Both Guido Werdnig, an Austrian neurologist from the University of Graz (16), and Johan Hoffmann, a German neurologist (17), in their original descriptions of the infantile form of SMA, pointed to the conspicuous loss of ventral horn cells along the entire length of the spinal cord. Some of the residual motor neurons are in the process of degenerating or are being phagocytized by microglial cells. Motor neurons in the brainstem, notably in the hypoglossal and motor trigeminal nuclei also are affected. Those cranial nerves innervating extraocular muscles and sacral motor nerves innervating the striated muscle of the urethral and rectal sphincters are selectively spared. Some authors describe suprasegmental lesions, including loss of large pyramidal cells from layers 5 and 6 of the motor cortex. These findings must be interpreted in light of the severe agonal anoxia that is commonly encountered. In general, the absence of upper motor neuron involvement is an important clinical feature that distinguishes SMAs from degenerative motor neuron diseases such as ALS.

More than 95% of patients experiencing the various forms of SMA have a homozygous deletion or absence of exons 7 and 8 for both copies of the SMN1 gene (13). Subjects who do not have detectable deletions have microdeletions or point mutations in the gene, or have their SMN1 gene converted to SMN2 (18,19). In some patients with SMA types 2 and 3, SMN1 is not deleted; rather, it is replaced by SMN2, the reverse form of “gene conversion” (19,20). Two other genes have been mapped to the SMA critical region. Homozygous deletions of neuronal apoptosis inhibitory protein gene (NAIP) are seen in up to 69% of patients with SMA type 1. By contrast, only some 12% to 18% of patients with SMA types 2 and 3 are deleted for this gene (21). A third gene in this region, shown to encode a subunit of the basal transcription factor (TFIIH) is deleted in approximately 15% of all types of SMA (21). NAIP and TFIIH as well as a multicopy microsatellite marker in close proximity to SMN1 have been proposed as SMA-modifying genes (22,23).

The genetic basis for the phenotypic variability of SMA is not completely clear. About one-half of severely affected SMA1 children also miss both homologues of a neighboring gene, the gene for neuronal apoptosis inhibitory protein (NAIP). Milder forms of SMA appear to have more than two copies of SMN2, and in asymptomatic or late-onset subjects with homozygous deletion of the SMN1 gene, there were four copies of the SMN2 gene (24,25).

The SMN protein is widely expressed in the cytoplasm and nucleus of brain, the motor neurons, and in a variety of non-CNS tissues (26). In the nucleoplasm the SMN protein is localized to discrete bodies called “gems” where it forms a stable complex with a group of proteins called the gamins (27). This complex is intimately involved in the assembly of spliceosomal small nuclear ribonucleoproteins, which function in the splicing of RNA. The reason for the effect of gene mutation on the spinal motor neurons is still unclear, and it is not known whether symptoms result from deficiencies in SMA functions that are specific to the motor neuron, or common to all cells but at a higher demand in the motor neuron. One attractive hypothesis is that SMN protein has an antiapoptotic effect (28), suggesting that that SMA is a primary disorder of apoptosis, with the condition representing a physiologic process that becomes pathologic because of continued degeneration of motor neurons in late fetal life as well as postnatally (29,30).

Prominent glial proliferation often occurs in the proximal portion of the anterior spinal roots, an abnormality initiated in fetal life, and which was thought to induce secondary neuronal degeneration (31). In some instances, the glial bundles also are demonstrated in the posterior roots, accompanied by shrinkage of the dorsal root ganglion cells (32). An inconstant finding in SMA is loss of myelin from the posterior columns of thoracic and lumbar segments and in the corticospinal tracts (33). These phenomena are now believed to be secondary reactive changes. Removal of the peripheral target of the anterior horn cells accentuates the normal process of motor neuron apoptosis (34,35,36), but there is no evidence that the primary disorder in this disease is in the muscle target or that there is a distal-to-proximal dying-back axonal degeneration in the nerve.

There is selective loss of the large motor neurons, but a striking preservation of several types of motor neurons, notably some of the cervical cord (37) and those innervating extraocular muscles. This histologic contrast is expressed clinically as preservation of normal eye movements, even in late stages of the disease. Some genes that program the differentiation and maintenance of motor neurons are expressed in all motor neurons, whereas others are expressed only in certain motor neurons and may provide a protective effect on oculomotor neurons by the principle of genetic redundancy (see Chapter 5 on neuroembryology).

The clinical picture of SMA is marked by reduction of muscle power and spontaneous movement (38). Muscle
weakness is symmetric and is more extensive in the proximal part of the limbs, and what little movement is left to the child is found in the small muscles of the hands and feet. At the same time, the affected muscles undergo atrophy, although this is concealed by the subcutaneous fat normally seen at this age. Muscles of the trunk, neck, and thorax are affected equally, but the diaphragm generally is spared until the late stages of the disease (39) (Fig. 16.1). Cardiac and smooth muscles are usually spared as well. With progression of the disease, involvement of bulbar musculature becomes more prominent, and atrophy and fasciculation of the tongue are noted. Deep tendon reflexes are nearly always markedly reduced or absent. There is no intellectual retardation or sphincter disturbance. Sensory nerve involvement has been demonstrated by nerve conduction studies and confirmed by demonstration of axonal loss on sural nerve biopsy and autopsy. Hypertrophy of unmyelinated axons of the sural nerve also is frequent (29). These sensory nerve changes have not been observed in SMA types 2 and 3 (40,41).

The age at which the first clinical manifestations become apparent is presented in Table 16.2. It is evident from this table that there are at least two populations, one with onset of symptoms before 6 months of age, SMA type 1, and another with its onset after 6 months of age, SMA types 2 and 3. About 10% of infants with SMA type 1 are born with arthrogryposis, and this may indicate the severe fetal form recently designated type 0 (13a,b).

In SMA type 1 (infantile SMA, Werdnig-Hoffmann disease), the onset is acute, and the disease progresses rapidly. Infants who were already severely hypotonic at birth rarely survive the first year of life, whereas those whose weakness appears postnatally tend to deteriorate more slowly (42,43). Some infants can even experience transient improvement. This improvement is partly caused by a true stationary period in the disease, such as was already noted by Hoffmann in one of his earliest patients (17). Maturation of partially paralyzed muscles also can give the impression of improvement. In most instances, however, the disease is fatal by 3 years of age, with death generally resulting from a respiratory infection.

Children who experience SMA type 2 [29% in Brandt’s series (38), 47% in the more recent series (2)] develop normally for the first 6 months of life, but by 18 months of age experience an arrest of their motor milestones. These children generally lack bulbar symptoms, and their disease has a less malignant course (43). One unusual feature of this form of SMA is the presence of a tremor that affects the upper extremities (44) and can even be recorded on the electrocardiogram as a tremor of the baseline (45). Serum CK activity is elevated to approximately five times normal in approximately one-half of these patients but is never in the thousands of units as in muscular dystrophy; hypertrophy of the gastrocnemius is not unusual (46).

SMA type 3, a milder form of SMA consistent with survival into adult life, was first described by Wohlfart and coworkers (47) and by Kugelberg and Welander (48). Muscular weakness develops after 18 months of age, and in some patients does not manifest until adult life. Adult onset SMA is referred to as SMA type 4. It is characterized by involvement of the predominantly proximal muscles and
thus bears close clinical resemblance to the muscular dystrophies. Unlike SMA types 1 and 2, impaired joint mobility is relatively common. The condition is differentiated from Duchenne muscular dystrophy by a less striking elevation in muscle enzymes, and from the other types of muscular dystrophies by the alterations seen on muscle biopsy (see Muscle Biopsy, later in this chapter). In some families, SMA types 1 and 2, or types 2 and 3, coexist. This observation represents a genetic puzzle because haplotype analysis has shown that this variability cannot be accounted for by different alleles at the SMA locus (49).

In some families, a condition that clinically resembles Kugelberg-Welander disease is transmitted in an autosomal dominant manner (50). X-linked pedigrees also have been reported. Hexosaminidase A deficiency can resemble Kugelberg-Welander disease, but patients demonstrate mental deterioration (51) (see Chapter 1).

A condition in which spinal muscular atrophy presents with early respiratory distress, and in which there also is intrauterine growth retardation, foot deformities, early involvement of the diaphragm, and a predominance of distal muscular weakness can be distinguished from SMA type 1. The gene for this condition has been mapped to chromosome 11 q13–q21. It encodes the immunoglobulin binding protein 2 (52).

The presenting signs of the infant with SMA type 1 (Werdnig-Hoffmann disease) are poor muscle tone and a marked delay in motor development. Because a variety of well-defined diseases present the picture of the floppy infant (Table 16.3), differential diagnosis on purely clinical grounds can be difficult. Unlike Walton writing in 1957 (57), we have found the most common cause for diminished muscle tone in a small infant to be atonic cerebral palsy, often secondary to cerebellar hypoplasia. Hypotonia also may result from major abnormalities of the cerebrum, both developmental malformations and disorders acquired in the perinatal period. Invariably, affected infants have considerable intellectual retardation. Spontaneous movements are present, and the tendon reflexes are easily elicited. Often when the infant is lifted by the trunk, the legs promptly become rigid, and a striking accentuation of the extensor thrust reflex is seen. Although some of these children remain hypotonic, others develop dyskinesias or a clear-cut hypertonia within 1 to 3 years. A more extensive discussion of this condition is found in Chapter 6.

Amyotonia congenita, now an obsolete term, was a clinical syndrome reported briefly in a single case by Oppenheim in 1900 (58). It represents a number of unrelated disease processes. It is important to differentiate these entities, now collectively termed congenital myopathies (benign congenital hypotonias), from the usually fatal SMA type 1. The term congenital myopathy is used to describe floppy infants with a marked delay in motor development. Some of these children recover completely, whereas others can be considered to have a stationary or, at worst, a slowly progressive muscular disorder. In these infants, the muscles are soft and flabby, and a remarkable range of passive movement is possible. Deep tendon reflexes are elicitable, and spontaneous movements are more prominent than in SMA type 1. Respiratory muscles are involved only slightly, and intellectual development is usually normal. Histochemical and electron microscopic studies of muscle biopsies have delineated numerous distinct entities, many of which demonstrate specific genetic mutations (see Congenital Myopathies, later in this chapter).

A relatively common clinical problem is that of a floppy infant with delayed gross motor milestones, notably delayed walking, but with normal or nearly normal fine motor development and speech and no demonstrable muscular disorder. This heterogeneous entity, termed congenital laxity of ligaments by the late Dr. Frank Ford (59), has more recently been designated as dissociated motor development (60) or benign maturation delay (61).

In a series of such infants reported by Lundberg, 52% achieved normal development between 17 months and 6 years of age (60). A further 24% continued to have delayed motor milestones without any apparent cause. Ultimately, 15% were found to have mild mental retardation. The remaining infants experienced various neuromuscular disorders, notably congenital deafness with hypoactive labyrinths and macrocephaly (61,62). Muscle biopsy revealed fiber size disproportion and showed a predominance of type 1 fibers, which persisted despite clinical improvement (61). Dissociated motor development should be distinguished from the less common Ehlers-Danlos syndromes, which are characterized by marked hyperelasticity of skin.

The syndrome of congenital fiber type disproportion (Table 16.4) (63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84) is part of a broader spectrum of muscle dysmaturation. Type 1 fibers are uniformly small and also more numerous than type 2 fibers that often exhibit compensatory hypertrophy. Many infants who demonstrate dysmaturation of muscle, particularly when type 2 fibers are affected, also have significant developmental retardation (85).

Rarer causes for infantile hypotonia include various forms of congenital or neonatal myasthenia gravis, some of which can be diagnosed by the striking improvement in muscle strength after administration of an anticholinesterase drug. For diagnostic purposes, a slowly metabolized drug, such as neostigmine administered subcutaneously or intramusculary, but never intravenously, is more suitable for infants than edrophonium chloride, whose effectiveness is often too fleeting to allow correct sequential assessment of muscle strength. Muscular dystrophy is only rarely seen in a small infant, but in no other condition is a significant elevation in serum enzymes, particularly in CK, common. In the absence of a family history of a dystrophic process, the diagnosis depends mainly on a muscle biopsy.

Finally, infantile botulism (see Chapter 10), Down syndrome, transection of the spinal cord, congenital polyneuritis, muscular hypotonia owing to Marfan syndrome or Prader-Willi syndrome, various chronic illnesses, malnutrition, or metabolic disorders (e.g., organic acidurias and mitochondrial disorders) also must be considered in the differential diagnosis of the hypotonic child.

Several rare conditions are transmitted as autosomal recessive traits in which amyotrophy of the limbs and of the bulbar musculature are combined with progressive pyramidal tract symptoms (juvenile ALS). These conditions are reviewed in Chapter 3.

Treatment for SMA is purely symptomatic and is of no value in altering the course of infantile SMA type 1. In the forms with slower progression, treatment should be directed at maintaining joint mobility and avoiding contractures. The child should be fitted with a lightweight support for the spine to prevent kyphoscoliosis. If at all possible, the youngster should be encouraged to walk with braces. Active exercise can help strengthen still functioning muscles (2,45). Dysphagia may be a late complication in some patients, and aspiration is a risk.

Several workers have suggested that SMN2 gene expression can be increased by administration of 4-phenylbutyrate, an inhibitor of histone deacetylase, an enzyme that promotes transcriptional repression (86). This compound has been proposed for the treatment of SMA 1.

Microscopic changes in myasthenia gravis can be minute, even in severely affected muscles. On electron microscopy, the nerve terminals are small, and the cleft between the nerve and the subneural apparatus is widened. Additionally, the area reactive for acetylcholinesterase is reduced, but with no abnormality in the number or size of synaptic vesicles. In 70% to 80% of patients, there are pathologic changes in the thymus. Usually, these consist of lymphoid
hyperplasia. Although thymomas occur in approximately 10% of all patients with myasthenia, they are rare in childhood. Myocardial abnormalities have been found in approximately half of autopsied patients.

The functional lesion in juvenile myasthenia gravis is located at the neuromuscular junction and is the consequence of an antibody-mediated autoimmune reaction against the postsynaptic acetylcholine receptors (AChR) in skeletal muscle (110). By contrast, the autoimmune response in Eaton-Lambert syndrome, a myasthenic syndrome seen almost exclusively in adults harboring a malignancy (most commonly a small cell carcinoma of the bronchus), is directed against the voltage-sensitive calcium channels on the presynaptic membrane.

Antibodies to the AChR protein have been demonstrated in the serum of a large proportion of patients with generalized juvenile myasthenia gravis (111), and the electrophysiologic features of the disease can be reproduced in animals by repeated injections of IgG derived from myasthenic subjects or by antibodies against the AChR (112). Several lines of evidence indicate that antibody production against AChR is T-cell dependent. Serum antibodies against AChR are usually absent in congenital myasthenia gravis (but not in the maternally transmitted neonatal form) and in many cases of myasthenia, that is limited to extraocular muscle involvement. A significant proportion of the small number of juvenile myasthenics who are AChR antibody negative have antibodies against a receptor tyrosine kinase (MuSK). MuSK has been localized to the neuromuscular junction and appears to be vital to its in utero development (112,113). Children and adults with anti-MuSK antibodies exhibit weakness of extraocular, pharyngeal and respiratory muscles and later should have shoulder girdle weakness. Plasma exchange and prednisone often are effective treatments, but cholinesterase inhibitors and thymectomy appear ineffective (113a). Some patients with congenital myasthenia gravis have been demonstrated to have anti-MuSK antibodies (113b). Still other congenital myasthenic infants with episodic apnea show mutations in the cholin acetyltransferase (CHAT) gene (113c).

By means of snake venom (bungarotoxin, which binds specifically to the AChR), AChRs have been localized to the postsynaptic folds. Myasthenic subjects show a 70% to 90% reduction in the number of functional AChR (114). The gross destruction of the AChR area, seen in subjects with long-standing myasthenia gravis, is probably the consequence of a cellular immune reaction. Three possible processes have been postulated to be operative: a complement-mediated lysis of the postsynaptic membrane, an IgG-induced accelerated rate of degradation by endocytosis of cross-linked acetylcholine receptors, or an antibody-mediated blockage of the active site of the receptors (112,114).

The factors that induce and sustain an autoimmune reaction against the AChR are still unknown, although there are some hints about the nature of the process. Administration of penicillamine to patients with rheumatoid arthritis can induce myasthenia that is reversible within a few months after withdrawal of the medication. Whereas this observation suggests an alteration of the AChR because of exogenous factors, Lindstrom and coworkers believe that patients with myasthenia gravis respond to some endogenous source of native AChR, rather than to a bacterial or viral coat protein that would not have the identical autoantibody specifications (110).

The initial anti-AChR sensitization probably occurs in the thymus. Extracts of thymic tissue have been found to contain acetylcholine receptors that are localized to myoid cells present in that tissue (115), and thymocytes of myasthenic patients produce AChR antibodies (116). In most instances, these antibodies are specific for the embryonic AChR (117). Whereas an environmental factor might initiate an immune response against the AChR in the thymus of genetically predisposed subjects, examination by immunofluorescence of thymus derived from patients with myasthenia gravis does not show these cells to be the foci of immunologic stimulation (118). Alternatively, a possibly viral-induced derangement of function or communication between the various types of cells that regulate the intensity and duration of an immune reaction (immune regulation) might be responsible for the breakdown in tolerance to AChR protein.

What appears most likely at present is that autoimmune myasthenia gravis is a heterogeneous group of diseases distinguishable by their clinical features, notably the age at onset of the illness and by their human leukocyte antigen types, with each entity having a different pathogenetic mechanism. Thus, in some 10% to 15% of adult myasthenic patients, antibodies against AChR cannot be detected, and evidence suggests that in these subjects, antibodies are directed to other parts of the end-plate, such as MuSK, rather than to the AChR (119). The immunopathology has been reviewed by Hughes and colleagues (120).

Whereas juvenile myasthenia gravis, like adult myasthenia gravis, appears to result from T-cell initiated antibodies directed against end-plate AChR protein, neonatal myasthenia is associated with the transfer of maternal AChR antibodies across the placenta. However, the story is not as simple as this. Maternal AChR antibodies are found in all infants of myasthenic mothers, whether infants are symptomatic or not, and myasthenic symptoms in an infant are not proportional to the amount of antibodies transferred to it from the mother (121,122). Rather, neonatal myasthenia appears to correlate with persistence of antibodies, possibly as a consequence of antibody synthesis by the myasthenic infant.

In the child, myasthenia gravis can take one of several forms (123,124).

Neonatal myasthenia is a transient disease seen in approximately one in five infants born to mothers who generally are suffering from active acquired myasthenia gravis (125). Symptoms usually appear during the first 24 hours or, at the latest, by the third day of life. All affected infants have a paresis of the lower bulbar muscles, causing a weak cry and difficulty in sucking or swallowing. Generalized hypotonia is found in approximately one-half of the infants. Antibody titers against the AChR are elevated in the mother and in most but not all infants. Symptoms respond promptly to anticholinesterase medication, and even if untreated, the illness usually lasts less than 5 weeks.

Congenital myasthenia gravis designates children with myasthenia born to mothers without the disease (126,127). Generally, antibodies against the AChR protein are undetectable. Several conditions have been recognized. These are outlined in Table 16.5 (126,127,128,129,130,131,132,133,134,135,136,137). Harper and Engel and coworkers have divided these into presynaptic, synaptic, and postsynaptic defects; primary AChR kinetic abnormalities; and the slow-channel congenital myasthenic syndrome (126,127).

Presynaptic defects include at least two autosomal recessive conditions caused by defects in acetylcholine resynthesis and mobilization (127,138,139). Postsynaptic defects include several forms associated with defects in the gene that codes for the collagenlike tail of acetylcholine esterase (131,140), and more than 60 mutations in one of the five genes coding for the adult or fetal subunits of the acetylcholine receptor (127). These entities are depicted in Table 16.5.

The most common congenital myasthenic syndrome is caused by a kinetic abnormality of AChR, the slow-channel syndrome. This is an autosomal dominant condition and is the consequence of an abnormally prolonged open-time of the acetylcholine-ion channels (127,135,141). Less common are the various mutations that cause the fast-channel syndrome. In these mutations, the postsynaptic
response to acetylcholine is markedly diminished, although the number of acetylcholine receptors per end-plate is normal (136,142). The numerous genetic defects that have been demonstrated in congenital myasthenic syndromes were recently summarized in tabular form, with references provided (143).

The clinical picture of congenital myasthenia also is heterogeneous. In approximately one-half of children, symptoms commence before 2 years of age, and more than one sibling can be affected (124,139). In many instances, fetal movements are reduced, and neonates can have feeding difficulties, ptosis, limitation of eye movements, and a weak cry. The initial symptoms in congenital myasthenia gravis are not as severe as in the neonatal variety, and the diagnosis is, therefore, more difficult. A few patients with congenital myasthenia have spontaneous remissions, but the course of the disease is usually protracted, with mild symptoms that often are refractory to both medical and surgical therapy (thymectomy).

Myasthenia can begin during childhood (juvenile myasthenia). In this form, girls are affected two to six times as frequently as boys. The onset of juvenile myasthenia can be insidious, although at times, it is rapid and often a sequel to an acute febrile illness. Generally, muscles innervated by the cranial nerves are affected first, with bilateral ptosis the most common presenting sign (Table 16.6 and Fig. 16.3). It was seen in 81% of children in the series of Afifi and Bell and was unilateral in 33% (111). Generalized weakness and dysphagia are less common presenting symptoms. The clinical course is highly variable. Approximately one-half of the patients experience one or more remissions, usually during the early years of the illness. In others, symptoms progress to a certain point and then become stationary. In 26% of cases in the series of Afifi and Bell, myasthenia was restricted to the extraocular musculature (111).

The characteristic feature of all forms of juvenile myasthenia gravis is the variability in muscular strength, with increasing weakness of the affected muscles with repeated contractions (Fig. 16.4). The child is usually at his or her best in the morning and becomes progressively weaker during the day, although partial or complete recovery may follow a nap. In approximately 10% to 20% of untreated cases, weakness becomes irreversible, and muscle wasting, particularly of the shoulder girdle and the extraocular muscles, becomes apparent. Despite hypotonia, tendon jerks are normal or even exaggerated, but they may disappear after repeated elicitation.

Other autoimmune diseases are sometimes associated with juvenile myasthenia gravis. The most common of these are rheumatoid arthritis, juvenile diabetes mellitus, and thyroid disease, usually thyrotoxicosis (144). For reasons as yet unexplained, seizures are seen in as many as 12.5% of patients (145,146). Malignancies were seen in 5%
of the Mayo Clinic pediatric series (147). Postinfectious myasthenia gravis in children is transitory and usually follows a varicella-zoster infection in 2 to 5 weeks as an immune response (147a).

Myasthenia also can be seen in association with collagen vascular disease, notably systemic lupus erythematosus. Dobkin and Verity and Rodolico and others have described a familial limb girdle myasthenic syndrome transmitted through an autosomal recessive gene and characterized by cardiomyopathy, excessive muscle fatigability with a predilection for the proximal musculature, and improvement with anticholinesterase drugs (148,149). Muscle biopsy revealed hypoplasia of type 1 muscle fibers and tubular aggregates of types 1 and 2 fibers.

The Eaton-Lambert myasthenic syndrome is rarely encountered in children. It has been observed after the administration of antibiotics (most frequently neomycin), in conjunction with surgery (150,151), as a complication of allogeneic bone marrow transplantation (152), and in acute leukemia (153).

The diagnosis of myasthenia gravis is based on a history of abnormal fatigability of voluntary muscles and evidence of a prompt improvement of muscle weakness with anticholinesterase drugs. It is supported by a history of remissions and exacerbations and by the absence of any concurrent illness that might contribute to the muscular weakness.

For diagnostic purposes, the most widely used drug is edrophonium chloride (Tensilon). Approximately 5 mg is given intravenously to a 3- to 5-year-old child. Within 1 minute after the injection, a transient improvement in muscle strength is observed, usually lasting 4 to 5 minutes. Positive responses are diagnostically reliable. In some infants, a positive response can be obscured by the response to the injection, in which case a longer-acting anticholinesterase drug such as neostigmine should be used. After intramuscular injection of 0.5 to 1.5 mg of neostigmine, muscle strength begins to improve in 10 to 15 minutes and reaches its peak by 30 minutes. Both tests are nearly 100% reliable in generalized myasthenia as well as in ocular myasthenia, which progresses to generalized myasthenia. Neostigmine should never be administered intravenously because it may induce fatal cardiac arrythmias. Edrophonium should be avoided in infancy for the same reason. In the series of Afifi and Bell, edrophonium gave positive test results in all cases of ocular myasthenia; neostigmine was positive only in 67% of cases (111). A number of conditions can give a false-positive result. These include drug-induced myasthenia gravis, botulism, brainstem gliomas, and Guillain-Barré syndrome (154). A confirmatory test, therefore, is required.

The presence of AChR antibodies in serum is the simplest diagnostic test in juvenile myasthenia, although false-negative results are not unusual, particularly in children whose symptoms are limited to the extraocular muscles. In the series of Afifi and Bell, AChR antibodies were found in 63% of cases (111). A similar incidence of positive serology has been reported in other series. When AChR antibodies are absent, it is necessary to consider one of the congenital myasthenic syndromes. This is not an academic exercise because in juvenile myasthenia gravis, therapy is not only supportive but also is directed against the immune-mediated response. Andrews and coworkers suggest that the rapid response to plasmapheresis frequently seen in children with juvenile myasthenia gravis can be used to distinguish this condition from congenital myasthenia gravis (155). It should be noted that antibody levels do not parallel disease severity.

Rapid stimulation of the distal (ulnar) or proximal (spinal, axillary, or facial) motor nerves produces a characteristic decrement in the amplitude of successive action potentials recorded from surface muscle electrodes and in the amplitudes of the mechanical excursions (see Fig. 16.4). This test is positive in some 80% of pediatric cases, but is usually negative in ocular myasthenia (156). Patients suspected of having myasthenia gravis on the basis of their clinical picture but who have a normal EMG study should undergo single-fiber EMG (157,158). The results of this study generally complement the results of the assay for AChR antibodies. Exceptions are seen in the various syndromes of congenital myasthenia gravis, in which single-fiber EMG is frequently positive; another exception is in children with the mild, predominantly ocular form of the disease (158).

In addition to penicillamine, a number of other drugs can induce or unmask myasthenia. These include β-adrenergic blockers, carnitine, aminoglycoside antibiotics, lithium carbonate, magnesium salts, trimethadione, and phenytoin (159).

Treatment of the patient with juvenile myasthenia is generally lifelong, extending into all areas of activity. The three approaches to therapy are symptomatic, immunologic, and surgical. Treatment of the congenital myasthenias is solely symptomatic (160). As a rule, the first step is remission induction. This is usually accomplished through the use of high-dose corticosteroids, frequently in conjunction with intravenous immunoglobulin or plasmapheresis. Maintenance of the remission is then usually accomplished by slow tapering of the corticosteroids along with the use of “steroid-sparing” agents, which include thymectomy and immunosuppressants.

When juvenile myasthenia is mild or is restricted to the ocular musculature, treatment is generally symptomatic (i.e., using anticholinesterase drugs). At the University of California, Los Angeles, UCLA School of Medicine, pyridostigmine bromide (Mestinon) is the preferred drug. It
is administered at a starting dosage of 15 mg two to three times a day (in tablet or syrup form) for a child 3 to 8 years old, or 0.5 to 1.0 mg/kg.

In the remaining patients, treatment should be as outlined above. Mann and coworkers and Vajsar suggest a course of oral prednisone, starting out at high dosages (1 mg/kg per day) and tapering when improvement is sustained or when side effects require reduction of the dosages (161,162). Sarnat and associates have advocated a starting dosage of 2 mg/kg given every other day (163). Cholinesterase inhibitors are used as needed while the patient is receiving corticosteroids. Exacerbation of myasthenia gravis can be seen during the early days of corticosteroid therapy, usually toward the end of the first week, and can last approximately 1 week. Improvement is noted within approximately 2 weeks and becomes maximal in approximately 3 months. Plasmapheresis lowers the level of antibodies against the acetylcholine receptor protein. Dau recommends this procedure to stabilize patients whose course worsens markedly during initiation of prednisone therapy and as primary therapy in combination with immunosuppressive drugs such as azathioprine (164). Plasmapheresis also has been used to treat patients who remain unresponsive to other forms of therapy, to improve respiratory function before thymectomy, and to hasten remission after thymectomy. Improvement, often dramatic, is seen within 1 to 3 days after the start of the course. Immunosuppression of refractory patients with azathioprine (2 to 3 mg/kg), cyclosporine, and cyclophosphamide (50 mg/kg per day) has been disappointing because of side effects such as bone marrow suppression and hepatotoxicity (162,165) and is not used at our institutions. Intravenous immune globulin has been used in conjunction with other modes of therapy, particularly corticosteroids and plasmapheresis, in rapidly deteriorating patients with bulbar symptoms (166). There is little difference between the efficacy of three plasma exchanges and intravenous immune globulin (0.4 mg/kg per day for 3 to 5 consecutive days), although as a rule, intravenous gammaglobulin is better tolerated (167). Intravenous immune globulin is ineffective in neonatal myasthenia gravis (168).

After establishment of maximal improvement, children should be considered for thymectomy (166,169,170), although the effectiveness of the procedure in the pediatric population has not been validated by controlled trials. In the German series of Lindner and coworkers, 82% of children were thymectomized (146). In general, the procedure is now indicated if symptoms recur after withdrawal of corticosteroids after 1 year of therapy or if corticosteroids fail to benefit the patient significantly. The best results from thymectomy may be predicted in children who have high titers of circulating antiacetylcholine receptor antibodies and who are symptomatic for less than 2 years. However, a long history of juvenile myasthenia gravis is not a contraindication to thymectomy; for both girls and boys, good operative results are possible. In the UCLA experience, the procedure is of considerable benefit when performed as early as the third year of life. The maximum benefit of thymectomy may be delayed for weeks or even several months, so absence of an immediate and dramatic postoperative improvement should not be discouraging.

Proceeding according to this treatment schedule, Mann and associates found that up to 90% of patients have significant improvement or complete remission of their myasthenic symptoms and that in some, corticosteroids and anticholinesterase drugs can even be tapered and discontinued (161). In the series of Lindner and colleagues, 60% of patients who underwent thymectomy went into remission, as compared with 29% of those who were not thymectomized (146). In the series of Rodriguez and coworkers, the remission rate was higher in children who underwent thymectomy within 12 months of the onset of symptoms. It also was higher in patients who had experienced bulbar symptoms before surgery, in those having involvement of extremities but neither ocular nor generalized weakness, and in those whose myasthenic symptoms presented between ages 12 and 16 years (147).

Patients with congenital forms of myasthenia may respond to anticholinesterases. When such treatment is unsatisfactory, Palace and colleagues have suggested 3,4-diaminopyridine. This substance blocks potassium conductance and increases the release of acetylcholine from the nerve terminal (171).

Despite differences in the clinical picture, the same pathologic findings are shared by all muscular dystrophies. The earliest stages of the disease show a dilated sarcoplasmic reticulum, with an irregular orientation of the triads (201). As the illness progresses, there are repeated episodes of necrosis and regeneration of muscle cells. This process is probably initiated by a breakdown of the muscle cell membrane, and electron microscopy may reveal the absence of the plasma membrane around all or part of the circumference of the muscle fibers (202). Small losses of membrane can be repaired, but generally, regeneration is inadequate. As a consequence of the membrane defect, an influx of calcium ions can occur, activating the endogenous proteases and inducing lysis of the Z-disc of the myofibril, which is probably the initial step in muscle breakdown. Subsequently, the number of muscle cells is reduced, and variability in fiber size is increased. Sarcolemmal nuclei are swollen and increased in number, a regenerative reaction to the injury of muscle fibers. Over the years, this reaction becomes more extreme, and muscle fibers appear enlarged, forked, hyalinized, or atrophied. With further progression of the disease, large accumulations of collagen and fat cells are seen between muscle fibers, and these cells are partly responsible for the muscular hypertrophy (Fig. 16.5) (45).

Neither heart nor smooth muscle is spared, and there is myocardial degeneration with fatty infiltration and fibrosis of the myocardial fibers.

When muscular dystrophy is associated with mental retardation, brain sections can be normal or can disclose various developmental anomalies of the cortex, such as pachygyria, heterotopia, and disorders of cortical architecture (203).

The elucidation of the gene defect in Duchenne and Becker muscular dystrophy represents one of the most important triumphs of molecular biology in the area of neurology, and was the first human disease whose nature was clarified by positional cloning (173). The gene for Duchenne and Becker muscular dystrophy is localized on Xq21.2. It is 10 times larger than any other gene characterized to date and consists of approximately 2 million base pairs; its product has been named dystrophin, a protein with a molecular weight of 427,000. The most common gene mutation in both Duchenne and Becker muscular dystrophies is a deletion. The phenotype of Duchenne and Becker muscular dystrophies does not always correlate with the size of the deletion in the dystrophin gene; some cases of undetectable dystrophin are paradoxically associated with only mild clinical manifestations (204). Rather, the effect of the deletion on dystrophin synthesis is important. If the deletion breaks up the codon triplet and thereby shifts the reading frame, a premature stop codon is quickly generated, and dystrophin synthesis comes to a halt, leaving a small, truncated protein molecule without its carboxy terminal, which is rapidly degraded. If the deletion removes a triplet codon in its entirety, the reading frame is maintained, resulting in the synthesis of a dystrophin molecule with a shortened rod domain but intact carboxy and amino domains. This is what occurs in Becker dystrophy (205).

Dystrophin is a low-abundance protein and constitutes but 0.002% of total muscle protein. It is a cytoskeletal protein with a globular amino domain, a central rodlike domain, and a globular carboxy domain. It is localized to the inner surface of the sarcolemma, aggregating as a homotetramer that is associated with actin at its amino terminus and with a glycoprotein complex at its carboxy terminus. The dystrophin-glycoprotein complex, by which the membrane cytoskeleton is linked to extracellular glycoproteins, consists of several dystrophin-associated glycoproteins and dystrophin-associated proteins (Fig. 16.6). The membrane complex is markedly reduced in Duchenne muscular dystrophy. Its synthesis is normal, but in the absence of dystrophin, the glycoproteins become unstable and are degraded (206). These associated glycoproteins include not only the dystroglycans and sarcoglycans, but also the syntrophin-dystrobrevin complex that is highly localized at the neuromuscular synaptic membrane and is later to appear in normal fetal development (206a).

Dystrophin is present not only in muscle, but in a variety of other cell types, including brain and retina (207,208,209). Although in situ hybridization demonstrates some expression of the gene in affected muscle (210), the complete dystrophin molecule is absent or is present in less than 3% of normal levels in more than 90% of patients with classic Duchenne muscular dystrophy. It is present in reduced amounts or in normal amounts but with an abnormal molecular configuration in boys with Becker muscular dystrophy (211).

The level of dystrophin expression in brain is lower than in muscle, and the structure of brain messenger RNA for dystrophin differs from that of muscle (212,213). This difference is because cortical dystrophin is transcribed from a promoter that is at least 90 kb upstream from the muscle promoter. Other, markedly truncated dystrophins can be found in normal brain and peripheral nerve. In particular, a 140-kD protein (Dp140) is found throughout the CNS (214,215).

Dystrophin is associated with other proteins at the sarcolemmal region, which also may be defective; these include α- and β-dystroglycans (216,217,218,219) and utrophin. Utrophin is an autosomal homologue of dystrophin, being encoded by a gene that has been mapped to the long arm of chromosome 6 (6q24). Like dystrophin, it is a large protein that is found at the neuromuscular synapse and the myotendinous junction and also is expressed in several other tissues, notably the lungs and intestines (220).