MYOPATHIES

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The myopathies are neuromuscular disorders in which the primary symptom is muscle weakness due to dysfunction of muscle fiber. Other symptoms of myopathy can include include muscle cramps, stiffness, and spasm. Myopathies can be inherited (such as the muscular dystrophies) or acquired (such as common muscle cramps). Myopathies are grouped as follows:
congenital myopathies: characterized by developmental delays in motor skills; skeletal and facial abnormalities are occasionally evident at birth
muscular dystrophies: characterized by progressive weakness in voluntary muscles; sometimes evident at birth
mitochondrial myopathies: caused by genetic abnormalities in mitochondria, cellular structures that control energy; include Kearns-Sayre syndrome, MELAS and MERRF
glycogen storage diseases of muscle: caused by mutations in genes controlling enzymes that metabolize glycogen and glucose (blood sugar); include Pompe’s, Andersen’s and Cori’s diseases
myoglobinurias: caused by disorders in the metabolism of a fuel (myoglobin) necessary for muscle work; include McArdle, Tarui, and DiMauro diseases
dermatomyositis: an inflammatory myopathy of skin and muscle
myositis ossificans: characterized by bone growing in muscle tissue
familial periodic paralysis: characterized by episodes of weakness in the arms and legs
polymyositis, inclusion body myositis, and related myopathies: inflammatory myopathies of skeletal muscle
neuromyotonia: characterized by alternating episodes of twitching and stiffness; and
stiff-man syndrome:  characterized by episodes of rigidity and reflex spasms
common muscle cramps and stiffness, and
tetany:  characterized by prolonged spasms of the arms and legs

Symptoms-

There are several different types of genetic myopathies, most of which have similar symptoms. These include:

• Muscle weakness
• Motor delay
• Respiratory impairment
• Bulbar muscle dysfunction (malfunction of the muscles responsible for swallowing and speech)

Bulbar muscle dysfunctions can be especially apparent in congenital myopathies (those present from birth), and can result in severe impairments to swallowing and speech abilities. Congenital myopathies also are characterized by developmental motor delays and, at times, facial or skeletal abnormalities.

Acquired myopathies may have symptoms similar to those of genetic myopathies and also may include:

• Muscle weakness
• Muscle soreness (myalgias)
• Cramps
• Stiffness
• Muscle wasting around the shoulders and hips

Causes and Risk Factors

Patients who have a blood relative with a genetic myopathy have an increased risk for developing the condition. Depending on how the myopathy is inherited, men can be at greater risk than women of developing the condition. Myopathies carried on the X chromosome affect more men than women, while those carried on chromosomes other than the sex chromosome affect both men and women equally.

Patients may be at increased risk of developing acquired myopathy if they have an autoimmune disorder, metabolic or endocrine disorder, are on certain drugs or are exposed to certain toxins.

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Classification

Myopathies may be divided into two main categories: inherited and acquired. The temporal course, the pattern of muscle weakness, and the absence or presence of a family history of myopathy help distinguish between the two types. An early age of onset with a relatively longer duration of disease suggests an inherited myopathy, and a sudden or subacute presentation at a later age is more consistent with an acquired myopathy. Inherited myopathies can be further subclassified as muscular dystrophies, congenital myopathies, mitochondrial myopathies, and metabolic myopathies. Acquired myopathies can be subclassified as inflammatory myopathies, toxic myopathies, and myopathies associated with systemic conditions. The more commonly seen inherited and acquired myopathies are listed in Box 1.

Box 1 Common Causes of Myopathy
Acquired Myopathies
Inflammatory Myopathy Polymyositis Dermatomyositis Inclusion body myositis
Infection Viral infections (HIV, influenza virus, Epstein-Barr virus) Bacterial pyomyositis (Staphylococcus aureus and streptococci are common organisms) Spirochete (Lyme disease) Parasitic infections such as trichinosis
Toxic Myopathy Medications Steroids Cholesterol-lowering medications: statins, fibrates, niacin, and ezetimibe Propofol Amiodarone Colchicine Chloroquine Antivirals and protease inhibitors Omeprazole Tryptophan Toxins Alcohol Toluene
Myopathy Associated with Systemic Diseases Endocrine disorders Thyroid Parathyroid Pituitary or adrenal dysfunction Systemic inflammatory diseases Systemic lupus erythematosus Rheumatoid arthritis Scleroderma Sjögren’s syndrome Mixed connective disease Sarcoidosis Electrolyte imbalance Potassium or magnesium abnormalities Hypophosphatemia Critical illness myopathy Nondepolarizing neuromuscular blocking agents Steroids Amyloid myopathy Primary amyloidosis Familial amyloidosis (TTR mutation)
Inherited Myopathies
Muscular Dystrophy Dystrophinopathy (Duchenne muscular dystrophy,Becker muscular dystrophy) Myotonic dystrophy 1 and 2 Facioscapulohumeral muscular dystrophy Oculopharyngeal muscular dystrophy Limb girdle muscular dystrophy
Congenital Myopathy Nemaline myopathy Central core myopathy
Metabolic Myopathy Acid maltase or acid alpha-1,4-glucosidase deficiency (Pompe’s disease) Glycogen storage disorders 3-11 Carnitine deficiency Fatty acid oxidation defects Carnitine palmitoyl transferase deficiency
Mitochondrial Myopathy Myoclonic epilepsy and ragged red fibers (MERRF) Mitochondrial myopathy, lactic acidosis, and strokes (MELAS) Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) Progressive external ophthalmoplegia (PEO)

DIAGNOSIS-

The clinical history is essential in identifying the presence of a myopathy and narrowing down the differential diagnosis. In particular, the patient should be questioned about medication and recreational drug history (especially alcohol), chemical exposures, exercise intolerance, childhood development, and family history of muscle disease or developmental motor delay.

Laboratory Testing

Serologic testing, which can indicate muscle damage, includes elevations in creatine phosphokinase (CPK), aldolase, lactate dehydrogenase (LDH), and liver function enzymes. A screening panel of laboratory tests may also be obtained to rule out more common causes of myopathy, which are listed in. In cases suspected to be a primary inflammatory myopathy, specific autoantibodies can be considered to determine the prognosis and rule out associated conditions. For example, the presence of anti-Jo antibody in dermatomyositis predicts a superimposed interstitial lung disease. In addition, these patients should also be evaluated for an underlying systemic autoimmune disease with an extensive autoimmune panel and angiotensin-converting enzyme (ACE) levels. In myopathies that are accompanied by polyneuropathy, renal involvement, and a restrictive cardiomyopathy, immunofixation electrophoresis studies in the serum and urine should be considered to rule out the possibility of amyloid disease. Genetic testing is available for some inherited myopathies. These are listed in

Box 2 Laboratory Evaluation for Suspected Myopathy
Confirm the Presence of Muscle Disease Creatine phosphokinase Aldolase Liver function tests Lactate dehydrogenase levels
Identify Etiology Complete blood count with differential Complete metabolic panel Thyroid function tests Parathyroid hormone level Sedimentation rate C-reactive protein and antinuclear antibody panel
Suspected Inflammatory Etiology Myositis-specific autoantibodies Anti–double stranded DNA antibody Anti-Scl 70 antibody Anti-SSA and SSB antibodies Anti-ribonucleoprotein antibody Rheumatoid factor Anti-PM1 antibody Angiotensin-converting enzyme levels
Suspected Mitochondrial or Metabolic Myopathy Serum lactate, pyruvate, ammonia, coenzyme Q10 levels Ischemic forearm lactate test Carnitine levels
Suspected Amyloid Myopathy Immunofixation electrophoresis of monoclonal proteins in serum and urine

Table 2 Commercially Available Genetic Tests in Diagnosis of a Myopathy

Myopathies with Known Genetic Defects	Gene Abnormalities	Pattern of Inheritance
Duchenne muscular dystrophy	Dystrophin gene	X-linked recessive
Becker muscular dystrophy	Dystrophin gene	X-linked recessive
Emery-Dreifuss muscular dystrophy	Emerin gene	X-linked recessive
Limb girdle muscular dystrophy	Lamin A/C Calpain Dysferlin Fukutin related protein	Some are autosomal dominant and others are recessive
Facioscapulohumeral muscular dystrophy	D4Z4 deletion	Autosomal dominant
Oculopharyngeal muscular dystrophy	GCG repeat expansion in poly A binding protein 2 gene	Autosomal dominant
Myotonic dystrophy 1 and 2	DMPK gene for type 1 CNBP (ZNF9) gene for type 2	Autosomal dominant
Mitochondrial myopathy	Specific point mutation analysis for diseases like MELAS POLG1 sequencing for MERRF available Southern blot analysis for mtDNA deletions and mtDNA sequencing	Maternally inherited. But other can be inherited as autosomal dominant or recessive disease
Amyloid myopathy from familial causes	Transthyretin mutation	Autosomal dominant
Statin myopathy (predictor of increased susceptibility)	SLCO1B1 gene	Unknown

MELAS, mitochondrial myopathy, lactic acidosis, and strokes; MERRF, myoclonic epilepsy and ragged red fibers; mtDNA, mitochondrial DNA.

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Ischemic Forearm Test

A traditional test used in the evaluation of a suspected metabolic myopathy is the ischemic forearm test. This is performed by obtaining baseline serum ammonia and lactate levels taken from the forearm. The patient then exercises that arm for 1 minute, after which repeat serum lactate and blood ammonia levels are measured. This is repeated at several intervals (1, 2, 5, and 10 minutes). In normal muscle, the resultant ischemia causes a 3- to 5-fold rise in lactate levels. In contrast, patients with glycogen storage disorders demonstrate no change in lactate levels after exercise.

Electrodiagnostic Studies

The electromyogram (EMG) is an electrical study of the nerves and muscles that plays an important role in confirming the presence, duration, and severity of a myopathy. The study can also disclose special findings such as myotonic potentials. This is the electrical equivalent of clinical myotonia, which is manifested as impaired relaxation of muscles after forceful contraction; for example, patients cannot release objects from their grip. Myotonic potentials have the characteristic sound of a dive bomb on EMG and can help point toward the diagnosis of myotonic dystrophy when found in the appropriate muscles.

Although integral in the evaluation of a myopathy, the EMG can be normal in mild myopathies, steroid myopathies, and a number of metabolic myopathies. Therefore, it is important to remember that a normal EMG does not exclude the presence of a myopathy.

Muscle Biopsy

Histopathologic examination of muscle may be helpful in determining the specific type of muscle disease, especially in patients with a suspected inflammatory or infectious myopathy. Selecting the optimal muscle to biopsy is very important because factors such as severe weakness and technical artifacts can hamper an accurate histologic diagnosis. The ideal muscle that should be sampled is one that is clinically involved but still antigravity in strength, because more-severe weakness can lead to unhelpful, nonspecific findings of fibrosis. Also avoid muscles that have been examined by an EMG because the needle portion of the electrical study might have caused local damage, which can result in spurious findings. Common biopsy sites include the biceps and deltoid muscles in the upper extremity and the quadriceps and gastrocnemius muscles in the lower extremity.

TREATMENT-

Treatments for the myopathies depend on the disease or condition and specific causes. Supportive and symptomatic treatment may be the only treatment available or necessary for some disorders. Treatment for other disorders may include drug therapy, such as immunosuppressives, physical therapy, bracing to support weakened muscles, and surgery.

The treatment of myopathies is multidisciplinary and depends on the type of myopathy. Certain types of myopathies can be treated with immune-suppressant agents and IVIG. Most myopathies require the use of supportive services, such as physical and occupational therapy, pulmonary medicine, cardiology, dietary management, and speech/swallowing therapists. Surgical treatment of spine and limb deformities is used in long-standing cases.

While there is no cure for genetic myopathy, many different treatment options are available to manage the symptoms. Treatments for both genetic and endocrine myopathy are most effective when the disease is diagnosed early and a comprehensive treatment plan is overseen by a knowledgeable medical team, such as those at Cedars-Sinai’s Neuromuscular Disorders Program.

For acquired myopathies due to the immune system, such as dermatomyositis and polymyositis, medications that work to reduce the body’s immune response and decrease inflammation, such as corticosteroids or other immunosuppressants, can help manage some symptoms. Physical therapy, supportive devices such as braces, and sometimes surgery may also be used as treatment tools.

Treatment of metabolic, toxic and endocrine-related myopathy generally focuses on the underlying cause of the condition. Medication or surgery may be used to address the symptoms.

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