3520 PART 13 Neurologic Disorders
disorder in which myotonia is brought on by consumption of too much
potassium-containing foods.
Muscle stiffness can refer to different phenomena. Some patients
with inflammation of joints and periarticular surfaces feel stiff. This
condition is different from the disorders of hyperexcitable motor
nerves causing stiff or rigid muscles. In stiff-person syndrome, spontaneous discharges of the motor neurons of the spinal cord cause
involuntary muscle contractions mainly involving the axial (trunk) and
proximal lower extremity muscles. The gait becomes stiff and labored,
with hyperlordosis of the lumbar spine. Superimposed episodic muscle
spasms are precipitated by sudden movements, unexpected noises, and
emotional upset. The muscles relax during sleep. Serum antibodies
against glutamic acid decarboxylase are present in approximately twothirds of cases. In acquired neuromyotonia (Isaacs’ syndrome), there is
hyperexcitability of the peripheral nerves manifesting as continuous
muscle fiber activity in the form of widespread fasciculations and
myokymia with impaired muscle relaxation. Muscles of the leg are stiff,
and the constant contractions of the muscle cause increased sweating
of the extremities. This peripheral nerve hyperexcitability is mediated
by antibodies that target voltage-gated potassium channels.
There are two painful muscle conditions of particular importance,
neither of which is associated with muscle weakness. Fibromyalgia is a
common, yet poorly understood myofascial pain syndrome in which
patients complain of severe muscle pain and tenderness, severe fatigue,
and often poor sleep. Serum CK, erythrocyte sedimentation rate (ESR),
EMG, and muscle biopsy are normal (Chap. 373). Polymyalgia rheumatica occurs mainly in patients aged >50 years and is characterized
by stiffness and pain in the shoulders, lower back, hips, and thighs
(Chap. 363). The ESR and CRP are elevated, while serum CK, EMG,
and muscle biopsy are normal.
Muscle Enlargement and Atrophy In most myopathies, muscle
tissue is replaced by fat and connective tissue, but the size of the muscle
is usually not affected. However, in many limb-girdle muscular dystrophies, enlarged calf muscles are typical. The enlargement represents
true muscle hypertrophy; thus, the term pseudohypertrophy should be
avoided when referring to these patients. The calf muscles remain very
strong even late in the course of these disorders. Muscle enlargement
can also result from infiltration by sarcoid granulomas, amyloid deposits, bacterial and parasitic infections, and focal myositis. In contrast,
muscle atrophy is characteristic of other myopathies. In Miyoshi myopathy, which can be caused by mutations in the genes that encode for
dysferlin and anoctamin 5, there is a predilection for early atrophy of
the gastrocnemius muscles, particularly the medial aspect. Atrophy of
the humeral muscles is characteristic of FSHD and EDMD.
■ LABORATORY EVALUATION
Various tests can be used to evaluate a suspected myopathy, including
CK levels, endocrine studies (e.g., thyroid function tests, parathyroid
hormone and vitamin D levels), autoantibodies (associated with myositis and systemic disorders), forearm exercise test, muscle biopsy, and
genetic testing. Electrodiagnostic studies can be useful to differentiate
myopathies from other neuromuscular disorders (motor neuron disease, peripheral neuropathies, neuromuscular junction disorders) but,
in most instances, do not help distinguish the specific type of myopathy.
Serum Enzymes CK is the most sensitive measure of muscle
damage. The MM isoenzyme predominates in skeletal muscle, whereas
CK-myocardial bound (CK-MB) is the marker for cardiac muscle.
Serum CK can be elevated in normal individuals without provocation,
presumably on a genetic basis or after strenuous activity, trauma, a prolonged muscle cramp, or a generalized seizure. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), aldolase, and lactate
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 could be
the cause. An elevated γ-glutamyl transferase (GGT) helps to establish
a liver origin because this enzyme is not found in muscle. Rarely, aldose
can be elevated in an inflammatory myopathy when CK, AST, and ALT
are normal, signifying that the inflammation predominantly affects
the perimysium (dermatomyositis, graft-versus-host disease) or the
surrounding fascia (fasciitis).
Electrodiagnostic Studies EMG, repetitive nerve stimulation,
and nerve conduction studies (NCS) (Chap. 446) are helpful in differentiating myopathies from motor neuron disease, neuropathies,
and neuromuscular junction diseases. Routine NCS 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 insertion and spontaneously that is
suggestive of a myopathy with active necrosis or muscle membrane
instability (inflammatory myopathies, dystrophies, toxic myopathies,
myotonic myopathies), whereas a lack of irritability is characteristic of
long-standing myopathic disorders (muscular dystrophies with severe
fibrofatty replacement, endocrine myopathies, disuse atrophy, and
many of the metabolic myopathies between bouts of rhabdomyolysis).
In addition, the EMG may demonstrate myotonic discharges that will
narrow the differential diagnosis (Table 449-1). Another important
EMG finding is the presence of short-duration, small-amplitude,
polyphasic motor unit action potentials (MUAPs). 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. An EMG is usually normal in steroid or disuse myopathy,
both of which are associated with type 2 fiber atrophy; this is because
the EMG preferentially assesses the physiologic function of type 1
fibers. The EMG can supplement the clinical examination in choosing
an appropriately affected muscle to biopsy.
Imaging Studies Skeletal MRI and ultrasound are increasing
utilized to assess the pattern of muscle involvement, which can help
in narrowing the diagnosis, and are often more sensitive than the clinical examination and EMG, particularly early in a disease course. For
FIGURE 449-5 Lordotic posture, exaggerated by standing on toes, associated with
trunk and hip weakness.
3521 Muscular Dystrophies and Other Muscle Diseases CHAPTER 449
example, there is early predilection of the vastus lateralis and medialis
muscles with relative sparing of the rectus femoris muscles on imaging
of thigh muscles in patients with inclusion body myositis, and this
can be appreciated on imaging prior to weakness being detected on
manual muscle testing. MRI can also demonstrate fasciitis when the
clinical examination and EMG are normal. Imaging can also be used
to help guide what muscle to biopsy in patients with weakness on
manual muscle testing and EMG abnormalities only in muscles that
are not typically biopsied (e.g., paraspinal or hip girdle). We have found
imaging helpful in patients with presumed muscular dystrophy when
the muscle biopsy is not diagnostic and genetic testing shows only a
variation of unclear significance. In this situation, the pattern of muscle involvement on imaging can support the known pattern of muscle
involvement of a specific hereditary myopathy. The cost and availability of MRI preclude routine use in some settings, but ultrasound is
more readily available and less expensive.
Genetic Testing This is increasingly available and is the gold
standard for diagnosing patients with hereditary myopathies. Nextgeneration sequencing panels are increasing utilized, but clinicians
need to know their limitations; large deletions and duplications can
be missed, as can mutations in noncoding (intronic) regions. Furthermore, testing often reveals sequence alterations of unclear significance.
Forearm Exercise Test With exercise-induced muscle pain and
myoglobinuria, there may be a defect in glycolysis. For safety, the test
should not be performed under ischemic conditions to avoid an unnecessary insult to the muscle, causing rhabdomyolysis. 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 deficiency and certain 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 individuals makes interpretation controversial.
Muscle Biopsy Muscle biopsy is extremely helpful in evaluation
of acquired myopathies but is performed less frequently in suspected
hereditary myopathies as genetic testing has become more widely
available. However, muscle biopsy can be helpful in cases of suspected
hereditary myopathy in which genetic testing was nondiagnostic.
Almost any superficial muscle can be biopsied, but it is important to
biopsy one that is affected clinically but not too severely (for example
grade 4 out of 5 strength or movement against moderate resistance by
manual muscle testing [Chap. 422]). A specific diagnosis can be established in many disorders.
HEREDITARY MYOPATHIES
Muscular dystrophy refers to a group of hereditary progressive diseases,
each with unique phenotypic and genetic features (Tables 449-3, 449-4,
and 449-5, and Fig. 449-6). The prognosis of dystrophies is slow progressive weakness, though the severity and course are variable between
and even within subtypes. Some are associated with cardiac and ventilatory muscle involvement, which are the leading causes of mortality.
Unfortunately, there are no specific medical therapies for most of the
muscular dystrophies, and treatment is aimed at maintaining function
with physical and occupational therapy. Noninvasive ventilation and
tracheostomy may be warranted. Those with cardiomyopathy may
require afterload reduction, antiarrhythmic agents, pacemakers or
intracardiac defibrillators, and occasionally cardiac transplantation.
We will focus primarily on those that manifest in adulthood.
■ DUCHENNE AND BECKER MUSCULAR
DYSTROPHY (DMD AND BMD)
DMD and BMD are X-linked recessive muscular dystrophies caused
by mutations in the dystrophin gene. Affecting 1 in 3000 male births,
DMD is the most common mutational disease affecting boys. The incidence of BMD is ~5 per 100,000.
Clinical Features Proximal muscles, especially of the lower
extremities, are prominently involved in both disorders. This becomes
evident in DMD very early; boys with DMD have difficulty climbing
stairs and never run well. As the disease progresses, weakness becomes
more generalized. Hypertrophy of muscles, particularly in the calves,
is an early and prominent finding. Most patients with BMD first
experience difficulties between ages 5 and 15 years, although onset
in the third or fourth decade or even later can occur. Life expectancy
for DMD and BMD is reduced, but most BMD cases survive into the
fourth or fifth decade. Intellectual disability may occur in both disorders but is less common in BMD. Cardiac involvement is common
in both DMD and BMD and may result in heart failure; some BMD
patients manifest with only heart failure. Other less common presentations of dystrophinopathy are asymptomatic hyper-CK-emia, myalgias
without weakness, and myoglobinuria.
Laboratory Features Serum CK levels are usually elevated. Muscle biopsies demonstrate dystrophic features. Western blot analysis of
muscle biopsy samples demonstrates absent dystrophin in DMD or
reduction in levels or size of dystrophin in BMD. In both disorders,
mutations can be established using DNA from peripheral blood leukocytes. In most cases, muscle biopsies are no longer performed when
DMD or BMD is suspected, as genetic testing is less invasive, less costly,
and routinely available. Deletions within or duplications of the dystrophin
gene are common in both DMD and BMD; in ~95% of cases, the mutation 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 and a milder clinical phenotype.
TREATMENT
Duchenne and Becker Muscular Dystrophy
Glucocorticoids slow progression in DMD, but their use has not
been adequately studied in BMD. Physical and occupational therapy are important in helping maintain function. As patients often
die from the associated cardiomyopathy, it is important to follow
patients with a cardiologist and treat appropriately. Recent studies
suggest that there is clinical benefit in selected cases of DMD from
short oligonucleotides that permit skipping of mutant exons, leading to expression of a short but nonetheless functional dystrophin
protein. In parallel, other studies suggest that small molecules
may permit read-through of protein-truncating mutations in some
DMD cases, again with clinical benefit.
■ LIMB-GIRDLE MUSCULAR DYSTROPHY
The limb-girdle muscular dystrophies (LGMDs) are a genetically
heterogenous group of dystrophies in which males and females are
affected equally, with typical 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 and are often clinically indistinguishable from DMD and BMD. Respiratory insufficiency
from weakness of the diaphragm may occur, as may cardiomyopathy.
Serum CKs are elevated, and the EMG is myopathic. Muscle biopsy
reveal dystrophic features, but the findings are not specific to differentiate subtypes from one another unless immunohistochemistry is
employed (e.g., immunostaining for various sarcoglycans, dysferlin,
alpha-dystroglycan, merosin) or there are features to suggest one of
the myofibrillar myopathies. Nonetheless, definitive diagnosis requires
genetic testing.
The traditional classification of LGMD is based on autosomal
dominant (LGMD1) and autosomal recessive (LGMD2) inheritance.
3522 PART 13 Neurologic Disorders
Superimposed on the backbone of LGMD1 and LGMD2, the classification uses a sequential alphabetical lettering system (LGMD1A,
LGMD2A, etc.) based on genotype. However, ever-expanding discoveries of new genes have outgrown the alphabet. The European Neuromuscular Centre (ENMC) recently proposed a new nomenclature in
which autosomal dominant cases are termed LGMD “D” and autosomal recessive as LGMD “R,” followed by a numerical number based on
genotype. Furthermore, this new classification only includes cases in
which at least two unrelated families have been reported, the predominant weakness at onset was proximal, independent ambulation was
achieved at some time, CK is elevated, and muscle biopsies or imaging revealed dystrophic features. Thus, mutations in the CPN3 gene
leading to a deficiency in calpain-3, which traditionally were classified
as LGMD2A, are classified as LGMDR1 by this new system. In contrast, mutations in myotilin (LGMD1A) and desmin (LGMD1E and
LGMD2R) and that often have more distal weakness and have biopsies
features of a myofibrillar myopathy are not classified as a LGMD in this
new scheme but rather as subtypes of myofibrillar myopathy. Likewise,
laminopathies (LGMD1B) are considered a subtype of EDMD rather
than an LGMD. This new classification of LGMD and distal muscular
dystrophies is summarized in Tables 449-3 and 449-4.
The prevalence of LGMD ranges from 80 to 700 per 100,000, while
estimated prevalences of individual specific subtypes of LGMDs vary.
The most common types of adult-onset LGMD are calpainopathy
(LGMD2A/LGMDR1), Fukutin-related protein (FKRP) deficiency
(LGMD2I/LGMDR9), and anoctaminopathy (LGMD2L/LGMDR12).
Calpainopathy (LGMD2A/LGMDR1), the most common cause of
LGMD in those with ancestry from Spain, France, Italy, and Great
Britain, is associated with marked scapular winging, lack of calf
muscle hypertrophy, and lack of cardiac and lung involvement. Of
note, autosomal dominant mutations in an intron of the calpain-3
gene is responsible for LGMD1I/LGMDD4. LGMD2I/LGMDR9
is more common in individuals with northern European ancestry,
is associated with calf muscle hypertrophy, and can have cardiac
and lung involvement out of proportion to extremity weakness.
LGMD2L/LGMDR12 accounts for ~7% of LGMD in the United
States, and the prevalence is higher in northern Europe; as seen in
dysferlinopathies (LGMD2B/LGMDR2 and Miyoshi myopathy type
1), anoctaminopathy has an early predilection for medial calf atrophy
and weakness.
Importantly, immune-mediated necrotizing myopathies can mimic
LGMD clinically and histopathologically (Chap. 365). Anyone suspected of having an LGMD but without definite pathogenic mutation(s) identified on genetic testing should be screened for the presence
of serum antibodies against HMGCR and SRP to assess for a treatable
autoimmune cause.
■ EMERY-DREIFUSS MUSCULAR DYSTROPHY
There are at least five genetically distinct forms of EDMD. Emerin
mutations are the most common 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
TABLE 449-3 Autosomal Dominant Limb-Girdle Muscular Dystrophies (LGMDs)
TRADITIONAL CLASSIFICATION/
PROPOSED NEW CLASSIFICATION
(WHEN APPLICABLE) CLINICAL FEATURES LABORATORY FEATURES
ABNORMAL
PROTEIN
LGMD1A/myofibrillar myopathy Onset second to eighth decade Serum CK 2× normal Myotilin
Muscle weakness affects proximal and distal limb
muscles, vocal cords, and pharyngeal muscles
EMG myopathic and may have pseudomotonic
discharges
Muscle biopsy: features of MFM
LGMD1B/EDMD2 Onset first or second decade Serum CK 3–5× normal Lamin A/C
Proximal lower limb weakness and cardiomyopathy
with conduction defects
EMG myopathic
Some cases indistinguishable from Emery-Dreifuss
muscular dystrophy (EDMD) with joint contractures
LGMD1C/rippling muscle disease Onset in early childhood Serum CK 4–25× normal Caveolin-3
Proximal weakness EMG myopathic
Gower sign, calf hypertrophy, rippling muscles
Exercise-related muscle cramps
LGMD1D/LGMDD1 Onset second to sixth decade Serum CK 2–3× normal DNAJB6
Proximal and distal muscle weakness EMG myopathic
Muscle biopsy: features of MFM
LGMD1E/myofibrillar myopathy Onset first to sixth decade Serum CK 2–4× normal Desmin
Proximal or distal muscle weakness EMG myopathic and may have pseudomotonic
discharges
Cardiomyopathy and arrhythmias Muscle biopsy: features of MFM
LGMD1F/LGMDD2 Onset infancy to sixth decade
Proximal or distal weakness
May have early contractures resembling
Emery-Dreifuss syndrome
Serum CK normal to 20× normal
EMG myopathic
Muscle biopsy may show enlarged nuclei
with central pallor, rimmed vacuoles, and
filamentous inclusions
TNPO3
LGMD1G/LGMDD3 Onset teens to sixth decade
Proximal weakness contractures of fingers and toes
Muscle biopsies show rimmed vacuoles
CK normal to 9× normal
HNRNPDL
LGMD1I/LGMDD4 Onset teens to ninth decade
Proximal weakness, scapular winging
CK normal to 50× normal
EMG myopathic
Calpain-3
Bethlem myopathy/LGMD1D5 Onset in childhood to adulthood
Contractures at elbows, distal fingers, knees, ankles
Hyperextensible fingers proximally
Keloids
CK normal to 3× normal
MRI and ultrasound of muscle show a
peripheral > central predilection for fibrofatty
replacement in individual muscles
Collagen VI alpha 1
chain
Abbreviations: CK, creatine kinase; EMG, electromyography; HNRNPDL, heterogeneous nuclear ribonucleoprotein D-like protein; MFM, myofibrillar myopathy.
3523 Muscular Dystrophies and Other Muscle Diseases CHAPTER 449
TABLE 449-4 Autosomal Recessive Limb-Girdle Muscular Dystrophies (LGMDs)
DISEASE CLINICAL FEATURES LABORATORY FEATURES ABNORMAL PROTEIN
LGMD2A/LGMDR1 Onset first or second decade Serum CK 3–15× normal Calpain-3
Scapular winging; no calf hypertrophy; no cardiac or
respiratory muscle weakness
EMG myopathic
Proximal and distal weakness; may have contractures at
elbows, wrists, and fingers
Muscle biopsy may show lobulated muscle
fibers
LGMD2B/LGMDR2 Onset second or third decade Serum CK 3–100× normal Dysferlin
Proximal muscle weakness at onset, later distal (calf) muscles
affected
EMG myopathic
Miyoshi myopathy is variant of LGMD2B with calf muscles
affected at onset
Inflammation on muscle biopsy may
simulate polymyositis; amyloid deposition
in endomysium
LGMD2C–F/LGMDR3–6 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/LGMDR7 Onset age 10–15 Serum CK 3–17× normal Telethonin
Proximal and distal muscle weakness EMG myopathic
Muscle biopsy may show rimmed vacuoles
LGMD2H/LGMDR8 Onset first to third decade Serum CK 2–25× normal Tripartite motif-containing 32
Allelic to sarcotubular congenital myopathy
Proximal muscle weakness
EMG myopathic
Muscle biopsy reveals dilated T-tubules
LGMD2I/LGMDR9 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
/LGMDR10 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/LGMDR11 Usually presents in infancy as Walker-Warburg syndrome but
can present in early adult life with proximal weakness and
only minor CNS abnormalities
CK 10–20× normal
EMG myopathic
POMT1
LGMD2L/LGMDR12 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 myopathy type 1
(dysferlinopathy)
LGMD2M/LGMDR13 Usually presents in infancy as Fukuyama congenital muscular
dystrophy but can present in early adult life with proximal
weakness and only minor CNS abnormalities
CK 10–50× normal
EMG myopathic
Fukutin
LGMD2N/LGMDR14 Usually presents in infancy as muscle-eye-brain disease but
can present in early adult life with proximal weakness and
only minor CNS abnormalities
CK 5–20× normal
EMG myopathic
POMGNT1
LGMD2O/LGMDR15 Usually presents in infancy as Walker-Warburg syndrome but
can present in early adult life with proximal weakness and
only minor CNS abnormalities
CK 5–20× normal
EMG myopathic
POMT2
LGMD2P/LGMD R16 One case reported presenting in early childhood CK >10× normal α-Dystroglycan
LGMD2Q/LGMDR17 Onset in infancy to fourth decade; proximal weakness; may
have ptosis and extraocular weakness; epidermolysis bullosa
(also considered a congenital myasthenic syndrome)
CK variable, but usually only mildly
elevated
EMG myopathic
Repetitive nerve stimulation may show
decrement
Plectin 1
LGMD2R/myofibrillar
myopathy
See LGMD1E (see Table 449-6) See LGMD1E Desmin
LGMD2S/LGMDR18 Onset in infancy to sixth decade of proximal weakness
Eye abnormalities common; truncal ataxia and chorea
Mild to moderate intellectual disability
Hutterite descent
CK 1.5–20× normal TRAPC11
LGMD2T/LGMDR19 Onset in early childhood to fourth decade
Proximal weakness
CNS abnormalities, cataracts, cardiomyopathy,
and neuromuscular junction dysfunction
CK 3 to >10× normal
EMG myopathic
GMPPB
(Continued)
3524 PART 13 Neurologic Disorders
(LMNA) are the most common cause of autosomal dominant EDMD
(also known as LGMD1B) and are also a common cause of hereditary
cardiomyopathy. Less commonly, autosomal dominant EDMD has
been reported with mutations in SYNE1, SYNE2, TMEM43, SUN1,
SUN2, and TTN genes encoding nesprin-1, nesprin-2, LUMA, SUN1,
SUN2, and titin, respectively.
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 present at the elbows, ankles, and neck. Muscle weakness affects
humeral and peroneal muscles at first and later spreads to a limbgirdle distribution (Table 449-1). 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 manifest with
a cardiomyopathy.
Laboratory Features Serum CK is usually slightly elevated, and
the EMG is myopathic. Muscle biopsy usually shows nonspecific
dystrophic features, 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. Electrocardiograms (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/C; in the
synaptic nuclear envelope protein 1 (SYNE1) or 2 (SYNE2) encoding
nesprin-1 and nesprin-2, respectively; and 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.
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 lifesaving.
■ MYOTONIC DYSTROPHY
There are two distinct forms of myotonic dystrophy (dystrophia
myotonica [DM]), namely myotonic dystrophy type 1 (DM1) and myotonic
dystrophy type 2 (DM2), also called proximal myotonic myopathy
(PROMM).
Clinical Features The clinical expression of DM1 varies widely
and involves many systems other than muscle. Affected patients may
have a “hatchet-faced” appearance due to temporalis, masseter, and
facial muscle atrophy and weakness. Frontal baldness is frequent.
Weakness of wrist and fingers occurs early, as does foot drop. Proximal
muscles are less affected. Palatal, pharyngeal, and tongue involvement
can lead to dysarthria and dysphagia. Some patients have diaphragm
and intercostal muscle weakness, resulting in ventilatory insufficiency.
Myotonia is usually apparent by the age of 5 years and is best demonstrable by percussion of the thenar eminence or asking patients to close
their fingers very tightly and then relax.
TABLE 449-4 Autosomal Recessive Limb-Girdle Muscular Dystrophies (LGMDs)
DISEASE CLINICAL FEATURES LABORATORY FEATURES ABNORMAL PROTEIN
LGMD2U/LGMDR20 Onset typically in early childhood of proximal weakness
May have CNS and ocular abnormalities
CK 5 to >20× normal ISPD
LGMD2V/late-onset
Pompe disease
Childhood or adult onset of proximal weakness
Ventilatory muscle weakness
CK normal to mildly elevated
EMG myopathic (may have myotonic
discharges)
Alpha-glucosidase
LGMD2W/PINCH2-
related myopathy
Reported in only one family
Childhood onset of proximal weakness
Macroglossia with broad-based, triangular tongue
Cardiomyopathy in third decade
CK 3 to >20× normal PINCH2
LGMD2Y/TOR1AIP1-
related myopathy
Reported in only one family
Childhood onset of proximal weakness
Rigid spine and contractures
CK normal to 4× normal
EMG myopathic
Lamina-associated polypeptide
1B
LGMD2Z/LGMDR21 Adult-onset proximal weakness
Scapular winging
CK mildly elevated POGLUT1
Bethlem myopathy
(recessive)/LGMDR22
Onset in childhood to adulthood
Contractures at elbows, distal fingers, knees, ankles
Hyperextensible fingers proximally
Keloids
CK normal to 3× normal
MRI and ultrasound of muscle show
a peripheral > central predilection for
fibrofatty replacement in individual
muscles
Collagen VI alpha 1, alpha 2, or
alpha 3 chains
Laminin alpha-2
muscular dystrophy/
LGMDR23
Congenital to adult onset
May have CNS abnormalities
CK 2–5× normal Laminin alpha 2 (merosin)
POMGNT-related
muscular dystrophy/
LGMDR24
Congenital to adult onset
May have CNS abnormalities
CK 5 to >20× normal POMGNT2
LGMD2X/LGMDR25 Adult onset of proximal weakness
Cardiac arrhythmias
CK 3 to >20× normal Popeye domain containing
protein 1
a
Udd-type distal myopathy is a form of titin deficiency with only distal muscle weakness (see Table 449-5).
Abbreviations: CK, creatine kinase; CNS, central nervous system; EMG, electromyography; GMPPB; guanosine diphosphate (GDP)-mannose pyrophosphorylase
B; ISPD, isoprenoid synthase domain containing; PINCH2, particularly interesting new cysteine-histidine rich protein 2; POGLUT1, protein O-glucosyltransferase 1;
POMGNT1, O-linked mannose beta 1,2-N-acetylglucosaminyltransferase; POMGNT2, protein O-mannose beta-1,4-N-acetylglucosaminyltransferase-2; POMT1, protein-Omannosyltransferase 1; POMT2, protein-O-mannosyltransferase 2; TNPO3, transportin 3; TOR1AIP1, DNA sequencing of torsinA-interacting protein 1; TRAPC11, transport
(trafficking) protein particle complex, subunit 11.
(Continued)
3525 Muscular Dystrophies and Other Muscle Diseases CHAPTER 449
TABLE 449-5 Distal Myopathies
DISEASE CLINICAL FEATURES LABORATORY FEATURES ABNORMAL PROTEIN
Welander distal myopathy Onset in fifth decade
Weakness begins in hands
Slow progression with spread to distal
lower extremities
Life span normal
Serum CK 2–3× normal
EMG myopathic
NCS normal
Muscle biopsy shows dystrophic features and
rimmed vacuoles
AD
TIA1
Tibial muscular dystrophy
(Udd)
Onset fourth to eighth decade
Distal lower extremity weakness (tibial
distribution)
Upper extremities usually normal
Life span normal
Serum CK 2–4× normal
EMG myopathic
NCS normal
Muscle biopsy shows dystrophic features and
rimmed vacuoles
Titin absent in M-line of muscle
AD
Titin
AR (associated with more proximal
weakness—LGMD2J)
Markesbery-Griggs distal
myopathy
Onset fourth to eighth decade
Distal lower extremity weakness (tibial
distribution) with progression to distal
arms and proximal muscles
Serum CK is usually mildly elevated
EMG reveals irritative myopathy
Muscle biopsies demonstrate rimmed vacuoles
and features of MFM
AD
Z-band alternatively spliced PDX motifcontaining protein (ZASP)
Laing distal myopathy Onset childhood to third decade
Distal lower extremity weakness (anterior
tibial distribution) and neck flexors
affected early
May have cardiomyopathy
Serum CK is normal or slightly elevated
Muscle biopsies do not typically show rimmed
vacuoles, but may show hyaline bodies with
accumulation of myosin
Large deposits of myosin heavy chain are seen in
type 1 muscle fibers
AD
Myosin heavy chain 7
GNE myopathy (Nonaka
distal myopathy and
autosomal recessive
hereditary inclusion body
myopathy)
Onset second to third decade
Distal lower extremity weakness (anterior
tibial distribution)
Mild distal upper limb weakness may be
present early
Progression to other muscles sparing
quadriceps
Ambulation may be lost in 10–15 years
Serum CK 3–10× normal
EMG myopathic
NCS normal
Dystrophic features on muscle biopsy plus rimmed
vacuoles and 15- to 19-nm filaments within
vacuoles
AR
GNE gene: UDP-N-acetylglucosamine
2-epimerase/N-acetylmannosamine
kinase
Allelic to a form of hereditary inclusion
body myopathy
Miyoshi myopathya Onset second to third decade
Lower extremity weakness in posterior
compartment muscles
Progression leads to weakness in other
muscle groups
Ambulation lost after 10–15 years in about
one-third of cases
Serum CK 20–100× normal
EMG myopathic
NCS normal
Muscle biopsy shows nonspecific dystrophic
features often with prominent inflammatory cell
infiltration; no rimmed vacuoles
AR
Dysferlin (allelic to LGMD2B)
ANO-5 (allelic to LGMD2L)
Williams myopathy Distal lower extremity weakness (anterior
tibial distribution)
Muscle biopsy may show rimmed vacuoles and
features of MFM
AD
Filamin-C
Myofibrillar myopathies Onset from early childhood to late adult
life
Weakness may be distal, proximal, or
generalized
Cardiomyopathy and respiratory
involvement are not uncommon
Serum CKs can be normal or moderately elevated
EMG is myopathic and often associated with
myotonic discharges
Muscle biopsy demonstrates abnormal
accumulation of desmin and other proteins, rimmed
vacuoles, and myofibrillar degeneration
Genetically heterogeneous
AD
Myotilin (also known as LGMD1A)
ZASP (see Markesbery-Griggs distal
myopathy)
Filamin-C
Desmin
Alpha B crystallin
Bag3
Titin
DNAJB6
TNPO3
AR, AD
Desmin
X-linked
FHL1
a
Miyoshi myopathy phenotype may also be seen with mutations in ANO-5 that encodes for anoctamin 5 (allelic to LGMD2L).
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CK, creatine kinase; EMG, electromyography; MFM, myofibrillar myopathy; NCS, nerve conduction
studies.
ECG abnormalities include first-degree heart block and more
extensive conduction system involvement. Complete heart block
and sudden death can occur. Congestive heart failure occurs infrequently but may result from cor pulmonale secondary to respiratory failure. Other associated features include intellectual
impairment, hypersomnia, posterior subcapsular cataracts, gonadal
atrophy, insulin resistance, and decreased esophageal and colonic
motility.
Congenital myotonic dystrophy is a more severe form of DM1 and
occurs in ~25% of infants of affected mothers. It is characterized by
severe facial and bulbar weakness, transient neonatal respiratory insufficiency, and intellectual disability.
3526 PART 13 Neurologic Disorders
DM2 or PROMM involves mainly proximal muscles. Other features
of the disease overlap with DM1, including cataracts, testicular atrophy,
insulin resistance, constipation, hypersomnia, and cognitive defects.
Cardiac conduction defects occur but are less common. The hatchet
face and frontal baldness are also less consistent features. A very striking
difference is the failure to clearly identify a congenital form of DM2.
Laboratory Features The diagnosis of myotonic dystrophy can
usually be made on the basis of clinical findings. Serum CK levels may
be normal or mildly elevated. EMG evidence of myotonia is present
in most cases of DM1 but is more patchy in DM2. Muscle biopsy is
not typically performed for diagnosis but is sometimes done when the
clinical features and electrophysiologic features are not recognized. The
major histopathologic features in both DM1 and DM2 are numerous
internalized nuclei in individual muscle fibers combined with many
atrophic fibers with pyknotic nuclear clumps.
DM1 and DM2 are autosomal dominant disorders. DM1 is transmitted by an intronic mutation consisting of an unstable expansion of
a CTG trinucleotide repeat in a serine-threonine protein kinase gene
(named DMPK). An increase in the severity of the disease phenotype
in successive generations (genetic anticipation) is accompanied by an
increase in the number of trinucleotide repeats. The unstable triplet
repeat in myotonic dystrophy can be used for prenatal diagnosis.
Congenital disease occurs almost exclusively in infants born to affected
mothers.
DM2 is caused by a DNA expansion mutation consisting of a CCTG
repeat in intron 1 of the CNBP gene encoding the CCHC-type zinc
finger nucleic acid binding protein. The DNA expansions in DM1
and DM2 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 sequester RNA-binding proteins essential for proper splicing
of a variety of other mRNAs. This leads to abnormal transcription of
multiple proteins in a variety of tissues/organ systems, in turn causing
the systemic manifestations of DM1 and DM2.
TREATMENT
Myotonic Dystrophy
The myotonia in DM1 and DM2 is usually not so bothersome to
warrant treatment, but when it is, mexiletine may be helpful. A
cardiac pacemaker or implantable cardioverter defibrillator should
be considered for patients with significant arrhythmia. Molded
ankle-foot orthoses help stabilize gait in patients with foot drop.
Excessive daytime somnolence with or without sleep apnea is not
FIGURE 449-6 Proteins involved in the muscular dystrophies. This schematic shows the location of various sarcolemmal, sarcomeric, nuclear, and enzymatic proteins
associated with muscular dystrophies. The diseases associated with mutations in the genes responsible for encoding these proteins are shown in boxes. Dystrophin, via
its interaction with the dystroglycan complex, connects the actin cytoskeleton to the extracellular matrix. Extracellularly, the sarcoglycan complex interacts with biglycan,
which connects this complex to the dystroglycan complex and the extracellular matrix collagen. Various enzymes are important in the glycosylation of the α-dystroglycan
and mediate its binding to the extracellular matrix and usually cause a congenital muscular dystrophy with severe brain and eye abnormalities but may cause milder LGMD
phenotype. Mutations in genes that encode for sarcomeric and Z-disk proteins cause forms of LGMD and distal myopathies (including myofibrillar myopathy, forms of
hereditary inclusion body myopathy) as well as nemaline rod myopathy and other “congenital” myopathies. Mutations affecting nuclear membrane proteins are responsible
for most forms of EDMD. Mutations in other nuclear genes cause other forms of dystrophy. (From AA Amato, J Russell: Neuromuscular Disorders, 2nd ed. McGraw-Hill,
2016, Figure 27-1, p. 657; with permission.)
3527 Muscular Dystrophies and Other Muscle Diseases CHAPTER 449
uncommon. Sleep studies, noninvasive respiratory support (biphasic positive airway pressure [BiPAP]), and treatment with modafinil
may be beneficial.
■ FACIOSCAPULOHUMERAL (FSHD)
MUSCULAR DYSTROPHY
There are two forms of FSHD that have similar pathogenesis. Most
patients have FSHD type 1 (95%), whereas ~5% have FSHD2. Both
forms are clinically and histopathologically identical. The prevalence
FSHD is ~5 per 100,000 individuals.
Clinical Features FSHD typically presents in childhood or young
adulthood. In most cases, facial weakness is the initial manifestation,
appearing as an inability to smile, whistle, or fully close the eyes. Loss
of scapular stabilizer muscles makes arm elevation difficult. Scapular
winging (Fig. 449-3) 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 foot
drop. In 20% of patients, weakness progresses to involve the pelvic muscles, and severe functional impairment and possible wheelchair dependency result. The heart is not involved, but there can be ventilatory
muscle weakness in 5% of affected individuals. There is an increased
incidence of nerve deafness. Coats’ disease, a disorder consisting of
telangiectasia, exudation, and retinal detachment, also occurs.
Laboratory Features The serum CK level may be normal or
mildly elevated. EMG and muscle biopsy show nonspecific abnormalities but on occasion can reveal a prominent inflammatory infiltrate
leading to an incorrect diagnosis of myositis (Chap. 365).
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 after early muscle development. In patients with
FSHD1, these deletions in the setting of a specific polymorphism lead
to hypomethylation of the region and toxic expression of the DUX4
gene. In cases of FSHD2, there is no deletion, but rather mutations in
three different genes have been identified, each of which interestingly
leads to hypomethylation of the DUX4 region and the permissive
expression of the DUX4 gene. Dominant mutations in the structural
maintenance of chromosomes hinge domain 1 (SMCHD1) gene is the
most common cause of FSHD2, but recently, heterozygous mutations
in the DNA methyltransferase 3B (DNMT3B) gene and homozygous
mutations in the ligand-dependent nuclear receptor-interacting factor
1 (LRIF1) gene have been reported in rare cases of autosomal recessive
FSHD2. These proteins normally interact with SMCHD1, and mutations lead to hypomethylation of the DUX4 region and, as in FSHD1,
to an overexpression of the DUX4 transcript.
TREATMENT
Facioscapulohumeral Muscular Dystrophy
No specific treatment is available; ankle-foot orthoses are helpful
for foot drop. Scapular stabilization procedures improve scapular
winging but may not improve function.
■ OCULOPHARYNGEAL DYSTROPHY (OPMD)
OPMD 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 OPMD has a late onset; it usually presents in the
fourth to sixth decade with ptosis or dysphagia. The extraocular muscle
impairment is less prominent in the early phase but may become severe
over time. The swallowing problem may lead to aspiration. Weakness
of the neck and proximal extremities can develop but is usually mild
in degree.
Laboratory Features The serum CK level may be two to three
times normal. EMG can identify myopathic changes in weak muscles.
Muscle biopsies are no longer necessary for diagnosis in most cases but,
when performed, demonstrate muscle fibers with rimmed vacuoles.
On electron microscopy, a distinctive feature of OPMD is the presence
of 8.5-nm tubular filaments in some muscle cell nuclei.
OPMD is an autosomal dominant disorder that has a high incidence
in certain populations (e.g., French-Canadians, individuals of Spanish
ancestry, and Ashkenazi Jews). The molecular defect in OPMD is an
expansion of a polyalanine repeat tract in a poly-RNA-binding protein
(PABP2) gene.
TREATMENT
Oculopharyngeal Dystrophy
Dysphagia can lead to significant undernourishment and aspiration. Cricopharyngeal myotomy may improve swallowing. Eyelid
crutches can improve vision when ptosis obstructs vision; candidates for ptosis surgery must be carefully selected—those with
severe facial weakness are not suitable.
■ DISTAL MYOPATHIES/DYSTROPHIES
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 distal myopathies are
summarized in Tables 449-1 and 449-5.
Clinical Features Welander, Udd, and Markesbery-Griggs type
distal myopathies are all late-onset, dominantly inherited disorders of
distal limb muscles, usually beginning after age 40 years. Welander
distal myopathy preferentially involves the wrist and finger extensors,
whereas the others are associated with anterior tibial weakness leading
to progressive foot drop. Laing distal myopathy is also a dominantly
inherited disorder heralded by tibial weakness; however, it is distinguished by onset in childhood or early adult life. GNE myopathy (also
known as Nonaka distal myopathy and autosomal recessive hereditary
inclusion body myopathy) and Miyoshi myopathy are distinguished by
autosomal recessive inheritance and onset in the late teens or twenties. GNE and Williams myopathy produce prominent anterior tibial
weakness, whereas Miyoshi 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 muscular dystrophies 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), LGMD1E and LGMD2R (caused by mutations in desmin),
and LGMD1A (caused by mutations in myotilin) are subtypes of MFM.
Laboratory Features Serum CK levels are markedly elevated
in Miyoshi myopathy, but in the other conditions, serum CK is only
slightly increased. EMGs are myopathic and can be irritable with myotonic discharges in MFM. Muscle biopsy shows nonspecific dystrophic
features and, with the exception of Laing and Miyoshi myopathies,
often shows rimmed vacuoles. MFM is associated with the accumulation of dense inclusions and amorphous material best seen on Gomori
trichrome staining along with myofibrillar 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
myopathy, and reduced or absent dysferlin in Miyoshi myopathy type 1.
TREATMENT
Distal Myopathies
Occupational therapy is offered for loss of hand function; anklefoot orthoses can support distal lower limb muscles. The MFMs
3528 PART 13 Neurologic Disorders
can be associated with cardiomyopathy (congestive heart failure
or arrhythmias) and respiratory failure that may require medical
management. Laing-type distal myopathy can also be associated
with a cardiomyopathy.
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 myoglobinuria to a chronic, progressive muscle weakness simulating muscular
dystrophy (Table 449-1). As with the muscular dystrophies, there are
no specific medical treatments available.
■ GLYCOGEN STORAGE AND GLYCOLYTIC DEFECTS
Disorders of Glycolysis Causing Exercise Intolerance Several
glycolytic defects are associated with recurrent myoglobinuria. The
most common is McArdle disease caused by mutations in the PYGM
gene leading to myophosphorylase deficiency. Symptoms of muscle
pain and stiffness usually begin in adolescence. With severe episodes,
myoglobinuria can occur.
Certain features help distinguish some enzyme defects. In McArdle disease, exercise tolerance can be enhanced by a slow induction
phase (warm-up) or brief periods of rest, allowing for the start of the
“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 intellectual disability; exercise intolerance 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. A forearm
exercise test reveals a blunted rise in venous lactate with a normal rise
in ammonia. A definitive diagnosis of glycolytic disease can be made by
muscle biopsy with appropriate staining and enzyme assays, but genetic
testing is now done in lieu of biopsy in most cases.
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.
Disorders of Glycogen Storage Causing Progressive Weakness
α-GLUCOSIDASE, OR ACID MALTASE, DEFICIENCY (POMPE DISEASE) Three clinical forms of α-glucosidase, or acid maltase, deficiency (type II glycogenosis) 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 insufficiency. Glycogen accumulation in motor neurons of the spinal cord and brainstem contributes to muscle weakness.
Death usually occurs by 1.5 years of age. In the childhood form, the
picture resembles DMD with delayed motor milestones resulting 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. Ventilatory weakness can be the
initial and only manifestation in 20–30% of late-onset cases.
The serum CK level is 2–10 times normal in infantile or
childhood-onset Pompe disease but can be normal in adult-onset
cases. EMG can demonstrate muscle membrane irritability, particularly 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 biopsies in late-onset Pompe disease
may demonstrate only nonspecific abnormalities. Enzyme analysis of
dried blood spots is a sensitive technique to screen for Pompe disease.
A definitive diagnosis is established by genetic testing.
Pompe 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 is beneficial
in infantile-onset Pompe disease. In late-onset cases, ERT has a more
modest benefit.
OTHER GLYCOGEN STORAGE DISEASES WITH PROGRESSIVE WEAKNESS In debranching enzyme deficiency (type III glycogenosis), a
slowly progressive 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;
hepatomegaly, growth retardation, and hypoglycemia are other manifestations. 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 manifestations are minor compared to liver failure.
Recently, the first autosomal dominant glycogen storage disease was
reported in a family and was caused by a mutation in the PYGM gene
that typically causes autosomal recessive McArdle disease. Affected
individuals presented with progressive proximal weakness, no exercise
intolerance, normal CK, and a normal lactic acid increase with exercise.
■ LIPID AS AN ENERGY SOURCE
AND ASSOCIATED DEFECTS
Lipid is an important muscle energy source during rest and during
prolonged, submaximal exercise. Oxidation of fatty acids occurs in
the mitochondria. To enter the mitochondria, a fatty acid must first be
converted to an “activated fatty acid,” acyl-CoA. The acyl-CoA must
be linked with carnitine by the enzyme CPT for transport into the
mitochondria.
Carnitine Palmitoyltransferase 2 Deficiency CPT2 deficiency
is the most common recognizable cause of recurrent myoglobinuria.
Onset is usually in the teenage years or early twenties. Muscle pain and
myoglobinuria typically occur after prolonged exercise but can also
be precipitated by fasting or infections; up to 20% of patients do not
exhibit myoglobinuria, however. Strength is normal between attacks.
In contrast to disorders caused by defects in glycolysis, in which muscle cramps follow short, intense bursts of exercise, the muscle pain in
CPT2 deficiency does not occur until the limits of utilization have been
exceeded and muscle breakdown has already begun.
Serum CK levels and EMG findings are both usually normal between
episodes. A normal rise of venous lactate during forearm exercise distinguishes this condition from glycolytic defects. Muscle biopsy does
not show lipid accumulation and is usually normal between attacks.
The diagnosis requires direct measurement of muscle CPT or genetic
testing. Attempts to improve exercise tolerance with frequent meals
and a low-fat, high-carbohydrate diet, or by substituting medium-chain
triglycerides in the diet, have not proven to be beneficial.
MITOCHONDRIAL MYOPATHIES
Mitochondria play a key role in energy production. Oxidation of the
major nutrients derived from carbohydrate, fat, and protein leads to the
generation of reducing equivalents. The latter are transported through
the respiratory chain in the process known as oxidative phosphorylation.
The energy generated by the oxidation-reduction reactions of the
respiratory chain is stored in an electrochemical gradient coupled to
ATP synthesis.
A novel feature of mitochondria is their genetic composition. Each
mitochondrion possesses a DNA genome that is distinct from that of
the nuclear DNA. Human mitochondrial DNA (mtDNA) consists of a
double-strand, circular molecule comprising 16,569 base pairs (bp). It
codes for 22 transfer RNAs, 2 ribosomal RNAs, and 13 polypeptides
of the respiratory chain enzymes. The genetics of mitochondrial diseases differ from the genetics of chromosomal disorders. The DNA of
mitochondria is directly inherited from the cytoplasm of the gametes,
mainly from the oocyte. The sperm contributes very little of its mitochondria to the offspring at the time of fertilization. Thus, mitochondrial genes are derived almost exclusively from the mother, accounting
for maternal inheritance of some mitochondrial disorders.
3529 Muscular Dystrophies and Other Muscle Diseases CHAPTER 449
Patients with mitochondrial myopathies have clinical manifestations that usually fall into three groups: chronic progressive external
ophthalmoplegia (CPEO), skeletal muscle–CNS syndromes, and pure
myopathy simulating muscular dystrophy or metabolic myopathy.
Unfortunately, no specific medical therapies are clearly beneficial,
although coenzyme Q10 supplements are often prescribed.
Kearns-Sayre Syndrome (KSS) This is a widespread multiorgan
system disorder with a defined triad of clinical findings: onset before
age 20, CPEO, and pigmentary retinopathy, plus one or more of the
following features: complete heart block, cerebrospinal fluid (CSF)
protein >1 g/L (100 mg/dL), or cerebellar ataxia. The cardiac disease
includes syncopal attacks and cardiac arrest related to the abnormalities in the cardiac conduction system: prolonged intraventricular
conduction time, bundle branch block, and complete atrioventricular
block. Death attributed to heart block occurs in ~20% of the patients.
Varying degrees of progressive limb muscle weakness and easy fatigability affect activities of daily living. Many affected individuals have
intellectual disabilities. Endocrine abnormalities are also common,
including gonadal dysfunction in both sexes with delayed puberty,
short stature, and infertility. Diabetes mellitus occurs in ~13% of KSS
patients. Other less common endocrine disorders include thyroid disease, hyperaldosteronism, Addison’s disease, and hypoparathyroidism.
Serum CK and lactate levels are normal or slightly elevated. EMG
is myopathic. NCS may be abnormal related to an associated neuropathy. Muscle biopsies reveal ragged red fibers and cytochrome oxidase
(COX)–negative fibers. By electron microscopy, there are increased
numbers of mitochondria that often appear enlarged and contain
paracrystalline inclusions.
KSS is a sporadic disorder caused by single mtDNA deletions that
are presumed to arise spontaneously in the ovum or zygote. The most
common deletion, occurring in about one-third of patients, removes
4977 bp of contiguous mtDNA. Monitoring for cardiac conduction
defects is critical. Prophylactic pacemaker implantation is indicated
when ECGs demonstrate a bifascicular block.
Progressive External Ophthalmoplegia (PEO) PEO can be
caused by nuclear DNA mutations affecting mtDNA and thus inherited
in a Mendelian fashion or by mutations in mtDNA. Onset is usually
after puberty. Fatigue, exercise intolerance, dysphagia, and complaints
of muscle weakness are typical. The neurologic examination confirms
the ptosis and ophthalmoplegia, usually asymmetric in distribution.
Patients do not complain of diplopia. Mild facial, neck flexor, and
proximal weakness is typical. Rarely, respiratory muscles may be progressively affected and may be the direct cause of death.
Serum CK and lactate can be normal or mildly elevated. The EMG
can be myopathic. Ragged red and COX-negative fibers are prominently displayed in the muscle biopsy.
This autosomal dominant form of CPEO is most commonly caused
by mutations in the genes encoding adenine nucleotide translocator 1
(ANT1), twinkle gene (C10orf2), and mtDNA polymerase 1 (POLG1).
Autosomal recessive PEO can also be caused by mutations in POLG1.
Point mutations have been identified within various mitochondrial
tRNA (Leu, Ile, Asn, Trp) genes in families with maternal inheritance
of PEO.
There is no specific medical treatment available; exercise may
improve function, but this will depend on the patient’s ability to
participate.
Myoclonic Epilepsy with Ragged Red Fibers (MERRF) The
onset of MERRF is variable, ranging from late childhood to middle
adult life. Characteristic features include myoclonic epilepsy, cerebellar
ataxia, and progressive proximal muscle weakness. The seizure disorder is an integral part of the disease and may be the initial symptom.
Cerebellar ataxia precedes or accompanies epilepsy. Other more variable features include dementia, peripheral neuropathy, optic atrophy,
hearing loss, and diabetes mellitus.
Serum CK levels and lactate may be normal or elevated. EMG
is myopathic, and in some patients, NCS show a neuropathy. The
electroencephalogram is abnormal, corroborating clinical findings of
epilepsy. Typical ragged red fibers are seen on muscle biopsy. MERRF
is caused by maternally inherited point mutations of mitochondrial
tRNA genes. The most common mutation found in 80% of MERRF
patients is an A to G substitution at nucleotide 8344 of tRNA lysine
(A8344G tRNAlys). Only supportive treatment is possible, with special
attention to epilepsy.
Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis,
and Stroke-like Episodes (MELAS) MELAS is the most common mitochondrial encephalomyopathy. The term stroke-like is appropriate because the cerebral lesions do not conform to a strictly vascular
distribution. The onset in the majority of patients is before age 20.
Seizures, usually partial motor or generalized, are common and may
represent the first clearly recognizable sign of disease. The cerebral
insults that resemble strokes cause hemiparesis, hemianopia, and cortical blindness. A presumptive stroke occurring before age 40 should
place this mitochondrial encephalomyopathy high in the differential
diagnosis. Associated conditions include hearing loss, diabetes mellitus, hypothalamic pituitary dysfunction causing growth hormone
deficiency, hypothyroidism, and absence of secondary sexual characteristics. In its full expression, MELAS leads to dementia, a bedridden
state, and a fatal outcome. Serum lactic acid is typically elevated.
The CSF protein is also increased but is usually ≤1 g/L (100 mg/dL).
Muscle biopsies show ragged red fibers. Neuroimaging demonstrates
basal ganglia calcification in a high percentage of cases. Focal lesions
that mimic infarction 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 usually caused by maternally inherited point mutations of mitochondrial tRNA genes. The A3243G point mutation in
tRNALeu(UUR) is the most common, occurring in ~80% of MELAS cases.
No specific treatment is available. Supportive treatment is essential for
the stroke-like episodes, seizures, and endocrinopathies.
Mitochondrial DNA Depletion Syndromes Mitochondrial
DNA depletion syndrome (MDS) is a heterogeneous group of disorders
that are inherited in an autosomal recessive fashion and can present in
infancy or in adults. MDS can be caused by mutations in several genes
(TK2, DGUOK, RRM2B, TYMP, SUCLA1, and SUCLA2) that lead to
depletion of mitochondrial deoxyribonucleotides (dNTP) necessary
for mtDNA replication. The other major cause of MDS is a set of
mutations in genes essential for mtDNA replication (e.g., POLG1 and
C10orf2). The clinical phenotypes associated with MDS vary. Patients
may develop a severe encephalopathy (e.g., Leigh’s syndrome), PEO,
an isolated myopathy, myo-neuro-gastrointestinal encephalopathy
(MNGIE), and a sensory neuropathy with ataxia.
DISORDERS OF MUSCLE MEMBRANE
EXCITABILITY
Muscle membrane excitability is affected in a group of disorders
referred to as channelopathies. These disorders usually present with
episodic muscle weakness (periodic paralysis) and sometimes myotonia or paramyotonia (Table 449-1).
■ CALCIUM CHANNEL DISORDERS OF MUSCLE
Hypokalemic Periodic Paralysis (HypoKPP) This is an autosomal dominant disorder with onset in adolescence. Males are more
often affected because of decreased penetrance in females. Episodic
weakness with onset after age 25 is almost never due to periodic paralyses, with the exception of thyrotoxic periodic paralysis. Attacks are
often provoked by meals high in carbohydrates or sodium and may
accompany rest following prolonged exercise. Weakness usually affects
proximal limb muscles more than distal. Ocular and bulbar muscles
are less likely to be affected. Respiratory muscles are usually spared, but
when they are involved, the condition may prove fatal. Weakness may
3530 PART 13 Neurologic Disorders
take as long as 24 h to resolve. Life-threatening cardiac arrhythmias
related to hypokalemia may occur during attacks. As a late complication, patients commonly develop severe, disabling proximal lower
extremity weakness.
Attacks of thyrotoxic periodic paralysis resemble those of primary
HypoKPP. Despite a higher incidence of thyrotoxicosis in women,
men, particularly those of Asian descent, are more likely to manifest
this complication. Attacks abate with treatment of the underlying thyroid condition.
A low serum potassium level during an attack, excluding secondary
causes, establishes the diagnosis. In the midst of an attack of weakness, motor conduction studies may demonstrate reduced amplitudes,
whereas EMG may show electrical silence in severely weak muscles.
In between attacks, the EMG and routine NCS are normal. However,
a long exercise NCS test may demonstrate decrementing amplitudes.
HypoKPP type 1 is the most common form and is caused by mutations in the voltage-sensitive, skeletal muscle calcium channel gene,
CALCL1A3. Approximately 10% of cases are HypoKPP type 2, arising
from mutations in the voltage-sensitive sodium channel gene (SCN4A).
In both forms, the mutations lead to an abnormal gating pore current
that predisposes the muscle cell to depolarize when potassium levels
are low.
TREATMENT
Hypokalemic Periodic Paralysis
Mild attacks usually do not require medical treatment. However,
severe attacks of weakness can be improved by the administration
of potassium. Oral KCl (0.2–0.4 mmol/kg) can be given every
30 min. Only rarely is IV therapy necessary (e.g., when swallowing
problems or vomiting is present). The long-term goal of therapy
is to avoid attacks. Patients should be made aware of the importance of a low-carbohydrate, low-sodium diet and consequences of
intense exercise. Prophylactic administration of acetazolamide or
dichlorphenamide can reduce attacks of periodic weakness. However, in patients with HypoKPP type 2, attacks of weakness can be
exacerbated with these medications.
■ SODIUM CHANNEL DISORDERS OF MUSCLE
Hyperkalemic Periodic Paralysis (HyperKPP) The term
hyperkalemic is misleading because patients are often normokalemic
during attacks. That attacks are precipitated by potassium administration best defines the disease. The onset is usually in the first decade;
males and females are affected equally. Attacks are brief and mild, usually lasting 30 min to several hours. Weakness affects proximal muscles, sparing bulbar muscles. Attacks are precipitated by rest following
exercise and fasting.
Potassium may be slightly elevated or normal during an attack. As
in HypoKPP, NCS in HyperKPP muscle may demonstrate reduced
motor amplitudes and the EMG may be silent in very weak muscles. A
long exercise NCS test can reveal diminished amplitudes as well. The
EMG may demonstrate myotonic discharges. HyperKPP is caused by
mutations of the voltage-gated sodium channel SCN4A gene. Acetazolamide or dichlorphenamide can reduce the frequency and severity of
attacks. Mexiletine may be helpful in patients with significant clinical
myotonia.
Paramyotonia Congenita In PC, the attacks of weakness are
cold-induced or occur spontaneously and are mild. Myotonia is a
prominent feature but worsens with muscle activity (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
inter-attack weakness as they do in other forms of periodic paralysis.
Serum CK is usually mildly elevated. Routine NCS are normal. Short
exercise NCS tests may be abnormal, 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 are responsible, and thus, this disorder is
allelic with HyperKPP. Mexiletine is reported to be helpful in reducing
the myotonia.
■ POTASSIUM CHANNEL DISORDERS
Andersen-Tawil Syndrome This rare disease is characterized
by episodic weakness, cardiac arrhythmias, and dysmorphic features
(short stature, 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
tachycardia. The disease is most commonly caused by mutations of
the inwardly rectifying potassium channel (Kir 2.1) gene that heighten
muscle cell excitability. The episodes of weakness may differ between
patients because of potassium variability. Acetazolamide may decrease
the attack frequency and severity.
■ CHLORIDE CHANNEL DISORDERS
Two forms of this disorder, autosomal dominant (Thomsen disease)
and autosomal recessive (Becker disease), are both caused by mutations in the chloride channel 1 gene (CLCN1). 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 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.
Mexiletine is helpful in relieving the myotonia.
ENDOCRINE AND METABOLIC
MYOPATHIES
Endocrinopathies can cause weakness, but fatigue is more common
than true weakness. 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
Hypothyroidism (Chap. 383) Patients with hypothyroidism
have frequent muscle complaints, and about one-third have proximal
muscle weakness. 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). EMG is typically normal. Muscle biopsy shows no distinctive morphologic abnormalities.
Hyperthyroidism (Chap. 384) Patients who are thyrotoxic
commonly have proximal muscle weakness, but they rarely complain
of myopathic symptoms. Activity of deep tendon reflexes may be
enhanced. Fasciculations may be apparent and, when coupled with
increased muscle stretch reflexes, may lead to an erroneous diagnosis
of amyotrophic lateral sclerosis. A form of hypokalemic periodic paralysis can occur in patients who are thyrotoxic. 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.
■ PARATHYROID DISORDERS (SEE ALSO CHAP. 410)
Hyperparathyroidism Proximal muscle weakness, muscle wasting, and brisk muscle stretch reflexes are the main features of this
endocrinopathy. Some patients develop neck extensor weakness (part
3531 Muscular Dystrophies and Other Muscle Diseases CHAPTER 449
of the dropped head syndrome). Serum CK levels are usually normal or
slightly elevated. Serum parathyroid hormone levels are elevated, while
vitamin D and calcium levels are usually reduced. Muscle biopsies
show only mild type 2 fiber atrophy.
Hypoparathyroidism An overt myopathy due to hypocalcemia rarely occurs. Neuromuscular symptoms are usually related to
localized or generalized tetany. Serum CK levels may be increased
secondary to muscle damage from sustained tetany. Hyporeflexia or
areflexia is usually present and contrasts with the hyperreflexia in
hyperparathyroidism.
■ ADRENAL DISORDERS (SEE ALSO CHAP. 386)
Conditions associated with glucocorticoid excess cause a myopathy;
steroid myopathy is the most commonly diagnosed endocrine muscle disease. Proximal muscle weakness combined with a cushingoid
appearance are the key clinical features. Serum CK and EMG are normal. Muscle biopsy, not typically done for diagnostic purposes, reveals
type 2b muscle fiber atrophy. In primary hyperaldosteronism (Conn’s
syndrome), neuromuscular complications are due to potassium depletion. The clinical picture is one of persistent muscle weakness. Longstanding hyperaldosteronism may lead to proximal limb weakness and
wasting. Serum CK levels may be elevated, and a muscle biopsy may
demonstrate necrotic fibers. These changes relate to hypokalemia and
are not a direct effect of aldosterone on skeletal muscle.
■ PITUITARY DISORDERS (SEE ALSO CHAP. 380)
Patients with acromegaly usually have mild proximal weakness. Muscles often appear enlarged but exhibit decreased force generation. The
duration of acromegaly, rather than the serum growth hormone levels,
correlates with the degree of myopathy.
■ DIABETES MELLITUS (SEE ALSO CHAP. 405)
Neuromuscular complications of diabetes mellitus are most often
related to neuropathy. The only notable myopathy is ischemic infarction of leg muscles, usually involving one of the thigh muscles but on
occasion affecting the distal leg. This condition occurs in patients with
poorly controlled diabetes and presents with the abrupt onset of pain,
tenderness, and edema of a thigh or calf. The area of muscle infarction
is hard and indurated. The muscles most often affected include the
vastus lateralis, thigh adductors, and biceps femoris. Computed tomography (CT) or MRI can demonstrate focal abnormalities in the affected
muscle. Diagnosis by imaging is preferable to muscle biopsy, if possible,
as hemorrhage into the biopsy site can occur.
MYOPATHIES OF SYSTEMIC ILLNESS
Systemic illnesses such as chronic respiratory, cardiac, or hepatic
failure are frequently associated with severe muscle wasting and complaints of weakness. Fatigue is usually a more significant problem than
weakness, which is typically mild.
DRUG-INDUCED OR TOXIC MYOPATHIES
The most common toxic myopathies are caused by the cholesterol-lowering agents and glucocorticoids. Others impact practice to a lesser
degree but are important to consider in specific situations. Table 449-6
provides a comprehensive list of drug-induced myopathies with their
distinguishing features.
■ MYOPATHY FROM LIPID-LOWERING AGENTS
All classes of lipid-lowering agents have been implicated in muscle
toxicity, including HMG-CoA reductase inhibitors (statins) and, to
a much lesser extent, fibrates, niacin, and ezetimibe. Myalgia and
elevated CKs are the most common manifestations. Rarely, patients
exhibit proximal weakness or myoglobinuria. Concomitant use of statins with fibrates and cyclosporine increases the risk of severe myotoxicity. EMG demonstrates irritability, and myopathic units and muscle
biopsies reveal necrotic muscle fibers in weak muscles. Severe myalgia,
weakness, marked elevations in serum CK (>3–5 times baseline), and
myoglobinuria are indications for stopping the drug. Patients usually
improve with drug cessation, although this may take several weeks.
Rare cases continue to progress after the offending agent is discontinued. It is possible that in such cases the statin may have triggered an
immune-mediated necrotizing myopathy, as these individuals require
immunotherapy (e.g., intravenous immunoglobulin or immunosuppressive agents) to improve and often relapse when these therapies are
discontinued (Chap. 365). Autoantibodies directed against HMG-CoA
reductase have been identified in many of these cases.
■ GLUCOCORTICOID-RELATED MYOPATHIES
Glucocorticoid myopathy occurs with chronic treatment or as “acute
quadriplegic” myopathy secondary to high-dose IV glucocorticoid use.
Chronic administration produces proximal weakness accompanied by
cushingoid manifestations, which can be quite debilitating; the chronic
use of prednisone at a daily dose of ≥30 mg/d is most often associated
with toxicity. Patients taking fluorinated glucocorticoids (triamcinolone, betamethasone, dexamethasone) appear to be at especially
high risk for myopathy. In chronic steroid myopathy, the serum CK is
usually normal. Serum potassium may be low. The muscle biopsy in
chronic cases shows preferential type 2 muscle fiber atrophy; this is not
reflected in the EMG, which is usually normal.
TABLE 449-6 Drug-Induced Myopathies
DRUGS MAJOR TOXIC REACTION
Lipid-lowering agents
HMG-CoA reductase inhibitors
Fibric acid derivatives
Niacin (nicotinic acid)
Drugs belonging to all three of the
major classes of lipid-lowering agents
can produce a spectrum of toxicity:
asymptomatic serum creatine kinase
elevation, myalgias, exercise-induced pain,
rhabdomyolysis, and myoglobinuria.
Glucocorticoids Acute, high-dose glucocorticoid
treatment can cause acute quadriplegic
myopathy. These high doses of steroids
are often combined with nondepolarizing
neuromuscular blocking agents, but the
weakness can occur without their use.
Chronic steroid administration produces
predominantly proximal weakness.
Nondepolarizing neuromuscular
blocking agents
Acute quadriplegic myopathy can
occur with or without concomitant
glucocorticoids.
Zidovudine Mitochondrial myopathy with ragged red
fibers
Drugs of abuse
Alcohol
Amphetamines
Cocaine
Heroin
Phencyclidine
Meperidine
All drugs in this group can lead to
widespread muscle breakdown,
rhabdomyolysis, and myoglobinuria.
Local injections cause muscle necrosis,
skin induration, and limb contractures.
Autoimmune myopathy
Statins
Check point inhibitors
D-Penicillamine
Use of statins may cause an immunemediated necrotizing myopathy associated
with HMG-CoA reductase antibodies.
Checkpoint inhibitors can be complicated
by myositis, myasthenia gravis, and
immune-mediated neuropathies.
Myasthenia gravis has also been reported
with penicillamine.
Amphophilic cationic drugs
Amiodarone
Chloroquine
Hydroxychloroquine
All amphophilic drugs have the potential
to produce painless, proximal weakness
associated with necrosis and autophagic
vacuoles in the muscle biopsy.
Antimicrotubular drugs
Colchicine
This drug produces painless, proximal
weakness especially in the setting of renal
failure. Muscle biopsy shows necrosis and
fibers with autophagic vacuoles.
