Diseases of Muscle and the Neuromuscular Junction Part 1

Approach to Patients with Neuromuscular Disease

The diseases of muscle and the neuromuscular junction constitute a heterogeneous group of acquired and hereditary disorders. At presentation, symptoms are varied and include fatigability, skeletal muscle weakness, atrophy, muscle cramps, and impaired function of respiratory, pharyngeal, facial, and ocular muscles. In general, the proximal muscles are more selectively and severely affected than the distal muscles. Thus, patients experience difficulty climbing stairs, rising from a low chair, running, combing their hair, and lifting themselves or turning in bed. Most myopathies affect only skeletal muscles, but smooth muscle and cardiac muscle may also be impaired. Patients with myopathy do not have sensory disturbances or autonomic dysfunction, because peripheral nerves and the autonomic nervous system are spared.

Clinical examination is aimed at localizing findings to muscle and excluding diseases that may cause myopathic symptoms and signs, such as motor neuron syndromes, motor neuropathies, and psychogenic diseases. A complete family history and examination of family members are often necessary to exclude a hereditary disease. Useful laboratory evaluations include (1) studies to exclude a systemic disease, exogenous factors, toxins, or viruses that may induce myopathy; (2) electromyography (EMG) to localize the lesion to the muscle or the neuromuscular junction and to exclude motor neuron or peripheral nerve disorders; (3) determination of serum levels of muscle enzymes; (4) measurement of specific autoantibodies directed against known or putative muscle antigens; (5) muscle biopsy for enzyme histochemistry, im-munocytochemistry, electron microscopy, biochemical measurement of a specific muscle enzyme or protein, and genetic studies; (6) ischemic exercise test to measure the production of lactate and ammonia in metabolic myopathies; (7) genetic tests on peripheral blood lymphocytes if the gene is known; and (8) muscle imaging, as dictated by the specific clinical problem being investigated.

Most myopathies are disabling or catastrophic if left untreated. Therefore, diagnosis must be established quickly to initiate early therapy. For patients with untreatable disorders, proper supportive care, rehabilitation, and genetic counseling are critical.

In this topic, the most common myopathies and disorders of the neuromuscular junction are described, with emphasis on the clinical picture, pathogenesis, diagnosis, and therapy.

Muscular Dystrophies

The muscular dystrophies constitute a heterogeneous group of congenital muscle diseases characterized by severe muscle weakness, atrophy, elevation of serum muscle enzyme levels, and destructive cytoarchitectural changes of muscle fibers. The traditional classification of muscular dystrophies into Duchenne, Becker, limb-girdle, and congenital has changed because genetic defects in muscle proteins responsible for most of these diseases have been identified and the deficiency of specific muscle proteins has been demonstrated as the cause of these diseases.

Molecular, biochemical, and immunocytochemical studies1,2 have identified the dystrophin-glycoprotein complex as a key multisubunit complex of proteins linking the cytoskeleton with the extracellular matrix [see Figure 1]. Deficiencies in certain components of this system cause sarcolemmal instability resulting in muscle fiber necrosis and specific clinical syndromes.1-3 The muscular dystrophies are now best classified according to the gene and the defective protein involved; the defective protein may be a component of the nucleus, the cytosol, the cytoskeleton, the sar-colemma, the extracellular matrix, or the intermediate filament. The most common muscular dystrophies, categorized in accordance with current molecular genetic analysis and mode of inheritance, are listed [see Table 1 ]. The role of each protein in supporting, reinforcing, or connecting the nucleus with the cytoskeleton, the sarcolemma, and the extracellular matrix [see Figure 1] is discussed in the sections that describe each specific disorder.

X-linked recessive muscular dystrophies


Dystrophinopathies are caused by a deficiency of dystrophin, a 427 kilodalton rod-shaped cytoskeletal protein. Dystrophin constitutes 5% of all sarcolemmal cytoskeletal proteins and serves to anchor F-actin (the filamentous form of actin) to the plasma membrane (sarcolemma) of muscle [see Figure 1].2-7 Dys-trophin appears to reinforce and stabilize the plasma membrane during the stress of muscle contraction by maintaining a mechanical link between the cytoskeleton and the extracellular matrix. Deficiency or absence of dystrophin is associated with various dystrophinopathies, the prototype of which is Duchenne muscular dystrophy (DMD).

Duchenne muscular dystrophy Duchenne muscular dystrophy, an X-linked recessive disorder [see Table 1], is caused by mutations in the dystrophin gene on the short arm of the X chromosome at position Xp21. The dystrophin gene spans more than 2,000 kilobases of DNA. In 65% to 70% of cases, DMD results from large deletions (several kilobases) in the dystrophin gene and a consequent lack of muscle dystrophin. Spontaneous mutations are also frequently noted in DMD patients.4-7 The absence of dystrophin weakens and disrupts the sarcolemmal membrane, thereby allowing calcium entry, which causes muscle fiber necrosis. The deletions, detected in the DNA extracted from peripheral blood lymphocytes, disrupt the open reading frame of the messenger RNA (mRNA) triplet codons and result in severe forms of DMD. Partial gene duplications account for 6% of the dystrophin mutations.

A multiplex polymerase chain reaction (PCR) test that examines so-called hot spots in two exons detects almost two thirds of cases of DMD by screening DNA from the blood. However, this technique does not detect small mutations (e.g., point mutations and splicing errors) that produce a truncated dystrophin protein and account for as many as 30% of DMD cases. A highly sensitive single-strand conformation polymorphism method screens all 79 exons of the dystrophin gene and detects 90% of DMD mutations by DNA analysis of the peripheral blood.7 Similar results are obtained with PCR followed by direct sequence analysis (i.e., single condition amplification internal/primer sequencing [SCAIP]).8

DMD occurs in one in 3,000 male births. Affected boys become symptomatic after they begin to walk, usually from 2 to 3 years of age. DMD occurs in girls only in extremely rare circumstances [see Female Carriers and Dystrophinopathy in Women, below].

The current conception of the molecular organization of the dystroglycan complex at the extrajunctional sarcolemma. The deficiency or absence of various proteins results in particular muscular dystrophies. Mutations in the gene for dystrophin produce Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD); mutations in the genes for the sarcoglycan complex produce various subtypes of limb-girdle muscular dystrophies (LGMDs); and mutations in the gene for a2-laminin (merosin) produce congenital muscular dystrophy (MDC). Other proteins in the region of the dystrophin-glycoprotein complex include caveolin, neuronal nitric oxide synthase (nNOS), dystrobrevin, the syntrophins, and actin. Collagen VI is a component of the basal lamina. (COOH—carboxyl terminus; Cys—cysteine-rich domain; NH2—amino terminus)

Figure 1 The current conception of the molecular organization of the dystroglycan complex at the extrajunctional sarcolemma. The deficiency or absence of various proteins results in particular muscular dystrophies. Mutations in the gene for dystrophin produce Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD); mutations in the genes for the sarcoglycan complex produce various subtypes of limb-girdle muscular dystrophies (LGMDs); and mutations in the gene for a2-laminin (merosin) produce congenital muscular dystrophy (MDC). Other proteins in the region of the dystrophin-glycoprotein complex include caveolin, neuronal nitric oxide synthase (nNOS), dystrobrevin, the syntrophins, and actin. Collagen VI is a component of the basal lamina. (COOH—carboxyl terminus; Cys—cysteine-rich domain; NH2—amino terminus)

Clumsiness of gait, lordotic posture, calf hypertrophy, joint contractures, and toe-walking are early manifestations. These are followed by progressive muscle weakness and wasting; getting up from the floor or a low chair, climbing stairs, and arm raising become difficult. Delayed gastric emptying can cause sudden episodes of vomiting and abdominal pain. The disease is relentlessly progressive. By 12 years of age, affected children are wheelchair bound, and by 25 years of age, they die of complications of respiratory failure. Although DMD is a disease of skeletal muscle, cardiac muscle is often affected, and congestive heart failure and arrhythmia may occur later in the dis-ease.9 Mild, nonprogressive central nervous system involvement also occurs and manifests as irritability, hyperactivity, or cognitive dysfunction. Patients with cognitive impairment have been found to have abnormal electroretinograms owing to defects in a dystrophin isoform expressed in the retina.7

Routine laboratory studies of patients with DMD initially show serum creatine kinase (CK) levels as high as 20,000 IU/L, which steadily decline as the muscle mass is depleted. Muscle biopsies reveal a severe destructive myopathy; some CD8+ T cells are often present and invade muscle fibers; a large number of macrophages are associated with phagocytosis of necrotic fibers; the amount of connective tissue is increased; and hyper-contracted muscle fibers are common. Diagnosis is confirmed by the absence of dystrophin or by levels lower than 3% of the normal dystrophin concentration; dystrophin levels are demonstrated either by immunocytochemistry on muscle biopsy sections or by immunoblots prepared from muscle biopsy specimens stained with antidystrophin antibodies.

Table 1 Muscular Dystrophies with Gene Locations and Products


Gene Locus

Gene Product

Allelic Disorders

X-linked recessive muscular dystrophies

Duchenne muscular dystrophy



Isolated cardiomyopathy, Becker muscular dystrophy

Becker muscular dystrophy



Isolated cardiomyopathy, Duchenne muscular dystrophy





Autosomal dominant LGMD




Myofibrillar myopathy



Lamin A and C

Autosomal dominant EDMD








7 q


Autosomal recessive LGMD



























Fukutin-related protein






MDC1A "classic" MDC


a2-Laminin (merosin)






Fukutin-related protein







Muscle-eye-brain disease



Walker-Warburg syndrome



Other MDCs

MDC with rigid spine myopathy


Selenoprotein N

Bethlem autosomal dominant myopathy


Collagen VIa1, a2

Ullrich myopathy


Collagen VIa3

Intermediate filament myopathy






Desmin, aB-Crystallin

Epidermolysis bullosa and muscular dystrophy






Autosomal dominant dystrophies with a unique


Myotonic dystrophy



Myotonin-protein kinase



Zinc finger protein 9

Facioscapulohumeral muscular atrophy


Oculopharyngeal muscular dystrophy


Poly A binding protein 2

EDMD—Emery-Dreifuss muscular dystrophy

FMDC—Fukuyama congenital muscular dystrophy

LGMD—limb-girdle muscular dystrophy

MDC—congenital muscular dystrophy

Treatment is entirely symptomatic, with emphasis on providing systematic respiratory and physical therapy as well as psychosocial support for both the patient and the family. Genetic counseling is highly appropriate. The presence of en-domysial inflammation has prompted the use of steroids to treat DMD. In a controlled study, use of steroids resulted in temporary, mild improvement and slowed disease progress.10 The long-term use of steroids is restricted by severe side effects, especially obesity, fractures, osteoporosis, diabetes, and hypertension. Deflazacort, a steroid with fewer mineralocorticoid side effects, appears to be a little safer.11 Creatine supplementation is often used, although its benefit is marginal.12 In a modified form of gene therapy, human myoblasts carrying normal dystrophin were injected into the muscles of patients with DMD, but the procedure failed to change the recipients’ muscle function.13 Several prospective, randomized, placebo-controlled trials involving repeated myoblast injections to the same muscles failed to demonstrate any improvement in strength. The finding in dystrophic mice that aminoglycoside antibiotics can "read through" nonsense mutations and generate a full-length protein, thereby restoring dystrophin func-tion,14 led to a trial examining the efficacy of gentamicin therapy in DMD patients who had a premature stop codon. The results were disappointing, although mild reduction in the serum CK level was noted.15 Future gene therapies may prove efficacious if proper vectors are found that can be used to effectively insert the gene into the muscle.16

Becker muscular dystrophy Becker muscular dystrophy (BMD) and DMD are allelic disorders [see Table 1], but BMD generally starts later and progresses more slowly.

About 65% of patients with BMD have in-frame deletions in the dystrophin gene, but the produced protein is often truncated and only semifunctional.2-6 Instances of duplication of the dystrophin gene have resulted in a longer dystrophin rod. Immuno-cytochemistry of BMD muscle using antidystrophin antibodies demonstrates preserved but attenuated sarcolemmal staining (not absence, as in DMD) and reveals membrane fragmentation in the immunostained areas of the sarcolemma. Immunoblots detect a reduced amount of a smaller than normal or larger than normal dystrophin.

The age at onset of BMD is variable. Cases may be recognized by as early as 3 years of age or as late as 70 years of age; the mean age at onset is 12 years. The spectrum of phenotypic expression of BMD is also wide. Mild forms manifest only as muscle cramps, exercise intolerance, myoglobulinuria, asymptomatic elevation of serum CK levels, mild muscle weakness, or quadriceps myopathy.2-6 Calf pain on exercise is often a presenting symptom, and calf enlargement is frequent. Most patients lose ambulation by the age of 40 (range, 10 to 70 years of age). The age of death also varies, from 23 to 89 years (mean age, 42 years). Patients present with proximal muscle weakness and serum CK levels as high as 20 times normal. The muscle biopsy findings are similar to those in DMD patients but are not as severe. In patients younger than 8 years, the presentation of BMD is usually indistinguishable from that of DMD. Cardiac manifestations are common, and cardiomyopathy can be severe. The severity of cardiac symptoms, however, is unrelated to the severity of the myopathy. There is no effective therapy for BMD.

Female carriers and dystrophinopathy in women Careful history and clinical examination of asymptomatic female carriers may reveal mild muscle weakness, muscle cramps, isolated calf hypertrophy, fatigue, and elevated serum CK levels.3-7 Muscle biopsy reveals dystrophin-negative fibers. In heterozy-gotes, when the specific deletion-prone exons within the dys-trophin gene are amplified using quantitative PCR, the deletions are recognized as a 50% reduction in the intensity of the amplified DNA band, compared with the band of the wild-type exons.4-7 This method detects about 98% of the deletions. Not infrequently, however, the affected boy’s mother does not carry his mutation in her blood. Such cases, linked to newly recognized DMD mutations, account for as many as 20% of new DMD cases and result from maternal gonadal mosaicism; that is, the mutations are found only in the oocytes.4-7 Women with these mutations may produce affected males or carrier females. Daughters of these women should be studied to identify carriers; however, because the mutation occurs in the oocytes, a woman’s sisters could not have inherited the mutations from their parents and need not be studied as potential carriers.4-7 The manifestation of DMD in heterozygote females occurs when the normal paternal X chromosome that harbors the normal dystrophin gene is inactivated in a large proportion of embryonic cells (Lyon hypothesis). The disease in these females may be as severe as in males.

X-linked dilated cardiomyopathy X-linked dilated car-diomyopathy results from dystrophin deficiency in cardiac but not skeletal muscle. Patients present with a progressive cardiac disorder; congestive heart failure occurs in the second or third decade of life. Female carriers manifesting the disease have a slow-onset cardiomyopathy that presents by the fifth decade. Deletions near exon 1 of the dystrophin gene, which affect the expression or function of dystrophin in cardiac muscle, have been proposed to cause the disease.

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