

DISTAL MD

Late adult-onset 1A (Welander) AD 2p15 Unknown

Late adult-onset 1B AD 2q31 Titin

Early adult-onset 1A (Nonaka) AR 9p1-q1 GNE

Early adult-onset 1B (Miyoshi)[†] AR 2q12-14 Dysferlin

Early adult-onset 1C (Laing) AD 14 MPD1

OTHER MD

Facioscapulohumeral AD 4q35 Deleted chromatin

Oculopharyngeal AD 14q11 Poly(A) binding protein 2

Myotonic dystrophy type 1 AD 19q13 RNA accumulation

Myotonic dystrophy type 2 AD 3q RNA accumulation

Myofibrillar myopathy AD 11q21-23 �-Crystallin

AD Zasp

AD 2q35 Desmin

Bethlem myopathy AD 21q22 Collagen VI

AD = autosomal dominant; AR = autosomal recessive; CMD = congenital muscular dystrophy; CNS = central nervous system; GNE = UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase; LGMD = limb-girdle muscular dystrophy; MD = muscular dystrophy; XR = X-linked recessive.

* Probably the same condition as Miyoshi distal MD.

† Probably the same condition as LGMD 2B.

Dystrophinopathies

The dystrophinopathies include X-linked disorders resulting from mutations of the large dystrophin gene located at Xp21. Dystrophin is a large 427-kD subsarcolemmal cytoskeletal protein that along with other components of the dystrophin-glycoprotein complex, provides support to the muscle membrane during contraction. The large size of the gene (2.4 megabases) accounts for the high mutation rate. Large deletions, several kilobases to more than 1 million base pairs, can be demonstrated in approximately two thirds of patients; duplications occur in 5% of cases, and the remainder have small mutations that are not readily detectable. Mutations disrupting the translational reading frame of the gene result in near-total loss of dystrophin (Duchenne's muscular dystrophy), whereas in-frame mutations result in the translation of semifunctional dystrophin of abnormal size or amount (Becker's muscular dystrophy).

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Duchenne's Muscular Dystrophy Epidemiology and Pathobiology

The incidence of Duchenne's muscular dystrophy is 1 in 3500 male births, and the prevalence approaches 1 per 18,000 males. A third of cases result from a new mutation. Most patients with Duchenne's muscular dystrophy have a frameshift mutation and total deficiency of dystrophin. Deficiency of dystrophin weakens the sarcolemma and thus permits the influx of calcium-rich extracellular fluid, which then activates intracellular proteases and complement and leads to fiber necrosis.

Clinical Manifestations

Duchenne's dystrophy is manifested as early as 2 to 3 years of age with delays in motor milestones and difficulty running. The proximal muscles are the most severely affected early (limb-girdle pattern), and the course is relentlessly progressive.

Cardiac muscle is also affected. Although patients are generally asymptomatic, heart failure and arrhythmias can occur late in the disease.

The smooth muscle of the gastrointestinal tract is also involved, and intestinal pseudo-obstruction occurs. The average intelligence quotient of affected boys is 1 SD below the normal mean, thus suggesting CNS involvement.

Diagnosis

A dystrophin gene deletion (or less often a duplication) can be detected by analysis of DNA from leukocytes (by polymerase chain reaction) in a blood sample in approximately two thirds of patients. The DNA from a muscle sample can be similarly tested, but it is no more specific than leukocyte DNA analysis. If the patient falls into the third of patients in whom a deletion cannot be detected, muscle biopsy is required to demonstrate dystrophin deficiency by either Western blot or immunostaining. Muscle biopsy will also demonstrate typical features of a muscular dystrophy: variability in fiber size, fiber necrosis and regeneration, and replacement with connective tissue and fat.

Serum CK levels are markedly elevated at birth (20 to 100 times normal). They remain elevated but tend to decline over the course of the disease, after severe loss of muscle mass has occurred. EMG shows fibrillation potentials and myopathic motor units. EMG and muscle biopsy are not necessary in Duchenne's dystrophy if the diagnosis can be established by molecular studies of lymphocytes.

Up to 90% of patients can have an abnormal electrocardiogram (ECG) consisting of tall right precordial R waves and deep left precordial Q waves. Echocardiography shows either hypokinesis or dilation of ventricular walls.

Prognosis

Patients begin to fall frequently by 5 to 6 years of age, have difficulty climbing stairs by the age of 8, and are usually confined to a wheelchair by 12 years of age. Joint contractures commonly appear between 6 and 10 years. Initially, calf hypertrophy is often present, but after ambulation is lost, all muscles atrophy. Paraspinal muscle weakness leads to progressive kyphoscoliosis. The proximal tendon reflexes (biceps, quadriceps) disappear by the age of 10, although gastrocnemius reflexes are often preserved until late in the disease. Respiratory function gradually declines, and decreased vital capacity can be detected after the age of 10. Most patients die of respiratory complications in their 20s.

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Becker's Muscular Dystrophy Epidemiology and Pathobiology

Becker's dystrophy is a milder form of dystrophinopathy and varies in severity, depending on the genetic lesion. It is less common than Duchenne's, with an incidence of 5 per 100,000 and prevalence of 2.4 per 100,000. Most patients with Becker's dystrophy have a non–frame-shifting mutation, so a reduced amount of an abnormal dystrophin is produced and results in a milder syndrome than Duchenne's muscular dystrophy.

Clinical Manifestations

The pattern of weakness resembles that of Duchenne's muscular dystrophy, but it is less severe. The mean age at onset of symptoms is later, between 5 and 15 years. Calf hypertrophy is often prominent, and patients may complain of exercise-induced calf pain as an early symptom. Patients usually remain ambulatory after the age of 15, and the average age when a wheelchair is required is 30 years. Children with Duchenne's muscular dystrophy cannot lift their head fully against gravity (MRC grade <3), whereas less severe, “outlier” children and those with Becker's dystrophy retain this ability. Cardiac abnormalities are similar to those described for Duchenne's muscular dystrophy.

Diagnosis

DNA analysis from blood leukocytes will show an Xp21 deletion in about 60% of cases. Results of immunostaining and Western immunoblot for dystrophin on muscle extracts reveal that the protein is not absent, as in Duchenne's muscular dystrophy, but is reduced in amount or abnormal in size. The serum CK level is moderately elevated, and needle EMG shows electrophysiologic signs of a myopathy, similar to the findings in Duchenne's muscular dystrophy.

Prognosis

Most patients with Becker's dystrophy experience slow progression. Death may occur from respiratory or cardiac complications after 40 years of age.

Other Dystrophinopathies

Other, milder dystrophinopathy phenotypes include exercise intolerance associated with myalgias, muscle cramps, or myoglobinuria; minimal limb-girdle weakness or quadriceps myopathy; asymptomatic elevation of the serum CK level; cardiomyopathy with only mild muscle weakness; and fatal X-linked cardiomyopathy without muscle weakness. The different dystrophin phenotypes are determined by the site of the mutation in the dystrophin gene and the effect or lack of effect of the mutation on expression of the cardiac isoform of dystrophin.

Female Carriers and Prevention

The daughters of males with a dystrophinopathy are obligate carriers of the mutated dystrophin gene, as are the mothers of affected children who also have a family history of Duchenne's or Becker's muscular dystrophy. Mothers and sisters of index cases of isolated Duchenne's or Becker's dystrophy are at risk for being carriers. There is a 50% chance that males born to carrier females will inherit the disease, and 50% of the carrier's daughters will become carriers themselves. Female carriers are generally asymptomatic, but they may rarely demonstrate moderate limb-girdle weakness.

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The CK level is elevated in about 50% of female carriers. A more accurate method of carrier detection is to look for an Xp21 deletion, which will be present if the affected males in the family are among the 60% who have a dystrophin gene deletion (or duplication). If a deletion is not present, linkage analysis of families can be performed. Prenatal genetic testing can be performed on amniotic fluid cells or chorionic villi.

Treatment

Controlled trials with prednisone, 0.75 mg/kg/day, in Duchenne's dystrophy have demonstrated moderate improvement in strength and delay in progression to a wheelchair or braces. Short-term and medium-term creatine supplements can improve muscle strength. Prednisone also delays respiratory compromise, but it cannot prevent deterioration and death. Side effects of therapy include weight gain, growth delay, and changes in behavior. Gene therapy for the dystrophinopathies and other muscular dystrophies with known genetic mutations is still in preclinical stages. Trials of myoblast transfer from the normal fathers of patients with Duchenne's dystrophy to their affected sons found no effect.

Emery-Dreifuss Dystrophy

Emery-Dreifuss dystrophy is an X-linked muscular dystrophy. The mutated gene in the Xq28 region codes for a protein product, emerin. Emerin is a 254–amino acid protein that localizes to the nuclear membranes of skeletal, cardiac, and smooth muscle fibers; its function is unknown.

Clinical Manifestations

The disease is characterized by the clinical triad of (1) early contractures of the elbows, ankles, and posterior cervical muscles; (2) slowly progressive muscle weakness, usually in a scapulohumeroperoneal distribution; and (3) cardiomyopathy with atrial conduction defects. The early elbow contractures are often an important phenotypic key to the diagnosis.

Diagnosis

The serum CK level is either normal or only moderately elevated. Muscle biopsy shows a range of myopathic changes but fewer dystrophic features than in Duchenne's or Becker's dystrophy. The ECG can demonstrate sinus bradycardia, prolongation of the PR interval, or more severe degrees of conduction block. Definitive diagnosis can be made by either leukocyte DNA analysis or immunostaining of muscle or skin tissue for emerin. The normal emerin perinuclear staining pattern in these tissues will be absent in Emery-Dreifuss dystrophy.

Prognosis

Although Emery-Dreifuss dystrophy usually begins in childhood, most patients remain ambulatory into their third or fourth decades. The cardiac conduction defects are potentially lethal and frequently require a pacemaker.

Bethlem Myopathy

Bethlem myopathy clinically resembles Emery-Dreifuss dystrophy because of a similar pattern of weakness and early contractures. However, Bethlem myopathy has no cardiac involvement, and the inheritance pattern is autosomal dominant. At least some cases of

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Bethlem myopathy are due to a mutation in the �1 and �2 subunits of collagen VI located on chromosome 21q.

Rigid-Spine Syndrome

The rigid-spine syndrome is a disorder in which muscle contractures involve the spine, as well as other joints. The genetic defect has been localized to chromosome 1p3, and the presumed gene product is selenoprotein. Because of the severe contractures, it must be distinguished from Emery-Dreifuss dystrophy and Bethlem myopathy. In most cases, the disease is sporadic and manifested in infancy as hypotonia, proximal weakness, and delayed motor milestones. The serum CK level is mildly elevated. Muscle biopsies demonstrate nonspecific myopathic features. Throughout the first decade, the child experiences progressive, severe scoliosis and limitations of spinal mobility, as well as elbow and knee contractures. The spinal deformities continue until about 7 to 13 years of age, at which time the disease appears to stabilize.

Limb-Girdle Muscular Dystrophies

Limb-girdle muscular dystrophies (LGMDs) include a large number of hereditary muscular dystrophies with a limb-girdle pattern of weakness. LGMDs are either autosomal recessive (the majority) or autosomal dominant and thus are clinically distinguished from the dystrophinopathies by an equal occurrence in both sexes. When LGMD occurs in early childhood, it resembles Duchenne's dystrophy and has been termed severe childhood recessive muscular dystrophy. Milder phenotypes can resemble Becker's dystrophy. The laboratory features (serum CK, EMG, muscle biopsy) are consistent with a muscular dystrophy. At least 10 subtypes of LGMD have been established on the basis of genetic mutations and the resulting protein defects. The less common autosomal dominant forms have been labeled type 1 (LGMD 1A, 1B, 1C, etc.), the autosomal recessive disorders are type 2 (LGMD 2A, 2B, etc.), and the list continues to grow.

Autosomal Recessive Limb-Girdle Muscular Dystrophies

A number of the autosomal recessive LGMDs are due to defects in one of the sarcoglycan components of the dystrophin-glycoprotein complex, termed sarcoglycanopathies (LGMD 2C, 2D, 2E, 2F).

The protein mutated in LGMD 2C, �-sarcoglycan, was previously known as adhalin—Arabic for “muscle.” These disorders may account for as many as 20% of the muscular dystrophies that have a Duchenne or Becker phenotype. LGMD 2C and 2D usually begin in childhood; LGMD 2E and 2F have a more variable age at onset, even within families. These LGMDs are not associated with intellectual impairment or cardiac abnormalities, in contrast to the dystrophinopathies.

The sarcoglycans are important components of the dystrophin-glycoprotein complex, but the exact role of these proteins is unknown. A deficiency in one of the sarcoglycans results in destabilization of the entire sarcoglycan complex. The results of muscle biopsy show normal dystrophin; however, immunostaining for each of the sarcoglycans is absent or diminished, regardless of the primary sarcoglycan mutation.

Other autosomal recessive LGMDs have known protein mutations that are not part of the dystrophin-glycoprotein complex. LGMD 2A, with an age at onset of between 3 and 30 years (mean, 13), is due to a genetic mutation producing a deficiency in the muscle-

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specific proteolytic enzyme calpain-3. Calpains are nonlysosomal intracellular cysteine proteases. In patients with LGMD 2B, weakness develops between the ages of 13 and 35 and CK levels are elevated up to 200 times normal. The LGMD 2B mutation localizes to a region on 2p13 that codes for a protein recently named dysferlin. Dysferlin shares amino acid sequence homology with the C. elegans spermatogenesis factor FER-1. LGMD 2B is also of interest because affected individuals can have one of two distinct phenotypes: limb-girdle or a distal myopathy pattern (see the later discussion of distal muscular dystrophy). How a mutation in the same protein can result in such dissimilar clinical manifestations is unclear.

Autosomal Dominant Limb-Girdle Muscular Dystrophies

The autosomal dominant LGMDs all have their onset in childhood or early adult life. Linkage to chromosome locations is known for LGMD 1A and 1B; the molecular defect for LGMD 1C produces a protein deficiency of caveolin-3. Caveolins may act as scaffolding proteins on which caveolin-interacting lipids and proteins are organized. Caveolin-3 is not considered part of the dystrophin-glycoprotein complex, although it is localized to the sarcolemma by immunostaining.

Differential Diagnosis of Limb-Girdle Syndromes

All patients with limb-girdle syndromes need to be investigated by EMG and muscle biopsy. In those with a positive family history, the differential diagnosis includes inherited metabolic myopathies (e.g., acid maltase deficiency or a lipid storage myopathy), morphologically distinct congenital myopathies or their late-onset variants (e.g., nemaline, central core, and myotubular myopathies), or the anterior horn cell disease spinal muscular atrophy. In sporadic cases of a limb-girdle syndrome, the differential diagnosis includes the same diseases and also inflammatory myopathies (polymyositis, inclusion body myositis, or sarcoidosis confined to muscle), endocrine myopathies, sporadic Duchenne's dystrophy, Duchenne's or Becker's dystrophy manifested in female carriers, other dystrophinopathies, and sporadic Emery-Dreifuss dystrophy before the appearance of joint contractures or cardiomyopathy.

Congenital Muscular Dystrophies

The congenital muscular dystrophies are a group of autosomal recessive disorders in which the onset of hypotonia and proximal weakness occurs during the prenatal period; muscle biopsy shows dystrophic findings. Affected infants often have joint contractures of the elbows, hips, knees, and ankles (arthrogryposis). Congenital muscular dystrophies can be broadly divided into those without and those with clinical evidence of CNS involvement (severe mental retardation, seizures, and visual loss from cerebro-ocular dysplasia). However, many patients without severe brain disease clinically, the so-called classic type, usually demonstrate cerebral hypomyelination on MRI. The congenital muscular dystrophies with significant brain and eye involvement generally have progressive courses and result in death by 10 to 12 years of age. Classic-type congenital muscular dystrophies without clinical CNS involvement have a more benign outlook with a nonprogressive course; affected patients may eventually walk independently.

Fifty percent of classic-type congenital muscular dystrophy is associated with a deficiency of the basal lamina protein �2-laminin, also known as merosin. Merosin is bound to the dystrophin-glycoprotein complex and anchors the basal lamina to the sarcolemma. Merosin-negative congenital muscular dystrophy can be diagnosed by immunostaining of muscle or skin. Other congenital muscular dystrophies without clinical CNS involvement

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are associated with a deficiency of integrin, a trans-sarcolemmal protein that is not part of the dystrophin-glycoprotein complex. Fukuyama-type congenital muscular dystrophy, occurring primarily in Japan, is associated with mutations in the gene encoding for a protein named fukutin. The same genetic defect probably accounts for the Walker-Warburg cerebro-ocular dysplasia syndrome. Fukutin is not associated with the sarcolemma and appears to be a secreted protein, but its function is unknown.

Facioscapulohumeral Dystrophy Epidemiology and Pathobiology

Inheritance of facioscapulohumeral dystrophy is autosomal dominant with high penetrance and variable expression within families. Affected family members may be unaware of their mild deficits, thus making examination of relatives of suspected patients very important. The incidence of facioscapulohumeral dystrophy is 1 in 20,000. Facioscapulohumeral dystrophy has been linked to the telomeric region of chromosome 4q35. Although the gene has not been isolated, a deletion in this region is present in virtually all patients with facioscapulohumeral dystrophy.

Clinical Manifestations

The disease is initially manifested in childhood or adult life. It involves the facial muscles early and then descends to the scapular stabilizers (serratus anterior, rhomboid, trapezius, latissimus dorsi), the muscles of the upper part of the arm (biceps, triceps), and the anterior leg muscles. Early physical signs include failure to bury the eyelashes on forced eye closure, an expressionless face, winging of the scapulas when the arms are raised, and prominent indentation of the anterior axillary folds. The deltoids are relatively spared when compared with the other proximal arm muscles. Distal muscle weakness occurs first in the tibialis anterior and may result in footdrop and lead to a scapuloperoneal pattern of weakness. Later, wrist and finger extensor weakness may develop.

Diagnosis

The serum CK level is normal or mildly elevated. Muscle biopsy shows moderate myopathic changes, but a prominent mononuclear inflammatory infiltrate can be confused with polymyositis. However, these patients do not respond to immunosuppressive therapy. A variant is associated with sensorineural hearing loss and with retinal telangiectasia and painless blindness (Coats' disease).

Differential Diagnosis

Scapuloperoneal muscular dystrophy is an autosomal dominant disorder that can resemble facioscapulohumeral dystrophy, but without facial weakness. In these families there is no linkage to chromosome 4q35.

Prognosis

The rate of progression and the extent to which the pelvic girdle and forearm muscles are eventually affected vary considerably between and within families. In general, cases with early onset have a worse prognosis. Some patients experience a late exacerbation of weakness after years of little or slow progression. Approximately 20% of these patients will eventually require a wheelchair. Joint contractures are uncommon.

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The Myotonic Dystrophies

Type 1 myotonic dystrophy (DM-1) is an autosomal dominant multisystemic disorder that affects skeletal, cardiac, and smooth muscle and other organs, including the eyes, endocrine system, and brain.

Epidemiology

DM-1 is the most common muscular dystrophy, with an incidence of 13.5 per 100,000 live births and a prevalence of 3 to 5 per 100,000. DM-1 can occur at any age, but the usual onset of symptoms is in the late second or third decade. However, some affected individuals may remain free of symptoms their entire life. The severity generally worsens from one generation to the next. A severe form with onset in infancy is known as congenital DM-1.

Pathobiology

The molecular defect in DM-1 is abnormal expansion of CTG repeats in a protein kinase gene on chromosome 19q13.2. Affected individuals have more than 50 CTG repeats, and the severity of the disease directly correlates with the size of the expanded triplet repeat. The protein kinase encoded by this gene has been termed myotonin. Studies of transgenic animals suggest that some, if not all manifestations of DM-1 result from the accumulation of abnormal RNA transcribed by the lengthy trinucleotide repeat on chromosome 19.

Clinical Manifestations

Typical patients exhibit facial weakness with temporalis muscle wasting, frontal balding, ptosis, and weakness of the neck flexor muscles . Weakness of the extremities usually begins distally and progresses slowly to affect the limb-girdle muscles proximally. Weakness is a more common symptom than muscle stiffness or myotonia, although patients may complain of an inability to relax the fingers after a handgrip. Patients may be areflexic, but findings on sensory examination are normal.

Associated manifestations include posterior subscapular cataracts, testicular atrophy and impotence, intellectual impairment, and hypersomnia from both central and obstructive sleep apnea. Respiratory muscle weakness may be severe. Elevated serum glucose levels occur as a result of end-organ unresponsiveness to insulin, but frank diabetes mellitus rarely develops. Involvement of smooth muscle in the gastrointestinal tract can produce dysphagia, reduced gut motility, and chronic pseudo-obstruction. Cardiac conduction defects are common and can produce sudden death. Chronic hypoxia can lead to cor pulmonale. Affected females may have a high rate of fetal loss.

Diagnosis

The serum CK level is normal or mildly increased. Muscle biopsies show excessive number of central nuclei, type 1 atrophy, and other nonspecific myopathic changes. EMG shows myopathic motor units in addition to myotonic potentials.

The diagnosis can be established by documenting an increased number of CTG expansions on chromosome 19q13.2 in leukocytes from a blood sample. Marked expansion of the CTG repeat usually occurs in the children of mothers with DM-1, thus accounting for anticipation and the severe phenotype of congenital DM-1.

Differential Diagnosis

A second myotonic dystrophy locus (DM-2) on chromosome 3q involves mutations that expand a tetranucleotide repeat sequence. The clinical features of DM-2 are similar, but

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weakness is more often proximal than in DM-1. DM-2 is also referred to as proximal myotonic myopathy (PROMM). A similar abnormality in RNA transcription is probably responsible for DM-2. Proximal extremity weakness and myalgias are characteristic of DM-2. Patients with DM-2 may have less cardiac muscle or other organ involvement than those with DM-1.

Treatment

In both DM-1 and DM-2, the myotonia is generally less symptomatic than weakness and may not require treatment. Phenytoin, usually 300 mg daily, is the safest drug for myotonia; quinine, tocainide, and mexiletine can exacerbate cardiac conduction abnormalities. Annual ECGs are recommended, and a pacemaker may be necessary. Positive pressure ventilation devices may assist DM-1 patients who have sleep apnea. Sedatives and opiates should be used with caution because they can depress the ventilatory drive. Patients with myotonic dystrophy are at risk for pulmonary and cardiac complications during general anesthesia. Braces can assist patients with footdrop.

Prognosis

The prognosis is extremely variable. Patients with mild weakness and myotonia can have very little progression, whereas those with severe weakness, cardiac conduction defects, and progressive disease have a shortened life expectancy.

Distal Dystrophies

Although a number of myopathies can have prominent distal weakness as a feature, some genetically distinct entities are classified as distal muscular dystrophies. There are two late adult-onset autosomal dominant forms.

Welander's Distal Dystrophy

Welander's distal dystrophy occurs in Scandinavia and is manifested between the fourth and sixth decades as selective weakness and atrophy of the forearm extensor and intrinsic hand muscles and then involves the anterior leg and small foot muscles. Tibial muscular dystrophy has been observed in Finnish, French, and U.S. patients and initially involves the anterior tibial muscles and later the distal ends of the upper extremities. A mutation in titin is responsible. The protein defect for autosomal recessive Nonaka distal muscular dystrophy (also known as hereditary inclusion body myopathy) has been identified in uridine diphosphate-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). GNE is involved in the post-translational glycosylation of proteins to form glycoproteins. Disturbed glycosylation is therefore now recognized as a molecular genetic defect for the muscular dystrophies. Serum CK level can be elevated in all of these disorders. Examination of muscle biopsy specimens shows variable degrees of dystrophic changes. All these disorders have progressive courses and over time can involve the proximal muscles and lead to loss of ambulation.

Myofibrillar Myopathy

Myofibrillar myopathy (also known as desmin myopathy) is a heterogeneous group of muscular dystrophies that can be manifested as either distal or limb-girdle patterns of weakness. Myofibrillar myopathy is not a single disorder: some kindreds have a molecular defect in the AB-crystallin chaperone protein on 11q21-23, others have a mutation in the desmin gene on 2q35, and still others have a mutation in Zasp (a Z disc–related protein). In

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most kindreds the disorder is inherited in an autosomal dominant fashion, but sporadic cases occur. Cardiomyopathy is common.

Oculopharyngeal Muscular Dystrophy

Oculopharyngeal muscular dystrophy is inherited as an autosomal dominant disorder. The molecular genetic defect is increased expansion of a triplet GCG repeat on chromosome 14q11 within the poly(A) binding protein 2 gene (PABP2). The function of PABP2 and the means by which mutation of this protein leads to muscle disease are unknown. This disease is manifested in the fifth or sixth decade as progressive ptosis followed by dysphagia. Later, all external ocular and other extremity muscles may become affected. Diplopia does not develop. Extremity weakness usually occurs in a limb-girdle pattern, but some variants have distal involvement. The serum CK level is normal or slightly increased. Patients may benefit from surgical correction (cricopharyngeal myotomy) for achalasia or a gastric feeding tube. Progression of the disease is usually slow. Death can result from aspiration pneumonia or starvation if adequate nutrition is not addressed.

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CONGENITAL MYOPATHIES

Congenital myopathies (Table 4) are distinguished from dystrophies in three respects: (1) characteristic morphologic alterations are demonstrated on biopsy, (2) they are manifested at birth as hypotonia and subsequent delayed motor development, and (3) most are relatively nonprogressive and more benign than the muscular dystrophies. However, there are exceptions to all three generalizations. Onset can occur later in childhood and even in early adulthood, and some congenital myopathies have a severe course and fatal outcome. Moreover, the molecular defect of some congenital myopathies can result in the phenotype of a muscular dystrophy.

Table 4 - MORPHOLOGICALLY DISTINCT CONGENITAL MYOPATHIES

Central core myopathy

Nemaline (rod) myopathy

Centronuclear (myotubular) myopathy Severe X-linked recessive form

Milder autosomal recessive and dominant forms Congenital fiber-type disproportion

Multicore/minicore myopathy

Fingerprint body myopathy

Sarcotubular myopathy

Reducing body myopathy

Trilaminar myopathy

Hyaline myopathy with focal lysis of myofibrils

Myofibrillar myopathy

Common clinical findings include reduced muscle bulk, slender body build and a long, narrow face with skeletal abnormalities (high-arched palate, pectus excavatum, kyphoscoliosis, dislocated hips, pes cavus), and absent or reduced muscle stretch reflexes. Most patients have limb-girdle weakness, although distal weakness occurs in some families. Serum CK is moderately elevated or normal, and EMG usually shows a myopathic pattern but may be normal. Inheritance patterns are variable.

Central Core Myopathy

Central core myopathy is autosomal dominant, but sporadic cases occur. The disorder is associated with a mutation on chromosome 19q13.1 in the ryanodine receptor gene. Some patients with malignant hyperthermia also have mutations in this gene, and thus the disorders may be allelic. The mechanism by which defects in the ryanodine receptor gene lead to these disorders is unknown.

Nemaline Myopathy

The histologic characteristic of nemaline myopathy, a congenital myopathy, is the presence of rods, or nemaline (Greek nema = “thread”) bodies, within muscle fibers. Nemaline

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myopathy can occur as an autosomal recessive or dominant condition. In most autosomal recessive families the disorder has been linked to 2q; nebulin is the probable candidate gene. In some autosomal dominant families, however, nemaline myopathy has been linked to a mutation in the �-tropomyosin gene on chromosome 1q. Other cases are sporadic. Clinically, the myopathy can be manifested as a severe neonatal form with respiratory (diaphragm) involvement that is generally fatal within the first year of life or as a mild static or slowly progressive condition present from birth or early childhood.

Centronuclear (Myotubular) Myopathy

The histologic hallmark of centronuclear (myotubular) myopathy is the presence of large central nuclei within many muscle fibers. The molecular defect is a mutation in the myotubularin gene on Xp28. Myotubularin is a phosphatase important in muscle cell growth and differentiation. As with nemaline myopathy, there are severe neonatal varieties and static or slowly progressive forms with onset from birth to adulthood. Ptosis and ophthalmoparesis commonly occur in all forms of centronuclear myopathy and may distinguish these patients from those with other congenital myopathies. The severe infantile form is usually X-linked recessive and is associated with respiratory insufficiency; most patients die in infancy, but a few survive into childhood, usually with major disabilities.

Congenital Fiber-Type Disproportion

The distinguishing morphologic finding in congenital fiber-type disproportion is an increased number of small type 1 muscle fibers. The genetic defect is unknown. Most patients have an onset at birth with hypotonia, and the course of the disorder is nonprogressive and relatively benign.

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METABOLIC MYOPATHIES

Metabolic myopathies include (1) glucose/glycogen metabolism disorders, (2) lipid metabolism disorders, and (3) mitochondrial disorders. A fourth group involving the utilization of adenine nucleotides is more controversial (Table 5).

Table 5 - METABOLIC AND MITOCHONDRIAL MYOPATHIES

GLYCOGEN METABOLISM DEFICIENCIES

Type II: �-1,4-Glucosidase (acid maltase)

Type III: Debranching

Type IV: Branching

Type V: Phosphorylase (McArdle's disease)[*]

Type VII: Phosphofructokinase (Tarui's disease)[*]

Type VIII: Phosphorylase B kinase[*]

Type IX: Phosphoglycerate kinase[*]

Type X: Phosphoglycerate mutase[*]

Type XI: Lactate dehydrogenase[*] LIPID METABOLISM DEFICIENCIES

Carnitine palmitoyltransferase[*]

Primary systemic/muscle carnitine deficiency

Secondary carnitine deficiency

�-Oxidation defects

Medications (valproic acid) PURINE METABOLISM DEFICIENCIES

Myoadenylate deaminase deficiency[*]

MITOCHONDRIAL MYOPATHIES

Pyruvate dehydrogenase complex deficiencies (including Leigh's syndrome)

Progressive external ophthalmoplegia (PEO)

Autosomal dominant with multiple mitochondrial DNA deletions Adenine nucleotide translocator 1 (ANT1)

TWINKLE

Polymerase gamma

Kearns-Sayre syndrome Mitochondrial encephalopathy with lactic acidosis and strokelike episodes (MELAS)

Myoclonic epilepsy and ragged red fibers (MERRF)

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Mitochondrial depletion syndrome

Leigh's syndrome and neuropathy, ataxia, and retinitis pigmentosa (NARP)

Succinate dehydrogenase deficiency [*] * Deficiency can produce exercise intolerance and myoglobinuria.

Glucose/Glycogen Metabolism Disorders

Glucose and its storage form glycogen are essential for the short-term, predominantly anaerobic energy requirements of muscle. Disorders of glucose and glycogen metabolism (grouped under the term glycogenoses) have two distinct clinical patterns. One group of disorders has dynamic manifestations consisting of exercise intolerance, pain, cramps, and myoglobinuria (types V, VII, VIII, IX, X, XI). The second, static group is associated with fixed weakness without features of exercise intolerance or myoglobinuria (types II, III, IV). Occasionally, there is overlap between the two groups. Of the 11 distinct glycogenoses, only glucose 6-phosphate (type I) and liver phosphorylase (type VI) deficiencies do not affect muscle. The glycogenoses that affect muscle are usually transmitted as autosomal recessive traits, except for phosphoglycerate kinase, which is X linked.

Glycogenoses with Exercise Intolerance/Myoglobinuria

The common clinical features of the glycogenoses characterized by exercise intolerance/myoglobinuria (myophosphorylase [type V], phosphofructokinase [PFK, type VII], phosphorylase B kinase [PBK, type VIII], phosphoglycerate kinase [PGK, type IX], phosphoglycerate mutase [PGM, type X], and LDH [type XI] deficiencies) are exercise intolerance in childhood followed by exertion-induced muscle pain and myoglobinuria in the second or third decade. Many patients note a “second-wind” phenomenon after a period of brief rest so that they can continue the exercise at the previous level of activity. The muscle pain is caused by electrically silent contractures and is not associated with depletion of ATP; the mechanism is not understood. Strength examination, CK levels, and findings on EMG between attacks are usually normal early in the disease but may become abnormal with advancing age. After episodes of severe myoglobinuria with rhabdomyolysis, needle EMG can show myopathic units and fibrillations. After forearm exercise, the venous lactate level fails to rise in myophosphorylase, PFK, and PGK deficiencies and rises only partially in PBK, PGM, and LDH deficiencies. Muscle biopsy shows scattered necrotic and regenerating fibers, especially after an episode of rhabdomyolysis.

In PFK deficiency, hyperuricemia and gout occur in some cases, and there is mild hemolytic anemia caused by a partial erythrocyte enzyme defect. PGK mutations result either in severe hemolytic anemia and neurologic deficits but no myopathy or in a myopathy with only the features described earlier. LDH deficiency is associated with a rash because M-lactate dehydrogenase is the dominant form of the enzyme expressed in skin.

Histochemical stains are readily available for myophosphorylase and PFK, but definitive diagnosis requires biochemical analysis to document the enzyme deficiency or molecular testing to define specific mutations. Mutations have been identified for all the

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glycogenoses except PBK deficiency. Oral sucrose ingestion improves exercise tolerance in patients with myophosphorylase deficiency. Otherwise, no specific treatment is available for these disorders, but aerobic exercise training and a high-protein diet have been proposed as sensible strategies.

Glycogenoses with Fixed Weakness and No Exercise Intolerance �-Glucosidase Deficiencies

�-Glucosidase, also known as acid maltase, is a lysosomal enzyme that breaks down glycogen to glucose; when its level is deficient, glycogen accumulates within lysosomes, as well as freely in the cytoplasm of cells. Mutations have been identified in the �-glucosidase gene on chromosome 17q21.

Clinical Manifestations

There are three clinical variants. The infantile type (Pompe's disease) is manifested in early infancy as generalized and rapidly progressive weakness and heart, tongue, and liver enlargement. There is widespread glycogen excess in tissues, including lower motor neurons. Death results from cardiorespiratory failure before the age of 2 years.

The childhood (juvenile) type is manifested in infancy or early childhood as a myopathy. Weakness is more proximal than distal, and there may be calf enlargement simulating muscular dystrophy. Glycogen excess is less marked and confined to muscle. The heart, but not the liver may be involved. Death results from respiratory failure before the age of 20.

The adult type is manifested between the second and seventh decades of life either as slowly progressive limb muscle weakness that mimics limb-girdle dystrophy or in a scapuloperoneal pattern. These patients often experience insidious ventilatory muscle weakness leading to respiratory failure. The adult form does not affect the heart or liver.

Diagnosis

In all three types, the serum CK level is moderately increased. The EMG in affected muscles shows myopathic changes and excessive abnormal electrical irritability, including myotonic discharges, particularly in the paraspinous muscles. However, there is no clinical myotonia. Muscle biopsy demonstrates a vacuolar myopathy with high glycogen content and acid phosphatase reactivity in the vacuoles. The diagnosis is confirmed by demonstrating �-glucosidase deficiency in either muscle, skin fibroblasts, or lymphocytes.

Differential Diagnosis

Danon's disease has clinical and histologic features similar to those of the adult form of �-glucosidase deficiency, including glycogen accumulation. The defect is a mutation in lysosome-associated membrane protein (LAMP).

Treatment and Prognosis

Enzyme replacement therapy with intravenous recombinant �-glucosidase (Myozyme) can be life-saving and was recently approved by the Food and Drug Administration for the infantile, childhood, and adult forms of the disease. With the advent of effective therapy, the prognosis is likely to improve.

Debranching Enzyme Deficiency

Debranching enzyme deficiency is a rare disease that can affect the liver, heart, or skeletal muscle. The gene for the enzyme maps to chromosome 1p21. The disease is most

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commonly manifested in childhood as hepatomegaly with fasting hypoglycemia that spontaneously resolves by adulthood. Patients less frequently have a disabling myopathy that affects both proximal and distal muscles and can appear in childhood or (more commonly) in adult life. Affected patients can experience exercise intolerance. There may be a depressed lactate response on forearm testing, but myoglobinuria is rare. The CK level is elevated, and the EMG shows myopathic changes and abnormal electrical irritability.

Branching Enzyme Deficiency

Deficiency of the branching enzyme is manifested in infancy as progressive liver and cardiac dysfunction, which leads to death in the first years of life. Muscle weakness is variable; if weakness is present, the tongue is severely affected.

Disorders of Fatty Acid Metabolism

Lipids are essential for the aerobic energy needs of muscle during sustained exercise. Serum long-chain fatty acids, which are the primary lipid fuel for muscle metabolism, are transported into the mitochondria as carnitine esters and are metabolized via �-oxidation. CPT I converts cytoplasmic acyl coenzyme A (acyl-CoA) to acylcarnitine, which is then transported into mitochondria by carnitine acyltransferase in exchange for carnitine. CPT II on the inner mitochondrial membrane reconstitutes acyl-CoA. A deficiency of carnitine, CPT, or the enzymes of �-oxidation can lead to impaired muscle lipid metabolism.

As with glycogen pathway defects, the myopathic manifestations of fatty acid metabolism can consist of dynamic exercise intolerance with myoglobinuria or static weakness with a lipid storage myopathy. A lipid storage myopathy can be caused by primary carnitine deficiency or by another defect in fatty acid oxidation with secondary carnitine deficiency. In addition, some disorders of lipid metabolism can produce multiorgan metabolic crises with hepatic failure and altered mental status (Reye's syndrome). Most lipid disorders occur sporadically; they are believed to be autosomal recessive.

Carnitine Palmitoyltransferase Deficiency

CPT occurs in two forms: types I and II. Deficiency of CPT I may be manifested in infancy or childhood as hepatic dysfunction. It causes a Reye syndrome–like illness with hypoketotic hypoglycemia, encephalopathy, hyperammonemia, and liver dysfunction.

Deficiency of CPT II typically causes exertional myalgias and myoglobinuria. The disorder is autosomal recessive, and mutations in the CPT II gene on chromosome 1p32 have been identified. These attacks are distinct from those associated with glycolytic defects in that they occur after prolonged exercise, fasting, febrile illness, or other provocations that may increase muscle dependence on free fatty acids. Unlike patients with McArdle's disease, those with CPT deficiency tolerate brief, intense exercise and have no second-wind phenomenon. Muscle strength and the CK level are normal at rest. Serum and muscle carnitine levels are typically normal. EMG is normal except for myopathic changes after episodes of rhabdomyolysis. Ammonia and lactate levels rise normally after forearm exercise. Findings on muscle biopsy are usually normal except for evidence of muscle myopathic injury after rhabdomyolysis. Diagnosis requires assay of CPT activity in muscle. Although there is no specific treatment, increasing intake of carbohydrates and the frequency of meals prevents episodes of rhabdomyolysis.

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Carnitine Deficiency

Primary carnitine deficiencies may cause a generalized systemic illness or a disorder confined to muscle. In the systemic form, the impaired transport of carnitine into multiple tissues results from nonfunctional high-affinity carnitine receptors. Patients have a myopathy with cardiac involvement, as well as episodes of hepatic dysfunction with hypoketotic hypoglycemia and altered mental status. Abnormal lipid storage is seen on muscle biopsy. Carnitine levels are reduced in serum, muscle, and other tissues. There is no urinary excretion of organic acids to suggest a secondary metabolic illness. Patients with this condition improve with carnitine supplementation.

When the disease is limited to muscle, patients are usually seen in childhood with limb-girdle myopathy. Patients have diminished muscle uptake of carnitine and a fixed lipid storage myopathy but a normal serum carnitine level. Carnitine replacement has been of inconsistent benefit.

Secondary Carnitine Deficiency

Most carnitine deficiencies are secondary to enzyme defects in �-oxidation (e.g., acyl-CoA dehydrogenase deficiencies), mitochondrial dysfunction, renal disease, impaired metabolism of medications such as valproic acid, or other metabolic disorders. Defects in lipid metabolism lead to accumulation of acyl-CoA molecules, which are converted to acylcarnitines, forms that are more readily excreted in urine. This process leads to negative carnitine balance and, ultimately, to carnitine deficiency. Impaired metabolism of valproic acid may similarly lead to excretion of valproylcarnitine and secondary carnitine deficiency. Most of these illnesses occur in early childhood or infancy and lead to Reye syndrome–like episodes. Some surviving adults experience a lipid storage myopathy with the clinical phenotype of a limb-girdle syndrome. Muscle biopsy reveals lipid storage. The free carnitine level is diminished, but that of esterified carnitine may be increased, especially after oral supplementation of depleted carnitine stores. Abnormal urinary excretion of organic acids is a critical clue to differentiate these disorders from primary carnitine deficiency. Different metabolic blocks in fatty acid metabolism lead to the excretion of distinct urinary acylcarnitine species, which can be distinguished by mass spectroscopy. Carnitine supplementation produces variable results, but some patients have fewer or less severe attacks. Some cases of multiple flavin-dependent dehydrogenase deficiency respond to riboflavin.

Disorders of Purine Nucleotide Metabolism: Myoadenylate Deaminase Deficiency

Myoadenylate deaminase (MAD), which is an enzyme in the purine nucleotide cycle, provides a short-term supply of ATP in muscle by catalyzing the conversion of adenosine monophosphate to inosine monophosphate through the removal of ammonia. If MAD is absent, less ATP is formed. MAD deficiency has been found in patients with exertional muscle pain and occasionally myoglobinuria. Forearm exercise results in a normal rise in the lactate level but no increase in the ammonia level. Muscle biopsy shows absent staining for MAD. The gene for MAD is on chromosome 1p13-21 and is mutated in most patients with MAD deficiency. However, the frequency of this mutation in the “normal” population is high, and patients without symptoms may have biochemical evidence of MAD deficiency. Therefore, it is still unclear whether MAD deficiency results in a metabolic myopathy or whether the enzyme deficiency is coincidental.

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Mitochondrial Myopathies

Mitochondrial myopathies produce slowly progressive weakness of the limb-girdle or external ocular and other cranial muscles and abnormal fatigability on sustained exertion; some affect multiple organs or systems, in addition to muscle. In many mitochondrial myopathies, a substantial proportion of the muscle fibers contain subsarcolemmal and intermyofibrillar accumulations of structurally and functionally abnormal mitochondria. These fibers appear “ragged red” with trichrome stain and may fail to react for cytochrome c oxidase. Other laboratory features frequently seen in mitochondrial myopathies are an elevated serum lactic acid level on exertion or at rest, as well as a modestly elevated CK level and myopathic findings on EMG. Cerebrospinal fluid protein is often elevated.

Mitochondrial DNA encodes for 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 13 messenger RNAs (mRNAs). The 13 mRNAs are translated into polypeptide subunits of the respiratory chain complex. A mutation in a mitochondrial tRNA gene can impair proper translation of the 13 mitochondrial mRNAs. However, the 13 proteins encoded by the mitochondrial genome account for less than 5% of mitochondrial proteins; the majority are encoded by nuclear DNA and are translated in the cytoplasm and transported into mitochondria.

Mitochondrial diseases can arise from mutations in nuclear or mitochondrial DNA. During fertilization, essentially all of the mitochondria are contributed by the mother's ovum; thus, all mutations in mitochondrial DNA either are maternally transmitted or arise de novo in the maternal ovum or in early embryonic life. However, because the majority of mitochondrial proteins (95%) are encoded from nuclear genes, mitochondrial disorders can also have autosomal dominant and even X-linked hereditary patterns.

From a biochemical standpoint, mitochondrial disorders can be due to defects proximal to the respiratory chain (involving substrate transport and utilization) or within the respiratory chain. Viewed in this way, the derangements in lipid metabolism can be considered “mitochondrial” dysfunctions. Acetyl-CoA feeds into the mitochondria to enter the Krebs cycle and the respiratory chain. However, the lipid disorders generally do not have structural defects of mitochondria or a “mitochondrial myopathy” phenotype. Among the exceptions are substrate utilization abnormalities secondary to pyruvate dehydrogenase complex defects, which can produce X-linked Leigh's syndrome or subacute necrotizing encephalomyopathy. Although muscle biopsy may show ragged red fibers, the CNS abnormalities overshadow the neuromuscular abnormalities.

Most mitochondrial disorders are due to biochemical defects in the mitochondrial respiratory chain that can involve coenzyme Q and the five distinct enzyme complexes: complex I (reduced nicotinamide adenine dinucleotide–coenzyme Q oxidoreductase); complex II (succinate dehydrogenase); complex III (coenzyme Q–cytochrome c oxidoreductase); complex IV (cytochrome c oxidase); and complex V (ATPase synthetase). Defects in the electron transport complexes are associated with marked clinical, biochemical, and genetic heterogeneity because each complex is composed of multiple subunits, different subunits of a given complex are encoded by different genes, some subunits of a given complex are encoded by mitochondrial rather than nuclear DNA, and some subunits are tissue specific.

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Specific Mitochondrial Disorders Affecting Muscle Progressive External Ophthalmoplegia

Severe ptosis and progressive external ophthalmoplegia are clinical hallmarks of mitochondrial disease. Ptosis is often the initial symptom and is generally first noted in childhood. As the ophthalmoplegia progresses, it often becomes complete. Patients do not have diplopia. A limb-girdle weakness pattern may occur with varying degrees of severity. Muscle biopsy reveals characteristic ragged red fibers, and EM shows structurally abnormal mitochondria with “parking lot” paracrystalline inclusions.

Progressive external ophthalmoplegia secondary to mitochondrial disease is associated with single or multiple mitochondrial DNA deletions. Patients with single mitochondrial deletions have the Kearns-Sayre syndrome, which includes retinitis pigmentosa, heart block, hearing loss, short stature, ataxia, delayed secondary sexual characteristics, peripheral neuropathy, and impaired ventilatory drive. The syndrome develops before 20 years of age. Kearns-Sayre syndrome, which is due to single large mitochondrial deletions, occurs as a sporadic mutation only.

By comparison, progressive external ophthalmoplegia with multiple mitochondrial deletions is autosomal dominant; in some kinships the defects have been localized to both chromosomes 10q22-23 and 3ql4-21, and maternally inherited point mutations in mitochondrial tRNA have been reported. This disease, which has a later onset of symptoms than Kearns-Sayre syndrome does, is often accompanied by various degrees of encephalomyopathy and neuropathy.

Myoclonic Epilepsy and Ragged Red Fibers

Patients affected by myoclonic epilepsy with ragged red fibers have varying symptoms of myoclonus, generalized seizures, ataxia, dementia, sensorineural hearing loss, and optic atrophy, as well as limb-girdle weakness. Some patients also have a sensorimotor peripheral neuropathy, cardiomyopathy, and cutaneous lipomas. Ptosis and ophthalmoparesis are not usually present. Most patients have a point mutation in the mitochondrial DNA encoding for tRNA, and the disease is maternally inherited.

Mitochondrial Encephalomyopathy with Lactic Acidosis and Strokelike Episodes

Patients with mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) have normal early development, experience migraine-like headaches and strokes before 40 years of age, and have lactic acidosis. Other features frequently include dementia, hearing loss, episodic vomiting, ataxia, and coma, as well as diabetes. Ptosis and ophthalmoparesis are uncommon. MELAS is inherited maternally and is caused by mitochondrial DNA mutations encoding for tRNA. Dichloroacetate seemed beneficial in anecdotal reports, but a placebo-controlled trial demonstrated that dichloroacetate causes peripheral neuropathy and is not of benefit.

Mitochondrial Neurogastrointestinal Encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is associated with sensorimotor polyneuropathy, ophthalmoplegia, leukoencephalopathy on MRI of the brain, and chronic intestinal pseudo-obstruction (POLIP syndrome). Patients have distal as well as proximal weakness and ptosis. There are multiple mitochondrial DNA deletions similar to those found in autosomal dominant progressive external ophthalmoplegia. MNGIE has been localized to chromosome 22q13 in some families.

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Mitochondrial DNA Depletion Syndrome

Mitochondrial DNA depletion is an autosomal recessive syndrome that is manifested at birth or shortly afterward as generalized hypotonia and weakness. Other features can include cardiomyopathy, renal tubular defects, seizures, and liver failure. Infants experience respiratory failure, and many die within the first year of life. There is also a benign infantile form in which the hypotonic infants can survive and appear normal by 2 or 3 years of age.

Leigh's Syndrome

Leigh's syndrome usually occurs in infancy or early childhood and consists of altered mental status, generalized weakness or hypotonia, vomiting, ataxia, ptosis and ophthalmoplegia, seizures, and respiratory failure. The molecular genetic characteristics are heterogeneous. The disease is generally fatal.

Mitochondrial Myopathies Associated with Recurrent Myoglobinuria

Recurrent myoglobinuria provoked by exercise is uncommon in mitochondrial disorders. Between attacks, the patient is normal. This genetically heterogeneous group of disorders includes multiple mitochondrial DNA deletions (autosomal recessive inheritance), mitochondrial point mutations (maternal inheritance), and nuclear DNA mutations encoding for succinate dehydrogenase (complex II).

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CHANNELOPATHIES (NONDYSTROPHIC MYOTONIAS AND PERIODIC PARALYSES)

The myotonias are grouped into dystrophic and nondystrophic disorders. The nondystrophic myotonias and the periodic paralyses are caused by mutations of various ion channels in muscle (Table 6). The term channelopathies is often used to describe this group of disorders.

Table 6 - CHANNELOPATHIES AND RELATED DISORDERS

Disorder Pattern of Clinical Features Inheritance Chromosome Gene

Chloride channelopathies

Myotonia congenita

Thomsen's disease Myotonia Autosomal dominant

7q35 CLC1

Becker's disease Myotonia and weakness

Autosomal recessive

7q35 CLC1

Sodium channelopathies

Paramyotonia congenita

Paramyotonia Autosomal dominant

17q13.1-13.3 SCNA4A

Hyperkalemic periodic paralysis

Periodic paralysis with myotonia and paramyotonia

Autosomal dominant

17q13.1-13.3 CNA4A

Hypokalemic periodic paralysis

Periodic paralysis Autosomal dominant

17q13.1-13.3 SCNA4A

Potassium-aggravated myotonias

Myotonia fluctuans Myotonia Autosomal dominant

17q13.1-13.3 SCNA4A

Myotonia permanens

Myotonia Autosomal dominant

17q13.1-13.3 SCNA4A

Acetazolamide-responsive myotonia

Myotonia Autosomal dominant

17q13.1-13.3 SCNA4A

Calcium channelopathies

Hypokalemic periodic paralysis

Periodic paralysis Autosomal dominant

1q31-32 Dihydropyridine receptor

Schwartz-Jampel syndrome (chondrodystrophic myotonia)

Myotonia, dysmorphic

Autosomal recessive

1q34.1-36.1 Perlecan

Rippling muscle disease

Muscle mounding/stiffness

Autosomal dominant

1q41 Caveolin-3

Andersen-Tawil Periodic paralysis, Autosomal 17q23 KCNJ2 (Kir 2.1)

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Disorder Pattern of Clinical Features Inheritance Chromosome Gene

syndrome cardiac arrhythmia, skeletal abnormalities

dominant

Brody's disease Delayed relaxation, no EMG myotonia

Autosomal recessive

16p12 Calcium ATPase

Malignant hyperthermia

Anesthetic-induced delayed relaxation

Autosomal dominant

19q13.1 Ryanodine receptor

ATPase = adenosine triphosphatase; EMG = electromyogram.

Chloride Channelopathies

Myotonia congenita is due to point mutations in the muscle chloride channel gene on chromosome 7q35. Both the autosomal dominant form (Thomsen's disease) and the autosomal recessive form (Becker's myotonia) are benign and associated with muscle hypertrophy and with action, percussion, and electrical myotonia. Cold increases the myotonia, and sustained exercise improves it (warm-up phenomenon). There is no involvement of the heart or other organs. Patients with Thomsen's disease are not weak, but those who have Becker's myotonia congenita have fluctuations in strength and may experience limb-girdle weakness. Patients with myotonia congenita seldom complain of pain, a feature that distinguishes them from those who have proximal myotonic myopathy (PROMM or DM-2). The membrane defect consists of markedly reduced chloride conductance with resulting hyperexcitability and afterdepolarization that produces involuntary myotonic potentials. Many patients do not require treatment, but drugs such as quinine, procainamide, phenytoin, and mexiletine may be effective in reducing symptomatic myotonia.

Sodium Channelopathies

Several autosomal dominant disorders are due to point mutations in the voltage-dependent sodium channel (SCN4A) gene on chromosome 17q23-25. All have symptoms that begin in the first decade and continue throughout life, and there is considerable clinical overlap between the disorders. Patients with paramyotonia congenita (Eulenburg's disease) have paradoxical myotonia in that the myotonia increases with repetitive movements; for example, after several attempts, patients cannot open their eyelids. Muscle stiffness is worsened by cold temperature. The myotonia can be treated with sodium-channel blockers such as mexiletine.

Hyperkalemic periodic paralysis is characterized by attacks of weakness lasting 1 or 2 hours. Attacks are precipitated by fasting, by rest after exercise, or by ingestion of potassium-rich foods or compounds. During attacks, patients are areflexic with normal sensation, and there is no ocular or respiratory muscle weakness. The serum potassium level may or may not be increased during the attack, and therefore a more appropriate term may be potassium-sensitive periodic paralysis. Strength is generally normal between attacks, but some patients can have mild interictal limb-girdle weakness. Some families with potassium-sensitive periodic paralysis also have either myotonia or paramyotonia. Episodes of weakness are rarely serious enough to require acute therapy; oral carbohydrates or glucose may improve the weakness. Treatment options to prevent attacks

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include acetazolamide, dichlorphenamide, thiazide diuretics, �-agonists, and preventive measures such as a low-potassium, high-carbohydrate diet and avoidance of fasting, strenuous activity, and cold.

Sodium-channel myotonias are a group of potassium-sensitive disorders caused by molecular defects in the sodium channel but not characterized by periodic paralysis or paramyotonia phenotypes. These disorders include acetazolamide-responsive myotonia, myotonia fluctuans (myotonia that fluctuates on a daily basis), and myotonia permanens.

Calcium Channelopathies

Hypokalemic periodic paralysis is due to abnormal muscle membrane excitability arising either from mutations in the muscle calcium-channel �-subunit on chromosome 1q31-32 or, in a small proportion of cases, from a mutation in the skeletal muscle sodium channel. The �1-subunit of the calcium channel contains the dihydropyridine receptor, which acts as a pore for conducting calcium ions in the T tubule. The mutation produces a reduction in the calcium current in the T tubule. During attacks, there is an influx of potassium into muscle cells, and the muscles become electrically inexcitable. Patients have increased sensitivity to the effects of insulin on potassium flux. However, the mechanism through which the shift in potassium from the extracellular to the intracellular space is associated with functional impairment of the calcium-channel dihydropyridine receptor is unknown.

Hypokalemic periodic paralysis is an autosomal dominant condition. It is the most frequent form of periodic paralysis, is more common in males, and has reduced penetrance in females. Attacks begin by adolescence and are aggravated by exercise, sleep, stress, alcohol, or meals rich in carbohydrates and sodium. The episodes last from 3 to 24 hours. A vague prodrome of stiffness or heaviness in the legs can occur, and if the patient performs mild exercise, a full-blown attack may be aborted. Rarely, the ocular, bulbar, and respiratory muscles can be involved in severe attacks. Early in the disease, patients have normal interictal examination findings except for eyelid myotonia (about 50%). Later, the frequency of attacks can diminish, but many patients have proximal weakness; in occasional patients, this weakness produces severe incapacity.

Preventive measures include a low-carbohydrate, low-sodium diet and drugs such as acetazolamide, dichlorphenamide, spironolactone, and triamterene. Acute attacks are treated with oral potassium every 30 minutes until strength improves; the ECG must be monitored. In severe episodes, particularly in patients with gastrointestinal symptoms, parenteral potassium therapy may be necessary.

Other Forms of Periodic Paralysis, Channelopathies, and Muscle Stiffness

Andersen's syndrome is an autosomal dominant disorder with periodic paralysis (hypo-, hyper-, or normo-kalemic), distinctive facial features (hypertelorism, short stature, low-set ears), a prolonged QT interval, and life-threatening ventricular arrhythmias. The genetic defect has been localized to chromosome 17q23 and is caused by a defect in the inward rectifying potassium channel gene KCNJ2 encoding Kir2.1.

Rippling muscle disease is an autosomal dominant disorder characterized by localized transient swelling or rippling of muscle induced by percussion or exercise. A pedigree has been localized to chromosome 1q41. Patients complain of tightness in the thighs or upper part of the arms.

Brody's disease is characterized by exercise-induced impaired relaxation and stiffness, but with no abnormalities indicated by muscle percussion or on EMG. The disorder is

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autosomal recessive and in some cases is caused by mutations in the SR calcium ATPase gene of type 2 muscle fibers located on chromosome 16p12.

Schwartz-Jampel syndrome is an autosomal recessive disorder of ATPase that occurs in early childhood and consists of chondrodystrophy, short stature, bone and joint deformities, hypertrichosis, blepharophimosis, and muscle stiffness. A mutation in perlecan is responsible for some cases. There is delayed muscle relaxation clinically resembling myotonia, but the EMG shows nonvariable (nonmyotonic) continuous high-frequency electrical activity.

Malignant hyperthermia is characterized by severe muscle rigidity, fever, and tachycardia precipitated by depolarizing muscle relaxants and inhaled anesthetic agents such as halothane. The symptoms usually occur during surgery but can first be noticed in the postoperative period. Patients may have previously undergone anesthesia without symptoms. During attacks, the CK level is markedly elevated and myoglobinuria develops. The disorder is caused by excessive calcium release by the SR calcium channel, the ryanodine receptor. Some patients have mutations in the ryanodine receptor gene on chromosome 19q13, which is the same gene mutated in central core disease. However, malignant hyperthermia appears to be genetically heterogeneous, and the defect in other families has been localized to different chromosomes. The symptoms are treated with dantrolene, and at-risk patients should not be given known provocative anesthetic agents. The occurrence of malignant hyperthermia in one member of a family should prompt consideration of whether other family members could also be at risk.

Neuromyotonia, or Isaacs' syndrome, is an autoimmune disorder with antibodies directed against voltage-gated potassium channels on peripheral nerves. Therefore, it is an acquired channelopathy, not a primary myopathy, that has a major secondary effect on muscle activity. Inactivation of these channels makes the motor nerve hyperexcitable and produces continuous muscle fiber activity that persists even during sleep. Clinically, there is involuntary muscle activity with stiffness, twitches, fasciculations, and continuous small, undulating movements of the overlying skin (myokymia). Patients may also experience excessive sweating, a peripheral neuropathy, and stiffness. EMG documents the myokymic potentials and very high-frequency bursts (150 to 300 Hz) of spontaneous motor activity, termed neuromyotonia. Some cases are associated with neoplasms: thymoma (with or without myasthenia gravis), small cell lung carcinoma, and lymphoma. The CK level can be mildly elevated, cerebrospinal fluid shows elevated protein and oligoclonal bands, and voltage-gated potassium channel antibodies are present in serum. Treatment consists of immunosuppressive agents, symptomatic therapy with phenytoin or carbamazepine, or removal of the malignancy. An autosomal dominant form of neuromyotonia exists; it is associated with ataxia or a peripheral neuropathy.

Stiff-Person Syndrome

Stiff-person syndrome, an acquired autoimmune condition, is characterized by severe muscle stiffness of the proximal and especially the paraspinous muscles. The muscle spasms produce hyperlordosis, and all movements are slow and laborious. There is excess motor unit activity because of autoantibodies to glutamic acid decarboxylase, which is a major enzyme in the synthesis of �-aminobutyric acid; the result is disinhibition in the CNS. The CK level is elevated, and EMG shows resting continuous motor unit activity that the patient cannot voluntarily suppress. Some patients also have antibodies to islet cells and thus are susceptible to the development of diabetes mellitus. Symptomatic treatment

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consists of diazepam; immunosuppressive treatment and intravenous immune globulin can markedly improve the condition.

Evaluation of Periodic Paralysis

In any patient with hypokalemia or hyperkalemia who is initially being evaluated for an attack of periodic paralysis, secondary causes need to be excluded (Table 7). In the primary forms of periodic paralysis, the serum potassium level decreases or increases but may be within the normal range during attacks; it is normal between attacks. By contrast, in secondary periodic paralysis caused by potassium wastage or retention, the serum potassium level is always markedly reduced or elevated during and even between attacks.

Table 7 - SECONDARY CAUSES OF PERIODIC PARALYSIS

HYPOKALEMIC

Thyrotoxic Primary hyperaldosteronism (Conn's syndrome) Renal tubular acidosis (e.g., Fanconi's syndrome) Juxtaglomerular apparatus hyperplasia (Barter's syndrome) Gastrointestinal potassium wastage Villous adenoma Laxative abuse Pancreatic non–insulin-secreting tumors with diarrhea Nontropical sprue Barium intoxication Potassium-depleting diuretics Amphotericin B Licorice Corticosteroids Toluene toxicity p-Aminosalicyclic acid Carbenoxolone

HYPERKALEMIC

Addison's disease Hypoaldosteronism Excessive potassium supplementation Potassium-sparing diuretics Chronic renal failure

Thyrotoxic periodic paralysis resembles hypokalemic periodic paralysis. It is most common in Asian and Latin American young male adults. �-Adrenergic blocking agents reduce the frequency and severity of attacks, but the ultimate treatment is directed against the thyrotoxicosis.

During an attack of periodic paralysis, potassium levels should be measured every 15 to 30 minutes to determine the direction of change when muscle strength is worsening or improving. An ECG is useful to demonstrate the changes of hypokalemia or hyperkalemia. The CK level is usually elevated during an attack but normal between attacks. Findings on routine EMG are normal between attacks, but the compound motor action potential may decline in amplitude after exercise (exercise test) and thus corroborate the presence (but

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not the cause) of periodic paralysis. Muscle biopsy between attacks may demonstrate vacuoles or tubular aggregates within fibers. Provocative testing for hypokalemic periodic paralysis consists of giving oral or intravenous glucose with or without insulin; for hyperkalemic periodic paralysis, testing consists of giving repeated doses of oral potassium under close supervision with cardiac monitoring and intravenous access.

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INFLAMMATORY AND OTHER MYOPATHIES Inflammatory Myopathies

Inflammatory myopathies include a heterogeneous group of acquired, nonhereditary disorders (Table 8) that are characterized by muscle weakness and evidence of inflammation on muscle biopsy. Most patients have elevated CK levels, myopathic findings on EMG, and a limb-girdle distribution of weakness. Occasionally, inflammatory myopathies have distal, focal, or other selective involvement of particular muscles. Most inflammatory myopathies are considered idiopathic; although the cause is unknown, an autoimmune origin is suspected. The three major categories of idiopathic inflammatory myopathy are dermatomyositis, polymyositis, and inclusion body myositis. These inflammatory myopathies are clinically, histologically, and pathogenically distinct (Tabe 9).

Table 8 - CLASSIFICATION OF INFLAMMATORY MYOPATHIES IDIOPATHIC

Polymyositis

Dermatomyositis

Inclusion body myositis

Overlap syndromes with other connective tissue disease (scleroderma, systemic lupus erythematosus, mixed connective tissue disease, Sjögren's syndrome, rheumatoid arthritis, polyarteritis nodosa)

Sarcoidosis and other granulomatous myositis

Behçet's syndrome

Inflammatory myopathies and eosinophilia Eosinophilic polymyositis

Diffuse fasciitis with eosinophilia Focal myositis

Myositis ossificans INFECTIOUS

Bacterial: Staphylococcus aureus, streptococci, Escherichia coli, Yersinia sp, Legionella sp, gas gangrene (Clostridium welchii), leprous myositis, Lyme disease (Borrelia burgdorferi)

Viral: acute myositis after influenza or other viral infections (adenovirus, coxsackievirus, echovirus, parainfluenza virus,

Epstein-Barr virus, arbovirus, cytomegalovirus), retrovirus-related myopathies (HIV, HTLV-1), hepatitis B and C

Parasitic: trichinosis (Trichinella spiralis), toxoplasmosis (Toxoplasma gondii), cysticercosis, sarcosporidiosis, trypanosomiasis (Taenia solium)

Fungal: Candida, Cryptococcus, sporotrichosis, actinomycosis, histoplasmosis

HIV = human immunodeficiency virus; HTLV-1 = human T-lymphotropic virus 1.

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Table 9 - IDIOPATHIC INFLAMMATORY MYOPATHIES: CLINICAL AND LABORATORY FEATURES

Sex

Typical Age at Onset Rash

Pattern of Weakness CK Level Muscle Biopsy

Response to IS Therapy

Common Associated Conditions

Dermatomyositis F > M Childhood and adult

Yes Proximal > distal

Increased (up to 50× normal)

Perimysial and perivascular inflammation; CD4+ T cells, B cells; MAC, Ig, C deposition on vessels

Yes Myocarditis, interstitial lung disease, vasculitis, other connective tissue diseases, malignancy

Polymyositis F > M Adult No Proximal > distal

Increased (up to 50× normal)

Endomysial inflammation; CD8+ T cells, Macros

Yes Myocarditis, interstitial lung disease, other connective tissue diseases; ?malignancy

Inclusion body myositis

M > F Elderly > (50 yr)

No Proximal = distal; predilection for finger/wrist flexors, knee extensors

Increased (< 10× normal)

Endomysial inflammation; CD8+ T cells, Macros; rimmed vacuoles; amyloid deposits; EM: 15- to 18-nm tubulofilaments

No Neuropathy

C = complement; CK = creatine kinase; F = female; Ig = immunoglobulin; IS = immunosuppressive; M = male; MAC = membrane attack complex; Macros = macrophages.

Clinical Manifestations and Diagnosis

Inclusion body myositis is characterized by an insidious onset of slowly progressive proximal and distal weakness. The slow evolution of the disease process contributes to the delay in diagnosis, which averages 6 years from the onset of symptoms. Inclusion body myositis typically begins after 50 years of age and is the most common inflammatory myopathy in the elderly. Men are more commonly affected than women. These patients have a distinctive pattern of muscle involvement consisting of early weakness and atrophy of the quadriceps (knee extensors), volar forearm muscles (wrist and finger flexors), and tibialis anterior (ankle dorsiflexors). Involvement of these muscle groups is frequently asymmetrical, in contrast to the symmetrical weakness in dermatomyositis and polymyositis. Patients have difficulty making a fist because of finger flexor weakness. Some degree of shoulder and hip girdle weakness is often present as well. Facial weakness occurs in a third of patients, and dysphagia occurs in nearly half. Although most patients

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have no sensory symptoms, evidence of a distal sensory peripheral neuropathy can be detected in nearly 30% of patients through clinical examination and electrophysiologic testing. Quadriceps muscle stretch reflexes are usually decreased when quadriceps atrophy is severe. Myalgias do not occur, but as the quadriceps muscles progressively weaken and genu recurvatum develops, patients frequently complain of knee pain. Patients do not have associated pulmonary, cardiac, or malignant disorders. No or only slight elevations in the CK level are seen, and the erythrocyte sedimentation rate is usually normal. Muscle biopsy is essential to establish the diagnosis of inclusion body myositis.

Treatment and Prognosis

Although immunotherapy can improve strength and function in patients with dermatomyositis and polymyositis, inclusion body myositis is usually refractory to immunosuppressive therapy, and intravenous gamma globulin is also ineffective. Life expectancy is normal, but patients frequently require a cane or wheelchair for long distances and some patients become severely incapacitated within 10 to 15 years of onset. Many patients with so-called steroid-resistant or refractory polymyositis in fact have inclusion body myositis.

Other Idiopathic Inflammatory Myopathies Overlap Syndromes

The term overlap syndromes denotes a group of disorders in which an inflammatory myopathy occurs in association with another well-defined connective tissue disorder, including scleroderma, systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, mixed connective tissue disease, and polyarteritis nodosa. Clinical and histologic features of either dermatomyositis or polymyositis can develop in up to 10% of each of these disorders. The myositis associated with overlap syndromes may be more responsive to immunosuppressive treatment than polymyositis is.

Eosinophilic Polymyositis

Eosinophilic polymyositis usually occurs as part of the hypereosinophilic syndrome. Peripheral eosinophilia in the absence of parasitic infection is associated with a multisystemic disorder of muscle, peripheral nerve, lung, heart, skin, and CNS. Response to immunosuppressive therapy is inconsistent, and the prognosis is generally poor.

Diffuse Fasciitis with Eosinophilia

In diffuse fasciitis with eosinophilia, also known as Shulman's syndrome, peripheral eosinophilia is associated with painful scleroderma-like skin changes, contractures, myalgia, arthralgia, and fever. However, unlike eosinophilic polymyositis, the heart, lungs, and other organs are not involved. Laboratory features include hypergammaglobulinemia, elevated erythrocyte sedimentation rate, and occasionally, an elevated CK level. Full-thickness biopsy from the skin to muscle is required to demonstrate the thickened fascia infiltrated by eosinophils and lymphocytes. The inflammation can invade adjacent underlying muscle. The prognosis is good, and patients usually respond rapidly to corticosteroid treatment. Relapses are infrequent.

Granulomatous Myopathy with and without Sarcoidosis

Patients with sarcoidosis can have asymptomatic granulomas in muscle or an elevated CK level. Occasionally, these patients have nodular swellings of subcutaneous tissue and underlying muscle. These lesions have histopathologic features indicative of sarcoid.

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Patients can also experience focal muscle pain or a generalized limb-girdle weakness pattern reflecting muscle involvement by sarcoid granulomas. Patients with symptomatic weakness are generally treated with corticosteroids but respond poorly.

Giant cell or granulomatous myopathy can occur in the absence of sarcoidosis. Most affected patients also have myasthenia gravis or thymoma. Myocarditis can be part of the disease process. These patients generally improve with corticosteroids.

Behçet's Syndrome

Behçet's syndrome, a multisystem disorder, is usually associated with mucocutaneous and ocular manifestations but may rarely be associated with myositis and myocarditis. The myositis can be focal or generalized, and there is a predilection for the calves. The myositis often responds to immunosuppressive therapy.

Focal Myositis

Focal myositis is an uncommon disorder that can develop at any age. It is manifested as a solitary, painful, and rapidly expanding skeletal muscle mass and must be distinguished from sarcoidosis, Behçet's disease, polyarteritis nodosa, or muscle tumors (sarcoma or rhabdomyosarcoma). The leg is the most common site of involvement, but myositis can occur in any region. The serum CK level is usually normal. Biopsy of lesions shows mononuclear inflammatory cells in the endomysium with muscle fiber necrosis. The myositis generally resolves spontaneously or after immunosuppressive treatment with corticosteroids. In rare cases, focal myositis is the heralding sign of typical polymyositis.

Infectious Myositis Viral An acute viral myositis can occur in the setting of an upper respiratory tract infection caused by an influenza virus. In addition to typical influenza-associated myalgias, these patients have proximal weakness, an elevated CK level, and myopathic motor units indicated on EMG. The disorder is self-limited, but when severe it is often associated with myoglobinuria and occasionally with renal failure. A similar syndrome can complicate infections with coxsackievirus, parainfluenza virus, mumps virus, measles virus, adenovirus, cytomegalovirus, hepatitis B virus, herpes simplex virus, Epstein-Barr virus, respiratory syncytial virus, and echovirus.

An inflammatory myopathy can occur in the setting of human immunodeficiency virus infection in either the early or later stages of acquired immunodeficiency syndrome. The neurologic manifestation of type 1 human T-lymphotropic virus infection typically consists of spastic paraparesis, but myositis can also develop.

Bacterial Pyomyositis refers to focal or multifocal abscesses associated with bacterial infection of muscle. Pyomyositis is more common in the tropics, in developing countries, and among intravenous drug users. It usually arises as an extension of an infection in adjacent tissues or from hematogenous spread. The most common organisms involved are Staphylococcus aureus, Streptococcus sp, Escherichia coli, Yersinia sp, and Legionella sp. Treatment consists of antibiotics for the underlying infection and, in severe infections, incision and drainage of abscesses.

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Fungal Fungal infections of muscle can occur rarely, usually in immunocompromised individuals. Candidiasis is the most common fungal myositis. Diffuse muscle pain, weakness, and fever are associated with a papular erythematous rash.

Parasitic

Trichinosis is the most common parasitic disease that can produce a diffuse inflammatory myositis and be confused with idiopathic polymyositis. Ingested larvae from undercooked pork migrate to muscle, with the subsequent development of fever, myalgias, weakness, myocarditis, and CNS manifestations. There is a peripheral eosinophilia, the CK level is elevated, and antibodies against Trichinella spiralis can be demonstrated 3 to 4 weeks after infection. Therapy consists of thiabendazole; in severe cases, corticosteroids may be indicated. An inflammatory myopathy can also occur in the course of cysticercosis (Taenia solium; and toxoplasmosis (Toxoplasma gondii).

Myopathies Caused by Endocrine Systemic Disorders, Toxins, and Myoglobinuria

Fatigue can be a symptom of any endocrine disorder, but objective muscle weakness secondary to a myopathy is less common. The serum CK level is often normal except in hypothyroidism. EMG shows normal findings or myopathic motor units, but generally without spontaneous electrical activity. The histologic alterations in muscle are often nonspecific. Muscle symptoms improve with successful treatment of the underlying endocrinopathy.

Adrenal/Glucocorticoid Disorders

Excess corticosteroids can result from endogenous Cushing's disease or can be due to exogenous glucocorticoid administration. Iatrogenic corticosteroid myopathy (or atrophy) is the most common endocrine-related myopathy. However, muscle weakness is rarely the initial manifestation of Cushing's disease, and other factors contribute to the weakness in virtually all instances of corticosteroid myopathy. Women are more susceptible to corticosteroid atrophy than men are, and divided daily doses are more toxic than single or alternate-day doses. Muscle biopsy shows type 2 muscle fiber atrophy, and the serum CK level and findings on EMG are normal. Therapy consists of reducing the corticosteroid dosage to the lowest possible level. Exercise and adequate nutrition prevent and may improve weakness. Muscle strength returns to normal within 1 to 4 months after therapy is stopped.

Addison's Disease

Addison's disease (adrenal insufficiency; is often associated with fatigue, but objective signs of myopathy are rare. Electrolyte disturbances can produce weakness and, when hyperkalemia occurs, simulate periodic paralysis.

Thyroid Disorders

Patients with hyperthyroidism often have some degree of weakness, but it is rarely the initial manifestation of thyrotoxicosis. Weakness is predominantly proximal, especially in the shoulder region, and there may be atrophy. Weakness of extraocular muscles and proptosis occur in Graves' disease. Thyrotoxic periodic paralysis was described earlier. Hypothyroid myopathy is associated with proximal weakness and myalgias, muscle enlargement, slow relaxation of the reflexes, and a marked (up to 100-fold) increase in the serum CK level.

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Parathyroid Disorders

Hyperparathyroidism (with hypercalcemia and hypophosphatemia) can be associated with proximal weakness, atrophy, and pain, especially in the setting of osteomalacia. Patients may also experience hoarseness, dysphagia, and neck extensor weakness. Hypoparathyroidism (with hypocalcemia and hyperphosphatemia) is not usually associated with a myopathy; however, paresthesias and tetany with Chvostek's sign and Trousseau's phenomenon can occur in hypocalcemic patients.

Pituitary Disorders

Acromegaly can be associated with mild proximal weakness, but not generally until late in the disease. Muscles can look enlarged despite being weak. Weakness as a result of nerve, root, or spinal cord compression is a more likely cause of the weakness. Panhypopituitarism results in weakness and fatigability, probably because of the combined influence of thyroid and adrenal deficiencies.

Diabetes Mellitus

Progressive, painless proximal weakness in a diabetic patient is seldom, if ever the result of diabetes-related myopathy. Asymmetrical, usually painful proximal leg weakness can occur from an ischemic radiculoplexopathy (“amyotrophy”). Rarely, acute muscle infarction can develop in the quadriceps or hamstring muscles.

Vitamin Deficiency

Vitamin E deficiency as a result of malabsorption can produce a myopathy along with gait ataxia and neuropathy. Vitamin D deficiency (from decreased intake or impaired absorption or metabolism) may also lead to chronic muscle weakness.

Systemic Amyloid Myopathy

The most common neurologic complication in various types of amyloidosis is a predominantly sensory-autonomic neuropathy. Amyloid deposition in muscle is frequent, but the muscle involvement is usually subclinical. Occasionally, amyloidosis is manifested as or associated with an overt myopathy characterized by muscle enlargement, macroglossia, stiffness, exertional muscle pain, and proximal or diffuse weakness. EMG shows myopathic features in proximal muscles with or without distal neuropathic changes. The amyloid deposits, identified by their metachromasia and affinity for Congo red stain, appear between and around the mural elements of the small vessels and extend into the interstitial spaces, where they tightly surround individual muscle fibers.

Myositis Ossificans

The localized form of myositis ossificans appears as a tender swelling after trauma to a muscle. After a few months, the lesion becomes hard and ossified. Therapy consists of excision. The generalized form is an autosomal dominant disease with variable expression that begins in childhood, involves many muscles, and causes progressive rigidity of body parts. The initial lesions appear in fascia and dermis and are associated with inflammation, hemorrhage, and proliferation of connective tissue. Cartilage and bone formation occur at a later stage. Other congenital malformations (microdactyly of the great toe, exostoses, absence of the upper incisors or ear lobules, and hypogenitalism) are found in most patients. There is no effective therapy.

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Toxic Myopathies

Many drugs have been associated with muscle damage, but it may occur more often with exposure to specific drugs (Table 10). Most drug-induced myopathies can produce proximal weakness, an elevated CK level, myopathic findings on EMG, and abnormalities on muscle biopsy. Symptoms generally improve after stopping the medication. Several drugs can produce an inflammatory myopathy on muscle biopsy, including penicillamine and cimetidine. Zidovudine causes a mitochondrial myopathy. A number of drugs can produce a necrotizing or vacuolar myopathy, including amiodarone, colchicine, chloroquine, and cyclosporine. Emetine (ipecac) produces proximal weakness and a myofibrillar myopathy. Isoretinoic acid, a vitamin A analogue used for acne, infrequently causes myalgias, elevation of the serum CK level, and reversible muscle damage.

Table 10 - TOXIC MYOPATHIES

INFLAMMATORY

Cimetidine D-Penicillamine Procainamide L-Tryptophan L-Dopa

NONINFLAMMATORY NECROTIZING OR VACUOLAR

Cholesterol-lowering agents Chloroquine Colchicine Emetine � -Aminocaproic acid Labetalol Cyclosporine and tacrolimus Isoretinoic acid (vitamin A analogue) Vincristine Alcohol

RHABDOMYOLYSIS AND MYOGLOBINURIA

Cholesterol-lowering drugs Alcohol Heroin Amphetamine Toluene Cocaine � -Aminocaproic acid Pentazocine Phencyclidine

MALIGNANT HYPERTHERMIA

Halothane Ethylene Diethyl ether Methoxyflurane Ethyl chloride

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Trichloroethylene Gallamine Succinylcholine

MITOCHONDRIAL

Zidovudine

MYOTONIA

2,4-D-Chlorophenoxyacetic acid Anthracene-9-carboxycyclic acid Cholesterol-lowering drugs Chloroquine Cyclosporine

MYOSIN LOSS

Nondepolarizing neuromuscular blocking agents Intravenous glucocorticoids

Clofibrate, gemfibrozil, the statins, and niacin can all produce a rapidly progressive myopathy with elevated CK levels, weakness, pain, and myoglobinuria. An acute necrotizing myopathy associated with myoglobinuria occurs in chronic alcoholics after a bout of drinking. Illicit drugs such as heroin, cocaine, amphetamines, and pentazocine can produce rhabdomyolysis through direct toxic effects, status epilepticus, or prolonged loss of consciousness, immobility, and secondary pressure.

Focal muscle injury can be caused by injection of certain drugs, particularly pentazocine and meperidine. Muscle necrosis is followed by fibrous connective tissue replacement and induration.

Critical Illness Myopathy

Also known as acute quadriplegic myopathy, critical illness myopathy develops in a patient in the intensive care setting and is often discovered when a patient is unable to be weaned off a ventilator. The cause of the diffuse weakness is prolonged daily use of either (often both) high-dose intravenous glucocorticoids (usually methylprednisolone) or nondepolarizing neuromuscular blocking agents (e.g., vecuronium). Patients often have had sepsis and multiorgan failure. The serum CK level is moderately elevated, and EMG shows myopathic units and fibrillations. On nerve conduction studies, motor amplitudes are small, and occasionally a decremental response can be seen on repetitive stimulation. The diagnosis can be confirmed by muscle biopsy, which shows loss of myosin thick filaments on EM. Treatment is supportive after discontinuing the offending agents. Strength recovers over a period of weeks or months, and patients can usually be weaned off the ventilator. Critical illness myopathy must be distinguished from critical illness neuropathy and can occasionally coexist with it.