(Fig.

462e-3) are characteristic of facioscapulohumeral dystrophy 462e-1

462e Muscular Dystrophies and (FSHD). Facial and distal limb weakness associated with hand grip
myotonia is virtually diagnostic of myotonic dystrophy type 1. When

Chapter 462e Muscular Dystrophies and Other Muscle Diseases

Other Muscle Diseases
Anthony A. Amato, Robert H. Brown, Jr.
Skeletal muscle diseases, or myopathies, are disorders with structural
changes or functional impairment of muscle. These conditions can be
differentiated from other diseases of the motor unit (e.g., lower motor
neuron or neuromuscular junction pathologies) by characteristic clini-
cal and laboratory findings.
Myasthenia gravis and related disorders are discussed in Chap.
461; dermatomyositis, polymyositis, and inclusion body myositis
are discussed in Chap. 388.
CLINICAL FEATURES
Most myopathies present with proximal, symmetric limb weakness
(arms or legs) with preserved reflexes and sensation. However, asym-
metric and predominantly distal weakness can be seen in some myopa-
thies. An associated sensory loss suggests injury to a peripheral nerve
or the central nervous system (CNS) rather than myopathy. On occa-
sion, disorders affecting the motor nerve cell bodies in the spinal cord
(anterior horn cell disease), the neuromuscular junction, or peripheral
nerves can mimic findings of myopathy.
Muscle Weakness  Symptoms of muscle weakness can be either
intermittent or persistent. Disorders causing intermittent weakness
(Fig. 462e-1) include myasthenia gravis, periodic paralyses (hypokale-
mic, hyperkalemic, and paramyotonia congenita), and metabolic energy
deficiencies of glycolysis (especially myophosphorylase deficiency),
fatty acid utilization (carnitine palmitoyltransferase deficiency), and
some mitochondrial myopathies. The states of energy deficiency cause
activity-related muscle breakdown accompanied by myoglobinuria,
appearing as light-brown- to dark-brown-colored urine.
Most muscle disorders cause persistent weakness (Fig. 462e-2). In
the majority of these, including most types of muscular dystrophy,
polymyositis, and dermatomyositis, the proximal muscles are weaker
than the distal and are symmetrically affected, and the facial muscles
are spared, a pattern referred to as limb-girdle. The differential diagno-
sis is more restricted for other patterns of weakness. Facial weakness
(difficulty with eye closure and impaired smile) and scapular winging
other cranial nerve muscles are weak, causing ptosis or extraocular
muscle weakness, the most important disorders to consider include
neuromuscular junction disorders, oculopharyngeal muscular dystro-
phy, mitochondrial myopathies, or some of the congenital myopathies
(Table 462e-1). A pathognomonic pattern characteristic of inclusion
body myositis is atrophy and weakness of the flexor forearm (e.g., wrist
and finger flexors) and quadriceps muscles that is often asymmetric.
Less frequently, but important diagnostically, is the presence of a
dropped head syndrome indicative of selective neck extensor muscle
weakness. The most important neuromuscular diseases associated
with this pattern of weakness include myasthenia gravis, amyotrophic
lateral sclerosis, late-onset nemaline myopathy, hyperparathyroidism,
focal myositis, and some forms of inclusion body myopathy. A final
pattern, recognized because of preferential distal extremity weak-
ness, is typical of a unique category of muscular dystrophy, the distal
myopathies.
It is important to examine functional capabilities to help disclose
certain patterns of weakness (Table 462e-2). The Gowers’ sign
(Fig. 462e-4) is particularly useful. Observing the gait of an individual
may disclose a lordotic posture caused by combined trunk and hip
weakness, frequently exaggerated by toe walking (Fig. 462e-5). A
waddling gait is caused by the inability of weak hip muscles to prevent
hip drop or hip dip. Hyperextension of the knee (genu recurvatum or
back-kneeing) is characteristic of quadriceps muscle weakness; and a
steppage gait, due to footdrop, accompanies distal weakness.
Any disorder causing muscle weakness may be accompanied
by fatigue, referring to an inability to maintain or sustain a force
(pathologic fatigability). This condition must be differentiated from
asthenia, a type of fatigue caused by excess tiredness or lack of energy.
Associated symptoms may help differentiate asthenia and pathologic
fatigability. Asthenia is often accompanied by a tendency to avoid
physical activities, complaints of daytime sleepiness, necessity for fre-
quent naps, and difficulty concentrating on activities such as reading.
There may be feelings of overwhelming stress and depression. Thus,
asthenia is not a myopathy. In contrast, pathologic fatigability occurs
in disorders of neuromuscular transmission and in disorders altering
energy production, including defects in glycolysis, lipid metabolism, or
mitochondrial energy production. Pathologic fatigability also occurs in
chronic myopathies because of difficulty accomplishing a task with less

Intermittent weakness

Myoglobinuria

No Yes

Variable weakness includes Exam normal between attacks Exam usually normal between attacks
EOMs, ptosis, bulbar and limb muscles Proximal > distal weakness during attacks Proximal > distal weakness during attacks

AChR or Musk AB positive EKG

Forearm exercise
Yes No Abnormal Normal

Decrement on 2–3 Hz repetitive Check for dysmorphic Myotonia on exam Reduced lactic acid rise Normal lactic acid rise
Acquired seropositive
nerve stimulation (RNS) or features Consider glycolytic defect Consider CPT deficiency
MG
increased jitter on single fiber Genetic testing for or other fatty acid
EMG (SFEMG) Anderson-Tawil syndrome metabolism disorders
No Yes
Check chest CT
for thymoma
Yes No Low potassium Normal or elevated
level potassium level Muscle biopsy
Lambert-Eaton Consider: defines specific defect
myasthenic syndrome Seronegative MG Hyperkalemic PP
Congenital MG* Hypokalemic PP
Paramyotonia congenita
Check: Psychosomatic
*Genetic testing weakness**
(Chap. 461) Voltage gated Ca
**If Abs, RNS, SFEMG channel Abs
are all normal or negative Chest CT for lung Ca DNA test confirms diagnosis

Figure 462e-1  Diagnostic evaluation of intermittent weakness. AChR AB, acetylcholine receptor antibody; CPT, carnitine palmitoyltransfer-
ase; EOMs, extraocular muscles; MG, myasthenia gravis; PP, periodic paralysis.
Copyright © 2015 McGraw-Hill Education. All rights reserved.
 462e-2
Persistent Weakness

Patterns of Weakness on Neurologic Exam

PART 17

Proximal > distal Ptosis, EOMs Facial and Facial, distal, Proximal & distal Distal Dropped head
PM; DM; muscular OPMD; scapular winging quadriceps; (hand grip), & Distal myopathy MG; PM; ALS;
dystrophies; mitochondrial (FSHD) handgrip myotonia quadriceps hyperpara-
mitochondrial myopathy; Myotonic muscular IBM thyroid
and metabolic myotubular dystrophy
myopathies; myopathy
Neurologic Disorders

toxic, endocrine
myopathies

Myopathic EMG confirms muscle disease and excludes ALS

Repetitive nerve stimulation indicates MG
CK elevation supports myopathy

May need DNA testing for further distinction of inherited myopathies

Muscle biopsy will help distinguish many disorders

Figure 462e-2  Diagnostic evaluation of persistent weakness. Examination reveals one of seven patterns of weakness. The pattern of weak-
ness in combination with the laboratory evaluation leads to a diagnosis. ALS, amyotrophic lateral sclerosis; CK, creatine kinase; DM, dermatomy-
ositis; EMG, electromyography; EOMs, extraocular muscles; FSHD, facioscapulohumeral dystrophy; IBM, inclusion body myositis; MG, myasthenia
gravis; OPMD, oculopharyngeal muscular dystrophy; PM, polymyositis.

muscle. Pathologic fatigability is accompanied by abnormal clinical or   TABLE 462e-1    Neuromuscular Causes of Ptosis or Ophthalmoplegia
laboratory findings. Fatigue without those supportive features almost Peripheral Neuropathy
never indicates a primary muscle disease.
Guillain-Barré syndrome
Muscle Pain (Myalgias), Cramps, and Stiffness  Muscle pain can be associ- Miller Fisher syndrome
ated with cramps, spasms, contractures, and stiff or rigid muscles. In Neuromuscular Junction
distinction, true myalgia (muscle aching), which can be localized or Botulism
generalized, may be accompanied by weakness, tenderness to palpa-
Lambert-Eaton syndrome
tion, or swelling. Certain drugs cause true myalgia (Table 462e-3).
Myasthenia gravis
There are two painful muscle conditions of particular importance,
neither of which is associated with muscle weakness. Fibromyalgia is Congenital myasthenia
a common, yet poorly understood, type of myofascial pain syndrome. Myopathy
Patients complain of severe muscle pain and tenderness and have Mitochondrial myopathies
specific painful trigger points, sleep disturbances, and easy fatigability.   Kearns-Sayre syndrome
Serum creatine kinase (CK), erythrocyte sedimentation rate (ESR),   Progressive external ophthalmoplegia
electromyography (EMG), and muscle biopsy are normal (Chap. 396).
Oculopharyngeal and oculopharyngodistal muscular dystrophy
Polymyalgia rheumatica occurs mainly in patients >50 years and is
Myotonic dystrophy (ptosis only)
characterized by stiffness and pain in the shoulders, lower back, hips,
and thighs (Chap. 385). The ESR is elevated, while serum CK, EMG, Congenital myopathy
and muscle biopsy are normal. Temporal arteritis, an inflammatory  Myotubular
  Nemaline (ptosis only)
Hyperthyroidism/Graves’ disease (ophthalmoplegia without ptosis)
Hereditary inclusion body myopathy type 3

disorder of medium- and large-sized arteries, usually involving one

Figure 462e-3  Facioscapulohumeral dystrophy with prominent
scapular winging.
Copyright © 2015 McGraw-Hill Education. All rights reserved.
or more branches of the carotid artery, may accompany polymy-
algia rheumatica. Vision is threatened by ischemic optic neuritis.
Glucocorticoids can relieve the myalgias and protect against visual loss.
Localized muscle pain is most often traumatic. A common cause
of sudden abrupt-onset pain is a ruptured tendon, which leaves the
muscle belly appearing rounded and shorter in appearance compared
to the normal side. The biceps brachii and Achilles tendons are par-
ticularly vulnerable to rupture. Infection or neoplastic infiltration of
the muscle is a rare cause of localized muscle pain.
A muscle cramp or spasm is a painful, involuntary, localized, muscle
contraction with a visible or palpable hardening of the muscle. Cramps
are abrupt in onset, short in duration, and may cause abnormal postur-
ing of the joint. The EMG shows firing of motor units, reflecting an
origin from spontaneous neural discharge. Muscle cramps often occur
  TABLE 462e-2    Observations on Examination That Disclose Muscle 462e-3
Weakness

Chapter 462e Muscular Dystrophies and Other Muscle Diseases

Functional Impairment Muscle Weakness
Inability to forcibly close eyes Upper facial muscles
Impaired pucker Lower facial muscles
Inability to raise head from prone Neck extensor muscles
position
Inability to raise head from supine Neck flexor muscles
position
Inability to raise arms above head Proximal arm muscles (may be only
scapular stabilizing muscles)
Inability to walk without hyperex- Knee extensor muscles
tending knee (back-kneeing or genu
recurvatum)
Inability to walk with heels touching Shortening of the Achilles tendon
the floor (toe walking)
Inability to lift foot while walking Anterior compartment of leg
(steppage gait or footdrop)
Inability to walk without a waddling Hip muscles
gait
Inability to get up from the floor Hip, thigh, and trunk muscles
without climbing up the extremities
(Gowers’ sign)
Inability to get up from a chair Hip muscles
without using arms

in neurogenic disorders, especially motor neuron disease (Chap. 452),

radiculopathies, and polyneuropathies (Chap. 459), but are not a fea-
ture of most primary muscle diseases. Duchenne muscular dystrophy
is an exception because calf muscle complaints are a common com-
plaint. Muscle cramps are also common during pregnancy.
A muscle contracture is different from a muscle cramp. In both con-
ditions, the muscle becomes hard, but a contracture is associated with
energy failure in glycolytic disorders. The muscle is unable to relax
after an active muscle contraction. The EMG shows electrical silence.
Confusion is created because contracture also refers to a muscle that
cannot be passively stretched to its proper length (fixed contracture)
because of fibrosis. In some muscle disorders, especially in Emery-
Dreifuss muscular dystrophy and Bethlem myopathy, fixed contrac-
tures occur early and represent distinctive features of the disease.
Muscle stiffness can refer to different phenomena. Some patients
with inflammation of joints and periarticular surfaces feel stiff. This Figure 462e-4  Gowers’ sign showing a patient using his arms to
condition is different from the disorders of hyperexcitable motor climb up the legs in attempting to get up from the floor.
nerves causing stiff or rigid muscles. In stiff-person syndrome, sponta-
neous discharges of the motor neurons of the spinal cord cause invol-
untary muscle contractions mainly involving the axial (trunk) and
the related term proximal myotonic myopathy (PROMM) is used to
proximal lower extremity muscles. The gait becomes stiff and labored,
describe this condition. Myotonia also occurs with myotonia congenita
with hyperlordosis of the lumbar spine. Superimposed episodic muscle
(a chloride channel disorder), but in this condition muscle weakness is
spasms are precipitated by sudden movements, unexpected noises, and
not prominent. Myotonia may also be seen in individuals with sodium
emotional upset. The muscles relax during sleep. Serum antibodies
channel mutations (hyperkalemic periodic paralysis or potassium-
against glutamic acid decarboxylase are present in approximately two-
sensitive myotonia). Another sodium channelopathy, paramyotonia
thirds of cases. In neuromyotonia (Isaacs’ syndrome), there is hyper-
congenita, also is associated with muscle stiffness. In contrast to other
excitability of the peripheral nerves manifesting as continuous muscle
disorders associated with myotonia in which the myotonia is eased by
fiber activity. Myokymia (groups of fasciculations associated with
repetitive activity, paramyotonia congenita is named for a paradoxical
continuous undulations of muscle) and impaired muscle relaxation are
phenomenon whereby the myotonia worsens with repetitive activity.
the result. Muscles of the leg are stiff, and the constant contractions of
the muscle cause increased sweating of the extremities. This peripheral Muscle Enlargement and Atrophy  In most myopathies muscle tissue is
nerve hyperexcitability is mediated by antibodies that target voltage- replaced by fat and connective tissue, but the size of the muscle is usu-
gated potassium channels. The site of origin of the spontaneous nerve ally not affected. However, in many limb-girdle muscular dystrophies
discharges is principally in the distal portion of the motor nerves. (and particularly the dystrophinopathies), enlarged calf muscles are
Myotonia is a condition of prolonged muscle contraction followed typical. The enlargement represents true muscle hypertrophy; thus
by slow muscle relaxation. It always follows muscle activation (action the term pseudohypertrophy should be avoided when referring to
myotonia), usually voluntary, but may be elicited by mechanical stimu- these patients. The calf muscles remain very strong even late in the
lation (percussion myotonia) of the muscle. Myotonia typically causes course of these disorders. Muscle enlargement can also result from
difficulty in releasing objects after a firm grasp. In myotonic muscular infiltration by sarcoid granulomas, amyloid deposits, bacterial and
dystrophy type 1 (DM1), distal weakness usually accompanies myo- parasitic infections, and focal myositis. In contrast, muscle atrophy is
tonia, whereas in DM2, proximal muscles are more affected; thus characteristic of other myopathies. In dysferlinopathies (LGMD2B)
Copyright © 2015 McGraw-Hill Education. All rights reserved.
 462e-4 from the muscle fiber to the serum. The MM isoenzyme predominates
in skeletal muscle, whereas creatine kinase-myocardial bound (CK-
MB) is the marker for cardiac muscle. Serum CK can be elevated in
normal individuals without provocation, presumably on a genetic
PART 17

basis or after strenuous activity, minor trauma (including the EMG

needle), a prolonged muscle cramp, or a generalized seizure. Aspartate
aminotransferase (AST), alanine aminotransferase (ALT), aldolase,
and lactic dehydrogenase (LDH) are enzymes sharing an origin in
both muscle and liver. Problems arise when the levels of these enzymes
are found to be elevated in a routine screening battery, leading to the
erroneous assumption that liver disease is present when in fact muscle
Neurologic Disorders

could be the cause. An elevated γ-glutamyl transferase (GGT) helps

Figure 462e-5  Lordotic posture, exaggerated by standing on toes,
associated with trunk and hip weakness.
and anoctaminopathies (LGMD2L), there is a predilection for early
atrophy of the gastrocnemius muscles, particularly the medial aspect.
Atrophy of the humeral muscles is characteristic of FSHD.
LABORATORY EVALUATION
A limited battery of tests can be used to evaluate a suspected myopa-
thy. Nearly all patients require serum enzyme level measurements and
electrodiagnostic studies as screening tools to differentiate muscle
disorders from other motor unit diseases. The other tests described—
DNA studies, the forearm exercise test, and muscle biopsy—are used
to diagnose specific types of myopathies.
Serum Enzymes  CK is the preferred muscle enzyme to measure in the
evaluation of myopathies. Damage to muscle causes the CK to leak
  TABLE 462e-3    Drugs That Cause True Myalgia
Cimetidine
Cocaine
Cyclosporine
Danazol
Emetine
Gold
Heroin
Labetalol
Methadone
d-Penicillamine
Statins and other cholesterol-lowering agents
l-Tryptophan
Zidovudine
to establish a liver origin because this enzyme is not found in muscle.
Electrodiagnostic Studies  EMG, repetitive nerve stimulation, and nerve
conduction studies (Chap. 442e) are essential methods for evalua-
tion of the patient with suspected muscle disease. In combination,
they provide the information necessary to differentiate myopathies
from neuropathies and neuromuscular junction diseases. Routine
nerve conduction studies are typically normal in myopathies but
reduced amplitudes of compound muscle action potentials may be
seen in atrophied muscles. The needle EMG may reveal irritability on
needle placement suggestive of a necrotizing myopathy (inflammatory
myopathies, dystrophies, toxic myopathies, myotonic myopathies),
whereas a lack of irritability is characteristic of long-standing myo-
pathic disorders (muscular dystrophies, endocrine myopathies, disuse
atrophy, and many of the metabolic myopathies). In addition, the
EMG may demonstrate myotonic discharges that will narrow the dif-
ferential diagnosis (Table 462e-4). Another important EMG finding
is the presence of short-duration, small-amplitude, polyphasic motor
unit action potentials (MUAPs). Such MUAPs can be seen in both
myopathic and neuropathic disorders; however, the recruitment or
firing pattern is different. In myopathies, the MUAPs fire early but at
a normal rate to compensate for the loss of individual muscle fibers,
whereas in neurogenic disorders the MUAPs fire faster. The EMG is
usually normal in steroid or disuse myopathy, both of which are asso-
ciated with type 2 fiber atrophy; this is because the EMG preferentially
assesses the physiologic function of type 1 fibers. The EMG can also
be invaluable in helping to choose an appropriately affected muscle to
sample for biopsy.
DNA Analysis  This serves as an important tool for the definitive diag-
nosis of many muscle disorders. Nevertheless, there are a number of
limitations in currently available molecular diagnostics. For example,
in Duchenne and Becker dystrophies, two-thirds of patients have dele-
tion or duplication mutations in the dystrophin gene that are easy to
detect, while the remainder have point mutations that are much more
difficult to find. For patients without identifiable gene defects, the
muscle biopsy remains the main diagnostic tool.
  TABLE 462e-4    Myotonic Disorders
Myotonic dystrophy type 1
Myotonic dystrophy type 2/proximal myotonic myopathy
Myotonia congenita
Paramyotonia congenita
Hyperkalemic periodic paralysis
Chondrodystrophic myotonia (Schwartz-Jampel syndrome)
Centronuclear/myotubular myopathya
Drug-induced
  Cholesterol-lowering agents (statin medications, fibrates)
 Cyclosporine
 Chloroquine
Glycogen storage disordersa (Pompe’s disease, branching enzyme deficiency,
debranching enzyme deficiency)
Myofibrillar myopathies (MFM)a
a
Associated with myotonic discharges on electromyography but no clinical myotonia.

Copyright © 2015 McGraw-Hill Education. All rights reserved.

Forearm Exercise Test  In myopathies with intermittent symptoms, and fibers are seen in polymyositis; similar endomysial infiltrates associated 462e-5
especially those associated with myoglobinuria, there may be a defect with muscle fibers containing rimmed vacuoles and amyloid deposits
in glycolysis. Many variations of the forearm exercise test exist. For consisting of SMI-31-, p62-, and TDP-43-positive inclusions within

Chapter 462e Muscular Dystrophies and Other Muscle Diseases

safety, the test should not be performed under ischemic conditions
to avoid an unnecessary insult to the muscle, causing rhabdomyoly-
sis. The test is performed by placing a small indwelling catheter into
an antecubital vein. A baseline blood sample is obtained for lactic
acid and ammonia. The forearm muscles are exercised by asking the
patient to vigorously open and close the hand for 1 min. Blood is then
obtained at intervals of 1, 2, 4, 6, and 10 min for comparison with the
baseline sample. A three- to fourfold rise of lactic acid is typical. The
simultaneous measurement of ammonia serves as a control, because it
should also rise with exercise. In patients with myophosphorylase defi-
ciency or other glycolytic defects, the lactic acid rise will be absent or
below normal, while the rise in ammonia will reach control values. If
there is lack of effort, neither lactic acid nor ammonia will rise. Patients
with selective failure to increase ammonia may have myoadenylate
deaminase deficiency. This condition has been reported to be a cause
of myoglobinuria, but deficiency of this enzyme in asymptomatic indi-
viduals makes interpretation controversial.
Muscle Biopsy  Muscle biopsy is an important step in establishing the
diagnosis of a suspected myopathy. The biopsy is usually obtained
from a quadriceps or biceps brachii muscle, less commonly from a del-
toid muscle. Evaluation includes a combination of techniques—light
microscopy, histochemistry, immunocytochemistry with a battery of
antibodies, and electron microscopy. Not all techniques are needed for
every case. A specific diagnosis can be established in many disorders.
Endomysial inflammatory cells surrounding and invading muscle
fibers are characteristic of inclusion body myositis; and perivascular,
perimysial inflammation associated with perifascicular atrophy is a fea-
ture of dermatomyositis. In addition, the congenital myopathies have
distinctive light and electron microscopy features essential for diag-
nosis. Mitochondrial and metabolic (e.g., glycogen and lipid storage
diseases) myopathies also demonstrate distinctive histochemical and
electron-microscopic profiles. Biopsied muscle tissue can be sent for
metabolic enzyme or mitochondrial DNA analyses. A battery of anti-
bodies is available for the identification of abnormal proteins to help
diagnose specific types of muscular dystrophies. Western blot analysis
on muscle specimens can be performed to determine whether specific
muscle proteins are reduced in quantity or are of abnormal size.
HEREDITARY MYOPATHIES
Muscular dystrophy refers to a group of hereditary progressive diseases
each with unique phenotypic and genetic features (Tables 462e-5,
462e-6, and 462e-7).
DUCHENNE MUSCULAR DYSTROPHY
This X-linked recessive disorder, sometimes also called pseudohyper-
trophic muscular dystrophy, has an incidence of ~1 per 5200 live-born
males.
Clinical Features  Duchenne dystrophy is present at birth, but the
disorder usually becomes apparent between ages 3 and 5 years. The
boys fall frequently and have difficulty keeping up with friends when

  TABLE 462e-5    Progressive Muscular Dystrophies

Defective Gene/ Other Organ Systems
Type Inheritance Protein Onset Age Clinical Features Involved
Duchenne XR Dystrophin Before 5 years Progressive weakness of girdle muscles Cardiomyopathy
Unable to walk after age 12 Mental impairment
Progressive kyphoscoliosis
Respiratory failure in second or third decade
Becker XR Dystrophin Early childhood to adult Progressive weakness of girdle muscles Cardiomyopathy
Able to walk after age 15
Respiratory failure may develop by fourth
decade
Limb-girdle AD/AR Several (Tables Early childhood to early Slow progressive weakness of shoulder and ± Cardiomyopathy
462e-6, 462e-7) adult hip girdle muscles
Emery-Dreifuss XR/AD Emerin, lamin A/C Childhood to adult Elbow/knee/ankle contractures, humeral and Cardiomyopathy
Nesprin-1, peroneal weakness
nesprin-2,
TMEM43
Congenital AR Several At birth or within first Hypotonia, contractures, delayed milestones CNS abnormalities
few months Progression to respiratory failure in some; static (hypomyelination,
course in others malformation)
Eye abnormalities
Myotonica AD DM1: Expansion Childhood to adult; pos- Slowly progressive weakness of face, shoulder Cardiac conduction
(DM1, DM2) CTG repeat sibly infancy if mother girdle, and foot dorsiflexion defects
DM2: Expansion affected (DM1 only) Preferential proximal weakness in DM2 Mental impairment
CCTG repeat Cataracts
Frontal baldness
Gonadal atrophy
FSHD1 AD DUX4 4q Childhood to adult Slowly progressive weakness of face, shoulder Deafness
girdle, and foot dorsiflexion
FSHD2 AD SMCHD1 Coats’ (eye) disease
Oculopharyngeal AD Expansion, poly- Fifth to sixth decade Slowly progressive weakness of extraocular, —
A RNA binding pharyngeal, and limb muscles
protein
Two forms of myotonic dystrophy, DM1 and DM2, have been identified. Many features overlap (see text).
a

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system; XR, X-linked recessive.

Copyright © 2015 McGraw-Hill Education. All rights reserved.

 462e-6   TABLE 462e-6    Autosomal Dominant Limb-Girdle Muscular Dystrophies (LGMDs)
Disease Clinical Features
LGMD1A Onset second to eighth decade
PART 17
Muscle weakness affects proximal and distal limb muscles, vocal
cords, and pharyngeal muscles
LGMD1B Onset first or second decade
Proximal lower limb weakness and cardiomyopathy with
conduction defects
Some cases indistinguishable from Emery-Dreifuss muscular
Neurologic Disorders
dystrophy with joint contractures
LGMD1C Onset in early childhood
Proximal weakness
Gowers’ sign, calf hypertrophy, rippling muscles
Exercise-related muscle cramps
LGMD1D Onset second to sixth decade
Proximal and distal muscle weakness
LGMD1E Onset first to sixth decade
Proximal or distal muscle weakness
Cardiomyopathy and arrhythmias
LGMD1F Onset infancy to sixth decade
Proximal or distal weakness
May have early contractures resembling Emery-Dreifuss syndrome
Abbreviations: CK, creatine kinase; EMG, electromyography; MFM, myofibrillar myopathy; NCS, nerve conduction studies.
playing. Running, jumping, and hopping are invariably abnormal. By
age 5 years, muscle weakness is obvious by muscle testing. On get-
ting up from the floor, the patient uses his hands to climb up himself
(Gowers’ maneuver [Fig. 462e-4]). Contractures of the heel cords and
iliotibial bands become apparent by age 6 years, when toe walking is
associated with a lordotic posture. Loss of muscle strength is progres-
sive, with predilection for proximal limb muscles and the neck flexors;
leg involvement is more severe than arm involvement. Between ages
8 and 10 years, walking may require the use of braces; joint contrac-
tures and limitations of hip flexion, knee, elbow, and wrist extension
are made worse by prolonged sitting. Prior to the use of glucocorti-
coids, most boys became wheelchair dependent by 12 years of age.
Contractures become fixed, and a progressive scoliosis often develops
that may be associated with pain. The chest deformity with scoliosis
impairs pulmonary function, which is already diminished by muscle
weakness. By age 16–18 years, patients are predisposed to serious,
sometimes fatal pulmonary infections. Other causes of death include
aspiration of food and acute gastric dilation.
A cardiac cause of death is uncommon despite the presence of a
cardiomyopathy in almost all patients. Congestive heart failure sel-
dom occurs except with severe stress such as pneumonia. Cardiac
arrhythmias are rare. The typical electrocardiogram (ECG) shows an
increased net RS in lead V1; deep, narrow Q waves in the precordial
leads; and tall right precordial R waves in V1. Intellectual impairment
in Duchenne dystrophy is common; the average intelligence quotient
(IQ) is ~1 standard deviation (SD) below the mean. Impairment of
intellectual function appears to be nonprogressive and affects verbal
ability more than performance.
Laboratory Features  Serum CK levels are invariably elevated to
between 20 and 100 times normal. The levels are abnormal at birth
but decline late in the disease because of inactivity and loss of muscle
mass. EMG demonstrates features typical of myopathy. The muscle
biopsy shows muscle fibers of varying size as well as small groups of
necrotic and regenerating fibers. Connective tissue and fat replace
lost muscle fibers. A definitive diagnosis of Duchenne dystrophy can
be established on the basis of dystrophin deficiency in a biopsy of
Copyright © 2015 McGraw-Hill Education. All rights reserved.
Laboratory Features Abnormal Protein
Serum CK 2× normal Myotilin
EMG myopathic and may have pseudomotonic
discharges
Muscle biopsy: features of MFM
Serum CK 3–5× normal Lamin A/C
EMG myopathic
Serum CK 4–25× normal Caveolin-3
EMG myopathic
Serum CK 2–3× normal DNAJB6
EMG myopathic
Muscle biopsy: features of MFM
Serum CK 2–4× normal Desmin
EMG myopathic and may have pseudomotonic
discharges
Muscle biopsy: features of MFM
Serum CK normal to 20× normal TNPO3
EMG myopathic
Muscle biopsy may show enlarged nuclei with
central pallor, rimmed vacuoles, and filamentous
inclusions
muscle tissue or mutation analysis on peripheral blood leukocytes, as
discussed below.
Duchenne dystrophy is caused by a mutation of the gene that
encodes dystrophin, a 427-kDa protein localized to the inner surface of
the sarcolemma of the muscle fiber. The dystrophin gene is >2000 kb
in size and thus is one of the largest identified human genes. It is local-
ized to the short arm of the X chromosome at Xp21. The most com-
mon gene mutation is a deletion. The size varies but does not correlate
with disease severity. Deletions are not uniformly distributed over the
gene but rather are most common near the beginning (5′ end) and
middle of the gene. Less often, Duchenne dystrophy is caused by a gene
duplication or point mutation. Identification of a specific mutation
allows for an unequivocal diagnosis, makes possible accurate testing of
potential carriers, and is useful for prenatal diagnosis.
A diagnosis of Duchenne dystrophy can also be made by Western
blot analysis of muscle biopsy specimens, revealing abnormalities on
the quantity and molecular weight of dystrophin protein. In addition,
immunocytochemical staining of muscle with dystrophin antibodies
can be used to demonstrate absence or deficiency of dystrophin local-
izing to the sarcolemmal membrane. Carriers of the disease may dem-
onstrate a mosaic pattern, but dystrophin analysis of muscle biopsy
specimens for carrier detection is not reliable.
Pathogenesis  Dystrophin is part of a large complex of sarcolemmal
proteins and glycoproteins (Fig. 462e-6). Dystrophin binds to F-actin
at its amino terminus and to β-dystroglycan at the carboxyl terminus.
β-Dystroglycan complexes to α-dystroglycan, which binds to laminin
in the extracellular matrix (ECM). Laminin has a heterotrimeric
molecular structure arranged in the shape of a cross with one heavy
chain and two light chains, β1 and γ1. The laminin heavy chain of skel-
etal muscle is designated laminin α2. Collagen proteins IV and VI are
also found in the ECM. Like β-dystroglycan, the transmembrane sar-
coglycan proteins also bind to dystrophin; these five proteins (desig-
nated α- through ε-sarcoglycan) complex tightly with each other. More
recently, other membrane proteins implicated in muscular dystrophy
have been found to be loosely affiliated with constituents of the dystro-
phin complex. These include caveolin-3, α7 integrin, and collagen VI.
  TABLE 462e-7    Autosomal Recessive Limb-Girdle Muscular Dystrophies (LGMDs) 462e-7
Disease Clinical Features Laboratory Features Abnormal Protein

Chapter 462e Muscular Dystrophies and Other Muscle Diseases

LGMD2A Onset first or second decade Serum CK 3–15× normal Calpain-3
Scapular winging; no calf hypertrophy; no cardiac or respiratory muscle EMG myopathic
weakness
Proximal and distal weakness; may have contractures at elbows, wrists, and Muscle biopsy may show lobulated
fingers muscle fibers
LGMD2B Onset second or third decade Serum CK 3–100× normal Dysferlin
Proximal muscle weakness at onset, later distal (calf ) muscles affected EMG myopathic
Miyoshi’s myopathy is variant of LGMD2B with calf muscles affected at onset Inflammation on muscle biopsy may
simulate polymyositis
LGMD2C–F Onset in childhood to teenage years Serum CK 5–100× normal γ, α, β, δ sarcoglycans
Clinical condition similar to Duchenne and Becker muscular dystrophies EMG myopathic
Cognitive function normal
LGMD2G Onset age 10 to 15 Serum CK 3–17× normal Telethonin
Proximal and distal muscle weakness EMG myopathic
Muscle biopsy may show rimmed
vacuoles
LGMD2H Onset first to third decade Serum CK 2–25× normal TRIM32 gene
Proximal muscle weakness EMG myopathic
LGMD2I Onset first to third decade Serum CK 10–30× normal Fukutin-related protein
Clinical condition similar to Duchenne or Becker dystrophies EMG myopathic
Cardiomyopathy and respiratory failure may occur early before significant
weakness
Cognitive function normal
LGMD2Ja Onset first to third decade Serum CK 1.5–2× normal Titin
Proximal lower limb weakness EMG myopathic
Mild distal weakness Muscle biopsy reveals rimmed
vacuoles
Progressive weakness causes loss of ambulation
LGMD2K Usually presents in infancy as Walker-Warburg syndrome but can present in CK 10–20× normal POMT1
early adult life with proximal weakness and only minor CNS abnormalities
EMG myopathic
LGMD2L Presents in childhood or adult life CK 8–20× normal Anoctamin 5
May manifest with quadriceps atrophy and myalgia EMG myopathic
Some present with early involvement of the calves in the second decade of
life, resembling Miyoshi’s myopathy (dysferlinopathy)
LGMD2M Usually presents in infancy as Fukuyama’s congenital muscular dystrophy but CK 10–50× normal Fukutin
can present in early adult life with proximal weakness and only minor CNS
abnormalities
EMG myopathic
LGMD2N Usually presents in infancy as muscle-eye-brain disease but can present in CK 5–20× normal POMGnT1
early adult life with proximal weakness and only minor CNS abnormalities
EMG myopathic
LGMD2O Usually presents in infancy as Walker-Warburg syndrome but can present in CK 5–20× normal POMT2
early adult life with proximal weakness and only minor CNS abnormalities
EMG myopathic
LGMD2P One case reported presenting in early childhood CK >10× normal α-Dystroglycan
LGMD2Q Onset in infancy to fourth decade; proximal weakness; may have ptosis and CK variable, but usually only mildly Plectin 1
extraocular weakness; epidermolysis bullosa (also considered a congenital elevated
myasthenic syndrome) EMG myopathic
Repetitive nerve stimulation may
show decrement
LGMD2R See LGMD1E (Table 462e-6) See LGMD1E Desmin
LGMD2S Onset in infancy to sixth decade CK 1.5–20× normal TRAPC11
Proximal weakness
Eye abnormalities common; truncal ataxia and chorea
Mild to moderate intellectual disability
Hutterite descent
Udd’s type distal myopathy is a form of titin deficiency with only distal muscle weakness (see Table 462e-9).
a

Abbreviations: CK, creatine kinase; EMG, electromyography; NCS, nerve conduction studies; POMT1, protein-O-mannosyltransferase 1; POMT2, protein-O-mannosyltransferase 2;
POMGNT1, O-linked mannose beta 1,2-N-acetylglucosaminyltransferase; TNPO3, transportin 3; TRAPC11, transport (trafficking) protein particle complex, subunit 11.

Copyright © 2015 McGraw-Hill Education. All rights reserved.

 462e-8 Extracellular
Collagen VI
Merosin
PART 17
Dystoglycan
complex Sarcoglycan
complex
α β
δ especially of the lower extremities, are prominently involved. As the
β γ α
β1 α7
Neurologic Disorders
nNOS
Caveolin-3 Integrin
Dystrophin Calpain Dysferlin complex
F-Actin
Golgi
POMT1
Intracellular
POMGnT1
Fukutin
Fukutin-related
protein
Figure 462e-6  Selected muscular dystrophy–associated proteins
in the cell membrane and Golgi complex.
Dystrophin localizes to the cytoplasmic face of the muscle cell
membrane. It complexes with two transmembrane protein complexes,
the dystroglycans and the sarcoglycans. The dystroglycans bind to the
extracellular matrix protein merosin, which is also complexed with β1
and α7 integrins (Tables 462e-5, 462e-6, and 462e-7). Dysferlin com-
plexes with caveolin-3 (which binds to neuronal nitric oxide synthase,
or nNOS) but not with the dystrophin-associated proteins or the inte-
grins. In some of the congenital dystrophies and limb-girdle muscular
dystrophies (LGMDs), there is loss of function of different enzymes
that glycosylate α-dystroglycan, which thereby inhibits proper binding
to merosin: POMT1, POMT2, POMGnT1, Fukutin, Fukutin-related
protein, and LARGE.
The dystrophin-glycoprotein complex appears to confer stability to
the sarcolemma, although the function of each individual component
of the complex is incompletely understood. Deficiency of one member
of the complex may cause abnormalities in other components. For
example, a primary deficiency of dystrophin (Duchenne dystrophy)
may lead to secondary loss of the sarcoglycans and dystroglycan.
The primary loss of a single sarcoglycan (see “Limb-Girdle Muscular
Dystrophy,” below) results in a secondary loss of other sarcoglycans
in the membrane without uniformly affecting dystrophin. In either
instance, disruption of the dystrophin-glycoprotein complexes weak-
ens the sarcolemma, causing membrane tears and a cascade of events
leading to muscle fiber necrosis. This sequence of events occurs repeat-
edly during the life of a patient with muscular dystrophy.
TREATMENT Duchenne Muscular Dystrophy
Glucocorticoids, administered as prednisone in a dose of 0.75 mg/kg
per day, significantly slow progression of Duchenne dystrophy for
up to 3 years. Some patients cannot tolerate glucocorticoid therapy;
weight gain and increased risk of fractures in particular represent a
significant deterrent for some boys. As in other recessively inherited
dystrophies presumed to arise from loss of function of a critical
muscle gene, there is optimism that Duchenne disease may benefit
from novel therapies that either replace the defective gene or miss-
ing protein or implement downstream corrections (e.g., skipping
mutated exons or reading through mutations that introduce stop
codons).
Copyright © 2015 McGraw-Hill Education. All rights reserved.
BECKER MUSCULAR DYSTROPHY
This less severe form of X-linked recessive muscular dystrophy results
from allelic defects of the same gene responsible for Duchenne dys-
trophy. Becker muscular dystrophy is ~10 times less frequent than
Duchenne.
Clinical Features  The pattern of muscle wasting in Becker muscular
dystrophy closely resembles that seen in Duchenne. Proximal muscles,
disease progresses, weakness becomes more generalized. Significant
facial muscle weakness is not a feature. Hypertrophy of muscles, par-
ticularly in the calves, is an early and prominent finding.
Most patients with Becker dystrophy first experience difficulties
between ages 5 and 15 years, although onset in the third or fourth
decade or even later can occur. By definition, patients with Becker
dystrophy walk beyond age 15, whereas patients with Duchenne
dystrophy are typically in a wheelchair by the age of 12. Patients with
Becker dystrophy have a reduced life expectancy, but most survive into
the fourth or fifth decade.
Mental retardation may occur in Becker dystrophy, but it is not
as common as in Duchenne. Cardiac involvement occurs in Becker
dystrophy and may result in heart failure; some patients manifest with
only heart failure. Other less common presentations are asymptomatic
hyper-CK-emia, myalgias without weakness, and myoglobinuria.
Laboratory Features  Serum CK levels, results of EMG, and muscle
biopsy findings closely resemble those in Duchenne dystrophy.
The diagnosis of Becker muscular dystrophy requires Western blot
analysis of muscle biopsy samples, demonstrating a reduced amount
or abnormal size of dystrophin or mutation analysis of DNA from
peripheral blood leukocytes. Genetic testing reveals deletions or
duplications of the dystrophin gene in 65% of patients with Becker
dystrophy, approximately the same percentage as in Duchenne dys-
trophy. In both Becker and Duchenne dystrophies, the size of the
DNA deletion does not predict clinical severity; however, in ~95%
of patients with Becker dystrophy, the DNA deletion does not alter
the translational reading frame of messenger RNA. These “in-frame”
mutations allow for production of some dystrophin, which accounts
for the presence of altered rather than absent dystrophin on Western
blot analysis.
TREATMENT Becker Muscular Dystrophy
The use of glucocorticoids has not been adequately studied in
Becker dystrophy.
LIMB-GIRDLE MUSCULAR DYSTROPHY
The syndrome of LGMD represents more than one disorder. Both
males and females are affected, with onset ranging from late in the
first decade to the fourth decade. The LGMDs typically manifest
with progressive weakness of pelvic and shoulder girdle musculature.
Respiratory insufficiency from weakness of the diaphragm may occur,
as may cardiomyopathy.
A systematic classification of LGMD is based on autosomal dom-
inant (LGMD1) and autosomal recessive (LGMD2) inheritance.
Superimposed on the backbone of LGMD1 and LGMD2, the clas-
sification uses a sequential alphabetical lettering system (LGMD1A,
LGMD2A, etc.). Disorders receive letters in the order in which they are
found to have chromosomal linkage. This results in an ever-expanding
list of conditions summarized in Tables 462e-6 and 462e-7. None of
the conditions is as common as the dystrophinopathies; however,
prevalence data for the LGMDs have not been systematically gathered
for any large heterogeneous population. In referral-based clinical
populations, Fukutin-related protein (FKRP) deficiency (LGMD2I),
calpainopathy (LGMD2A), anoctaminopathy (LGMD2L), and to a
lesser extent dysferlinopathy (LGMD2B) have emerged as the most
common disorders.
EMERY-DREIFUSS MUSCULAR DYSTROPHY
There are at least five genetically distinct forms of Emery-Dreifuss
muscular dystrophy (EDMD). Emerin mutations are the most com-
mon cause of X-linked EDMD, although mutations in FHL1 may
also be associated with a similar phenotype, which is X-linked as well.
Mutations involving the gene for lamin A/C are the most common
cause of autosomal dominant EDMD (also known as LGMD1B) and
are also a common cause of hereditary cardiomyopathy. Less com-
monly, autosomal dominant EDMD has been reported with mutations
in nesprin-1, nesprin-2, and TMEM43.
Clinical Features  Prominent contractures can be recognized in early
childhood and teenage years, often preceding muscle weakness. The
contractures persist throughout the course of the disease and are pres-
ent at the elbows, ankles, and neck. Muscle weakness affects humeral
and peroneal muscles at first and later spreads to a limb-girdle distri-
bution. The cardiomyopathy is potentially life threatening and may
result in sudden death. A spectrum of atrial rhythm and conduction
defects includes atrial fibrillation and paralysis and atrioventricular
heart block. Some patients have a dilated cardiomyopathy. Female
carriers of the X-linked variant may have cardiac manifestations that
become clinically significant.
Laboratory Features  Serum CK may be elevated two- to tenfold. EMG
is myopathic. Muscle biopsy usually shows nonspecific dystrophic fea-
tures, although cases associated with FHL1 mutations have features of
myofibrillar myopathy. Immunohistochemistry reveals absent emerin
staining of myonuclei in X-linked EDMD due to emerin mutations.
ECGs demonstrate atrial and atrioventricular rhythm disturbances.
X-linked EDMD usually arises from defects in the emerin gene
encoding a nuclear envelope protein. FHL1 mutations are also a cause
of X-linked scapuloperoneal dystrophy, but can also present with an
X-linked form of EDMD. The autosomal dominant disease can be
caused by mutations in the LMNA gene encoding lamin A and C;
in the synaptic nuclear envelope protein 1 (SYNE1) or 2 (SYNE2)
encoding nesprin-1 and nesprin-2, respectively; and most recently in
TMEM43 encoding LUMA. These proteins are essential components
of the filamentous network underlying the inner nuclear membrane.
Loss of structural integrity of the nuclear envelope from defects in
emerin, lamin A/C, nesprin-1, nesprin-2, and LUMA accounts for
overlapping phenotypes (Fig. 462e-7).
TREATMENT Emery-Dreifuss Muscular Dystrophy
Supportive care should be offered for neuromuscular disability,
including ambulatory aids, if necessary. Stretching of contractures
is difficult. Management of cardiomyopathy and arrhythmias (e.g.,
early use of a defibrillator or cardiac pacemaker) may be life saving.
CONGENITAL MUSCULAR DYSTROPHY (CMD)
This is not one entity but rather a group of disorders with varying
degrees of muscle weakness, CNS impairment, and eye abnormalities.
Clinical Features  As a group, CMDs present at birth or in the first few
months of life with hypotonia and proximal or generalized muscle
weakness. Calf muscle hypertrophy is seen in some patients. Facial
muscles may be weak, but other cranial nerve–innervated muscles
are spared (e.g., extraocular muscles are normal). Most patients have
joint contractures of varying degrees at elbows, hips, knees, and
ankles. Contractures present at birth are referred to as arthrogryposis.
Respiratory failure may be seen in some cases.
The CNS is affected in some forms of CMD. In merosin and FKRP
deficiency, cerebral hypomyelination may be seen by magnetic reso-
nance imaging (MRI), although only a small number of patients have
mental retardation and seizures. Three forms of congenital muscular
dystrophy have severe brain impairment. These include Fukuyama’s
congenital muscular dystrophy (FCMD), muscle-eye-brain (MEB)
disease, and Walker-Warburg syndrome (WWS). Patients are severely
disabled in all three of these conditions. In MEB disease and WWS, but
Copyright © 2015 McGraw-Hill Education. All rights reserved.
462e-9
α Dystroglycans Extracellular
β
Chapter 462e Muscular Dystrophies and Other Muscle Diseases
Intracellular
Dystrophin
Myotilin Nebulin
Nucleus Actin
α-Actinin
Telethonin
Myosin
Titin
Emerin
Z-band
Nuclear
pore Contractile proteins
in sarcomere
Lamin A/C
Figure 462e-7  Selected muscular dystrophy–associated proteins
in the nuclear membrane and sarcomere. As shown in the exploded
view, emerin and lamin A/C are constituents of the inner nuclear
membrane. Several dystrophy-associated proteins are represented in
the sarcomere including titin, nebulin, calpain, telethonin, actinin, and
myotilin. The position of the dystrophin-dystroglycan complex is also
illustrated.
not in FCMD, ocular abnormalities impair vision. WWS is the most
severe congenital muscular dystrophy, causing death by 1 year of age.
Laboratory Features  Serum CK is markedly elevated in all of these
conditions. The EMG is myopathic and muscle biopsies show nonspe-
cific dystrophic features. Merosin, or laminin α2 chain (a basal lamina
protein), is deficient in surrounding muscle fibers in merosin defi-
ciency. Skin biopsies can also demonstrate defects in laminin α2 chain.
In the other disorders (FKRP deficiency, FCMD, MEB disease, WWS),
there is abnormal α-dystroglycan staining in muscle. In merosin
deficiency, cerebral hypomyelination is common, and a host of brain
malformations are seen in FCMD, MEB disease, and WWS.
All forms of CMD are inherited as autosomal recessive disorders.
Chromosomal linkage and specific gene defects are presented in Table
462e-8. With the exception of merosin, the other gene defects affect
posttranslational glycosylation of α-dystroglycan. This abnormality is
thought to impair binding with merosin and leads to weakening of the
dystrophin-glycoprotein complex, instability of the muscle membrane,
and/or abnormalities in muscle contraction. CMDs with brain and
eye phenotypes probably involve defective glycosylation of additional
proteins, accounting for the more extensive phenotypes.
TREATMENT Congenital Muscular Dystrophy
There is no specific treatment for CMD. Proper wheelchair seating
is important. Management of epilepsy and cardiac manifestations is
necessary for some patients.
MYOTONIC DYSTROPHY
Myotonic dystrophy is also known as dystrophia myotonica (DM). The
condition is composed of at least two clinical disorders with overlap-
ping phenotypes and distinct molecular genetic defects: myotonic
dystrophy type 1 (DM1), the classic disease originally described by
Steinert, and myotonic dystrophy type 2 (DM2), also called proximal
myotonic myopathy (PROMM).
 462e-10   TABLE 462e-8    Congenital Muscular Dystrophiesa
Disease Clinical Features Laboratory Features Abnormal Protein
Merosin deficiency Onset at birth with hypotonia, joint contractures, delayed Serum CK 5–35× normal Laminin α2 chain
milestones, generalized muscle weakness
PART 17

EMG myopathic
Cerebral hypomyelination, less often cortical dysplasia NCS abnormal in some cases
Normal intelligence usually, some with MR (~6%) and
seizures (~8%)
Partial deficiency leads to milder phenotype (LGMD
picture)
Fukutin-related protein Onset at birth or shortly after Serum CK 10–50× normal Fukutin-related protein
Neurologic Disorders

deficiencyb Hypotonia and feeding problems EMG myopathic

Fukuyama’s congenital
muscular dystrophyb
Muscle-eye-brain disease
Walker-Warburg syndromeb
a
All are inherited as recessive traits.  bThere is phenotypic overlap between disorders related to defective glycosylation. In muscle, this is a consequence of altered glycosylation of dystro-
glycans; in brain/eye, other glycosylated proteins are involved. Clinically, Walker-Warburg syndrome is more severe, with death by 1 year.
Weakness of proximal muscles, especially shoulder NCS normal
girdles
Hypertrophy of leg muscles
Joint contractures
Cognition normal
Onset at birth Serum CK 10–50× normal Fukutin
Hypotonia, joint contractures EMG myopathic
Generalized muscle weakness NCS normal
Hypertrophy of calf muscles MRI shows hydrocephalus and
Seizures, MR periventricular and frontal hypomyelination
Cardiomyopathy
Onset at birth, hypotonia Serum CK 5–20× normal N-Acetyl-glucosaminyl
Eye abnormalities include: progressive myopia, cataracts, MRI shows hydrocephalus, cobblestone transferase
and optic nerve, glaucoma, retinal pigmentary changes lissencephaly, corpus callosum and cerebel- (POMGnT1)
Progressive muscle weakness lar hypoplasia, cerebral hypomyelination
Joint contractures
Seizures, MR
Onset at birth, hypotonia Serum CK 5–20× normal O-Mannoxyl-
Generalized muscle weakness MRI shows cobblestone lissencephaly, transferase-1 (POMT1)
Joint contractures hydrocephalus, encephalocele, absent
corpus callosum
Microphthalmos, retinal dysplasia, buphthalmos,
glaucoma, cataracts
Seizures, MR

Abbreviations: CK, creatine kinase; EMG, electromyography; LGMD, limb-girdle muscular dystrophy; MR, mental retardation; MRI, magnetic resonance imaging; NCS, nerve conduction
studies.

Clinical Features  The clinical expression of DM1 varies widely and Congenital myotonic dystrophy is a more severe form of DM1 and
involves many systems other than muscle. Affected patients have a typ- occurs in ~25% of infants of affected mothers. It is characterized by
ical “hatchet-faced” appearance due to temporalis, masseter, and facial severe facial and bulbar weakness, transient neonatal respiratory insuf-
muscle atrophy and weakness. Frontal baldness is also characteristic of ficiency, and mental retardation.
the disease. Neck muscles, including flexors and sternocleidomastoids, DM2, or PROMM, has a distinct pattern of muscle weakness affect-
and distal limb muscles are involved early. Weakness of wrist exten- ing mainly proximal muscles. Other features of the disease overlap
sors, finger extensors, and intrinsic hand muscles impairs function. with DM1, including cataracts, testicular atrophy, insulin resistance,
Ankle dorsiflexor weakness may cause footdrop. Proximal muscles constipation, hypersomnia, and cognitive defects. Cardiac conduction
remain stronger throughout the course, although preferential atrophy defects occur but are less common, and the hatchet face and frontal
and weakness of quadriceps muscles occur in many patients. Palatal, baldness are less consistent features. A very striking difference is the
pharyngeal, and tongue involvement produce a dysarthric speech, failure to clearly identify a congenital form of DM2.
nasal voice, and swallowing problems. Some patients have diaphragm
and intercostal muscle weakness, resulting in respiratory insufficiency. Laboratory Features  The diagnosis of myotonic dystrophy can usually
Myotonia, which usually appears by age 5 years, is demonstrable be made on the basis of clinical findings. Serum CK levels may be nor-
by percussion of the thenar eminence, the tongue, and wrist extensor mal or mildly elevated. EMG evidence of myotonia is present in most
muscles. Myotonia causes a slow relaxation of hand grip after a forced cases of DM1 but may be more patchy in DM2. Muscle biopsy shows
voluntary closure. Advanced muscle wasting makes myotonia more muscle atrophy, which selectively involves type 1 fibers in 50% of
difficult to detect. cases, and ringed fibers in DM1 but not in DM2. Typically, numerous
Cardiac disturbances occur commonly in patients with DM1. ECG internalized nuclei can be seen in individual muscle fibers as well as
abnormalities include first-degree heart block and more extensive con- atrophic fibers with pyknotic nuclear clumps in both DM1 and DM2.
duction system involvement. Complete heart block and sudden death can Necrosis of muscle fibers and increased connective tissue, common in
occur. Congestive heart failure occurs infrequently but may result from other muscular dystrophies, are less apparent in myotonic dystrophy.
cor pulmonale secondary to respiratory failure. Mitral valve prolapse also DM1 and DM2 are both autosomal dominant disorders. New muta-
occurs commonly. Other associated features include intellectual impair- tions do not appear to contribute to the pool of affected individuals.
ment, hypersomnia, posterior subcapsular cataracts, gonadal atrophy, DM1 is transmitted by an intronic mutation consisting of an unstable
insulin resistance, and decreased esophageal and colonic motility. expansion of a CTG trinucleotide repeat in a serine-threonine protein
Copyright © 2015 McGraw-Hill Education. All rights reserved.
kinase gene (named DMPK) on chromosome 19q13.3. An increase in
the severity of the disease phenotype in successive generations (genetic
anticipation) is accompanied by an increase in the number of trinucle-
otide repeats. A similar type of mutation has been identified in fragile
X syndrome (Chap. 451e). The unstable triplet repeat in myotonic dys-
trophy can be used for prenatal diagnosis. Congenital disease occurs
almost exclusively in infants born to affected mothers; it is possible
that sperm with greatly expanded triplet repeats do not function well.
DM2 is caused by a DNA expansion mutation consisting of a CCTG
repeat in intron 1 of the ZNF9 gene located at chromosome 3q13.3-
q24. The gene is believed to encode an RNA-binding protein expressed
in many different tissues, including skeletal and cardiac muscle.
The DNA expansions in DM1 and DM2 almost certainly impair
muscle function by a toxic gain of function of the mutant mRNA. In
both DM1 and DM2, the mutant RNA appears to form intranuclear
inclusions composed of aberrant RNA. These RNA inclusions seques-
ter RNA-binding proteins essential for proper splicing of a variety of
other mRNAs. This leads to abnormal transcription of multiple pro-
teins in a variety of tissues/organ systems, in turn causing the systemic
manifestations of DM1 and DM2.
TREATMENT Myotonic Dystrophy
The myotonia in DM1 rarely warrants treatment, although some
patients with DM2 are significantly bothered by the discomfort
related to the associated muscle stiffness. Phenytoin and mexiletine
are the preferred agents for the occasional patient who requires an
antimyotonia drug; other agents, particularly quinine and procain-
amide, may worsen cardiac conduction. A cardiac pacemaker should
be considered for patients with unexplained syncope, advanced
conduction system abnormalities with evidence of second-degree
heart block, or trifascicular conduction disturbances with marked
prolongation of the PR interval. Molded ankle-foot orthoses help
stabilize gait in patients with foot drop. Excessive daytime somno-
lence with or without sleep apnea is not uncommon. Sleep studies,
noninvasive respiratory support (biphasic positive airway pressure
[BiPAP]), and treatment with modafinil may be beneficial.
FACIOSCAPULOHUMERAL (FSH) MUSCULAR DYSTROPHY
This form of muscular dystrophy has a prevalence of ~1 in 20,000.
There are two forms of FSHD that have similar pathogenesis, as
will be discussed. Most patients have FSHD type 1 (95%), whereas
approximately 5% have FSHD2. FSHD1 and FSHD2 are clinically and
histopathologically identical. FSHD is not to be confused with the
genetically distinct scapuloperoneal dystrophies.
Clinical Features  The condition typically has an onset in childhood or
young adulthood. In most cases, facial weakness is the initial manifes-
tation, appearing as an inability to smile, whistle, or fully close the eyes.
Weakness of the shoulder girdles, rather than the facial muscles, usu-
ally brings the patient to medical attention. Loss of scapular stabilizer
muscles makes arm elevation difficult. Scapular winging (Fig. 462e-3)
becomes apparent with attempts at abduction and forward movement
of the arms. Biceps and triceps muscles may be severely affected, with
relative sparing of the deltoid muscles. Weakness is invariably worse
for wrist extension than for wrist flexion, and weakness of the anterior
compartment muscles of the legs may lead to footdrop.
In most patients, the weakness remains restricted to facial, upper
extremity, and distal lower extremity muscles. In 20% of patients,
weakness progresses to involve the pelvic girdle muscles, and severe
functional impairment and possible wheelchair dependency result.
Characteristically, patients with FSHD do not have involvement
of other organ systems, although labile hypertension is common, and
there is an increased incidence of nerve deafness. Coats’ disease, a dis-
order consisting of telangiectasia, exudation, and retinal detachment,
also occurs.
Laboratory Features  The serum CK level may be normal or mildly ele-
vated. EMG usually indicates a myopathic pattern. The muscle biopsy
Copyright © 2015 McGraw-Hill Education. All rights reserved.
shows nonspecific features of a myopathy. A prominent inflammatory 462e-11
infiltrate, which is often multifocal in distribution, is present in some
biopsy samples. The cause or significance of this finding is unknown.
Chapter 462e Muscular Dystrophies and Other Muscle Diseases
An autosomal dominant inheritance pattern with almost complete
penetrance has been established, but each family member should be
examined for the presence of the disease, since ~30% of those affected
are unaware of involvement. FSHD1 is associated with deletions of
tandem 3.3-kb repeats at 4q35. The deletion reduces the number of
repeats to a fragment of <35 kb in most patients. Within these repeats
lies the DUX4 gene, which usually is not expressed. In patients with
FSHD1 these deletions in the setting of a specific polymorphism leads
to hypomethylation of the region and toxic expression of the DUX4
gene. In patients with FSHD2, there is no deletion, but a mutation
in SMCHD1. Interestingly, in the setting of the same polymorphism,
there again is seen hypomethylation of the region and the permissive
expression of the DUX4 gene. In both FSHD1 and FSHD2, there is
overexpression of the DUX4 transcript.
TREATMENT Facioscapulohumeral Muscular
Dystrophy
No specific treatment is available; ankle-foot orthoses are helpful for
footdrop. Scapular stabilization procedures improve scapular wing-
ing but may not improve function.
OCULOPHARYNGEAL DYSTROPHY
This form of muscular dystrophy represents one of several disorders
characterized by progressive external ophthalmoplegia, which consists
of slowly progressive ptosis and limitation of eye movements with
sparing of pupillary reactions for light and accommodation. Patients
usually do not complain of diplopia, in contrast to patients having
conditions with a more acute onset of ocular muscle weakness (e.g.,
myasthenia gravis).
Clinical Features  Oculopharyngeal muscular dystrophy has a late
onset; it usually presents in the fourth to sixth decade with ptosis and/
or dysphagia. The extraocular muscle impairment is less prominent in
the early phase but may be severe later. The swallowing problem may
become debilitating and result in pooling of secretions and repeated
episodes of aspiration. Mild weakness of the neck and extremities also
occurs.
Laboratory Features  The serum CK level may be two to three times
normal. Myopathic EMG findings are typical. On biopsy, muscle fibers
are found to contain rimmed vacuoles, which by electron microscopy
are shown to contain membranous whorls, accumulation of glycogen,
and other nonspecific debris related to lysosomes. A distinct feature of
oculopharyngeal dystrophy is the presence of tubular filaments, 8.5 nm
in diameter, in muscle cell nuclei.
Oculopharyngeal dystrophy has an autosomal dominant inheri-
tance pattern with complete penetrance. The incidence is high in
French-Canadians and in Spanish-American families of the south-
western United States. Large kindreds of Italian and of eastern
European Jewish descent have been reported. The molecular defect in
oculopharyngeal muscular dystrophy is a subtle expansion of a mod-
est polyalanine repeat tract in a poly-RNA-binding protein (PABP2)
in muscle.
TREATMENT Oculopharyngeal Dystrophy
Dysphagia can lead to significant undernourishment and inanition,
making oculopharyngeal muscular dystrophy a potentially life-
threatening disease. Cricopharyngeal myotomy may improve swal-
lowing, although it does not prevent aspiration. Eyelid crutches can
improve vision when ptosis obstructs vision; candidates for ptosis
surgery must be carefully selected—those with severe facial weak-
ness are not suitable.
 462e-12 DISTAL MYOPATHIES
A group of muscle diseases, the distal myopathies, are notable for their
preferential distal distribution of muscle weakness in contrast to most
muscle conditions associated with proximal weakness. The major dis-
PART 17
tal myopathies are summarized in Table 462e-9.
Clinical Features  Welander’s, Udd’s, and Markesbery-Griggs type dis-
tal myopathies are all late-onset, dominantly inherited disorders of
distal limb muscles, usually beginning after age 40 years. Welander’s
distal myopathy preferentially involves the wrist and finger exten-
sors, whereas the others are associated with anterior tibial weakness
Neurologic Disorders
leading to progressive footdrop. Laing’s distal myopathy is also a
dominantly inherited disorder heralded by tibial weakness; however,
it is distinguished by onset in childhood or early adult life. Nonaka’s
distal myopathy and Miyoshi’s myopathy are distinguished by auto-
somal recessive inheritance and onset in the late teens or twenties.
Nonaka’s and Williams’ myopathy entails anterior tibial weakness,
whereas Miyoshi’s myopathy is unique in that gastrocnemius muscles
are preferentially affected at onset. Finally, the myofibrillar myopathies
(MFMs) are a clinically and genetically heterogeneous group of disor-
ders that can be associated with prominent distal weakness; they can
be inherited in an autosomal dominant or recessive pattern. Of note,
Markesbery-Griggs myopathy (caused by mutations in ZASP) and
LGMD1B (caused by mutations in myotilin) are in fact subtypes of
myofibrillar myopathy.
Laboratory Features  Serum CK level is particularly helpful in diagnos-
ing Miyoshi’s myopathy because it is very elevated. In the other condi-
tions, serum CK is only slightly increased. EMGs are myopathic. In the
MFMs, myotonic or pseudomyotonic discharges are common. Muscle
biopsy shows nonspecific dystrophic features and, with the exception
of Laing’s and Miyoshi’s myopathies, often shows rimmed vacuoles.
MFM is associated with the accumulation of dense inclusions, as well
as amorphous material best seen on Gomori trichrome and myofibril-
lar disruption on electron microscopy. Immune staining sometimes
demonstrates accumulation of desmin and other proteins in MFM,
large deposits of myosin heavy chain in the subsarcolemmal region
of type 1 muscle fibers in Laing’s myopathy, and reduced or absent
dysferlin in Miyoshi’s myopathy.
The affected genes and their gene products are listed in Table 462e-9.
TREATMENT Distal Myopathies
Occupational therapy is offered for loss of hand function; ankle-
foot orthoses can support distal lower limb muscles. The MFMs can
be associated with cardiomyopathy (congestive heart failure or
arrhythmias) and respiratory failure that may require medical man-
agement. Laing’s-type distal myopathy can also be associated with
a cardiomyopathy.
CONGENITAL MYOPATHIES
These rare disorders are distinguished from muscular dystrophies by
the presence of specific histochemical and structural abnormalities in
muscle. Although primarily disorders of infancy or childhood, three
forms that may present in adulthood are described here: central core
disease, nemaline (rod) myopathy, and centronuclear (myotubular)
myopathy. Sarcotubular myopathy is caused by mutations in TRIM-32
and is identical to LGMD2H. Other types, such as minicore myopathy
(multi-minicore disease), fingerprint body myopathy, and cap myopa-
thy, are not discussed.
CENTRAL CORE DISEASE
Patients with central core disease may have decreased fetal movements CENTRONUCLEAR (MYOTUBULAR) MYOPATHY
and breech presentation. Hypotonia and delay in motor milestones, Three distinct variants of centronuclear myopathy occur. A neonatal
particularly in walking, are common. Later in childhood, patients form, also known as myotubular myopathy, presents with severe hypo-
develop problems with stair climbing, running, and getting up from tonia and weakness at birth. The late infancy–early childhood form
the floor. On examination, there is mild facial, neck-flexor, and prox- presents with delayed motor milestones. Later, difficulty with running
imal-extremity muscle weakness. Legs are more affected than arms. and stair climbing becomes apparent. A marfanoid, slender body habi-
Skeletal abnormalities include congenital hip dislocation, scoliosis, tus, long narrow face, and high-arched palate are typical. Scoliosis and
Copyright © 2015 McGraw-Hill Education. All rights reserved.
and pes cavus; clubbed feet also occur. Most cases are nonprogres-
sive, but exceptions are well documented. Susceptibility to malignant
hyperthermia must be considered as a potential risk factor for patients
with central core disease. Recent series have demonstrated that many
cases of late-onset axial myopathy in which patients manifest with
bent spine (camptocormia) or neck extensor weakness (neck extensor
myopathy) are caused by mutations in the ryanodine receptor gene
(RYR1). This illustrates the interesting spectrum of RYR1 mutations.
The serum CK level is usually normal. Needle EMG demonstrates a
myopathic pattern. Muscle biopsy shows fibers with single or multiple
central or eccentric discrete zones (cores) devoid of oxidative enzymes.
Cores occur preferentially in type 1 fibers and represent poorly aligned
sarcomeres associated with Z disk streaming.
Autosomal dominant inheritance is characteristic; sporadic cases
also occur. As alluded above, this myopathy is caused by point muta-
tions of RYR1, encoding the calcium-release channel of the sarcoplas-
mic reticulum of skeletal muscle; mutations of this gene also account
for some cases of inherited malignant hyperthermia (Chap. 23).
Malignant hyperthermia is an allelic condition; C-terminal mutations
of the RYR1 gene predispose to this complication.
Specific treatment is not required, but establishing a diagnosis of
central core disease is extremely important because these patients have
a known predisposition to malignant hyperthermia during anesthesia.
NEMALINE MYOPATHY
The term nemaline refers to the distinctive presence in muscle fibers
of rods or threadlike structures (Greek nema, “thread”). Nemaline
myopathy is clinically heterogeneous. A severe neonatal form presents
with hypotonia and feeding and respiratory difficulties, leading to early
death. Nemaline myopathy usually presents in infancy or childhood
with delayed motor milestones. The course is nonprogressive or slowly
progressive. The physical appearance is striking because of the long,
narrow facies, high-arched palate, and open-mouthed appearance
due to a prognathous jaw. Other skeletal abnormalities include pectus
excavatum, kyphoscoliosis, pes cavus, and clubfoot deformities. Facial
and generalized muscle weakness, including respiratory muscle weak-
ness, is common. An adult-onset disorder with progressive proximal
or distal weakness may be seen. Myocardial involvement is occasion-
ally present in both the childhood and adult-onset forms. The serum
CK level is usually normal or slightly elevated. The EMG demonstrates
a myopathic pattern. Muscle biopsy shows clusters of small rods
(nemaline bodies), which occur preferentially, but not exclusively, in
the sarcoplasm of type 1 muscle fibers. Occasionally, the rods are also
apparent in myonuclei. The muscle often shows type 1 muscle fiber
predominance. Rods originate from the Z disk material of the muscle
fiber.
Six genes have been associated with nemaline myopathy. Five of
these code for thin filament–associated proteins, suggesting disturbed
assembly or interplay of these structures as a pivotal mechanism.
Mutations of the nebulin (NEB) gene account for most cases, includ-
ing both severe neonatal and early childhood forms, inherited as
autosomal recessive disorders. Neonatal and childhood cases, inher-
ited as predominantly autosomal dominant disorders, are caused by
mutations of the skeletal muscle a-actinin (ACTA1) gene. In milder
forms of the disease with autosomal dominant inheritance, mutations
have been identified in both the slow a-tropomyosin (TPM3) and
β;-tropomyosin (TPM2) genes accounting for <3% of cases. Muscle
troponin T (TNNT1) gene mutations appear to be limited to the Amish
population in North America. Mutations may also be seen in NEM6
that encodes a putative BTB/Kelch protein. No specific treatment is
available.
  TABLE 462e-9    Distal Myopathies
Disease
Welander’s distal myopathy
Tibial muscular dystrophy (Udd’s)
Markesbery-Griggs distal myopathy
Laing’s distal myopathy
Nonaka’s distal myopathy (autosomal
recessive hereditary inclusion body
myopathy)
Miyoshi’s myopathya
Williams’ myopathy
Myofibrillar myopathies
Miyoshi’s myopathy phenotype may also be seen with mutations in ANO-5 that encodes for anoctamin 5 (allelic to LGMD2L).
a
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CK, creatine kinase; EMG, electromyography; MFM, myofibrillar myopathy; NCS, nerve conduction studies.
462e-13
Clinical Features Laboratory Features Abnormal Protein
Chapter 462e Muscular Dystrophies and Other Muscle Diseases
Onset in fifth decade Serum CK 2–3× normal AD
Weakness begins in hands EMG myopathic Chromosome 2p13
Slow progression with spread to distal NCS normal TIA1
lower extremities Muscle biopsy shows dystrophic
Lifespan normal features and rimmed vacuoles
Onset fourth to eighth decade Serum CK 2–4× normal AD
Distal lower extremity weakness (tibial EMG myopathic Titin
distribution) NCS normal AR (associated with more proximal
Upper extremities usually normal Muscle biopsy shows dystrophic weakness—LGMD2J)
Lifespan normal features and rimmed vacuoles
Titin absent in M-line of muscle
Onset fourth to eighth decade Serum CK is usually mildly elevated AD
Distal lower extremity weakness (tibial EMG reveals irritative myopathy Z-band alternatively spliced PDX
distribution) with progression to distal Muscle biopsies demonstrate rimmed motif-containing protein (ZASP)
arms and proximal muscles vacuoles and features of MFM
Onset childhood to third decade Serum CK is normal or slightly AD
Distal lower extremity weakness (ante- elevated Myosin heavy chain 7
rior tibial distribution) and neck flexors Muscle biopsies do not typically show
affected early rimmed vacuoles, but may show
May have cardiomyopathy hyaline bodies with accumulation of
myosin
Large deposits of myosin heavy chain
are seen in type 1 muscle fibers
Onset: second to third decade Serum CK 3–10× normal AR
Distal lower extremity weakness EMG myopathic GNE gene: UDP-N-acetylglucosamine
(anterior tibial distribution) 2-epimerase/N-acetylmannosamine
NCS normal
Mild distal upper limb weakness may kinase
Dystrophic features on muscle biopsy
be present early plus rimmed vacuoles and 15- to Allelic to hereditary inclusion body
Progression to other muscles sparing 19-nm filaments within vacuoles myopathy
quadriceps
Ambulation may be lost in 10–15 y
Onset: second to third decade Serum CK 20–100× normal AR
Lower extremity weakness in posterior EMG myopathic Allelic to LGMD2B (see Table 462e-7)
compartment muscles NCS normal Dysferlin
Progression leads to weakness in Muscle biopsy shows nonspecific
other muscle groups dystrophic features often with promi-
Ambulation lost after 10–15 y in about nent inflammatory cell infiltration; no
one-third of cases rimmed vacuoles
Distal lower extremity weakness Muscle biopsy may show rimmed X-linked
(anterior tibial distribution) vacuoles and features of MFM Filamin-C
Onset from early childhood to late Serum CKs can be normal or moder- Genetically heterogeneous
adult life ately elevated AD
Weakness may be distal, proximal, or EMG is myopathic and often associ-  Myotilin (also known as LGMD 1A)
generalized ated with myotonic discharges
 ZASP (see Markesbery-Griggs distal
Cardiomyopathy and respiratory Muscle biopsy demonstrates abnor- myopathy)
involvement is not uncommon mal accumulation of desmin and
other proteins, rimmed vacuoles, and  Filamin-C
myofibrillar degeneration  Desmin
  Alpha B crystallin
 Bag3
 Titin
 DNAJB6
 TNPO3
AR
 Desmin
X-linked
 FHL1
Copyright © 2015 McGraw-Hill Education. All rights reserved.
 462e-14 clubbed feet may be present. Most patients exhibit progressive weak-
ness, some requiring wheelchairs. Progressive external ophthalmople-
gia with ptosis and varying degrees of extraocular muscle impairment
are characteristic of both the neonatal and the late-infantile forms. A
PART 17
third variant, the late childhood–adult form, has an onset in the second
or third decade. Patients have full extraocular muscle movements and
rarely exhibit ptosis. There is mild, slowly progressive limb weakness
that may be distally predominant (some of these patients have been
classified as having Charcot-Marie-Tooth disease type 2 [CMT2;
Chap. 459]).
Normal or slightly elevated CK levels occur in each of the forms.
Neurologic Disorders
Nerve conduction studies may reveal reduced amplitudes of distal
compound muscle action potentials, in particular in adult-onset
cases that resemble CMT2. EMG studies often give distinctive results,
showing positive sharp waves and fibrillation potentials, complex and
repetitive discharges, and rarely myotonic discharges. Muscle biopsy
specimens in longitudinal section demonstrate rows of central nuclei,
often surrounded by a halo. In transverse sections, central nuclei are
found in 25–80% of muscle fibers.
A gene for the neonatal form of centronuclear myopathy has been
localized to Xq28; this gene encodes myotubularin, a protein tyrosine
phosphatase. Missense, frameshift, and splice-site mutations predict
loss of myotubularin function in affected individuals. Carrier identifi-
cation and prenatal diagnosis are possible. Autosomal recessive forms
are caused by mutations in BIB1 that encodes for amphyphysin-2,
whereas some autosomal dominant cases, which are allelic to a form
of CMT2, are associated with mutations in the gene that encodes
dynamin-2. No specific medical treatments are available at this time.
DISORDERS OF MUSCLE ENERGY METABOLISM
There are two principal sources of energy for skeletal muscle—fatty
acids and glucose. Abnormalities in either glucose or lipid utilization
can be associated with distinct clinical presentations that can range
from an acute, painful syndrome with rhabdomyolysis and myoglo-
binuria to a chronic, progressive muscle weakness simulating muscular
dystrophy.
GLYCOGEN STORAGE AND GLYCOLYTIC DEFECTS
Disorders of Glycogen Storage Causing Progressive Weakness •  α-
Glucosidase, or acid maltase, deficiency (Pompe’s disease)  Three clinical (warm-up) or brief periods of rest, allowing for the start of the
forms of α-glucosidase, or acid maltase, deficiency (type II glycogeno-
sis) can be distinguished. The infantile form is the most common, with
onset of symptoms in the first 3 months of life. Infants develop severe
muscle weakness, cardiomegaly, hepatomegaly, and respiratory insuf-
ficiency. Glycogen accumulation in motor neurons of the spinal cord
and brainstem contributes to muscle weakness. Death usually occurs
by 1 year of age. In the childhood form, the picture resembles muscu-
lar dystrophy. Delayed motor milestones result from proximal limb
muscle weakness and involvement of respiratory muscles. The heart
may be involved, but the liver and brain are unaffected. The adult form
usually begins in the third or fourth decade but can present as late as
the seventh decade. Respiratory failure and diaphragmatic weakness
are often initial manifestations, heralding progressive proximal muscle
weakness. The heart and liver are not involved.
The serum CK level is 2–10 times normal in infantile or childhood-
onset Pompe’s disease but can be normal in adult-onset cases. EMG
examination demonstrates a myopathic pattern, but other features are
especially distinctive, including myotonic discharges, trains of fibril-
lation and positive waves, and complex repetitive discharges. EMG
discharges are very prominent in the paraspinal muscles. The muscle
biopsy in infants typically reveals vacuoles containing glycogen and
the lysosomal enzyme acid phosphatase. Electron microscopy reveals
membrane-bound and free tissue glycogen. However, muscle biop-
sies in late-onset Pompe’s disease may demonstrate only nonspecific
abnormalities. Enzyme analysis of dried blood spots is a sensitive
technique to screen for Pompe’s disease. A definitive diagnosis is LIPID AS AN ENERGY SOURCE AND ASSOCIATED DEFECTS
established by enzyme assay in muscle or cultured fibroblasts or by Lipid is an important muscle energy source during rest and dur-
genetic testing.
Copyright © 2015 McGraw-Hill Education. All rights reserved.
Pompe’s disease is inherited as an autosomal recessive disorder
caused by mutations of the α-glucosidase gene. Enzyme replacement
therapy (ERT) with IV recombinant human α-glucosidase has been
shown to be beneficial in infantile-onset Pompe’s disease. Clinical
benefits in the infantile disease include reduced heart size, improved
muscle function, reduced need for ventilatory support, and longer life.
In late-onset cases, ERT has not been associated with the dramatic
response that can be seen in classic infantile Pompe’s disease, yet it
appears to stabilize the disease process.
Other glycogen storage diseases with progressive weakness  In de-
branching enzyme deficiency (type III glycogenosis), a slowly progres-
sive form of muscle weakness can develop after puberty. Rarely,
myoglobinuria may be seen. Patients are usually diagnosed in infancy,
however, because of hypotonia and delayed motor milestones, hepa-
tomegaly, growth retardation, and hypoglycemia. Branching enzyme
deficiency (type IV glycogenosis) is a rare and fatal glycogen storage
disease characterized by failure to thrive and hepatomegaly. Hypotonia
and muscle wasting may be present, but the skeletal muscle manifesta-
tions are minor compared to liver failure.
Disorders of Glycolysis Causing Exercise Intolerance  Several glycolytic
defects are associated with recurrent myoglobinuria: myophosphory-
lase deficiency (type V glycogenosis), phosphofructokinase deficiency
(type VII glycogenosis), phosphoglycerate kinase deficiency, phosphory-
lase kinase deficiency (type IX glycogenosis), phosphoglycerate mutase
deficiency (type X glycogenosis), lactate dehydrogenase deficiency (gly-
cogenosis type XI), and β-enolase deficiency. Myophosphorylase defi-
ciency, also known as McArdle’s disease, is by far the most common
of the glycolytic defects associated with exercise intolerance. These
glycolytic defects result in a common failure to support energy pro-
duction at the initiation of exercise, although the exact site of energy
failure remains controversial.
Clinical muscle manifestations in these conditions usually begin
in adolescence. Symptoms are precipitated by brief bursts of high-
intensity exercise such as running or lifting heavy objects. A history
of myalgia and muscle stiffness usually precedes the intensely painful
muscle contractures, which may be followed by myoglobinuria. Acute
renal failure accompanies significant pigmenturia.
Certain features help distinguish some enzyme defects. In McArdle’s
disease, exercise tolerance can be enhanced by a slow induction phase
“second-wind” phenomenon (switching to utilization of fatty acids).
Varying degrees of hemolytic anemia accompany deficiencies of both
phosphofructokinase (mild) and phosphoglycerate kinase (severe). In
phosphoglycerate kinase deficiency, the usual clinical presentation is a
seizure disorder associated with mental retardation; exercise intoler-
ance is an infrequent manifestation.
In all of these conditions, the serum CK levels fluctuate widely and
may be elevated even during symptom-free periods. CK levels >100
times normal are expected, accompanying myoglobinuria. All patients
with suspected glycolytic defects leading to exercise intolerance should
undergo a forearm exercise test. An impaired rise in venous lactate is
highly indicative of a glycolytic defect. In lactate dehydrogenase defi-
ciency, venous levels of lactate do not increase, but pyruvate rises to
normal. A definitive diagnosis of glycolytic disease is made by muscle
biopsy and subsequent enzyme analysis or by genetic testing.
Myophosphorylase deficiency, phosphofructokinase deficiency, and
phosphoglycerate mutase deficiency are inherited as autosomal reces-
sive disorders. Phosphoglycerate kinase deficiency is X-linked recessive.
Mutations can be found in the respective genes encoding the abnormal
proteins in each of these disorders.
Training may enhance exercise tolerance, perhaps by increasing
perfusion to muscle. Dietary intake of free glucose or fructose prior to
activity may improve function but care must be taken to avoid obesity
from ingesting too many calories.
ing prolonged, submaximal exercise. Fatty acids are derived from
circulating very-low-density lipoprotein (VLDL) in the blood or from codes for 22 transfer RNAs, 2 ribosomal RNAs, and 13 polypeptides 462e-15
triglycerides stored in muscle fibers. Oxidation of fatty acids occurs in of the respiratory chain enzymes. The genetics of mitochondrial dis-
the mitochondria. To enter the mitochondria, a fatty acid must first be eases differ from the genetics of chromosomal disorders. The DNA of

Chapter 462e Muscular Dystrophies and Other Muscle Diseases

converted to an “activated fatty acid,” acyl-CoA. The acyl-CoA must mitochondria is directly inherited from the cytoplasm of the gametes,
be linked with carnitine by the enzyme carnitine palmitoyltransferase mainly from the oocyte. The sperm contributes very little of its mito-
(CPT) I for transport into the mitochondria. CPT I is present on the chondria to the offspring at the time of fertilization. Thus, mitochon-
inner side of the outer mitochondrial membrane. Carnitine is removed drial genes are derived almost exclusively from the mother, accounting
by CPT II, an enzyme attached to the inside of the inner mitochondrial for maternal inheritance of some mitochondrial disorders.
membrane, allowing transport of acyl-CoA into the mitochondrial Patients with mitochondrial myopathies have clinical manifesta-
matrix for β-oxidation. tions that usually fall into three groups: chronic progressive external
ophthalmoplegia (CPEO), skeletal muscle–CNS syndromes, and pure
Carnitine Palmitoyltransferase Deficiency  CPT II deficiency is the most myopathy simulating muscular dystrophy or metabolic myopathy.
common recognizable cause of recurrent myoglobinuria, more com-
mon than the glycolytic defects. Onset is usually in the teenage years
PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA SYNDROMES
or early twenties. Muscle pain and myoglobinuria typically occur after
WITH RAGGED RED FIBERS
prolonged exercise but can also be precipitated by fasting or infections;
The single most common sign of a mitochondrial myopathy is CPEO,
up to 20% of patients do not exhibit myoglobinuria, however. Strength
occurring in >50% of all mitochondrial myopathies. Varying degrees
is normal between attacks. In contrast to disorders caused by defects
of ptosis and weakness of extraocular muscles are seen, usually in the
in glycolysis, in which muscle cramps follow short, intense bursts of
absence of diplopia, a point of distinction from disorders with fluctuat-
exercise, the muscle pain in CPT II deficiency does not occur until the
ing eye weakness (e.g., myasthenia gravis).
limits of utilization have been exceeded and muscle breakdown has
already begun. Episodes of rhabdomyolysis may produce severe weak-
KEARNS-SAYRE SYNDROME (KSS)
ness. In young children and newborns, CPT II deficiency can present
KSS is a widespread multiorgan system disorder with a defined triad of
with a very severe clinical picture including hypoketotic hypoglycemia,
clinical findings: onset before age 20, CPEO, and pigmentary retinopa-
cardiomyopathy, liver failure, and sudden death.
thy, plus one or more of the following features: complete heart block,
Serum CK levels and EMG findings are both usually normal
cerebrospinal fluid (CSF) protein >1 g/L (100 mg/dL), or cerebellar
between episodes. A normal rise of venous lactate during forearm
ataxia. Some patients with CPEO and ragged red fibers may not fulfill
exercise distinguishes this condition from glycolytic defects, especially
all of the criteria for KSS. The cardiac disease includes syncopal attacks
myophosphorylase deficiency. Muscle biopsy does not show lipid
and cardiac arrest related to the abnormalities in the cardiac conduc-
accumulation and is usually normal between attacks. The diagnosis
tion system: prolonged intraventricular conduction time, bundle
requires direct measurement of muscle CPT or genetic testing.
branch block, and complete atrioventricular block. Death attributed
CPT II deficiency is much more common in men than women (5:1);
to heart block occurs in ~20% of the patients. Varying degrees of pro-
nevertheless, all evidence indicates autosomal recessive inheritance.
gressive limb muscle weakness and easy fatigability affect activities of
A mutation in the gene for CPT II (chromosome 1p36) causes the
daily living. Endocrine abnormalities are common, including gonadal
disease in some individuals. Attempts to improve exercise tolerance
dysfunction in both sexes with delayed puberty, short stature, and
with frequent meals and a low-fat, high-carbohydrate diet, or by sub-
infertility. Diabetes mellitus is a cardinal sign of mitochondrial disor-
stituting medium-chain triglycerides in the diet, have not proven to
ders and is estimated to occur in 13% of KSS patients. Other less com-
be beneficial.
mon endocrine disorders include thyroid disease, hyperaldosteronism,
Myoadenylate Deaminase Deficiency  The muscle enzyme myoadenylate Addison’s disease, and hypoparathyroidism. Both mental retardation
deaminase converts adenosine-5′-monophosphate (5′-AMP) to ino- and dementia are common accompaniments to this disorder. Serum
sine monophosphate (IMP) with liberation of ammonia. Myoadenylate CK levels are normal or slightly elevated. Serum lactate and pyruvate
deaminase may play a role in regulating adenosine triphosphate (ATP) levels may be elevated. EMG is myopathic. Nerve conduction studies
levels in muscles. Most individuals with myoadenylate deaminase defi- may be abnormal related to an associated neuropathy. Muscle biopsies
ciency have no symptoms. There have been a few reports of patients reveal ragged red fibers, highlighted in oxidative enzyme stains, many
with this disorder who have exercise-exacerbated myalgia and myoglo- showing defects in cytochrome oxidase. By electron microscopy, there
binuria. Many questions have been raised about the clinical effects of are increased numbers of mitochondria that often appear enlarged and
myoadenylate deaminase deficiency, and, specifically, its relationship contain paracrystalline inclusions.
to exertional myalgia and fatigability, but there is no consensus. KSS is a sporadic disorder. The disease is caused by single mtDNA
deletions presumed to arise spontaneously in the ovum or zygote.
The most common deletion, occurring in about one-third of patients,
MITOCHONDRIAL MYOPATHIES removes 4977 bp of contiguous mtDNA. Monitoring for cardiac
In 1972, Olson and colleagues recognized that muscle fibers with sig- conduction defects is critical. Prophylactic pacemaker implantation
nificant numbers of abnormal mitochondria could be highlighted with is indicated when ECGs demonstrate a bifascicular block. In KSS, no
the modified trichrome stain; the term ragged red fibers was coined. benefit has been shown for supplementary therapies, including multi-
By electron microscopy, the mitochondria in ragged red fibers are vitamins or coenzyme Q10. Of all the proposed options, exercise might
enlarged and often bizarrely shaped and have crystalline inclusions. be the most applicable but must be approached cautiously because of
Since that seminal observation, the understanding of these disorders defects in the cardiac conduction system.
of muscle and other tissues has expanded (Chap. 82).
Mitochondria play a key role in energy production. Oxidation of PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA (PEO)
the major nutrients derived from carbohydrate, fat, and protein leads This condition is caused by nuclear DNA mutations affecting mtDNA
to the generation of reducing equivalents. The latter are transported copy number and integrity and is thus inherited in a Mendelian
through the respiratory chain in the process known as oxidative phos- fashion. Onset is usually after puberty. Fatigue, exercise intolerance,
phorylation. The energy generated by the oxidation-reduction reac- and complaints of muscle weakness are typical. Some patients notice
tions of the respiratory chain is stored in an electrochemical gradient swallowing problems. The neurologic examination confirms the ptosis
coupled to ATP synthesis. and ophthalmoplegia, usually asymmetric in distribution. A senso-
A novel feature of mitochondria is their genetic composition. Each rineural hearing loss may be encountered. Mild facial, neck flexor,
mitochondrion possesses a DNA genome that is distinct from that of and proximal weakness are typical. Rarely, respiratory muscles may
the nuclear DNA. Human mitochondrial DNA (mtDNA) consists of be progressively affected and may be the direct cause of death. Serum
a double-strand, circular molecule comprising 16,569 base pairs. It CK is normal or mildly elevated. The resting lactate level is normal or
Copyright © 2015 McGraw-Hill Education. All rights reserved.
 462e-16 slightly elevated but may rise excessively after exercise. CSF protein
is normal. The EMG is myopathic, and nerve conduction studies are
usually normal. Ragged red fibers are prominently displayed in the
muscle biopsy. Southern blots of muscle reveal a normal mtDNA band
PART 17
are present predominantly in the occipital and parietal lobes. Strict
vascular territories are not respected, and cerebral angiography fails to
demonstrate lesions of the major cerebral blood vessels.
MELAS is caused by maternally inherited point mutations of

at 16.6 kb and several additional mtDNA deletion bands with genomes
varying from 0.5 to 10 kb.
This autosomal dominant form of CPEO has been linked to loci
on three chromosomes: 4q35, 10q24, and 15q22–26. In the chromo-
some 4q-related form of disease, mutations of the gene encoding the
heart and skeletal muscle–specific isoform of the adenine nucleotide
translocator 1 (ANT1) gene are found. This highly abundant mito-
Neurologic Disorders
mitochondrial tRNA genes. Most of the tRNA mutations are lethal,
accounting for the paucity of multigeneration families with this
syndrome. The A3243G point mutation in tRNALeu(UUR) is the most
common, occurring in ~80% of MELAS cases. About 10% of MELAS
patients have other mutations of the tRNALeu(UUR) gene, including
3252G, 3256T, 3271C, and 3291C. Other tRNA gene mutations have
also been reported in MELAS, including G583A tRNAPhe, G1642A

chondrial protein forms a homodimeric inner mitochondrial channel tRNAVal, G4332A tRNAGlu, and T8316C tRNALys. Mutations have also
through which adenosine diphosphate (ADP) enters and ATP leaves been reported in mtDNA polypeptide-coding genes. Two mutations
the mitochondrial matrix. In the chromosome 10q–related disorder, were found in the ND5 subunit of complex I of the respiratory chain.
mutations of the gene C10orf2 are found. Its gene product, twinkle, A missense mutation has been reported at mtDNA position 9957 in the
co-localizes with the mtDNA and is named for its punctate, starlike gene for subunit III of cytochrome C oxidase. No specific treatment is
staining properties. The function of twinkle is presumed to be criti- available. Supportive treatment is essential for the strokelike episodes,
cal for lifetime maintenance of mitochondrial integrity. In the cases seizures, and endocrinopathies.
mapped to chromosome 15q, a mutation affects the gene encoding
mtDNA polymerase (POLG), an enzyme important in mtDNA replica- PURE MYOPATHY SYNDROMES
tion. Autosomal recessive PEO has also been described with mutations Muscle weakness and fatigue can be the predominant manifesta-
in the POLG gene. Point mutations have been identified within various tions of mtDNA mutations. When the condition affects exclusively
mitochondrial tRNA (Leu, Ile, Asn, Trp) genes in families with mater- muscle (pure myopathy), the disorder becomes difficult to recognize.
nal inheritance of PEO. Occasionally, mitochondrial myopathies can present with recurrent
Exercise may improve function but will depend on the patient’s myoglobinuria without fixed weakness and thus resemble a glycogen
ability to participate. storage disorder or CPT deficiency.
Mitochondrial DNA Depletion Syndromes  Mitochondrial DNA deple-
MITOCHONDRIAL DNA SKELETAL MUSCLE–CENTRAL NERVOUS SYSTEM tion syndrome (MDS) is a heterogeneous group of disorders that are
SYNDROMES inherited in an autosomal recessive fashion and can present in infancy
Myoclonic Epilepsy with Ragged Red Fibers (MERRF)  The onset of or adults. MDS can be caused by mutations in genes (TK2, DGUOK,
MERRF is variable, ranging from late childhood to middle adult life. RRM2B, TYMP, SUCLA1, and SUCLA2) that lead to depletion of
Characteristic features include myoclonic epilepsy, cerebellar ataxia, pools of mitochondrial deoxyribonucleotide (dNTP) pools necessary
and progressive muscle weakness. The seizure disorder is an integral for mtDNA replication The other major cause of MDS is a set of
part of the disease and may be the initial symptom. Cerebellar ataxia mutations in genes essential for mtDNA replication (e.g., POLG1 and
precedes or accompanies epilepsy. It is slowly progressive and general- C10orf2). The clinical phenotypes associated with MDS vary. Patients
ized. The third major feature of the disease is muscle weakness in a may develop a severe encephalopathy (e.g., Leigh’s syndrome), PEO,
limb-girdle distribution. Other more variable features include demen- an isolated myopathy, myo-neuro-gastrointestinal-encephalopathy
tia, peripheral neuropathy, optic atrophy, hearing loss, and diabetes (MNGIE), and a sensory neuropathy with ataxia.
mellitus.
Serum CK levels are normal or slightly increased. The serum lac- DISORDERS OF MUSCLE MEMBRANE EXCITABILITY
tate may be elevated. EMG is myopathic, and in some patients nerve
conduction studies show a neuropathy. The electroencephalogram is Muscle membrane excitability is affected in a group of disorders
abnormal, corroborating clinical findings of epilepsy. Typical ragged referred to as channelopathies. The heart may also be involved, result-
red fibers are seen on muscle biopsy. MERRF is caused by maternally ing in life-threatening complications (Table 462e-10).
inherited point mutations of mitochondrial tRNA genes. The most
common mutation found in 80% of MERRF patients is an A to G CALCIUM CHANNEL DISORDERS OF MUSCLE
substitution at nucleotide 8344 of tRNA lysine (A8344G tRNAlys). Hypokalemic Periodic Paralysis (HypoKPP)  Onset occurs at adolescence.
Other tRNAlys mutations include base-pair substitutions T8356C and Men are more often affected because of decreased penetrance in
G8363A. Only supportive treatment is possible, with special attention women. Episodic weakness with onset after age 25 is almost never
to epilepsy. due to periodic paralyses, with the exception of thyrotoxic periodic
paralysis (see below). Attacks are often provoked by meals high in
Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike carbohydrates or sodium and may accompany rest following pro-
Episodes (MELAS)  MELAS is the most common mitochondrial enceph- longed exercise. Weakness usually affects proximal limb muscles more
alomyopathy. The term strokelike is appropriate because the cerebral than distal. Ocular and bulbar muscles are less likely to be affected.
lesions do not conform to a strictly vascular distribution. The onset Respiratory muscles are usually spared, but when they are involved,
in the majority of patients is before age 20. Seizures, usually partial the condition may prove fatal. Weakness may take as long as 24 h to
motor or generalized, are common and may represent the first clearly resolve. Life-threatening cardiac arrhythmias related to hypokalemia
recognizable sign of disease. The cerebral insults that resemble strokes may occur during attacks. As a late complication, patients commonly
cause hemiparesis, hemianopia, and cortical blindness. A presump- develop severe, disabling proximal lower extremity weakness.
tive stroke occurring before age 40 should place this mitochondrial Attacks of thyrotoxic periodic paralysis resemble those of primary
encephalomyopathy high in the differential diagnosis. Associated HypoKPP. Despite a higher incidence of thyrotoxicosis in women,
conditions include hearing loss, diabetes mellitus, hypothalamic men, particularly those of Asian descent, are more likely to manifest
pituitary dysfunction causing growth hormone deficiency, hypothy- this complication. Attacks abate with treatment of the underlying
roidism, and absence of secondary sexual characteristics. In its full thyroid condition.
expression, MELAS leads to dementia, a bedridden state, and a fatal A low serum potassium level during an attack, excluding second-
outcome. Serum lactic acid is typically elevated. The CSF protein is ary causes, establishes the diagnosis. Interattack muscle biopsies show
also increased but is usually ≤1 g/L (100 mg/dL). Muscle biopsies show the presence of single or multiple centrally placed vacuoles or tubular
ragged red fibers. Neuroimaging demonstrates basal ganglia calcifica- aggregates. Provocative tests with glucose and insulin to establish a
tion in a high percentage of cases. Focal lesions that mimic infarction diagnosis are usually not necessary and are potentially hazardous.
Copyright © 2015 McGraw-Hill Education. All rights reserved.
  TABLE 462e-10    Clinical Features of Periodic Paralysis and Nondystrophic Myotonias 462e-17
Calcium Channel Sodium Channel Potassium Channel

Chapter 462e Muscular Dystrophies and Other Muscle Diseases

Feature Hypokalemic PP Hyperkalemic PP Paramyotonia Congenita Andersen-Tawil Syndromea
Mode of inheritance AD AD AD AD
Age of onset Adolescence Early childhood Early childhood Early childhood
Myotoniab No Yes Yes No
Episodic weakness Yes Yes Yes Yes
Frequency of attacks of weakness Daily to yearly May be 2–3/d With cold, usually rare Daily to yearly
Duration of attacks of weakness 2–12 h From 1–2 h to >1 d 2–24 h 2–24 h
Serum K+ level during attacks of Decreased Increased or normal Usually normal Variable
weakness
Effect of K+ loading No change Increased myotonia, then Increased myotonia No change
weakness
Effect of muscle cooling No change Increased myotonia Increased myotonia, then No change
weakness
Fixed weakness Yes Yes Yes Yes
Dysmorphic features and cardiac arrhythmias are distinguishing features (see text).  May be paradoxical in paramyotonia congenita.
a b

Abbreviations: AD, autosomal dominant; PP, periodic paralysis.

In the midst of an attack of weakness, motor conduction studies

may demonstrate reduced amplitudes, whereas EMG may show elec-
trical silence in severely weak muscles. In between attacks, the EMG
and routine nerve conduction studies are normal. However, a long
exercise test may demonstrate a decrementing amplitude, and myo-
pathic MUAPs may be seen on EMG in patients with fixed weakness. Sodium channel α subunit
HypoKPP is caused by mutations in either of two genes. HypoKPP I II III IV
type 1, the most common form, is inherited as an autosomal dominant
disorder with incomplete penetrance. These patients have muta- Outside
tions in the voltage-sensitive, skeletal muscle calcium channel gene, 1 234 5 6
CALCL1A3 (Fig. 462e-8). Approximately 10% of cases are HypoKPP
type 2, arising from mutations in the voltage-sensitive sodium channel 1
Inside
gene (SCN4A). In either instance, the mutations lead to an abnormal NH3 COO2
gating pore current that predisposes the muscle cell to depolarize when
potassium levels are low. It is also now recognized that some cases of HyperKPP PC PAM
thyrotoxic HypoKPP are caused by genetic variants in a potassium
channel (Kir 2.6), whose expression is regulated by thyroid hormone. Calcium channel α subunit

The chloride channel is envisioned to have 10 membrane-spanning I II III IV

domains. The positions of mutations causing dominantly and reces- H H G
Outside
sively inherited myotonia congenita are indicated, along with muta-
R R
tions that cause this disease in mice and goats.
Inside
TREATMENT Hypokalemic Periodic Paralysis 1
NH3
The acute paralysis improves after the administration of potassium. COO2
Muscle strength and ECG should be monitored. Oral KCl (0.2–0.4 Chloride channel
mmol/kg) should be given every 30 min. Only rarely is IV therapy 2
Δ Outside
necessary (e.g., when swallowing problems or vomiting is pres-
ent). Administration of potassium in a glucose solution should be
1 3 4 5 6 7 8 9 11 12
avoided because it may further reduce serum potassium levels.
Mannitol is the preferred vehicle for administration of IV potas- Δ
13 Inside
sium. The long-term goal of therapy is to avoid attacks. This may 10
reduce late-onset, fixed weakness. Patients should be made aware 1
NH3 Δ
COO2
of the importance of a low-carbohydrate, low-sodium diet and
consequences of intense exercise. Prophylactic administration of Myotonia Congenita Myotonia Congenita ADR (murine)
acetazolamide (125–1000 mg/d in divided doses) reduces or may Dominant Recessive insertion
abolish attacks in HypoKPP type 1. Paradoxically the potassium is Myotonic goat adrmto (murine)
Ala Pro stop
lowered, but this is offset by the beneficial effect of metabolic aci-
dosis. If attacks persist on acetazolamide, oral KCl should be added. Figure 462e-8  The sodium and calcium channels are depicted
Some patients require treatment with triamterene (25–100 mg/d) or here as containing four homologous domains, each with six
spironolactone (25–100 mg/d). However, in patients with HypoKPP membrane-spanning segments. The fourth segment of each domain
type 2, attacks of weakness can be exacerbated with acetazolamide. bears positive charges and acts as the “voltage sensor” for the chan-
nel. The association of the four domains is thought to form a pore
through which ions pass. Sodium channel mutations are shown along
SODIUM CHANNEL DISORDERS OF MUSCLE with the phenotype that they confer. HyperKPP, hyperkalemic period-
Hyperkalemic Periodic Paralysis (HyperKPP)  The term hyperkalemic is ic paralysis; PC, paramyotonia congenita; PAM, potassium-aggravated
misleading because patients are often normokalemic during attacks. myotonia. See text for details.
Copyright © 2015 McGraw-Hill Education. All rights reserved.
 462e-18 The fact that attacks are precipitated by potassium administration best
defines the disease. The onset is in the first decade; males and females
are affected equally. Attacks are brief and mild, usually lasting 30 min
to 4 ho. Weakness affects proximal muscles, sparing bulbar muscles.
PART 17
Attacks are precipitated by rest following exercise and fasting. In a
variant of this disorder, the predominant symptom is myotonia with-
out weakness (potassium-aggravated myotonia). The symptoms are
aggravated by cold, and myotonia makes the muscles stiff and painful.
This disorder can be confused with paramyotonia congenita, myotonia
congenita, and proximal myotonic myopathy (DM2).
Potassium may be slightly elevated but may also be normal during
Neurologic Disorders
an attack. As in HypoKPP, nerve conduction studies in HyperKPP
muscle may demonstrate reduced motor amplitudes and the EMG
may be silent in very weak muscles. In between attacks of weakness,
the conduction studies are normal. The EMG will often demonstrate
myotonic discharges during and between attacks.
The muscle biopsy shows vacuoles that are smaller, less numerous,
and more peripheral compared to the hypokalemic form or tubular
aggregates. Provocative tests by administration of potassium can induce
weakness but are usually not necessary to establish the diagnosis.
HyperKPP and potassium-aggravated myotonia are inherited as autoso-
mal dominant disorders. Mutations of the voltage-gated sodium chan-
nel SCN4A gene (Fig. 462e-8) cause these conditions. For patients with
frequent attacks, acetazolamide (125–1000 mg/d) is helpful. We have
found mexiletine to be helpful in patients with significant myotonia.
Paramyotonia Congenita  In paramyotonia congenita (PC), the attacks
of weakness are cold-induced or occur spontaneously and are mild.
Myotonia is a prominent feature but worsens with muscle activ-
ity (paradoxical myotonia). This is in contrast to classic myotonia
in which exercise alleviates the condition. Attacks of weakness are
seldom severe enough to require emergency room treatment. Over
time patients develop interattack weakness as they do in other forms
of periodic paralysis. PC is usually associated with normokalemia or
hyperkalemia.
Serum CK is usually mildly elevated. Routine sensory and motor
nerve conduction studies are normal. Short exercise test may be abnor-
mal however, and cooling of the muscle often dramatically reduces the
amplitude of the compound muscle action potentials. EMG reveals
diffuse myotonic potentials in PC. Upon local cooling of the muscle,
the myotonic discharges disappear as the patient becomes unable to
activate MUAPs.
PC is inherited as an autosomal dominant condition; voltage-gated
sodium channel mutations (Fig. 462e-8) are responsible, and thus this
disorder is allelic with HyperKPP and potassium-aggravated myo-
tonia. Patients with PC seldom seek treatment during attacks. Oral
administration of glucose or other carbohydrates hastens recovery.
Because interattack weakness may develop after repeated episodes,
prophylactic treatment is usually indicated. Thiazide diuretics (e.g.,
chlorothiazide, 250–1000 mg/d) and mexiletine (slowly increase dose
from 450 mg/d) are reported to be helpful. Patients should be advised
to increase carbohydrates in their diet.
POTASSIUM CHANNEL DISORDERS
Andersen-Tawil Syndrome  This rare disease is characterized by episodic
weakness, cardiac arrhythmias, and dysmorphic features (short stat-
ure, scoliosis, clinodactyly, hypertelorism, small or prominent low-set
ears, micrognathia, and broad forehead). The cardiac arrhythmias
are potentially serious and life threatening. They include long QT,
ventricular ectopy, bidirectional ventricular arrhythmias, and tachy-
cardia. For many years, the classification of this disorder was uncertain may lead to an erroneous diagnosis of amyotrophic lateral sclerosis. A
because episodes of weakness are associated with elevated, normal, or
reduced levels of potassium during an attack. In addition, the potas-
sium levels differ among kindreds but are consistent within a fam-
ily. Inheritance is autosomal dominant, with incomplete penetrance
and variable expressivity. The disease is caused by mutations of the
inwardly rectifying potassium channel (Kir 2.1) gene that heighten
muscle cell excitability. The treatment is similar to that for other forms (Graves’ ophthalmopathy). Serum CK levels are not elevated in thy-
of periodic paralysis and must include cardiac monitoring. The epi-
sodes of weakness may differ between patients because of potassium
Copyright © 2015 McGraw-Hill Education. All rights reserved.
variability. Acetazolamide may decrease the attack frequency and
severity.
CHLORIDE CHANNEL DISORDERS
Two forms of this disorder, autosomal dominant (Thomsen’s disease)
and autosomal recessive (Becker disease), are related to the same gene
abnormality. Symptoms are noted in infancy and early childhood. The
severity lessens in the third to fourth decade. Myotonia is worsened by
cold and improved by activity. The gait may appear slow and labored
at first but improves with walking. In Thomsen’s disease, muscle
strength is normal, but in Becker disease, which is usually more severe,
there may be muscle weakness. Muscle hypertrophy is usually present.
Myotonic discharges are prominently displayed by EMG recordings.
Serum CK is normal or mildly elevated. The muscle biopsy shows
hypertrophied fibers. The disease is inherited as dominant or reces-
sive and is caused by mutations of the chloride channel gene (Fig.
462e-8) that increase muscle cell excitability. Many patients will not
require treatment and learn that the symptoms improve with activity.
Medications that can be used to decrease myotonia include quinine,
phenytoin, and mexiletine.
ENDOCRINE AND METABOLIC MYOPATHIES
Many endocrine disorders cause weakness. Muscle fatigue is more
common than true weakness. The cause of weakness in these disorders
is not well defined. It is not even clear that weakness results from dis-
ease of muscle as opposed to another part of the motor unit, since the
serum CK level is often normal (except in hypothyroidism) and the
muscle histology is characterized by atrophy rather than destruction of
muscle fibers. Nearly all endocrine myopathies respond to treatment.
THYROID DISORDERS
(See also Chap. 405) Abnormalities of thyroid function can cause a
wide array of muscle disorders. These conditions relate to the impor-
tant role of thyroid hormones in regulating the metabolism of carbo-
hydrates and lipids as well as the rate of protein synthesis and enzyme
production. Thyroid hormones also stimulate calorigenesis in muscle,
increase muscle demand for vitamins, and enhance muscle sensitivity
to circulating catecholamines.
Hypothyroidism  Patients with hypothyroidism have frequent muscle
complaints, and proximal muscle weakness occurs in about one-
third of them. Muscle cramps, pain, and stiffness are common. Some
patients have enlarged muscles. Features of slow muscle contraction
and relaxation occur in 25% of patients; the relaxation phase of muscle
stretch reflexes is characteristically prolonged and best observed at the
ankle or biceps brachii reflexes. The serum CK level is often elevated
(up to 10 times normal), even when there is minimal clinical evidence
of muscle disease. EMG is typically normal. The cause of muscle
enlargement has not been determined, and muscle biopsy shows no
distinctive morphologic abnormalities.
Hyperthyroidism  Patients who are thyrotoxic commonly have proxi-
mal muscle weakness and atrophy on examination, but they rarely
complain of myopathic symptoms. Activity of deep tendon reflexes
may be enhanced. Bulbar, respiratory, and even esophageal muscles
may occasionally be affected, causing dysphagia, dysphonia, and aspi-
ration. When bulbar involvement occurs, it is usually accompanied by
chronic proximal limb weakness, but occasionally it presents in the
absence of generalized thyrotoxic myopathy. Fasciculations may be
apparent and, when coupled with increased muscle stretch reflexes,
form hypokalemic periodic paralysis can occur in patients who are thy-
rotoxic. Recently, mutations in the KCNJ18 gene that encodes for the
inwardly rectifying potassium channel, Kir 2.6, have been discovered
in up to a third of cases. Other neuromuscular disorders that occur in
association with hyperthyroidism include myasthenia gravis (Chap.
461) and a progressive ocular myopathy associated with proptosis
rotoxic myopathy, the EMG is normal, and muscle histology usually
shows only atrophy of muscle fibers.
PARATHYROID DISORDERS Progressive external ophthalmoplegia is a distinctive finding. It has not 462e-19
(See also Chap. 424) been established that deficiency of other vitamins causes a myopathy.

Chapter 462e Muscular Dystrophies and Other Muscle Diseases

Hyperparathyroidism  Muscle weakness is an integral part of primary
and secondary hyperparathyroidism. Proximal muscle weakness, MYOPATHIES OF SYSTEMIC ILLNESS
muscle wasting, and brisk muscle stretch reflexes are the main features Systemic illnesses such as chronic respiratory, cardiac, or hepatic
of this endocrinopathy. Some patients develop neck extensor weakness failure are frequently associated with severe muscle wasting and com-
(part of the dropped head syndrome). Serum CK levels are usually plaints of weakness. Fatigue is usually a more significant problem than
normal or slightly elevated. Serum parathyroid hormone levels are weakness, which is typically mild.
elevated. Serum calcium and phosphorus levels show no correlation Myopathy may be a manifestation of chronic renal failure
with the clinical neuromuscular manifestations. Muscle biopsies show (CRF), independent of the better known uremic polyneuropathy.
only varying degrees of atrophy without muscle fiber degeneration. Abnormalities of calcium and phosphorus homeostasis and bone
metabolism in chronic renal failure result from a reduction in
Hypoparathyroidism  An overt myopathy due to hypocalcemia rarely
1,25-dihydroxyvitamin D, leading to decreased intestinal absorption
occurs. Neuromuscular symptoms are usually related to localized or
of calcium. Hypocalcemia, further accentuated by hyperphosphatemia
generalized tetany. Serum CK levels may be increased secondary to mus-
due to decreased renal phosphate clearance, leads to secondary hyper-
cle damage from sustained tetany. Hyporeflexia or areflexia is usually
parathyroidism. Renal osteodystrophy results from the compensatory
present and contrasts with the hyperreflexia in hyperparathyroidism.
hyperparathyroidism, which leads to osteomalacia from reduced cal-
ADRENAL DISORDERS cium availability and to osteitis fibrosa from the parathyroid hormone
(See also Chap. 406) Conditions associated with glucocorticoid excess excess. The clinical picture of the myopathy of CRF is identical to that
cause a myopathy; in fact, steroid myopathy is the most commonly of primary hyperparathyroidism and osteomalacia. There is proximal
diagnosed endocrine muscle disease. Glucocorticoid excess, either limb weakness with bone pain.
endogenous or exogenous (see “Drug-Induced Myopathies,” below), Gangrenous calcification represents a separate, rare, and sometimes
produces various degrees of proximal limb weakness. Muscle wasting fatal complication of CRF. In this condition, widespread arterial cal-
may be striking. A cushingoid appearance usually accompanies clinical cification occurs and results in ischemia. Extensive skin necrosis may
signs of myopathy. Histologic sections demonstrate muscle fiber atro- occur, along with painful myopathy and even myoglobinuria.
phy, preferentially affecting type 2b fibers, rather than degeneration
or necrosis of muscle fibers. Adrenal insufficiency commonly causes DRUG-INDUCED MYOPATHIES
muscle fatigue. The degree of weakness may be difficult to assess but is
Drug-induced myopathies are relatively uncommon in clinical prac-
typically mild. In primary hyperaldosteronism (Conn’s syndrome), neu-
tice with the exception of those caused by the cholesterol-lowering
romuscular complications are due to potassium depletion. The clinical
agents and glucocorticoids. Others impact practice to a lesser degree
picture is one of persistent muscle weakness. Long-standing hyperaldo-
but are important to consider in specific situations. Table 462e-11
steronism may lead to proximal limb weakness and wasting. Serum CK
provides a comprehensive list of drug-induced myopathies with their
levels may be elevated, and a muscle biopsy may demonstrate degener-
distinguishing features.
ating fibers, some with vacuoles. These changes relate to hypokalemia
and are not a direct effect of aldosterone on skeletal muscle. MYOPATHY FROM LIPID-LOWERING AGENTS
PITUITARY DISORDERS All classes of lipid-lowering agents have been implicated in muscle
(See also Chap. 403) Patients with acromegaly usually have mild toxicity, including fibrates (clofibrate, gemfibrozil), HMG-CoA reduc-
proximal weakness without muscle atrophy. Muscles often appear tase inhibitors (referred to as statins), niacin (nicotinic acid), and
enlarged but exhibit decreased force generation. The duration of acro- ezetimibe. Myalgia, malaise, and muscle tenderness are the most com-
megaly, rather than the serum growth hormone levels, correlates with mon manifestations. Muscle pain may be related to exercise. Patients
the degree of myopathy. may exhibit proximal weakness. Varying degrees of muscle necrosis
are seen, and in severe reactions rhabdomyolysis and myoglobinuria
DIABETES MELLITUS occur. Concomitant use of statins with fibrates and cyclosporine is
(See also Chap. 417) Neuromuscular complications of diabetes mel- more likely to cause adverse reactions than use of one agent alone.
litus are most often related to neuropathy, with cranial and peripheral Elevated serum CK is an important indication of toxicity. Muscle
nerve palsies or distal sensorimotor polyneuropathy. Diabetic amyot- weakness is accompanied by a myopathic EMG, and muscle necrosis
rophy is a clumsy term because the condition represents a neuropathy is observed by muscle biopsy. Severe myalgias, muscle weakness, sig-
affecting the proximal major nerve trunks and lumbosacral plexus. nificant elevations in serum CK (>three times baseline), and myoglo-
More appropriate terms for this disorder include diabetic proximal binuria are indications for stopping the drug. Patients usually improve
neuropathy and lumbosacral radiculoplexus neuropathy. with drug cessation, although this may take several weeks. Rare cases
The only notable myopathy of diabetes mellitus is ischemic infarc- continue to progress after the offending agent is discontinued. It is
tion of leg muscles, usually involving one of the thigh muscles but possible that in such cases the statin may have triggered an immune-
on occasion affecting the distal leg. This condition occurs in patients mediated necrotizing myopathy, as these individuals require aggres-
with poorly controlled diabetes and presents with abrupt onset of sive immunotherapy (e.g., prednisone and sometimes other agents)
pain, tenderness, and edema of one thigh. The area of muscle infarc- to improve and often relapse when these therapies are discontinued.
tion is hard and indurated. The muscles most often affected include Interestingly, antibodies directed against the 100-kDa HMG-CoA
the vastus lateralis, thigh adductors, and biceps femoris. Computed reductase receptor on muscle fibers have been identified in many of
tomography (CT) or MRI can demonstrate focal abnormalities in the these cases.
affected muscle. Diagnosis by imaging is preferable to muscle biopsy,
if possible, as hemorrhage into the biopsy site can occur. GLUCOCORTICOID-RELATED MYOPATHIES
Glucocorticoid myopathy occurs with chronic treatment or as “acute
VITAMIN DEFICIENCY quadriplegic” myopathy secondary to high-dose IV glucocorticoid use.
Vitamin D deficiency (Chap. 96e) due to decreased intake, decreased Chronic administration produces proximal weakness accompanied by
absorption, or impaired vitamin D metabolism (as occurs in renal dis- cushingoid manifestations, which can be quite debilitating; the chronic
ease) may lead to chronic muscle weakness. Pain reflects the underlying use of prednisone at a daily dose of ≥30 mg/d is most often associated
bone disease (osteomalacia). Vitamin E deficiency may result from with toxicity. Patients taking fluorinated glucocorticoids (triamcino-
malabsorption. Clinical manifestations include ataxic neuropathy lone, betamethasone, dexamethasone) appear to be at especially high
due to loss of proprioception and myopathy with proximal weakness. risk for myopathy. In chronic steroid myopathy, the serum CK is
Copyright © 2015 McGraw-Hill Education. All rights reserved.
 462e-20   TABLE 462e-11    Drug-Induced Myopathies Myopathy is a well-established complication of this agent. Patients pres-
ent with myalgias, muscle weakness, and atrophy affecting the thigh and
Drugs Major Toxic Reaction
calf muscles. The complication occurs in about 17% of patients treated
Lipid-lowering agents Drugs belonging to all three of the with doses of 1200 mg/d for 6 months. The introduction of protease
major classes of lipid-lowering agents
PART 17

  Fibric acid derivatives
  HMG-CoA reductase inhibitors
  Niacin (nicotinic acid)
Glucocorticoids
Neurologic Disorders
can produce a spectrum of toxicity:
asymptomatic serum creatine kinase
elevation, myalgias, exercise-induced
pain, rhabdomyolysis, and myoglo-
binuria.
Acute, high-dose glucocorticoid
treatment can cause acute quad-
inhibitors for treatment of HIV infection has led to lower doses of zid-
ovudine therapy and a decreased incidence of myopathy. Serum CK is
elevated and EMG is myopathic. Muscle biopsy shows ragged red fibers
with minimal inflammation; the lack of inflammation serves to distin-
guish zidovudine toxicity from HIV-related myopathy. If the myopathy
is thought to be drug related, the medication should be stopped or the
dosage reduced.

riplegic myopathy. These high doses

of steroids are often combined with
nondepolarizing neuromuscular DRUGS OF ABUSE AND RELATED MYOPATHIES
blocking agents but the weakness Myotoxicity is a potential consequence of addiction to alcohol and
can occur without their use. Chronic illicit drugs. Ethanol is one of the most commonly abused substances
steroid administration produces pre- with potential to damage muscle. Other potential toxins include
dominantly proximal weakness.
cocaine, heroin, and amphetamines. The most deleterious reactions
Nondepolarizing neuromuscular Acute quadriplegic myopathy can occur from overdosing leading to coma and seizures, causing rhabdo-
blocking agents occur with or without concomitant
myolysis, myoglobinuria, and renal failure. Direct toxicity can occur
glucocorticoids.
from cocaine, heroin, and amphetamines causing muscle breakdown
Zidovudine Mitochondrial myopathy with ragged
and varying degrees of weakness. The effects of alcohol are more con-
red fibers
troversial. Direct muscle damage is less certain, since toxicity usually
Drugs of abuse All drugs in this group can lead to
occurs in the setting of poor nutrition and possible contributing fac-
 Alcohol widespread muscle breakdown, rhab-
domyolysis, and myoglobinuria. tors such as hypokalemia and hypophosphatemia. Alcoholics are also
 Amphetamines prone to neuropathy (Chap. 467).
Local injections cause muscle
 Cocaine necrosis, skin induration, and limb Focal myopathies from self-administration of meperidine, heroin,
 Heroin contractures. and pentazocine can cause pain, swelling, muscle necrosis, and hemor-
 Phencyclidine rhage. The cause is multifactorial; needle trauma, direct toxicity of the
drug or vehicle, and infection may all play a role. When severe, there
 Meperidine
may be overlying skin induration and contractures with replacement
Autoimmune toxic myopathy Use of this drug may cause polymyo-
of muscle by connective tissue. Elevated serum CK and myopathic
  d-Penicillamine sitis and myasthenia gravis.
EMG are characteristic of these reactions. The muscle biopsy shows
Amphophilic cationic drugs All amphophilic drugs have the widespread or focal areas of necrosis. In conditions leading to rhabdo-
 Amiodarone potential to produce painless, myolysis, patients need adequate hydration to reduce serum myoglo-
proximal weakness associated with
 Chloroquine bin and protect renal function. In all of these conditions, counseling is
autophagic vacuoles in the muscle
 Hydroxychloroquine biopsy. essential to limit drug abuse.
Antimicrotubular drugs This drug produces painless, proximal
 Colchicine weakness especially in the setting of DRUG-INDUCED AUTOIMMUNE MYOPATHIES
renal failure. Muscle biopsy shows As mentioned previously, an autoimmune necrotizing myopathy
autophagic vacuoles. associated with autoantibodies directed against HMG-CoA rarely
occurs in the setting of statin use. An inflammatory myopathy also
usually normal. Serum potassium may be low. The muscle biopsy in may occur with d-penicillamine, sometimes used in the treatment
chronic cases shows preferential type 2 muscle fiber atrophy; this is not of Wilson’s disease scleroderma, rheumatoid arthritis, and primary
reflected in the EMG, which is usually normal. biliary cirrhosis. The incidence of this inflammatory muscle disease is
Patients receiving high-dose IV glucocorticoids for status asthmati- about 1%. Myasthenia gravis is also induced by d-penicillamine, with
cus, chronic obstructive pulmonary disease, organ transplantation, or a higher incidence estimated at 7%. These disorders resolve with drug
other indications may develop severe generalized weakness (critical withdrawal, although immunosuppressive therapy may be warranted
illness myopathy). This myopathy, also known as acute quadriplegic in severe cases.
myopathy, can also occur in the setting of sepsis. Involvement of the Scattered reports of other drugs causing an inflammatory myopa-
diaphragm and intercostal muscles causes respiratory failure and thy are rare and include a heterogeneous group of agents: cimetidine,
requires ventilatory support. In these settings, the use of glucocorti- phenytoin, procainamide, and propylthiouracil. In most cases, a cause-
coids in combination with nondepolarizing neuromuscular blocking and-effect relationship is uncertain. A complication of interest was
agents potentiates this complication. In critical illness myopathy, the related to l-tryptophan. In 1989 an epidemic of eosinophilia-myalgia
muscle biopsy is abnormal, showing a distinctive loss of thick fila- syndrome (EMS) in the United States was caused by a contaminant in
ments (myosin) by electron microscopy. By light microscopy, there is the product from one manufacturer. The product was withdrawn, and
focal loss of ATPase staining in central or paracentral areas of the incidence of EMS diminished abruptly following this action.
muscle fiber. Calpain stains show diffusely reactive atrophic fibers.
Withdrawal of glucocorticoids will improve the chronic myopathy. In OTHER DRUG-INDUCED MYOPATHIES
acute quadriplegic myopathy, recovery is slow. Patients require sup- Certain drugs produce painless, largely proximal, muscle weakness.
portive care and rehabilitation. These drugs include the amphophilic cationic drugs (amiodarone,
chloroquine, hydroxychloroquine) and antimicrotubular drugs (col-
DRUG-INDUCED MITOCHONDRIAL MYOPATHY chicine) (Table 462e-11). Muscle biopsy can be useful in the identifica-
Zidovudine, used in the treatment of HIV infection, is a thymidine ana- tion of toxicity because autophagic vacuoles are prominent pathologic
logue that inhibits viral replication by interrupting reverse transcriptase. features of these toxins.

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