Introduction
Muscular dystrophies are genetically determined disorders that have a wide variation in age of
onset, sex distribution, location of maximal mus-cle atrophy, and phenotypic signs. The most com-mon and most serious muscular dystrophy is Duchenne muscular dystrophy (DMD), a lethal childhood disorder associated with a marked defi-ciency or absence of dystrophin. A large gene on the X chromosome at Xp21 encodes dystrophin.
DMD is the most common disease associated with genetic mutations of the dystrophin gene. Collec-tively these diseases are called dystrophinopathies.
As DMD is transmitted by X-linked recessive inheritance, nearly all patients are male. About 10% of female carriers have mild muscle weakness.
The incidence of DMD is 30/100,000 male births, with prevalence in the general population of 3/100,000. New mutations account for about 1/3 of cases.
Pathophysiology
The dystrophin gene is among the largest known, spanning about 2.3 megabases of DNA or almost 40 FUNDAMENTALS OF NEUROLOGIC DISEASE
Table 4-2 Distinguishing Characteristics of Limb Weakness
Upper Motor Lower Motor
Neuron Neuron
Neuro-(Corticospinal (Peripheral Distal Poly- muscular Skeletal
Characteristic Tract) Nerve) neuropathy Junction Muscle
Muscle Involved Distal more than Distal more than Distal more Proximal more Proximal proximal and proximal than proximal than distal more
often unilateral than distal
Muscle Atrophy Minimal Marked Moderate Minimal Moderate
Normal Strength No No No Yes No
that Quickly Fatigues
Fasciculations No Common No No No
Deep Tendon Increased Decreased to Decreased to Normal or Normal to
Reflexes absent absent slightly decreased
decreased proportional to weakness
Sensory Loss May be unilateral Yes Yes No No
Positive Family Uncommon Uncommon Uncommon Uncommon Common
History
CK Elevation No No No No Yes
EMG and nerve None Denervation on Abnormal EMG Minimal Myopathic
conduction EMG or slow and nerve changes on motor units
findings motor nerve studies EMG or on EMG
conduction velocity nerve studies CK = creatine kinase; EMG = electromyogram.
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1% of the entire X chromosome. Muscle dys-trophin is a large 427-kd molecular weight protein of 3,685 amino acids that is found primarily within skeletal, smooth, and cardiac muscle. Dys-trophin isoforms are also present in cortical neu-rons, Purkinje cell neuneu-rons, glia, and Schwann cells. Dystrophin accounts for 5% of sarcolemmal cytoskeletal proteins in muscle. The protein is rod shaped and resides just beneath the sarcolemmal membrane as two parallel fibers (Figure 4-1). The amino terminus is attached to actin and the car-boxyterminus binds to a transmembrane protein complex that is located on the transmembrane. In muscle, dystrophin links myofibrillar elements with the sarcolemma, affording stability and flexi-bility to the muscle fiber of patients with DMD.
Of these patients, 75% demonstrate large-scale deletions in the gene or have partial gene duplica-tions; the remainder are poorly characterized. Nearly 80% of deletions occur in the center of the protein.
The remaining 25% of patients have small or point mutations. Frame-shift mutations usually produce truncated molecules lacking the carboxyterminus and thus produce DMD. Non–frame-shift muta-tions usually result in an abnormal protein that has a carboxyterminus and can partially function. Muta-tions of this type are often seen in Becker muscular dystrophy, a milder form of DMD where the amount of dystrophin is less than normal but not absent. Thus, the old adage of “1 gene = 1 protein = 1 disease” is an oversimplification.
Dystrophin gene mutations that cause DMD result in either the absence of dystrophin protein production or markedly truncated proteins that cannot attach to the transmembrane protein com-plex and are rapidly catabolized. The net result is the virtual absence of dystrophin and the dys-trophin-associated protein (DAP) complexes along the sarcolemmal membrane. Quantitative studies of dystrophin have shown less than 3% of normal dystrophin content is present in DMD muscle (Figure 4-2).
The absence of dystrophin leads to membrane instability, myofiber leakiness of creatine kinase (CK), and susceptibility to injury from normal muscle contractions. Over time, the damaged muscle cell wall allows abnormal influxes of cal-cium and subsequent activation of cell proteases with amplification of disturbed calcium home-ostasis. This results in fiber necrosis, secondary inflammation, and apoptosis.
Although mature muscle fibers are postmitotic, skeletal muscle contains mononuclear muscle pre-cursor cells that proliferate and fuse in response to stimuli from degenerating muscle fibers. Since these regenerating muscle fibers also lack dys-trophin, the process repeats itself. Over time, fibro-sis and scarring develop in the muscle, and fat cells invade, replacing the degenerating muscle cells.
The net process may transiently give rise to enlarged doughy muscles that have a pseudohy-pertrophic appearance.
CHAPTER 4—Disorders of Muscle 41
Dystrophin
Syntrophin
F-Actin Sarcolemma
Membrane
N C
N C
Figure 4-1 Dystrophin molecule beneath external muscle membrane (sarcolemma).
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Major Clinical Features
Although children with DMD have disease activity in the neonatal period (elevated serum CK and necrosis on muscle biopsy) they rarely have clini-cal symptoms until age 3 to 4 years. Parents usually report difficulty in running or climbing, frequent falls, and enlargement of the calf muscles, which feel firm and rubbery. By 4 to 5 years of age, the gait becomes wide-based and waddling and the child often walks on his or her toes because of heel cords contractures. The weakness is greatest in proximal muscles, producing a Gowers maneuver (placing hands on the knees and climbing up the thighs to stand) (Figure 4-3).
In the early school years, the limb weakness progresses and is accompanied by excessive lordo-sis. There is relative clinical sparing of extraocular muscles and muscles of bladder and bowel sphinc-ters, as for unknown reasons these muscles lack dystrophin. By age 10 to 12 years, the child is unable to walk and is confined to a wheelchair.
Deep tendon reflexes are lost and joint contractors appear at the hip flexors and heel cords. By late teens the weakness is profound, scoliosis is marked, and joint contractures are frequent.
About 25% of children have IQ scores below 75 and the average IQ score is 1 standard deviation below the mean. Some children develop smooth muscle involvement with gastric hypomotility and constipation. Cardiomyopathy, cardiac muscle damage, slowly develops. Kyphoscoliosis and weakness of respiratory muscles produce a decreasing lung vital capacity and low maximal inspiratory and expiratory pressures.
The terminal stages of DMD are characterized by recurrent pulmonary infections and often con-gestive heart failure. The age of death ranges from 10 to 30 years, with a mean of 18 years. Only 5%
live beyond 26 years.
Female carriers are usually normal, but 10%
demonstrate mild weakness of proximal muscles.
Carriers usually can be identified by pedigree analysis and presence of mildly elevated serum CK levels. (CK elevation is not seen in all carriers.)
Major Laboratory Findings
In young children, serum CK level is always markedly elevated, often 100 times above the nor-mal upper limit. In the late stages of DMD, the CK 42 FUNDAMENTALS OF NEUROLOGIC DISEASE
Figure 4-2 Quantitative studies of dystrophin have shown less than 3% of normal dystrophin content is present in Duchenne muscular dystrophy muscle (Courtesy of Alan Pestrank, MD).
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level falls as muscle mass disappears. The electro-cardiogram is abnormal in 2/3 of patients.
The EMG demonstrates myopathic motor unit potentials and occasionally fibrillation potentials from segmental necrosis of muscle fibers (see Chapter 3, “Common Neurologic Tests”).
Muscle biopsy demonstrates a mixture of fiber sizes, containing necrotic, regenerating, and large hyaline (hypercontracted, opaque, or large dark) fibers. Necrotic fibers have a glassy appearance from loss of the intermyofibrillar membranous network and are invaded by macrophages (Figure 4-2). Fiber type grouping of remaining muscle fibers is normal. Electron microscopy of non-necrotic muscle fibers demonstrates defects in the plasma membrane, where abnormal calcium influx occurs. Later in the disease, fibrosis and fatty replacement of muscle fibers is seen. Immunohis-tochemical staining demonstrates absence or near absence of dystrophin along the sarcolemma membranes.
It is now possible to use PCR analysis to detect deletions in the dystrophin gene to account for about 75% of all DMD cases. How-ever, the PCR study does not determine whether there is a frame-shift abnormality. This makes it more difficult to separate DMD from Becker’s dystrophy, which contains the carboxyterminus.
If the DMD mutation is a deletion, prenatal diagnosis can be made by PCR studies of
chori-onic villus tissue. If the type of DMD mutation is unknown, experimental studies of 19-week fetal muscle biopsies can determine the presence or absence of dystrophin.
Principles of Management and Prognosis
Management must be multidisciplinary. No drugs have yet proven to reverse the pathologic process.
However, corticosteroid administration may improve strength and performance for up to 1 year. Management involves use of joint bracing and prevention or release of contractures to main-tain walking for as long as practical. The wheel-chair should be viewed as a passport to mobility and not a failure to walk. Once the child is con-fined to a wheelchair, attention should be directed toward posture and bracing to minimize scoliosis.
Occasionally, surgical procedures to improve pos-ture or correcting joint contracpos-tures are indicated.
Education should proceed in a normal fashion.
Terminally, attention is directed to maximizing pulmonary function and minimizing respiratory infections.
Considerable research is underway to replace the mutated dystrophin gene by introduction of a normal gene into muscle fibers via a plasmid or viral vector or by inoculation of genetically normal myoblasts, which fuse with the patient’s
regenerat-CHAPTER 4—Disorders of Muscle 43
Figure 4-3 Gowers maneuver.
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ing muscle fibers. To date all results have been dis-appointing.