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1 2 3 4 223 Muscular Dystrophies 5 6 Brenda L Banwell 7 8 9 10 11 Historical overview Epidemiology 12 Descriptions of boy with progressive motor paralysis The incidence of several forms of muscular dystrophy 13 (now known as “Duchenne muscular dystrophy”) is listed in Table 223.1. Some dystrophies show 14 date back to reports by Dr. Charles Bell in 1830.1 Dr. regional variability due to founder effects or the rela- 15 Edward Meryon, in his book Practical and Pathological tive frequency of consanguineous marriages. The inci- 16 Researches on the Various Forms of Paralysis published dence of milder forms of dystrophy, mild variants of 17 in 1864, described the clinical and pathological find- more severe dystrophies, and severe forms of dystro- 18 ings in eight affected boys from three families. He phy that result in death before diagnosis is likely 19 was the first to recognize the maternal inheritance of underestimated. 20 this disorder.1 In his report he stated that “fibers were 21 found to be completely destroyed, the sarcous Etiology 22 element being diffused, and in many places converted The genetically distinct forms of muscular dystrophy 23 into oil globules and granular matter, whilst the sar- that have been recognized result from mutations in 24 colemma and tunic of the elementary fiber was encoding integral structural of the sar- 25 broken down and destroyed.”1 colemmal membrane (, , , and , inte- 26 Over the next 100 years, genetic and phenotypi- grin 7) and structural proteins associated with the 27 cally distinct forms of muscular dystrophy were inner (, plectin) or outer (laminin 2, colla- 28 recognized. In the late 1970s, genetic studies linked gen type VI) or specialized regions of the 29 the Duchenne to Xp21, and the (), with the inner nuclear membrane 30 cDNA and product, dystrophin, were discov- (emerin, lamin A/C, plectin), with muscle-specific 31 ered in 1987.2,3 Many other genes encoding structural protein kinases (myotonic dystrophy protein kinase), 32 proteins associated with the sarcolemma, nuclear with muscle-specific proteases (calpain), and with 33 membrane proteins, and proteins involved in proteins whose function remains to be defined (dys- 34 myofiber metabolism have now been sequenced and ferlin). The distribution within muscle of proteins 35 mutations ascribed to specific forms of dystrophy. implicated in the various muscular dystrophies is 36 The genes for other dystrophies have yet to be discov- outlined schematically in Figure 223.1. In dys- 37 ered. trophinopathies, ultrastructural studies have shown 38 This chapter discusses the management of patients focal loss of the sarcolemma4 and increased calcium in 39 with muscular dystrophy and highlights issues perti- the muscle fiber regions underlying the sarcolemmal 40 nent to specific forms of dystrophy. Even with the defects.5 A similar loss of sarcolemmal integrity likely 41 best current management, the inexorable downhill underlies the pathological changes of the limb-girdle 42 progression of the dystrophic process cannot be dystrophies associated with sarcoglycan mutations.6 43 arrested. The recent rapid advances in gene therapy, The defects in sarcolemmal-associated proteins likely 44 however, hold promise that the course of these dis- predisposes the fiber to damage during contraction. 45 eases eventually may be mitigated. How deficiency of proteins not associated with the 46 47 48 49 Table 223.1 Incidence and prevalence of common muscular dystrophies 50 51 Disease Incidence/prevalence Reference 52 53 Duchenne muscular dystrophy 1/3300 5 54 Becker muscular dystrophy 1/18 000–1/31 000 5 55 Female dystrophinopathy carriers 40/100 000 5 Manifesting female dystrophinopathy carriers 1/100 000 5 56 Emery–Dreifuss muscular dystrophy 1/100 000 87 57 Myotonic dystrophy 1/8000 53 58 Oculopharyngeal muscular dystrophy 1/200 000 70 59 Fascioscapulohumeral muscular dystrophy 1/20 000 74 60 Muscle–eye–brain disease 1/50 000 (Finland) and isolated cases elsewhere 98 61 Fukuyama congenital muscular dystrophy 7–12/100 000 (Japan) 97 62 709_Neurological_ch.223 9/7/2002 10:32 am Page 2

223.2 XII Section Title

1 2 3 Collagen type VI Collagen type IV 4 5 6 7 8 Laminin 2 9 10 11 - 12 Sarcolemma 13 7 14 -dystroglycan 1 calpain 3 MDPK 15 integrins plectin 16 caveolin 3 17 Emerin 18 dystrophin 19 () 20 plectin Nucleus 21 22 23 H band desmin 24 Z disk 25 Nuclear Lamina 26 (with Lamin A/C) 27 M line Z disk I band A band 28 29 Sacromere 30 31 32 Figure 223.1 Representation of various proteins implicated in muscle disease and their distribution within the myofiber. (Only 33 proteins discussed in the chapter are shown.) Collagen type IV and type VI, laminin 2, and -dystroglycan are components of 34 the basement membrane surrounding muscle; -, -, -, -, and ε-sarcoglycan, sarcospan, -dystroglycan, and 7- and 1- 35 integrins span the sarcolemma, and caveolin 3 exists in specialized regions of the sarcolemma termed “caveolae.” Emerin is 36 located in the inner nuclear membrane, and lamin A/C is a component of the inner nuclear lamina. Proteins localized to the 37 subsarcolemmal region include dystrophin, - and -, and dystrobrevin. Desmin and plectin are concentrated at the 38 region of the Z-disk and also form important cross-linkages throughout the cytosol. The cellular distribution of dysferlin, calpain 39 3, and MDPK (myotonic dystrophy protein kinase) have not been fully elucidated; for convenience, these proteins are depicted 40 in the cytosol near the sarcolemmal membrane. In the lower part of the figure, the contractile apparatus of the myofiber, the 41 “,” is outlined. As shown, electron-dense bands termed “Z-disks” delineate the sarcomere. Thin filaments emanate 42 from the Z-disk, forming the I band on either side of the Z-disk. The thin filaments are joined together at the Z-disk by the protein -actinin (not shown). The I band is composed of thin filaments that extend from the Z-disk to intersect with thick 43 filaments of the A band, and (not shown), which form a complex important for contractile regulation, and a 44 large intermediate filament protein, . The A band is composed of thick filaments interlaced with thin filaments for part of 45 its length and a central region devoid of thin filaments. Thick filaments are composed primarily of myosin as well as C protein, 46 H protein, X protein, AMP deaminase, creatine kinase, M protein, and myomesin (not shown) and are associated along their 47 length with the giant protein titin. The midpoint of the A band is termed the “H band,” which is of lower density owing to the 48 absence of thin filaments in this region. The midpoint of the H band is termed the “M line.” 49 50 51 52 sarcolemma results in disease is unknown. Why are and the available genetic information are listed in 53 only some forms of dystrophy manifest at birth? Why Tables 223.2 to 223.5. 54 is there regional muscle involvement in most forms of 55 dystrophy, with severely affected muscles immedi- Diagnosis 56 ately adjacent to muscles showing minimal disease? The clinical manifestations of the muscular dystro- 57 The answers to these questions await better under- phies vary with the age of the patient and the type of 58 standing of the function, regulation, and interactions dystrophy. Features common to childhood-onset dys- 59 of the mutant proteins. trophies include neonatal hypotonia, generalized 60 muscle weakness, recurrent aspiration, weak cry, 61 Genetic classification prominent head lag, decreased muscle bulk, reduced 62 The current classification of the muscular dystrophies or absent tendon reflexes, and delayed acquisition of 709_Neurological_ch.223 9/7/2002 10:32 am Page 3

Muscular Dystrophies 223.3

1 motor milestones. Later onset dystrophies present with Laboratory investigation of patients, and occasion- 2 generalized or regional muscle weakness and atrophy ally also of family members, includes determination 3 and reduced exercise tolerance. Patients may report of the serum level of creatine kinase (CK), electromyo- 4 symptoms of cardiac or respiratory failure (described graphy (EMG) studies, electrocardiography, muscle 5 below). The family history may document relatives biopsy, and genetic studies. The serum level of CK is 6 who have muscle disease, cardiac disease, sudden increased in most forms of muscular dystrophy, but it 7 death, reactions to anesthesia, recurrent fetal loss, or also is increased in other metabolic and acquired 8 neonatal deaths. Examination of family members is muscle diseases. EMG demonstrates myopathic fea- 9 important, especially in myotonic dystrophy or fas- tures (short-duration polyphasic potentials 10 cioscapulohumeral dystrophy in which mildly affected and, often, fibrillation potentials), and differentiates 11 persons are often unaware of their disease. myopathy from neuropathy. Imaging studies, including 12 13 14 15 Table 223.2 Autosomal recessive dystrophies 16 17 18 Disease Locus Gene product Gene 19 LGMD 2A 15q15 Calpain 3 CAPN3 20 LGMD 2B 2p13 Dysferlin DYSF 21 LGMD 2C 13q12 -Sarcoglycan SGCG 22 LGMD 2D 17q12–21.33 -Sarcoglycan SGCA 23 LGMD 2E 4q12 -Sarcoglycan SGCB 24 LGMD 2F 5q33–q34 -Sarcoglycan SGCD 25 LGMD 2G 17q11–12 26 LGMD 2H 9q31–q34.1 27 Distal myopathy with rimmed vacuoles 9p1–q1 28 Miyoshi myopathy 2q12–14 Dysferlin DYSF Oculopharyngo-distal myopathy 29 Hereditary inclusion body myopathy 9p1–q1 30 Epidermolysis bullosa simplex with muscular dystrophy 8q24 Plectin PLEC1 31 32 LGMD, limb-girdle muscular dystrophy. 33 Modified from Neuromuscular Disorders107 34 35 36 37 Table 223.3 Autosomal dominant dystrophies 38 39 40 Disease Locus Gene product Gene 41 LGMD 1A 5q22–q34 42 LGMD 1B 1q11–21 43 LGMD 1C 3p25 Caveolin CAV3 44 Fascioscapulohumeral dystrophy 4q35 45 Fascioscapulohumeral dystrophy type 2 46 Myotonic dystrophy 19q13 Myotonin-protein kinase 47 Myotonic dystrophy type 2 3q 48 Oculopharyngeal muscular dystrophy 14q11.2–q13 Poly(A) binding protein 2 PABP2 49 Bethlem myopathy 21q22.3 Collagen type VI 1 or 2 subunit COL6A1 COL6A2 50 51 Bethlem myopathy 2q37 Collagen type VI 3 subunit COL6A3 Emery–Dreifuss autosomal dominant type 1q11–q23 Lamin A/C LMNA 52 Myofibrillar myopathy* 11q22 B-crystallin CRYAB 53 2q35 Desmin DES 54 Tibial muscular dystrophy 2q 55 Autosomal dominant distal myopathy 14 56 Welander distal myopathy 57 Familial dilated cardiomyopathy with 58 conduction defect and muscular dystrophy 6q23 59 LGMD, limb-girdle muscular dystrophy. 60 *Genetically heterogeneous. 61 Modified from Neuromuscular Disorders107 62 709_Neurological_ch.223 9/7/2002 10:32 am Page 4

223.4 XII Section Title

1 2 Table 223.4 X-Linked dystrophies 3 4 Disease Locus Gene product Gene 5 6 Duchenne muscular dystrophy Xp21.2 Dystrophin DYS 7 Becker muscular dystrophy Xp21.2 Dystrophin DYS Emery–Dreifuss muscular dystrophy Xq28 Emerin EMD 8 9 Modified from Neuromuscular Disorders107 10 11 12 13 Table 223.5 Congenital dystrophies 14 15 16 Inheritance Disease Locus Gene product Gene 17 18 AR CMD with merosin deficiency* 6q2 Laminin- 2 chain LAMA2 AR CMD without merosin deficiency 19 AR CMD with integrin deficiency 12q13 Integrin-7 ITGA7 20 AR CMD with rigid spine 1p35–36 21 AR Fukuyama muscular dystrophy 9q31–q33 22 AR Muscle–eye–brain disease 1p32–p34 23 AR Walker–Warburg syndrome 24 25 AR, autosomal recessive; CMD, congenital muscular dystrophy. *Late-onset variants exist. 26 Modified from Neuromuscular Disorders107 27 28 29 30 computed tomography (CT), magnetic resonance progression of some inflammatory myopathies can be 31 imaging (MRI), and ultrasonography of muscle may insidious. Moreover, some dystrophies appear to 32 be useful. In Duchenne dystrophy, ultrasonographic present more acutely either because of concomitant 33 examination is very sensitive for detecting fibrosis.7 In illness or because early symptoms were not recog- 34 other diseases, such as Miyoshi distal dystrophy, CT nized. 35 of the lower limbs shows a characteristic pattern of 36 muscle involvement.8 For most dystrophies, muscle Management and treatment: general 37 biopsy is still the cornerstone of diagnosis. Appropri- considerations 38 ately stained or reacted frozen sections typically show General health 39 myopathic features—that is, necrotic and regenerat- 40 ing fibers, fiber size variation, fiber splitting, internal- Avoidance of obesity is extremely important for all 41 ized nuclei, and endomysial and perimysial patients with muscular dystrophy because excess 42 fibrosis—as well as disease-specific features described weight increases the work that muscles must perform 43 below. Immunocytochemistry using the currently for ambulation, compromises seating, exacerbates res- 44 available antibodies may be diagnostic for dys- piratory insufficiency, and hinders self or assisted 45 trophinopathies, sarcoglycanopathies, and the dystro- transfer.5 The total caloric requirements vary with 46 phies caused by deficiency of laminin 2 (merosin), lean body mass, decreasing by at least 10% in nonam- 47 emerin, integrin 7, or plectin. Commercially avail- bulatory patients even if the lean body mass remains 48 able genetic studies alone can be used to diagnose unchanged. A well-balanced high-fiber diet is essen- 49 myotonic dystrophy or dystrophinopathy. tial to prevent constipation, a problem that can be 50 It is important to exclude an acquired myopathy very serious in nonambulatory patients. Patients 51 from genetically determined dystrophy. Inflamma- should consume adequate fluids, both to reduce con- 52 tory myopathy, viral or parasitic myositis, toxic stipation and to help keep respiratory secretions thin. 53 myopathy due to exposure to toxins or certain med- A urine specific gravity between 1.010 and 1.015 is 54 ications, or metabolic myopathy may present with ideal. Dependent peripheral edema develops in many 55 weakness and increased serum levels of CK. The nonambulatory patients. Edema results in increased 56 absence of previous neuromuscular complaints, a weight and decreased mobility, and it predisposes to 57 history of recent illness, onset of illness with exposure skin ulcers and infection. Elevating the legs periodi- 58 to a new medication, and rapid progression suggest cally, maximizing mobility, performing range of 59 an acquired process. Severe muscle pain favors an motion exercises, reducing dietary sodium, and the 60 inflammatory or metabolic disorder. There are excep- judicious use of diuretics may be helpful. Any patient 61 tions to these generalizations. Muscle pain is a fre- in whom edema develops should be examined for 62 quent symptom of Becker dystrophy, and the signs of cardiomyopathy, respiratory insufficiency, 709_Neurological_ch.223 9/7/2002 10:32 am Page 5

Muscular Dystrophies 223.5

1 and cor pulmonale. Certain medications, namely - includes the following preventive measures: avoid- 2 blockers, nonsteroidal anti-inflammatory agents, and ance of smoking or exposure to second-hand smoke, 3 calcium channel blockers, can also cause dependent annual influenza vaccination, early and aggressive 4 edema and should be avoided if possible. recognition and treatment of pulmonary infections, 5 avoidance of large evening meals, and avoidance of Physical and occupational therapy 7 6 cough suppressants and nocturnal sedatives. A high 7 The goal of physical therapy is to prolong ambulation protein, low calorie diet sufficient to maintain ideal 8 and to prevent contractures.7 Muscle fibrosis and body weight is recommended because obesity 9 imbalance between flexor and extensor muscles can increases the risk of obstructive sleep apnea and 10 result in hip, knee, or ankle contractures.5 Passive further compromises respiratory function.18 11 range-of-motion exercises, performed after a brief One of the earliest symptoms of respiratory failure 12 warm-up, for approximately 30 minutes daily delay is exertional dyspnea.17 Baseline pulmonary function 13 or even prevent contractures and improve ambula- studies should be performed on all patients at the 14 tion.7 Excessive exercise, indicated by muscle pain time muscular dystrophy is diagnosed and then per- 15 after exertion, should be avoided because it may formed routinely with a frequency dictated by the 16 increase muscle damage.5 As disability proceeds, indi- type of dystrophy and the rate of disease progression. 17 vidualized aids may be of enormous benefit. Door Weakness of the respiratory muscles results in a 18 handle modifications, handrails in the bathroom, restrictive ventilatory defect and eventual hypercap- 19 computers, and companion dogs are a few examples. nia.7 Maximal inspiratory (PImax) and expiratory 20 The overall goal is to increase independence and to (PEmax) pressures are often reduced by more than 21 allow patients to pursue educational, vocational, and 50%.7 Subsequently, the patient’s vital capacity and 9 22 leisure activities. Muscular Dystrophy: The Facts and forced expiratory volume in 1 second (FEV1) decrease. 23 numerous publications by the Muscular Dystrophy Reduction of the vital capacity closely reflects the 24 Association of the United States and of Great Britain degree of general disability18 and predicts the need 25 contain further information. for artificial ventilation.19 A vital capacity less than 26 1.5 L, especially in combination with hypercarbia Orthopedic management 27 (PaCO2 > 45 mm Hg) or hypoxemia (PaO2 < 75 mm Hg), 28 The development of contractures impedes ambulation indicates that ventilatory support is needed.7 As 10,11 29 and function of patients with muscular dystrophy. PEmax decreases below 40 cm H2O, cough becomes 30 Flexion contractures of the knees and hips produce ineffective, causing mucous plugging and microat- 31 hyperlordosis of the lower spine, and Achilles tendon electasis, which will eventually decrease O2 diffusing 32 contractures produce toe-walking.10 capacity and lead to hypoxemia. During the period of 33 The surgical management of contractures is indi- intercostal and accessory muscle atonia associated 34 vidualized but may include one or more of the follow- with REM sleep, ventilation is supported by move- 35 ing: release of flexion contractures of the hips, release ments of the diaphragm muscle. Diaphragmatic 36 of the tensor fasciae latae to correct abduction con- weakness, particularly prominent in Duchenne dys- 37 tractures, and tenotomy of the Achilles tendon com- trophy, results in orthopnea, and REM-sleep associ- 38 bined with a posterior tibial-tendon transfer to allow ated hypoventilation.12 Paradoxical inward movement 39 dorsiflexion and eversion rather than excessive of the abdominal muscles during inspiration and 40 plantar flexion and inversion.11 If performed while the more than 20% decrease in vital capacity on lying 41 patient is still ambulatory but already showing gait down from sitting also indicate diaphragmatic weak- 42 impairment, contracture release may prolong ambula- ness. Chest wall deformities caused by shortening or 43 tion by 1 to 3 years.11 However, lengthening already fibrosis of intercostal and accessory muscles or by 44 severely weakened muscles may further decrease progressive scoliosis decrease chest wall compliance 45 strength, and intervention to restore walking after a and further compromise respiratory function.18 46 patient has been nonambulatory for more than 3 to 6 Many patients with relatively static forms of dys- 47 months is of no benefit.11 The orthopedic management trophy have nocturnal hypoxemia and complain of 48 of scoliosis is described below in the section on symptoms related to nocturnal hypoventilation.20 49 Duchenne dystrophy. Poor sleep, frequent nocturnal awakenings, night 50 As with any operative procedure, appropriate terrors or nightmares, nocturnal seizures, morning 51 anesthesia must be used (see below), and cardiac and headaches, reduced school performance, and daytime 52 respiratory function must be investigated and moni- hypersomnolence are symptoms of nocturnal 53 tored carefully. Early and active physiotherapy is hypoventilation.7,12,13 In these patients, routine 54 crucial in the postoperative period, and immobiliza- daytime pulmonary function tests may fail to detect 55 tion must be minimized.10 the degree of respiratory compromise. Polysomnogra- 56 phy in combination with oximetry and transcuta- Respiratory care 57 neous CO2 measurements are required for adequate 58 Respiratory compromise in patients with muscular assessment.13 For these patients, long-term nocturnal 59 dystrophy may be associated with intercurrent chest ventilation at home can dramatically improve the 60 infection or may develop as a chronic component of quality of life.17 Biphasic positive airway pressure 61 the underlying muscle disease.12–17 (BiPAP) delivered via nasal mask is well tolerated. It 62 Respiratory management, outlined in Figure 223.2, rapidly improves nocturnal hypoxemia, restores 709_Neurological_ch.223 9/7/2002 10:32 am Page 6

223.6 XII Section Title

1 2 3 Respiratory functional inquiry 4 and basic management (a) 5 6 7 8 Baseline PFTs (b) 9 10 11 12 13 SS of noct. 14 FVC 60% predicted FVC 40Ð60% predicted FVC 40% predicted 15 hypovent. (c) 16 17 18 19 Overnight oximetry PFTs every 4 months Arterial blood gases 20 (even if PFTs PFTs 1-2x/year Deep breathing exercises Overnight oxiometry 21 are normal) Regular chest physiotherapy Exclude infection 22 23 24 25 FVC persistently 40% predicted 26 27 28 29 Noninvasive 30 nocturnal ventilation 31 32 33 Overnight polysomnography 34 at regular intervals to assess 35 efficacy, proper fit of facial mask, 36 and ensure patient compliance 37 and comfort 38 39 40 41 If patient pulmonary 42 function declines or daytime 43 ventilation is required 44 45 46 47 Invasive ventilation (with 48 tracheostomy) and regular 49 monitoring of efficacy 50 51 52 53 Figure 223.2 A general guide for the respiratory management of patients with neuromuscular disease. The suggested 54 pulmonary function variables are similar to those outlined by the Muscular Dystrophy Association in its pamphlet, “Breathe 55 Easy.” The importance of general health maintenance and careful inquiry into clinical features of nocturnal hypoventilation are stressed. (a) Basic respiratory management of all patients with marked muscle weakness includes healthy diet with adequate 56 protein, avoidance of obesity, scoliosis screening and management, early recognition and treatment of chest infection (chest 57 physiotherapy, postural drainage, adequate hydration to thin secretions, antibiotics), and annual influenza vaccination. (b) 58 Patients should be encouraged to exert their maximal effort, testing mask or tubing should be properly fitted for the patient, and 59 intercurrent or recent illness should be noted. (c) Symptoms of nocturnal hypoventilation: daytime hypersomnolence, morning 60 headache, poor or declining school/work performance, excessive fatigue, unexplained weight loss, or failure to gain weight 61 (infant or child). FVC, forced vital capacity; noct. hypovent., nocturnal hypoventilation; PFTs, pulmonary function tests; SS, 62 symptoms and signs. 709_Neurological_ch.223 9/7/2002 10:32 am Page 7

Muscular Dystrophies 223.7

1 normal sleep patterns, eliminates morning headaches, initial discussion should occur when both parents are 2 reduces daytime somnolence, and prevents cor pul- present. The decision to include the child in the initial 3 monale.20 Assisted ventilation is discussed further in discussion depends on the age and cognitive maturity 4 the section on Duchenne muscular dystrophy. of the child. Open, accurate, and honest discussions 5 with the child over time increase understanding of the 6 Cardiovascular management disease and encourage discussion of frustrations, 7 Involvement of can be prominent in fears, and expectations. It is important to encourage 8 patients and manifesting carriers of dystro- independence and to recognize a child’s need for 9 phinopathies and in patients with Emery–Dreifuss privacy. In late adolescence, these issues become 10 muscular dystrophy or myotonic dystrophy.21–24 pressing, as the teenager attempts to form peer and 11 Rarely, heart disease develops in patients with fas- sexual relationships, establish educational and voca- 12 cioscapulohumeral,23 congenital muscular dystrophy tional goals, and achieve independent living arrange- 13 associated with merosin deficiency,25 or sarcogly- ments. Independent living or group home 14 canopathies.26,27 Syncope or palpitations should arrangements can be achieved in many cases by 15 prompt immediate cardiac assessment. Additional careful planning and with home assessment by an 16 studies, including Holter monitoring, His bundle elec- occupational therapist. 17 trocardiograms, or echocardiography, should be per- 18 formed on symptomatic patients under the guidance Gene therapy 19 of a cardiologist.22 Despite reasons for optimism, numerous hurdles 20 remain before gene therapy can be realized for mus- 21 Anesthetic issues cular dystrophy.28 Trials of dystrophin replacement 22 Anesthetic complications can occur in patients with using local intramuscular injections of paternally 23 muscular dystrophy, particularly in those with dys- derived myoblasts failed to result in long-term dys- 24 trophinopathies5 or myotonic dystrophy.24 The com- trophin expression in mature muscle fibers and did 25 plications include tachycardia, atrial and ventricular not improve muscle strength or patient outcome in 26 fibrillation, a malignant hyperthermia-like reaction, boys with Duchenne muscular dystrophy.29 27 and, rarely, cardiac arrest.1 These complications occur In a recent review, Karpati28 proposed five strat- 28 even in the absence of overt cardiomyopathy.1 Post- egies for gene therapy: (1) specifically designed phar- 29 operatively, a marked increase in the CK level and macotherapy, (2) protein replacement (not applicable 30 myoglobinuria may occur in Duchenne patients.1 for structural proteins), (3) upregulation of a func- 31 Anesthetists should avoid the use of nondepolarizing tional protein analogue, (4) RNA repair, and (5) 32 blocking agents and be alert to the risk of complica- somatic gene replacement. Of these strategies, the 33 tions in any patient with muscular dystrophy. latter three hold the most promise. Utrophin, a 34 protein encoded on chromosome 6, has 80% sequence 35 Psychological issues homology to dystrophin.30 In mature muscle, 36 The diagnosis of a progressive neuromuscular dis- utrophin is localized to the postsynaptic sarcolemma 37 order has an enormous impact on the psychological of the .31,32 In fetal muscle, 38 well-being of the patient and the patient’s family. utrophin is also expressed at the extrajunctional sar- 39 Both the patient and the family should be provided colemma.32 In the dystrophin-deficient (mdx) mouse 40 with information about local and national support and in muscle from patients with Duchenne muscular 41 groups and be offered specific counseling as needed. dystrophy, utrophin expression resembles the fetal 42 Because the psychological effects of a chronic disease pattern.30 However, this naturally occurring up-regu- 43 may not be manifested immediately, it is important to lation of utrophin is not sufficient to prevent ongoing 44 periodically ask the patient and family about their muscle damage in patients with Duchenne muscular 45 emotional well-being. Many parents are reluctant to dystrophy.5 The mdx mouse, a murine model for 46 ask for help because they feel that this reflects a lack Duchenne muscular dystrophy, has absence of dys- 47 of compassion or commitment to their child. It is trophin expression in muscle, increased levels of CK, 48 crucial that parents spend time together as a couple pathological features of mild dystrophy in selected 49 and have time to focus attention on their other chil- muscles, and mild weakness.5 In recent studies, mdx 50 dren. The incidence of marital discord is greater than mice genetically engineered to overexpress a trun- 51 50% and the divorce rate is higher than 25% for cated utrophin minigene or full-length utrophin 52 couples with a chronically ill child.9 Many communit- showed improved mechanical strength, normal or 53 ies have a local Muscular Dystrophy Association minimally increased serum levels of CK, and little or 54 chapter that enables parents to derive support from no dystrophic changes in muscle.30,33,34 A search for 55 other parents and allows affected children to spend methods to up-regulate utrophin expression in 56 time with other similarly affected children. Summer humans is under way. 57 camp programs provide invaluable independence RNA repair involves the use of targeted antisense 58 and recreation for children as well as respite for famil- oligonucleotides designed to bind to mutated RNA 59 ies. In the case of an affected adult, a few hours each regions, change the reading frame, and bypass the 60 day of in-home nursing services provides relief for original mutation.28 It is postulated that RNA repair 61 the spouse or care-giver. occurs spontaneously in the small number of dys- 62 Whenever a specific dystrophy is diagnosed, the trophin-positive (revertant) fibers found in muscle of 709_Neurological_ch.223 9/7/2002 10:32 am Page 8

223.8 XII Section Title

1 patients with Duchenne muscular dystrophy. Early biopsy findings, and genetic studies. The serum level 2 studies of this technique are also under way. of CK is elevated 10- to 50-fold at age 3 years and 3 Somatic gene cell replacement for muscular dystro- declines by approximately 20% per year thereafter.37 4 phy holds great promise, but numerous methodo- Because of the enormous size of the dystrophin gene, 5 logical issues remain to be solved. In general terms, only certain regions are screened by commercially 6 replacement of a defective gene requires the follow- available molecular DNA studies. Large scale deletions 7 ing: are detected in only 60% to 70% of affected patients.7 It 8 is important to recognize that a Duchenne or Becker • Knowledge of the target gene and its promoters 9 muscular dystrophy phenotype cannot be predicted • The ability to construct a full-length gene, or a 10 reliably on the basis of the type of mutation alone.37 In functional “minigene” 11 families in which no mutation is found, linkage analy- • The ability to insert the gene or minigene into a 12 sis looking for markers that cosegregate with the X- vector 13 chromosome of a patient with Duchenne muscular • Creation of a vector large enough to receive the 14 dystrophy can be performed provided a sufficient insert, small enough to infect the tissue of interest, 15 number of family members are available. Muscle and modified enough to prevent vector-related 16 biopsy studies using antibodies directed against the disease or malignancy 17 carboxyl and amino termini and rod domain of dys- • Delivery of the vector (with the inserted gene) to a 18 trophin can be helpful in distinguishing Duchenne significant proportion of affected muscles 19 from Becker muscular dystrophy and for establishing • Failure of the vector to disrupt other proteins 20 the diagnosis of a dystrophinopathy in the 30% to 40% • Processing of the newly inserted gene by the host 21 of such patients in whom no mutation was found.5 cell must lead to continual expression and appro- 22 Most patients with Duchenne muscular dystrophy priate cellular localization of the target protein 23 show absence of dystrophin immunoreactivity in all • The ability of the newly expressed protein to asso- 24 but a few “revertant” fibers.5 However, patients with ciate with its appropriate binding partners 25 partially preserved dystrophin expression cannot be • Tolerance of the patient’s immune system to both 26 guaranteed to have a Becker muscular dystrophy phe- the vector and the newly expressed protein 27 notype. Western blot analysis of the muscle shows 28 Several dystrophin minigenes have been engineered decreased dystrophin content and an abnormal size of 29 successfully into viral vectors, but human trials must the mutated protein.7 Muscle biopsy specimens may 30 await the development of safe and efficient delivery show patchy dystrophin immunoreactivity in mani- 31 systems. festing female carriers or in unaffected mothers.5 32 Because only 70% of female carriers have increased 33 Disease-specific management issues serum levels of CK, this test alone is not sufficient to 34 exclude carrier status.37 35 Duchenne and Becker muscular dystrophies 36 Dystrophin is a large cytoskeletal protein (427 kDa) Genetic counseling Genetic counseling should be 37 expressed in many tissues.5 It is particularly import- provided to parents and siblings of patients with 38 ant at the sarcolemma of , where it Duchenne or Becker muscular dystrophy. Female car- 39 forms a complex with a group of membrane-associ- riers have a 50% chance of producing an affected son, 40 ated glycoproteins.35,36 In general, frame-shifting dele- and 50% of female offspring will be carriers. Not all 41 tions cause a virtual absence of dystrophin expression cases of dystrophinopathy are familial, because of the 42 in muscle and result in the Duchenne muscular dys- high spontaneous mutation rate in the dystrophin 43 trophy phenotype, whereas in-frame deletions or gene. The risk in these families for a subsequently 44 missense mutations with attenuated dystrophin affected son is approximately 7%.37 45 expression produce the milder Becker muscular dys- Prenatal diagnosis of dystrophin deficiency can be 46 trophy phenotype.5 performed on amniocytes or chorionic villus 47 samples.37 Preimplantation diagnosis performed after 48 Clinical features Boys with Duchenne muscular dys- a single cell biopsy at the blastomere stage before in 49 trophy present around the age of 3 years with a clumsy vitro fertilization is available for families with known 50 gait, frequent falls, and toe walking. The disease pro- mutations.38 Needle biopsy specimens from a limb 51 gresses such that ambulation is typically lost by age 13 muscle of an at-risk fetus can be analyzed with dys- 52 years, and death ensues in the second or third decade. trophin antibodies, but there is a 3% to 5% mis- 53 Patients with Becker muscular dystrophy may present carriage rate with the procedure.39 Specialized 54 similarly but retain the ability to walk past age 13 techniques, such as transfection studies of fetal 55 years, or they may be mildly affected and not present amniocytes or chorionic villus cells using the muscle 56 until adulthood. Some patients with Becker muscular promoter myoD with analysis of dystrophin expres- 57 dystrophy, and some female carriers of dystrophin sion in transfected cells, are performed at a few 58 mutations, present with an isolated cardiomyopathy.5,23 research centers.40 Fetuses with absent dystrophin 59 expression can then be detected. 60 Diagnosis The diagnosis of either Duchenne or 61 Becker muscular dystrophy rests on the history, phys- Treatment Despite reasons for optimism about the 62 ical examination, serum level of CK (increased), muscle future of genetic therapies, current treatment for boys 709_Neurological_ch.223 9/7/2002 10:32 am Page 9

Muscular Dystrophies 223.9

1 with Duchenne or Becker muscular dystrophy The subsequent rate of decline in muscle strength 2 revolves around the prevention or limitation of sec- is decreased in comparison with that of untreated 3 ondary complications and maximizing the quality of historical controls, and this effect is sustained for at 4 life. least 3 years.43 These benefits must be weighed 5 against the potentially severe side effects of 6 1. Physical therapy: Parents and caregivers need to be long-term prednisone administration (weight 7 taught by an experienced therapist the appropriate gain, cushingoid appearance, avascular necrosis 8 techniques to prevent contractures. Range of of the femoral head, osteopenia, hyperglycemia, 9 motion exercises may cause minor discomfort. If cataracts, and gastrointestinal distress). Treatment 10 pain is elicited, the exercise should be stopped and with an equivalent anti-inflammatory dose of 11 the child examined for fracture or joint injury. deflazacort produces benefits similar to those 12 Physical therapy in combination with appropriate observed with prednisone.48 In the initial trial, 13 surgical intervention may prolong ambulation for 1 patients given deflazacort had less weight gain but 14 to 5 years.7 Therapy should consist of range of developed significantly more cataracts than 15 motion exercises, passive stretching, and participa- patients given prednisone.48 Immunosuppression 16 tion in enjoyable exercises and sports in the early with azathioprine (Imuran) alone or in combina- 17 phase (age 2 to 8 years) and continuation of stretch- tion with prednisone was found to be of no value.46 18 ing and participation in concentric exercises such a A 3-month pilot trial using the anabolic steroid 19 supervised swimming in the intermediate phase oxandrolone (0.1 mg/kg daily) showed statistically 20 (age 8 to 12 years).7 The use of long-leg orthotics significant improvement in muscle strength scores 21 (Dubowitz braces) may prolong the ability to stand comparable to the results achieved in the cortico- 22 by up to 3.9 years.7 Fitting of these braces may steroid trials.49 No side effects were reported. 23 require release of existing ankle and hip contrac- 4. Respiratory management: Seventy percent of deaths 24 tures. in Duchenne muscular dystrophy are respiratory.18 25 2. Scoliosis: The development of scoliosis is invariant Mechanical ventilation of patients with a progres- 26 in Duchenne muscular dystrophy but is delayed if sive disability raises numerous ethical, financial, 27 ambulation is prolonged into adolescence.41 The emotional, and practical issues for affected boys 28 scoliotic curve progresses at a rate of 1 to 2 degrees and their families. These issues must be discussed 29 per month after ambulation is lost.42 Bracing and openly and, preferably, well before respiratory 30 proper seating (narrow width chair, proper back intervention has to be considered. In Japan, nearly 31 support) slow the progression of scoliosis, but sur- all affected boys offered assisted ventilation chose 32 gical intervention is eventually required. Surgical to pursue this option.19 33 intervention is indicated when the spinal curvature Respiratory assessment requires detailed pul- 34 reaches 40 degrees or if it is rapidly progressive.5 monary function studies. Baseline studies should 35 Spinal stabilization using the sublaminar wire be performed shortly after diagnosis and then 36 technique (Luque instrumentation) and spinal repeated every 6 to 12 months. After ambulation 37 arthrodesis decreases spinal curvature by approxi- has been lost, pulmonary function must be moni- 38 mately 50% and results in substantial improvement tored more frequently. The first stage of respiratory 39 in seating, comfort, cosmetic appearance, and failure, due to a weak cough, results in accumu- 40 quality of life.42 Respiratory function is not lated secretions and microatelectasis.50 Incentive 41 markedly improved with spinal stabilization.11,42 spirometry, used before a marked decline in pul- 42 As with any operative procedure, appropriate monary function, may help reduce atelectasis. 43 anesthesia must be administered (see below), and However, the use of spirometry to improve respi- 44 cardiac and respiratory function should be investi- ratory muscle strength is of no benefit.51 Intermit- 45 gated and monitored carefully. Patients with dys- tent use of an Emerson In-Exsufflator, a small 46 trophin deficiency also have platelet dysfunction, electrical machine that pushes a fixed volume of air 47 despite normal bleeding time, and may require into the lungs and then forcefully withdraws air 48 extensive blood replacement during a spinal opera- and mucus, may be helpful in patients with a weak 49 tion.7 Early and active physiotherapy are crucial cough, especially during intercurrent pulmonary 50 postoperatively, and immobilization must be mini- infections. The second stage of ventilatory failure 51 mized. relates to nocturnal hypoventilation.50 At this point, 52 3. Corticosteroids: Ambulation is prolonged in patients the vital capacity is usually less than 30% of pre- 53 with Duchenne muscular dystrophy treated with dicted and polysomnography demonstrates hypox- 54 corticosteroids.43–46 The beneficial effects of corti- emia that is most prominent during REM sleep. 55 costeroids may be due to increased muscle mass When vital capacity decreases to 10% to 20% of 56 (decreased protein catabolism or increased protein predicted or is less than 1 L, assisted ventilation 57 synthesis), sarcolemmal membrane stabilization, or should be considered.19 The use of assisted ventila- 58 suppression of the immune response directed tion can prolong life by as much as 10 years.52 Both 59 against degenerating fibers.47 The best results are negative and positive pressure ventilation systems 60 achieved with prednisone at a dose of 0.75 mg/kg are available for nocturnal or full-time ventilation. 61 daily.43 Improvement in strength testing is noted Negative pressure ventilation, initially pioneered as 62 by 10 days and becomes maximal by 2 months.45 the iron lung and now as the cuirass tank or wrap 709_Neurological_ch.223 9/7/2002 10:32 am Page 10

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1 (poncho), provides ventilatory support using negat- Myotonic dystrophy 2 ive pressure to expand the chest. Although used “Myotonic dystrophy” is the most common form of 3 extensively in Japan until 1992, use of this system is muscular dystrophy in adults.53 4 waning, largely because of its lack of portability, 5 discomfort (skin abrasions, coldness), difficulty in Genetics The myotonic dystrophy gene localizes to 6 fitting the device to the chest wall leading to air chromosome 19q13.3. The genetic defect results from 7 leaks, and, most importantly, increased episodes of a trinucleotide (CTG) expansion in the 3′ noncoding 8 obstructive apnea.52 For those who use this form of region of the myotonic dystrophy protein kinase 9 ventilation, additional nasal continuous positive (DMPK) gene.54 The number of (CTG) repeats corre- 10 55 airway pressure is advocated to decrease the risk of lates positively with disease severity. Patients with 11 7 upper airway obstruction. Positive airway pressure minimally expanded repeats (CTG)38–60 may be 12 ventilation can be provided using nasal or facial asymptomatic and have normal findings on elec- 13 tromyography.56 Genetic anticipation, the tendency 14 masks or via tracheostomy. For many patients, therapy is initiated with noninvasive nasal or facial for disease severity (and number of expanded 15 repeats) to increase in subsequent generations, occurs 16 masks, and when ventilatory requirements and is especially likely when the mother is the 17 increase, tracheostomy is performed. Tracheostomy affected parent.24 DMPK is a transmembrane protein 18 provides access for suction and improved pul- localized to the and appears 19 monary toilet. The use of a Passy–Muir valve to be expressed predominantly in type I fibers, at the 20 allows enough air to pass around the tracheostomy neuromuscular junction, and in intrafusal fibers of 21 cannula to permit speech. All patients with tra- the .54 The function of DMPK and the 22 cheostomies need humidified O to reduce thicken- 2 mechanism whereby expansion in the noncoding 23 ing of secretions. Safety measures must be 24 region of the protein results in disease are not under- observed: a back-up ventilator must be present if stood. Recent studies have shown a reduction in 25 the patient is ventilator-dependent, ventilator main- 26 expression of DMPK in muscle specimens from tenance must be performed routinely, caregivers affected patients, suggesting a dominant negative 27 must be adept at cannula replacement, and alarm 28 effect of the trinucleotide expansion at the RNA systems (including chest wall apnea monitors) must level.57 Alternatively, the expanded region may 29 7 be used. A helpful booklet, Breathe Easy—Respira- disrupt function of a contiguous gene, such as the 30 tory Care for Children With Muscular Dystrophy, is 31 myotonic dystrophy-associated homeobox gene distributed by the Muscular Dystrophy Association. 58 32 (DMAHP). 5. Cardiac management: Essentially all patients with 33 Clinical features 34 Duchenne muscular dystrophy will show signs of 35 cardiac disease by their 18th birthday. Changes in Myotonic dystrophy is a multisystem disorder of vari- 36 the electrocardiogram (ECG), including conduction able severity, and many mildly affected patients are 37 37 defects and sinus tachyarrhythmias, are present unaware of their diagnosis. Affected patients have 38 by age 10 years but are of limited value in predict- weakness of facial (ptosis, long myopathic facies), jaw 39 ing marked cardiac compromise. Patients should (temporomandibular dislocations), distal limb, and, to 40 be followed by a cardiologist after 8 years of age a lesser degree, proximal muscles of the shoulder and 24 41 and should have echocardiography annually pelvic girdle. Limb weakness is usually mild and 42 beginning at age 10.7 Cardiac failure may be helped progresses slowly. Weakness of ankle dorsiflexion as 43 by treatment with angiotensin-converting enzyme well as more proximal weakness necessitates use of a 44 cane or wheelchair by more severely affected inhibitors. Digoxin may cause severe arrhythmias 24 45 and must be used with extreme caution.7 patients. “Action myotonia” is often described by 46 6. Gastrointestinal management: Dystrophin is also patients as difficulty in releasing their grip or in initi- ating voluntary movements. “Percussion myotonia” 47 expressed in .5 Many patients with is best demonstrated in the tongue, hand, or finger 48 Duchenne muscular dystrophy have impaired extensor muscles by firmly tapping the muscle with a 49 gastric motility and can present with severe gastric reflex hammer. 50 distention and intestinal pseudo-obstruction.37 51 Cardiac manifestations, including conduction block Acute abdominal pain should receive immediate 52 and tachyarrhythmias due to degeneration of the medical attention. 53 cardiac conducting system, can occur in otherwise 54 7. Education: Although the role of dystrophin in the mildly affected patients. More than 90% of patients 55 central nervous system is unknown, a functional with myotonic dystrophy show gradually progressive 56 role is suggested by the fact that the average intelli- ECG abnormalities, which may require His-bundle as 57 gence quotient of boys with Duchenne muscular well as routine ECG recordings for diagnosis.24 58 dystrophy is 1 standard deviation below the mean Sudden death is well documented. 59 (even in comparison with siblings),37 and 30% of The diaphragm is often involved, resulting in noc- 60 the boys have significant learning disabilities or are turnal respiratory compromise and manifesting as 61 mentally retarded. Educational needs must be daytime hypersomnolence.59 Although weakness of 62 assessed and modified if required. respiratory and facial muscles and craniofacial abnor- 709_Neurological_ch.223 9/7/2002 10:32 am Page 11

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1 malities, including micrognathia, predispose to respi- procainamide, and quinidine used to treat other 2 ratory compromise, an additional defect in central myotonic disorders may exacerbate cardiac 3 respiratory drive has also been suggested.13 arrhythmias and should be avoided.24 4 The involvement of smooth muscle causes dis- 2. Anesthesia: A malignant hyperthermia-like reaction, 5 turbed swallowing, constipation, weakness of the anal postulated to be due to abnormal calcium influx 6 sphincter (especially notable in affected children and from the extracellular space, may occur with depo- 7 often mistaken for abuse), and delayed gallbladder larizing muscle relaxants and neostigmine.24 It is 8 emptying, with an increased incidence of gallstones.24 critical that anesthetists be aware of the diagnosis 9 Cataracts develop in most patients with myotonic of myotonic dystrophy preoperatively. A medic 10 dystrophy, and retinal degeneration also can occur. alert bracelet is advised. 11 Examination with a slit lamp to look for multicolored 3. Cardiac: Signs of progressive conduction defects or 12 subcapsular cataracts and a detailed retinal examina- symptoms of syncope or palpitations should 13 tion should be performed annually.24 prompt immediate cardiac assessment and Holter 14 Endocrine manifestations include testicular monitoring. Pacemaker insertion may be 15 atrophy, reduced fertility, hyperglycemia with required.53 16 increased insulin resistance (true diabetes is rare), and 4. Respiratory: Hypersomnia may be improved but not 17 early-onset frontal balding.24,53 entirely reversed by nocturnal assisted ventilation. 18 The combination of effects on the uterine smooth In these patients, methylphenidate may enhance 19 muscle and the endocrine system results in a high alertness.13,59 Respiratory muscle training can 20 incidence of pregnancy complications, including fetal improve respiratory strength.62 Opiates, barbitu- 21 loss, hydramnios, prolonged labor, retained placenta, rates, and benzodiazepines can cause marked respi- 22 postpartum hemorrhage, and an increased risk of pre- ratory depression and should be prescribed with 23 mature delivery.24 caution. Nocturnal sedatives should be avoided.24 24 A more severe form of myotonic dystrophy occurs 25 in congenitally affected neonates. Affected infants Patients with an autosomal dominant disorder that 26 have severe bifacial weakness with a “tented mouth,” shares many of the features of myotonic dystrophy 27 poor feeding, diffuse hypotonia, thin ribs, elevated but without an expanded trinucleotide repeat on 63–66 28 diaphragms, and respiratory failure often requiring chromosome 19 have been reported. The disorder 29 artificial ventilation. Some infants also have arthro- is genetically and clinically heterogeneous. The terms 30 gryposis and hydrocephalus.24,60 Neonatal mortality is “proximal myotonic dystrophy” and “myotonic dys- 31 high. In one study, all infants who required ventila- trophy type 2” have been applied and some kindreds 7,66–68 32 tion for more than 4 weeks eventually succumbed, have been linked to chromosome 3q. 33 even if they were weaned successfully from ventila- Oculopharyngeal muscular dystrophy 34 tory support.61 In less severely affected infants, motor 35 development is delayed but ambulation eventually is Genetics Genetic studies show an expanded (GCG) 60 36 achieved. Cognition is significantly impaired in at repeat from (GCG)6 to (GCG)8–13 in the amino termi- 37 least two-thirds of affected children, and few are of nus of the poly(A) binding protein 2 gene (PABP2) 38 normal intelligence.24 located on chromosome 14q11.69 Inheritance in these 39 families follows an autosomal dominant pattern. Two 40 Diagnosis Serum CK levels are normal or minimally percent of the normal population harbor a single copy 24 41 increased. Muscle biopsy findings include increased of an alternative (GCG)7 allele, which when combined 42 central nuclei, ringed fibers, type I fiber atrophy, sar- with an expanded (GCG)8–13 allele produces a particu- 43 coplasmic masses, and a variable degree of fibrosis.24 larly severe phenotype. Patients homozygous for the 44 EMG studies show electrical myotonia consisting of (GCG)7 allele are mildly symptomatic, and these kin- 45 discharges that wax and wane in frequency and ampli- dreds show an autosomal recessive pattern of inheri- 46 tude as well as positive sharp waves, fibrillation poten- tance.69 Although the function of the PABP2 gene has 47 tials, and myopathic motor units. EMG studies rarely yet to be elucidated, it is postulated that expansions of 48 show myotonia until late childhood. The presence of the polyalanine tract may cause aggregation and pos- 49 myotonia early in life suggests the diagnosis of a sibly defective degradation of the poly(A) binding 50 nondystrophic myotonic disorder.24 Because many protein. These abnormal aggregates may correspond 51 mildly affected women are unaware of their condition to the filamentous 7- to 10-nm nuclear inclusions that 52 until the birth of an affected child, EMG should be per- are the pathological signature of the disease.70 53 formed on all mothers of severely hypotonic neonates. 54 Clinical features Oculopharyngeal muscular dystro- 55 Management phy presents in the 5th to 6th decade of life with pro- 56 1. Myotonia: Unlike other myotonic disorders, the gressive dysphagia, ptosis, and proximal muscle 57 myotonia of myotonic dystrophy is rarely dis- weakness.69,70 When ptosis is severe, the patient tilts 58 abling.24 In the few patients with marked myotonia, the head back and contracts the frontalis muscle in 59 phenytoin (100 mg 3 times daily) may be of benefit. order to see.70 60 Women must be warned about the risk of teratoge- 61 nesis, and phenytoin therapy should be stopped Diagnosis The serum levels of CK usually are 62 before conception. Medications such as tocainide, normal, and EMG studies show a myopathic 709_Neurological_ch.223 9/7/2002 10:32 am Page 12

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1 pattern.70 Increased serum levels of IgA and IgG were involvement of lower extremity muscles in about 20% 2 reported in French-Canadian pedigrees, but this of cases.74 Weakness of the anterior tibial muscles pro- 3 could have been related to intercurrent pulmonary duces a footdrop gait, which can become disabling for 4 infections due to chronic aspiration.70 Muscle biopsy some patients.78 Weakness of the shoulder girdle 5 specimens show atrophic fibers, rimmed vacuoles results in scapular instability, marked limitation in 6 (especially in atrophic fibers), scattered ragged red arm abduction, and the characteristic “scapular 7 fibers, and degenerating fibers.70 Intranuclear inclu- winging.”79 Hearing loss and retinal venous anom- 8 sions consisting of 7- to 10-nm filaments are alies are common but may be subclinical.78 The risk of 9 demonstrated by electron microscopy.70 Coats disease (retinal telangiectasias, exudate, and 10 In the presence of a strong family history of late- retinal detachment) is increased.78 11 onset ptosis and dysphagia, the diagnosis of ocu- A more severe congenital variant presents with one 12 lopharyngeal muscular dystrophy is straightforward. or more of the following: severe facial diplegia, 13 Mitochondrial myopathy and myasthenia gravis are marked sensorineural hearing loss, Coats disease, and 14 the main differential diagnoses. Short stature, deaf- weakness that may progress to wheelchair depen- 15 ness, central nervous system involvement, increased dence in the second decade of life.80,81 16 serum levels of lactate, pigmented retinopathy and 17 night blindness, onset before age 20 years, and a Diagnosis Pathological changes in muscle are vari- 18 maternal pattern of inheritance suggest a mitochon- able and reflect the regional and asymmetrical distrib- 19 drial disorder. The presence of circulating acetyl- ution of the disease. A biopsy specimen from a mild 20 choline receptor antibodies, a decremental response to to moderately affected muscle shows increased fiber 21 repetitive stimulation during EMG, and a history of size variation, increased central nuclei, occasional 22 fatiguable weakness point to a myasthenic disorder. necrotic fibers, fibers with a lobulated distribution of 23 oxidative enzymes, and increased endomysial and 24 Treatment perimysial connective tissue.78 In some cases, small 25 1. Dysphagia: Patients with oculopharyngeal muscular perivascular, endomysial, or perimysial collections of 26 dystrophy have dysfunction of the striated muscle mononuclear cells are also present.78 Approximately 27 of the upper one-third of the esophagus (cricopha- 60% to 80% of patients with fascioscapulohumeral 28 ryngeal achalasia). The failure of the cricopharyn- muscular dystrophy have a modest increase in the 29 geal muscles to contract properly results in pooling serum level of CK, and EMG demonstrates a myo- 30 of secretions and food in the hypopharynx and pre- pathic pattern.78 31 disposes to aspiration.71 Severe difficulty with 32 swallowing leads to reduced oral intake and sub- Treatment Many patients with fascioscapulo- 33 sequent malnutrition. Patients who require more humeral muscular dystrophy are affected only mildly 34 than 7 seconds to drink 80 mL of ice water are and require no specific treatment. 35 likely to have significant achalasia, and formal 72 1. Scapular arthrodesis: For patients with severe limita- 36 swallowing studies should be performed. tion of arm abduction, scapular arthrodesis can be 37 Cricopharyngomyotomy provides dramatic relief 73 considered. Scapular arthrodesis involves the use 38 of the obstruction. of an iliac crest bone graft and wiring to fix the 39 2. Ptosis: Ptosis, defined as a palpebral fissure width 79 73 scapula to the thoracic rib cage. The procedure 40 less than 8 mm, may be improved with the use of offers long-lasting improvement in shoulder move- 41 lid crutches or may be corrected with blepharo- 70 ment, but it is associated with the risk of periopera- 42 plasty. tive pneumothorax and pulmonary atelectasis.79 43 Fascioscapulohumeral muscular dystrophy 2. Medications: Treatment with corticosteroids does 44 not increase a patient’s strength.82 A pilot trial of 45 Genetics Fascioscapulohumeral muscular dystrophy the 2-agonist albuterol showed a 12% improve- 46 is an autosomal dominant disorder, with 10% of cases 83 74,75 ment in muscle strength over 3 months. 47 due to spontaneous mutations. The most severely 3. Ophthalmology: Visual loss due to Coats disease 48 affected patients are more likely to have spontaneous may be prevented by early diagnosis and therapeu- 49 mutations or to have inherited the disorder from their 80 76 tic photocoagulation of abnormal vessels. 50 mother. The genetic locus for this condition is at the 4. Audiology: The sensorineural hearing loss in con- 51 telomeric region 4q35 and is associated with deletion genitally affected patients may be improved with 52 of an integral number of tandemly arrayed 35- to 300- 77 hearing aids. Early recognition and intervention 53 kb repeats. This likely exerts an adverse effect on are important for language development. 54 upstream genes (position effect variegation), but the 55 genes whose functions are altered have not been dis- 77 Emery–Dreifuss muscular dystrophy 56 covered. There is a direct correlation between the 57 number of deleted repeats and the severity of Genetics Two phenotypically similar diseases are 58 disease.76 termed “X-linked” and “autosomal dominant” 59 Emery–Dreifuss muscular dystrophy. The X-linked 60 Clinical features Fascioscapulohumeral muscular form is due to mutations in the nuclear membrane- 61 dystrophy is characterized by weakness of the facial, associated protein emerin.84 The gene for the auto- 62 upper limb, and shoulder girdle muscles, with later somal dominant form encodes the nuclear 709_Neurological_ch.223 9/7/2002 10:32 am Page 13

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1 lamina-associated protein lamin A/C85 and appears to protein, is unknown.97 “Muscle–eye–brain disease” 2 be an allelic disorder to the autosomal dominant limb has been reported predominantly in Finland and is 3 girdle dystrophy associated with cardiac involvement linked to chromosome 1p32–p34.98 The third and most 4 (LGMD 1B).86 How mutations in these genes result in severe form is Walker–Warburg syndrome. The locus 5 muscular dystrophy is not understood. for this disorder has not been mapped.99 6 7 Clinical features Both forms of Emery–Dreifuss Clinical features Neonates have marked hypotonia, 8 muscular dystrophy are characterized by the early weakness, increased serum levels of CK, and delayed 9 onset of elbow, neck, and Achilles tendon contrac- motor development. Many also have or develop con- 10 tures, slowly progressive wasting and weakness of tractures and have marked respiratory and feeding 11 the proximal muscles, and potentially lethal cardiac difficulties.91,100 12 conduction block and cardiomyopathy.85 Patients with merosin-deficient congenital muscu- 13 lar dystrophy have severe nonprogressive weakness; 14 Diagnosis The serum level of CK is moderately they are able to sit by age 3 years but have poor head 15 increased, and EMG shows myopathic features with control and most remain wheelchair-dependent. 16 rare fasciculations.87 Muscle biopsy studies demon- Rarely, patients with partial merosin deficiency 17 strate myopathic features and angulated atrophic type present with a limb-girdle distribution of weakness,101 18 I fibers.87 In the X-linked form of the disease, which may manifest in adulthood.102 Cognition is 19 immunostains for the nuclear lamina-associated usually normal in congenital or late-onset cases, 20 protein emerin show reduced or absence of nuclear despite MRI scans that demonstrate abnormally high 21 membrane staining. Emerin is also expressed in skin, T2 signal in the white matter.95 However, a seizure 22 and the diagnosis of an affected male or a carrier disorder develops in up to 30% of patients.103 Merosin 23 female can be made by immunostaining skin biopsy is also expressed in Schwann cells, and merosin-defi- 24 specimens.88 cient patients have a mild demyelinating peripheral 25 neuropathy.91 Rarely, there is cardiac involvement.25 26 Treatment Treatment in Emery–Dreifuss muscular Congenital muscular dystrophy associated with 27 dystrophy is aimed at preventing the cardiac compli- normal cognition, normal findings on neuroimaging, 28 cations of the disease. Up to 40% of the patients and preserved merosin expression is termed 29 die suddenly, most without preceding cardiac “merosin-positive,” or “pure,” congenital muscular 30 symptoms.89 Thus, early diagnosis of the disease is dystrophy. These children usually are affected less 31 essential. All patients should be monitored closely by severely than those with merosin-negative congenital 32 a cardiologist. Timely insertion of a cardiac pace- muscular dystrophy, and ambulation may eventually 33 maker is lifesaving.87 be achieved.91 34 Fukuyama congenital muscular dystrophy, muscle– 35 Congenital muscular dystrophy eye–brain disease, and Walker–Warburg syndrome 36 Genetics Congenital muscular dystrophies are are associated with severe central nervous system 37 degenerative disorders of muscle with in utero or malformations (one or more of the following: 38 early infantile onset. “Merosin-deficient congenital lissencephaly, polymicrogyria, polymacrogyria, 39 muscular dystrophy” is associated with mutations in hydrocephalus, encephalocele, malformations of the 40 the LAMA2 gene encoding the laminin 2 chain cerebellum and midline structures, and abnormal 41 (merosin), a component of the basement membrane white matter) and ocular manifestations (retinal 42 surrounding muscle.90–92 Congenital muscular dystro- detachment, severe myopia, macrocornea).91,99,100,104,105 43 phy with preserved laminin 2 expression and Patients with Fukuyama congenital muscular dys- 44 without severe structural abnormalities of the central trophy are weak and few attain ambulation. Most are 45 nervous system is likely a genetically heterogeneous mentally retarded, with IQ scores between 20 and 90, 46 disorder.91 A small number of these patients have and 20% have epilepsy.91 Ocular abnormalities may 47 been reported to have mutations in the integrin 7 be present, but most patients have some functional 48 gene.93 vision.91 Survival is into the second decade of life.91 49 Prenatal diagnosis of merosin-deficient congenital Muscle–eye–brain disease is associated with facial 50 muscular dystrophy can be performed on trophoblast dysmorphism (prominent forehead, narrow temporal 51 tissue obtained from chorionic villus sampling.94 This areas) and severe central nervous system and ocular 52 test is reliable only in families with a complete malformations. Patients may survive into late adult- 53 absence of laminin 2 (merosin). Confirmatory hood but are severely retarded.98 54 linkage analysis should also be performed.94 Patients with Walker–Warburg syndrome typically 55 Three forms of congenital muscular dystrophy are die within the first 6 months of life, have brain and 56 associated with severe central nervous system anom- ocular malformations, and are clinically blind.99 57 alies.95 “Fukuyama congenital muscular dystrophy” is 58 the second commonest form of muscular dystrophy in Diagnosis Muscle biopsy findings in all the forms of 59 Japan,96 but it is not restricted to the Asian popu- congenital muscular dystrophy show prominent fiber 60 lation. It is an autosomal recessive disorder due to size variation and fibrosis. Necrotic fibers are rare and 61 mutations in the protein fukutin encoded on chromo- help to differentiate congenital muscular dystrophy 62 some 9q31.97 The function of fukutin, a secreted from Duchenne dystrophy.106 Antibodies directed 709_Neurological_ch.223 9/7/2002 10:32 am Page 14

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1 against the laminin 2 chain are attenuated or absent 12. Barbe F, Quera-Salva MA, McCann C, et al. Sleep- 2 in muscle and skin in merosin-deficient patients; thus, related respiratory disturbances in patients with 3 biopsy of either tissue may be useful.91 It is important Duchenne muscular dystrophy. Eur Respir J 1994;7(8):1403–1408 4 to note that some merosin-deficient patients have 5 13. Barthlen GM. Nocturnal respiratory failure as an indi- attenuated reactivity only with antibodies directed cation of noninvasive ventilation in the patient with 6 against the 300-kD fragment that contains the N ter- neuromuscular disease [see comments]. Respiration 7 minal region of the laminin 2 chain and preserved 1997;64 Suppl 1:35–38 8 reactivity with antibodies directed against the 80-kD 14. Birnkrant DJ, Pope JF, Eiben RM. Management of the 9 isoform that contains the C terminal end of the mole- respiratory complications of neuromuscular diseases 10 cule.91 Thus, both antibodies should be used if in the pediatric intensive care unit. J Child Neurol 11 merosin deficiency is suspected. 1999;14(3):139–143 12 15. Howard RS, Wiles CM, Hirsch NP, Spencer GT. Respi- 13 Treatment Management of children with congenital ratory involvement in primary muscle disorders: 14 assessment and management. Q J Med 1993; muscular dystrophy centers on prevention of contrac- 86(3):175–189 15 tures and scoliosis and requires close monitoring of 16 16. Kelly BJ, Luce JM. The diagnosis and management of respiratory function. Seizures should be treated with neuromuscular diseases causing respiratory failure. 17 conventional anticonvulsant agents. Chest 1991;99(6):1485–1494 18 17. Polkey MI, Lyall RA, Moxham J, Leigh PN. Respira- 19 Summary tory aspects of neurological disease. J Neurol Neuro- 20 This chapter highlights specific issues in the manage- surg Psychiatry 1999;66(1):5–15 21 ment of the more common forms of muscular dystro- 18. Smith PE, Calverley PM, Edwards RH, et al. Practical 22 phy. As the disease loci are mapped, the candidate problems in the respiratory care of patients with mus- 23 genes sequenced, and the physiological function and cular dystrophy. N Engl J Med 1987;316(19):1197–1205 19. Fukunaga H, Okubo R, Moritoyo T, et al. Long-term 24 cellular localization of the putative proteins discov- 25 follow-up of patients with Duchenne muscular dystro- ered, specific therapies and possibly cures for these phy receiving ventilatory support. Muscle Nerve 26 debilitating conditions may emerge. 27 1993;16(5):554–558 20. Heckmatt JZ, Loh L, Dubowitz V. Nocturnal hypoven- 28 References tilation in children with nonprogressive neuromuscu- 29 1. Emery A. Duchenne Muscular Dystrophy. 2nd edn. lar disease. 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