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.