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Harrison’s Manual of Medicine



Muscular Dystrophies

Duchenne Dystrophy

Myotonic Dystrophy

Facioscapulohumeral Dystrophy

Limb-Girdle Dystrophy

Oculopharyngeal Dystrophy (Progressive External Ophthalmoplegia)
Inflammatory Myopathies
Metabolic Myopathies
Mitochondrial Myopathies
Periodic Paralyses
Miscellaneous Disorders

Muscle diseases usually present as intermittent or persistent weakness. These disorders are usually painless; however, myalgias, or muscle pains, may occur. Myalgias must be distinguished from muscle cramps, i.e., painful muscle contractions, usually due to neurogenic disorders. A muscle contracture due to an inability to relax after an active muscle contraction is associated with energy failure in glycolytic disorders. Myotonia is a condition of prolonged muscle contraction followed by slow muscle relaxation. It is important to distinguish between true muscle weakness and a complaint of fatigue; fatigue without abnormal clinical or laboratory findings almost never indicates a true muscle disorder. An approach to pts with muscle weakness is summarized in Fig. 197-1 and Fig. 197-2.

FIGURE 197-1. Diagnostic evaluation for intermittent weakness. EOMs, extraocular muscles; AChR AB, acetylcholine receptor antibody; PP, periodic paralysis, CPT, carnitine palmityl transferase; MG, myasthenia gravis.

FIGURE 197-2. Diagnostic evaluation for persistent weakness. EOM, extraocular muscle; OPMD, oculopharyngeal muscular dystrophy; FSHD, facioscapulohumeral muscular dystrophy; IBM, inclusion body myositis; DM, dermatomyositis; PM, polymyositis; MG, myasthenia gravis, ALS, amyotrophic lateral sclerosis; CK, creatine kinase.

A group of inherited, progressive degenerations of muscle that vary widely in their clinical and pathologic features and mode of inheritance.
Duchenne Dystrophy
X-linked recessive mutation of the dystrophin gene that affects males almost exclusively. Onset is by age 5; symmetric and progressive weakness in hip and shoulder girdle muscles leading to difficulty in climbing, running, jumping, hopping, etc. By age 8–10, most children require leg braces; by age 12, the majority are nonambulatory. Survival beyond age 25 is rare. Becker dystrophy is a less severe form, with a slower course and later age of onset (5–15) but similar clinical, laboratory, and genetic features.
Associated problems include tendon and muscle contractures (e.g., heel cords), progressive kyphoscoliosis, impaired pulmonary function, cardiomyopathy, and intellectual impairment. Palpable enlargement and firmness of some muscles (e.g., calves) results initially from hypertrophy and later from replacement of muscle by fat and connective tissue.
Laboratory Findings   Include massive elevations (20–100 × normal) of muscle enzymes (CK, aldolase), a myopathic pattern on EMG testing, and evidence of groups of necrotic muscle fibers with regeneration, phagocytosis, and fatty replacement of muscle on biopsy. Diagnosis is established by determination of dystrophin in muscle tissue by western blot and/or immunochemical staining. Mutations in the dystrophin gene can be identified in approximately two-thirds of pts using a battery of cDNA probes. ECG abnormalities (increased net RS in V1, deep Q in precordial leads) reflect the presence of cardiomyopathy. Serum CK is elevated in 50% of female carriers. Testing is now available for detecting carriers and prenatal diagnosis.

Glucocorticoids [prednisone, 0.75 (mg/kg)/d] may significantly alter progression of disease for up to 3 years, but complications of chronic use often outweigh the benefits. Passive stretching of muscles, tenotomy, bracing, physiotherapy, mechanical assistance devices, and avoidance of prolonged immobility provide symptomatic benefit.

Myotonic Dystrophy
The most common adult muscular dystrophy. Autosomal dominant with genetic anticipation. Weakness typically becomes obvious in the second to third decade and initially involves the muscles of the face, neck, and distal extremities. This results in a distinctive facial appearance (“hatchet face”) characterized by ptosis, temporal wasting, drooping of the lower lip, and sagging of the jaw. Myotonia manifests as a peculiar inability to relax muscles rapidly following a strong exertion (e.g., after tight hand grip), as well as by sustained contraction of muscles following percussion (e.g., of tongue or thenar eminence).
Associated problems can include frontal baldness, posterior subcapsular cataracts, gonadal atrophy, respiratory and cardiac problems, endocrine abnormalities, intellectual impairment, and hypersomnia. Cardiac complications, including complete heart block, may be life-threatening. Respiratory function should be carefully followed, as chronic hypoxia may lead to cor pulmonale.
Laboratory Studies   Normal or mildly elevated CK, characteristic myotonia and myopathic features on EMG, and a typical pattern of muscle fiber injury on biopsy, including selective type I fiber atrophy. Pts have an unstable region of DNA with an increased number of trinucleotide CTG repeats at chromosome location 19q13.3. The expanded repeat may alter expression of a nearby protein kinase gene. Genetic testing for early detection and prenatal diagnosis is possible.

Phenytoin, procainamide, and quinine may help myotonia, but they must be used carefully in pts with heart disease as they may worsen cardiac conduction. Pacemaker insertion may be required for syncope or heart block. Orthoses may control foot drop, stabilize the ankle, and decrease falling.

Facioscapulohumeral Dystrophy
An autosomal dominant, slowly progressive disorder with onset in the third to fourth decade. Weakness involves facial, shoulder girdle, and proximal arm muscles and can result in atrophy of biceps, triceps, scapular winging, and slope shoulders. Facial weakness results in inability to whistle and loss of facial expressivity. Foot drop and leg weakness may cause falls and progressive difficulty with ambulation.
Laboratory Studies   Normal or slightly elevated CK and mixed myopathic- neuropathic features on EMG and muscle biopsy. Pts have deletions at chromosome 4q35. A genetic probe can be used in carrier detection and prenatal diagnosis. Orthoses and other stabilization procedures may be of benefit for selected pts.
Limb-Girdle Dystrophy
A constellation of diseases with proximal muscle weakness involving the arms and legs as the core symptom. Age of onset, rate of progression, severity of manifestations, inheritance pattern (autosomal dominant or autosomal recessive) and associated complications (e.g., cardiac, respiratory) vary with the specific subtype of disease. Laboratory findings include elevated CK and myopathic features on EMG and muscle biopsy. At least eight autosomal recessive forms have been identified by molecular genetic analysis.
Oculopharyngeal Dystrophy (Progressive External Ophthalmoplegia)
Onset in the fifth to sixth decade of ptosis, limitation of extraocular movements, and facial and cricopharyngeal weakness. Most patients are Hispanic or of French-Canadian descent.
The most common group of acquired and potentially treatable skeletal muscle disorders. Three major forms: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). Usually present as progressive and symmetric muscle weakness; extraocular muscles spared but pharyngeal weakness and neck drop common. IBM is characterized by early involvement of quadriceps and distal muscles. Progression is over weeks or months in PM and DM, but typically over years in IBM. Skin involvement in DM may consist of a heliotrope rash (blue-purple discoloration) on the upper eyelids with edema, a flat red rash on the face and upper trunk, or erythema over knuckles. A variety of cancers, including ovarian, breast, melanoma, and colon cancer, are associated with DM. Diagnostic criteria are summarized in Table 197-1.

Table 197-1 Criteria for Definite Diagnosis of Inflammatory Myopathies

Often effective for PM and DM but not for IBM. Step 1: Glucocorticoids [prednisone, 1 (mg/kg)/d for 3–4 weeks, then tapered very gradually]; step 2: Azathioprine [up to 3 (mg/kg)/d] or methotrexate (7.5 mg/week gradually increasing to 25 mg/week); step 3: Intravenous immunoglobulin (2 g/kg divided over 2–5 d); step 4: Cyclosporine, chlorambucil, cyclophosphamide, or mycophenolate mofetil. IBM is generally resistant to immunosuppressive therapies; many experts recommend a short trial of glucocorticoids together with azathioprine or methotrexate.

These disorders result from abnormalities in utilization by muscle of glucose or fatty acids as sources of energy. Pts present with either an acute syndrome of myalgia, myolysis, and myoglobinuria or chronic progressive muscle weakness. Definitive diagnosis requires biochemical-enzymatic studies of biopsied muscle. However, muscle enzymes, EMG, and muscle biopsy are all typically abnormal and may suggest specific disorders.
Glycogen storage disorders can mimic muscular dystrophy or polymyositis. In some types the presentation is one of episodic muscle cramps and fatigue provoked by exercise. The ischemic forearm lactate test is helpful as normal postexercise rise in serum lactic acid does not occur. In adults, progressive muscle weakness beginning in the third or fourth decade can be due to the adult form of acid maltase deficiency, or debranching enzyme deficiency. Exercise intolerance with recurrent myoglobinuria may be due to myophosphorylase deficiency (McArdle’s disease) or phosphofructokinase deficiency. Disorders of fatty acid metabolism present with similar clinical picture. In adults, the most common cause is carnitine palmitoyltransferase deficiency. Exercise-induced cramps, myolysis, and myoglobinuria are common; the picture can resemble polymyositis or muscular dystrophy. Some pts benefit from special diets (medium-chain triglyceride-enriched), oral carnitine supplements, or glucocorticoids.
More accurately referred to as mitochondrial cytopathies because multiple tissues are usually affected, these disorders result from defects in mitochondrial DNA. The clinical presentations vary enormously: muscle symptoms may include weakness, ophthalmoparesis, pain, stiffness, or may even be absent; age of onset ranges from infancy to adulthood; associated clinical presentations include ataxia, encephalopathy, seizures, strokelike episodes, and recurrent vomiting. The characteristic finding on muscle biopsy is “ragged red fibers,” which are muscle fibers with accumulations of abnormal mitochondria. Genetics show a maternal pattern of inheritance because mitochondrial genes are inherited almost exclusively from the oocyte.
Characterized by muscle stiffness due to electrical irritability of the muscle membrane (myotonia), usually without significant muscle weakness until late in the course. Onset is usually in childhood or adolescence. Episodes typically occur after rest or sleep, often following earlier exercise. May be due to genetic disorders of calcium (hypokalemic periodic paralysis), sodium (hyperkalemic period paralysis), or chloride channels. Acute attacks of hypokalemic periodic paralysis are treated with potassium chloride, and prophylaxis with acetazolamide (125–1000 mg/d in divided doses) or dichorphenamide (50–200 mg/d) is usually effective.
Myopathies may be associated with endocrine disorders, especially those involving hypo- or hyperfunction of the thyroid, parathyroid, pituitary, and adrenal glands. Drugs (esp. glucocorticoids) and certain toxins (e.g., alcohol) are commonly associated with myopathies (Table 197-2), as are deficiencies of vitamins D and E. In most cases weakness is symmetric and involves proximal limb girdle muscles. Weakness, myalgia, and cramps are common symptoms. Diagnosis often depends on resolution of signs and symptoms with correction of underlying disorder or removal of offending agent.

Table 197-2 Toxic Myopathies


For a more detailed discussion, see Mendell JR: Approach to the Patient with Muscle Disease, Chap. 381, p. 2520; Dalakas MC: Polymyositis, Dermatomyositis, and Inclusion Body Myositis, Chap. 382, p. 2524; Brown RH Jr., Mendell JR: Muscular Dystrophies and Other Muscle Diseases, Chap. 383, p. 2529, in HPIM-15.

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